Topics in Antiviral Medicine®

Volume 19 Issue 2 May/June 2011 Topics in Antiviral Medicine®

A publication of the IAS–USA

Highlights of the 18th Conference on Retroviruses and Opportunistic Infections Factors Influencing Virus–Host Cell Interplay 31 Mario Stevenson, PhD Viral Replication and Cell Cycle • Virologic Synapse: Sensitivity to Neutralization • HIV/Flavivirus GB Virus C Coinfection • Studies on Viral Uncoating • Viral Integration • Mechanisms of Latency • Cellular Restriction • Pathogenesis • Strategies for Viral Eradication

HIV Vaccine Development 36 David I. Watkins, PhD Neutralizing Antibodies Against HIV • HIV-Specific Cellular Responses • Results From Vaccinated Monkeys After Heterologous Challenge

HIV Epidemiology and Breakthroughs in Prevention 38 30 Years Into the AIDS Epidemic Susan P. Buchbinder, MD The US HIV Epidemic • Populations at High Risk of HIV-1 Acquisition • Herpes Simplex Virus Type 2 • HIV Testing Strategies • HIV Prevention Strategies

Central Nervous System Complications of HIV Infection 48 Serena S. Spudich, MD, and Beau M. Ances, MD, PhD Introduction—What’s in a Name? • New Biomarkers of HIV-Associated Neurocognitive Disorder • Neuropathogenesis of HIV and Simian Immunodeficiency Virus Infection • Treatment With Antiretroviral or Adjunctive Therapies and Biomarkers of HIV-Associated Neurocognitve Disorder • Early Injury

Complications of HIV Disease and Antiretroviral Therapy 58 Anne F. Luetkemeyer, MD, Diane V. Havlir, MD, and Judith S. Currier, MD Viral Hepatitis • Cardiovascular Disease • Bone Loss: Host Factors, Antiretroviral Drugs, or HIV Disease? • Lipodystrophy • Renal Disease • Malignancy • Tuberculosis • Cryptococcal Meningitis • Influenza A (H1N1)

Advances in Antiretroviral Therapy 69 Barbara Taylor, MD, MS, Susan Olender, MD, Timothy J. Wilkin, MD, MPH, and Scott M. Hammer, MD Investigational Drugs • Clinical Trials of Antiretroviral Therapy in Treatment-Naive Patients • Clinical Trials of Antiretroviral Therapy in Treatment-Experienced Patients • Antiretroviral Treatment Strategies • Predictors of Antiretroviral Therapy Response From Large Cohort Studies • Antiretroviral Treatment in Resource-Limited Settings • Mother-to-Child Transmission of HIV Infection • Resistance • Pharmacokinetic Considerations IAS–USA Topics in Antiviral Medicine Topics in Antiviral Medicine®

Editorial Board IAS–USA Board of Directors

Douglas D. Richman, MD Steven G. Deeks, MD Constance A. Benson, MD Donna M. Jacobsen Editor in Chief Associate Clinical Professor of Medicine Professor of Medicine President/Executive Director Professor of Pathology and Medicine University of California San Francisco University of California San Diego International Antiviral Society–USA University of California San Diego and Roy M. Gulick, MD, MPH Peter C. Cassat, JD Douglas D. Richman, MD Veterans Affairs San Diego Healthcare System Professor of Medicine Member Professor of Pathology and Medicine Constance A. Benson, MD Weill Medical College of Cornell University Dow Lohnes PLLC University of California San Diego and Special Contributions Editor Martin S. Hirsch, MD Judith S. Currier, MD Veterans Affairs San Diego Healthcare System Professor of Medicine Professor of Medicine Professor of Medicine Michael S. Saag, MD University of California San Diego Harvard Medical School University of California Los Angeles Professor of Medicine Charles C. J. Carpenter, MD Daniel R. Kuritzkes, MD Carlos del Rio, MD The University of Alabama at Birmingham Professor of Medicine Professor of Medicine Professor of Medicine Robert T. Schooley, MD Brown University School of Medicine Harvard Medical School Emory University Professor of Medicine Judith S. Currier, MD Joel E. Gallant, MD, MPH University of California San Diego Professor of Medicine Professor of Medicine Paul A. Volberding, MD University of California Los Angeles The Johns Hopkins University Chief of the Medical Service Roy M. Gulick, MD, MPH San Francisco Veterans Affairs Medical Center Professor of Medicine Professor of Medicine Staff and Contributors Weill Medical College of Cornell University University of California San Francisco Donna M. Jacobsen - Executive Editor Karen Lee - Editorial Coordinator Ann McGuire - Managing Editor Frank Paredes, Gregory Kaplowitz - Michelle Tayag Valderama - Production and Layout/Graphics Web Manager Eagle Press - Print and Mail Services

Topics in Antiviral Medicine® Topics in Antiviral Medicine (formerly Topics in we do require that permission to reproduce or HIV Medicine) is published by the IAS–USA. This use any part of the journal be obtained from the journal is intended to be a resource for physi- IAS–USA. In the case of reprinted or adapted cians and other health care practitioners who materials where the IAS–USA does not own the are actively involved in the care of patients with copyright, permission to reproduce these materials HIV or other viral infections. must be obtained directly from the original source. For more information about reprints, please send Editorial Policy an e-mail to topics2011“at”iasusa.org. The views and opinions expressed in this journal are those of the contributors and do not neces- Subscription Information sarily reflect the views or recommendations of Topics in Antiviral Medicine is published 4 to 6 the IAS–USA. Topics in Antiviral Medicine is sup- times a year. To obtain a complimentary sub- Grant Support ported through educational grants from several scription or notify the IAS–USA of a change in commercial companies that are committed to address, please contact the IAS–USA at the ad- Support for the 2011 Improving supporting CME about HIV and other viral infec- dress listed below or use the Subscription Request/ the Management of HIV Disease tions. In the interest of an objective, balanced, Address Change form at the back of this issue. and scientifically rigorous publication, the IAS– continuing medical education (CME) USA seeks funding from companies with com- Correspondence program, including preparation of peting products; these companies have no input Topics in Antiviral Medicine welcomes editorial this issue, is from the following: or control over the journal content or the selec- correspondence. Address letters to: tion of contributors. Major Supporters All authors and contributors provide disclo- Editor, Topics in Antiviral Medicine sures of financial interests, and this information IAS–USA Gilead Sciences, Inc is available at the end of each article. 425 California Street, Suite 1450 Merck & Co, Inc This journal may contain information about San Francisco, CA 94104-2120 the investigational uses of drugs or products that are not approved by the US Food and Drug Ad- Phone: (415) 544-9400 Substantial Supporters ministration. Please consult full prescribing in- Fax: (415) 544-9401 Bristol-Myers Squibb formation before using any medication or prod- Web site: http://www.iasusa.org Tibotec Therapeutics uct mentioned in Topics in Antiviral Medicine. E-mail: topics2011“at”iasusa.org Financial Disclosures On the Web Generous Supporters Financial disclosures for members of the IAS– Current and previous issues of Topics in Antiviral Abbott Laboratories USA Board of Directors and the Editorial Board Medicine (as well as Topics in HIV Medicine) are ViiV Healthcare of Topics in Antiviral Medicine are available online available online at www.iasusa.org. at www.iasusa.org. ISSN 2161-5861 (Print) Copyrights and Reprints ISSN 2161-5853 (Online) The contents of Topics in Antiviral Medicine are protected by copyright. We welcome reference Printed in USA on acid-free paper to and use of portions of this journal; however, ©2011 IAS–USA IAS–USA Volume 19 Issue 2 May/June 2011 Topics in Antiviral Medicine® A publication of the IAS–USA

Highlights of the 18th Conference on Retroviruses and Opportunistic Infections Factors Influencing Virus–Host Cell Interplay 31 Mario Stevenson, PhD

HIV Vaccine Development 36 David I. Watkins, PhD

HIV Epidemiology and Breakthroughs in Prevention 38 30 Years into the AIDS Epidemic Susan P. Buchbinder, MD

Central Nervous System Complications of HIV Infection 48 Serena S. Spudich, MD, and Beau M. Ances, MD, PhD

Complications of HIV Disease and Antiretroviral Therapy 58 Anne F. Luetkemeyer, MD, Diane V. Havlir, MD, and Judith S. Currier, MD

Advances in Antiretroviral Therapy 69 Barbara Taylor, MD, MS, Susan Olender, MD, Timothy J. Wilkin, MD, MPH, and Scott M. Hammer, MD

Abstracts Cited 99

Announcements Continuing Medical Education Information 30 Continuing Medical Education Activity Posttest and Evaluation Form 107 Educational Programs of the IAS–USA 98 Cases on the Web – Online CME Activities 47 Subscription Request/Address Change Form 111 Guidelines for Authors and Contributors 112 IAS–USA Topics in Antiviral Medicine Topics in Antiviral Medicine® Continuing Medical Education The articles in this issue, which highlight presentations from the 18th Conference on Retroviruses and Opportunistic Infections, are available for CME credit.

Instructions Conflicts of Interest and Financial Disclosures

This journal-based continuing medical education (CME) activity provides IAS–USA policy requires that the IAS–USA resolve any real or appar- a review of new data presented at the 18th Conference on Retro- ent conflict of interest that may influence the development, content, viruses and Opportunistic Infections (CROI). It offers a maximum of or delivery of its educational activity prior to the activity’s being deliv- 8 CME credits. To complete the activity, the learner is instructed to: ered to learners. The IAS–USA has several mechanisms for resolving • Read the articles in this issue conflicts of interest in educational activities. If the conflict of interest cannot be resolved through these mechanisms, the party will be re- • Review a selection of the references moved from the activity. • Reflect on how the information might be applied to the clinical practice Dr Ances has received research grants from Pfizer Inc. • Take the posttest (see pages 107–108) Dr Buchbinder has no relevant disclosures to report. • Complete the evaluation and CME claim forms on pages 108–109, and send them with the completed posttest to the IAS–USA office Dr Currier has received research grants awarded to the University of along with payment of $35. California Los Angeles from Merck & Co, Inc, Schering-Plough Corp, and Tibotec Therapeutics. Dr Hammer has served as scientific advisor for Merck & Co, Inc, and Learning Objectives Progenics Pharmaceuticals, Inc. Upon completion of this activity, learners will be able to describe re- Dr Havlir has received study drugs for use in research from Abbott sults of recent research presented at the 18th CROI and the potential Laboratories. clinical implications for their patients in the following subject areas: • Factors influencing virus–host cell interplay Dr Luetkemeyer has received research grants awarded to the Uni- versity of California San Francisco from Bristol-Myers Squibb, Gilead • HIV vaccine development Sciences Inc, Merck & Co, Inc, and Pfizer Inc. • HIV epidemiology, testing strategies, and prevention interventions Dr Olender has no relevant disclosures to report. • Neurologic disorders in HIV disease and their treatment Dr Spudich has no relevant disclosures to report. • Infectious and metabolic complications of HIV disease and antiretroviral treatment, including tuberculosis and hepatitis coinfec- Dr Stevenson has served as a consultant or scientific advisor to Merck tions & Co, Inc, Johnson & Johnson, Inc, and Abbott Laboratories and • Advances in antiretroviral therapy, including prevention of mother- has received research grants from Merck & Co, Inc, and Johnson & to-child transmission and HIV resistance to antiretroviral drugs Johnson, Inc. Dr Taylor has no relevant disclosures to report. Accreditation Statement Dr Watkins has served as a consultant to Pfizer Inc.

The IAS–USA is accredited by the Accreditation Council for Continu- Dr Wilkin has served as a consultant to Pfizer Inc, ViiV Healthcare, ing Medical Education to provide continuing medical education for and Quest Diagnostics and has received research grants from Tibotec physicians. Therapeutics.

The IAS–USA designates this journal-based CME activity for a maximum of 8 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity is offered from June 8, 2011, to June 8, Intended Audience 2012. Participants who receive a passing score on the posttest and submit the registration and evaluation forms are eligible to receive credit. Physicians (MDs, DOs, and international This activity is intended for physicians involved in the care of patients equivalents) may receive CME credit for completing this activity. infected with HIV or other viruses. It is also relevant to nurse practitio- Nonphysician health care practitioners will receive a certificate ners, physician assistants, nurses, and other health professionals who of attendance. provide care for people with viral diseases.

30 Conference Highlights—Virus–Host Cell Interplay Volume 19 Issue 2 May/June 2011

Factors Influencing Virus–Host Cell Interplay

Mario Stevenson, PhD

The Conference on Retroviruses and Opportunistic Infections (CROI) induced nuclear factor kB (NF-kB)- provides an annual international forum for basic scientists and clinical dependent luciferase activity in both and global health researchers to present and become current on the most HIV-1 and simian immunodeficiency recent advances in the field of HIV and AIDS research. The 18th conference virus (SIV). The second tyrosine of contained a number of strong basic science sessions. HIV-1 infection of the cell the cytoplasmic tail was important for is opposed by cellular factors that attack the viral replication cycle at various the induction of NF-kB activity. Acti- points. However, the virus has evolved defenses against these innate cellular vation of NF-kB was independent of antiviral proteins. CROI continues to be a strong forum for presentation of the activation of either nuclear factor the most recent developments in this area of research. In addition, there of activated T cells (NF-AT) or activat- were numerous presentations on cellular factors that regulate virus–host ing protein 1 (AP-1). Several important cell interplay as well as on research that is providing detailed insight into questions arise from the study. For the mechanism of action of integrase inhibitors. Some presentations focused example, it will be necessary to deter- on approaches to studying and intervening with viral latency, particularly in mine whether envelope glycoprotein, primary cell models. Research on the use of zinc-finger nucleases to knock within the context of an intact virion, out CC chemokine receptor R5 expression in CD34+ stem cells also received a is able to induce sufficient NF-kB to in- lot of interest. The hope is that these strategies will provide new therapeutic crease target-cell permissivity during approaches to generate resistance to HIV-1 infection. infection given the consensus that tru- ly quiescent CD4+ T cells are not permissive to HIV-1 infection. It is unlikely In the Bernard Fields Lecture, Cullen Viral Replication and Cell Cycle that such a mechanism is sufficient to discussed the role of a novel class of render quiescent T cells permissive to small regulatory RNA molecules, called Infection of a cell is initiated by in- infection. However, there may be dif- microRNAs (miRNAs), in the replica- teractions of the viral envelope glyco- ferent activation states between phas- tion of viruses, in particular, herpes protein with receptor and coreceptor es G0 and G1 in which envelope-de- viruses (Abstract 17). MiRNAs bind to molecules on the cell surface. Expo- pendent signaling may be sufficient to messenger RNA (mRNA) molecules sure of fusogenic domains on the viral render the cell permissive to infection. that have partially or fully complemen- envelope leads to fusion between viral Establishment and maintenance of tary sequences and as a result are able and cellular membranes; this fusion latency in primary, infected CD4+ to impair mRNA translation and re- allows the viral core, which contains T cells in vitro is difficult. This has duce mRNA stability. Cullen described the viral nucleic acid, to be inserted hampered detailed investigation of the miRNAs that play a central role in the into the cytoplasm of the target cell. molecular mechanisms regulating vi- regulation of herpes virus latency as Sessions 24 and 50 included presenta- ral latency in a physiologically relevant well as virus-encoded miRNAs that reg- tions on studies that focused on regula- system. Research has indicated that ulate cellular functions important for tion of virus entry. In quiescent CD4+ quiescent T cells are difficult to infect virus survival in the host. The search T cells, infection events leading up in vitro, and this hampers the establish- to establishment of a complementary ment of a latency model using primary for miRNAs that regulate HIV-1 replica- 1,2 tion is ongoing, and whether there are DNA (cDNA) are inefficient. However, lymphocytes. Abstract 174 presented microRNAs encoded by HIV-1 is still a latent infection is established in qui- evidence that quiescent T cells can be matter of debate. Cullen discussed the escent T cells, and it is unclear how infected through an endosomal route. role of virus-encoded miRNAs in the latency is initiated. One possibility is The authors produced HIV-1 variants maintenance of Epstein-Barr virus la- that some infection events in cycling that were pseudotyped with an R5-trop- tency. He described how miRNAs par- CD4+ cells result in latent infection if ic HIV-1 envelope and with the fusogen- ticipate not only in the maintenance the cell rapidly returns to a state of ic G gycloprotein of vesicular stomatitis of latency, but also in maintenance of quiescence after establishment of the virus (VSV-G). They demonstrated that B-cell transformation that is important integrated provirus. An alternative pos- both CD4+-dependent binding and to sustain the viral reservoir. sibility is that binding of the virus to a subsequent VSV-G fusion were neces- quiescent cell may engender a signal sary for infection of naive CD4+T cells. that would increase the permissivity of This study could be important because the cell to infection, thereby facilitating it would provide an approach for the es- Dr Stevenson is professor of medicine and the establishment of a latent infection. tablishment of latent infection in vitro, chief of the Division of Infectious Diseases Abstract 88 demonstrated that chi- thereby allowing detailed investigation at the University of Miami Leonard M. Miller meric constructs between human CD8α of the mechanisms regulating latency School of Medicine in Miami, Florida. and the cytoplasmic tail of gp41 (gp41CT) in a physiologically relevant model.

31 IAS–USA Topics in Antiviral Medicine

Virologic Synapse: Sensitivity to the recycling of cellular glycoproteins compared with HIV-1-infected individ- Neutralization to the plasma membrane. The authors uals without GBV-C. CD4+ cell count demonstrated that a dominant nega- and percentage were statistically sig- In lymphoid tissue, where there is a tive mutant of Rab11a did not affect nificantly higher in GBV-C-seropositive high density of substrate CD4+T cells, envelope incorporation, but expres- individuals than in GBV-C-uninfected viral spread may occur not only as free sion of a constitutively active form of subjects. viral particles but also directly between Rab11a appeared to direct the enve- However, in contrast to results from cells through cell-to-cell contact. HIV-1 lope glycoprotein to a cellular location Abstract 26, there were no differences has been reported to form virologic for degradation, thus dramatically de- in CCR5 or CXC chemokine receptor 4 synapses (VS) between the HIV-1-increasing envelope incorporation into (CXCR4) expression on CD4+ cells be- fected cell and the target cell’s inter- released virions. Therefore, the Rab11a tween GBV-C-seropositive and -nega- face. Formation of VS involves interac- family of interacting proteins appears tive subjects. In individuals who had tion between the viral envelope and to be a key mediator of viral envelope detectable HIV-1 viremia, CD4+ cell CD4+cell–coreceptor complexes and glycoprotein trafficking. proliferation was lower in GBV-C-sero- further requires cytoskeletal rearrange- positive subjects than in GBV-C-unin- ments and stabilization of infected and fected subjects, and activation levels of HIV/Flavivirus GB Virus C target-cell membranes by adhesion CD4+ cells and CD8+ cells were also Coinfection molecules. The nature of the VS has lower in this group. Therefore, GBV-C prompted speculation that this mode The regulation of cellular activation viremia appears to be associated with of viral transfer may afford the virus state and CC chemokine receptor 5 decreased CD4+ T-cell proliferation some degree of protection from neu- (CCR5) down-regulation were reported and activation, which may contribute tralizing antibodies or from inhibitors to provide mechanisms for limiting to improved survival in HIV-1 subjects that prevent interactions with receptor HIV-1 target-cell availability in individ- coinfected with GBV-C. and coreceptor molecules. uals coinfected with the flavivirus GB Research presented in Abstract virus C (GBV-C). GBV-C infects approxi- 181 provided evidence that the VS Studies on Viral Uncoating mately 30% of individuals with HIV-1, During Infection may provide an infection route that and coinfected individuals have longer is less sensitive to some broadly neu- average survival times than HIV-1- After fusion of HIV-1 with the host cell tralizing antibodies. The investigators infected individuals without GBV-C.3,4 surface, the viral capsid core enters observed that although most neutral- The mechanisms underlining the GBV-C the cytoplasm. The viral capsid deas- izing antibodies blocked both cell-free benefits are not well understood. sembles to release viral nucleic acids and cell-associated HIV-1 infection, a Abstract 26 examined the frequen- into the cytoplasm to be reverse-tran- 17b antibody that is reactive against cies of CCR5+ CD4+ T cells in GBV-C- scribed. How the reverse transcription a CD4-induced binding site of enve- seropositive and -seronegative HIV-1- and uncoating processes are coordi- lope glycoprotein as well as patient se- infected individuals. The investigators nated during infection remains poorly rum both inhibited cell-free infection determined that levels of the cytokine understood. Abstract 90 presented evi- more effectively than they inhibited RANTES (regulated on activation nor- dence that drugs that inhibit reverse VS-mediated infection. Deletion of the mal T-cell expressed and secreted), a transcription delayed the uncoating gp41CT enhanced sensitivity to 17b af- ligand for CCR5, were higher in GBV- process. The study used a fluores- ter VS-mediated infection. C-seropositive individuals than in GBV- cence-based uncoating assay as well Abstract 182 presented evidence C-seronegative subjects. The plasma as an owl monkey kidney cell line as- that 2- to 3-fold higher concentrations level of RANTES was inversely cor- say that manifests TRIM-CypA-mediat- of entry or fusion inhibitors including related with the frequency of CCR5+ ed restriction. maraviroc, enfuvirtide, and the investi- CD4+ memory T cells, which itself was Data from both assays indicated gational drug AMD 3100 were required related to the median fluorescence in- that uncoating is initiated within an to disrupt transinfection between ma- tensity of CCR5. Therefore, one of the hour of viral fusion. Inhibition of re- ture dendritic cells and CD4+ T cells mechanisms underlying the survival verse transcription using nevirapine than were required for cell-free virus benefits conferred by GBV-C infection delayed uncoating from approximate- infection of CD4+ T cells. might involve higher plasma levels ly 40 minutes to 2 hours. Further- Abstract 89 presented evidence for of CCR5-binding chemokines, subse- more, analysis of reverse transcription cellular factors that regulate envelope quent down-regulation of CCR5 ex- products in owl monkey kidney cells incorporation into the virion. During pression, and a reduction in target-cell indicated that appearance of early re- assembly of the HIV-1 particle at the availability. verse transcription products coincided plasma membrane, the viral envelope Abstract 27 presented additional with the intiation of uncoating. This glycoprotein is incorporated into the evidence for decreases in CD4+ and suggests that reverse transcription fa- budding virus particle. The cellular CD8+ cell activation and proliferation cilitates, but is not required for, HIV-1 protein Rab11a plays a central role in in GBV-C/HIV-1–coinfected individuals uncoating in infected cells.

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Viral Integration which interrupts the interaction be- deacetylase (HDAC) inhibitors and tween HIV-1 integrase and LEDGF. other immune activators in reactivat- In a plenary presentation, Cherepanov These data reinforce the critical role of ing HIV-1 latency. The authors ob- presented structural insights into the LEDGF as a cofactor in HIV-1 integra- served statistically significant variation process of retroviral integration and tion. The mechanism by which HIV-1 in the potency and toxicity of a vari- the mechanism of action of strand- is able to integrate in the absence of ety of HDAC inhibitors, including the transfer inhibitors (Abstract 75). After LEDGF is under investigation. lymphoma drug vorinostat and the in- reverse transcription, the viral inte- vestigational cancer drugs pamabino- grase enzyme binds to the viral DNA stat and etinostat as well as cytokines Mechanisms of Latency ends to form a stable nucleoprotein including interleukin 7 (IL-7), tumor complex, the intasome. In the nucleus, The site of integration has also been necrosis factor alpha (TNF-α), and pro- the intasome interacts with target-cell proposed as an important component stratin. HDAC inhibitors showed vary- DNA and catalyzes the joining of viral of the mechanism by which HIV-1 la- ing degrees of activity in the primary with cellular DNA. Using the proto- tency is regulated. Both HIV-1 integra- model of HIV-1 latency. However, tox- type foamy virus (PFV) integrase as a tion and latent proviruses appear to icity in peripheral blood mononuclear model system, Cherepanov presented occur in actively expressed host genes. cells was also observed with concen- the crystal structure of the PFV inta- As a consequence, transcriptional in- trations close to those required to re- some, which comprises an integrase terference between the HIV-1 long-ter- activate HIV-1 latency. Vorinostat ex- tetramer tightly associated with a pair minal repeat (LTR) and the juxtaposed hibited the lowest toxicity and highest of viral DNA ends. Integration inhibi- cellular transcription unit has been potency in the primary T-cell model of tors, including raltegravir, elvitegravir, proposed in epigenetic regulation of HIV-1 latency, underscoring a poten- and related strand-transfer inhibitors, HIV-1 latency.7 To further understand tial role for this drug in clinical trials to were found to bind within the active the mechanisms regulating HIV-1 la- eliminate the resting cell reservoir. site of the PFV intasome to dislocate tency, Abstract 197 described the de- the reactor viral DNA. Furthermore, velopment of a dual promoter system Cellular Restrictions because of strong sequence conser- that examined the interaction between vation within the active sites of PFV the HIV-1 LTR and upstream promot- The area of cellular restrictions con- and HIV-1 integrase, the mechanism ers. The authors demonstrated that the tinued to draw strong interest at the by which raltegravir resistance muta- maintenance of latent HIV-1 infection conference. As a virus with a limited tions impact antiviral activity could be depends upon the level of expression genetic repertoire, HIV-1 comman- visualized within the PFV intasome of the gene proximal to the provirus. deers cellular factors at various stages model. The availability of crystal struc- This provides a model for how latent in its replication cycle. The seminal tures for the retroviral intasome is an infection can be established in actively discovery, by Malim’s research group, important step in the development of expressed cellular genes. of the cellular restriction APOBEC 3G next-generation integrase inhibitors. Equally important to an understand- revealed the existence of cellular fac- Integration of viral DNA into host ing of the mechanisms by which laten- tors that oppose viral infection.9 chromatin is not a random process cy is established is an understanding Since that discovery, additional cel- but appears to occur preferentially in of the processes that can trigger reac- lular factors that antagonize viral repli- transcription units. Lens epithelium- tivation from latency. Because the la- cation have been identified. For exam- derived growth factor (LEDGF) is a tent reservoir is considered the most ple, TRIM5α exerts a species-specific cellular cofactor of HIV-1 integrase important obstacle to viral eradication, effect on viral uncoating, and tetherin/ that promotes viral integration into many investigators have turned their BST2 interferes with disassociation of gene-rich regions of host chromatin.5,6 attention to strategies that reactivate viral particles from the cell surface. Abstract 191 examined the ability of latency to reduce the size of the latent The existence of these potent antiviral HIV-1 to replicate in the absence of reservoir. In Abstract 198, Wightman restrictions has forced primate lenti- LEDGF in a human LEDGF knock-out and colleagues described the develop- viruses to adopt evasion strategies, and cell line. In the absence of LEDGF, in- ment of a primary resting-T-cell model almost all of the viral counterdefenses tegration did not occur in transcription of HIV latency. In this model, resting are directed by the viral accessory units but instead, showed a prefer- CD4+ T cells are incubated with the CC proteins. The Vif protein antagonizes ence for the genomic regions termed chemokine receptor 7 (CCR7) ligand APOPEC 3G by promoting its prema- CpG islands. Although spreading HIV-1 CCL19. The authors have previously ture proteasomal destruction, and the replication was delayed in the knock- demonstrated that treatment of resting protein Vpu antagonizes tetherin/BST2 out cell line, residual replication was CD4+ T cells with certain chemokines by directing it away from sites of virus observed. Nevertheless, the authors such as CCL19 is sufficient to render assembly. Because Vpu is not encod- demonstrated that this residual repli- them permissive to HIV-1 infection.8 ed by the majority of SIV variants or cation was still sensitive to the inves- They used this model to examine by HIV-2, an important question is how tigative compound termed LEDGIN, the potency and toxicity of histone these viruses evade the antiviral action

33 IAS–USA Topics in Antiviral Medicine

of tetherin/BST2. Studies by Evans it would be important to determine mune activation and low-level vire- previously established that SIV Nef whether the ability of HIV-1 to remain mia was observed in HIV-1-infected proteins antagonize tetherin/BST2.10 sensitive to the myeloid cell restriction individuals who exhibited poor CD4+ Abstract 85 presented further in- impacts its biology within the host. T-cell recovery during suppressive an- sight into the mechanism by which Abstract 28LB presented evidence tiretroviral therapy (Abstract 304). SIV Nef antagonizes tetherin/BST2. that some form of antiviral restriction The researchers examined the asso- Nef proteins have previously been may be playing a role in viral control ciation between CD4+ T-cell gains and demonstrated to bind adaptor protein within elite controllers. Research from T-cell activation (CD38+HLADR+CD8 2 (AP-2).11,12 SIV Nef mutants incapable Crumpacker and colleagues demon- cells), markers of microbial transloca- of binding AP-2 were unable to antago- strated that the cyclin-dependent ki- tion (LPS and 16S ribosomal DNA), as nize tetherin, and down-regulation of nase inhibitor p21 restricted HIV-1 well as monocyte activation (soluble tetherin/BST2 from the cell surface infection of primary hematopoietic CD14). In 71 participants, no markers was observed with wild-type Nef but cells.15 In Abstract 28LB, Huang and of bacterial translocation were associ- not with AP-2-binding-site mutants. colleagues examined p21 expression ated with CD4+ T-cell counts. Nor was Therefore, SIV Nef proteins antagonize in CD4+ T cells from elite controllers there a correlation of CD4+ T-cell count tetherin/BST2 in an AP-2-dependent and HIV-1 progressors. Expression or immune activation with low-level mechanism that allows displacement of p21 was statistically significantly plasma HIV RNA. There was an asso- of tetherin/BST2 from the site of virus higher in CD4+ T cells from elite con- ciation of CD8+ lymphocyte activation assembly or down-regulation of teth- trollers, and silencing of p21 by RNA with lower CD4+ cell count. Therefore, erin/BST2 from the cell surface. interference increased HIV-1 replica- additional studies are required to iden- Recent studies from our research tion. This group demonstrated that tify biological correlates of a nontreat- group have presented evidence that p21 interacted with the cyclin-depen- ment response in patients receiving primate lentiviral Vpx proteins en- dent kinase 9 (CDK9), which is essen- suppressive therapy. hance infection of myeloid cells by tial for HIV transcriptional elongation. 13,14 antagonizing a cellular restriction. The authors proposed that p21 acts as Strategies for Viral Eradication Although the identity of the restriction an inhibitor of CDK9-mediated tran- as well as its viral target are yet to be scriptional elongation of HIV-1 in elite There has been a single documented revealed, the restriction appears to be controllers. case of HIV-1 eradication: the “Berlin a major barrier to infection of myeloid patient,” an HIV-1-infected individual cells. Our published studies have dem- 17 Pathogenesis with leukemia. He received chemo- onstrated that although HIV-1 Vpr is therapy followed by transplanted he- unable to neutralize the myeloid cell Several clear mechanisms have emerged matopoietic stem cells from a CCR5- restriction, HIV-1 is sensitive to restric- to explain the processes of lentiviral negative donor. This case has provided tion, and packaging of Vpx within HIV-1 pathogenesis. In pathogenic primate proof-of-concept for strategies that substantially increases its infectivity lentiviral infection, viral replication engineer stem cells to become CCR5- for macrophages. depletes TH17 cells that are neces- negative. Abstracts 164 and 165 dis- In Abstract 87, Sunseri and col- sary to maintain the integrity of the cussed the potential use of zinc-finger leagues presented evidence that in- gut mucosa. A subsequent loss in gut- nucleases to edit the CCR5 gene in creasing HIV-1 infectivity for macro- mucosal integrity leads to transloca- stem cells. In Abstract 164, Cannon phages and dendritic cells after Vpx tion of bacterial products that drive and colleagues discussed the use of packaging within HIV-1 virions led to cell activation, including lipopolysac- zinc-finger nucleases to knock out an enhanced innate immune response. charide (LPS). This increases the pool the CCR5 gene in human CD34+ stem Vpr and Vpx proteins are packaged of cells permissive to viral infection cells. Those stem cells were then trans- into virions through association with and erodes the architecture of the planted into immune-deficient mice. the p6 domain of Gag. The authors lymphoid tissue. As originally hypo- Infection of these mice with R5-tropic constructed a chimeric HIV-1 Gag con- thesized by Giorgi and colleagues, im- strains of HIV-1 led to the preferential taining the SIV p6 domain, and this mune activation (as measured by fre- survival of CCR5-negative T cells, sub- allowed packaging of Vpx into HIV-1 quency of activated CD8+ T cells) cor- stantial declines in HIV-1 viremia, and virions. HIV-1 that was engineered to relates with plasma viral load and is eventual restoration of normal levels package Vpx was more infectious in a strong predictor of disease progres- of CD4+ T cells in lymphoid tissues of both macrophages and dendritic cells sion.16 Immune activation persists in the mouse. and induced a strong type 1 interferon HIV-1-infected individuals, is not nor- Abstract 165 discussed the applica- response. It is intriguing to speculate malized by antiretroviral suppression, tion of this strategy to humans in on- that HIV-1 has evolved to lack a strat- and undermines CD4+ cell count gains going phase I clinical trials involving a egy to neutralize a myeloid cell restric- during treatment. group of patients for whom 2 or more tion in order to avoid activating an In one study, no correlation be- antiretroviral regimens have failed and innate immune response. Therefore, tween bacterial translocation and im- who remain viremic and a second

34 Conference Highlights—Virus–Host Cell Interplay Volume 19 Issue 2 May/June 2011 group of patients who are doing well References 10. Jia B, Serra-Moreno R, Neidermyer W, et al. Species-specific activity of SIV Nef on antiretroviral therapy. In this study, and HIV-1 Vpu in overcoming restric- the CCR5 locus is disrupted with zinc- 1. Zack JA, Arrigo SJ, Weitsman SR, Go AS, tion by tetherin/BST2. PLoS Pathog. finger nucleases, and then the CCR5- Haislip A, Chen IS. HIV-1 entry into qui- 2009;5:e1000429. escent primary lymphocytes: molecular 11. Greenberg ME, Bronson S, Lock M, deficient T cells are transplanted into analysis reveals a labile, latent viral struc- Neumann M, Pavlakis GN, Skowronski the patients. ture. Cell. 1990;61:213-222. J. Co-localization of HIV-1 Nef with the Although these are exciting stud- 2. Stevenson M, Stanwick TL, Dempsey MP, AP-2 adaptor protein complex correlates Lamonica CA. HIV-1 replication is with Nef-induced CD4 down-regulation. ies, an important question arises as controlled at the level of T cell activa- EMBO J. 1997;16:6964-6976. to whether the preexisting viral res- tion and proviral integration. EMBO J. 12. Piguet V, Trono D. The Nef protein of 1990;9:1551-1560. ervoirs will persist in individuals who primate lentiviruses. Rev Med Virol. 3. Tillmann HL, Heiken H, Knapik-Botor A, 1999;9:111-120. receive transplanted CCR5-negative et al. Infection with GB virus C and re- 13. Sharova N, Wu Y, Zhu X, et al. Primate cells. The success of the Berlin patient duced mortality among HIV-infected pa- lentiviral Vpx commandeers DDB1 to tients. N Engl J Med. 2001;345:715-724. counteract a macrophage restriction. likely hinged on the fact that the ex- 4. Xiang J, Wünschmann S, Diekema DJ, et PLoS Pathog. 2008;4:e1000057. isting reservoir was depleted through al. Effect of coinfection with GB virus C 14. Kaushik R, Zhu X, Stranska R, Wu Y, chemotherapy. However, in allogeneic on survival among patients with HIV in- Stevenson M. A cellular restriction dic- fection. N Engl J Med. 2001;345:707-714. tates the permissivity of nondividing stem cell transplantation, for which 5. Shun MC, Raghavendra NK, Vandegraaff monocytes/macrophages to lentivirus chemotherapy is not necessary, the N, et al. LEDGF/p75 functions down- and gammaretrovirus infection. Cell Host preexisting latent reservoir is likely stream from preintegration complex for- Microbe. 2009;6:68-80. mation to effect gene-specific HIV-1 inte- 15. Zhang J, Scadden DT, Crumpacker CS. to persist. Therefore, at best, CCR5 gration. Genes Dev. 2007;21:1767-1778. Primitive hematopoietic cells resist removal through allogeneic stem cell 6. Christ F, Voet A, Marchand A, et al. Ra- HIV-1 infection via p21. J Clin Invest. transplantation may offer a means for tional design of small-molecule inhibi- 2007;117:473-481. tors of the LEDGF/p75-integrase interac- 16. Giorgi JV, Hultin LE, McKeating JA, et viral control but may not achieve the tion and HIV replication. Nat Chem Biol. al. Shorter survival in advanced human goal of viral eradication. 2010;6:442-448. immunodeficiency virus type 1 infec- 7. Hakre S, Chavez L, Shirakawa K, Verdin tion is more closely associated with T E. Epigenetic regulation of HIV latency. lymphocyte activation than with plasma Financial Disclosure: Dr Stevenson has Curr Opin HIV AIDS. 2011;6:19-24. virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859-870. served as a consultant or scientific advisor 8. Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR. CCR7 ligands 17. Hütter G, Nowak D, Mossner M, et al. to Merck & Co, Inc., Johnson & Johnson, Inc., CCL19 and CCL21 increase permissive- Long-term control of HIV by CCR5 Del- and Abbott Laboratories and has received ness of resting memory CD4+ T cells to ta32/Delta32 stem-cell transplantation. research grants from Merck & Co, Inc. and HIV-1 infection: a novel model of HIV-1 N Engl J Med. 2009;360:692-698. latency. Blood. 2007;110:4161-4164. Johnson & Johnson, Inc. 9. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is sup- A list of all cited abstracts pressed by the viral Vif protein. Nature. Top Antivir Med. 2011;19(2):31–35 appears on pages 99–106. 2002;418:646-650. © 2011, IAS–USA

35 IAS–USA Topics in Antiviral Medicine Conference Highlights—HIV Vaccines Volume 19 Issue 2 May/June 2011

HIV Vaccine Development David I. Watkins, PhD

Presentations at the 2011 Conference on Retroviruses and Opportunistic cides. The new VRC01 antibody had Infections reflected the resurging interest in antibody responses against undergone extensive somatic mutation HIV given the encouraging results of the Thai vaccine trial. A plenary talk and binds to the conserved CD4 bind- and an entire symposium were devoted to HIV-specific antibody responses ing site of gp120. Indeed, VRC01 dif- describing newly isolated, potent neutralizing monoclonal antibodies. fers from the germ line sequences by These antibodies undergo extensive somatic mutation to achieve their 30%, and if changes are made so that remarkable neutralizing properties. Inducing these types of antibodies by sequences are reverted to the germ vaccination, however, still represents a challenge. New data were presented line, the antibody loses its affinity and suggesting that neutralizing antibodies, but not binding antibodies, can neutralizing capabilities. This indicates provide protection against infection in the nonhuman primate (NHP) model. that somatic mutation is crucial to the Several interesting discoveries were also reported showing that cellular development of the affinity and neu- immune responses recognizing HLA-C and HLA class II molecules might also tralizing properties of these broadly be important in control of viral replication. Finally, new vaccine studies in neutralizing antibodies. These findings the NHP model showed that electroporated DNA, along with the adjuvant suggest immunization strategies to in- interleukin 12 may be an efficacious vaccine regimen. duce such effective antibodies. Verkoczy and colleagues discussed the possibility that membrane-prox- Over the past few years, several new, izing antibodies against HIV. Nussen- imal external region (MPER)-specific potent neutralizing antibodies have zweig’s group sorted gp140-staining, neutralizing antibodies may be under been described in the HIV vaccine single B cells from HIV-infected indi- stringent tolerance control (Abstract field. These studies have come from viduals and then cloned the antibody 63). Sundling and colleagues showed many different groups, including those genes from these cells. They showed that even if macaques made antibody at Rockefeller University, International that, after expression, most of these responses against a vaccine of soluble AIDS Vaccine Initiative (IAVI), and the antibodies neutralized tier-1 strains Env trimers, these antibodies provided Vaccine Research Center (VRC). These of HIV (ie, strains highly susceptible moderate protection against a simian new studies have shed considerable to neutralization), whereas only a few HIV (SHIV) challenge (Abstract 64). On light on how these critically impor- of them neutralized the more difficult- behalf of his colleagues, Kim discussed tant antibodies develop. The interest- to-neutralize tier-2 strains (ie, strains the latest analyses of the results of the ing properties of many of these novel moderately susceptible to neutraliza- RV144 Thai phase III trial (Abstract antibodies were discussed at the 2011 tion). These antibodies had undergone 65). He also presented ongoing studies Conference on Retroviruses and Op- extensive somatic hypermutation, fa- showing that there were antibody rec- portunistic Infections. Additionally, cilitating high-affinity binding to Enve- ognition profiles that were associated novel vaccination methods gave the lope. Nussenzweig showed that T cells with RV144 vaccination. field hope that a vaccine for HIV might played a crucial role in the maturation Moore and colleagues showed that eventually be possible. of these highly specific antibody re- neutralizing antibodies provide pro- sponses. tection in a nonhuman primate (NHP) Neutralizing Antibodies One symposium was devoted en- model, whereas nonneutralizing anti- Against HIV tirely to anti-HIV antibodies (Session bodies provided no or partial protec- 18). Mascola initiated the session and tion (Abstract 142). The nonneutral- Nussenzweig gave a plenary talk out- reminded attendees that HIV was un- izing b6 antibody directed against the lining developments in the discovery usual in that broadly reactive, HIV-spe- CD4 binding site on gp120 did not proof neutralizing antibodies against HIV cific neutralizing antibodies take more vide protection in 4 of 4 macaques in (Abstract 20). The IAVI Neutralizing An- than 2 years to develop in infected 1 study or in 5 of 5 macaques in a sec- tibody Center at the Scripps Research individuals (Abstract 62). He then dis- ond study. Interestingly, topically ap- Institute, the VRC, and now Nussenz- cussed the new neutralizing antibodies plied F240 antibody directed against weig’s group have recently discovered from the VRC, highlighting the discov- anti-gp41 (nonneutralizing) protected new, highly potent, broadly neutral- ery of a broadly reactive neutralizing 2 of 5 animals and resulted in rela- antibody, VRC01. He suggested that tively low viral loads in 2 of 3 of the Dr Watkins is professor in the Department these broad neutralizing antibodies infected animals. By contrast, as has 1 of Pathology and a member of the AIDS could be used for passive transfer for been found before, the neutralizing Vaccine Research Laboratory at University prevention of mother-to-child trans- antibody b12 protected all animals in of Wisconsin–Madison. mission, gene delivery, and microbi- these SHIV-challenge studies.

36 Conference Highlights—HIV Vaccines Volume 19 Issue 2 May/June 2011

Trokla presented data implicat- fect on replication, both in vivo and in that DNA vaccination alone or in coming the V1 and V2 loops in protection vitro, on the SIVsmE543-3 clone. Interest- bination with aldrithiol 2–inactivated against antibodies directed against ingly, it was more difficult to see these SIV resulted in protection after a het- V3 (Rusert et al, Abstract 141LB). TRIM5 effects on the closely related erologous low-dose mucosal challenge With several elegant experimental ap- SIVsmE660 isolate. This may be related (Abstract 360). Indeed, of the 24 vac- proaches, the researchers showed that to the use of several different stocks cinated macaques, 2 animals showed antibodies directed against the V3 loop of this quasispecies; some stocks may no evidence of viral replication, and in 1 peplomer were inhibited from be more sensitive to TRIM5 variation 9 macaques showed a peak plasma binding by the V1 and V2 loops from than others. However, the message for SIV RNA level of 100,000 copies/mL the adjacent peplomer on the trimeric the NHP vaccine field is that vaccine to 1,000,000 copies/mL, followed by Envelope. Thus, the V1 and V2 loops in and control groups should be typed for complete control of viral replication. the quarternary structure of the gp120 these TRIM5 alleles. By contrast, none of the 8 naive con- trimer may play a crucial role in con- Soghoian and colleagues presented trol animals showed this kind of con- ferring resistance to neutralizing anti- intriguing data suggesting that HIV- trol of viral replication. The authors bodies directed against the V3 loop. specific cytolytic CD4+ cells may be speculated that a mixture of vaccine- involved in control of HIV replication induced antibodies and cellular immune responses were responsible for HIV-Specific Cellular Responses (Abstract 158). They studied 12 acutely infected individuals and divided this control of viral replication. Several genome-wide association stud- them into 2 groups: those that exerted ies have confirmed that a portion a measure of control and those that Financial Disclosure: Dr Watkins has served of individuals with HLA-B57 or -B27 did not. Even though peak viremia was as a consultant to Pfizer Inc. control viral replication. However, similar in the 2 groups, those that con- another polymorphism in the major trolled viral replication exhibited high- A list of all cited abstracts histocompatibility complex (MHC) re- er levels of HIV-specific CD4+ T cells appears on pages 99–106. gion, close to HLA-C, was also shown expressing granzyme, perforin, and to be associated with control of viral CD107a (markers of cytotoxic activity). replication. Carrington elegantly dem- These data suggest that cytolytic CD4+ Reference onstrated that this polymorphism may T cells may play an important role be involved in regulation of HLA-C ex- in the initial control of HIV replication. 1. Veazey RS, Shattock RJ, Pope M, et al. pression (Abstract 105). Whether this Prevention of virus transmission to macaque monkeys by a vaginally applied polymorphism is exerting its effect Results From Vaccinated monoclonal antibody to HIV-1 gp120. Nat through interactions with cytotoxic T Monkeys After Heterologous Med. 2003;9:343-346. lymphocytes or natural killer cells is Challenge still unknown. In the same symposium, Hirsch Vaccination using electroporated DNA and colleagues delineated the effects along with the adjuvanting cytokine of TRIM5 polymorphism on simian interleukin 12 is among the most immunodeficiency virus (SIV) replica- exciting breakthroughs in vaccine tion (Abstract 107). They showed that development recently. Pavlakis and Top Antivir Med. 2011;19(2):36–37 TRIM5 alleles can have a profound ef- colleagues presented data showing © 2011, IAS–USA

37 IAS–USA Topics in Antiviral MedicineConference Highlights—Epidemiology and Prevention Volume 19 Issue 2 May/June 2011

HIV Epidemiology and Breakthroughs in Prevention 30 Years Into the AIDS Epidemic Susan P. Buchbinder, MD

Thirty years after the first AIDS cases were reported in the United States, the at particularly high risk. In examin- HIV epidemic continues to be heavily concentrated among men who have sex ing drivers of the epidemic in MSM, with men (MSM) in the United States. MSM are heavily impacted throughout numerous studies have shown lower most of the world and are the predominant risk group throughout the levels of reported sexual risk and drug Americas and Western Europe; heterosexuals are the predominant risk group use among black and Latino MSM in sub-Saharan Africa; and injection drug users predominate throughout than among white MSM. These racial Eastern Europe and Southeast Asia. In the United States, blacks and Latinos and ethnic disparities may arise as a continue to be disproportionately affected, despite overall advances in HIV result of differences in background testing and care. The 2011 Conference on Retroviruses and Opportunistic prevalence, patterns of intraracial mix- Infections focused on populations heavily impacted throughout the world: ing, prevalence of sexually transmit- adolescents, women, MSM, and serodiscordant couples. Several presentations ted infections, access to antiretroviral focused on the unique relationship between herpes simplex virus type 2 therapy, and rates of undiagnosed HIV (HSV-2) and HIV-1; although many opportunistic infections increase HIV infection, all of which may drive in- acquisition risk, HSV-2 is likely the only one whose effective prevention or creased rates in black and Latino MSM. treatment could substantially influence HIV infection rates, because of the high Millett and colleagues also present- prevalence and persistence of HSV-2. The 2011 conference also celebrated the ed data from 1214 black and Latino substantial advances made in the use of antiretroviral drugs for prevention of MSM enrolled in the Brothers y Her- HIV acquisition (eg, oral preexposure prophylaxis, topical microbicides) and manos study in New York City, Phila- transmission (eg, antiretroviral therapy). Further progress is also being made delphia, and Los Angeles (Abstract in evaluating other prevention strategies and their rollout, including male 131LB). Overall, 12% were HIV-sero- condoms, male circumcision, and HIV testing and linkage to care. positive and unaware of their infection, with a higher rate among black The US HIV Epidemic the United States who have ever been than Latino men (18% vs 5%, respec- tested for HIV has risen to 45%, and tively; P < .001). Among both groups, Mermin provided an overview of the the proportion of persons with AIDS having a low perceived risk of testing US epidemic and strategies for imple- diagnosed within 12 months of their HIV-seropositive and endorsing the menting high-impact prevention (Ab- first HIV-seropositive test has dropped belief that having sex with men of the stract 19). He reminded the audience to 32%. However, given limited re- same race or ethnicity reduces the risk of the substantial disparities in HIV sources, Mermin called for targeted of HIV acquisition were independently infection, with new infections more prevention strategies based on knowl- associated with being HIV-seroposi- than 40 times more likely to be in men edge of effectiveness, cost, scalability, tive and unaware. Among black MSM, who have sex with men (MSM) than and coverage of affected populations. having disclosed sexual identity to a in other men and women and more Millett further explored the US epi- health care practitioner, having health than 8 times more likely in blacks and demic in MSM, the only risk group insurance, and having fewer than 3 times more likely in Latinos than in in the United States in whom new 3 lifetime HIV tests were also indepen- whites. Tremendous strides have been infections continue to rise (Abstract dently associated with HIV-seroposi- made in prevention, with community- 69). Modeling suggests that even if tive–unaware status. initiated behavior change leading to an MSM and heterosexuals had similar Millett pointed to the need to ad- 89% reduction in the transmission rate numbers of sexual partners and rates dress the misperceived risk of HIV ac- per 100 HIV-infected persons, thereby of unprotected intercourse, incidence quisition, including the risk associated averting an estimated 350,000 new rates in MSM would be higher because with intraracial partnerships. He also HIV infections since the beginning of of higher background prevalence rates, highlighted the responsibility of prac- the epidemic. Through expanded HIV increased risk of anal versus vaginal titioners to offer frequent HIV tests to testing, the proportion of people in sex, and role versatility in which many MSM, as even black MSM who disclose MSM serve both insertive and recep- their risk to health care practitioners tive roles, thereby accelerating trans- and who have health insurance appear Dr Buchbinder is director of the HIV Re- search Section at the San Francisco Depart- mission through partner networks. to be at elevated risk of HIV seroposi- ment of Public Health and associate clinical MSM are disproportionately affect- tivity. Millett also called for multilevel professor of medicine and epidemiology at ed within all racial and ethnic groups, approaches to prevention and treat- the University of California San Francisco. and young black and Latino MSM are ment for MSM, including those using

38 Conference Highlights—Epidemiology and Prevention Volume 19 Issue 2 May/June 2011 individual-, interpersonal-, and struc- study of seroadaptive behavior among sented from a study conducted in Can- tural-level interventions. 1207 men recruited from December ada. Brenner and colleagues reported Heffelfinger and colleagues report- 2007 to October 2008 in San Fran- on the spread of HIV among MSM ed on recent HIV infections among cisco (Abstract 133). Behavioral prac- in Montreal, Canada, from December MSM in 21 high-prevalence US cities tices were evaluated at the individual, 2005 to September 2009 (Abstract enrolled in the 2008 National HIV Be- dyad, and episode levels, and were cat- 1046). HIV sequence data were col- havioral Surveillance System (NHBS) egorized into mutually exclusive prac- lected from surveillance of primary (Abstract 130). Of 6864 evaluable tices based on highest to lowest HIV HIV-1 infections (PHIs) and divided MSM, 4% had new infections, defined transmission risk. Seroadaptation was into unique transmissions, small clus- as having an HIV-seropositive test re- reported consistently by 39% of men, ters (2−4 PHIs), and large clusters sult with a reported last HIV-serone- whereas only 25% reported 100% con- (5−31 PHIs). Large clusters of infec- gative test result within the past 12 dom use, 14% no oral or anal sex, and tion accounted for the fastest grow- months. Independent risk factors for 12% oral sex only. When the unit of ing subepidemic, accounting for 25% recent infection (compared with unin- evaluation was partnerships, 100% of all transmissions in 2005 to 39% fected men) were younger than age 30 condom use was the most common in 2009 (P < .001). The 34% of infec- years; black, non-Hispanic race; His- practice (33%) compared with sero- tions occurring from MSM born out- panic ethnicity; other nonwhite race or adaptation (26%). When the unit of side of Canada were predominantly ethnicity; completing less than a high evaluation was sexual episode, oral sex unique transmission events. Given school education; having no insurance was the most common practice (65% the unique sociodemographic and be- or public insurance; and having had of acts), and anal sex with a condom havioral characteristics of these 3 dif- 2 or more HIV tests in the prior 24 was next most common (16%). Over- ferent types of transmission groups, months. Risk practices were not sta- all, more than 90% of all individuals, prevention strategies may need to be tistically significantly associated with dyads, and episodes used some form targeted differently to reach all 3 sub- recent infection. of safer sex or seroadaptation, suggest- populations of MSM contributing to this This report extends the data reporting that MSM use several strategies to epidemic. ed by Millett and colleagues about the manage their HIV risk. independent association of sociode- Golden and colleagues presented Populations at High Risk of mographic variables with HIV acqui- data on the differential impact of sero- HIV-1 Acquisition sition risk, in the absence of reported sorting by race among MSM in Seattle, differences in sexual practices or drug Washington (Abstract 1037). In their Youth use. Heffelfinger suggested 3 possible study of 7620 white and black MSM explanations: (1) increased prevalence who received HIV testing at a sexually Pettifor reminded the audience that and sexual mixing patterns within transmitted diseases clinic in Seattle approximately half of all new HIV subgroups; (2) differences in access to from 2006 to 2010, 266 participants infections globally occur in persons care among subgroups; and (3) differ- received a new diagnosis of HIV infec- younger than 25 years, with 35% oc- ential underreporting of risk practices. tion. White and black MSM reported curring in 15- to 24-year-olds (Abstract Regardless of reason, successful, cul- serosorting (unprotected anal sex only 66). There are also marked sex dispari- turally appropriate interventions need with partners of the same serostatus) ties: young women have HIV infection to be developed and tested in high-in- at 30% and 28% of their clinic visits, rates 2 to 3 times those of men in sub- cidence populations. respectively. Although serosorting was Saharan Africa, but HIV-infected men Oster and colleagues reported on a associated with lower HIV infection substantially outnumber HIV-infected network analysis of 23 black men aged risk among white MSM (odds ratio women in the Americas and Europe, 17 years to 25 years newly diagnosed [OR], 0.48; 95% confidence interval where the epidemic occurs predomi- with HIV infection from 2006 to 2008 [CI], 0.35−0.66), there was no such nantly in MSM. Many potential factors in Jackson, Mississippi (Abstract 1044). protection among black MSM (OR, drive this epidemic in younger per- They found that all men were linked 1.04; 95% CI, 0.47−2.30; P value for sons, including biological susceptibili- by few venues, suggesting that these interaction, .02). The reasons for these ty, increased individual behavioral risk, venues should be targeted for testing differences are not clear, as the mean as well as societal forces such as age and prevention intervention. time since the last HIV test was not dif- and power inequities within relation- ferent between newly diagnosed white ships and poverty driving the need for Seroadaptation and black men. A possible explanation transactional sex. is a higher rate of undiagnosed or un- Pettifor focused on recent prom- Several presentations focused on disclosed HIV infection among part- ising results from cash-transfer pro- seroadaptation, the practice of alter- ners of black men. grams whereby families receive cash ing sexual behavior based on self- Additional data on the possible con- incentives either unconditionally or and partner HIV serostatus. Truong tribution of sexual mixing patterns in conditional upon some requirements and colleagues presented data from a transmission among MSM were pre- (eg, girls must attend school). The

39 IAS–USA Topics in Antiviral Medicine

Schooling Income and HIV Risk (SIHR) HIV incidence in pregnant women in could substantially alter the overall Trial conducted in Malawi and re- sub-Saharan Africa is high (4.3/100 HIV epidemic (Abstract 68). In a com- ported at the 2010 International AIDS women-years; 95% CI, 3.9−4.6). Data prehensive review of global prevalence Society meeting in Vienna found that comparing the peripartum risk with data in MSM, Beyrer split countries into HIV prevalence was 60% lower in com- risk in nonpregnant women suggest a 4 scenarios: (1) countries where the munities randomly assigned to the modest increase in HIV acquisition risk epidemic predominantly affects MSM conditional and unconditional cash- (OR, 1.3; 95% CI, 0.96−1.6). Several (much of the Americas, Ghana); (2) transfer groups than in control com- factors may lead to this increase in HIV epidemics driven by injection drug us- munities.1 It appears that changes in acquisition, including behavior change ers (IDUs) (Eastern Europe and Central individual risk behavior accounted for in male partners, or the biological fea- Asia); (3) countries with a generalized less than half of the beneficial effect; a tures (hormonal, immunologic, and lo- heterosexual epidemic (much of sub- possible mechanism was that girls in cal genital tract changes) that occur in Saharan Africa); and (4) countries with the intervention groups were less likely pregnancy. This is of concern for the a mixed epidemic in MSM, IDU, and to have older male partners and less women and their infants, as the risk heterosexuals (South and Southeast likely to receive cash from their male of HIV transmission through breast Asia, Senegal, Egypt). Unfortunately, partners. milk is substantially elevated during there are 94 countries for which there Ott and colleagues also presented the acute infection period. Moreover, are no data for MSM available, includ- data on age mixing in sexual relation- if women are not aware of their HIV- ing three-fourths of African countries. ships from a population-based surveil- seropositive status, they may also be Of note, HIV prevalence is high in MSM lance study in rural KwaZulu-Natal, less likely to receive antiretroviral ther- in all 4 scenarios. South Africa (Abstract 1030). In this apy for prevention of mother-to-child In sub-Saharan Africa, prevalence community, casual relationships with transmission (PMTCT). in MSM exceeds that in heterosexu- “sugar daddies” (ie, men at least 10 The authors stated that in the period al men in all countries and exceeds years younger than their casual part- before initiation of PMTCT programs prevalence in women in all countries ners) are much less common than in Zimbabwe, acute HIV infection ac- except South Africa, Botswana, and marriages in which the woman is sub- counted for only an estimated 6% of Namibia. In modeling the impact of in- stantially younger than the man, lead- infant infections, whereas after PMTCT creasing prevention and treatment for ing to an increased risk of HIV acquisi- programs began, acute infection could MSM (condom and lubricant availabil- tion in young women. account for 44% of new infections in ity, community-based prevention pro- Santelli and colleagues found de- infants. John-Stewart outlined poten- grams, and antiretroviral therapy avail- mographic factors, risk practices, and tial behavioral and biomedical preven- ability for HIV-infected MSM), Beyrer sexually transmitted infections increased tion strategies to prevent peripartum showed that such programs would the rate of HIV acquisition among infections that include recognizing have a substantial impact in countries youth 15 years to 24 years of age en- the desire for pregnancy among many in all 4 types of scenarios, enhanced rolled in the Rakai Community Cohort women and studying the safety and by drug treatment for IDUs in scenar- Study (Abstract 690). Incidence in efficacy of prevention strategies in the ios 2 and 4. He ended with a tribute this group remained at 1% to 2% per peripartum period. to David Kato, the Ugandan activist year from 1999 to 2008. In multivari- Meditz and colleagues explored im- recently murdered for his work on hu- ate analysis, independent risk factors munologic reasons for an increasing man rights for MSM. Beyrer reminded for women and men were lower lev- rate of infections in women aged 40 the audience that improving access to els of education, increased numbers years of age or older (Abstract 33). prevention and treatment and address- of sexual partners, being separated or They reported that 24 postmeno- ing human rights issues are central to divorced, and having sexually trans- pausal women had higher CC chemo- the HIV practitioner community’s abil- mitted disease symptoms. Alcohol kine receptor 5 (CCR5) expression on ity to impact the global HIV epidemic. use was an independent risk factor for CD4+ cells and a higher proportion New data were presented on men, whereas for women, alcohol use of activated CD4+ cells in the periph- MSM in Kenya and Thailand as well. by the last partner was an important eral blood and the cervix than did 21 Sanders and colleagues reported that risk factor. premenopausal women. This disparity HIV-1 incidence was 6.5 per 100 per- may provide some explanation for in- son-years among 666 men with vari- Women creased susceptibility in these women. ous sex partners or recent anal sex (within 3 months of screening) at a John-Stewart and colleagues reported Men Who Have Sex With Men clinic in coastal Kenya (Abstract 1042). on the peripartum risk of HIV acqui- Incidence was highest among men re- sition and factors that drive increased Beyrer described the current state of porting sex with men only (21.7/100 HIV acquisition risk among pregnant knowledge of the global epidemic in person-years; 95% CI, 15.9−29.5), inter- women (Abstract 67). In combining a MSM and provided modeling for how mediate in men who reported sex with number of studies, they observed that increased prevention and treatment men and women (4.9/100 person-years;

40 Conference Highlights—Epidemiology and Prevention Volume 19 Issue 2 May/June 2011

95% CI, 3.3−7.4), and lowest among 0.49; 95% CI, 0.32−0.77), reminding 3.9; 95% CI, 1.3−12.4). Among 164 men who reported sex only with women practitioners of the challenges of con- women, HSV-2 incidence was 22.1 (1.1/100 person-years; 95% CI, 0.4−2.8). dom acceptability among men. per 100 person-years (P < .001 com- Edwards-Jackson and colleagues re- Hughes and colleagues studied a pared with men) and was associated ported on 200 HIV-seropositive MSM cohort of 3297 serodiscordant couples with incident HIV-1 infection (aIRR, recruited from an anonymous clinic in to probe factors affecting the per-act 8.9; 95% CI, 3.6−21.8). Interestingly, Bangkok, Thailand (Abstract 1039). At infectivity of HIV-1 (Abstract 135). genital washing with soap was protec- their most recent sexual encounter, 17% They observed a 2.9-fold increase in tive against HSV-2 acquisition in men of men reported engaging in unpro- infectivity per 1 log10 increase in plas- (aIRR, 0.3; 95% CI, 0.1−0.8), but vagi- tected anal sex, and only 26% disclosed ma viral load in the infected partner. nal washing with soap increased the their HIV-seropositive status. Despite Differences in male-to-female and fe- risk of HSV-2 acquisition in women the lack of disclosure, men were more male-to-male transmission rate were (aIRR, 1.9; 95% CI, 1.0−3.4). likely to report condom use during anal driven by the plasma viral load in the Tenofovir gel halved the risk of sex with partners of unknown serosta- HIV-infected partner, herpes simplex HSV-2 acquisition in the CAPRISA tus (91%) and HIV-seronegative part- virus type 2 (HSV-2) serostatus, and (Center for the AIDS Programme of ners (85%) than with HIV-seropositive the age of the HIV-uninfected partner. Research in South Africa) 004 study.2 partners (61%; P = .001). Baeten and colleagues evaluated Lama and colleagues presented data the association of genital tract HIV-1 from the iPrEx (Chemoprophylaxis for Serodiscordant Couples RNA levels with the risk of HIV trans- HIV Prevention in Men) trial of 2499 mission in the same cohort of serodis- MSM, half of whom were assigned to Transmission between partners in sta- cordant couples (Abstract 154). They receive oral tenofovir/emtricitabine ble serodiscordant relationships may reported that genital tract HIV-1 RNA and half placebo (Abstract 1002). In account for a substantial proportion of level was independently associated this study, HSV-2 incidence was simi- new HIV infections globally. Ndase and with HIV-1 transmission risk after ad- lar among those assigned to the active colleagues point out that interventions justing for plasma HIV-1 RNA levels. A study drug and those assigned to pla- for serodiscordant couples also need to total of 11 transmissions occurred in cebo (6.2 vs 5.8 per 100 person-years, take into account the possibility of out- couples with very low or undetectable respectively). There was no difference side partnerships (Abstract 1040). In genital HIV-1 RNA, but all had detect- in the proportion of genital ulcers in their study of 3380 HIV-1 serodiscor- able plasma HIV-1 RNA. the 2 groups, although there was a re- dant couples observed over a minimum duction in participants with anal ulcers of 24 months, there was a statistically Herpes Simplex Virus Type 2 (relative risk [RR], 0.4 vs placebo; 95% significant decline in the proportion of CI, 0.22−0.85) and a trend toward couples who engaged in sexual activity HSV-2 causes genital ulcerations and a reduction in herpes genital ulcer– (from 94% at enrollment to 73% at 24 has previously been associated with defined adverse events of grade 2 or months; P < .001) and an increase in an increased rate of HIV acquisition higher (13 in the treatment group vs the proportion of HIV-uninfected persons among heterosexual men and women 24 in the placebo group; P = .06). having an outside partner (from 3% to as well as MSM. McClellan and col- Tan and colleagues reported no de- 14%, respectively; P < .001). The rate leagues reported that HSV-2 preva- crease in HSV-1 or HSV-2 shedding of outside partnerships is likely higher lence and incidence were substantially from oral, genital, or anal mucosa than reported, as 22% of seroconvert- higher among women than men en- among 40 HIV-infected patients taking participants who reported no outside rolled in a cohort study of 5543 Zim- ing oral tenofovir compared with those partners were infected with genetically babweans (Abstract 1028). Prevalent not receiving tenofovir (Abstract 979). distinct viruses from their seropositive HSV-2 infection more than doubled the These data suggest that higher levels main partner. This proportion was sub- odds of acquiring HIV-1 infection in of tenofovir at mucosal surfaces may stantially higher among seroconverting men and women in the study. Hughes be required to reduce the risk of HSV participants who did report outside part- and colleagues also found a dou- acquisition and viral shedding among nerships (86%; P < .001). bling of HIV-1 acquisition risk among those already HSV-infected. Ngolobe reported on 444 serodiscor- HSV-2-seropositive men and women in dant couples in Uganda (Abstract 1041). 3297 heterosexual HIV-1–serodiscor- HIV Testing Strategies On multivariate analysis, condom use dant couples in Africa (Abstract 135). was not associated with antiretroviral Okuku and colleagues evaluated HIV testing among at-risk persons re- drug use (adjusted odds ratio [AOR], risk factors for HSV-2 acquisition in a mains suboptimal globally, as does 1.26; 95% CI, 0.81−1.96), suggesting cohort study in Kenya (Abstract 29). knowledge of HIV serostatus. Oster no risk compensation associated with Among 443 men, HSV-2 incidence was and colleagues reported on adherence treatment. However, condom use at last 9.0 per 100 person-years and was as- to HIV testing guidelines among 7271 sex was inversely associated with male- sociated with incident HIV-1 infection MSM participating in the 2008 NHBS controlled sexual decision making (AOR, (adjusted incidence rate ratio [aIRR], (Abstract 1048). Older men were less

41 IAS–USA Topics in Antiviral Medicine

likely than younger men to have been this clinical testing within 90 days dom use reduced risk by 78% (95% CI, tested in the previous year, and there (P < .001). Both Los Angeles and San 58%−89%). Bachanas and colleagues were no differences in testing rates Francisco Public Health Departments reported on condom use by 3538 HIV- by race or ethnicity. However, among plan to use an RTA at all of their test seropositive patients attending clin- men reporting an HIV test within the sites by July 2011. ics in Kenya, Namibia, and Tanzania prior year, the proportion testing new- Choko and colleagues reported on (Abstract 136). Overall, 54% of partici- ly positive was 14% for blacks, 7% for the first evaluation of self-testing in Af- pants had an HIV-seronegative partner Hispanics, and 3% for whites. Of the rica using an oral HIV test kit (Abstract or a partner of unknown serostatus. 5864 (81%) of the sample reporting 42). Four geographic areas in Blantyre, Inconsistent condom use was statisti- 1 or more high-risk characteristics Malawi, were selected for participa- cally significantly associated with be- for whom testing is recommended tion, and 92% of participants opted ing female, desiring pregnancy, being at least every 6 months, only 44% for self-testing over clinic-based or no a spouse (compared with casual and reported receiving an HIV test in the HIV testing. Sensitivity and specificity steady, nonmarital partners), and not past 6 months. This suggests the need were excellent (97.9% and 100%, re- taking antiretroviral therapy. for both better adherence to testing spectively), and overall, 99.2% of self- guidelines and guidelines targeted test users read an accurate result on Male Circumcision for highest incidence populations. their first try. However, 10% of partici- Calderon and colleagues reported on pants needed help beyond the initial Kong and colleagues reported on long- a novel community pharmacy–based instructions, 10% made some type of term effects of male circumcision in HIV testing and counseling program in error in preparing the test, and more Rakai, Uganda (Abstract 36). Overall, New York City (Abstract 1052). Nearly than half stated that they thought that 80% of control subjects returning for three-fourths of eligible patients of- some type of additional counseling a visit chose male circumcision. Over- fered HIV testing accepted. was needed with HIV testing. Overall, all efficacy remains high through 4.8 Delaney and colleagues presented 99% stated that they would be likely to years of follow-up (adjusted effective- data from a randomized trial of a rapid self-test again, and self-testing was the ness, 73%; 95% CI, 55%−84%). Risk HIV testing algorithm (RTA), in which most common choice for the next test behavior increased comparably in both a second rapid test was used to con- that participants would like to take. circumcised and uncircumcised men, firm an initial positive rapid test result The same test was evaluated for suggesting that risk compensation (Abstract 132LB). This approach was 987 participants in Singapore (Abstract has not been observed in this setting. compared with standard HIV testing: 1075). Among HIV–seronegative, at-risk Tobian and colleagues reported that one rapid test followed by off-site con- participants, sensitivity and specificity male circumcision does not decrease firmatory laboratory testing. An RTA of self-testing was 100%. As reported human papillomavirus (HPV) trans- was implemented at 9 testing sites in in the previous abstract, participants mission from HIV-seropositive men to Los Angeles and San Francisco to eval- responded favorably to the testing (eg, their female partners (Abstract 1008). uate the impact on referral to health 89% liked the privacy of testing, and Several other abstracts focused on care practitioners and on CD4+ cell 96% found the instructions easy to fol- strategies for scale-up of male circum- counts or viral load within 90 days low), but nearly three-fourths felt the cision services (Abstracts 1005−1007). of the initial positive rapid test, as need for confidential pre- and posttest compared with standard testing at 23 counseling. This suggests that self-test- Preexposure Prophylaxis control sites. ing may increase the uptake of testing The positive predictive value of the in various populations but that accom- Efficacy, adherence, safety and resis- RTA was 100% and of the initial rapid modations should be made to provide tance. This year, 1 plenary (Session 35) test using a standard algorithm was additional counseling, as needed. and 2 oral abstract sessions (Sessions 86%. All persons receiving the RTA 8 and 25) focused on the strategy of received referrals to medical care, HIV Prevention Strategies using topical or oral antiretroviral whereas only 47% of those with a drugs to prevent HIV acquisition, that positive rapid test result who received Conference presentations on HIV vac- is, preexposure prophylaxis (PrEP). Ce- standard testing (requiring that they cine development are reviewed by lum provided a framework for think- return for their confirmatory test re- Watkins elsewhere in this issue (see ing about how and when antiretroviral sults) actually returned for care. Over- pages 36–37). drugs are used for prevention: drugs all, two-thirds of participants referred initiated before exposure (PrEP), drugs to care received a CD4+ cell count or Condoms used for postexposure prophylaxis viral load test within 90 days of their (PEP), and those used as therapy after initial test (regardless of whether they Hughes and colleagues reported data infection (Abstract 120). were referred from the intervention or on determinants of per-contact HIV-1 Grant and colleagues presented up- control groups), whereas only half of infectivity among serodiscordant cou- dated data from the iPrEx trial, a ran- those not receiving a referral received ples (Abstract 135). Self-reported con- domized, placebo-controlled trial of

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daily tenofovir/emtricitabine in 2499 respectively; P < .001). Drug was most design (Abstract 995). Tenofovir levels MSM and transgender women in North commonly detected in men report- in scalp hair were strongly correlated and South America, Africa, and Asia ing unprotected receptive anal sex, with dose, suggesting that this may be (Abstract 92). Extending data from less common in sexually active men a useful strategy for monitoring adher- the published interim analysis cen- without this risk, and least common in ence in clinical trials. sored on May 1, 2010,3 Grant and col- men reporting no sexual activity in the Concerns have been raised about leagues presented safety and efficacy prior 12 weeks (in 76%, 59%, and 35%, whether tenofovir-based regimens data through August 2010, including respectively; P=.003), suggesting that would be associated with an unaccept- HIV seroconversions occurring by 8 men may have used sexual risk to de- able rate of adverse events (AEs) in an weeks after the study drug was discon- termine whether or not to take the otherwise healthy population. Grant tinued. There were 37 additional HIV study drug. and colleagues reported that partici- infections since the interim analysis, Celum reviewed data from the IAVI pants randomly assigned to take te- but overall efficacy remained largely (International AIDS Vaccine Initiative) nofovir/emtricitabine in the iPrEx trial unchanged (modified intention-to- E001 and E002 studies and reminded had no higher rate of serious, grade treat analysis; efficacy, 42%; 95% CI, attendees that adherence by electronic 3, or grade 4 AEs than did placebo 18%−60%). These efficacy analyses measurement of opening pill bottles participants (Abstract 92). The only did not vary by age, race, education, or was highest with daily dosing; inter- symptoms reported more common- geographic location. mediate with fixed-dose, twice-per- ly in participants in the active study In exploratory analyses, efficacy week dosing; and lowest for fixed-dose group than in the placebo recipients was somewhat lower in uncircumcised plus postcoital dosing (Abstract 120). were nausea (2% vs <1%, respectively; than in circumcised men (efficacy, 36% There also appears to be substantial P=.04) and weight loss (2% vs 1%, re- vs 83%, respectively; P = .10) and lower heterogeneity between populations, spectively; P = .04). Participants given among men not reporting unprotected with adherence higher among 34 US tenofovir/emtricitabine were some- receptive anal sex at baseline than iPrEx study participants than among what more likely to have elevated cre- among men who did report this risk 145 non-US iPrEx study participants atinine levels (2% vs 1%, respectively; (efficacy, −25% vs 52%, respectively; (P < .0001) (Abstract 96LB). In an ad- P = .08), although only 5 participants P = .03). These estimates are not adherence substudy from the Partners in the tenofovir/emtricitabine group justed for other potentially confound- PrEP efficacy trial in Uganda, median had elevated creatinine levels lasting ing variables but raise the possibility adherence as measured by pill count for 2 or more visits. All creatinine el- of differential PrEP efficacy by route and unannounced home visits was evations resolved after drug discontin- of exposure. Efficacy data from het- greater than 99% (Abstract 488). uation; 4 of the participants restarted erosexual men and women and IDUs Amico and colleagues reported on the study drug and exhibited no recur- should be available in the next few years the correlation of self-report, pill count, rence of creatinine elevation. (see Global Advocacy for HIV Prevention drug dispensation records, and blood Mulligan and colleagues reported Web site, http://www.avac.org). detection of study drug among the on bone mineral density (BMD) among Grant and colleagues also presented same 179 iPrEx study participants in- a subset of 503 iPrEx trial participants data demonstrating that efficacy was cluded in Anderson’s presentation (Ab- on 4 continents (Abstract 94LB). At highest among those reporting taking stract 95LB). Men had a median self- baseline, before initiation of the study their study drug more than 90% of the reported adherence level of 100% by drug, BMD was low (ie, z score, <−1.0) time, intermediate in those reporting each of 4 measures, despite no detect- in 36% of participants in the spine and 50% to 90% adherence, and lowest in able study drug in half of the samples in 18% in the hip. There were small those reporting taking less than half (ef- tested. Even among men self-reporting but statistically significant decreases ficacy estimates, 68%, 34%, and 16%, never missing a pill in the prior month, in BMD in participants receiving te- respectively). Anderson and colleagues study drug was detectable in only 68%. nofovir/emtricitabine compared with reported on drug levels among a sub- On the other hand, reports of low lev- those receiving placebo for the total sample of 179 iPrEx trial participants els of adherence (less than half of pills hip (−0.65 at 24 weeks; −0.95 at 48 in the active study drug group at the taken) were uncommon (2%), but in weeks) and spine (−0.95 at 24 weeks), 24-week study visit (Abstract 96LB). this group, study drug was substantially although no difference was observed Overall, 50% had detectable metabo- less likely to be detected (22%). between the groups in bone fractures lites of tenofovir and emtricitabine in Clearly, better measures of ad- or international standards for low BMD their peripheral blood mononuclear herence than self-reporting and pill (z score,<−2.0). cells (PMBCs), indicating no study counts are needed. Liu and colleagues Liu and colleagues also reported on drug had been taken for at least 1 reported on drug levels present in hair BMD changes in a group of 200 HIV- week to 2 weeks before the visit. Par- samples among 15 HIV-uninfected seronegative men in San Francisco ticipants 25 years or older were more persons taking tenofovir for 2, 4, or 7 enrolled in a phase II tenofovir PrEP likely to have detectable drug than days per week under modified directly study (Abstract 93). They reported that younger participants (73% vs 44%, observed dosing, in a cross-over study 10% of men had low BMD at baseline

43 IAS–USA Topics in Antiviral Medicine

(z score, < −2.0). In addition, low BMD rectal challenges with SHIV162p3M184V. became infected compared with 3 of 4 was statistically significantly higher All 5 control animals became infected control animals (14% vs 75%, respec- in men reporting amphetamine (OR, (P = .0008). This suggests that oral tively; P = .04). Silicone vaginal rings 5.9; P <.001) or amyl nitrite (OR, 4.6; PrEP may protect against some resis- tested without study drug were report- P =.002) use and statistically signifi- tant viral strains. ed to be safe and well tolerated among cantly lower in men reporting use of 169 women in South Africa and Tanza- multivitamins, calcium, or vitamin D Drug penetration into genital tissue. nia (Abstract 1004). (OR, 0.3; P <.001). Men receiving teno- Celum reminded attendees that the Hendrix and colleagues reported fovir also had small but statistically sig- effectiveness of PrEP will depend on on the relative safety, adherence, and nificant decreases in BMD in the femo- “getting the right drug to the right acceptability of oral versus vaginal te- ral neck (−0.4%; P =.004) and total hip place at the right time” (Abstract 120). nofovir (Abstract 35LB). In total, 144 (−0.8%; P =.003) but not in the spine Several presentations focused on the women were enrolled at 4 US and 3 (−0.7%; P =.13). There was no statisti- timing and levels of drug penetration African sites and assigned to receive cally significant decrease in BMD after into genital tissues. Dobard and col- sequential 6-week periods of vaginal, 12 months on the study drug, and no leagues presented in vitro data sug- oral, or both formulations. Although differences were observed in fractures gesting that tenofovir/emtricitabine relatively infrequent, women reported between study groups. The clinical provides protection only 2 hours after substantially more nausea, diarrhea, importance of both the higher-than- challenge, whereas raltegravir provides and headache during periods when expected proportion of men with low protection up to 8 hours to 10 hours they were taking tenofovir orally. Self- BMD at baseline and the small reduc- after challenge (Abstract 30). In a low- reported adherence was high, but drug tions in BMD in MSM taking tenofovir- dose, twice-weekly, vaginal-challenge was detected in only 35% to 65% of based PrEP regimens is not yet known. model, 1% raltegravir gel administered samples, with no difference between Drug resistance is another concern 3 hours after challenge protected 5 of 6 study groups. Tissue levels observed that has been raised about the use of macaques through 20 challenges. All 4 with vaginal dosing were more than PrEP. Grant and colleagues reported control animals became infected. This 100 times higher than with oral dos- no additional cases of drug resistance suggests that integrase inhibitors may ing; addition of oral dosing did not in the iPrEx study; the only cases pre- be particularly useful as PEP drugs. further raise tissue levels. US women viously reported consisted of 3 partici- Brown and colleagues reported on preferred the oral formulation, where- pants who were already HIV-infected concentrations of darunavir, ritonavir, as African women were evenly divid- at enrollment (Abstract 92). Liegler and and etravirine in seminal plasma and ed between preference for oral and colleagues searched for minor variant rectal tissue of 12 HIV-seropositive vaginal use. drug resistance among iPrEx trial par- men, to consider these drugs’ utility ticipants and found 1 K65R minor vari- for PrEP in HIV-uninfected persons Rectal delivery of pre- and postex- ant and 1 M184V minor variant in 2 (Abstract 992). Seminal plasma levels posure prophylaxis. Anton and col- placebo recipients (Abstract 97LB). No were 80% to 93% lower than blood leagues reported on the safety and ac- minor variants were found among par- plasma levels for the 3 drugs, and ceptability of this 1% tenofovir gel used ticipants given active drug, including rectal tissue levels were 3 to 13 times rectally among 18 men and women. the 3 participants with breakthrough higher, perhaps reflecting fecal elimi- This hyperosmolar gel was neither well infections, in whom low levels of study nation of these drugs. tolerated (ie, many reported lower-gas- drug were detected at the first-infec- Nel and colleagues presented phar- trointestinal AEs) nor highly accept- tion time point. Levels of drug-resis- macokinetic and safety data on the able (ie, only 25% of participants liked tant virus in the 2 participants HIV-in- investigational dapivirine vaginal ring the gel) (Abstract 34LB). However, a fected at baseline who received study in 48 women (Abstract 1001). The ring single rectal dose resulted in 100 times drug declined to below the lower limit was well tolerated and was not associ- the rectal tissue concentration of teno- of detection (< 0.5%) through week 40 ated with serious AEs. Drug concentra- fovir compared with a single oral dose. of follow-up, suggesting that drug-resis- tions remained high through 35 days Dezzutti and colleagues presented tant virus, when it emerges, may revert of use. Celum reported on plans to data on a reformulated tenofovir gel quickly to wild type. conduct an efficacy trial of the dapiv- prepared for rectal use (Abstract 983). Garcia-Lerma presented data on irine ring (Abstract 120). The reformulated gel had lower os- the efficacy of oral tenofovir/emtric- Singer and colleagues reported on molality, increased spreadability, en- itabine against an emtricitabine-resis- the ethylene-vinyl acetate (EVA) ring hanced transepithelial resistance, and tant simian-HIV (SHIV) variant (Cong containing 100 mg of the investiga- elimination of the epithelial stripping et al, Abstract 31). In this study, all 5 tional nonnucleoside analogue reverse of the colorectal implants that was ob- animals treated with twice-weekly oral transcriptase inhibitor (NNRTI) MIV- served with tenofovir gel. The anti-HIV tenofovir/emtricitabine (3 days be- 150 in a macaque high-dose, vaginal- activity was similar between gels, sug- fore and 2 hours after challenge) were challenge model (Abstract 1003). Only gesting that the reformulated gel may protected against 14 weekly, low-dose, 2 of 14 animals with the MIV-150 ring be a useful rectal microbicide.

44 Conference Highlights—Epidemiology and Prevention Volume 19 Issue 2 May/June 2011

Leyva and colleagues evaluated 3 drop below 350/µL, PrEP again be- among a cohort of IDUs in Baltimore enemas of varying osmolality in 9 men comes more cost-effective at lower (Abstract 484). Castel and colleagues re- (Abstract 993). Hyperosmolar enemas thresholds of effectiveness because of ported on CVL as a population-based bio- (sodium phosphate) caused the most the lower possibility of transmission marker of HIV transmission in Washing- epithelial disruption in the colorectum. from partners with CD4+ cell counts ton, DC, from 2004 to 2008 (Abstract Hypoosmolar enemas (distilled water) above 350/µL. 1023). Although only half of the more had the greatest colonic permeability. Park presented an evaluation of the than 15,000 HIV cases diagnosed dur- Isoosmolar enemas had the best co- cost-effectiveness of PrEP in South Af- ing that time had a viral load measure- lonic distribution and retention and rican women (Walensky et al, Abstract ment available, mean CVL decreased were the most preferred by partici- 37LB). At the efficacy ranges observed substantially over that time. CVL was pants, suggesting that if larger quanti- in the CAPRISA 004 and iPrEx trials, highest in geographic areas with the ties of rectal microbicides are required, they report that PrEP would be cost- highest levels of poverty and unem- isoosmolar enemas may be explored effective (≤ $4600/year of life saved). ployment and the lowest proportion as a vehicle for microbicide delivery. If PrEP could be targeted to women at of high school graduates. The mean of very high risk (ie, incidence >9%/year), the most recent viral load was highest Models and surveys on preexposure be very effective (ie, >70%), and cost among women, blacks, and those in- prophlaxis. Abbas and colleagues (Ab- less than $40 per year, PrEP could be fected heterosexually, through IDU or stract 98LB) and Hallett and colleagues cost-saving for South African women. “other” modes of transmission. (Abstract 99LB) modeled the relative Mayer and colleagues examined Laraque and colleagues also showed benefits and risks of using only anti- practitioner preferences for oral ver- disparities in CVL in New York City, retroviral therapy for HIV-infected per- sus topical PrEP (Abstract 1000). More with higher viral loads observed in sons versus combining antiretroviral than two-thirds of the 121 physicians men, young and middle-aged adults, therapy with PrEP for HIV-uninfected in Massachusetts completing the sur- MSM, persons with AIDS or low CD4+ persons; the models examined effects vey preferred topical PrEP, because cell counts, persons with more recently on the HIV epidemic in South Africa of perceptions of fewer AEs (93%), in- diagnosed cases, and persons in spe- and among serodiscordant couples, creased ease of use (66%), and com- cific neighborhoods (Abstract 1024). respectively. In Abbas and colleagues’ mon use of lubricants for sex (54%). Terzian and colleagues also reported model, the use of both antiretroviral Nearly all (97%) stated that the major on CVL in New York City to monitor therapy and PrEP in a community led factor influencing their prescribing the effectiveness of care (Abstract to a larger prevention impact on the PrEP would be formal guidelines from 1025). Most HIV-seropositive persons epidemic than either alone. Antiretro- the US Centers for Disease Control and had repeated viral load testing, sug- viral therapy is predicted to contribute Prevention (CDC). gesting they were receiving ongoing substantially more HIV resistance at a clinical care. Although nearly half had community level than PrEP, although Treatment as Prevention fully suppressed viral load over the inadvertent PrEP use among HIV-in- prior year, a small proportion had sus- fected persons would also contribute One themed discussion session (Ses- tained high viral load, and these per- to cases of resistance. sion 42) and several additional posters sons were more likely to be younger, Hallett and colleagues posed the addressed how summary measures of black, or female. question of whether it would be more viral load within communities (com- Several models suggest that although cost-effective in preventing HIV trans- munity viral load, CVL) are related to treatment is likely to have a beneficial ef- mission to provide PrEP to the HIV- HIV infection rates and provision of fect on HIV transmission rates, preven- uninfected partner or antiretroviral care in different US cities. Das and tion interventions must also be used to therapy earlier to the HIV-seropositive colleagues reported that progress change the course of the current HIV partner. Assuming all HIV-seropositive has been made in San Francisco in epidemic. Prabhu and colleagues used partners are treated when CD4+ cell mean CD4+ cell count at diagnosis, data from South Africa, Kenya, Malawi, count falls below 200/µL, PrEP would rates of antiretroviral therapy initia- and Mozambique to project the probe more cost-effective only if the cost tion, and time to virologic suppres- portion of new infections attributable of PrEP is less than 40% of the cost sion (Abstract 1022). In particular, to different stages of HIV infections of antiretroviral therapy and if PrEP time from diagnosis of HIV infection (Abstract 482). Less than 10% of new is more than 60% as effective. PrEP to virologic suppression decreased infections are attributable to untreat- would be more cost-effective at lower substantially from 32 months in 2004 to ed HIV infection, whereas two-thirds levels of effectiveness when used by 8 months in 2008 (P<.001). Decreases in to three-fourths of new infections are higher-risk couples (eg, in couples for CVL also correlated with decreases associated with chronic, undiagnosed whom the HIV-uninfected partner may in newly diagnosed and reported HIV infection, and one-fifth to one-fourth be at risk from outside partners). Addi- cases (P <.001). are attributable to acute infection. This tionally, if all HIV-seropositive persons Similarly, HIV incidence decline corre- would suggest that substantial effort are treated when CD4+ cell counts lated temporally with a reduction in CVL should be focused on increasing HIV

45 IAS–USA Topics in Antiviral Medicine

testing uptake, particularly for those over time. Only by adding prevention 2. Abdool Karim Q, Abdool Karim SS, with established infection. to treatment would new infections Frohlich JA, et al. Effectiveness and safety Van Sighem and colleagues used a and AIDS deaths decline and costs of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection mathematic model to evaluate the im- decline over time. This led to the con- in women. Science. 2010;329:1168-1174. pact of various interventions on the an- clusions from this report that “treat- 3. Grant RM, Lama JR, Anderson PL, et al. nual number of new infections in MSM ment costs…are unsustainable” and Preexposure chemoprophylaxis for HIV in the Netherlands (Abstract 483). Al- “greater emphasis must be placed on prevention in men who have sex with though immediate treatment for all prevention of new infections.” men. N Engl J Med. 2010;363:2587-2599. HIV-infected persons would lead to a 4. Institute of Medicine Board on Global Health. Preparing for the future of HIV/ rapid decrease in HIV infection rates, Financial Disclosure: Dr Buchbinder has no AIDS in Africa: a shared responsibil- this decline would not be sustained. relevant financial affiliations to disclose. ity. November 29, 2010. http://www. Decreasing risk practices and reducing iom.edu/Reports/2010/Preparing-for-the- the time from infection to diagnosis Future-of-HIVAIDS-in-Africa-A-Shared- (leading to a decrease in risk behav- A list of all cited abstracts Responsibility.aspx. Accessed April 17, 2011. iors) are needed to fundamentally alter appears on pages 99–106. the trajectory of new HIV infections. Bongaarts presented models from a 2010 Institute of Medicine report (Bon- References gaarts and Pelletier, Abstract 173).4 In 1. World Bank. Malawi and Tanzania re- projecting the future of the African epi- search shows promise in preventing demic, increasing rates of treatment HIV and sexually transmitted infections. would slow the rates of new infections July 18, 2010. http://go.worldbank.org/ Top Antivir Med. 2011;19(2):38–46 and AIDS deaths but increase costs YVMPZBKC00. Accessed April 17, 2011. ©2011, IAS–USA

Dermatologic Manifestations of HIV Infection in Africa Resource Card

Based onCards the Topics Available in HIV Medicine article from February/March 2010, this folding card is available on request by visiting www.iasusa.org. Included are brief descriptions of selected dermatologic manifestations, along with their differential diagnoses and treatment options.

46 Volume 19 Issue 2 May/June 2011

www.iasusa.org/cow Cases on the Web (COW) is a series of case-driven continu- Treatment of Opioid Dependence in Patients with ing medical education activities sponsored by the IAS–USA. The HIV/AIDS COW program was created to offer convenient online access to Hillary Kunins, MD, MPH, MS, and Chinazo Cunningham, MD, MS top-quality education in the management of HIV and other viral CME Credit Available: 1.75 AMA PRA Category 1 CreditsTM infections. Level: Advanced NEW Diagnosis and Treatment Options for Acute HIV-infected patients with opioid dependence can now receive HIV Infection buprenorphine treatment in HIV care, primary care, or substance Elizabeth Reddy, MD, and Charles B. Hicks, MD abuse treatment settings. Offering colocated treatment provides CME Credit Available: 1.75 AMA PRA Category 1 CreditsTM the opportunity to improve HIV outcomes and to reduce sub- Level: Advanced stance use among patients. This COW presentation discusses the use of opioid agonist medications and explains specific pharma- “Acute” HIV infection generally refers to the phase of rapidly cotherapeutic properties of buprenorphine that can pose chal- evolving HIV antibody test results when viral replication is at its lenges in clinical practice. peak. “Primary” HIV infection often refers to the entire period from transmission through the first year of infection. Despite its Human Papillomavirus Infection in the HIV-Infected perceived importance, diagnosing primary or acute HIV infection Woman remains challenging for many reasons. Health care practitioners Erna Milunka Kojic, MD, and Susan Cu-Uvin, MD who are likely to come in contact with newly infected persons CME Credit Available: 1.75 AMA PRA Category 1 CreditsTM should be versed in recommendations and options for diagnosis Level: Advanced and treatment. This COW presentation discusses important con- cepts in the diagnosis of and treatment options for acute HIV The widespread use of potent antiretroviral therapy has resulted infection. in dramatic improvements in life expectancy among HIV-infected women, but the incidence of human papillomavirus (HPV)-relat- NEW Dermatologic Complications of HIV Infection ed diseases remains high and continues to rise. This COW pre- Jennifer Cafardi, MD, and John Cafardi, MD sentation discusses the epidemiology of HPV among HIV-infected CME Credit Available: 2.5 AMA PRA Category 1 CreditsTM women, explains the effect of antiretroviral therapy on HPV-relat- Level: Advanced ed anogenital diseases, and reviews the use of the prophylactic HPV vaccine. A variety of common skin conditions often develop in HIV-infected patients that may be difficult to treat and may provide Management of Depression and Alcohol Dependence in clues to the patients’ underlying immune status. Three major an HIV/HCV Coinfected Patient categories of skin conditions are observed: dermatoses specific Gareen Hamalian, MD, MPH, and Joseph Z. Lux, MD to HIV infection, common dermatoses that occur with greater CME Credit Available: 1.5 AMA PRA Category 1 CreditsTM frequency in HIV infection and AIDS, and less common condi- Level: Advanced tions that have been reported in association with HIV. This COW presentation discusses a selection of some common and some Treatment of psychiatric illness in HIV-infected patients, especially serious cutaneous diseases and the options for treating them. when this illness is accompanied by substance abuse, is a common and complex concern for HIV health care providers. On comple- HIV and Hepatitis B Virus Coinfection tion of this COW activity, the learner will be able to compare psy- Elizabeth Reddy, MD, and Susanna Naggie, MD CME chopharmacologic treatment options for depressed HIV-infected Credit Available: 1.75 AMA PRA Category 1 CreditsTM patients, discuss neuropsychiatric concerns related to the use of Level: Advanced efavirenz, and discuss prophylaxis and treatment options for HIV/ Hepatitis B virus (HBV) infection rates are higher among HIV- hepatitis C virus coinfected patients on interferon alfa therapy. infected persons than in the general population, owing to common modes of transmission and a decreased likelihood that the HBV infection will clear. In addition, HIV/HBV-coinfected persons are more susceptible to liver disease and related mortality than CREDITS monoinfected persons. This COW presentation discusses risks of acquiring HBV infection, means of prevention, and treatment These enduring-material activities have been approved for options for coinfected persons. AMA PRA Category 1 CreditTM.

For information about any of these Cases on the Web, please contact the IAS–USA. Phone: (415) 544-9400 • Fax: (415) 544-9401 • E-mail: info2011”at”iasusa.org • Web site: www.iasusa.org/cow

47 IAS–USA Topics in Antiviral Medicine Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011

Central Nervous System Complications of HIV Infection

Serena S. Spudich, MD, and Beau M. Ances, MD, PhD

Issues relevant to the nervous system garnered substantial attention glucose metabolism, prolonged ex- at the 18th Conference on Retroviruses and Opportunistic Infections. posure to therapeutic drugs including Several topics emerged as areas of importance both for informing current psychiatric medications and antiretro- understanding of HIV-related neurologic disorders and their treatment, and viral drugs, and natural neurodegen- for spurring future investigations. Measurable biomarkers of HIV-associated eration occurring with aging. Thus, neurocognitive disorder (HAND) were a major theme, with studies ranging in review of the data presented at the from new investigations of known laboratory and imaging markers to 2011 Conference on Retroviruses and identification of novel molecules that might be investigated as potential Opportunistic Infections (CROI), it means to follow disease activity as well as to better understand etiology continues to be important to keep in of disease. Studies of pathogenesis of HAND and simian immunodeficiency mind the complex features that likely virus–mediated neurologic injury added to prior understanding of lentivirus underlie HAND, the subject popula- neuropathogenesis. Another broad area of investigation was the interplay tion examined in each study, and how between treatment with antiretroviral or adjunctive therapies and biomarkers HAND was assessed in each analysis. of HAND. New data were presented on the potential importance of acute and Studies of animal models continue early infection on the integrity of the central nervous system, complemented to provide a more controlled setting in by studies of the effects of early treatment interventions. which to investigate the direct effects of lentiviruses in the nervous system, Introduction—What’s in a be perceived by patients (mild neuro- and many important studies reported Name? cognitive disorder, or MND) or recog- at CROI 2011 employed such models nized only through NP testing (asymp- to inform an understanding of human Several recent studies indicate that tomatic neurocognitive impairment, or disease. Future studies need to ad- HIV-associated neurocognitive disor- ANI), HAND is frequently detected in dress rigorous characterization of sub- der (HAND) persists in patients taking patients receiving antiretroviral treat- ject populations, comorbid factors that potent antiretroviral therapy, with a ment. Even HIV-associated dementia may affect results, and detailed under- prevalence that ranges from 39% to (HAD), which overlaps in clinical pre- standing and integration of systemic 1,2 52% in varied settings. HAND is a sentation considerably with severe parameters into study analyses. Such potentially multifactorial condition de- forms of ADC as described in the past, definitions will allow the effects of fined by a combination of the patient’s includes a spectrum of disease from HIV-1 in the CNS to be understood for reported symptoms and measured ab- inactive to active and may reflect neu- patients in a variety of circumstances, normalities on neuropsychologic (NP) ropathologic events within the central including those with optimal viral test performance. Unlike other demen- nervous system (CNS) distinct from suppression with treatment, virologic tias, the diagnosis of HAND does not those associated with dementia that failure during treatment, treatment formally include additional biomark- occurs solely in the absence of antiret- complicated by comorbidities such as ers (either from the cerebrospinal fluid roviral therapy. mental illness and substance depen- [CSF] or through neuroimaging). Patients now assessed as having dence, and delayed therapy resulting In the current treatment era, HAND HAND likely have a complex interplay from limited access to treatment. represents a broader spectrum of dis- of factors affecting their neurologic ease than that underlying the classic status. Current HIV-1 infection and at- New Biomarkers of HIV- AIDS dementia complex (ADC) de- tendant immune activation within the scribed in the era before potent antiret- Associated Neurocognitive CNS may be important. Past events Disorder roviral treatment was widely available, (eg, CD4+ cell count nadir, prior expo- perhaps with a greater heterogeneity sure to neurotoxic antiretroviral drugs Numerous studies presented at the in presentation, and importantly, etiol- or drugs subject to abuse) may have in- conference sought to identify and vali- ogy. Predominantly characterized by creasing impact on a patient’s current date new biomarkers of HAND. Some mild forms of disease that may either status as individuals with HIV survive aimed to judge the relevance to the longer and have more time for such ef- nervous system of biomarkers from Dr Spudich is associate professor in the De- partment of Neurology at Yale University in fects to accumulate. With longer-term blood or other clinical sources that are New Haven, Connecticut. Dr Ances is assis- survival of HIV-1-infected individuals, known to be important in systemic tant professor in the Department of Neu- HAND is also perhaps influenced by HIV progression. Others investigated rology at Washington University in St Louis, distinct factors in the current era such biomarkers considered specifically rel- Missouri. as cerebrovascular disease, abnormal evant to the CNS, assessing their role 48 Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011 in or association with the presence of was no change in HIV-1 RNA level af- HIV infection. The percentage of ab- HAND. A few studies employed means ter intensification with raltegravir. Elite normal values correlated inversely to generate new candidates for bio- controllers also had extremely low lev- with current CD4+ cell count across markers relevant to the presence or els of HIV measured in the CNS despite the span of disease. At the ends of the prediction of CNS disease in lentiviral slightly more detectable virus in the spectrum, 79% of patients with CD4+ infection in primates. Although the fol- periphery. The single-copy assay thus cell counts below 50/µL and only 7% of lowing reports focused on identifica- can be applied to CSF and can mea- those with counts higher than 350/µL tion of biomarkers, many studies in- sure low-level HIV-1 RNA in some cas- had abnormal NFL levels. NFL level cor- vestigating pathogenesis of HIV in the es in CSF in suppressed subjects. The related with level of CSF neopterin, a nervous system and effects of treat- subject population for the study was macrophage-activation marker, but not ment in the CNS employed neurologic highly selected for treatment adher- with CSF viral load. This new assay pro- biomarkers as endpoints or further ex- ence and successful viral suppression vides promise as a tool for assessment amined the mechanisms of such mark- measured by standard assays (requir- of “subclinical” progressive neurologic ers in producing HAND, indicating the ing evidence of plasma HIV-1 RNA level injury in people with HIV infection. central importance of such markers in < 50 copies/mL for at least 1 year and These findings suggest that active inju- the investigation and management of CSF HIV-1 RNA level < 50 copies/mL at ry in currently asymptomatic patients the neurologic complications of HIV. baseline); it attracted highly treated is especially prevalent in advanced im- subjects including those receiving 4- or munosuppression and occurs in asso- New Insights Into Recognized 5-drug antiretroviral regimens. Future ciation with CNS immune activation. Biomarkers studies of subjects treated with more Nath presented a complementary standard current regimens and under report investigating the potential util- Detection and measurement of HIV-1 more routine circumstances may re- ity of measures of the heavy chain of RNA. In the early epidemic, measur- veal the importance of low-level repli- neurofilament (neurofilament H) in de- able levels of HIV-1 RNA within the cation of HIV-1 RNA as detected by the tecting neuronal injury in asymptom- CNS were ubiquitous in patients with single-copy assay in CSF. atic HIV infection (Anderson et al, Ab- classic HAD. Although presence of CSF stract 407). Density measurements of HIV-1 RNA was not specific to demen- Neuronal injury markers. Three stud- Western blot bands confirmed by anti- tia, and levels of HIV-1 RNA did not ies focused on CSF markers utilized as sera to neurofilament H were obtained consistently associate with severity of markers of neurodegeneration. Krut in CSF samples from 44 HIV-infected disease, declines in HIV-1 RNA level and colleagues reported on a new, subjects mostly receiving antiretrovi- could be observed with the initiation more sensitive assay for the light sub- ral treatment and from HIV-uninfected of therapy, and these changes corre- unit of the neurofilament protein (NFL) subjects with other neurologic disor- lated with improvements in neurologic with which they observed a broad spec- ders or clinically stable multiple sclero- performance. In the current era, HAND trum of values within the lower range sis. Neurofilament H level was higher can be detected in patients whose (Abstract 392). Whereas the prior CSF overall in the HIV-infected group than treatment successfully suppresses plas- NFL assay had value as a predictor of in either HIV-uninfected group. Fur- ma and CSF HIV-1 RNA levels to those dementia in some subjects not receiv- thermore, when HIV-infected subjects below the level of detection by stan- ing treatment and indicated very high were separated into diagnostic groups dard assays (< 50 copies/mL), render- NFL values in patients with progressive according to the clinical definitions of ing assessment of the “activity” of HIV HAND or HAD, the older NFL assay neurocognitively normal, ANI, MND, infection in the context of neurologic also showed NFL levels to be normal in and HAD, neurofilament H level was disease difficult. A major question is most subjects in the neuroasymptom- elevated without variation across the the extent to which persistent, low- atic stages of HIV infection. This group spectrum of disease. Subjects who level HIV-1 RNA replication in the CNS demonstrated, however, that the new clinically deteriorated over 6 months may underlie ongoing neurocognitive NFL assay has different “upper-limit had larger increases in neurofilament impairment in treated patients. of normal” values for HIV-uninfected H levels during this period than did Dahl and colleagues presented a subjects that vary according to age, those with no change or with improve- novel application of the single-copy as- discriminating between younger and ment in neurologic status. say for HIV-1 RNA detection to paired older noninfected subjects. These results corroborate the find- blood and CSF samples in 17 treated, Using this new assay, the investiga- ings in the NFL report, in that CSF neu- suppressed subjects before and after tors found NFL levels high for median rofilament H may indicate smoldering addition of raltegravir in an intensi- age in neuroasymptomatic HIV-1-in- neuronal injury during neuroasymp- fication study, as well as in 11 “elite fected patients across the spectrum of tomatic HIV infection. However, the controllers” (subjects with endogenous CD4+ cell counts from below 50/µL to finding that neurofilament H levels in control of HIV) (Abstract 423). Very above 350/µL, suggesting that the new subjects with overt HAD were similar low levels of CSF HIV-1 RNA were de- test is sensitive to subtle neural injury to those in neurocognitively normal tected in treated subjects, and there that may accompany asymptomatic subjects is surprising. This may be ex-

49 IAS–USA Topics in Antiviral Medicine plained by variable levels of treatment enced by age.5,6 Future studies might The plasma level of soluble CD14 and viral suppression in the different investigate whether alterations in CSF (sCD14), a protein secreted by traf- diagnostic groups. That is, a larger pTau levels reflect distinct HIV- or non– ficking monocytes and perivascular number of subjects in the “normal” HIV-related neuropathologic processes macrophages in response to LPS stim- group may have had ongoing high lev- occurring at different ages and further ulation, is an independent predictor els of HIV replication and inflamma- clarify the relationships between CSF of systemic disease progression and tion, driving active CNS injury, where- pTau levels and comorbid factors. mortality in chronic HIV infection. Pri- as subjects in the progressively more or studies of plasma sCD14 level and “abnormal” groups might have had Inflammatory markers. The variable HAND in the current era have yielded more suppression of current patholog- utility of currently recognized plasma inconsistent results; one group found ic processes, with performance based and CSF biomarkers of HIV-associated associations with information process- on prior irreversible injury. Alternately, immune activation has fostered in- ing speed but not global impairment,7 HAD in the current era may represent vestigation into new biomarkers of whereas another found an association processes not associated with en- inflammation relevant to CNS HIV dis- with NP test performance.8 hanced detection of neurofilament H. ease. Plasma lipopolysaccharide (LPS), Lyons and colleagues compared Future studies should clarify the rela- an indicator of microbial translocation, plasma sCD14, LPS, and CC chemo- tionship between neurofilament H levels may contribute importantly to chronic kine ligand 2 (CCL2) levels to neuro- and active neuropathologic processes systemic immune activation and im- cognitive test scores (normalized in people with HIV infection and in munopathogenesis in HIV infection. global and domain-specific T scores) various treatment scenarios. Prior work has shown a correlation be- from 97 subjects in the National Neu- Tau proteins are microtubule-asso- tween plasma LPS levels and presence roAIDS Tissue Consortium (NNTC) ciated proteins that stabilize microtu- of HAD,6 but assessment of a more and the CHARTER (CNS HIV Antiretro- bules in axons. Total Tau (tTau) protein mildly affected group with chronic HIV viral Therapy Effects Research) study in CSF is elevated in neurologic disease infection receiving antiretroviral ther- with nadir CD4+ cell counts less than associated with HIV infection, presum- apy showed no correlation between 300/µL (Abstract 405). Approximately ably reflecting disruption of neurons. degree of impairment and LPS level.7 three-fourths of the subjects were re- However, a hyperphosphorylated Tau To further investigate the utility of ceiving antiretroviral treatment; the protein (pTau) is thought to promote LPS level in predicting milder forms median CD4+ cell count (87 cells/µL) neurofibrillary “tangles” in the brain, of HAND, Carsenti-Dellamonica and was low; and there was a broad dis- and recent studies have found CSF colleagues performed a subanalysis tribution of HAND diagnoses. In this pTau level to be normal in HIV dis- of data from 179 subjects in the Neur- group, plasma sCD14 (but not LPS or ease3-5 but elevated in Alzheimer dis- adapt study, measuring plasma LPS CCL2) level was associated with worse ease and other “Tauopathies.” levels in association with NP test per- global neurocognitive performance Letendre and colleagues investigated formance (Abstract 404). Among sub- and impairment in specific domains the relationships between HIV infec- jects with mostly mild neurocognitive (attention and learning T scores). Us- tion, age, and pTau levels in 23 HIV-un- impairment (only 3% with HAD), blood ing area under the receiver operating infected subjects, 53 HIV-infected sub- LPS level was associated with presence characteristic curve analysis, plasma jects on antiretroviral therapy, and 17 of impairment (P < .0001), and there sCD14 level was also more closely as- HIV-infected subjects off antiretroviral were statistically significant differenc- sociated with impaired scores than therapy (Abstract 406). HIV-infected es between unimpaired subjects and were plasma or CSF HIV-1 RNA levels patients had elevated CSF pTau. Analy- each HAND subgroup. Impairment or CD4+ cell count. It is possible that ses of only the HIV-infected subjects of attention, concentration, speed of the interaction between plasma sCD14 indicated that CSF pTau levels corre- information processing, and motor level and cognition identified in this lated with older age, larger change in speed were associated with higher LPS study was also influenced by variable CD4+ cell count from nadir to current levels. In multivariable analysis, plas- antiretroviral treatment status or co- measure, antiretroviral therapy use, ma LPS levels higher than 120 pg/mL, morbidities, including use of narcotics and worse prospective memory perfor- plasma HIV-1 RNA levels greater than or cocaine and HCV infection. mance but not with worse global neu- 40 copies/mL, and hepatitis C virus rocognitive impairment. HIV-infected (HCV) coinfection were independent Markers of blood-brain barrier integ- subjects in this study were substantial- risk factors for neurocognitive impair- rity. The blood-brain barrier provides a ly older than HIV-uninfected controls ment. Future studies should determine protective environment for the CNS by (median ages, 45 years and 36 years, whether LPS level is a direct indicator naturally restricting diffusion of large respectively), suggesting that the dif- of pathologic processes relevant to the molecules and potential neurotoxins ferences observed in this study and in CNS or a more nonspecific marker of into the brain. Markers of blood-brain another by Brew, both of which con- ongoing systemic immune activation barrier disruption have been associ- trast with others finding normal pTau in patients at risk of HAND developing ated with severity of HIV-associated levels in HIV infection, may be influ- through other mechanisms. neurologic disease.9,10 However, data

50 Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011 presented at this year’s conference by tors. Multivariable linear regression Valcour and colleagues performed Letendre and colleagues introduced analysis revealed that only diabetes MRS in a cohort of acutely HIV-infect- the suggestion that a less permeable and abnormal cIMT values were indeed patients, chronically HIV-infected blood-brain barrier might have a nega- pendently associated with poorer NP patients, and HIV-uninfected control tive impact on HIV-1 RNA suppression performance. Higher education levels subjects from Bangkok (Abstract 54). within the CNS (Abstract 408). Using and current abacavir use were associ- Acutely infected patients tended to one measure of blood-brain barrier ated with better NP performance. have higher choline (Cho) ratios (a permeability, the CSF to serum albu- measure of cell turnover, as compared min ratio (CSAR), this group assessed Neuroimaging markers. The role of with creatine [Cr], a stable measure of data from 190 treated CHARTER neuroimaging in understanding the energy metabolism) within the basal subjects, most of whom had normal pathogenesis of HAND continues to ganglia than those of either chronically CSAR for age. Using cutpoint analy- grow as evidenced by the burgeoning infected patients or uninfected control ses, which divided values within the number of posters and talks at the 2011 subjects. A correlation was observed normal range of CSAR values, lower CROI. Many presentations highlighted between MRS-measured metabolites CSAR values in patients treated with roles for morphometry, magnetic reso- and CSF biomarkers for acutely in- low-CNS-penetrating regimens was as- nance spectroscopy (MRS), and diffu- fected individuals. Cho:Cr ratios from sociated with higher CSF HIV-1 RNA sion tensor imaging (DTI) as possible the frontal lobe were positively corre- level as well as with global neurocog- noninvasive techniques to assess the lated with MCP-1 values. These results nitive impairment. These preliminary effects of HIV infection in the brain. suggest that even in acute infection, studies require further assessment of Ragin and colleagues performed a changes can be observed within sub- the biological importance of the spec- cross-sectional study of subjects at a cortical structures; they also validate trum of CSAR values within the normal mean of 1 year after HIV transmission previous neuroimaging studies of early range, their relationship to markers of (n = 43) and compared results with HIV-infected individuals. neuroinflammation, and the potential those of age- and sex-matched HIV- Similar results were also observed specific relationships between lower seronegative control subjects (n = 22) in chronically HIV-infected individu- CSAR values and levels and effects of (Abstract 55LB). Volumetric analysis us- als. Navia and colleagues showed that antiretroviral drugs within the CNS. ing semiautomated tools demonstrat- neuronal injury was present in chroni- ed a statistically significant reduction cally infected participants despite anti- Markers of vascular disease. Several in cortical structures in HIV-seroposi- retroviral therapy (Abstract 56). Both groups have shown that cardiovascu- tive patients at this early stage of infec- current CD4+ cell counts and baseline lar disease (CVD) risk factors such as tion compared with HIV-seronegative MRS-measured metabolite values (spe- hyperlipidemia, hypertension, and past control subjects. These results nicely cifically, decreases inN -acetylaspartate history of CVD are associated with complement posters by Tate and col- [NAA] and Cho levels in the basal gan- reduced neurocognitive performance leagues (Abstract 443), Kallianpur and glia) were good predictors of progres- in HIV-infected subjects.11–13 Fabbiani colleagues (Abstract 441), and Ortega sion from unimpaired to subclinical and colleagues reported on CVD risk and colleagues (Abstract 442), who impairment. Letendre and colleagues indicators including carotid intima- studied brain volumetric measures in investigated associations between media thickness (cIMT) in associa- chronically HIV-infected patients. Sta- plasma and CSF biomarkers associ- tion with performance on NP testing tistically significant decreases in brain ated with systemic and CNS immune (Abstract 403). This cross-sectional volume were observed in HIV-infected activation with imaging biomarkers study enrolled 247 patients, with 87% patients and may be related to sex (fe- in a group of chronically infected sub- receiving antiretroviral treatment. male > male), race (African American jects. Subjects had a mean CD4+ cell Subjects underwent NP examination > white), nadir CD4+ cell count, pres- count nadir less than 50/µL, with the via 11 tests, and assessments of CVD ence of detectable plasma or CSF HIV-1 majority receiving suppressive antiret- risk factors and common cIMT were RNA, or duration of antiretroviral ther- roviral therapy (Abstract 444). A total also performed. The group had mild apy. Ragin and colleagues showed an of 212 subjects underwent blood sam- to moderate neurocognitive disease, association between plasma levels of pling, lumbar puncture, and cerebral with a median of 2 of 11 tests indicat- monocyte chemoattractant protein-1 metabolite measurement by MRS. In ing “pathologic” scores. A total of 40% (MCP-1) as measured by multiplex as- plasma, findings included associations of patients showed at least 2 CVD risk says and evidence of brain injury by between MCP-1 levels and levels of factors. Having 2 or more CVD risk analyzing brain volume fractions for markers of both neuronal integrity (ra- factors was associated with poorer a variety of regions in 10 HIV-infected tio of NAA to creatine [Cr]) and inflam- neurocognitive performance on test- subjects (Abstract 446). Larger longi- mation (Cho:Cr ratio). In CSF, MCP-1 ing. Subjects with diabetes, hyperten- tudinal studies of both HIV-infected levels also directly correlated with sion, and abnormal cIMT values each and -uninfected patients are needed to lower NAA:Cr ratios in some regions, showed lower cognitive performance tease out the possible impact of each whereas fractalkine level inversely cor- than subjects without these risk fac- of these components. related with NAA:Cr ratios, and levels

51 IAS–USA Topics in Antiviral Medicine

of sCD14 and interferon-inducible pro- been linked to senescence and CNS cused directly on the identification of tein-10 were directly correlated with disease. mechanisms of HIV- and SIV-related Cho:Cr ratios. MRS-measured metabo- Another study employed high- CNS injury. Studies examining proper- lite abnormalities were also observed throughput proteomic methods to ties of HIV associated with neurologic in perinatally HIV-infected patients identify novel proteins expressed in injury, including genetic analyses of (Abstract 450). All of these MRS find- the CSF in HIV infection and through CSF and blood species, were comple- ings support the hypothesis that im- the course of antiretroviral treatment. mented by studies focusing on the mune activation within the brain oc- Price presented an analysis comparing host characteristics associated with curs soon after seroconversion and CSF samples from HIV-uninfected and the development of HAND, centering may persist even during effective sys- -infected subjects to identify peptides on host CNS immunologic characteris- temic virologic control with antiretro- (> 2000 peptides per sample) with in- tics in HIV and SIV infections. viral therapy. creased abundance in the HIV-infected The conference also highlighted patients, and to identify recognized Virologic Determinants of HIV- DTI, an imaging technique that mea- proteins (> 300 proteins per sample) Associated Neurocognitive Disorder sures the restricted diffusion of water present in CSF (Angel et al, Abstract within the brain in order to visualize 61). This study also assessed peptides Swanstrom reported on the env gene neural fiber tracts. Results from HIV- identified in 11 longitudinal sample sequences of HIV-1 derived from monoinfected participants were com- sets from subjects at different stages paired CSF and plasma samples in a pared with those from individuals of HIV-related CNS disease, before and study to determine phylogenetic rela- coinfected with HIV and HCV (Abstract after initiation of antiretroviral treat- tionships between blood and CSF in 448). Gongvatana and colleagues dem- ment. These investigators used corre- subjects with HAD in the absence of onstrated that the coinfected patients lation with CSF neopterin, a pteridine antiretroviral treatment (Schnell et al, had statistically significant decreases in marker of macrophage activation, as Abstract 58). The study also sought white matter integrity (ie, decreased a “probe.” Thus, proteins identified to evaluate entry properties of HIV-1 fractional anisotropy and increased by the proteomic discovery that either species associated with distinct decay mean diffusivity) in all lobes of the brain. positively (eg, complement) or nega- characteristics. All subjects with HAD tively (eg, autotaxin) correlated with had highly compartmentalized HIV-1 between the CNS and the plasma, but Identification of Novel Biomarkers the known marker CSF neopterin were highlighted as potential novel bio- HIV-1 species from subjects with rapid Witwer and colleagues used an accel- markers with mechanistic importance reduction in CSF HIV-1 RNA levels in erated simian immunodeficiency virus in the etiology of HAND. response to antiretroviral treatment (SIV) macaque model of HIV, in which These investigators also used Inge- showed no infectivity in cells express- AIDS and CNS disease occur within nuity Pathway Analysis (IPA) to map ing low levels of CD4 receptors, sug- 3 months of infection, to unveil new known interconnections between iden- gesting that these species must be in- biomarkers potentially associated with tified proteins, suggesting pathways of fecting and independently replicating the development of CNS disease in pri- disease mechanism. IPA mapped 3 within T lymphocytes in the CNS. mate lentiviral infection (Abstract 409). major networks of identified proteins Viral species from subjects with This group previously demonstrated that correlated with neopterin and slower decline in CSF HIV-1 RNA levels that levels of CSF HIV-1 RNA, CSF in- were potentially associated with neu- after initiation of antiretroviral therapy terleukin 2 (IL-2), and MCP-1 are pre- rologic function and disease. Applying were more complex, suggesting that dictive of CNS disease in this acceler- state-of-the-art proteomic technologies they had been growing as separate ated SIV model.14 MicroRNA (miRNA) to CSF samples of well-characterized populations for a long period of time, was identified in plasma to seek mole- HIV-infected subjects provides a pow- and were able to enter cells with low cules associated with progression to SIV erful discovery method for identifying levels of CD4 receptors, indicating encephalitis (SIVE). Profiles of miRNA new biomarkers and, potentially, the replication within macrophages or mi- were assessed in plasma sampled from pathways of HIV-related CNS disease. croglia. These macrophage-infecting animals before acute SIV infection and viruses were almost exclusively found in CSF viruses rather than virus from 10 days after infection. A total of 45 Neuropathogenesis of HIV and miRNA molecules were differentially plasma. In one subject, a macrophage- Simian Immunodeficiency Virus tropic virus was detected within the expressed in acutely infected and un- Infection infected samples, revealing a plasma CNS 2 years before the onset of de- miRNA “signature” of acute infection. Whereas many biomarker and treat- mentia. This study provides novel evi- Of these miRNA molecules, at least 6 ment studies presented at the confer- dence for 2 types of compartmental- were statistically significantly different ence had implications for understand- ized CNS infection in patients with HIV between animals that did or did not ing the pathogenesis of HAND across infection and dementia: a form sup- develop encephalitis. Two of these lat- the spectrum from mild disease to ported by T-lymphocyte infection and ter miRNA molecules have previously HAD, a number of presentations fo- another fostered by infection within

52 Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011 macrophages and microglia. These Database,” presented by Holman and of host immune function, plausibly investigators also showed the first evi- colleagues (Abstract 436, http://www. contribute to the systemic and CNS dence of CNS compartmentalization of hivbrainseqdb.org/). This group assem- immune responses involved in HIV subtype-C HIV-1 species. bled a database of clonal HIV env se- neuropathogenesis. Hightower and colleagues present- quences available in the National In- In an effort to understand the re- ed data on the degree of genetic di- stitutes of Health genetic sequence lationships among lentiviral primate versity within plasma HIV species in database, GenBank, relevant to CNS infection, the CNS host immune re- chronic infection (Abstract 57). They HIV infection. Importantly, sequences sponse to infection, and the devel- used a method derived from a popu- included had to be either derived from opment of neuronal injury, Fell and lation-based sequence that takes into the CNS (from the brain, meninges, or colleagues examined blood, CSF, account the number of mixed bases CSF; n= 1272) or from other tissues from brain tissue, and patterns of cerebral occurring in the sequence, normalized subjects for whom CNS sequences metabolites in an accelerated (CD8- by the total sequence length, which were also available (n = 1245). Numer- depleted) SIV macaque model wherein produced a Total Mixed Base Index. ous annotation details were assem- 85% of animals develop SIVE (Abstract They validated this approach as a mea- bled for each subject at each point of 59). They quantified SIV RNA levels in sure of intra-individual HIV-1 popula- sampling, including antiretroviral drug CSF, plasma, and frontal cortex of the tion diversity by comparison of these history, current laboratory indices in- brain, and they obtained MRS results findings with Shannon entropy and cluding CD4+ cell count and HIV-1 every 2 weeks in 24 animals, includ- average pair-wise distance. Multivari- RNA levels, and cognitive and patho- ing 7 placed on minocycline for weeks able logistic regression was used to logic diagnoses. The database was de- 4 through 8 postinfection and 4 ani- model the relationship between viral signed to be readily searchable by all mals administered antiretroviral drugs diversity and AIDS, and viral diversity annotation criteria as well as sequence for weeks 6 through 12 postinfection. and NP. Blood HIV-1 population diver- and tissue criteria. They also quantified activated mono- sity was found to be associated with cytes (identified as CD14+CD16+ both presence of AIDS and presence of Host Features Associated with HIV- cells) in the blood over time in these neurocognitive impairment. Associated Neurocognitive Disorder animals. Diversity and compartmentalization In the absence of treatment, NAA:Cr of SIV variants were investigated in a Schrier and colleagues investigated ratio steadily decreased through the more controlled setting through stud- host genetic factors associated with early weeks postinfection, with a 20% ies utilizing the accelerated macaque development of HAND in a study of reduction below baseline by 8 weeks model of neuroAIDS (accelerated via HIV-infected subjects in Anhui, China postinfection. The percentage of ac- infection with neurovirulent SIVmac251) (Abstract 390). A prior study by this tivated monocytes correlated with (Abstract 437). This group examined group found an association between plasma and brain SIV RNA levels but gp120 SIV sequences from plasma and the presence of the HLA allele HLA- not with CSF SIV RNA levels. A statis- postmortem brain tissue in 2 animals DR*04 and a diagnosis of HAND in tically significant inverse correlation euthanized at 21 days postinfection 191 participants recruited within the was identified between the percentage and 4 animals with disease that pro- United States. The current investiga- of CD14+CD16+ monocytes in blood gressed to meningitis or encephalitis tion confirmed this finding in 178 and concentrations of NAA and Cr in and died. A V2-C2 amino acid variant HIV-infected Chinese subjects with the frontal cortex. Both minocycline associated with macrophage tropism a distinct genetic background and a and antiretroviral treatments prevent- unique to brain and lung tissue (and different spectrum of comorbidities ed further decline in the NAA:Cr ratio absent from all plasma samples) was (including a 94% prevalence of HCV and halted expansion of the monocyte identified in 4 animals, suggesting infection). subset, but neuronal recovery was not selective outgrowth of a macrophage- Furthermore, in subjects with de- observed. These data suggest that neu- tropic variant in these tissues. These tectable plasma HIV-1 RNA, cognitive ronal dysfunction in the early stages studies support the possibility that decline was greater in the HLA-DR*04 of SIV infection in an accelerated ma- specific macrophage-tropic variants group than in the non–HLA-DR*04 caque model is associated with the present in low quantities in transmit- group over a 12-month interval. No presence of activated monocytes in ted HIV species in humans might se- individual class I HLA allele (A,B), the periphery. lectively replicate within the CNS and recognized as associated with slower Cells of the monocyte and macro- be associated with predisposition to systemic HIV progression, had an ap- phage lineage were the focus of an- immune dysregulation and develop- parent protective effect against HAND. other study employing an accelerated ment of HAND. However, subjects with at least 1 pro- macaque model of neuroAIDS (us- Further investigation of the viral de- tective allele had better NP perfor- ing the neurovirulent strain SIVmac251), terminants of HAND will be fostered mance scores and less progression of in this case in an investigation of the by the development of a novel, pub- HAND over 12 months. HLA alleles, time course of monocyte recruitment licly available “HIV Brain Sequence which confer important characteristics into the CNS and of the characteris-

53 IAS–USA Topics in Antiviral Medicine

tics of perivascular macrophages ac- finger tapping, and semantic verbal jects at baseline and at 6 months, at cumulating during SIV infection and fluency) along with standardized neu- which point the study was terminated SIVE (Abstract 430). Nowlin and col- rologic examinations and dementia as- because of increased AIDS and non– leagues used intracranial injection of sessments were obtained at each visit. AIDS-related complications in the epi- dextran conjugated to different fluo- Statistically significant improve- sodic treatment group. Subjects were rescent labels at distinct timepoints to ments in NP test performance were de- a median of 40 years of age, were demonstrate greater accumulation of tected in all treatment groups at each composed of 42% women, and had a perivascular macrophages in menin- follow-up visit over the 192 weeks. Al- baseline median CD4+ cell count of ges and brain in animals with SIVE, though practice effects from the repeat 513/µL and abnormal NP test perfor- occurring mostly between days 20 and testing could have contributed to this mance (mean QNPZ-5, −0.7). During 49 postinfection. Perivascular macro- improvement, antiretroviral treatment the 6-month follow-up period, 86% phage recruitment was estimated to may also have positively affected the of subjects in the episodic treatment be increased 6-fold in animals with CNS through control of HIV replication group had started antiretroviral treat- SIV infection without encephalitis, and related processes. The proportions ment according to study indications; and increased 8-fold in animals with of patients with neurologic abnor- thus, the total average exposure to anti- SIVE. These studies also revealed that malities, dementia, or milder forms of retroviral treatment in this group was although CD163+ macrophages are HAND also decreased over the study 3.6 months versus 5.9 months in the a main component of perivascular period. continuous treatment group. macrophages in SIV-uninfected and This study confirms that in re- In both treatment-strategy groups, -infected animals, in animals with SIV, source-limited settings, the initiation improvement in QNPZ-5 scores and in a distinct population of macrophages of antiretroviral therapy is associated each individual test was noted between lacking SCD163 is also recruited. with improvement in NP test perfor- study entry and 6-month follow-up. mance. The fact that the regimens in There were no clear correlations be- Treatment With Antiretroviral the first and third treatment groups tween changes in NP test performance or Adjunctive Therapies and are currently initial treatment recom- and CD4+ cell count (which declined Biomarkers of HIV-Associated mendations from the World Health Or- in the episodic group and rose in the Neurocognitive Disorder ganization underscores the clinical im- continuous group) or plasma HIV RNA portance of witnessing performance level (which rose in the episodic group Effects of Standard Antiretroviral improvement in these 2 groups. Addi- and declined in the continuous group). Treatment on Biomarkers tionally, although the 3 different treat- The authors note that because there ments comprised regimens with dis- were changes in both groups inde- Important information on the effects tinct levels of presumed effectiveness pendent of the usual laboratory-based of initiation of antiretroviral treatment in penetrating the blood-brain barrier predictors of NP test performance, the on CNS function in antiretroviral-naive (with “clinical penetration effective- performance improvement between subjects in diverse resource-limited ness [CPE],” scores of 9, 6, and 7, re- baseline and follow-up might have settings was presented by Robertson spectively15,16), similar improvement been influenced by practice effect. The and colleagues (Abstract 428, AIDS was observed in all groups. study did not find a difference in im- Clinical Trials Group [ACTG] 5199, The Improved NP performance in pa- provement between the 2 groups but International Neurological Study). A to- tients receiving antiretroviral therapy was underpowered to detect a differ- tal of 860 subjects recruited in Africa (6 in a broad variety of geographic set- ence as a result of the early closure of sites), India (2 sites), and South Ameri- tings was also observed in an analy- the study. Further studies of treatment ca (3 sites) were randomly assigned to sis of data obtained from baseline to strategies that use repeated NP testing 1 of 3 antiretroviral regimens for initial month 6 in the SMART (Strategies for would be enhanced by inclusion of a therapy and monitored for changes in Management of Antiretroviral Thera- well-matched control group to assess NP test performance every 24 weeks; py) study (Abstract 402). A total of 292 the effect of learning. final analysis was done at 192 weeks. participants with CD4+ cell counts Ongoing low-level CNS immune ac- Subjects had CD4+ cell counts less greater than 350/µL were enrolled in tivation during antiretroviral treatment than 300/µL at entry and were a me- Australia, the United States, Brazil, and may contribute to the persistence of dian of 34 years old; a majority (53%) Thailand and randomly assigned to ei- HAND in patients receiving suppres- were women. Randomization led to ther episodic antiretroviral treatment sive treatment in the current era.17,18 equal distribution among the 3 treat- (if CD4+ cell count fell below 250/µL) Yilmaz and colleagues sought to inves- ment groups: efavirenz/lamivudine/zi- or continuous antiretroviral treatment. tigate the response of CSF neopterin dovudine, emtricitabine/atazanavir/di- Five NP tests (grooved pegboard av- level, as a biomarker of intrathecal mac- danosine (enteric coated), or efavirenz/ erage, color trails 1 and 2, timed gait, rophage activation, to initiation of anti- emtricitabine/tenofovir. Results from a and finger tapping, summarized as the retroviral treatment in chronic HIV in- short battery of language-adjusted NP quantitative NP z-score of the 5 tests fection (Abstract 429). Subjects (n = 114) tests (grooved pegboard, timed gait, [QNPZ-5]) were administered to sub- who were antiretroviral-naive or had

54 Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011 been off treatment for at least 6 months the antiretroviral regimens of subjects outcomes at baseline and at weeks 4, 8 underwent lumbar puncture before with progressive HAND (Abstract 421). (blood only), and 12. A total of 14 sub- and after initiation of a variety of anti- This study was conducted as a ran- jects (including roll-over subjects), pre- retroviral regimens that successfully domized, double-blind, placebo-con- selected for no detectable plasma or suppressed plasma HIV RNA to levels trolled trial with an endpoint of change CSF viral burden by standard assays, below standard detection. A total of in NP test performance (on a battery were administered raltegravir intensi- 107 neuroasymptomatic subjects had of 8 tests, summarized as NPZ-8) fication; their results were compared a median CD4+ cell count of 190/µL after 28 weeks of therapy. The 107 with those of 9 subjects without intensi- and abnormal median levels of CSF subjects had a mean CD4+ cell count fication. Overall baseline CSF neopter- neopterin (26.3 nmol/L) and plasma of 543/µL; 86% had suppression of in levels were within the normal range neopterin (24.2 nmol/L) at baseline. plasma HIV RNA level to less than 30 (mean, 5.6 nmol/L; normal, < 5.8 A mixed-effects model, which took copies/mL; and most had subclinical nmol/L), and no change in CSF neop- into account each subject’s serial ne- or mild neurocognitive disease at base- terin level was observed in either treat- opterin values and the days of follow- line. The subjects were equally divided ment group. Raltegravir intensification up after treatment initiation, was used between 2 treatment groups of oral also had no effect on most other to examine the decay pattern and final minocycline or placebo. CSF markers of inflammation exam- “set point” of CSF neopterin for the Minocycline treatment showed no ined (white blood cell [WBC] count or group. After a median 89 weeks of sup- evident effect distinct from placebo on CD38+HLA-DR+ CD8+ T-lymphocyte pressive treatment during follow-up, the NPZ-8 scores or on any individual percentages), blood-brain barrier integ- the estimated CSF neopterin set point scores except the grooved-pegboard rity (CSAR), or QNPZ-4 score. was 7.7 nmol/L, statistically signifi- test, which did not reach statistical sig- cantly higher than the upper normal nificance after correction for multiple Early Injury limit of CSF neopterin in HIV-uninfect- comparisons. After 50% of the targeted healthy subjects (5.8 nmol/L). Sev- ed enrollment completed the 24-week The possibility that the earliest phases en subjects with HAD were evaluated treatment phase, an interim review of HIV infection set the stage for subse- separately. Despite similar plasma lev- by the study’s data safety monitoring quent neurologic injury by seeding the els, they had higher baseline levels of board recommended early termina- CNS with persistent HIV infection, caus- CSF neopterin, slower decay, and sta- tion for futility. ing early injury to the nervous system, tistically similar elevations in final CSF The concept that ongoing brain in- or initiating a cascade of neuroinflam- levels compared with the neuroasymp- jury during antiretroviral treatment mation, has received increasing focus tomatic group. This longitudinal study may be facilitated by low levels of in recent years. Several presentations provides a window into the dynamics persistent HIV-1 replication driving this year focused on the effects of early of the intrathecal inflammatory re- immune activation within the CNS lentiviral infection in animal models sponse after initiation of standard anti- provides rationale for attempted “in- and in human infection with HIV. retroviral treatment, and it provides tensification” of standard regimens further evidence that immune activa- to better suppress these potential re- Natural History of Early Central tion persists in the CNS for a prolonged sidual processes. Price and colleagues Nervous System Infection period during treatment that reduces presented a pilot study of raltegravir HIV-1 RNA below levels of standard intensification, in which 18 subjects Dash and colleagues presented multi- detection. (mean CD4+ cell count, 513/µL) with modal findings of the CNS effects of evidence of sustained suppression of acute and early HIV-1 infection in a Effects of Adjunctive or Intensified HIV-1 in the plasma and successful humanized mouse model, which was Therapy During Antiretroviral antiretroviral treatment of CSF HIV-1 created by reconstituting immunode- Treatment to levels below 50 copies/mL were ran- ficient mice with human CD34+ cells domly assigned to receive either treat- derived from fetal liver (Abstract 438). Because residual neuroimmune acti- ment intensification with the addition Longitudinal blood sampling indicated vation during antiretroviral treatment of the integrase inhibitor raltegravir or that HIV-1-infected humanized mice may be a contributing mechanism no treatment intensification (Abstract had changes in absolute CD4+ and of HAND, treatment with adjunctive 424). Subjects maintained the assign- CD8+ cell counts similar to those ac- therapies that directly suppress CNS ment for 12 weeks, and those in the companying typical acute HIV-1 infec- inflammatory processes might provide no-intensification group had the op- tion in humans, with peak elevation in additional benefit in amelioration of tion to roll over to receive raltegravir plasma HIV-1 RNA levels at 4 weeks HAND. Sacktor and colleagues pre- intensification after that time. Sam- postinfection. Serial 7 Tesla brain MRS sented findings from an ACTG study pling of blood and CSF and NP testing over the first 15 weeks of infection re- investigating the effect of the addition (timed gait, grooved pegboard, finger vealed reduced NAA concentrations in of minocycline, an antiviral drug with tap, and digit symbol; QNPZ-4) was the cerebral cortex of HIV-infected mice possible immunomodulatory effects, to performed for clinical and laboratory at weeks 8 through 15 compared with

55 IAS–USA Topics in Antiviral Medicine

baseline measures, corresponding to have specific neurologic manifesta- rience of fatigue, although tied closely reduced mean diffusivity and fraction- tions related to recent infection either to symptoms of depression, may be in al anisotropy in this region as detected before or at evaluation; manifesta- part related specifically to inflamma- by DTI. Postmortem examination of tions included meningitis, encephali- tory processes within the CNS. animals euthanized at 15 weeks of tis, facial palsy, and peripheral nerve infection showed human cells infiltrat- disorders. Age, CD4+ cell count, sex, Effects of Treatment During Early ing meninges and perivascular spaces, and number of days since HIV trans- Infection activation of microglia and astrocytes, mission were similar between the and decreased levels of neuronal and subjects with or without neurologic Several studies focused on the effect astrocyte markers (including synap- symptoms. Abnormalities in CSF were of early antiretroviral treatment on the tophysin, neurofilament, microtubule- common in both neurosymptomatic CNS. Though numerous studies have associated protein 2 [MAP2], and glial and neuroasymptomatic subjects dur- evaluated the effect of early initiation filbrillary acid protein) compared with ing primary infection. Of laboratory of therapy on the course and outcomes those of uninfected humanized mice. factors including blood and CSF HIV of systemic HIV infection, these stud- Two studies employing neuroimag- RNA level, CSAR, and CSF WBC count, ies have not been conclusive regarding ing biomarkers as crucial endpoints only CSF WBC count was indepen- the value of early treatment for sys- focused upon the effects of HIV infec- dently associated with the presence of temic outcomes. Whether early treat- tion in the human brain during the neurologic symptoms in a logistic re- ment may be effective in suppressing early stages of infection (Abstracts gression multivariable analysis. These HIV RNA levels, preventing establish- 54 and 55LB). Valcour and colleagues results suggest that host CNS immune ment of viral reservoirs, and control- found not only CNS inflammation dur- response (rather than primarily CSF vi- ling neuroimmune activation within ing acute infection by detection of el- ral burden) is a determining factor in the CNS has not been systematically evated cerebral metabolites with MRS, the neurologic manifestations of HIV investigated. but also documented some of the ear- during primary infection. Graham and colleagues examined liest evidence of HIV neuroinvasion Grill and colleagues investigated the the effects of extremely early initiation in humans, detecting CSF HIV-1 RNA association between reported fatigue of antiretroviral therapy in an acceler- as early as 8 days after HIV transmis- and CNS changes as indicated by mea- ated SIV macaque model of neuroAIDS sion (Abstract 54). This group charac- sures of systemic and intrathecal viral (Abstract 410). At 4 days after intrave- terized the relationship between CSF burden and inflammation in 43 men nous inoculation with SIV, 3 animals and plasma levels of HIV-1 RNA in 17 with recent HIV infection (at a median were treated with saquinavir, atazana- subjects with acute HIV infection (a estimated 129 days after transmission) vir, and an integrase inhibitor; 3 ani- median of 15 days after transmission), (Abstract 413). Degree of fatigue was mals were treated with atazanavir and finding that mean CSF HIV-1 RNA measured by the “fatigue subscore” an integrase inhibitor; and 6 animals levels were approximately 2.5 log10 portion of the Profile of Mood States were untreated. The animals were eu- copies/mL lower than levels in the inventory and correlated with scores thanized at 21 days, and tissues were plasma. Three subjects had undetect- on the Beck Depression Inventory examined for presence of SIV RNA, able CSF HIV-1 RNA despite having de- (BDI) as well as laboratory measure- SIV DNA, and cell and cytokine levels. tectable virus in plasma that reached ments that included blood and CSF In treated animals, CSF SIV RNA levels of almost 300,000 copies/mL. HIV RNA levels, CSF WBC count, and was statistically significantly reduced CSF cytokines correlated with neuro- CSF levels of neopterin, cytokines reg- compared with untreated animals at imaging indices of CNS inflammation ulating cellular trafficking, interferon- days 7 and 10 after inoculation, as was in certain brain regions. gamma-inducible protein 10 [IP-10], CSF MCP-1 (also known as CCL2) at Additional studies sought to investi- and MCP-1. In linear regression analy- day 10. Levels of CD4+ and CD8+ T gate the mechanisms underlying neu- sis of fatigue subscore and individual lymphocytes were increased in treated rologic and behavioral characteristics markers, CSF MCP-1 levels were statis- animals, and SIV RNA levels were represent in the first months after HIV tically significantly associated with de- duced in brain tissue at day 21. How- transmission. Lee and colleagues per- gree of fatigue. Fatigue subscore also ever, SIV DNA levels in brain did not formed a cross-sectional study assess- strongly correlated with levels of de- differ between treated and untreated ing the relationship between the occur- pression as measured on the BDI. In a animals, and some measures of in- rence of neurologic disorders during multivariable regression model incor- flammatory responses within the CNS, primary infection and blood, CSF, and porating CSF WBC count (a marker of including major histocompatibility clinical parameters assessed in a group inflammation), CD4+ cell count, and complex class II molecules and glial of 85 subjects evaluated at a median HIV RNA levels in plasma and CSF as fibrillary acid protein, were elevated of 75 days after HIV transmission (Ab- possible predictors of fatigue, only CSF in all infected animals. These findings stract 411). Of the 85 participants, 17 WBC count was independently corre- in an animal model of lentiviral infec- were determined by a neurologist’s lated with fatigue subscore. During the tion that leads to accelerated brain in- history and physical examination to first months of HIV infection, the expe- jury suggest beneficial effects of hyper-

56 Conference Highlights—CNS Complications Volume 19 Issue 2 May/June 2011 acute treatment of SIV. Such effects that mild intrathecal immune activa- 9. Abdulle S, Hagberg L, Gisslén M. Effects include reducing the burden of viral tion may persist even in subjects who of antiretroviral treatment on blood-brain replication (SIV RNA level), preserv- initiate antiretroviral therapy early dur- barrier integrity and intrathecal immu- noglobulin production in neuroasymp- ing elements of the immune response ing the course of HIV infection. NPZ-4 tomatic HIV-1-infected patients. HIV Med. within the CNS, and reducing markers scores improved in response to antiret- 2005;6:164-169. of immune activation associated with roviral treatment in the primary-infec- 10. Andersson LM, Hagberg L, Fuchs D, macrophage recruitment and the in- tion subjects in parallel with expected Svennerholm B, Gisslén M. Increased flammatory cascade within the CNS. improvements in the chronic-infection blood-brain barrier permeability in neuro- subjects. This phenomenon may have asymptomatic HIV-1-infected individuals- In a related presentation, Mankowski -correlation with cerebrospinal fluid HIV-1 reported that maraviroc monotherapy been the result of practice effect but RNA and neopterin levels. J Neurovirol. given to rhesus macaques 24 days af- also might indicate that treatment ini- 2001;7:542-547. ter SIV inoculation reduced brain and tiation even during primary infection 11. Becker JT, Kingsley L, Mullen J, et al. Vas- CSF levels of SIV RNA and levels of has benefit to neurocognitive perfor- cular risk factors, HIV serostatus, and brain markers of macrophage activa- mance. cognitive dysfunction in gay and bisexual men. Neurology. 2009;73:1292-1299. tion (CD68+ cells) and neuronal de- Financial Disclosures: Dr Spudich has no rel- 12. Wright EJ, Grund B, Robertson K, et generation (accumulation of amyloid evant disclosures to report. Dr Ances has real. Cardiovascular risk factors associ- precursor protein) in the brain in a ceived research grant support from Pfizer Inc. ated with lower baseline cognitive perfor- similar accelerated model of lentiviral mance in HIV-positive persons. Neurology. CNS disease in primates (Kelly et al, 2010;75:864-873. Abstract 60LB). A list of all cited abstracts 13. Foley J, Ettenhofer M, Wright MJ, et al. Neu- appears on pages 99–106. rocognitive functioning in HIV-1 infection: A study examining the effects of effects of cerebrovascular risk factors and early initiation of antiretroviral therapy age. Clin Neuropsychol. 2010;24:265-285. on the CNS in humans with recent HIV References 14. Witwer KW, Gama L, Li M, et al. Coordi- infection was presented by Muthul- nated regulation of SIV replication and ingam and colleagues (Abstract 412). 1. Heaton RK, Clifford DB, Franklin DR, Jr., immune responses in the CNS. PLoS One. et al. HIV-associated neurocognitive disor- 2009;4:e8129. Results from longitudinal blood, CSF, ders persist in the era of potent antiretro- 15. Letendre S, FitzSimons C, Ellis R, et al. and NP (grooved pegboard, timed gait, viral therapy: CHARTER Study. Neurology. Correlates of CSF viral loads in 1221 vol- finger tapping, and digit symbol; the 2010;75:2087-2096. unteers of the CHARTER cohort. [Abstract NPZ-4) testing were obtained for 14 2. Robertson KR, Smurzynski M, Parsons 172.] 17th Conference on Retroviruses subjects with laboratory-confirmed TD, et al. The prevalence and incidence of and Opportunistic Infections (CROI). Feb- primary HIV infection who initiated neurocognitive impairment in the HAART ruary 16-19, 2010; San Francisco, CA. era. AIDS. 2007;21:1915-1921. 16. Letendre SL, Ellis RJ, Ances BM, Mc- antiretroviral therapy at a median 3. Clifford DB, Fagan AM, Holtzman DM, et Cutchan JA. Neurologic complications of of 6.4 months after HIV transmis- al. CSF biomarkers of Alzheimer disease HIV disease and their treatment. Table 1. sion. Changes in laboratory values and in HIV-associated neurologic disease. Top HIV Med. 2010;18:45-55. NPZ-4 scores over time after initiation Neurology. 2009;73:1982-1987. 17. Yilmaz A, Price RW, Spudich S, Fuchs D, of therapy were examined in longitu- 4. Gisslén M, Krut J, Andreasson U, et al. Hagberg L, Gisslén M. Persistent intrathe- dinal follow-up over a median of 458 Amyloid and tau cerebrospinal fluid bio- cal immune activation in HIV-1-infected markers in HIV infection. BMC Neurol. individuals on antiretroviral therapy. days; results were compared with 2009;9:63. JAIDS. 2008;47:168-173. those from a group of nondemented 5. Brew BJ, Pemberton L, Blennow K, Wal- 18. Eden A, Price RW, Spudich S, Fuchs D, subjects who initiated antiretroviral lin A, Hagberg L. CSF amyloid beta42 and Hagberg L, Gisslén M. Immune activa- therapy during chronic HIV infection tau levels correlate with AIDS dementia tion of the central nervous system is still (at a median of 93 months after diag- complex. Neurology. 2005;65:1490-1492. present after >4 years of effective highly 6. Ancuta P, Kamat A, Kunstman KJ, et al. active antiretroviral therapy. J Infect Dis. nosis) with a median 328 days of fol- Microbial translocation is associated 2007;196:1779-1783. low-up. Although treatment regimens with increased monocyte activation and were variable, CPE scores were similar dementia in AIDS patients. PLoS One. between the 2 groups. In response to 2008;3:e2516. antiretroviral therapy, primary-infec- 7. Sun B, Abadjian L, Rempel H, Calosing tion subjects demonstrated complete C, Rothlind J, Pulliam L. Peripheral biomarkers do not correlate with cognitive suppression of detectable HIV-1 RNA impairment in highly active antiretrovi- in plasma and CSF, but treatment in ral therapy-treated subjects with human a subset of chronic-infection subjects immunodeficiency virus type 1 infection. failed to completely suppress plasma J Neurovirol. 2010;16:115-124. and CSF HIV RNA levels in follow-up. 8. Ryan LA, Zheng J, Brester M, et al. Plasma Median CSF WBC count, a nonspecific levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate marker of inflammation, did not reach with cognitive dysfunction during human normal levels in either group by the immunodeficiency virus type 1 infection. Top Antivir Med. 2011;19(2):48–57 end of the follow-up period, suggesting J Infect Dis. 2001;184:699-706. ©2011, IAS–USA

57 IAS–USA Topics in Antiviral Medicine Conference Highlights—HIV Complications Volume 19 Issue 2 May/June 2011

Complications of HIV Disease and Antiretroviral Therapy Anne F. Luetkemeyer, MD, Diane V. Havlir, MD, and Judith S. Currier, MD

Studies on new direct-acting antivirals (DAAs) for hepatitis C virus infection guided group, and the 44-week bocepre- were a focus of the 2011 Conference on Retroviruses and Opportunistic vir group, respectively. As anticipated, Infections. Although the majority of the data were from HIV-uninfected cure rates in the black cohort were less patients, much-needed work has begun to characterize DAA and antiretroviral than in the nonblack group, with SVR drug interactions and to evaluate performance of DAAs for HIV/HCV-coinfect- attained in 23%, 42%, and 53%, respec- ed patients. There was continued emphasis on pathogenesis, management, tively. and prevention of the long-term complications of HIV disease and its Overall, patients receiving 44 weeks therapies, including cardiovascular disease, lipodystrophy, renal disease, and of boceprevir had SVR rates almost alterations in bone metabolism. Malignancies, particularly non–AIDS-defining double those of the control group, cancers, have emerged as a leading complication and cause of death in HIV and boceprevir response-guided ther- infection that may not be fully mitigated by immune reconstitution with apy led to equivalent SVR rates in the antiretroviral therapy. This year’s conference also highlighted important data nonblack participants. In those with on the optimal timing of antiretroviral therapy in tuberculosis coinfection, a favorable response to the initial as well as the treatment and prevention of common coinfections including 4-week pegylated interferon/ribavirin cryptococcal meningitis and influenza. treatment (≥ 1 log10 drop in HCV RNA level), SVR was 2-fold higher than in those without initial favorable results. Viral Hepatitis of drug resistance; however, develop- In patients not attaining SVR, those ment of entirely oral, interferon-spar- who responded to the lead-in treat- Hepatitis C Virus Protease Inhibitors: ing HCV treatment is actively being ment experienced reduced boceprevir Boceprevir and Telaprevir pursued. resistance compared with those not responding to the lead-in treatment Some of the most exciting data pre- Sulkowski and colleagues evaluated (4% vs 35%−47%, respectively). The sented at the 2011 Conference on Ret- the use of boceprevir in HIV-uninfect- most common adverse effects asso- roviruses and Opportunistic Infections ed HCV-genotype-1-infected, treat- ciated with boceprevir were anemia, came from the rapidly evolving field of ment-naive patients in the SPRINT-2 which developed in 49% of boceprevir- new oral direct-acting antivirals (DAAs) (Serine Protease Inhibitor Therapy 2) treated participants, and dysgeusia. for the treatment of hepatitis C virus study (Abstract 115). After an initial Boceprevir treatment also led to (HCV) infection, with the majority of 4-week lead-in treatment period with robust SVR rates in HCV-treatment- data coming from HCV-monoinfected pegylated interferon alfa plus ribavirin, experienced, HIV-uninfected patients. patients. Zeuzem gave an exceptional patients were randomly assigned to 1 Boceprevir more than doubled SVR plenary presentation summarizing the of 3 groups: a control group receiv- rates in patients with previous HCV current status of the HCV drug pipeline ing 44 weeks of pegylated interferon/ treatment relapse (ie, undetectable for both HIV-infected and -uninfected ribavirin; a group receiving bocepre- HCV RNA at the end of therapy with- patients (Abstract 121). Data were previr plus pegylated interferon/ribavirin out subsequent attainment of SVR), sented on boceprevir and telaprevir, for 44 weeks; and a group receiving with SVR rates of 29%, 69%, and 75%, both of which are oral HCV NS3 pro- boceprevir plus pegylated interferon/ respectively, after 48-week treatment tease inhibitors (PIs), the class of oral ribavirin in a response-guided strategy. with pegylated interferon/ribavirin, HCV drugs furthest along in develop- In the response-guided group, partici- 44 weeks of boceprevir, or boceprevir ment. Both NS3 PIs currently need to pants with undetectable HCV RNA be- response-guided therapy (32 weeks of be given with pegylated interferon alfa tween week 4 and week 20 of 3-drug boceprevir plus pegylated interferon/ and ribavirin to avoid the emergence therapy discontinued treatment after a total of 24 weeks, whereas those with ribavirin, with an additional 12 weeks detectable HCV RNA between week of pegylated interferon/ribavirin for Dr Luetkemeyer is assistant professor of 4 and week 20 of triple-drug therapy those with detectable HCV RNA at medicine at the University of California San received an additional 24 weeks of 4 weeks of triple therapy) (Abstract Francisco (UCSF). Dr Havlir is professor of pegylated interferon/ribavirin. 116). As observed in other HCV treat- medicine at UCSF and chief of the HIV/AIDS Division at San Francisco General Hospital. In the nonblack cohort, sustained ment series, patients previously non- Dr Currier is professor of medicine and chief virologic response (SVR) was attained responsive to HCV treatment (ie, those of the Division of Infectious Diseases at the in 40%, 67%, and 68% for the con- showing a ≥ 2 log10 IU/mL decrease in University of California Los Angeles. trol group, the boceprevir response- HCV RNA by week 12 from baseline

58 Conference Highlights—HIV Complications Volume 19 Issue 2 May/June 2011 but with detectable HCV RNA on the of triple-drug therapy) in 68% versus fection with pegylated interferon alfa– remaining course of treatment) had 14%, respectively. These high early based regimens, with higher SVR rates lower rates of SVR than did patients response rates with telaprevir treat- occurring in HCV genotypes 2 or 3 with relapse, with SVR rates of 7%, ment in hard-to-treat HIV/HCV-coin- than in genotypes 1 or 4 (85% vs 61%, 40%, and 52%, in the 3 groups, respec- fected patients are very promising; respectively; P =.003). Heterogenous tively. As in treatment-naive patients, SVR data from this trial are forthcom- treatment regimens were used, but the response to the initial 4-week leading. There was a trend toward lower median duration was 24 weeks, which in therapy predicted SVR, with SVR cEVR rates with atazanavir-based is shorter than the 48 weeks typically rates of 33% to 34% (if<1 log10 IU/mL antiretroviral therapy (57%) versus recommended for treatment of chron- HCV RNA drop at week 4 from baseline) efavirenz-based antiretroviral thera- ic HCV infection in HIV coinfection. increasing to 73% to 79% (if ≥ 1 log10 py (75%) or no antiretroviral therapy Ribavirin may not be needed for the IU/mL decrease) in the boceprevir (71%). However, the study was small full 24 weeks of pegylated interferon groups, and from 0% increasing to 26%, (n=60) and had insufficient power to alfa administration for the treatment respectively, in the control group. distinguish the effect of antiretroviral of acute HCV infection in those with a In terms of anticipated drug interac- therapy on treatment response. favorable early response in HCV RNA tions between boceprevir and antiret- Van Heeswijk and colleagues exam- level. In a pilot study of a kinetically roviral drugs, boceprevir appears to be ined the pharmacokinetic interactions guided treatment strategy, in which a strong inhibitor and modest substrate of telaprevir and antiretroviral therapy ribavirin was discontinued after 12 of cytochrome P450 3A4 (CYP3A4) (Abstract 119). Like boceprevir, telapre- weeks if HCV RNA was undetectable at (Abstract 118). Ritonavir coadministra- vir is also a substrate and inhibitor of week 8 and week 12, all patients who tion had only a minimal effect on bo- CYP3A4. Despite increasing telaprevir discontinued ribavirin attained an SVR ceprevir steady state and reduced the dosing schedule to 1125 mg every 8 after 24 weeks of pegylated interferon boceprevir area under the curve (AUC) hours for coadminstration with efavi- alfa, as did all patients who attained by 19%, whereas efavirenz coadminis- renz, treatment with efavirenz plus tel- undetectable HCV RNA at week 4 (ie, tration reduced the boceprevir mini- aprevir still leads to an 18% reduction RVR) (Abstract 959). mum plasma concentration (Cmin) by in telaprevir AUC and a 25% reduction 44%, the clinical importance of which in telaprevir Cmin. Genetic Predictor of HCV Clearance: is unclear. Conversely, boceprevir mod- Telaprevir had a heterogenous ef- IL28B estly increased efavirenz AUC by 20% fect on HIV PI levels, raising atazana- and maximum plasma concentration vir and lopinavir levels and decreas- Interleukin 28B (IL28B) single nucleotide (Cmax) by 11%. Studies of boceprevir ing darunavir and fosamprenavir polymorphisms (SNPs) have emerged for HIV-infected, treatment-naive and levels. Telaprevir modestly decreased as an important predictor of treatment -experienced, HCV-coinfected patients efavirenz levels and had minimal ef- response and spontaneous clearance are planned. fect on tenofovir plasma levels. Until of HCV in HCV mono- and HIV/HCV- The first interim data on HCV PI more data are available on appropri- coinfected patients. Favorable IL28B use in HIV-coinfected, HCV-genotype- ate dosing of coadministered telapre- haplotypes predicted spontaneous 1-infected patients were presented vir and antiretroviral therapy, caution clearance of HCV (Abstract 944) as well by Sulkowski and colleagues (Ab- is advisable with telaprevir use in as response to pegylated interferon/ stract 146LB). The NS3 HCV PI tela- antiretroviral-treated HIV/HCV-coin- ribavirin treatment for patients with previr was administered for 12 weeks fected individuals, once telaprevir HCV genotypes 1 and 4 (Abstracts 945 with pegylated interferon/ribavirin, becomes available after US Food and and 946) but interestingly not for those followed by 36 weeks of pegylated Drug Administration (FDA) approval, with genotype 3, for unclear reasons interferon/ribavirin alone, and re- which is anticipated to occur later (Abstract 945). Consistent with data sults were compared with those of a in 2011. from HCV-monoinfected patients,2 control group receiving 48 weeks of IL28B genetic polymorphisms do not pegylated interferon/ribavirin. Unlike Acute Hepatitis C Virus Infection appear to predict treatment response for boceprevir, studies of telaprevir for patients with acute HCV infection have not used a 4-week lead-in treat- As has been demonstrated in HCV (Abstract 943). ment. Telaprevir treatment was asso- monoinfection,1 treatment of acute The favorable C/C IL28B geno- ciated with rapid virologic response HCV infection (typically defined as the type was associated with a higher (RVR, defined as undetectable HCV period up to 1 year since infection oc- baseline level of HCV RNA, which is RNA after 4 weeks of triple-drug ther- curred) in HIV/HCV-coinfected patients somewhat counterintuitive, as a high apy) in 70% of participants, compared leads to superior cure rates over those HCV RNA level is associated with a with 4.5% of control patients; it was with chronic HCV infection. Boesecke worse response to therapy (Abstract also associated with complete early and colleagues (Abstract 113) reported 947). The authors postulate that this virologic response (cEVR, defined as an overall 65% SVR rate in HIV-infect- genotype may be associated with low undetectable HCV RNA at 12 weeks ed patients treated for acute HCV in- endogenous levels of interferon alfa,

59 IAS–USA Topics in Antiviral Medicine

thus permitting high HCV RNA levels ing the need for early initiation of ated with a 3.74 higher hazard ratio to develop, with enhanced sensitivity antiretroviral therapy for HIV/HCV- (95% confidence interval [CI], 1.57−8.9) to exogenous interferon–based thera- coinfected patients to avoid immuno- of mild renal impairment (defined as py and resultant higher SVR rates. Giv- suppression and progression of liver glomerular filtration rate <80 min/ en the predictive value of IL28B status, disease. Low-density lipoprotein (LDL) mL/1.73 m2 by the Chronic Kidney this genetic marker is anticipated to cholesterol level has also emerged as Disease Epidemiology Collabora- become an important part of risk-ver- an important predictor of progression tion [CKD-EPI] equation) in HIV/HBV- sus-benefit analyses of optimal timing to hepatic fibrosis (Abstract 925). It is coinfected patients treated with of HCV treatment. postulated that HCV uses the LDL cho- tenofovir (Abstract 977). Monitoring lesterol receptor to enter hepatocytes of renal function may be of particular Complications of HIV/HCV Coinfection and disrupts the LDL cholesterol secre- importance for HIV/HBV-coinfected, tion pathway; low serum levels of LDL antiretroviral drug–treated patients Evidence for the nonhepatic complica- cholesterol may therefore reflect high with advanced fibrosis. tions of chronic HCV infection contin- levels of HCV intrahepatic activity. HBV/HIV-coinfected patients tradi- ues to accumulate. HIV and HCV infec- Two studies were a sobering remind- tionally have a disappointing response tions are both known to independently er for clinicians to counsel patients to HBV vaccination.3 Potsch and col- reduce bone mineral density (BMD). A that they remain susceptible to HCV re- leagues report a promising hepatitis B cohort study of Medicaid patients indi- infection after HCV infection has surface antibody (HBsAb) seroconver- cated that HIV/HCV-coinfected patients cleared spontaneously or with treat- sion rate of 83% with an accelerated treated with antiretroviral therapy had ment. In a cohort of 58 HIV/HCV- schedule of a 40-µg HBV vaccination a higher adjusted hazard ratio of both coinfected men who have sex with administered at 0 months, 1 month, spine and hip fractures than did either men (MSM) studied longitudinally, and 2 months, which increased to 91% HIV-monoinfected or HIV/HCV-unin- 21% were found to have a differ- with an additional dose administered fected patients. Coinfected patients ent strain of HCV virus from that at at 6 months (Abstract 971). As in other also had a higher relative hazard of hip baseline, indicating interim reinfec- series,4 a CD4+ cell count greater than fracture than did HCV-moninfected pation (Abstract 912). Similarly, 6 of 26 350/µL was associated with a higher tients; the fracture risk was higher for HIV-infected MSM successfully treat- response rate to the additional dose at HIV/HCV-coinfected women than for ed for acute HCV infection were re- 6 months (85% for the 3-dose sched- coinfected men (Abstract 914). infected with a different strain during ule and 93% for the additional dose). Viral hepatitis may also be associat- a median follow-up period of 1.1 years ed with increased intestinal permeabil- (Abstract 958). Cardiovascular Disease ity and an associated proinflammatory state, as indicated by findings from 3 Hepatitis B Virus Infection There continues to be strong interest studies: higher levels of gut-microbe- in the relationship between HIV infec- associated lipopolysaccharides (LPS) Although HCV coinfection with HIV tion and cardiovascular disease (CVD), in HIV/HCV-coinfected patients than in infection is more common in the with additional studies confirming in- HIV-monoinfected patients (Abstract United States, coinfection with HBV dependent contributions of HIV infec- 936); higher LPS and soluble CD14 remains an important contributor to tion (Abstract 809) and immunode- (sCD14) levels in HIV/hepatitis B virus morbidity and mortality. In the MACS ficiency (Abstract 810) to myocardial (HBV)-coinfected patients than in HIV- (Multicenter AIDS Cohort Study) of infarction (MI) risk in large cohorts. monoinfected patients (Abstract 937); HIV-infected and -uninfected MSM, New data on the pathogenesis, clini- and higher LPS, sCD14, and interleu- liver-related death was statistically cal outcomes, and risk factors for CVD kin 6 (IL-6) levels in HCV- and HBV- significantly higher for patients with were presented this year. The relation- monoinfected patients (Abstract 939) chronic HBV infection than for those ship between markers of inflammation than in uninfected control subjects. with HCV infection (incidence rate ra- and disordered coagulation remain an Treatment of HIV and viral hepatitis in- tio [IRR], 2.04; P = .03), including pa- active area of investigation. fections was associated with reduction tients with HIV coinfection (IRR, 2.26), of these markers in some but not all of in whom the majority of liver-related Endothelial Function and these studies. deaths occurred (Abstract 968). Altered Coagulation In terms of predicting progression HIV/HBV-coinfected patients are fre- of liver fibrosis, low CD4+ cell count quently treated with tenofovir-based Measurement of the capacity of en- nadir and coinfection with HCV were regimens for the drug’s anti-HBV ac- dothelium to release tissue type plas- independently associated with pro- tivity. In a model adjusted for several minogen activator (t-PA) is one index gression from no or moderate fibrosis variables including race, CD4+ cell of endothelial function. Mestek and (fibrosis stages F0−F2) to advanced count, and plasma HIV RNA level, the colleagues previously reported that fibrosis (stages F3−F4) over a 5-year presence of advanced liver fibrosis treatment-naive, HIV-infected patients time period (Abstract 921), support- (fibrosis stages F3−F4) was associ- have impaired release of t-PA as as-

60 Conference Highlights—HIV Complications Volume 19 Issue 2 May/June 2011 sessed by the response to infusion of a more complex interaction of factors Using age- and gender-matched cases bradykinin and nitroprusside into the contributing to vascular events. On the (n=100) and controls (n=176), the ra- brachial artery.5 At this year’s meet- other hand, higher levels of D-dimer, tio of apolipoprotein B to apolipopro- ing, the group examined t-PA release along with P-selectin and hyaluronic tein A1 and the ratio of total choles- in treated HIV-infected patients and in acid, independently predicted the risk terol level to high-density lipoprotein age-matched and older HIV-uninfected of venous thromboembolic events in a (HDL) cholesterol level had similar adults and found that the HIV-infected case-control study of HIV-infected pa- predictive value and provided more in- group, regardless of treatment status, tients (Abstract 799). formation about MI risk than did indi- had impaired endothelial t-PA release Morse and colleagues from the Na- vidual lipoprotein measures in HIV-in- (Abstract 802). Of note, the HIV-infect- tional Institutes of Health compared fected patients. Finally, measurement ed patients had a level of impairment biomarkers of coagulation and en- of soluble CD163, a marker of acti- comparable with that of uninfected dothelial function in a group of HIV- vated macrophages, was shown to be adults 25 years to 30 years older, sug- infected patients with those of unin- increased in men with well-controlled gesting that vascular aging might be fected control subjects (Abstract 798). HIV disease and was associated with contributing to the higher rates of CVD Higher levels of D-dimer correlated the presence of noncalcified coronary observed in HIV-infected patients. with levels of plasma HIV-1 RNA, mark- plaque, as measured by multidetector The SMART (Strategies for Manage- ers of endothelial function, and tumor computed tomography (CT) angiogra- ment of Antiretroviral Therapy) study necrosis factor alpha (TNF-α) in the phy (Abstract 813). demonstrated a strong relationship HIV-infected group. Higher levels of The outcomes of acute coronary between levels of D-dimer at base- the endothelial activation markers sol- syndromes in HIV-seropositive pa- line and all-cause mortality in patients uble intracellular adhesion molecule tients were compared with those of who either discontinued or continued (sICAM), soluble vascular adhesion HIV-seronegative control subjects antiretroviral therapy.6 The relation- molecule (sVCAM), TNF-α, IL-6, and using data from the Nationwide In- ship between D-dimer and mortality tissue factor, but not D-dimer, were patient Sample, a database of almost was further explored using stored sam- noted in the HIV-infected group. These 300,000 patients at US hospitals (Ab- ples from the completed, randomized authors hypothesize that HIV infection stract 801). Excluding patients over the trials of interleukin 2 (IL-2), ESPRIT may increase D-dimer levels through age of 65 years, the authors reported (European/Australasian Stroke Preven- induction of endothelial activation, that HIV-infected patients admitted to tion in Reversible Ischaemia Trial), and mediated by TNF-α released from the hospital with acute coronary syn- SILCAAT (Study of Interleukin 2 in monocyte and macrophage activation. drome were younger and more likely People with Low CD4+ T-Cell Counts to have a history of renal disease but on Active Anti-HIV Therapy) (Abstract Risk of Myocardial Infarction less likely to have hypertension, hy- 375). Overall, higher D-dimer levels perlipidemia, or diabetes than unin- were associated with mortality. Of Novel markers that might help identify fected control patients. Importantly, note, those with the D-dimer levels in increased CVD risk continue to be eval- HIV-seropositive patients had an in- the highest quartile had an excess risk uated. Müllerian inhibiting substance creased risk of in-hospital death (3.3%) of death if they were assigned to re- (MIS), a marker of ovarian reserve, is compared with HIV-seronegative pa- ceive IL-2; the mechanism explaining an objective measure of menopause in tients (2.3%) and were more likely to this association remains elusive. women. LaCross and colleagues exam- incur acute renal failure during the Hsue and colleagues performed ined the association between levels of hospitalization. These findings suggest a comprehensive assessment of co- MIS and surrogate markers of athero- that clinicians need to remain vigilant agulation biomarkers, comparing 308 sclerosis, carotid intima media thick- for signs and symptoms of coronary HIV-seropositive men with a small ness (IMT), and coronary artery cal- syndromes in younger patients with group (n=38) of uninfected control cium (CAC) in HIV-seropositive women HIV infection who may not have tradi- men to determine which abnormali- (Abstract 804). Low levels of MIS, but tional risk factors. ties were more prevalent in treated not self-reported menopausal status, The relationship between recent and untreated HIV-infected patients was strongly associated with the pres- abacavir exposure and MI risk remains than in control subjects (Abstract ence of CAC but not carotid IMT after controversial. An FDA meta-analysis 797). Untreated HIV infection was control for age. The authors conclude of 26 randomized clinical trials with associated with a decrease in throm- that measurement of MIS might help nearly 10,000 patients attempted to bin generation (which did not appear identify HIV-seropositive women who lay the issue to rest (Abstract 808). The to be further altered by antiretroviral are candidates for more aggressive risk analysis found no association between therapy) and an increase in a thrombin factor management to prevent CVD. abacavir treatment and MI events, and inhibitor, whereas no difference in D- The prognostic values of different the authors calculated that the sample dimer, tissue factor, or other coagula- lipid indices as predictors of MI risk size evaluated had sufficient power to tion markers were noted in this group were evaluated in a case-control study exclude an MI-risk difference of 1%. of asymptomatic patients, suggesting from the SMART study (Abstract 807). The lack of independent adjudica-

61 IAS–USA Topics in Antiviral Medicine

tion of MI events and the comparison a 5% or more loss in BMD at the femo- vitamin D status, in addition to skin of abacavir to PI-based antiretroviral neck in this study. Together, these color as contributors to BMD status ral therapy in many of the trials still studies demonstrate that low bone (Abstract 823). leaves some degree of lingering density appears to be common among In one of the first randomized in- uncertainty. Studies evaluating in young MSM at risk for HIV infection tervention studies for bone health vitro and in vivo (animal model) effects and that exposure to tenofovir, either among HIV-seropositive youth, peri- of abacavir on leukocyte adhesion alone or combined with emtricitabine, natally HIV-infected children and ado- suggest a potential mechanism that and in the absence of HIV infection, lescents aged 6 years to 16 years were could underlie this uncertain associa- is associated with a small but statisti- randomly assigned to receive vitamin tion (Abstract 815). cally significant decline in BMD. The D (100,000 IU bimonthly) and calcium clinical importance of these changes (1 g daily) (n=30) or placebo for both is currently unknown and requires (n=29) for 2 years (Abstract 707). At Bone Loss: Host Factors, further study. follow-up, 25-hydroxy vitamin D con- Antiretroviral Drugs, or Peak bone mass is achieved in early centrations were higher among the HIV Disease? adulthood, hence the effects of HIV in- treated patients at 1 year and 2 years. Several studies this year helped untangle fection and exposure to antiretroviral However, although BMD improved in the contributions of host factors, HIV therapy among younger patients has both groups, there was no additional disease status, and antiretroviral drugs become an active area of research, improvement in the group receiv- to the prevalent condition of bone loss with several groups reporting new data ing the supplemental vitamin D and observed in patients with treated HIV this year (Abstracts 705−707, 823). calcium. The observation that three- infection. Randomized clinical trials Investigators in the Adolescent Trials fourths of the children in the interven- of tenofovir/emtricitabine or tenofovir Network examined associations be- tion group had vitamin D levels below alone used as preexposure prophylaxis tween antiretroviral therapy exposure 30 ng/mL at least once during study (PrEP) in HIV-uninfected MSM provid- and HIV serostatus on BMD in a cross- follow-up suggested that challenges ed the opportunity to evaluate the con- sectional study of age-matched and with adherence may have undermined tribution of these drugs to bone loss in race- or ethnicity-matched youth aged the benefits of the supplements evalu- the absence of HIV infection. 14 years to 25 years (Abstract 705). Im- ated in this trial. Mulligan and colleagues reported portantly, norms for the DEXA z scores the results of a bone substudy from the included in this study were from a sim- Is Bone Loss Mediated by Immune larger iPrEx (Preexposure Prophylaxis ilarly aged population. Reconstitution? Initiative) trial (Abstract 94LB).7 Dual- Total and regional fat measures were energy x-ray absorptiometry (DEXA) higher in the HIV-seronegative groups Several studies have demonstrated scans measuring BMD at the hip and and lower in the antiretroviral therapy– that bone loss occurs within the first spine were performed at 24-week in- naive groups. Lean body mass and total 6 months after the initiation of anti- tervals in 503 men randomly assigned and regional fat measures were lower retroviral therapy but then stabilizes. to receive tenofovir/emtricitabine or in all HIV-seropositive groups and high- To date, much of the work in this area placebo. The groups were well matched er in the HIV-seropositive group that has focused on the contributions of at baseline; notably, 36% had low BMD was antiretroviral therapy–naive than antiretroviral therapy to bone loss. (z score <−1) in the spine and 18% in in those receiving treatment. Mean Ofotokun and colleages from Emory the hip. BMD tended to increase in the BMD and z scores were consistently University examined the time course placebo group (as would be expected lower among HIV-seropositive partici- of changes in bone resorption among in young men); however, the decrease pants receiving antiretroviral therapy, a small group of treatment-naive in the tenofovir/emtricitabine group re- particularly in those receiving PIs, than HIV patients initiating antiretroviral sulted in a modest (−0.7% to −1.0%) in the HIV-seronegative group. therapy (tenofovir/emtricitabine/lopi- but statistically significant difference Of note, the low BMD in those re- navir/ritonavir) (Abstract 78). The re- between the groups by week 24. ceiving antiretroviral therapy was not searchers measured changes in the se- In the smaller tenofovir PrEP safety explained solely by tenofovir use. Bra- rum biomarker C-terminal telopeptide study (Abstract 93), conducted in men zilian investigators identified low BMD of type 1 collagen (CTx), an index of in with a median age of 40 years, there in about a third of perinatally infected vivo bone resorption, and in the recep- was a 1.1% decrease in mean BMD in youth and a strong correlation between tor activator of nuclear factor kappa-B the tenofovir versus pretreatment or low BMD and lean body mass, highlight- ligand (RANKL, an osteoclastogenic placebo groups at the femoral neck ing the importance of interventions to cytokine that can be secreted by T cells) and a 0.8% net decline at the total improve nutrition to prevent bone loss at weeks 0, 2, 12, and 24. hip; both decreases reached statisti- in this age group (Abstract 706). An During the early timepoints, they cal significance. Overall, 13% of the Israeli study of young women with HIV observed statistically significant in- tenofovir recipients compared with infection reinforced the importance creases in both of these markers, sug- 6% of the placebo group experienced of sun exposure, calcium intake, and gesting that early improvements in

62 Conference Highlights—HIV Complications Volume 19 Issue 2 May/June 2011

immune cell function might mediate trial, rosiglitazone did not reduce BMD term, antiretroviral therapy may not bone loss. The same group also exam- compared with placebo (Abstract 832). be an important contributor to frac- ined the effects of T-cell reconstitution The impact of tesamorelin, a growth ture risk. by the adoptive transfer of T-cells into hormone–releasing hormone agonist T-cell null, T-cell receptor beta chain recently approved for the treatment Vitamin D (TCRβ) knockout mice and found of fat accumulation in HIV-infected that when the mice received the new patients, on markers of bone turnover There continues to be great interest T cells, a loss of bone density occurred (osteocalcin and N-terminal telopep- in the relationship between vitamin D that mirrored the effects observed in tide [NTx]), was evaluated over 26 deficiency and a variety of outcomes humans, with a rise in levels of CTx weeks in a randomized, placebo-con- in HIV-infected populations. Inves- and RANKL. trolled study among HIV patients with tigators from the WIHS confirmed Early changes in markers of bone excess abdominal fat (Abstract 834). the high prevalence of low vitamin resorption were also identified in the Treatment with tesamorelin 2 mg daily D levels in HIV-infected women and MEDICLAS (Metabolic Effect of Differ- resulted in higher increases, relative to observed the absence of the expect- ent Classes of Antiretrovirals) study, a placebo, in markers of bone formation ed variation with season (Abstract randomized clinical trial that demon- (osteocalcin) than in NTx, a marker of 822). Stored serum samples from strated a greater degree of bone loss resorption. Whether these changes in the ECHO (Efficiency Comparison with zidovudine/lamivudine/lopinavir/ bone turnover markers will translate in Treatment-Naive HIV-Infected Sub- ritonavir than with nevirapine/lopi- into improvement in BMD remains to jects of TMC278 and Efavirenz) trial navir/ritonavir (Abstract 833). Bone be seen. were used to compare changes in 25- biomarkers of resorption (tartrate-re- hydroxy vitamin D (25(OH)D) serum sistant acid phosphatase 5b [TRAP5b] Fracture Risk and Antiretroviral levels and proportions of patients with and CTx) and biomarkers of bone for- Therapy 25(OH)D deficiency in patients receiv- mation (bone-specific alkaline phos- ing the investigational drug TMC278 phatase [BAP] and procollagen type 1 Cohort studies have suggested that (rilpivirine) versus efavirenz over 48 N-propeptide [P1NP]) were measured HIV-infected adults are at higher risk weeks (Abstract 79LB). The study on stored samples at baseline and at of fracture than the general popula- demonstrated a decline in 25(OH)D months 3, 12, and 24. Peak resorption tion.8 Whether specific antiretroviral with efavirenz (−6.2 ng/dL) and no appeared to occur by month 3; no data drugs contribute to this risk remains change with TMC278 (−0.6 ng/dL). from earlier timepoints were avail- an active area of investigation. Yin and Patients with an insufficiency or defi- able. Together these studies suggest a ACTG (AIDS Clinical Trials Group) col- ciency in 25(OH)D at baseline had a sta- possible early-intervention window to leagues examined the association be- tistically significantly lower risk of expe- prevent bone loss after the initiation tween antiretroviral drug classes and riencing severe 25(OH)D deficiency with of antiretroviral therapy. In addition, risk of fracture in the ALLRT (ACTG TMC278 (4%) than with efavirenz (20%). these findings suggest that a compo- Longitudinal Linked Randomized Tri- Low levels of vitamin D and use of nent of early bone loss may be medi- als) study, a long-term follow-up study tenofovir both appear to be associated by immune reconstitution. of patients who have been enrolled ated with elevations in parathormone in randomized trials of antiretroviral (PTH) levels in HIV-infected patients Connections Between Bone Density therapy (Abstract 830). In this analy- (Abstract 825). The impact of vitamin and Fat Depots sis of 3372 mostly male (83%) HIV- D3 replacement on levels of vitamin seropositive participants with a me- D and PTH was evaluated in an Ado- Associations between regional body dian age of 39 years, the incidence of lescent Trials Network randomized, fat and bone density were explored in new fractures was 0.3 per 100 person- placebo-controlled trial of directly ob- a cross-sectional study from the Wom- years (95% CI, 0.2−0.4). In univariate served, monthly dosing of 50,000 IU en’s Interagency HIV study (WIHS) analysis, no single class of antiretro- vitamin D3 or placebo for 12 weeks. (Abstract 835). Total fat and lean viral drug (PI, nucleoside analogue Subjects were 18- to 24-year-olds strat- mass were independently associated reverse transcriptase inhibitor [nRTI], ified by use of tenofovir. At week 12, with greater BMD in HIV-infected and or nonnucleoside analogue reverse 52% in the vitamin D–replacement -uninfected women. Of note, greater transcriptase inhibitor [NNRTI]) or in- group had sufficient 25(OH)D serum amounts of leg fat correlated with low- dividual drug (tenofovir or efavirenz) levels, an increase from 17% at base- er BMD, suggesting that regional fat examined was associated with frac- line, compared with 16% at baseline depots may contribute to changes in ture. In a multivariate analysis, factors and at week 12 in the placebo group BMD independently. associated with increased fracture risk (P<.001). A statistically significant The impact on bone density of were HCV coinfection and a diagnosis decline in PTH levels (−6 pg/mL) was drugs used to manage lipodystrophy of osteoporosis at study entry, where- observed only in the tenofovir group in HIV infection was evaluated in 2 as Hispanic ethnicity was protective. receiving vitamin D3. These results sug- studies. In a small, randomized clinical These data suggest that over the long gest that vitamin D3 replacement may 63 IAS–USA Topics in Antiviral Medicine

mitigate hyperparathyroidism in patients The relationships among visceral changes from baseline to week 96 in taking tenofovir; whether this translates fat, coronary plaque, and coronary VAT and the ratio of VAT to total adi- into improvements in bone density must artery calcification were examined pose tissue by CT scan (Abstract 77). await the DEXA data from this trial. in HIV-infected and -uninfected men The study demonstrated that trunk Other studies evaluated the rela- using data from the MACS (Abstract fat and VAT increased 28% and 19%, tionship between vitamin D and dia- 806). Noninvasive coronary computed respectively, for all subjects, with great- betes and surrogate markers for CVD. tomography angiography (CCTA) was er gains for those receiving atazanavir/r A retrospective Italian study suggested used to measure total plaque area than for those receiving efavirenz, 36.5% that vitamin D3 supplementation was and coronary artery calcium (CAC). versus 21.1%, respectively. Similar in- associated with a lower risk of incident Abdominal (total, visceral, and sub- creases in trunk fat and VAT were diabetes (Abstract 827); however, data cutaneous) fat was measured by non- observed between those receiving on vitamin D levels were not reported. contrast CT scans; liver fat was also as- abacavir/lamivudine and those taking No improvement in brachial artery sessed. After adjustment for age, there tenofovir/emtricitabine. The clinical flow-mediated dilation (FMD) was ob- were stronger associations observed importance of the greater amounts served in a randomized controlled trial between visceral abdominal tissue of VAT gained in the atazanavir/r arm of vitamin D3 supplementation (4000 (VAT) and subclinical atherosclerotic are not immediately clear and may IU daily for 12 weeks) (Abstract 829). plaque (defined as CCTA-diagnosed, depend on the baseline starting point. Although the study was adequately combined calcified and noncalcified These findings highlight the concept powered to detect a 3% improvement plaque) in HIV-uninfected men than that different antiretroviral regimens in FMD, it was notable that during the in HIV-infected men. No associations may vary in their contributions to vari- relatively short period of follow-up, were found between measures of CAC ous metabolic and body fat changes. vitamin D3 replacement led to only and specific fat depots in either group. The question of whether switching modest increases in vitamin D levels. Epicardial adipose tissue (EAT) can from a PI/r-based to a raltegravir-based Recent recommendations for screen- be measured when coronary calcium antiretroviral regimen might reverse ing and replacement of vitamin D may is measured with noncontrast CT changes in abdominal and subcutane- provide a starting place for patients scans. EAT was associated with older ous fat was evaluated in the 48-week with HIV infection until more defini- age, greater amounts of VAT, male sex, SPIRAL (Switching from Protease In- tive studies are available.9 waist girth, and liver fat in an Italian hibitor to Raltegravir in HIV Stable Pa- study (Abstract 805). Not surprisingly, tients) study (Abstract 845).12 In this Lipodystrophy increased amounts of EAT were asso- study, patients (n=73) who were viro- ciated with greater amounts of fat in logically suppressed with any PI/r regi- Fat in All the Wrong Places other places (VAT and liver) and with men were randomly assigned to either CAC. The only clinical variable associ- continue the same treatment or switch There is little doubt that increased ated with greater amounts of EAT was to a raltegravir-based regimen. visceral fat is associated with poor CD4+ cell count increase from nadir, After 48 weeks, statistically signifi- long-term outcomes in HIV-uninfected suggesting that immune reconstitution cant increases in total abdominal fat adults,10 but the contribution of vis- might play a role in the pathogenesis area and visceral fat area as measured ceral fat to mortality in HIV-infected of the excess fat observed. by CT were observed in the PI/r group, persons has not been well studied. In- without changes in the subcutaneous vestigators from the Fat Redistribution Antiretroviral Therapy and Body Fat fat area or in the ratio of subcutaneous and Metabolic Change in HIV Infection Changes: Coming and Going fat to visceral fat. At the same time, no (FRAM) study (Abstract 76) examined statistically significant changes were the relationships between muscle Weight and body fat content are known observed within the raltegravir group mass, visceral fat, and survival in the to increase when antiretroviral therapy or between treatment groups. No sig- HIV-infected cohort of this observa- is initiated, especially among those nificant changes were observed within tional study. Participants in the high- with more advanced disease and pre- or between groups in body fat distri- est tertile for visceral fat had a 2-fold treatment weight loss. Newer regimens bution measured by DEXA (measures higher mortality than those in the low- have been assumed to have minimal of limbs, trunk, total fat, and fat mass est tertile. Causes of death were not effects on body composition before ratio). Although statistically significant known, nor was it possible to compare now. A metabolic substudy of the increases occurred in total BMD and the magnitude of the effect of viscer- ACTG study 520211 was a 4-arm trial of femoral BMD within the raltegravir al fat on mortality with that from an HIV-infected, treatment-naive subjects group, these differences were not sta- uninfected population. Despite these randomly assigned equally to double- tistically significant when compared limitations, the findings serve as a re- blinded abacavir/lamivudine versus te- with the PI/r group. These findings, minder that excess visceral fat may nofovir/emtricitabine with open-label while not definitive, suggest that with a have important long-term consequenc- efavirenz or ritonavir-boosted (/r) ata- larger sample size or longer follow-up es in patients with HIV infection. zanavir. Endpoints in A5224s included period, differences between the study

64 Conference Highlights—HIV Complications Volume 19 Issue 2 May/June 2011

treatment groups might emerge. Results lipid profiles (unfavorable total choles- through 2009 (Abstract 789). Together, from comparative studies in treatment- terol: HDL cholesterol ratios and apoli- NADM and ADM accounted for 25.8% naive patients examining these issues poprotein B: apolipoprotein A1 ratios) of all deaths, in this largely antiret- may provide more definitive results. were associated with higher cystatin C roviral therapy–treated cohort. HCV Earlier studies demonstrated that levels but not with estimated glomeru- coinfection status substantially impact- zidovudine and stavudine are both lar filtration rate (GFR) (Abstract 839). ed the cause of death. Liver disease associated with loss of subcutaneous Another analysis from SMART ob- (excluding hepatocellular carcinoma) fat.13 The degree to which this fat loss served that the rate of new or progres- was the most frequent cause of death improves when zidovudine is switched sive CKD was higher among patients (27.2%) in HCV-coinfected individu- to tenofovir has not been well studied randomly assigned to discontinue an- als, whereas NADM (24.2%) was most but is important to determine as teno- tiretroviral therapy and that among common in HCV-uninfected persons. fovir becomes more widely available those who continued antiretroviral The risk of death from NADM, as in resource-limited settings. A compre- therapy, progression of CKD was pre- well as from liver disease and CVD, hensive, randomized study examined dicted by hepatitis coinfection and, as appears to increase with cumulative changes in limb fat, subcutaneous ab- expected, by diabetes, hypertension, exposure to antiretroviral therapy in dominal fat, and mitochondrial DNA and older age (Abstract 837). the EuroSIDA cohort, compared with (mtDNA) quantity and quality as well As the availability of tenofovir con- those receiving antiretroviral therapy as adipocyte size and measures of gene tinues to expand in resource-limited for less than 2 years (Abstract 790). expression in patients who continued settings, it is important to understand These data suggest that HIV viral con- with zidovudine or switched to tenofo- the patient characteristics that might trol alone may be insufficient to re- vir (Abstract 846). The tenofovir group preclude the safe use of fixed-dose verse the higher rates of malignancy experienced statistically significant in- regimens. In a randomized 3-arm trial, associated with HIV infection. The US creases in both subcutaneous adipose a small but statistically significant and HIV Outpatient Study (HOPS) also re- tissue and limb fat at week 48, with a nonprogressive decline in GFR was ob- ported an increase in rates of non–in- statistically significant between-group served when tenofovir/emtricitabine fection-related NADM but stable rates difference in percentage of change in was combined with atazanavir/r com- of infection-related NADM (Abstract subcutaneous adipose tissue at week pared with efavirenz or abacavir/zid- 867). Encouragingly, however, HOPS 48. In the molecular substudy, switch ovudine (Abstract 841). Investigators data also indicated that survival in HIV- to tenofovir resulted in statistically sig- from the University of North Carolina infected patients with any cancer diag- nificantly greater increases in mtDNA Project in Malawi reviewed data on pa- nosis improved over time. content and quality at weeks 24 and tients (predominantly young women) In a German cohort with limited im- 48 and an increase in adipocyte size. who were screened for clinical trials munosuppression and high uptake of that required a creatinine clearance antiretroviral therapy, mortality caused of greater than 50 mL/min; the study Renal Disease by lung cancer remained high, with a aimed to identify factors associated 2-year overall survival rate of 23.7% for Chronic kidney disease (CKD) remains with exclusion to inform strategies HIV-infected patients with lung cancer an important cause of morbidity in for antiretroviral treatment programs. (Abstract 868). Fifty of 51 (98%) of these HIV patients. Investigators from the UK Fortunately, among the 1224 patients patients were former or current heavy Consumer Health Information Consor- eligible for antiretroviral therapy (those smokers, a reminder that smoking ces- tium examined the effects of baseline with CD4+ cell counts <350/µL), 98% sation is a key part of cancer prevention renal function to long-term outcomes had creatinine clearance above the re- in the HIV-infected population, in whom in more than 20,000 patients ob- quired 50 mL/min level (Abstract 838). smoking rates remain alarmingly high.14 served for a median of nearly 6 years Only lower BMI predicted reduced Records from US children diag- (Abstract 836). Although the results renal function. These results suggest nosed with HIV infection between are not surprising—lower baseline that few patients would need to be ex- 1980 and 2008 indicate that the risks measures of renal function predicted cluded from a tenofovir-based initial of Kaposi sarcoma and non–Hodg- which patients were at greater risk of regimen in this setting. kin lymphoma remain elevated but progression of renal disease and risk have declined with widespread anti- of death—these findings underscore Malignancy retroviral therapy use and that rates the importance of careful monitoring of NADM have remained stable, with of renal function in patients who enter AIDS-defining malignancy (ADM) and a persistent, elevated risk of leiomyo- care with impairment. non–AIDS-defining malignancy (NADM) sarcoma in particular (Abstract 82LB). Investigators from the SMART study continue to grow as important causes Persons diagnosed with HIV infection evaluated the relationship between lip- of mortality. The Swiss HIV Cohort in childhood will need ongoing surveil- id levels and measures of renal func- Study (SHCS) reported that NADM lance for cancer in adulthood, despite tion using stored samples from 396 (19.1%) surpassed AIDS (16.4%) as the adequate immune reconstitution with patients. They found that unfavorable primary cause of death from 2005 antiretroviral therapy.

65 IAS–USA Topics in Antiviral Medicine

Human Papillomavirus ating TB therapy) (Abstract 38). This immediate-treatment group also had treatment strategy study included more antiretroviral drug switches than Human papillomavirus (HPV) is an im- persons with either confirmed (46%) did those in the early-treatment group. portant driver of malignancy in HIV or probable (54%) TB and enrolled pa- In a symposium titled “Colliding infection, and the risks of HPV acquisi- tients from 4 continents. At the end of Epidemics: Controlling HIV-Related TB,” tion and related complications do not 48 weeks, there was no difference be- Burman summarized the results and appear to decline with antiretroviral tween groups in the primary endpoint insights from the STRIDE, SAPIT, and treatment. Hoffmann and colleagues of death or AIDS-defining condition CAMELIA (Cambodian Early Versus found the development of anal squa- (12.9% in the immediate-treatment Late Introduction of Antiretrovirals)15 mous cell carcinoma was not associat- group vs 16.1% in the early-treatment studies (Abstract 166). The impor- ed with level of immunodeficiency or group). However, in the prespecified tant message from these studies is HIV viremia and that disease-related analysis of those patients with a CD4+ that combined antiretroviral therapy mortality after a median of 2 years was cell count less than 50/µL, there was and TB therapy reduces mortality. 13% (Abstract 870). In a group of HIV- a 42% reduction in AIDS or death at For patients with CD4+ cell counts infected MSM, 24 months of antiret- 48 weeks, favoring the immediate- less than 50/µL, antiretroviral treat- roviral therapy did not reduce rates of over the early-treatment arm (15.5% ment needs to be initiated within 2 acquisition of HPV, with 23% and 12% vs 26.6%, respectively; P=.02). At 48 weeks of TB therapy initiation to re- acquiring new oncogenic HPV strains weeks, neither viral suppression rates duce AIDS or mortality. For those 16 and 18, respectively (Abstract 871). (>70%) nor CD4+ cell count rise dif- with higher CD4+ cell counts, antiretro- It was notable that HPV infection in fered between the treatment groups. viral therapy can be initiated after the this group was dynamic, with 29% and The frequency of TB immune reconsti- intensive phase of TB therapy (8 weeks) 57% clearing HPV strains 16 and 18, tution inflammatory syndrome (IRIS) to avoid higher rates of TB IRIS that respectively. was statistically significantly higher in occur when antiretroviral treatment is In several HIV-infected cohorts the immediate- (11%) than in the early- initiated early. of men and women from the United treatment group (5%) (P=.009). Burman pointed out that TB men- States and international settings, HPV In the SAPIT (Starting Antiretro- ingitis may be the one exception to strain 16 prevalence ranged from viral Therapy at Three Points in Tuber- these recommendations because a pri- 30% to 50% and HPV strain 18 from culosis Therapy) study, 429 HIV-sero- or randomized study in this population 12% to 23% (Abstracts 762, 763, and positive subjects in South Africa with revealed no benefit, and possible det- 871), suggesting that HPV vaccination CD4+ cell counts less than 500/µL and rimental effects, of initiating antiretro- in HIV-infected individuals may have culture-positive TB were randomly as- viral therapy immediately in this situa- the potential to prevent acquisition of signed to initiate antiretroviral therapy tion.16 Challenges to implementing the further oncogenic strains. However, a either within 4 weeks of TB therapy new findings from the STRIDE, SAPIT, Thai study reported that 43% of high- initiation or within 4 weeks of com- and CAMELIA investigations include grade anal intraepithelial neoplasia pletion of the intensive phase of TB ramping up HIV testing rates in TB was associated with non-HPV 16 or therapy (Abstract 39LB). There was no patients, improving linkages between 18 strains, highlighting the limitations difference between the 2 groups in the HIV and TB treatment programs, im- of currently available HPV vaccines to primary endpoint of AIDS or death. proving access to antiretroviral thera- prevent all oncogenic HPV infections Similar to findings in the STRIDE study, py for patients with HIV and TB, and (Abstract 872). in a prespecified analysis of those with equipping practitioners with informa- CD4+ cell counts less than 50/µL, the tion to manage TB IRIS. Tuberculosis rates for AIDS or death were lower In this year’s posters on TB in HIV- in the immediate-treatment (8.5/100 infected patients, a large observational The optimal timing of antiretroviral person-years) than in the early-treat- study of 4908 HIV-seropositive pa- treatment during therapy for tuber- ment (26.3/100 person-years) group tients with TB living in western Kenya culosis (TB) was addressed in 2 large, (IRR, 0.32; P=.06). reported improved survival among randomized clinical trials. The ACTG Rates of viral suppression and CD4+ those starting early antiretroviral ther- 5221 STRIDE (Strategy Study of Im- cell count rise did not differ between apy, consistent with the results of the mediate Versus Deferred Initiation groups, but rates for TB IRIS were high- randomized clinical studies (Abstract of Antiretroviral Therapy) randomly er in the immediate-treatment than in 881). In a clinic-based study evaluating assigned 806 HIV-seropositive per- the early-treatment group (46.8/100 1499 patients with HIV and TB from sons with CD4+ cell counts less than person-years vs 9.9/100 person-years, South Africa, it was similarly reassur- 250/µL initiating treatment for TB to respectively, in those with CD4+ cell ing that there was no compromise in receive either immediate antiretrovi- counts <50/µL; IRR, 4.71; P=.01 and viral suppression rates or CD4+ cell ral therapy (within 2 weeks of initiat- 15.8/100 person-years and 7.2/100 per- count restitution among those initiating TB therapy) or early antiretroviral son-years in those with CD4+ cell counts ing antiretroviral therapy earlier than therapy (within 8−12 weeks of initi- ≥ 50/µL; IRR, 2.2; P=.02). Patients in the later (Abstract 882).

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New TB diagnostics is a very active Combining HIV and TB care poses tients with cryptococcal meningitis to and exciting field, although there was additional challenges, as highlighted standard treatment of amphotericin surprisingly little data presented at by work presented by Bassett and col- B plus 5-fluorocytosine versus stan- this meeting. Neither the interferon- leagues (Abstract 886). Among 144 dard treatment plus either interferon- gamma-release assay measuring free subjects identified with TB by sputum gamma 2-dose therapy (on days 1 and interferon gamma levels nor the urine culture in an HIV care clinic in Durban, 3 of treatment) or 6-dose therapy (on lipoarabinomannan test showed good South Africa, only 42% had document- days 1, 3, 5, 8, 10, and 12) (Abstract performance for the diagnosis of TB ed TB treatment completion at the 40). The primary outcome of the study in HIV-seropositive patients (Abstracts end of 1 year. Twenty-five percent of was the decline in quantitative crypto- 877 and 878). the treatment-noncompleter subjects coccal cultures from the cerebrospinal However, in a very interesting ab- died, and 16% were lost to follow-up. fluid. Rates of fungal clearance were stract by Van Rie and colleagues, in- The authors suggested that financial faster in each of the 2 interferon- vestigators from South Africa evalu- constraints and poor TB education rep- gamma groups than in the standard ated the performance of a new rapid resented barriers to accessing care in treatment group. There was no in- polymerase chain reaction (PCR) assay this population. crease in cryptococcal IRIS or toxic- (manufacturer: Cepheid, Sunnyvale, On a more optimistic note, Brown ity in the interferon-gamma groups. CA) as a diagnostic test for Mycobac- and colleagues examined the time to Of note, mortality was 31% overall at terium tuberculosis and for resistance antiretroviral therapy initiation among 10 weeks and did not differ between to rifamycin for the diagnosis of TB patients with TB at a Khayelitsha, the groups. from lymph node aspirates (Abstract South Africa, clinic both before and Muzoora and colleagues present- 879). They reported a sensitivity after the clinic integrated HIV and TB ed results of a single-arm pilot study of 100% and a specificity of 93.8% care (Abstract 890). The median time evaluating a short-course amphotericin compared with TB culture using a to antiretroviral therapy initiation de- B–containing regimen in western Ugan- Mycobacteria growth indicator tube. creased from 110 days to 58 days for da (Abstract 894). Subjects were treat- Importantly, the PCR assay results pre- and postintegration, respectively. ed with amphotericin B (1 mg/kg/day) were used to justify TB treatment ini- Comparing outcomes with those of a plus fluconazole for 5 days and then tiation in 19 of 51 subjects. clinic without treatment integration, fluconazole for the remainder of the Prior studies indicated that the per- the authors confirmed that “one-stop” treatment regimen. Serial quantitative formance of this rapid assay would be care for HIV and TB was associated cryptococcal cultures showed a con- excellent using sputum specimens17,18; with a shorter time to antiretroviral sistent decline that continued beyond data from this pilot study now suggest treatment initiation, and that TB out- the administration of amphotericin B. that the assay may also be clinically comes were not adversely affected. Patients tolerated the treatment well, useful for lymph node specimens. Ad- and there were no interruptions for ditional studies are needed to evaluate Cryptococcal Meningitis toxicity. Mortality was also high in this other aspiration sites, including cere- study—28% at 10 weeks. bral spinal fluid for the diagnosis of Cryptococcal meningitis remains a In a third study, 80 patients with TB meningitis. major cause of morbidity and mor- cryptococcal meningitis were randomly Another important topic and ob- tality, even in areas that have experi- assigned to 1 of 4 groups: amphotericin stacle to implementing optimal treat- enced rapid scale-up of antiretroviral B plus 5-fluorocysteine; amphotericin B ment of TB in HIV-infected patients is therapy in resource-limited settings. plus fluconazole 800 mg daily; ampho- the effective integration of HIV and TB Amphotericin-based regimens remain tericin B plus fluconazole 1200 mg services and care delivery. MacPher- the gold standard in the developed daily; or amphotericin B plus voricon- son and colleagues presented sobering world,19 but even properly treated pa- azole 300 mg twice daily (Abstract results in an analysis from Zimbabwe tients with severe disease still have 893). There was no difference in of outcome of HIV-infected and HIV- suboptimal outcomes; amphotericin fungicidal activity as measured by the uninfected patients suspected of TB toxicity is substantial, and cost and de- decline in cerebrospinal fluid crypto- who had negative results on acid-fast livery are challenging for many areas coccal burden between the 4 treatment bacteria smears (Abstract 887). In a in Africa, where the burden of disease groups. Mortality was 39% at 10 weeks. cohort of 1234 patients, mortality was is high. For these reasons, investiga- Together, these studies demonstrate 16.5% in the HIV-infected TB suspects, tors have designed a new generation the possibility of deploying all oral, nearly 5-fold greater than for the HIV- of treatment studies for cryptococcal more effective, and more affordable uninfected TB suspects. Antiretroviral meningitis in attempts to improve ef- regimens. However, much more work therapy was initiated in only 14.7% ficacy and identify alternatives to the is needed in this area as evidenced of eligible HIV-infected patients, in standard amphotericin regimens. by the extraordinarily high mortality large part because of the fragmenta- Several pilot studies were presented rates (30%) observed among these pation in care between HIV and TB treat- at the conference this year. Jarvis and tients in a carefully monitored, clinical ment programs. colleagues randomly assigned 90 pa- trials setting.

67 IAS–USA Topics in Antiviral Medicine

Influenza A (H1N1) Financial Disclosure: Dr Luetkemeyer has is an independent predictor of all-cause received research grants awarded to the mortality in men. Obesity (Silver Spring). The focus on influenza A (H1N1) this University of California San Francisco from 2006;14:336-341. 11. year at the conference was not on Bristol-Myers Squibb, Gilead Sciences, Inc, Daar ES, Tierney C, Fischl MA, et al. Ata- zanavir plus ritonavir or efavirenz as part clinical aspects of influenza A, as the Merck & Co, Inc, and Pfizer Inc. Dr Havlir has received study drugs for use in research of a 3-drug regimen for initial treatment number of cases has waned globally of HIV-1: a randomized trial. Ann Intern from Abbott Laboratories. Dr Currier has re- over the past 2 years. Rather, several Med. 2011;154:445-456. ceived research grants awarded to the Univer- 12. Martinez E, Larrousse M, Llibre JM, et al. new and follow-up studies examined sity of California Los Angeles from Merck & the frequency, intensity, and durability Substitution of raltegravir for ritonavir- Co, Inc, Schering-Plough Corp, and Tibotec boosted protease inhibitors in HIV-in- of immunologic responses elicited by Therapeutics. fected patients: the SPIRAL study. AIDS. various H1N1 influenza A vaccination 2010;24:1697-1707. strategies. A list of all cited abstracts 13. Dubé MP, Komarow L, Mulligan K, et al. Bickel and colleagues evaluated appears on pages 99–106. Long-term body fat outcomes in antiret- 135 HIV-seropositive patients after the roviral-naive participants randomized to first and second dose of adjuvanted nelfinavir or efavirenz or both plus dual References nucleosides. Dual X-ray absorptiom- H1N1 influenza A vaccine (Abstract etry results from A5005s, a substudy of 906). Seroconversion was 68% after 1. Chung RT. Acute hepatitis C virus infec- Adult Clinical Trials Group 384. JAIDS. the first dose and increased to 92% tion. Clin Infect Dis. 2005;41(Suppl 1): 2007;45:508-514. after the second dose; low CD4+ S14-S17. 14. Tesoriero JM, Gieryic SM, Carrascal A, cell count was associated with lower 2. Grebely J, Petoumenos K, Hellard M, et Lavigne HE. Smoking among HIV positive rates of seroconversion. Cooper and al. Potential role for interleukin-28B geno- New Yorkers: prevalence, frequency, and type in treatment decision-making in re- opportunities for cessation. AIDS Behav. colleagues examined the effects of cent hepatitis C virus infection. Hepatol- 2010;14:824-835. a booster to an initial HIN1 adjuvant ogy. 2010;52:1216-1224. 15. Blanc FX, Sok T, Laureillard D, et al. Signif- vaccine immunization in a random- 3. Kim HN, Harrington RD, Crane HM, icant enhancement in survival with early ized study of HIV-infected adults Dhanireddy S, Dellit TH, Spach DH. Hep- (2 weeks) vs. late (8 weeks) initiation of (Abstract 907). Seroconversion and atitis B vaccination in HIV-infected adults: highly active antiretroviral treatment current evidence, recommendations and (HAART) in severely immunosuppressed seroprotection titers with the first practical considerations. Int J STD AIDS. HIV-infected adults with newly diagnosed vaccine were comparable to historical 2009;20:595-600. tuberculosis. [Abstract THLBB106.] 18th controls and were increased from the 4. Fonseca MO, Pang LW, de Paula CN, Bar- International AIDS Conference (IAC). July initial range of 73% to 76% to levels in one AA, Heloisa Lopes M. Randomized 18-23, 2010; Vienna, Austria. the range of 83% to 94% in persons trial of recombinant hepatitis B vaccine 16. Torok ME, Yen NTB, Chau TTH, et al. who received the booster, at days 21 in HIV-infected adult patients comparing Randomized controlled trial of immedi- a standard dose to a double dose. Vaccine. ate versus deferred antiretroviral therapy and 42, respectively. Similar changes 2005;23:2902-2908. in HIV-associated tuberculous meningitis. were not observed in the control group. 5. Mestek M, Stauffer B, Westby C, et al. En- [Abstract H-1224.] 49th Interscience Con- In a follow-up study from France dothelial fibrinolytic capacity is impaired ference on Antimicrobial Agents and Che- that showed the benefit of adjuvant in HIV-1-infected men. [Abstract 728.] motherapy (ICAAC). September 12-15, over nonadjuvant H1N1 influenza A 16th Conference on Retroviruses and Op- 2009, San Francisco, CA 17. vaccine, Durier and colleagues dem- portunistic Infections (CROI). February Helb D, Jones M, Story E, et al. Rapid de- 8-11, 2009; Montreal, Canada. tection of Mycobacterium tuberculosis and onstrated that seroprotective titers 6. Kuller LH, Tracy R, Belloso W, et al. In- rifampin resistance by use of on-demand, persisted at 12 months in 60% of ad- flammatory and coagulation biomarkers near-patient technology. J Clin Microbiol. juvant-vaccine recipients and that pre- and mortality in patients with HIV infec- 2010;48:229-237. dictors of a durable response included tion. PLoS Med. 2008;5:e203. 18. Boehme CC, Nabeta P, Hillemann D, et al. use of adjuvant versus nonadjuvant 7. Grant RM, Lama JR, Anderson PL, et al. Rapid molecular detection of tuberculosis Preexposure chemoprophylaxis for HIV and rifampin resistance. N Engl J Med. vaccine and the use of antiretroviral prevention in men who have sex with 2010;363:1005-1015. therapy (Abstract 909). men. N Engl J Med. 2010;363:2587-2599. 19. Kaplan JE, Benson C, Holmes KH, Brooks In an ongoing study comparing 8. Triant VA, Brown TT, Lee H, Grinspoon JT, Pau A, Masur H. Guidelines for preven- 2 single doses of adjuvanted H1N1 SK. Fracture prevalence among human tion and treatment of opportunistic infec- influenza vaccine in HIV-infected and immunodeficiency virus (HIV)-infected tions in HIV-infected adults and adoles- HIV-uninfected adults, seroconversion versus non-HIV-infected patients in a cents: recommendations from CDC, the large U.S. healthcare system. J Clin Endo- National Institutes of Health, and the HIV and seroprotection H1N1 titers were crinol Metab. 2008;93:3499-3504. Medicine Association of the Infectious higher among HIV-infected patients 9. Institute of Medicine. Report: dietary ref- Diseases Society of America. MMWR than among HIV-uninfected patients. erence intakes of calcium and vitamin Recomm Rep. 2009;58:1-207. Within the strata of HIV-infected pa- D. November 30, 2010. http://www.iom. tients with CD4+ cell counts less than edu/Reports/2010/Dietary-Reference- 200/µL, seroconversion was higher with Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed April 15, 2011. the double than with the single dose 10. Kuk JL, Katzmarzyk PT, Nichaman MZ, Top Antivir Med. 2011;19(2):58–68 (Abstract 910). Church TS, Blair SN, Ross R. Visceral fat ©2011, IAS–USA 68 Conference Highlights—Antiretroviral Therapy Volume 19 Issue 2 May/June 2011

Advances in Antiretroviral Therapy

Barbara Taylor, MD, MS, Susan Olender, MD, Timothy J. Wilkin, MD, MPH, and Scott M. Hammer, MD

The 18th Conference on Retroviruses and Opportunistic Infections maintained remaining CD4+ T cells were treated its tradition of being the preeminent forum for detailing the state-of- with an adenoviral vector to introduce the-art in antiretroviral therapy. There were important presentations on the zinc-finger nuclease that targeted investigational antiretroviral drugs, clinical trials in treatment-experienced the CCR5 gene for disruption. These patients, and new antiretroviral strategies. Relevant data on resistance cells were expanded in vitro and then to antiretroviral drugs and pharmacokinetic interactions were discussed. infused back into the participant as a There were extensive presentations on antiretroviral therapy in resource- single dose. limited settings, including large-scale clinical trials, scale-up of antiretroviral The authors presented data on 2 therapy, adherence, retention in care, and treatment outcomes for children dosing cohorts of 3 participants each. and adults. Prevention of mother-to-child transmission continued to be an The participants were all men with important part of the conference. longstanding HIV infection, were receiving antiretroviral therapy, had a plasma HIV-1 RNA level below the Investigational Drugs copies/mL and 5.03 log10 copies/mL. limit of detection, and had a CD4+ cell The primary endpoint was time-weight- count in the range of 269/µL to 450/µL. GS-7340 ed average plasma HIV-1 RNA level re- There were no serious adverse events duction over 2 weeks of dosing. related to the infusion, but milder, Zolopa presented study data on GS- The viral load change was greater in infusion-related events such as fever, 7340, a novel amidate prodrug of te- both the 50-mg and 150-mg GS-7340 chills, and sweats were common. The nofovir designed to deliver high con- recipients than in the tenofovir group CD4+ T-cell count increased in all 6 centrations of tenofovir diphosphate to (−0.95 log10 copies/mL and −1.07 log10 participants by amounts ranging from lymphatic tissues in an effort to mini- copies/mL for GS-7340 doses vs −0.54 100/µL to 500/µL. These changes gen- mize systemic exposure and toxic ef- log10 copies/mL for tenofovir; P = .03, erally persisted throughout follow-up, fects while maximizing efficacy (Mar- and P = .001, respectively). The first- which ranged from 3 months to 12 kowitz et al, Abstract 152LB). Eligible phase decay in plasma HIV-1 RNA level months. The modified cells appeared participants were HIV-infected adults was statistically significantly greater in to engraft and expand after infusion in naive to antiretroviral therapy who the 2 GS-7340 groups than in the teno- 5 of the 6 participants. One participant had plasma HIV-1 RNA levels greater fovir group. Both GS-7340 groups had who had high adenoviral antibody lev- than 15,000 copies/mL and CD4+ cell lower plasma levels of tenofovir and els before infusion had modified cells counts of at least 200/µL. Participants higher intracellular tenofovir diphos- that were detectable but did not ap- were randomly assigned to tenofo- phate levels in peripheral blood mono- pear to expand in vivo. These modi- vir disproxil fumarate 300 mg daily nuclear cells (PBMCs). There were no fied CD4+ T cells were also found in (n = 10), GS-7340 50 mg daily (n = 10), safety concerns identified in this small the rectal mucosa and persisted in 5 of or GS-7340 150 mg daily (n = 10). All study with limited follow-up. The au- the 6 participants. subjects received monotherapy for 14 thors noted that the lower dose of CXC chemokine receptor 4 (CXCR4)- days. The mean baseline plasma HIV-1 GS-7340 may allow for coformulations tropic HIV-1 is found commonly in pa- RNA level was between 4.72 log10 that are not possible with tenofovir tients with HIV infection, especially and may reduce manufacturing costs, those with longstanding infection who which could expand access to tenofo- have been treated with several differ- Dr Taylor is assistant professor in the Divi- vir in resource-limited settings (RLS). ent antiretroviral regimens.1 Potential sion of Infectious Diseases at the University of Texas Health Science Center in San Anto- gene therapies targeting CCR5 alone nio and instructor of clinical medicine at Co- Zinc-finger nucleases. Lalezari and col- would not be sufficient to treat patients lumbia University College of Physicians and leagues presented data on 6 participants with CXCR4-tropic HIV-1. Small-mol- Surgeons. Dr Olender is assistant professor who received autologous CD4+ T cells ecule CXCR4 antagonists have not of clinical medicine at Columbia University that had been treated with a zinc-finger been developed successfully for treat- Medical Center. Dr Wilkin is associate profes- nuclease targeting the CC chemokine ment of HIV-1 infection. Wilen and col- sor of medicine at the Weill Cornell Medical receptor 5 (CCR5) gene for disruption leagues presented data on using zinc- College. Dr Hammer is Harold C. Neu professor of medicine at the Columbia Univer- (Abstract 46). The participants under- finger nucleases to disrupt the CXCR4 sity College of Physicians and Surgeons and went leukapheresis to collect a large gene in CD4+ T cells (Abstract 47). chief of the Division of Infectious Diseases at volume of PBMCs, and the monocytes They were able to disrupt the CXCR4 Columbia University Medical Center. and CD8+ T cells were depleted. The gene in vitro, and this did not appear

69 IAS–USA Topics in Antiviral Medicine

to adversely affect cell growth. They in vitro activity of BMS-626529 in vari- Prior presentations reported on the showed that these cells were protected ous clinical isolates (Abstract 518). They inferiority of once-daily administra- from infection by CXCR4-tropic strains. found that 27% of HIV-1 subtype B, tions of atazanavir, didanosine, and Using a humanized mouse model, they 58% of subtype C, and 72% of subtype lamivudine. This analysis reported on found that mice receiving the CXCR4- A isolates had 50% effective concentra- the comparison of efavirenz plus zid- disrupted cells were protected from tions greater than 1 µmol. ovudine/lamivudine versus efavirenz CXCR4-tropic HIV. Dual-tropic HIV-1 plus tenofovir/emtricitabine. The pri- species eventually emerged in these Nonnucleoside Analogue Reverse mary endpoint was time to treatment mice, suggesting that a strategy target- Transcriptase Inhibitors failure, defined as death, virologic failing CXCR4 and CCR5 was needed. ure (plasma HIV-1 RNA level > 1000 GSK2248761 is a nonnucleoside ana- copies/mL at week 16 or later), or HIV Oral Attachment Inhibitor logue reverse transcriptase inhibitor disease progression. HIV-1-infected (NNRTI) that is currently in phase IIB adults with a CD4+ cell count less Nettles and colleagues presented data clinical trials. Vavro and colleagues than 300/µL and naive to antiretrovi- on the pharmacodynamics of BMS- compared the in vitro activity of this ral therapy were eligible. Participants 663068 (Abstract 49). This compound compound with that of efavirenz, etra- were enrolled from 12 sites in 8 RLS is a prodrug of BMS-626529, which virine, and rilpivirine (Abstract 520). in addition to the United States. There binds to gp120 and interferes with the The compound appeared more potent were 526 and 519 participants en- attachment of HIV to the CD4 receptor. than the other NNRTIs. The highest rolled in the tenofovir/emtricitabine This was an open-label trial of 5 dif- 50% inhibitory concentration (IC50) was and zidovudine/lamivudine groups, ferent dosing schemes of BMS-663068 41 nM for a strain with K103N, Y181C, respectively. The study population with and without ritonavir. Each cohort and G190A mutations in reverse tran- consisted of 46% women and had ex- enrolled 10 HIV-1-infected adults who scriptase. This compound was additive tensive racial and ethnic diversity. The were not receiving other antiretrovi- or synergistic with all other antiretrovi- median baseline CD4+ cell count was ral therapy for at least 8 weeks before ral medications tested. 162/µL and 169/µL for the tenofovir/ dosing. Two subjects were found to be emtricitabine and zidovudine/lamivu- ineligible after dosing began and were Integrase Inhibitor dine groups, respectively. The median excluded from the analysis. plasma HIV-1 RNA level was 5.0 log10 The median maximal decline in plas- Fenwick and colleagues presented data copies/mL and 5.1 log10 copies/mL, ma HIV-1 RNA level ranged from 1.2 on BI-C, an HIV-1 integrase inhibitor that respectively. There was no difference log10 copies/mL to 1.8 log10 copies/mL prevents the processing of the 3‘ end of between groups in the primary end- over 8 days of dosing, including all 48 the viral DNA but not the strand-trans- point or any of the components, and subjects. There were 7 participants who fer reaction (Abstract 523). BI-C was the CD4+ cell counts were similar be- were found to have HIV-1 strains that among a series of compounds the in- tween groups. At 3 years of follow-up, required more than 1 µmol of BMS- vestigators identified in a high-through- approximately 20% of subjects in both 626529 (the active drug) to inhibit 50% put assay. X-ray crystallography showed groups reached the primary endpoint. of the growth and 2 additional subjects that these compounds bind a pocket on There were statistically significant who did not have a baseline sample integrase targeted by lens epithelium- differences between groups in the for analysis. When excluding these 9 derived growth factor (LEDGF). BI-C safety analyses. The zidovudine/lami- subjects, the median maximal decline has promising in vitro activity against a vudine group was more likely to have in plasma HIV-1 RNA level was 1.6 variety of isolates, including ones high- grade 3 or grade 4 laboratory abnor- log10 copies/mL to 1.8 log10 copies/mL. ly resistant to other integrase inhibitors malities and more likely to require a The addition of ritonavir raised the area that target the strand-transfer reaction drug substitution. The reason for drug under the curve (AUC) and minimum (the integrase strand-transfer inhibi- substitution was almost entirely be- plasma concentration (Cmin) values tors, or INSTIs). The authors reported cause of grade 3 or grade 4 anemia moderately but did not appear to im- that this compound was moving into and neutropenia: 59 cases occurred in prove antiviral activity. There were no phase I trials. the zidovudine/lamivudine group com- serious adverse events. The most compared with 0 cases in the tenofovir/ mon adverse events were headache Clinical Trials of Antiretroviral emtricitabine group. These differenc- and rash, which were mild to moder- Therapy in Treatment-Naive es were more pronounced in women ate. This study establishes the short- Patients than in men. The authors concluded term efficacy of this compound but that both regimens are efficacious and suggests that there are subpopulations AIDS Clinical Trials Group Study A5175 that tenofovir/emtricitabine has safety of HIV-1 strains that are somewhat re- advantages over zidovudine/lamivu- sistant to this compound. Nowicka-Sans Campbell and colleagues presented dine. Furthermore, they asserted that and colleagues further characterized data from AIDS Clinical Trials Group this safety advantage should prompt these subpopulations by examining the (ACTG) study 5175 (Abstract 149LB). use of tenofovir/emtricitabine in popu-

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lations at higher risk of adverse events, therapy for HIV-1-infected adults (Ab- plasma HIV RNA level or achievement including women. stract 551). This study enrolled 112 of a plasma HIV-1 RNA level less than participants: 88% men, 56% nonwhite; 400 copies/mL after 11 days. There Once-Daily Raltegravir median age, 36 years. A total of 44% were 27 and 24 subjects in the once- had a baseline plasma HIV-1 RNA level and twice-daily groups, respectively. Eron and colleagues presented data greater than 100,000 copies/mL, and The mean plasma HIV-1 RNA levels from the QDMRK study, which com- 36% had a CD4+ cell count less than were 4.5 log10 copies/mL and 4.3 log10 pared once- and twice-daily dosing 200/µL. Fifteen participants left the copies/mL, respectively. The median of raltegravir as initial antiretroviral study before week 48, including 1 par- baseline fold-changes to dolutegravir therapy in HIV-1-infected adults (Ab- ticipant who died of cryptosporidiosis. were 1.5 and 2.7, respectively. stract 150LB). This was a randomized, At week 48, 71% had a plasma HIV-1 Among subjects with the mutation double-blind, active-controlled clinical RNA level less than 50 copies/mL in an pattern of Q148H/K/R plus at least 1 trial. Participants were randomly as- intent-to-treat analysis in which miss- secondary mutation, 3 of 9 (33%) re- signed to receive tenofovir/emtricita- ing values are ignored. Twenty-eight ceiving once-daily dolutegravir achieved bine with raltegravir either 400 mg subjects had virologic failure (a com- the primary endpoint, compared with twice daily or 800 mg once daily. The posite of early failure and confirmed 11 of 11 (100%) receiving twice-daily primary objective was to show the non- plasma HIV-1 RNA detection at week dosing. Among subjects with other inferiority of once-daily to twice-daily 24 or later). No darunavir resistance mutational pathways, 18 of 18 (100%) dosing of raltegravir. The study includ- mutations emerged, and INSTI re- receiving once-daily dosing and 12 of ed 770 participants (median age, 38 sistance emerged in 5 subjects, all of 13 (92%) receiving twice-daily dosing years; ~80% men; ~30% nonwhite). whom had baseline plasma HIV-1 RNA achieved the primary endpoint. The The proportions of participants with levels greater than 100,000 copies/mL. twice-daily dose has been selected for plasma HIV-1 RNA level less than 50 Virologic failure was associated with a future phase III studies of dolutegravir copies/mL (noncompleters = failures) baseline plasma HIV-1 RNA level great- in INSTI-experienced patients. were 88.9% and 83.2% in the twice- and er than 100,000 copies/mL and a base- once-daily groups, respectively (over- line CD4+ cell count less than 200/µL. Second-Line Therapy After Failure all difference between once-daily and of 3 Nucleoside Analogue Reverse twice-daily dosing, −5.7%; 95% confi- Clinical Trials of Antiretroviral Transcriptase Inhibitors dence interval [CI], −10.7% to −0.83%). Therapy in Treatment- This did not exclude the noninferior- Experienced Patients Mambule and colleagues randomly as- ity margin of −10%. In addition, the signed 202 participants with failure of 95% CI excluded zero and established Dolutegravir an initial regimen of only nucleoside the statistical inferiority of the once- analogue reverse transcriptase inhibi- daily arm. Among those with a base- Eron and colleagues presented data tors (nRTIs) to receive ritonavir-boosted line plasma HIV-1 RNA level greater on dolutegravir (S/GSK1349572), an (/r) lopinavir plus a NNRTI with either than 100,000 copies/mL, 84.2% of the investigational INSTI (Abstract 151LB). didanosine, lamivudine, or a regimen twice-daily group and 74.3% of the This study enrolled participants who with no nRTI (Abstract 541). The CD4+ once-daily group had levels less than had current or prior virologic failure cell count increases after 24 weeks 50 copies/mL (−9.9%; 95% CI, −19% to with raltegravir and evidence of resis- were similar among the 3 groups, −0.8%). Among those with a baseline tance. A prior cohort in this study re- with increases of 143/µL, 124/µL, plasma HIV-1 RNA level of 100,000 ceived dolutegravir 50 mg once daily; and 148/µL after 24 weeks, respec- copies/mL or less, 91.9% and 89.1%, this cohort received 50 mg twice daily. tively. At week 24, 66%, 76%, and 68%, respectively, had levels of less than The results of both cohorts are present- respectively, achieved a plasma HIV-1 50 copies/mL (−2.7%; 95% CI, −8.3% ed for comparison. Participants were RNA level less than 50 copies/mL. to 2.7%). Virologic failure and develop- divided into 2 groups based on their ment of resistance was more common INSTI resistance pattern (Q148H/K/R Lopinavir/Ritonavir Alone as in the once-daily group. These trends plus ≥ 1 secondary mutation, or other Second-Line Therapy were similar across strata of plasma mutational patterns). HIV-1 RNA level. Subjects added dolutegravir to their Two studies examined results of mono- existing antiretroviral therapy regi- therapy with lopinavir/r as second-line Darunavir/Ritonavir Plus Raltegravir men for 11 days followed by optimiza- therapy. Bartlett and colleagues pre- tion of the background regimen. They sented 24-week results from ACTG Taiwo and colleagues presented data must have had 1 or more active drugs 5230, a pilot study of 123 patients from from ACTG A5262, a single-arm, open- to add into the optimized background 3 sites in Africa and 2 in Asia with doc- label trial of darunavir/ritonavir 800 regimen to be eligible for the twice- umented virologic failure, defined as mg/100 mg plus raltegravir 400 mg daily cohort. The primary endpoint plasma HIV-1 RNA levels between 1000 twice daily as initial antiretroviral was a 0.7-log10 copy/mL reduction in copies/mL and 200,000 copies/mL,

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after at least 6 months of continuous, monotherapy had plasma HIV-1 RNA ly plus 2 nRTIs (triple-therapy group) NNRTI-based initial antiretroviral ther- levels less than 200 copies/mL (69% or darunavir/r alone (monotherapy apy (Abstract 583). At baseline, medi- vs 86%, respectively; P = .01) and less group). At 48 weeks, participants were an age was 39 years, median plasma than 50 copies/mL (61% vs 83%, re- changed to darunavir/r 800 mg/100 mg HIV-1 RNA level was 164/µL, and 76% spectively; P < .01). Major protease in- once daily. Participants were observed of patients had received nevirapine- hibitor (PI) mutations (M46I, I50V) at for an additional 48 weeks. based antiretroviral therapy. These failure were detected in 1 participant At week 96, the proportion remain- patients, having met criteria for failure receiving monotherapy. The authors ing on the randomized treatment was of their initial regimen, were switched conclude that lopinavir/r alone should similar between the 2 groups, 90 of to lopinavir/r monotherapy as second- either not be recommended as a sec- 112 participants in the monothera- line treatment. ond-line regimen or used with caution. py group versus 91 of 113 in the tri- After 24 weeks of lopinavir/r 400 mg/ ple-therapy group. The number of 100 mg twice daily, 107 (87%; 95% CI, Darunavir/Ritonavir, Raltegravir, participants experiencing virologic 80%−92%) remained virologically sup- Etravirine failure (defined as 2 consecutive mea- pressed with plasma HIV RNA levels sures of plasma HIV-1 RNA level > less than 400 copies/mL. HIV-1 geno- Fagard and colleagues presented the 400 copies/mL) were 5 and 4 in the 2 types were available for 11 of 15 partic- long-term results of the TRIO (Efficacy groups, respectively. Participants in the ipants meeting criteria for virologic fail- of Darunavir/Ritonavir, Etravirine, and darunavir/r-alone group experienced ure, and 4 new major mutations were Raltegravir in HIV Patients with Re- more low-level viremia than the triple- observed (2 A71T and 2 V82F). Thir- sistant Viruses) study (Abstract 549). therapy group, but there was no emer- teen participants for whom monother- This was a single-arm, open-label trial gence of resistance to darunavir. In an apy was failing intensified their anti- enrolling patients for whom several intent-to-treat analysis, the proportion retroviral therapy with the addition of antiretroviral regimens had failed. All with suppressed plasma HIV-1 RNA tenofovir/emtricitabine/r, and 11 (85%) participants received darunavir/r, etra- level did not differ between groups achieved virologic suppression. Grade virine, and raltegravir plus an investi- (88% vs 84%, respectively). 3 or grade 4 adverse events were ob- gator-selected background regimen. served in 31 participants (25%). The No participants discontinued the study Predictors of Antiretroviral authors note that the lack of a compar- regimen except for 1 participant, who Therapy Response From Large ator group limits the utility of the find- discontinued raltegravir because of an Cohort Studies ings. Long-term follow-up of the study adverse event at week 8. One partici- participants will continue through anti- pant died before week 96 and 2 partic- Many presentations used existing co- retroviral therapy week 104, which will ipants withdrew consent. At week 96, hort studies to examine potential de- determine durability of the treatment 88% of participants had a plasma HIV-1 terminants of treatment outcomes. response as well as outcomes for those RNA level less than 50 copies/mL. Althoff and colleagues determined who intensify failing monotherapy Although 19 participants experienced trends in plasma HIV-1 RNA levels in with tenofovir/emtricitabine. virologic failure before week 96, fail- HIV-1-infected patients from 13 clini- Bunupuradah and colleages pre- ure generally occurred with low-level cal cohorts participating in the North sented a needed corollary to the above viremia, and virus was resuppressed American AIDS Cohort Collaboration findings by comparing lopinavir/r without the participants changing region Research and Design (NA-ACCORD) monotherapy with tenofovir/lamivu- mens. This study supports the long- (Abstract 548). Investigators deter- dine plus lopinavir/r in a randomized term efficacy of this combination of mined antiretroviral therapy usage at controlled trial of 200 patients with antiretroviral drugs in patients with the time of the highest plasma HIV-1 documented virologic failure (plasma prior virologic failure. RNA level per individual per year and HIV-1 RNA levels > 1000 copies/mL) found that, of 91,569 patients receiv- of an initial NNRTI-based regimen in Antiretroviral Treatment ing care between 1997 and 2007, 77% Thailand (Abstract 584). In an inten- Strategies used antiretroviral therapy at some tion-to-treat analysis of 48-week out- point. The proportion of patients re- comes, for which missing or adding Darunavir/Ritonavir Alone ceiving antiretroviral therapy who tenofovir/lamivudine was treated as achieved virologic suppression, de- failure, the proportion of participants Valantin and colleagues presented fined as plasma HIV RNA level of 500 achieving virologic suppression (plas- week-96 data from a randomized, copies/mL or less, increased each year ma HIV RNA level < 400 copies/mL) controlled trial of daraunavir/r alone and reached more than 50% by 2005 in the monotherapy group was 75%, as maintenance antiretroviral ther- to 2007. compared with 86% in the tenofovir/ apy (Abstract 534). This study ran- For those receiving antiretroviral lamivudine plus lopinavir/r group (P = domly assigned 225 patients taking therapy, initial disparities in median .053). A statistically significantly lower suppressive antiretroviral therapy to plasma HIV-1 RNA level by HIV trans- percentage of participants receiving darunavir/r 600 mg/100 mg twice dai- mission group narrowed over time,

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with injecting drug users having sta- Two presentations examined switch- emtricitabine, excluding those taking tistically significantly higher annual es to second-line antiretroviral therapy efavirenz, and (3) fixed-dose emtric- median levels from 1997 to 2006, and in non-RLS. The first, presented by Ab- itabine/tenofovir/efavirenz for those converged at a median below 500 cop- grall and colleagues, used data from receiving tenofovir, efavirenz, and ei- ies/mL for all groups in 2007. Similarly, the ART-CC to determine antiretroviral ther lamivudine or emtricitabine. black patients consistently had a higher therapy outcomes after transition to For all 3 analyses, the use of a fixed- annual median plasma HIV-1 RNA level second-line therapy for those at least dose combination was inversely asso- from 1997 to 2006 than that of white 16 years of age who started antiretro- ciated with regimen switch compared patients (P < .01), but disparities by all viral therapy after 2002 using either with those not using fixed-dose combi- racial or ethnic categories (black, white, PI/r or NNRTI plus at least 2 nRTIs (Ab- nations after adjustment for age, sex, Hispanic, other/unknown) converged stract 578). history of injection drug use, year of in 2007. These are encouraging data Of 15,008 patients, 40% switched antiretroviral therapy start, pre–anti- in terms of the potential for decreasing and 16.5% interrupted initial treat- retroviral therapy plasma HIV-1 RNA median community plasma HIV-1 RNA ment. The hazard ratio (HR) for AIDS- level, and geographic location. For levels and in the diminishing dispari- defining illness or death was 2.49 comparison 1, the adjusted odds ra- ties of those achieving virologic success (95% CI, 2.21−2.81) for those who tio (aOR) for the inverse association during antiretroviral therapy. interrupted treatment compared with was 0.20 (95% CI, 0.10−0.40); for Data from 18 cohorts in Europe par- those who switched antiretroviral comparison 2, aOR was 0.40 (95% CI, ticipating in the Antiretroviral Therapy therapy regimens. This association 0.24−0.68); and for comparison 3, Cohort Collaboration (ART-CC) were remained statistically significant af- aOR was 0.20 (95% CI, 0.15−0.44). examined by Jarrin and colleagues for ter adjustment for risk-transmission Virologic suppression was also more differences in mortality among treated group, age, AIDS diagnosis, calendar likely when using fixed-dose combi- patients according to race or ethnic- year, duration of initial regimen, and nations of abacavir/lamivudine and ity and geographic origin (Abstract many other potential confounders. emtricitabine/tenofovir/efavirenz. Al- 558). Data on geographic origin were Those who switched regimens for though this study is limited by the fact available for European and Canadian treatment failure had a higher risk of that data are derived from an obser- cohorts; origins were classified as Eu- death or AIDS event (HR, 5.91; 95% CI, vational cohort with the potential for rope; Northern Africa and Middle East; 3.38−10.33) than those who switched unmeasured confounders, the findings sub-Saharan Africa; Asia; and Caribbe- for regimen simplifications. Those who imply that the use of fixed-dose com- an, South, and Central America. Data switched because of a physician’s deci- binations may lead to less regimen for race or ethnicity were available for sion, side effect, or patient’s decision switching and, in some cases, increased Canadian and US cohorts. Thus, the in- also had higher risks of AIDS or death likelihood of virologic suppression. vestigators conducted separate analy- than those who switched for regimen Three different cohorts determined ses for Europe (n = 34,614), Canada simplification in the adjusted analysis. causes of death in treated HIV infec- (n = 1387 for geographic origin, and The investigators also found that more tion. Ruppik and colleagues examined n = 1710 for race or ethnicity), and the than 50% of switches were exchanging 459 deaths between 2005 and 2009 United States (n = 7928). In Europe, or adding drugs within the same anti- among 9053 Swiss HIV Cohort par- HIV-infected migrants from sub-Saha- retroviral therapy class and that most ticipants observed during that period ran Africa and Asia had lower mor- of the switches, discontinuations, or (Abstract 789). They were able to de- tality than HIV-infected nationals, in deaths occurred within the first year of termine cause of death in all but 11 unadjusted analysis (odds ratio [OR], antiretroviral therapy. of these individuals and found that 0.52; 95% CI, 0.44−0.61 for sub-Sa- Hull and colleagues determined the non–AIDS-defining malignancies were haran Africa; and OR, 0.52; 95% CI, effect of fixed-dose combination for- the most common cause of death 0.33−0.81 for Asia). These associa- mulations of antiretroviral therapy on (19%), including hepatocellular carci- tions remained statistically significant switches to second-line therapy among noma (2.8% of total deaths), followed after adjustment for sex, age, trans- 2144 HIV-1-infected adults initiating by AIDS-defining illnesses (16.4%) and mission group, AIDS status, CD4+ cell antiretroviral therapy between 2000 liver diseases excluding hepatocellular count, and pre–antiretroviral therapy and 2010 with efavirenz, atazanavir, carcinoma (15%). plasma HIV-1 RNA level. In the United or lopinavir-based regimens in the Ca- Kowalska and colleagues deter- States, black race was associated with nadian Observational Cohort Collabo- mined risk of cause-specific death over higher mortality than white race (OR, ration (CANOC) (Abstract 579). They time in relationship to antiretroviral 1.18; 95% CI, 1.07−1.31). None of the examined the following 3 associations: therapy exposure among HIV-1-infect- racial or ethnic categories in Canada (1) fixed-dose abacavir/lamivudine for ed patients in the EuroSIDA cohort (Ab- (black, Hispanic, Asian, or indigenous) patients receiving abacavir and lami- stract 790). They found that the risk of had statistically significantly different vudine, (2) fixed-dose lamivudine or non–AIDS-related deaths (non–AIDS- mortality from that of white Canadians emtricitabine/tenofovir for those re- related infections, liver disease, non– in the cohort. ceiving tenofovir plus lamivudine or AIDS-defining malignancies, cardio-

73 IAS–USA Topics in Antiviral Medicine

vascular disease, other, and unknown) genome single-nucleotide polymor- ern Europe and some parts of Asia, increased with cumulative exposure to phism (SNP) arrays on 1622 samples it is driven by injection drug use. In antiretroviral therapy. Among 11,982 from individuals taking efavirenz and southern Africa, data suggest that the patients in antiretroviral therapy, the 792 samples from people using abaca- highest HIV infection risk is in women adjusted incidence rate ratio (aIRR) vir. Samples were stratified by ethnic- in their 20s, driven by heterosexual for non–AIDS-related death was lower ity, and approximately 500,000 SNPs risk. There are also many perinatally in the first 2 years after antiretroviral were examined for association with infected adolescents who are now therapy initiation than in years 2 to 4 the following 3 outcomes: (1) early “aging up” into this group and who of antiretroviral therapy (aIRR, 0.64; virologic response (defined as plasma face additional challenges because of 95% CI, 0.52−0.80). This relationship HIV-1 RNA level < 50 copies/mL at their extensive treatment experience. was driven by those initiating antiret- or before 16 weeks of antiretroviral The Joint United Nations Programme roviral therapy before 2002. The trend therapy), (2) virologic relapse (plasma on HIV/AIDS (UNAIDS) estimates that remained statistically significant after HIV-1 RNA level > 200 copies/mL after there are 1 million new infections each controlling for age when examined for achieving a level < 200 copies/mL), year in young adults. the following specific causes of death: and (3) virologic response (plasma Agwu and colleagues examined dis- cardiovascular disease, liver-related HIV-1 RNA level < 50 copies/mL at or parities in antiretroviral therapy utiliza- disease, other, and unknown but not before 48 weeks). All subanalyses in- tion in a cohort of 247 non–perinatally for the other causes of death. cluded only those individuals who did HIV-infected youth aged 12 years to Zhang and colleagues used data not report missed doses, and they spe- 24 years receiving care at 14 differ- from the AIDS Therapy Evaluation cifically interrogated SNPs within 100 ent treatment sites between 2002 and Project, Netherlands (ATHENA) co- kilobases of a selected group of drug- 2008 (Abstract 692). Inclusion criteria hort to determine the association be- absorption, distribution, metabolism, for the cohort were being antiretrovi- tween CD4+ cell count and plasma and elimination (ADME) genes. ral therapy–naive and having at least 2 HIV-1 RNA level before and after anti- Results did not show any SNP that CD4+ cell count measurements of no retroviral therapy initiation and non– met criteria for genomewide statistical more than 350/μL. The median age of AIDS-related endpoints: cardiovascu- significance P( < 5 × 10-8) for association the cohort was 21 years (interquartile lar disease, renal failure, liver disease, with any of the outcome categories. range [IQR], 20−23 years), 72% were and a combined endpoint incorporat- The authors reported approximately boys or men, and 68% were black. The ing all 3 (Abstract 791). Incidence of 80% power to detect OR value greater majority (78%) were receiving care at non–AIDS-related events was lower than 2.1 for virologic failure in the efa- adult HIV treatment sites. A total of before than after antiretroviral therapy virenz group and approximately 80% 198 (69%) of the cohort initiated anti- initiation for cardiovascular disease power to detect OR value greater than retroviral therapy. (0.18/100 person-years vs 0.49/100 3.7 for virologic failure in the abacavir In multivariate analysis, antiretro- person-years, respectively; P < .001) group. They concluded that there were viral therapy initiation was associated and for the combined endpoint but no large-effect (OR > 2) common vari- with CD4+ cell count less than 200/μL not for renal failure or liver disease. ants found to contribute to virologic (adjusted hazard ratio [aHR], 2.02; The investigators found that higher failure in this combined cohort but 95% CI, 1.40−2.90) and attending 4 or CD4+ cell counts were inversely as- that common variants with modest more outpatient HIV practitioner visits sociated with non–AIDS-related events effects or rare variants would not be in the year after meeting treatment cri- both before initiation (adjusted relative discovered in this analysis and could teria (aHR, 2.23; 95% CI, 1.50−3.31). risk [aRR], 0.60; 95% CI, 0.53−0.68) contribute to the outcomes tested. Potential predictors that were not sta- and after initiation (aRR, 0.40; 95% CI, tistically significant in the multivariate 0.35−0.47). There was no statistically Treatment Outcomes Among Young analysis included race or ethnicity, HIV significant association between plas- Adults acquisition risk, insurance coverage, ma HIV-1 RNA level before antiretro- year meeting treatment criteria, and viral therapy initiation and non–AIDS- A themed discussion (Session 14) cov- being at an adult treatment center. related events. ered 4 poster presentations on anti- The investigators also examined Several studies applied genome- retroviral therapy use and outcomes risk of discontinuing first antiretro- wide association analysis to existing in youth. Rudy introduced the session viral therapy regimen, which occurred longitudinal cohorts, including one with an overview of epidemiology in in 117 individuals in the cohort (41%): by McLaren and colleagues, who used this important group of approximately 50 switched antiretroviral therapy regi- samples from subjects in ACTG studies 10 million people living with HIV who mens, and 67 discontinued antiretro- (A5202, A5142, A5095, and ACTG 384) are between the ages of 15 years and viral therapy. Discontinuation of the to assess genetic influence on virologic 24 years. In North and Latin America initial antiretroviral regimen occurred outcomes of patients taking efavirenz and in Central and Western Europe, statistically significantly more rapidly or abacavir (Abstract 477). Genotypic this epidemic is driven by men who (within 297 days; IQR, 18−896 days) testing was performed using whole- have sex with men (MSM), and in East- among those cared for at adult clinic

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sites than among those cared for at The young-adult population was 54% ations varied statistically significantly pediatric sites (within 594 days; IQR, black, 61% women, and 59% preg- after adjustment for sex, age, school 229−999 days). The overall aHR for nant patients. The primary endpoint grade, baseline or current CD4+ discontinuation was 2.06 (95% CI, was achievement of virologic suppres- cell count, orphan status, or the other 1.20−3.55) for those receiving care sion (plasma HIV-1 RNA level < 400 of the 2 predictors. at adult sites compared with pediatric copies/mL) 6 months after antiretro- sites. Of those who discontinued, 67% viral therapy initiation or after estab- Acute Infection remained in care the year following lishment of care in the clinic for those discontinuation; all 15 who received already receiving antiretroviral therapy. Treatment of acute HIV infection. care at pediatric sites were receiving The investigators found that 58.7% The benefit of treatment for acute HIV antiretroviral therapy, compared with of young adults achieved virologic sup- infection remains unclear. The follow- only 78% of the 49 patients receiving pression at 6 months compared with ing studies focused on the impact of care at the adult sites (P = .04). 78.2% of adults (P = .025), and the treatment during acute or recent HIV Saavedra-Lozano and colleagues de- young adults had a 6-fold higher likeli- infection in terms of treatment out- termined the clinical status of 74 mem- hood of being lost to follow-up (LTFU, comes, viral load set point, or immune bers of the Madrid Cohort of HIV-infect- also indicates loss to follow-up) than activation. Grijsen and colleagues re- ed children at the time of their transfer did the adults, defined as no clinic ported results of a multicenter, open- to an adult clinic (Abstract 693). The attendance for 12 months or longer. label, randomized control trial compar- mean age at transfer was 18.9 years These differences were particularly ing no treatment with 24 weeks or 60 (range, 13−22 years), the mean abso- dramatic in black patients. Young- weeks of temporary 4-drug antiret- lute CD4+ cell count was 710/μL; 54% adult black patients had a statistically roviral therapy during primary HIV had plasma HIV-1 RNA levels less than significantly lower probability of viro- infection (Abstract 161). Only those 400 copies/mL; and 54% received a logic suppression than either young patients for whom treatment was in- clinical diagnosis of lipodystrophy. The nonblack patients (44% vs 77%, re- dicated were randomly assigned to 1 majority of the patients were receiving spectively) or nonblack adults (91%). of the 2 treatment groups. There were 1 PI and 2 nRTIs (28%) or 1 NNRTI and Lowenthal and colleagues deter- 36 patients in the untreated group, 2 nRTIs (27%), and 75% had received 2 mined the ability of a screening tool 40 patients in the 24-week treatment or more antiretroviral regimens at the for pediatric psychosocial dysfunc- group, and 39 in the 60-week treat- time of transfer. Thirty-nine (53%) of tion, the Pediatric Symptom Checklist ment group. Patients were treated with these patients underwent HIV-1 geno- (PSC), and of age at antiretroviral ther- 2 nRTIs, an NNRTI, and a PI. Primary typic testing, although criteria for ge- apy initiation to predict virologic failure endpoints were plasma viral load at notypic testing in the cohort were not of antiretroviral therapy in a cohort of 36 weeks after randomization or treat- provided. Of these, 21 had PI- and re- HIV-infected children in Botswana (Ab- ment interruption and total time off verse transcriptase inhibitor–associ- stract 695). They conducted a cross- therapy. Subjects had serologic test re- ated resistance mutations, and 3 had sectional analysis of 8- to 16-year-old, sults consistent with acute HIV infec- only PI-associated resistance muta- HIV-infected children receiving care at tion in 73% of cases, and symptoms tions. The authors concluded that the a single site, and they translated, cul- were present in 83% of cases. Antiret- patients had relatively well-preserved turally adapted, and validated the PSC, roviral therapy was initiated for subclinical and immunologic condition using receiver operating characteris- jects with an incident AIDS diagnosis after many years of antiretroviral tic (ROC) analysis to determine opti- or a CD4+ cell count less than 350/µL. therapy but that prevalence of lipodys- mal cutoff scores. The study enrolled At 36 weeks after randomization or trophy and drug resistance mutations 635 children who had been receiving treatment interruption, the mean viral were high in the cohort. antiretroviral therapy for more than set point was statistically significantly Ryscavage and colleagues con- 6 months, 24% of whom met criteria higher in the untreated group: 4.8 log10 ducted a retrospective, matched case- for virologic failure and 17% of whom copies/mL in the untreated group com- control study comparing 46 HIV-1- had PSC scores of more than 20, the pared with 3.9 log10 copies/mL and 4.2 infected young adults aged 17 years threshold for positivity determined in log10 copies/mL in the 24- and 60-week to 24 years with adults aged 25 years the ROC analysis. treatment groups, respectively (P < to 40 years, all newly receiving care The OR for virologic failure among .001). Authors also analyzed time off in an adult-oriented, university-based those with PSC scores of 20 or higher treatment and found that the median clinic (Abstract 694). The adult control was 1.64 (95% CI, 1.04−2.57) com- was 0.7 years (95% CI, 0.2−1.2 years) group was randomly selected from the pared with those with PSC scores less in the untreated group and 3.1 years clinic and matched 1:1 with the young than 20. Initiating antiretroviral thera- (95% CI, 2.3−3.8 years) and 2.1 years adults for ethnicity, sex, pregnancy py at age 10 years or older was also (95% CI, 0.4−3.8 years) in the 24- during the study period, pre–antiretro- statistically significantly associated and 60-week groups, respectively (P < viral therapy plasma HIV-1 RNA level, with virologic failure (HR, 3.08; 95% .001). There was no statistically signifi- and HIV genotypic susceptibility score. CI, 2.01−4.71). Neither of the 2 associ- cant difference in time off treatment

75 IAS–USA Topics in Antiviral Medicine

between the 2 treatment groups. The sured in the blood and sigmoid colon, unclear. Liegler and colleagues studied authors suggested that temporary anti- and mononuclear mucosal cells and minor resistance variants in 6 patients retroviral therapy during primary HIV PBMCs were analyzed in 16 and 8 pa- from the UCSF Options Cohort who infection lowers the setpoint and defers tients, respectively. were found to have the M184V trans- the start time for continuous antiretro- The authors highlighted the finding mitted drug resistance mutation dur- viral therapy for chronic HIV infection. that patients with infection classified ing primary HIV infection (Abstract Markowitz and colleagues sought as Feibig stage III (classified as detect- 513). Results of population-based se- to understand whether antiretroviral able HIV-1 RNA, p24 antigen positive, quencing and quantitative minor vari- therapy initiated during early HIV in- HIV seropositive on enzyme-linked ant assays were observed over time in fection and targeting entry, reverse immunosorbent assay, and negative individuals enrolled within 6 months transcriptase, integrase, and protease on HIV Western blot testing) at en- of infection whose transmitted drug would improve outcomes compared rollment had statistically significantly resistance mutation M184V had revert- with a 3-drug, PI-based regimen (Ab- reduced numbers of CD4+CCR5+ ed to wild type after discontinuation of stract 148LB). The authors presented T cells in the mononuclear mucosal antiretroviral therapy. 48-week data from a randomized, cells compared with both healthy in- The sensitive polymerase chain re- open-label trial of a 5-drug regimen dividuals and with persons with dis- action (PCR)-based minor variant as- compared with a 3-drug standard PI- ease in Feibig stage I (defined as HIV-1 say detected reversion at an average based antiretroviral regimen initiated RNA detectable, p24 antigen negative, of 18 weeks compared with 28 weeks during acute and early HIV-1 infection. and HIV-antibody negative). The au- using population-based sequencing. Patients were randomly assigned 1:2 to thors suggested that 5-drug treatment Loss of detectable M184V (less than receive 3 drugs or 5 drugs. Both treat- in early-Feibig-stage, acute HIV infec- 0.5%) occurred at a mean of 36 weeks ment groups received tenofovir/em- tion may prevent CD4+ cell depletion from infection and persisted for up to tricitabine and either atazanavir/r or in the sigmoid colon and render gut 5 years of monitoring. After M184V darunavir/r; the 5-drug group also re- and peripheral HIV RNA undetectable, detection by population sequencing, ceived maraviroc and raltegravir. Data thereby reducing the viral burden and loss of detectable M184V occurs rapid- were available from 11 patients in the promoting immune restoration. ly at a mean of 10 weeks. The authors 3-drug group and 23 patients in the Investigators from the University of suggested that the rapid overgrowth 5-drug group. California San Francisco (UCSF) Op- of wild-type virus may indicate that At week 48 of treatment, there were tions Project compared the effect of reverse transcriptase 184 declines to no statistically significant differences antiretroviral therapy initiation dur- levels that are not clinically important in percent of subjects with plasma ing acute or early HIV infection with 1 year after reversion. HIV-1 RNA levels below detection us- later antiretroviral therapy initiation Gianella and colleagues also looked ing the single-copy assay, increase in on various immunologic and virologic at minority resistance variants during CD4+ T cell count, or immune activa- outcomes (Abstract 517). There were early HIV-1 infection and compared tion markers. There were 3 individuals 34 participants in the early-treatment bulk sequencing with ultra-deep se- in the 5-drug group for whom treat- group and 32 in the later-treatment quencing on baseline blood samples ment failed to suppress viral load at group. Participants were included in of 23 recently infected individuals 48 weeks by standard assay; this result the analysis if they maintained at least (Abstract 514). Several findings sug- was unexpected but not statistically 2 years of viral suppression after ini- gested that such minority mutants significant. Researchers noted that ad- tiation of either early or late antiretro- are unlikely to be transmitted to, and ditional studies are under way to com- viral therapy. The authors analyzed maintained in, the recipient host. The pare the effects of the 3-drug regimen markers of CD4+ and CD8+ activation authors showed that ultra-deep se- with those of the 5-drug regimen on and found that the late-antiretroviral quencing revealed a higher frequen- the gastrointestinal tract and on the la- therapy group had statistically signifi- cy of resistance mutations (93.7%) tent reservoir. cantly higher levels of activated CD4+ than found through bulk sequencing Ananworanich and colleagues also and CD8+ T cells, statistically signifi- (12.5%). Furthermore, 60% of the drug investigated the effects of a 5-drug reg- cantly higher proviral DNA levels, and resistance mutations in the ultra-deep imen on acute HIV infection (Abstract statistically significantly higher viral sequencing group were present at 516). The team sought to understand reservoirs than the early-treatment less than 1% (mean 0.56%; 95% CI, the impact of this regimen on HIV sup- group. They suggested that earlier anti- 0.43%−0.69%), and there was wide pression, the viral reservoir, and resto- retroviral therapy initiation may be as- variability in the drug resistance muta- ration of immunity in the peripheral sociated with lower T-cell activation tions with repeated runs. There was no blood and sigmoid colon. A total of 20 and smaller HIV reservoirs. correlation between minority drug re- study participants were treated for 6 sistance mutations and negative clini- months with tenofovir, emtricitabine, Resistance and acute HIV infection. cal outcomes with initial antiretroviral efavirenz, raltegravir, and maraviroc. The relevance of minor resistance vari- regimens. The authors suggested that Levels of HIV RNA and DNA were mea- ants at the time of acute infection is the majority of detected low-frequency

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drug resistance mutations are likely to mission (PMTCT) of HIV infection, 27 Médecins Sans Frontières (Doc- be the consequence of HIV-1 within- which reach only 35% of HIV-infected tors Without Borders, MSF)-sponsored host diversification or evolution, or of mothers and children, and LTFU of pa- programs.9 Sow also emphasized the methodology-related error. tients with HIV infection who have not importance of the 2010 WHO guide- yet initiated antiretroviral therapy. The lines for the initiation of antiretroviral Antiretroviral Treatment in 2010 WHO guidelines for antiretrovi- therapy at CD4+ cell counts less than Resource-Limited Settings ral therapy and PMTCT will help with 350/μL and the need for treatment of these endeavors,3,4 but the lack of ac- HIV-associated comorbidities, such as Overview cess to CD4+ cell count monitoring cardiovascular disease, in RLS. remains a major obstacle to progress. Walensky discussed several issues The opening session N’Galy-Mann Lec- Harries proposed universal HIV test- relevant to the cost-effectiveness of ture, delivered by Harries, focused on ing and immediate antiretroviral ther- antiretroviral therapy in RLS (Abstract the history of the HIV epidemic in Ma- apy initiation, as promoted by Granich 74). She discussed the limitations of lawi, where HIV infection prevalence and colleagues in 2009.5 Malawi re- cost-effectiveness literature in general reached 14% of the general population cently adopted a policy of “antiretro- and the application of WHO cost-ef- by 1995 (Abstract 18). Harries remind- viral therapy for life” with tenofovir, fectiveness standards to RLS. The eco- ed the audience that, before antiretro- lamivudine, and efavirenz for all HIV- nomic value of antiretroviral therapy viral therapy availability in Malawi, infected pregnant women regardless in RLS was first addressed in a 2006 90% of adults receiving a diagnosis of of CD4+ cell count. Harries acknow- publication, which examined the cost- stage 4 HIV disease were dead within ledged that such a program will re- effectiveness of antiretroviral therapy 12 months, and half of all children quire careful monitoring of the safety, in Côte d’Ivoire by WHO Gross Domes- receiving an HIV infection diagnosis acceptability, feasibility, and outcomes tic Product comparison standards.10 were dead within 2 years of diagnosis. of the program, but he believes that Subsequent studies examined cost- Harries and his colleagues envisioned this intervention, combined with tar- effectiveness of CD4+ cell count mon- a directly observed-therapy–like strat- geted prevention interventions such itoring, plasma HIV-1 RNA level moni- egy for antiretroviral treatment in Ma- as microbicides, preexposure prophy- toring, and initial and second-line lawi in August 2001, and they received laxis (PrEP), and male circumcision antiretroviral therapy. These showed resources from the Global Fund to Fight should form the next salvo in the battle that antiretroviral therapy costs, rather AIDS, Tuberculosis, and Malaria for against the HIV epidemic in Malawi. than laboratory-monitoring costs, were antiretroviral therapy scale-up in 2002. Sow gave a “Global Antiretroviral higher in regions offering plasma HIV-1 Scale-up emphasized simplicity and Therapy Update” during a workshop RNA monitoring, as the viral load standardization of regimens to ensure for new investigators and trainees (Ab- monitoring led to transitions to more ease of delivery and equity of access stract 6). He emphasized the unprec- costly second-line regimens.11 throughout the country, with 1 initial edented success of global antiretroviral Walensky and colleagues also applied and 1 second-line regimen available. therapy scale-up and highlighted chal- clinical efficacy and cost-effective- Monitoring and evaluation procedures lenges to continued success. These ness analysis to the 2010 WHO treat- were built into the efforts early on challenges include high mortality af- ment guidelines, which recommend- and included quarterly, in-person site ter antiretroviral therapy initiation, ed antiretroviral therapy initiation at visits within that program. Data from difficulty managing HIV infection in CD4+ cell counts less than 350/μL, the program showed that Harries and patients with tuberculosis coinfec- increased number of sequential an- colleagues achieved 60% coverage for tion, retention in care, lack of labora- tiretroviral regimens (ie, availability antiretroviral therapy by September tory monitoring, and lack of access to of second-line therapy), and replace- 2010, and the percentage of patients in- second-line regimens or regimens for ment of stavudine with tenofovir.12 The itiating antiretroviral therapy at World repeated antiretroviral therapy failure. clinical impact model determined that Health Organization (WHO) clinical Sow selected 4 “top” papers of the the initiation of antiretroviral therapy stage 4 diminished from 25% in 2005 past year, 2 that highlighted the mor- at CD4+ cell counts less than 350/μL to 10% in 2010. The efforts have yield- tality benefits of early initiation of anti- conferred the greatest survival benefit, ed results at a population scale, with retroviral therapy, even in patients re- followed by the availability of second- overall mortality declining dramati- ceiving tuberculosis treatment,6,7 1 that line antiretroviral therapy, followed by cally, whether measured by traditional demostrated the importance of gener- replacement of stavudine by tenofovir. registers or by nontraditional mortality ic antiretroviral therapy to cost savings The cost-effectiveness analysis showed measurements such as coffin sales and achieved within President’s Emergen- that earlier initiation of antiretroviral church funerals.2 cy Plan for AIDS Relief (PEPFAR)-sup- therapy and replacement of stavudine Harries argued that the future will ported programs,8 and 1 that described by tenofovir would be important first require a focus on prevention of new factors associated with increased mor- steps, followed by access to second- HIV infections, expansion of programs tality in patients receiving second-line line therapy. Overall, the introduction for prevention of mother-to-child trans- antiretroviral therapy in a cohort of of all 3 WHO-recommended measures

77 IAS–USA Topics in Antiviral Medicine

was shown to be very cost effective, antiretroviral drugs in RLS, such as ril- than US $12 million annually. Long even for many RLS, with a ratio of US pivirine in a fixed-dose combination acknowledged that the study’s limita- $2370 per life-year saved. or long-acting tenofovir; and (6) new tions included lack of generalizability treatment strategies including induc- and confounding by unmeasured vari- tion or maintenance of monotherapy ables that differ between study groups, Advances in Antiretroviral Therapy Scale-Up and Care Delivery in with ritonavir-boosted PIs, which have but he concluded that shifting care to Resource-Limited Settings mixed results in early trials but deserve nurses could result in increased treat- more investigation. Vitoria concluded ment capacity without compromise of Several presentations highlighted new that a combination of innovative strat- patient outcomes. strategies for antiretroviral therapy egies can help antiretroviral therapy Bendavid and colleagues estimated scale-up and care delivery in RLS. Vi- scale-up move into its second decade the contributions that the decreasing toria of the WHO gave an overview of and achieve further success. price of initial antiretroviral therapy current and future strategies for anti- Long and colleagues used results and increasing foreign assistance for retroviral therapy optimization at the from a recent randomized control HIV care had on antiretroviral therapy global level, and began by highlighting trial showing noninferiority of nurse coverage in RLS (Abstract 568). The the dramatic success of the past de- versus physician management of HIV- authors used data from the WHO Glob- cade of antiretroviral therapy scale-up infected patients receiving antiretro- al Price Reporting Mechanism and the (Abstract 108). He noted the 13-fold in- viral therapy as background for an French National Agency for Research crease in access to antiretroviral thera- examination of the impact of shifting on AIDS and Viral Hepatitis (ANRS) py over the past 6 years and that 5.25 the management of patients on stable Economics of AIDS and Access to HIV/ million people now receive antiretrovi- antiretroviral therapy from physicians AIDS Care in Developing Countries ral therapy in low- and middle-income to nurses in South Africa in a routine- Project to create a price index for ini- countries. care setting (Abstract 43).15 The study tial antiretroviral therapy for 13 coun- Antiretroviral therapy has been included patients initially managed by tries in sub-Saharan Africa. The index shown to impact country-level health physicians and eligible for nurse man- described costs per country per year indicators. Notable examples include agement, as determined by stable an- and represented 84% of Africa’s esti- antiretroviral therapy–associated re- tiretroviral therapy for longer than 6 mated total number of people living ductions in overall mortality in South months, undetectable plasma HIV-1 with HIV or AIDS. Foreign assistance Africa and antiretroviral therapy– RNA level, CD4+ cell count greater was measured as disbursements from associated declines in tuberculosis in- than 200/μL, and less than 5% weight the World Bank, the Global Fund to cidence in Botswana. However, global loss over the past 3 clinic visits. The Fight AIDS, Tuberculosis, and Malaria, coverage of antiretroviral therapy re- patients were divided into 2 groups: and PEPFAR, and data on antiretroviral mains at 36% for adults with respect to those managed by doctors (n = 1620) therapy coverage was obtained from the 2010 WHO guidelines criteria, 28% and those managed by nurses (n = UNAIDS. for children, and 53% for PMTCT in 540); the groups were matched for age, The authors found that the mean 2009, and stark inequalities in terms sex, CD4+ cell count, time on anti- annual price of initial antiretroviral of drug price compared with national retroviral therapy, and antiretroviral therapy dropped from US $1177 in incomes persist. The joint UNAIDS/ regimen. Baseline characteristics were 2003 to $96 in 2008, and antiretrovi- WHO “Treatment 2.0” initiative advo- comparable across the 2 groups: sub- ral therapy coverage increased from cates specific strategies to catalyze the jects had been receiving antiretroviral 5.7% to 51.2% over the same time pe- next phase of scale-up in HIV disease therapy for a mean of 13.2 months riod. Multivariate analysis, adjusting treatment.13 and were receiving either stavudine/ for public health expenditures, gross The strategies proposed by this ini- lamivudine/efavirenz or zidovudine/ domestic product, HIV prevalence, and tiative include (1) the promotion of lamivudine/efavirenz. government effectiveness, showed fixed-dose combinations, which bring Primary outcomes—LTFU, mortali- that antiretroviral therapy coverage programmatic, clinical, and economic ty, virologic rebound, and mean CD4+ was associated more closely with price benefit; (2) potential dose reductions cell count response—did not differ reductions at lower prices and that, in antiretroviral therapy based on data statistically significantly between the together, price reductions and foreign from phase II trials indicating virologic 2 groups. The cost savings were mod- assistance for HIV care explained half outcomes were similar for several dos- est: a US $48 reduction per year per of the increase in antiretroviral thera- es of many drugs14; (3) reformulation patient in care and responding to treat- py coverage observed between 2003 of existing drugs to make them easier ment. However, when extrapolated and 2008. The authors concluded that to take and less toxic; (4) improve- to the approximately 25% of South price reductions, even to very low lev- ments in bioavailability of drugs, in- Africa’s current population receiving els, are unlikely to be associated with cluding alterations of crystalline forms antiretroviral therapy and eligible for substantial additional gains in anti- and the potential use of nanopharma- nurse-managed care, this shift in care retroviral therapy coverage and that ceuticals; (5) the potential role of new would represent a savings of more achievement of universal coverage

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will require a substantial increase in Bangsberg concluded with a re- low pre–antiretroviral therapy CD4+ foreign assistance and national public minder that the most important chal- cell count (median, 48/μL), and male health expenditures for HIV care. lenge in sustaining adherence success sex predicted all outcomes other than in RLS is posed by restriction in fund- maintenance in care. Interestingly, LTFU Retention in Care and Adherence to ing sources. If the time to treatment decreased over time as the program Antiretroviral Therapy in Resource- increases, which Geng and colleagues expanded. Ahonkhai also noted that Limited Settings showed occurs when funding sources baseline risk factors did not distinguish are unstable, then those taking anti- interrupted care from LTFU, but these 2 Bangsberg discussed adherence and re- retroviral therapy are likely to share events had strikingly different outcomes. sistance to antiretroviral therapy (Ab- their medications with ill family and Braitstein and colleagues presented stract 111). He began his presentation by friends.24 This practice could erode data from an evaluation of LTFU in pro- reminding the audience of a 2006 me- treatment success for those undergo- grams participating in the IeDEA (In- ta-analysis of 228 studies, which dem- ing antiretroviral therapy and lead to ternational Epidemiologic Databases onstrated that adherence in RLS was the emergence of resistance in those to Evaluate AIDS) cohort collaboration 77% (95% CI, 67%−86%), a level sta- not “officially” receiving antiretroviral (Abstract 1015). They included data tistically significantly greater than in therapy but with whom the medica- from 29 antiretroviral therapy clin- resource-rich countries (55%; 95% CI, tions are shared. ics in East Africa with 43,175 eligible 48%−61%).16 He stressed the positive- Nachega introduced Session 16, patients (age ≥ 18 years, and receiving feedback loop of social capital and its “Retention and Adherence to Care in antiretroviral therapy at last visit) and promotion of adherence as proposed Resource-Limited Settings,” with an used a Weibull survival model with the by Ware and colleagues,17 and he em- overview of how adherence fits into fixed covariates of age, sex, CD4+ cell phasized that the major barriers to the larger framework of HIV care out- count at antiretroviral therapy initia- treatment adherence in RLS—primarily comes and the demonstrated cost tion, and WHO stage at antiretroviral structural and economic factors—can savings of antiretroviral therapy ad- therapy initiation to explore program be neutralized by the protective effects herence.25 He highlighted differences characteristics associated with LTFU. of social capital. in methods of measuring adherence The authors determined that clinics Unfortunately, adherence does decline and mentioned the effectiveness and using only telephone to reach lost pa- over time, a phenomenon well known in scalability of some of the interven- tients and without dedicated outreach resource-rich settings and shown in RLS tions, particularly a pill-monitor and staff have an aHR for risk of LTFU, deas well.18 Recently, 2 adherence inter- text-messaging intervention described fined as absence from the clinic for ventions in RLS showed the potential for above by Bangsberg; he noted that 6 months or longer, of 3.36 (95% CI, text-message reminders to substantially retention in care is also essential. Al- 1.72−6.57) compared with clinics us- increase adherence. Adherence was in- though much of the LTFU in RLS, up to ing dedicated staff for LTFU-prevention creased from 48% to 57% in one study 40% in some scenarios, is because of outreach. Furthermore, clinics that and from 47% to 63% in a second study, death, Nachega emphasized the need used only public means for outreach, both comparing those receiving text for improved methods of tracking and defined as outreach by bicycle or foot, messages to those not receiving text retention in care to improve the cur- had an aHR for LTFU of 3.12 (95% CI, messages, respectively.19,20 Bangsberg rent situation, in which up to 50% of 1.41−6.88) compared with those that highlighted a new monitoring technol- people can be LTFU by 24 months of used all available means for outreach, ogy, in which a medication dispenser antiretroviral therapy.26 including the use of a private vehicle. records when it is opened and sends Ahonkhai and colleagues presented Clinics that waited more than 30 days a wireless message to a central server, results from a retrospective cohort after a missed visit were more likely which then can send appropriate re- study of 11,397 patients initiating anti- to have LTFU than those who did not minders to either patients or caregiv- retroviral therapy in South Africa be- (aHR, 2.32; 95% CI, 1.26−4.24). ers.21 He noted the potential limitation tween 2004 and 2008 (Abstract 1014). Matovu and colleagues showed re- to this technology is that an interven- Median follow-up within the cohort sults from a randomized, controlled tion must be made quickly because was 2.4 years, and at study conclusion noninferiority trial comparing patients treatment interruptions longer than 3 63% of patients remained in care, 11% receiving an intervention using nurses days to 4 days are associated with loss interrupted care but returned within and peer educators to support adher- of virologic control.22 However, given 1 year, 17% were LTFU with no ap- ence to antiretroviral therapy after that pharmacy-refill data can be bet- pointments within a year, and 9% died initiation to those receiving standard ter than CD4+ cell count monitoring at within the first 7 months of antiretro- care from a physician and counselor detecting virologic failure,23 Bangsberg viral therapy. Of those who interrupted (Abstract 1016). They randomly as- speculated that the costs of more ef- care, 84% had plasma HIV-1 RNA levels signed 92 antiretroviral therapy–naive fective adherence monitoring and sup- less than 400 copies/mL, and median patients eligible for initial antiretroviral port devices could be covered by the CD4+ cell count was 257/μL upon re- therapy, 50 to the intervention group cost savings of improved adherence. turn. Early death was predicted by and 42 to the standard-counseling

79 IAS–USA Topics in Antiviral Medicine

group. The authors found that the plies that more than 1 million eligible ported dead, 4% were alive but had proportion of patients achieving the patients who presented to care have discontinued antiretroviral therapy, primary outcome, plasma HIV-1 RNA failed to initiate antiretroviral therapy. and 25% were LTFU. Poor retention level less than 400 copies/mL, was Kohler and colleagues analyzed the was associated with being a young similar in the 2 models: 91% in the results of a program change in a single adult, male sex, having poor baseline standard group and 88% in the inter- site in Kenya where free trimethoprim/ clinical or functional status, or having vention group, P = .73. There was also sulfamethoxazole prophylaxis began a CD4+ cell count less than 50/µL. No- no difference in a pill-count adherence to be offered to all patients, regardless tably for a program in the midst of a measure, CD4+ cell count, or weight of CD4+ cell count (Abstract 1018). greater than 1000% scale-up, retention change over the 6-month to 12-month They compared 1-year retention rates and clinical outcomes did not vary by follow-up period, suggesting that task- among 610 individuals enrolled before initiation period. shifting of follow-up care visits to nurs- the free regimen was available with Achieng and colleagues conducted es and peers could be effective for pa- retention rates among 414 subjects an observational study to determine tients initiating antiretroviral therapy. enrolled after. The 2 groups had no which components of a comprehen- These task-shifting findings are similar statistically significant differences in sive clinic and community adherence to those of Long and colleagues (Ab- age, sex, tuberculosis prevalence, body and retention program were most ef- stract 43), discussed above. mass index, or CD4+ cell count. fective in an antiretroviral therapy pro- Geng and colleagues examined fail- They found a statistically significant- gram in central Kenya (Abstract 1020). ure to initiate antiretroviral therapy, ly higher retention rate (84% vs 63%, The study prospectively enrolled 301 LTFU, and mortality among patients respectively) for patients ineligible for patients and collected data on partici- during the pre–antiretroviral therapy antiretroviral therapy who enrolled af- pation in home visits, support groups, initiation period at a single site in ter the free prophylaxis was available postpharmacy counseling, and phy- Uganda (Abstract 1017). They assessed compared with those ineligible for anti- sician-conducted pill counts over the outcomes in the clinic and used a ran- retroviral therapy who enrolled before first 6 months of antiretroviral therapy, dom-sample tracking method for 89 free prophylaxis was available (P < as well as the outcomes of virologic of the 514 patients LTFU before anti- .001). No statistically significant differ- failure, antiretroviral therapy discon- retroviral therapy initiation. Updated ence was observed in LTFU for those tinuation, death, and LTFU for the first outcomes were ascertained for 80% of receiving antiretroviral therapy during 12 months of antiretroviral therapy. those originally LTFU in the subsample. the same time periods. The authors Time to treatment failure (virologic Overall, a total of 1772 patients (58% speculated that the improved retention rebound, death, or LTFU) was deter- women) met immunologic criteria for rates could be the result of decreased mined by Kaplan-Meier survival analy- antiretroviral therapy initiation, with a morbidity, the perception of receiving sis and was associated with participa- median CD4+ cell count of 121/μL. treatment, lower costs of care, or the tion in support groups, postpharmacy The cumulative incidence of anti- establishment of care-seeking habits. counseling, accurate pill counts, and retroviral therapy initiation rose slowly Somi and colleagues presented a home visits. However, in the multi- over the first 90 days from 20.6% at 30 retrospective review of results from variate analysis, statistically significant days (95% CI, 18.6%−21.9%) to 63.4% the Tanzanian national HIV treatment reductions in risk of treatment failure at 90 days (95% CI, 61.4%−66.0%) program, which scaled up from man- were observed only for accurate pill but tapered off with a total cumulative aging the care of 11,363 patients in counts (aHR, 0.19; P < .001) and partic- incidence of antiretroviral therapy ini- 2004 to 197,412 patients in 2009 (Ab- ipation in support groups (aHR, 0.43; tiation at 365 days of 67.5% (95% CI, stract 1019). The investigators used a P < .003). The authors concluded that 65.1%−69.7%). A total of 21% (95% multistage, random-sampling model these 2 components are the most es- CI, 19.3%−22.6%) were LTFU before to achieve a nationally representative sential to maintain in their adherence antiretroviral therapy initiation at 1 sample of antiretroviral therapy–naive structure and noted during the ques- year, and the mortality in the sub- patients at least 15 years of age who tion period that the physician-conduct- sample for whom patient tracking initiated antiretroviral therapy between ed pill count traditionally takes less was implemented was 30.8% (95% October 2004 and August 2007 in 43 than 1 minute and is effective without CI, 22.9%−40.6%). Extrapolating data health facilities. They found that young requiring many resources. from the subsample to the entire clinic adults, 15 years to 29 years of age, Leisegang and colleagues con- of all antiretroviral therapy–eligible were more likely to have poor baseline ducted a retrospective cohort study of patients, 9% died before antiretroviral clinical status (CD4+ cell count < 50/µL women receiving antiretroviral therapy therapy initiation, 7% disengaged from or WHO clinical stage 4) with an OR of in a private managed care program in care, 16% were in care awaiting antiret- 1.63 (95% CI, 1.35−1.97) after adjust- South Africa to determine the impact roviral therapy, and 69% initiated anti- ment for sex and location. of pregnancy on antiretroviral therapy retroviral therapy. If these data can be Retention in care for the cohort adherence (Abstract 1021). Women extrapolated to the antiretroviral ther- was 70% at 12 months and 63% at 24 were classified as never pregnant (n = apy scale-up in RLS to date, this im- months. By 24 months, 8% were re- 4549), pregnant at initiation of long-

80 Conference Highlights—Antiretroviral Therapy Volume 19 Issue 2 May/June 2011

term antiretroviral therapy (n = 293), 2 weeks later above a threshold of 400 (Nevirapine Resistance Study), a ran- or pregnant after initiating antiretro- copies/mL to 10,000 copies/mL. At domized, controlled trial of treat- viral therapy (n = 128). baseline, median CD4+ cell count was ment strategies in which HIV-infected The authors found that for women 121/µL (IQR, 55/µL−184/µL); 57% ini- children with prior exposure to ne- who were never pregnant and women tiated antiretroviral therapy with stavu- virapine for PMTCT were switched to who became pregnant after initiation dine/lamivudine/efavirenz; and more nevirapine-based therapy after initial of antiretroviral therapy, improved than 65% had disease classified as suppression with a PI-based regimen treatment adherence as assessed by WHO clinical stage 3 or stage 4. (Abstract 128). The 52-week results of monthly pharmacy refills was associ- Median time from antiretroviral this trial have already been reported,27 ated with shorter time on antiretroviral therapy initiation to treatment failure but Kuhn presented follow-up data for therapy, older age, receiving second- was 16 months (IQR, 12−24 months) 18 months to 53 months postrandom- line antiretroviral therapy, pregnancy, for the 10% of patients who met at ization. Beginning at 18 months after and the 6-month postpartum period. least 1 failure definition. The threshold randomization and continuing through Median adherence was much lower in chosen for the second confirmatory 48 months, children who were in the the group who were pregnant at anti- plasma HIV-1 RNA level elevation af- group that switched back to nevirap- retroviral therapy initiation (54%) than fected cumulative estimates of failure, ine-based antiretroviral therapy were in those who were never pregnant increasing levels by 1.4-fold and 1.6- less likely to have a postrandomization (79%; P < .001). The time to antiretrovi- fold if set at 5000 copies/mL and 1000 plasma HIV-1 RNA level greater than ral therapy default, defined as no anti- copies/mL, respectively, when com- 50 copies/mL, the primary endpoint retroviral therapy claimed for at least pared with a threshold of 10,000 cop- of the study, than were children who 6 months, was also shorter in women ies/mL. Failure was predicted by lower continued treatment with lopinavir/r- who were pregnant at antiretroviral age, male sex, nevirapine use, year based regimens. However, when the se- therapy initiation than in the never- initiating antiretroviral therapy, a base- condary endpoint of a confirmed plas- pregnant group. The investigators line CD4+ cell count less than 25/µL, ma HIV-1 RNA level greater than 1000 concluded that adherence is improved and a baseline plasma HIV-1 RNA level copies/mL was assessed, more children during pregnancy and immediately of 1,000,000 copies/mL or higher. Only in the nevirapine group than in the postpartum for those who become 33% of those with documented virolog- lopinavir/r group met this endpoint. pregnant while receiving antiretroviral ic failure switched to second-line anti- The authors pointed out that the therapy but that adherence is more dif- retroviral therapy after a median of 5.5 patterns of failure differed between ficult for women who initiate antiretro- months after the first elevated plasma the 2 groups: by 6 months, 59% of the viral therapy while pregnant. They are HIV-1 RNA level. Switch was predicted treatment failures, as determined by expanding their analysis to include a by low CD4+ cell count at the time of plasma HIV-1 RNA levels greater than larger sample to more thoroughly ex- switch and CD4+ cell count decline 1000 copies/mL, were detected in the plore these interactions. over time. Thus, there remains a sub- nevirapine group; by 12 months, all stantial delay in switching, and many of the treatment failures had been de- Outcomes of Treatment for Adults in of those meeting criteria for antiretro- tected. In contrast, by 12 months, only Resource-Limited Settings viral therapy failure do not transition 60% of the failures had been detected to second-line antiretroviral therapy. in the lopinavir/r group. Pretreatment There were at least 23 presentations Some of these studies of HIV-in- drug resistance genotypic testing data, on treatment outcomes and predictors fected adults in RLS are summarized determined by population sequencing, of response to therapy in RLS; here, we in Table 1, which includes studies in showed a clear relationship between call attention to a few abstracts from children. Other presentations of rel- treatment failure in the nevirapine the session on outcomes of second- evance to adult outcomes of antiretro- group and the presence of NNRTI mu- line antiretroviral therapy in RLS. Fox viral therapy in RLS include Abstracts tations in the baseline genotype. The and colleagues analyzed data from the 537−539, 541, 552, 554, 555, 557, authors concluded that a switch strate- IeDEA cohort to determine rates and 559−567, 581, and 582. gy to an NNRTI-based regimen for chil- predictors of failure of initial antiret- dren exposed to nevirapine for PMTCT roviral therapy and switch to second- Outcomes of Treatment for Infants could be employed safely in settings line antiretroviral therapy in 44,204 and Children in Resource-Limited where plasma HIV-1 RNA level moni- patients in South Africa (Abstract 580). Settings toring is available. They also noted They included antiretroviral therapy– that pretreatment screening for drug naive patients receiving NNRTI-based Although data on treatment outcomes resistance mutations would optimize initial antiretroviral therapy with at for infants and children in RLS remain the switch strategy by screening out least 24 weeks of follow-up. Virologic limited, there were several presenta- those for whom an NNRTI-based regi- failure was defined as a plasma HIV-1 tions of interest at the 2011 CROI. men would likely fail, offering a novel RNA level of at least 400 copies/mL, Kuhn and colleagues presented long- way to integrate genotypic testing into followed by a second measure at least term outcomes of the NEVEREST treatment-strategy studies in children.

81 IAS–USA Topics in Antiviral Medicine Table 1. Selected Studies on Failure to Initiate, Loss to Follow-Up (LTFU), and Switching to Second-Line Antiretroviral Therapy (ART) in Resource-Limited Settings Abstract No. Location Study Design Key Findings Study Description Cohort Participants Conclusions Definitions Abstract 1014. South Africa Retrospective cohort; • 63% remained in care, and 37% missed appointments in first year Early death, care n = 11,397; ≥ 15 years after ART start: interruption, and South African old; initiating ART – 11% interrupted care, 17% were LTFU, 9% died LTFU in adults from a Catholic Bishops 2004–2008; median • Of interrupters: 84% had HIV-1 RNA ≤ 400 copies/mL, 88% had large South African Conference, follow-up, 2.4 years increase in median CD4+ count at return to care community treatment Catholic Relief LTFU: missing all ap- • LTFU: decreased with increasing calendar year of enrollment program Services HIV pointments in first 12 treatment pro- months after ART start Conclusion: Baseline factors did not distinguish interrupted care from gram (71 sites) Interruption: missing LTFU, despite very different clinical implications of these 2 outcomes. some appointments but returning to care by 12 months

Abstract 1015.a Uganda, Retrospective cohort; • LTFU: 16.5/100 person-years (py) (95% confidence interval [CI], Association of pro- Tanzania, Kenya n = 43,175; ≥ 18 years 16.2–16.9/100 py) varied widely between sites (1–79.5/100 py) gram characteristics old; on ART at last visit; • Clinics without dedicated staff or with telephone-only outreach had with patient LTFU IeDEA East Africa data from 2007–2009; hazard ratio (HR) 3.36 (95% CI, 1.72–6.57) for risk of LTFU compared in adults on ART in (29 clinics) 61% women; mean with clinics with dedicated staff for outreach International Epide- age, 38 years • Clinics with only public means for outreach (bicycle/walking): HR, miological Databases LTFU: absent from clinic 3.12 (95% CI, 1.41–6.88) for LTFU compared with clinics with private to Evaluate AIDS ≥ 6 months vehicles for outreach (IeDEA) East Africa • Clinics that searched for patients LTFU > 30 days after a missed visit: Consortium HR, 2.32 (95% CI, 1.26–4.24) for LTFU compared with those that searched ≤ 30 days of a missed visit Conclusion: Patients at sites with outreach programs with dedicated staff and vehicles and early tracking of LTFU patients had lower risk of LTFU.

Abstract 1017. Uganda Retrospective cohort • ART start: 20.6% (95% CI, 18.6%–21.9%) at 30 days; 63.4% (95% Failure to initiate with intensive tracking CI, 61.4%–66.0%) at 90 days; 67.5% (95% CI, 65.1%–69.7%) at ART, LTFU, and mor- Immune of a random sample to 365 days tality among adult Suppression assess outcome; • LFTU: 21% (95% CI, 19.3%–22.6%) HIV-infected patients Syndrome Clinic, n = 1772; enrolling in • 1-year mortality in subsample (n = 134) of those LTFU with outcome qualifying for ART in Mbarara (single care and meeting crite- tracking: 30.8% (95% CI, 22.9%–40.6%) Uganda site) ria for ART; 2007–2009; • Extrapolating subsample results to cohort: 69% initiate, 16% in care 58% women; median awaiting ART, 7% disengaged from care, 9% died before ART CD4+ count, 121/μL initiation LTFU: 60 days late for appointment Conclusion: Failure to initiate ART may be an important issue; more work is needed to determine and eliminate its causes.

Abstracts 680, 681. Côte d’Ivoire Retrospective cohorts Abstract 680: Outcomes in ART- Abstract 680: • 31% of children died, transferred out, or were LTFU before ART start naive children in Aconda Program n = 1724; ART-naive; • Mortality rate: 13.2/100 child-years (cy) (95% CI, 10.0–13.4/100 cy) Abidjan, Côte d’Ivoire June 2004–November • Mortality correlated with pre-ART CD4+ count in all age strata 2007; median age, 54 Abstract 681: months • Observed risk of a serious morbid event: 17.8/100 cy at 18 months Abstract 681: of follow-up n = 405; ART-naive; • Cumulative mortality: 3.62/100 cy at 18 months (95% CI, 2004–2009; median 3.5–8.1/100 cy) age, 4.5 years; median • LTFU: 6.36/100 cy (95% CI, 6.16–6.55/100 cy); highest for those follow-up, 12 months; 2–5 years of age (9.37/100 cy; 95% CI, 8.92–9.81/100 cy) 28% met World Health Conclusion: Mortality is high among ART-naive children who qualify Organization criteria for for treatment initiation, as are rates of LTFU and serious morbid immunodeficiency events. These events may be preventable by earlier ART initiation.

(Continued on next page)

82 Conference Highlights—Antiretroviral Therapy Volume 19 Issue 2 May/June 2011 Table 1. Selected Studies on Failure to Initiate, Loss to Follow-Up (LTFU), and Switching to Second-Line Antiretroviral Therapy (ART) in Resource-Limited Settings (continued) Abstract No. Location Study Design Key Findings Study Description Cohort Participants Conclusions Definitions

Abstract 580. South Africa Retrospective cohort; • 10% of patients met at least 1 definition of treatment failure Rates and predictors n = 44,204 (96,937 • Median time from ART start to failure, 16 months (interquartile of failure of initial IeDEA Southern py); NNRTI-based initial range, 12–24 months) regimen and switch Africa (8 pro- ART for ≥ 24 weeks; • Failure predicted by lower age, male sex, nevirapine use, year initiat- to second-line ART in grams) 59% women; pre-ART ing ART, baseline CD4+ count < 25/µL, and baseline HIV-1 RNA South Africa median CD4+ count, ≥ 1,000,000 copies/mL 121/μL; 57% on • 33% of those with virologic failure switched to second-line ART at a stavudine/lamivudine/ median 5.5 months after first elevated HIV-1 RNA efavirenz • Switch predicted by low CD4+ count at time of switch and rapid Virologic failure: HIV-1 CD4+ count decline over time RNA ≥ 400 copies/mL Conclusion: A substantial delay in switching exists, and many of those after 24 weeks of ART meeting criteria for ART failure do not transition to second-line ART. followed by second value 400–10,000 copies/mL Switch: initiation of PI plus change in nRTI(s)

Abstract 684. Western Kenya Prospective tracking • Community health workers were able to locate or determine vital Outcomes of of random sample of status for 82% of children: HIV-infected and AIDSRelief-Kenya children LTFU; n = 97 (of – 11 died: 7 on ART, 2 HIV-exposed, 2 HIV-unknown serostatus HIV-exposed children 308 meeting inclusion) • Primary reasons for LTFU for those with known HIV serostatus: fear of LTFU in Western LTFU: absent from clinic family/community discrimination or disclosure issues Kenya ≥ 6 months for children • For HIV-exposed LTFU: 14/46 never returned because guardians had on ART who were not disclosed own serostatus or fear of family/community stigma HIV-exposed or had un- Conclusion: Fear of family/community discrimination was an impor- known HIV serostatus; tant cause of LTFU in this cohort and should be considered in future absent from clinic ≥ 12 interventions months for HIV-infected children not on ART aUpdated data provided in oral presentation differs from the published abstract. ART indicates antiretroviral therapy; HIV-1 RNA, plasma HIV-1 RNA level; NNRTI, nonnucleoside analogue reverse transcriptase inhibitor; nRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor.

Malateste and colleagues described ond study examined morbidity, mor- for earlier initiation of antiretroviral outcomes for children before antiretro- tality, and LTFU in a cohort of 405 HIV- therapy for children in RLS, a strategy viral therapy initiation in a large pedi- infected children in 2 health facilities currently recommended by the WHO atric antiretroviral therapy program in who had a median age of 4.5 years but still not available to many children. Abidjan, Côte d’Ivoire (the Aconda Pro- (Desmonde et al, Abstract 681). Risks Barlow-Mosha and colleagues re- gram) (Abstracts 680 and 681). One were estimated using a competing risk ported on a cohort of 142 children study determined the relationships survival analysis, with antiretroviral in Uganda, aged 1 year to 12 years, between absolute CD4+ cell count and therapy as a competing cause of the who had been receiving initial anti- percentage and risk of death in 1724 primary outcome. The observed risk retroviral therapy for at least 1 year antiretroviral therapy–naive, HIV-in- of a serious morbid event was 17.8 and were enrolled in an ongoing, ran- fected children with a median age of per 100 cy at 18 months of follow-up. domized controlled trial (Abstract 682). 54 months (Abstract 680). Of these, Risk was lower for children previously The mean age of the children was 528 (31%) died, transferred out of the exposed to antiretroviral therapy for 7.3 years, 44% were girls, all were on clinic, or were LTFU before starting PMTCT and for children under 5 years NNRTI-based regimens, the median antiretroviral therapy. Child mortality of age. Cumulative mortality was 3.62 duration of antiretroviral therapy was was much higher than that observed per 100 cy at 18 months (95% CI, 50 months (IQR, 30−63 months), 37% in European countries, with an overall 3.5−8.1 per 100 cy). Risk of LTFU was were exposed to single-dose nevirap- mortality rate per 100 child-years (cy) 6.36 per 100 cy (95% CI, 6.16−6.55 ine for PMTCT, and 79% had disease in of 13.2 (95% CI, 10.0−13.4), and the per 100 cy), and was highest for those WHO clinical stage 2 or 3. risk of death was inversely correlated between 2 years and 5 years of age The authors found that median with pre–antiretroviral therapy CD4+ (9.37/100 cy; 95% CI, 8.92−9.81 per CD4+ cell percentage was 35% (IQR, cell counts in all age strata. The sec- 100 cy). Together, these results argue 29%−42%), and 65% had a plasma

83 IAS–USA Topics in Antiviral Medicine

HIV-1 RNA level below 400 copies/mL. the largest categories in this group of 7 men and higher staff costs. The investi- Children exposed to single-dose nevi- children. The authors pointed out that gators highlighted that, although pedi- rapine had reduced odds of achieving the sampling of those LTFU more re- atric treatment costs approximately an undetectable plasma HIV-1 RNA cently may have led to a higher rate the same or less than adult treatment level (OR, 0.36; 95% CI, 0.17−0.74). of successful tracking than might oc- (average per adult per first year, US There was poor correlation between cur when tracking children LTFU for $448 in Zambia and US $699 in South CD4+ cell percentage and having a a longer time. Africa), very few young children have detectable plasma HIV-1 RNA level Meyer-Rath and colleagues estimat- access to antiretroviral therapy in ei- (r = 0.015). As one-third of the children ed the average outpatient cost of the ther country. Some of these studies of receiving antiretroviral therapy had de- first 2 years of outpatient antiretroviral HIV-infected children in RLS are sum- tectable plasma HIV-1 RNA levels de- therapy for pediatric patients in Zam- marized in Table 1. spite good immunologic response, the bia and South Africa (Abstract 685). authors concluded that plasma HIV-1 The investigators selected 120 chil- Strategies for Laboratory Monitoring RNA monitoring is important for early dren in Zambia and 148 in South Af- in Resource-Limited Settings detection of treatment failure, particu- rica who were initiating therapy at up larly for children with prior exposure to 12 years of age between 2005 and Hosseinipour gave an overview of lab- to single-dose nevirapine who are re- 2008 and who remained in the same oratory and clinical monitoring strate- ceiving nevirapine-based initial antiret- clinical setting for the first 24 months gies in Session 33, “Getting the Most roviral therapy. of antiretroviral therapy. They deter- From Global HIV Scale-Up” (Abstract Braitstein and colleagues described mined patient outcomes (HIV serosta- 109). She emphasized issues specific the results of aggressive tracking of a tus, CD4+ cell count, plasma HIV-1 to RLS, where the poor performance random sample of children LTFU in RNA level, and clinical condition) and characteristics of clinical and immu- western Kenya who were HIV-infected resource utilization at 12 months and nologic criteria to determine antiretro- and receiving antiretroviral therapy, 24 months of antiretroviral therapy. viral therapy failure can lead to chal- HIV-infected and not receiving antiret- The median age at antiretroviral lenges at both ends of the spectrum: roviral therapy, HIV-exposed, or of un- therapy initiation was 5.45 years (IQR, premature switch to second-line ther- known HIV serostatus (Abstract 684). 2.21−8.28 years) in Zambia and 4.01 apy for patients for whom virologic LTFU was defined as absent from the years (IQR, 1.62−7.16 years) in South control has been achieved but is not clinic for at least 6 months for children Africa, and the median CD4+ cell recognized because of the lack of vi- who were receiving antiretroviral ther- percentages at initiation were 12.5% rologic monitoring versus prolonged apy, HIV-exposed, or of unknown HIV (IQR, 8.60%−16.40%) and 13.23% treatment with suboptimal antiretrovi- serostatus, and as absent from the clin- (IQR, 7.09%−17.58%) in Zambia and ral therapy followed by the emergence ic for at least 12 months for HIV-infect- South Africa, respectively. The major- of resistant virus when clinical and im- ed children not receiving antiretroviral ity of patients in Zambia received ei- munologic criteria allow for prolonged therapy. A total of 308 children met ther stavudine/lamivudine/nevirapine treatment without virologic suppres- these inclusion criteria, and of those, or zidovudine/lamivudine/nevirapine, sion. Hosseinipour reviewed data from the investigators randomly selected 97 and the majority of patients in South the DART (Development of Antiretro- children (19 from a rural district hos- Africa received stavudine/lamivudine/ viral Therapy in Africa) trial, which pital and 78 from an urban hospital) efavirenz or stavudine/lamivudine plus showed a small but statistically signifi- for aggressive tracking by community lopinavir/r. Patients were classified as cant mortality benefit to immunologic health workers equipped with detailed follows: in care and responding (un- monitoring over clinical monitoring af- patient locator information collected detectable plasma HIV-1 RNA level, ter 5 years of antiretroviral therapy.28 on the last known visit. acceptable CD4+ cell percentage and A prior study of home-based antiretro- The community health workers clinical condition); in care and not re- viral care29 (showed an increased risk were able to locate 82% of the children sponding (detectable plasma HIV-1 of death or AIDS–defining events in in the sample. Of these, 11 (11%) had RNA level, unacceptable CD4+ cell the clinical group compared with the died: 7 (16%) receiving antiretroviral percentage or clinical condition); or no immunologic and virologic monitoring therapy, 2 (4%) HIV-exposed, and 2 longer in care (died or LTFU). group but found no statistically signifi- (29%) of unknown HIV serostatus. The Rates of retention in care were ap- cant difference between the immuno- primary reason the majority of children proximately 75% at both sites at 12 logic- and virologic-monitoring groups did not return to the clinic, of those months. The average cost per year for a for the same outcome at 3 years of with known HIV infection or HIV expo- patient remaining in care was US $367 follow-up. sure, was because of fear of family or in year 1 and $346 in year 2 in Zam- Hosseinipour also mentioned data community discrimination or disclo- bia, and US $1068 in year 1 and $707 on monitoring strategies (Abstracts 44 sure issues. Of children with unknown in year 2 in South Africa. The higher and 45LB, reviewed below). She con- HIV serostatus, 2 were not located and costs in South Africa were attributed to cluded that a moderate advantage to 2 were confirmed dead, making these the more expensive antiretroviral regi- immune monitoring can be observed

84 Conference Highlights—Antiretroviral Therapy Volume 19 Issue 2 May/June 2011

primarily beyond 2 years, and al- nor was the risk of death (4.4% vs WHO disease stage 3 or stage 4 or though no mortality benefit to virolog- 3.5%, respectively). Anemia, CD4+ cell AIDS–defining event for the clinical- ic monitoring has been documented, count less than 150/μL, plasma HIV-1 monitoring-only group. A total of 459 virologic monitoring is associated with RNA levels over 10,000 copies/mL, and patients were randomly assigned, and increased switch to second-line thera- body mass index less than 18.5 kg/m2 characteristics were similar between py and decreased duration of viremia. were associated with risk of clinical the laboratory- and clinical-monitor- She then reviewed studies that evalu- failure in an adjusted multivariate anal- ing groups (median CD4+ cell count, ate the WHO immunologic criteria, all ysis. Median time to switch was lower 179/µL and 182/μL, respectively). Two- of which showed low sensitivity and in the viral load monitoring group (11.7 thirds of all patients in both groups low positive predictive value,30-34 and months) than in the CD4+ cell count received stavudine/lamivudine/nevira- similar data for the WHO clinical cri- monitoring group (24.7 months; P = pine, and LTFU was 9% in the clinical- teria to identify failure.31,32 Data from .001 for comparison), but virologic monitoring group and 8% in the labo- the ART-LINC (Antiretroviral Therapy and immunologic response at 3 years ratory-monitoring group. in Lower Income Countries) cohort were similar in both groups. Of the 31 The primary outcome analysis collaboration have also shown that, patients in the CD4+ cell count moni- showed a difference in the mean of individuals who met WHO criteria toring group, 15 switched to PI-based change in CD4+ cell count between for treatment failure, only 24% were regimens while their HIV-1 RNA level the 2 groups of a 31/μL decrease (clini- switched to second-line antiretroviral was undetectable, and 7% of patients cal monitoring vs laboratory monitor- therapy, and failure to switch was as- required a treatment substitution for ing; 95% CI, 63/µL decrease to 2/μL sociated with mortality.35 Hosseinipour toxicity, with no statistical difference increase). These results did not reach also discussed resistance in RLS (Ab- between the 2 study groups. There the noninferiority margin of a 52/μL stracts 53 and 618, reviewed below was no statistical difference in future decrease (95% CI, 58/µL decrease to under Resistance) and second-line drug options between the 2 groups. 45/μL decrease), as the lower bound- treatment outcomes (Abstract 583, re- The investigators concluded that the ary of the 95% CI of the difference viewed above under Clinical Trials of additional time spent using failing regi- (62/μL decrease) was lower than that Antiretroviral Therapy in Treatment- mens in the CD4+ cell count monitor- allowed to prove noninferiority (58/μL Experienced Patients). ing group did not lead to a decrease in decrease). Thirteen patients in the Lallemant presented data from a future drug options for those patients, laboratory-monitoring group were randomized controlled trial in Thai- but they emphasized the need for ad- switched to second-line antiretroviral land, powered for noninferiority herence support and third-line regi- therapy because of treatment failure, analysis, comparing the use of CD4+ men availability in RLS. compared with none switched to sec- cell count with the use of plasma Kouanfack and colleagues asked ond-line antiretroviral therapy in the HIV-1 RNA level monitoring to dic- a similar question in Cameroon, us- clinical-monitoring group (P < .001). tate changes in antiretroviral regimen ing a randomized noninferiority trial There were comparable results in viro- (Jourdain et al, Abstract 44). Inclusion to compare laboratory monitoring logic suppression, HIV drug resistance, criteria were HIV-seropositive with (plasma HIV-1 RNA level, CD4+ cell mortality, disease progression, adher- CD4+ cell count between 50/μL and count) plus clinical monitoring every 6 ence and toxicity between the 2 groups. 250/μL, no coinfection with either hepa- months with clinical monitoring alone The investigators concluded that titis B virus (HBV) or hepatitis C virus (Abstract 45LB). Inclusion criteria were clinical monitoring was not noninfe- (HCV), and initiating NNRTI-based anti- as follows: HIV-infected, antiretrovi- rior to laboratory monitoring and that retroviral therapy. A total of 716 people ral therapy–naive adults; WHO stage switch to second-line antiretroviral were randomly assigned to CD4+ cell 3 or stage 4 disease or WHO stage 2 therapy was statistically significantly count or plasma HIV-1 RNA level moni- disease with total lymphocyte count increased in the laboratory-monitoring toring every 3 months, and the pri- less than 1200 cells/μL; and initiating group. Both conclusions support the mary endpoint was a combination of antiretroviral therapy in 1 of 9 district WHO recommendation to use labora- confirmed CD4+ cell count below 50/μL, hospitals. The primary outcome was tory monitoring in RLS. However, the new AIDS–defining event, or death. The the mean increase in CD4+ cell count authors added the caveat that, because 2 groups were well balanced for baseline after 2 years of antiretroviral therapy, of the overall limited differences be- characteristics; mean age was 36 years, and noninferiority was defined as a tween the 2 strategies, clinical moni- and median baseline CD4+ cell count difference of no more than 25% in the toring could be used within the first 2 was 144/μL. LTFU was minimal (7%) at mean increase in CD4+ cell count be- years of scale-up to allow for financial the end of the study. tween the 2 groups. and structural limitations in RLS. The risk of clinical failure was not Switch to second-line therapy was Rawizza and colleagues used a Mar- statistically significantly different be- required for the following scenarios: kov simulation model to assess the tween the 2 groups—8.3% in the viral persistent plasma HIV-1 RNA level impact of CD4+ cell count monitor- load monitoring group and 7.7% in the above 5000 copies/mL for the labora- ing compared with plasma HIV-1 RNA CD4+ cell count monitoring group— tory-monitoring group, and persistent level monitoring to determine antiret-

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roviral therapy failure on lifetime cost The second DART presentation, by monitoring in RLS. Table 2 summariz- of care and life expectancy in Nigeria Kityo and colleagues, retrospectively es these studies on monitoring strate- (Abstract 675). They used data from determined virologic response to treat- gies in RLS. 9690 HIV-infected patients receiving ment in 1164 patients who continued care through the Harvard PEPFAR/ initial antiretroviral therapy in the Mother-to-Child Transmission of AIDS Prevention Initiative in Nigeria. immunologic- or clinical-monitoring HIV Infection Using a Monte Carlo simulation, they arms of the DART trial (Abstract 677). determined that routine plasma HIV-1 The investigators found that virologic Pregnancy and Prevention of RNA level monitoring resulted in a lon- suppression (plasma HIV-1 RNA level Mother-to-Child Transmission ger per-person life expectancy than < 200 copies/mL) after a median of CD4+ cell count monitoring alone: 64 months of therapy was common Harries, as part of his N’Galy Mann 10.0 years compared with 7.1 years, (933 participants, 80%) and was as- Lecture discussed above, described a respectively. The per-person lifetime sociated with older age, female sex, proposed 2011 Malawi initiative to test cost of virologic monitoring was US and higher pre–antiretroviral therapy all pregnant women for HIV infection $13,545 versus the $12,192 per-person CD4+ cell count. However, when a and treat all who tested HIV-seropositive lifetime cost for CD4+ cell count moni- conservative estimate of overall rates for life, initially with once-daily tenofo- toring, and the incremental cost-ef- of virologic suppression was used that vir/lamivudine/efavirenz, in the hope of fectiveness ratio of virologic monitor- assumed lack of suppression for those creating a “Born HIV Free” generation ing was $467 per life-year saved. The who died or switched to second-line by 2015 (Abstract 18). The approach authors concluded that, considering antiretroviral therapy based on clinical recognizes the nation’s weak health in- the low sensitivity and specificity of or immunologic criteria, the estimated frastructure, insufficient availability of CD4+ cell count criteria for detection suppression rate at the end of the trial and capacity for CD4+ cell count mon- of virologic failure, plasma HIV-1 RNA was 54.8% (95% CI, 52.5%−57.0%). itoring, and high total fertility rate, plus level monitoring is cost-effective in Ni- The authors argued that the low rates the desire to send a simple message geria. They also concluded, however, of virologic failure in this trial, which to the community that antiretroviral that further studies are needed to de- did not monitor virologic outcomes of therapy is to be taken for life. It is an- termine the additional potential cost antiretroviral therapy, prospectively ticipated that this approach would be of the emergence of viral resistance in call into question the need for virologic simple to implement, reduce mother- patients in the CD4+ cell-count moni- monitoring in RLS. to-child transmission (MTCT), protect toring group with delayed identifica- Keiser and colleagues used data babies born in subsequent pregnan- tion of treatment failure. from the IeDEA cohort collaboration cies, improve maternal health, reduce Additional monitoring data from the to examine immunologic response to risk of tuberculosis, and provide treat- DART trial were presented. Gilks and antiretroviral therapy and mortality in ment of HBV coinfection. colleagues examined the correlation 18,706 South African patients receiv- Session 146 was also dedicated to between CD4+ cell count and virologic ing care in clinics where plasma HIV-1 plans for PMTCT of HIV. Dryden-Peter- suppression in 221 patients enrolled in RNA level monitoring is available and son and colleagues reported compel- a larger trial comparing clinical moni- in 80,937 patients from sites in Zam- ling data in support of maternal highly toring with immunologic monitoring bia and Malawi where such monitoring active antiretroviral therapy from a in Africa (Abstract 676). Overall, 15% is not available (Abstract 678). Patients prospective observational study of of those with immunologic monitoring at the virologic-monitoring sites had HIV-infected women who participated and 28% of those with clinical moni- lower CD4+ cell counts at antiretroviral in the Botswana PMTCT Programme toring had plasma HIV-1 RNA levels therapy initiation (93/μL) than patients (Abstract 740). Investigators observed below 400 copies/mL, determined ret- at sites without virologic monitoring 427 women during pregnancy. Women rospectively, at the time of diagnosis of had (132/μL; P = .001). After 3 years with CD4+ cell counts below 250/µL treatment failure by either immuno- of antiretroviral therapy, the median were treated with antiretroviral ther- logic or clinical criteria. In the clinical- CD4+ cell count was 415/μL at sites apy, and those with CD4+ cell counts monitoring group, only 7 of 82 patients with virologic monitoring and 372/μL of 250/µL or above were treated with (9%) with CD4+ cell counts of at least at sites without (P < .001). At sites with zidovudine starting at 28 weeks gesta- 250/μL at the time of switch had plasma virologic monitoring, the risks of death tion (and a single dose of nevirapine HIV-1 RNA levels below 400 copies/mL and LTFU were also lower among the if the zidovudine was taken for less The authors proposed that, by using a patients, and the likelihood of switch- than 4 weeks). All HIV-exposed babies “tie breaker” CD4+ cell count of at least ing to second-line antiretroviral ther- received single-dose nevirapine and zi- 250/μL, the majority of those switches apy was higher (aHR, 4.44; 95% CI, dovudine for 1 month. that were made based on clinical or im- 3.95−4.98). The authors conclud- Of 432 live-born babies, 262 infants munologic criteria yet occurred in pa- ed that these data, contrary to those were born to mothers taking antiret- tients with undetectable plasma HIV-1 from the DART trial reported in Ab- roviral therapy, and 170 infants were RNA level could have been avoided. stract 677 above, support virologic born to mothers taking zidovudine

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Table 2. Selected Studies Addressing the Impact of Laboratory Monitoring Strategies to Determine Antiretroviral Therapy (ART) Treatment Response in Resource-Limited Settings (RLS)

Abstract No. Location Study Design Key Findings Study Description Name of Participants Conclusions Study Definitions Abstract 44. Thailand Randomized, double- • Risk of clinical failure similar: 8.3% in HIV-1 RNA group; 7.7% in Randomized trial blind (preswitch) trial of CD4+ count group (P = .74) comparing CD4+ Perinatal HIV CD4+ count vs HIV-1 • Risk of death similar: 4.4% in HIV-1 RNA group; 3.5% in CD4+ count vs virologic Prevention RNA monitoring every 3 count group monitoring strategies Trial-3 months; • Median time to switch: 11.7 months in HIV-1 RNA group; 24.7 n = 716; initiating months in CD4+ count group (P = .001) NNRTI-based ART; • 15/31 patients in CD4+ count group switched when HIV-1 RNA median pre-ART CD4+ < 50 copies/mL count, 144/μL; mean • No statistical difference between groups in future drug options age, 36 years Follow-up: 3 years Conclusion: Rates of clinical failure were low at 3 years and did not differ between the 2 monitoring strategies, nor did CD4+ count monitoring diminish future treatment options. Abstract 45LB. Cameroon Randomized, non- • Median CD4+ count after 2 years: 182/μL in clinical group, 179/μL Randomized trial inferiority trial of clinical in laboratory-monitoring group comparing virologic, Stratall ANRS monitoring vs CD4+ • Mean increase in CD4+ count between groups did not meet criteria CD4+ count, and 12110/ESTHER count and HIV-1 RNA for noninferiority (a difference ≤ 25% between groups) clinical monitoring Trial (9 rural dis- monitoring every 6 • 13 patients in laboratory-monitoring group switched to second-line to clinical monitoring trict hospitals) months; ART, none in clinical-monitoring group alone n = 459; ART-naive; • Otherwise, comparable results in virologic suppression, HIV drug World Health Organiza- resistance mutations, mortality, disease progression, adherence, and tion (WHO) stage 3/4; toxicity between groups loss to follow-up (LTFU): 9% in clinical arm, 7% Conclusion: Clinical monitoring was not noninferior to laboratory in laboratory-monitor- monitoring; laboratory monitoring was associated with higher rates ing arm of switch to second-line ART. Authors suggest the minimal overall Follow-up: 2 years differences make 2 years of clinical monitoring feasible, but longer follow-up period is needed.

Abstracts 676, 677. Uganda, Randomized, unblinded • At time of treatment failure determination: 15% of those with CD4+ Examining virologic Zimbabwe trial of clinical moni- count monitoring and 28% of those with clinical monitoring had outcomes from a toring vs CD4+ count HIV-1 RNA < 400 copies/mL randomized trial of DART (Develop- monitoring every 12 • Only 7/82 (9%) of those with CD4+ count ≥ 250/μL at time of switch CD4+ count and ment of Antiret- weeks; had HIV-1 RNA < 400 copies/mL clinical monitoring vs roviral Therapy in n = 3315; ART-naive, • Of 1174 who remained on initial ART: 80% had HIV-1 RNA < 200 clinical monitoring Africa) trial CD4+ count < 200/μL copies/mL after a median of 64 months of ART alone Follow-up: 5 years • Authors argue that rates of virologic failure were low, and that use of Clinical failure: new a CD4+ count tiebreaker at a level ≥ 250/μL could avoid switches in WHO stage 4 event or patients with undetectable HIV-1 RNA ≥ 1 WHO stage 3 event Immunologic failure: Conclusion: Although overall rates of virologic suppression are high in CD4+ count < 100/μL those remaining on initial ART, if patients who switched or died are included as failures, rates of virologic “success” drop to 55%. CD4+ count monitoring is a potential strategy in RLS, but pitfalls exist. Abstract 678. South Africa, Retrospective cohort • After 3 years: median CD4+ count, 415/μL at sites with virologic Comparing CD4+ Zambia, Malawi South Africa (virologic monitoring and 372/μL at sites without (P < .001) count response to monitoring): n = 18,706; • Risk of death and LTFU were lower at sites with virologic monitoring ART and mortality in International pre-ART median CD4+ • Adjusted hazard ratio for switch to second-line ART was higher at programs with and Epidemiological count, 132/μL sites with virologic monitoring than those without: 4.44; 95% CI, without virologic Databases to Zambia and Malawi (no 3.95–4.98 monitoring in south- Evaluate AIDS virologic monitoring): ern Africa (IeDEA) cohort n = 80,937; pre-ART Conclusion: These data differ from those presented above in that they collaboration median CD4+ count, support a role for virologic monitoring in RLS but are limited by the 93/μL (P = .011 for dif- fact that they are drawn from an observational cohort, albeit a very ference with virologic large one. monitoring) Follow-up: 3 years

ANRS indicates French National Agency for Research on AIDS and Viral Hepatitis; ESTHER, Ensemble pour une Solidarité Thèrapeutique Hospitalière En Réseau (Network for Therapeutic Solidarity in Hospitals); HIV-1 RNA, plasma HIV-1 RNA level; NNRTI, nonnucleoside analogue reverse transcriptiase inhibitor.

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alone. A total of 10 infants were infect- antiretroviral therapy were 3 times sented compelling data in support of ed with HIV. Only 1 HIV-infected infant as likely to become antiretroviral postexposure prophylaxis (PEP) with (0.4%; 95% CI, 0.01%−2.3%) was born therapy–eligible within 24 months as 2- or 3-drug antiretroviral regimens in- to a woman taking antiretroviral ther- women receiving short-course anti- stead of zidovudine alone for preven- apy, compared with 9 HIV-infected in- retroviral prophylaxis (HR, 3.37; 95% tion of intrapartum HIV transmission fants (5.9%; 95% CI, 2.7%−10.9%) born CI, 1.96−5.79; P < .001). The authors to infants born to women not receiv- to women taking zidovudine alone urged consideration of lifelong antiret- ing antiretroviral therapy before labor (P< .001). Thai investigators Phanuphak roviral treatment for pregnant women (Abstract 124LB). Babies of mothers and colleagues also reported excel- with CD4+ cell counts less than 500/µL. not receiving antiretroviral drugs were lent safety and efficacy of maternal tri- identified at labor or postpartum. In ple-drug antiretroviral therapy regard- Mother-to-Child Transmission and this international study, babies were less of maternal CD4+ cell count from Breast-feeding randomly assigned within 48 hours of the Thai Red Cross PMTCT Program birth to 1 of 3 groups: zidovudine alone from 2004 to 2010. The transmission Maldonado presented HIV Prevention for 6 weeks; zidovudine for 6 weeks rate to babies was 1% (Abstract 742). Trials Network (HPTN) 046 data com- plus nevirapine for 3 doses in the first Ciaranello and colleagues modeled paring an extended course of daily week; or zidovudine for 6 weeks plus combinations of treatment options nevirapine for infants through age 6 lamivudine and nelfinavir for 2 weeks. within the context of scale-up of ante- months with 6 weeks of nevirapine All babies were formula-fed, and fol- natal care that could result in virtual for postnatal prevention of HIV infec- low-up continued until 6 months. elimination of MTCT in Zimbabwe and tion acquired through breast-feeding Of the 1684 babies included in the predicted that an approach stratified (Coovadia et al, Abstract 123LB). Af- analysis, 8.3% overall were infected, by CD4+ cell count could reduce MTCT ter 6 weeks of daily nevirapine, 1522 with 5.5% infected in utero and 2.8% in- to near or less than 5% (Abstract 739). breast-feeding infants were randomly fected intrapartum. Intrapartum infec- Mothers who have a CD4+ cell count assigned to either continuation of daily tion in the zidovudine-alone group oc- less than 350/µL would be treated with nevirapine or placebo until 6 months curred in 4.9%, compared with 2.2% in antiretroviral therapy, and mothers postpartum. At randomization, 29% the zidovudine-plus-nevirapine group who have a count greater than 350/µL of mothers in each group were re- (P = .045) and 2.5% in the zidovudine- would receive short-course zidovudine ceiving antiretroviral therapy for their plus-lamivudine-and-nelfinavir group during pregnancy and extended nevi- own health; at 6 months, this amount (P = .034). In addition to the associa- rapine treatment for the infant during increased to 31% in the extended- tion with treatment regimen, maternal breast-feeding. In a talk dedicated to nevirapine group and 32% in the pla- viral load was associated with trans- applying principles of cost-effective- cebo group. mission on multivariate analysis. There ness to HIV care programs, Walensky At 6 months, the rate of HIV infection was statistically significantly more addressed the issue of PMTCT and cost- was statistically significantly lower in neutropenia in the zidovudine-plus- effectiveness, reporting that effective the extended-nevirapine group (1.1%) lamivudine-and-nelfinavir group (15%; programs for PMTCT are often associ- than in the placebo group (2.4%; P = P < .0001) than in the other 2 groups. ated with cost savings (Abstract 74). .048); however, this difference was not For infants born to HIV-infected moth- Ekouevi and colleagues reported observed at 9 months or 12 months. ers not receiving antiretroviral drugs, on maternal HIV disease progression Stratification by maternal antiretro- investigators suggested administering after the interruption of triple-drug viral therapy status showed a very low 2- or 3-drug antiretroviral treatment antiretroviral therapy or short-course rate of infant transmission (0.2%) at 6 within 48 hours of birth for infants antiretroviral treatment for PMTCT us- months for the mothers receiving treat- rather than zidovudine alone. ing data from 13 programs in Africa ment compared with the mothers not In an effort to identify maternal anti- and Thailand from the MTCT-Plus Ini- receiving antiretroviral therapy (2.4%; retroviral regimens that would still pre- tiative (Abstract 753). Among 1027 P = .027). For mothers not receiving vent infection to infants but would pos- HIV-infected pregnant women with antiretroviral therapy, there was a sta- sibly be less toxic to the mother and CD4+ cell counts greater than 400/µL, tistically significant difference in infant child during treatment, the Primeva/ investigators compared rates of CD4+ HIV infection at 6 months (1.4% for ANRS 135 trial studied maternal treat- cell count decline according to PMTCT infants receiving extended nevirapine ment with lopinavir/r monotherapy treatment: antiretroviral therapy (n = vs 3.4% for infants receiving placebo; compared with lopinavir/r plus zidovu- 113; 11%), single-dose nevirapine (n = P = .027). There were no differences dine/lamivudine (Abstract 125LB). A 444; 43.2%), short-course antiretro- in mortality or serious adverse events total of 105 women were randomly as- viral prophylaxis (n = 353; 34.4%), or between the extended-nevirapine- and signed in a 2:1 ratio to begin lopinavir/r no prophylaxis (n = 117; 11.4%). After placebo-treated infants. monotherapy (n = 69) or treatment adjusting for age, country, CD4+ cell Nielsen-Saines, on behalf of the with lopinavir/r plus zidovudine/lami- count, and WHO stage of disease at HPTN 040/PACTG (Pediatric AIDS vudine (n = 36; control group) at 26 enrollment, women who received Clinical Trials Group) 1043 study, pre- weeks’ gestation; follow-up continued

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until 12 weeks postpartum. All babies Eshleman and colleagues reported HIV transmission, compare the risk were treated postpartum with 4 weeks on the use of a multiassay algorithm of CMV infection in HIV-infected and to 6 weeks of zidovudine and observed to determine recency of HIV infec- -uninfected mothers, and examine risk for 24 months. Changes of antiretrovi- tion in pregnant women in the PEPI factors for CMV transmission in HIV- ral drugs because of intolerance were (Postexposure Prophylaxis for Infants)- infected infants. Women and infants statistically significantly less frequent Malawi trial (Abstract 737). Subjects who had participated in a clinical trial in the monotherapy group (1.4%) than were 2561 women enrolled in the PEPI- for PMTCT in Thailand were included in the control group (11.1%; P = .046). Malawi trial who were in labor; their in the study. Ninety-seven HIV-infected Based on an intention-to-treat analy- infants were randomly assigned to 1 of infants were matched 1:2 with HIV- sis, the primary endpoint of plasma 3 postnatal infant regimens. A multi- uninfected infants by baseline mater- HIV RNA level below 200 copies/mL assay algorithm was performed within nal viral load. CMV infection was de- at week 8 of treatment was achieved 3 days of delivery on samples from all termined by CMV IgG antibody testing at comparable rates in both groups: women; 73 women were identified as at 18 months and timed by CMV IgM 88.4% of women receiving monother- having been recently infected. The risk antibody testing or CMV DNA detec- apy and 94.4% of control women (P = of in utero transmission of HIV was tion in plasma or blood at birth and .5). Monotherapy patients had statis- found to be 17.9% among women re- thereafter. tically significantly less viral suppres- cently infected and 6.7% in women CMV infections were more common sion (plasma HIV RNA level < 50 cop- whose infection was not recent. in HIV-infected infants than in HIV- ies/mL) at delivery (79.7% vs 97.2% in Several other abstracts examined uninfected infants: congenital (14% vs controls; P = .01). Of the 105 children risk factors for MTCT. Tubiana and col- 3%, respectively), intrapartum (41% vs born, there was 1 case of transmission leagues reported extremely low risk of 28%, respectively), acquired (80% vs in the control group and none in the MTCT of HIV in women starting anti- 63%, respectively), and overall (84% monotherapy group. Studies of geno- retroviral therapy before pregnancy in vs 63%, respectively). CMV infection toxicity, mitochondrial toxicity, cardiac the French Perinatal Cohort (Abstract in utero was associated with increased toxicity, and hematologic toxicity in in- 735). Nearly 6000 women enrolled in odds of intrauterine HIV infection (OR, fants are ongoing. the ANRS French Perinatal Cohort were 8.1; P = .01). Intrapartum HIV infection included in the analysis of HIV trans- was associated with both congenital Risk of HIV Transmission During mission risk and stratified according and intrapartum CMV infection (OR, Pregnancy to when their antiretroviral treatment 2.5; P = .04). Overall, HIV infection was was initiated. The HIV transmission associated with CMV infection (OR, John-Stewart gave a presentation on rate was 0.5% if treatment had begun 2.9; P = .001). In HIV-infected infants, transmission risk in pregnancy in before conception, 0.6% if initiated in the risk of CMV infection was statisti- which she discussed risk of acquiring the first trimester, 1.2% if initiated dur- cally significantly associated with pre- HIV infection during pregnancy and ing the second trimester, and 2.6% if maturity, intrapartum HIV infection, postpartum, specific issues related to initiated after 28 weeks. When the ma- and vaginal delivery. the pregnancy and postpartum peri- ternal plasma HIV-1 RNA level was less ods, and strategies for HIV prevention than 50 copies/mL at delivery, the trans- Effects of Antiretroviral Therapy during and after pregnancy (John- mission rates dropped to 0%, 0%, 0.5%, During Pregnancy on Infant Health Stewart et al, Abstract 67). Biological and 0.8% in the 4 strata, respectively. changes associated with pregnancy French and colleagues looked at the Sessions 147 and 148 were dedicated may put pregnant women at higher effect of subsequent pregnancies on to understanding the effect of anti- risk of HIV infection. Examples in- MTCT risk (Abstract 736). In review- retroviral exposure during the perinatal clude hormonal changes, immune ing 9807 pregnancies in HIV-infected period on infant health. Two studies re- activation, and changes in the genital women in the United Kingdom and ported on PI use and preterm delivery. mucosa. In some studies, pregnancy Ireland, monitored through the Na- Sibiude and colleagues reported find- and lactation have been identified as tional Study of HIV in Pregnancy and ings from a retrospective analysis of cofactors influencing risk of HIV infec- Childhood, they found no evidence of 13,957 singleton pregnancies in HIV- tion. John-Stewart reported historical an increased risk of MTCT in subse- infected women of the ANRS French data from Rwanda, which indicate that quent pregnancies. Cohort from 1990 to 2009 (Abstract the risk of transmission to infants from Khamduang and colleagues pre- 743). The authors reported steadily mothers with acute HIV infection (up to sented data on the interrelated trans- increasing rates of preterm delivery 29%) is higher than transmission rates mission of HIV-1 and cytomegalovirus from 9.2% (1990−1993: no anti- for women with chronic HIV infection (CMV) during gestation and delivery retroviral therapy available) to 9.6% (16%). As PMTCT becomes more effec- in the children of HIV-infected moth- (1994−1996: zidovudine available), tive, the proportion of HIV infections in ers (Abstract 122). Investigators sought 12.4% (1997−1999: double-nRTI ther- children of mothers with acute HIV in- to understand the timing of CMV apy and some multiclass antiretro- fection is expected to rise substantially. transmission and its relationship to viral therapy available), and 14.3%

89 IAS–USA Topics in Antiviral Medicine

(2005−2009: routine combination Statistically significantly more deaths malization with age. Furthermore, an antiretroviral therapy available). Analy- occurred in mothers and infants af- inverse relationship between complex sis also revealed that for women not ter weaning and antiretroviral therapy IV activity and mitochondrial DNA receiving treatment at the time of cessation at 6 months than occurred levels was observed at all time points. conception and who initiated PI treat- during treatment. The authors urged The authors suggested that mitochon- ment during pregnancy, the rate of a higher threshold for continuous ma- drial DNA levels may be upregulated in preterm delivery was higher in those ternal antiretroviral therapy and fur- an effort to compensate for antiretro- treated with a PI/r regimen than in ther evaluation of optimal weaning viral drug–related organelle damage. those treated with a PI alone (14.4% vs strategies. Williams and colleagues presented 9.1%, respectively; aHR, 2.0 [1.1−3.9]; Storfer and colleagues examined reassuring findings on a lack of asso- P = .03). the risk of birth defects in children ciation between in utero antiretroviral Powis and colleagues also reported exposed to nevirapine according to drug exposure and late language emer- an association between PI use and the trimester of first exposure in the gence in HIV-uninfected children born preterm delivery from a randomized Antiretroviral Pregnancy Registry and to HIV-infected women (Abstract 751). control trial of 530 women comparing compared risks to those of external PI-based antiretroviral treatment with control subjects from 1989 to 2010 Mother-to-Child Transmission and triple-nRTI antiretroviral treatment (Abstract 749). Investigators reported Resistance for PMTCT (Abstract 746). In contrast, on 2327 nevirapine-exposed pregnant González-Tomé and colleagues report- enrollees in the Registry, of whom 970 Foulongne and colleagues reported on ed no association between any kind were exposed to nevirapine in the first the issue of drug resistance in pregnant of antiretroviral regimen and preterm trimester (1001 babies) and 1182 were women in the Kesho Bora trial in South delivery in a multicentre cohort of HIV- exposed starting in the second or third Africa (Abstract 758). This study was a infected pregnant women in Spain trimester (1201 babies). There was no randomized controlled trial comparing from 2000 to 2008 (Abstract 744). Of association of birth defects with first- use of triple-drug antiretroviral therapy 803 babies born, 21% were born pre- trimester exposure or with nevirapine during pregnancy through the breast- term, and 53% of mothers received a exposure in general. feeding period with use of zidovudine PI-containing regimen. Important fac- Two abstracts looked at the ef- plus single-dose nevirapine treatment tors that were associated with preterm fects of antiretroviral drug exposure stopping at delivery. The rate of resis- birth in this cohort were illicit drug use, on HIV-uninfected children of HIV- tance mutations present at follow-up HCV coinfection, lack of antiretroviral infected mothers. Noguera-Julian and was 25% in the zidovudine plus sin- therapy, and older maternal age. colleagues reported lower mitochon- gle-dose nevirapine group and 0% in drial-encoded complex IV activity in the triple-drug antiretroviral therapy Effects of Antiretroviral Therapy antiretroviral drug–exposed, HIV-unin- group. Additional analysis of resistance During Pregnancy on Child Health fected healthy infants from a prospec- in infants is planned. Outcomes tive observational study of 135 HIV- WHO guidelines recommend a uninfected, antiretroviral drug–ex- brief course of antiretroviral treatment Shapiro and colleagues showed an as- posed babies (Abstract 750). Mito- (a “tail”) for women after single-dose sociation between increased maternal chondrial DNA was measured using nevirapine treatment for PMTCT. Two and infant mortality after completion quantitative real-time PCR, and mito- abstracts presented data in favor of of antiretroviral therapy and breast- chondrial respiratory chain enzymatic this practice. McMahon and colleagues feeding at 6 months postpartum in a activity of complex IV and mitochon- found a trend toward superior out- randomized control trial of PMTCT in drial mass were assessed from PBMCs comes in prevention of emergence of Botswana, the Mma Bana Study (Ab- obtained at 6 weeks and at months 3, resistance after single-dose nevirapine stract 747). A total of 560 pregnant, 6, and 12. The control group included administration for PMTCT with a 21- HIV-infected women were randomly healthy infants of women with HCV in- day tail compared with a 7-day tail of assigned to either a triple-nRTI regi- fection (n = 32). A total of 87% of study either tenofovir/emtricitabine, zidovu- men or lopinavir/r plus zidovudine/la- women received antiretroviral therapy dine/lamivudine, or lopinavir/ritonavir mivudine initiated at 26 weeks to 34 for a median of 34 weeks, followed by (Abstract 759). Ngo-Giang-Huong and weeks gestation and continued until intravenous zidovudine at delivery. colleagues showed that 1 week of treat- weaning at 6 months postpartum. An Although no infant had clinical evi- ment with zidovudine plus lamivudine observational group included 170 HIV- dence of mitochondrial disease, and after exposure to single-dose nevirap- infected women who began continu- mitochondrial mass was similar in ine virtually eliminated the emergence ous antiretroviral therapy because of control and observational groups, the of nevirapine resistance mutations at low CD4+ cell counts and received ne- complex IV activity was statistically 7-day, 10-day, and 1-month follow-up virapine plus zidovudine/lamivudine. significantly lower in the antiretro- analysis of 117 women who partici- Mortality data were collected on all 730 viral drug–exposed children at all time pated in the Thai PHPT (Perinatal HIV women and their 709 live-born infants. points. There was a trend toward nor- Prevention Trial)-5 (Abstract 760).

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Fogel, on behalf of colleagues in the any resistance, 5% NNRTI resistance, mainly to NNRTIs (12%) and some to PEPI-Malawi Study, reported cases of 2.7% nRTI resistance, 2% double-class nRTIs (7%). No surveys showed mod- multidrug-resistant HIV infection de- resistance, and 0.5% PI resistance; erate levels of PI resistance, but all re- tected in breast-feeding infants whose 77% had subtype-C HIV. The most ported low levels. Bertognolio pointed mothers began antiretroviral therapy common mutations were Y181/C/I, out those geographic areas with mod- postpartum (Abstract 761). Infant HIV K103N/S, and M184I/V. Of the 128 in- erate resistance that warrant addition- genotypic analyses were available for dividuals for whom antiretroviral ther- al attention. 37 HIV-infected babies whose mothers apy failed at 12 months, 67% had any Additional abstracts dedicated to initiated postpartum treatment with drug resistance, 65% had NNRTI resis- understanding resistance across the stavudine, lamivudine, and nevirapine. tance, 55% had nRTI resistance, 55% globe were presented in Session 119 Thirty (81.1%) of the 37 infants had had double-class resistance, and 3% (Abstracts 619−626). Dross and col- NNRTI resistance, and 11 (29.7%) of had any PI resistance. The most com- leagues illustrated the impact of TDR the infants had multiclass resistance. mon mutations conferred resistance to on antiretroviral efficacy, reporting on Earlier postpartum antiretroviral thera- nevirapine, efavirenz, and lamivudine. nevirapine- and lamivudine-resistant py use was statistically significantly as- The authors noted that a statistically HIV-1 detected in antiretroviral ther- sociated with multiclass resistance (P significant proportion of patients also apy–naive Kenyans initiating NNRTI- = .0009). This was observed only in in- had 3 or more thymidine analogue– based antiretroviral therapy (Abstract fants who were exclusively breast-fed. associated mutations (TAMs) (4.7%) 620). Of 400 treatment-naive adults and the K65R mutation (5%). Such who began nevirapine-based antiret- Resistance mutations would negatively impact roviral therapy, 42 had virologic failure effectiveness of the second-line regi- at follow-up. Genotypic testing of base- Resistance in Resource-Limited mens that contain tenofovir or zidovu- line blood samples showed mutations Settings dine. Of patients who were retained in associated with nevirapine resistance care and alive, 90% had viral load sup- or with lamivudine resistance in 26% As part of global antiretroviral therapy pression (plasma HIV RNA level < 1000 of patients with virologic failure. scale-up, the WHO recommends pro- copies/mL), which dropped to 70% Yang and colleagues reported on grammatic assessment informed by when including LTFU and patients dis- the global surveillance of TDR in 330 surveillance of acquired drug resistance continuing treatment in the analysis. plasma or dried blood spot samples (ADR) and transmitted drug resistance A total of 75% of clinics were able to from PEPFAR-supported countries in- (TDR) to help inform best practices and meet a goal of having 70% of patients cluding Botswana, China, Kenya, Ma- minimize emergence of HIV drug resuppressed at 12 months. These re- lawi, Tanzania, and Vietnam (Abstract sistance. Bertagnolio, on behalf of the sults are similar to resource-rich-set- 619). All sites showed TDR of less than WHO, reported on 2 major surveillance ting cohorts. The authors pointed out 5% except for the site in Ho Chi Minh initiatives from RLS (Abstract 52). The that, given the patterns of resistance, City, which had a moderate level of re- ADR report consisted of surveys from a second-line regimen including PI/r sistance (5%−15%). The authors urged 16 resource-limited sites from 2002 plus tenofovir or zidovudine should be further understanding of this concern- to 2010. The survey results represent effective at the population level. ing trend. 2150 patients who initiated antiret- Bertagnolio and colleagues also re- Rates of TDR in Kampala, Uganda roviral therapy (and were either treat- ported surveys of TDR in recently in- (Abstract 621), and Mexico City (Ab- ment naive or experienced at initiation) fected, antiretroviral therapy–naive stract 623) were also reported to be at 15 sites in Burundi, India, Malawi, populations. Age less than 24 years, moderate at 5% to 15%, whereas in- Mozambique, and Nigeria. Nearly three- first pregnancy, first HIV risk–defin- vestigators from Brazil reported rates fourths of patients were taking stavudine/ ing event within the past 3 years, and of TDR ranging from moderate to high lamivudine/NNRTI (74%), 22% were tak- CD4+ cell count greater than 500/µL (> 15%) in some areas (Abstract 624). ing zidovudine/lamivudine/NNRTI, 3.2% were used as surrogates for recent in- Hamers and colleagues compared were taking tenofovir/lamivudine/ fection. Results represent geographic rates of drug resistance to year of anti- NNRTI, and 0.8% used other regimens. areas as opposed to specific clinics or retroviral therapy scale-up in sub-Saha- A total of 90% of patients had virologic nations. There were 41 surveys from ran Africa. Earlier year of scale-up was suppression (HIV RNA level <1000 20 countries during 2005 to 2007. The more strongly associated with preva- copies/mL) at 12 months. There were majority of surveys were from sites in lence of drug resistance (Abstract 622). 128 patients (10%) in whom genotypic Africa, Asia, and Mexico. Truncated se- analysis was performed because of quential sampling was used to classify Viral Load Monitoring in Resource- a plasma HIV RNA level greater than prevalence of TDR as low (less than Limited Settings 1000 copies/mL at 12 months. Analy- 5%), moderate (5%−15%), or high (> sis of patients with baseline genotyp- 15%). The results showed that 81% of Reynolds and colleagues reported on ic testing results (n = 1503) revealed sites had low levels of TDR and 17% of the effect of routine viral load moni- the following resistance pattern: 6% sites showed moderate levels of TDR, toring on the rate of accumulated

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genotypic evidence of resistance to Nonnucleoside Analogue Reverse antiretroviral therapy in the SMART commonly used antiretroviral drugs in Transcriptase Inhibitor Resistance (Strategies for the Management of Anti- Uganda (Abstract 53). A cross-section- retroviral Therapy) study (Abstract al, observational study in infectious Session 114 was dedicated to new in- 596). They compared virologic out- diseases clinics of Kampala, Uganda, sights in resistance to NNRTIs. In an comes with respect to the modality compared a cohort of 559 antiretrovi- effort to explain the association of the of treatment interruption, Cytochrome ral-naive patients who had CD4+ cell E138K rilpivirine-associated muta- P450 2B6/constitutive androstane re- count and viral load monitoring every tion with the M184I mutation (rather ceptor (CYP2B6/CAR) host genotype, 6 months with 998 clinic patients who than M184V), Hu and Kuritzkes cre- NNRTI clearance rates, and pres- had been receiving antiretroviral ther- ated recombinant viruses carrying ence of drug resistance mutations as apy and had CD4+ cell count monitor- E138K plus M184I or M184V muta- detected by allele-specific PCR and ing only. Viral load monitoring was per- tions and compared relative infectivity ultra-deep sequencing. Of the 132 sub- formed at the end of 36 months to 40 and fitness profiles (Abstract 594). The jects who underwent interruption of months in all patients in the CD4+ cell E138K/M184I virus had higher relative an NNRTI-based regimen (60.6% with count-only group, and genotypic anal- infectivity than the E138K/M184V re- efavirenz, 38.6% with nevirapine, and ysis was also performed if the plasma combinant in the presence of a second- 0.8% with delavirdine), 63 discontin- HIV RNA level was greater than 2000 generation NNRTI. Drug-susceptibility ued nRTIs and the NNRTI simultane- copies/mL. In the viral load–monitor- data showed that the E138K/M184I ously, and 69 either continued nRTIs ing group, viral loads were assessed at virus also had a greater fold-increase alone or switched to nRTIs plus a PI. months 12, 24, and 36, with genotypic in the IC50 for etravirine, efavirenz, and Median plasma nevirapine levels were testing of patients with levels exceed- lamivudine than the E138K/M184V vi- 0.96 ng/mL (IQR, 0.5−3.2 ng/mL) af- ing 2000 copies/mL. Mutations were rus. The authors concluded the E138K/ ter a median of 32 days and 16 ng/mL classified according to the IAS–USA M184I combination confers a mean- (IQR, 9−55 ng/mL) for efavirenz after panel listing36 and the Stanford Uni- ingful replication advantage and high- a median of 30 days. versity HIV Drug Resistance Database er levels of resistance to etravirine and The CYP2B6/CAR genotype was pre- (www.hivdb.stanford.edu). lamivudine compared with the E138K/ dictive of efavirenz concentrations, At 36 months, the viral load–moni- M184V double-mutant. This may ex- with the highest levels observed in toring group showed 57% resistance to plain why the E138K/M184I combi- the TT/CC profile (P = .02). Major nRTI NNRTI; 43% had the M184V mutation, nation was observed in patients with resistance was detected in 20% of pa- 7% had K65R, and 7% had a single TAM. virologic failure in trials of rilpivirine. tients and major NNRTI resistance was The immunologic-monitoring group Mackie and colleagues examined detected in 11% of patients by bulk se- showed 90% resistance to NNRTI; 87% the prevalence and clinical importance quencing and slightly more by allelle- had the M184V mutation, 1% had the of baseline polymorphisms in antiret- specific PCR, 24% and 16%, respec- K65R mutation, 43% had a single TAM, roviral-naive subjects initiating NNRTI- tively. Although 81% of patients with 23% had 2 TAMs, and 10% had 3 or based antiretroviral therapy (Abstract suppressed viremia who interrupted more TAMs. Viral load monitoring was 595). Baseline genotypic testing re- and then restarted NNRTI-based anti- associated with reduced resistance in sults were obtained from the UK HIV retroviral treatment regained viral sup- all categories. The most dramatic re- drug resistance database and linked to pression, 19% did not. Predictors of duction in resistance mutations in the clinical cases. There were 2058 sub- virologic suppression at 12 months to viral load–monitoring group was in the jects included in the analysis, of whom 18 months after restarting antiretrovi- TAMs. Only 23% of the participants in 1704 initiated efavirenz-based antiret- ral treatment included simultaneous the viral load–monitoring group had roviral regimens and 354 initiated ne- interruption of antiretroviral therapy 4 or more etravirine mutations, com- virapine-based therapy. Reverse tran- (as opposed to stagger-switch), longer pared with 40% in the immunologic- scriptase polymorphisms of interest in- duration of treatment interruption, monitoring group. cluded those on codons 90 to 108, 135 and older age. The authors issued cau- The additional resistance that accu- to 138, 179 to 190, and 225 to 348. tion regarding the risk of resistance mulated during immunologic monitor- A total of 40% of subjects were identi- with treatment interruptions, suggesting has implications for the effective- fied as having at least 1 polymorphism ing the use of stagger-switch methods ness of second-line regimens. Gupta at baseline. Neither single nor double rather than simultaneous interruption. and colleagues echoed these findings, polymorphisms had an effect on plas- They proposed additional studies to showing a rapid accumulation of TAMs ma HIV RNA level reduction at week better understand the possible utility in the absence of viral load monitoring 4 or on achieving a plasma HIV RNA of CYP2B6/CAR genotypic testing as a with nevirapine-based or triple-nRTI level less than 200 copies/mL at week predictor of delayed NNRTI clearance. regimens. This information has serious 24 compared with wild-type virus. Cozzi-Lepri and colleagues reported implications for the use of zidovudine, Geretti and colleagues analyzed the an analysis of predictors of virologic abacavir, or tenofovir in second-line virologic outcomes of patients who in- response to etravirine-containing anti- antiretroviral regimens (Abstract 618). terrupted and restarted NNRTI-based retroviral regimens in the EuroSIDA

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cohort (Abstract 598). There were bility to darunavir compared with the N-terminal domain and second extra- 320 patients identified as having ini- parental AG virus. cellular loop (ECL2), suggesting that the tiated etravirine-containing antiretro- Larrouy and colleagues reported resistant envelope may have adapted viral regimens from 2001 to 2009, of on the positive impact of the HIV-1 to utilize drug-bound receptor by more whom 68% had at least 1 genotypic gag CS A431V mutation on virologic efficient utilization of the N-terminus test before treatment. Expert-based response to darunavir/r in treatment- and ECL2 regions of the CCR5. interpretation of resistance was calcu- experienced patients (Abstract 604). Similarly, Jubb and colleagues also lated based on the 3 most frequently The A431V gag CS mutation was as- described how maraviroc-resistant vi- used expert calculations for resistance: sociated with short-term virologic re- ruses use the ECL2 and the N-terminal the ANRS score (http://www.hivfrench sponse. The investigators hypothesized domain of CCR5 (Abstract 590). Svi- resistance.org), the Stanford University that a specific gag CS mutation might cher and colleagues showed an asso- database score (http://hivdb.stanford. not have the same impact on virolog- ciation between dual tropism and sig- edu/), and the Rega score (http:// ic outcome, according to the PI used, nature mutations in the V3 bridging regaweb.med.kuleuven.be/) as well as and could have a direct impact on sheet domain of HIV-1 gp120 and how 2 etravirine-specific scores developed PI susceptibility in an inhibitor-specific these mutations modulate the interac- by the commercial firms Tibotec and manner. tion at the CCR5 N-terminus (Abstract Monogram. Depatureaux and colleagues re- 591). The study analyzed 498 V3 and There were 399 person-years of ported on protease-region resistance 242 gp120 sequences from 740 HIV-1 follow-up and 42 cases of virologic mutations in the highly diverse HIV-1 subtype B–infected patients from the failure (10.5/100 person-years; 95% CI, group O in both treatment-naive and Los Alamos Database. Three V3 deter- 7.7−14.0 per 100 person-years). The on-treatment individuals infected with minants—T2M, I26R, and I12V—were ANRS score was the only interpreta- HIV-1 group O virus (Abstract 605). statistically significantly associated tion instrument that was statistically Logistic regression analysis revealed a with phenotypically defined dual tro- significantly associated with risk of statistically significant association with pism. These determinants occurred in virologic failure caused by resistance. lopinavir/r treatment and the following negligible amounts in pure R5 and X4 An increased risk of failure was ob- mutations: I15I, G48M, L63K, and T74S viruses (0%, 0%, and 2%, respectively) served for patients with K101E, and (P < .005). but at much higher rates in dual-mixed the K103N mutation was indepen- virus (9.3%, 4.9%, and 14.2%, respec- dently associated with a reduced risk CC Chemokine Receptor 5 Antagonist tively; P < .001). The mutations I12V of failure. The authors pointed out the Resistance and I26R both decreased N-terminus uncertainty in predictions of antiviral binding affinity for gp120. activity for etravirine in clinical prac- Session 113 was dedicated to corecep- Other mutations associated with tice and urged further elucidation of tor usage and resistance to CCR5 in- dual-mixed virus outside the V3 loop the possible relationship between the hibitors. Putcharoen and colleagues include T102S, M105V, and R398Q, K103N mutation and etravirine hyper- described kinetics and mechanism of all of which are in the gp120 bridg- susceptibility. resistance of vicriviroc-resistant HIV-1 ing domain. These mutations were subtype B clinical isolates from sub- present at 15.8%, 16.7%, and 33.3%, Protease Inhibitor Resistance jects in the ACTG 5211 trial (Abstract respectively, in dual-mixed virus, com- 589). Pseudoviruses were constructed pared with less than 3% in pure R5 or Novel insight into the emergence of that expressed cloned or uncloned X4 virus. The authors pointed out that drug resistance mutations in protease HIV-1 envelope obtained at baseline dual-tropic viruses represent HIV spe- was the subject of Session 115 (Ab- and at virologic failure in 3 subjects in cies that are structurally different from stracts 599−605). Fun and colleagues whom resistance to the investigational pure R5 and X4 viruses, as opposed to presented data on how the genetic bar- drug vicriviroc emerged. Resistant vi- being just a mixture. rier to resistance is decreased by gag ruses had slower entry kinetics than Coakley and colleagues described polymorphisms (Abstract 603). The wild-type virus, and in the presence a comparison between V3-sequen- investigators performed in vitro selec- of the investigational small-molecule cing-based prediction and corecep- tions with molecular clones of HIV sub- coreceptor antagonist TAK-779, the en- tor tropism as determined by an en- types B, C, and AG in the presence of try kinetics were restored to wild-type hanced-sensitivity coreceptor tropism increasing darunavir concentrations, level, suggesting that vicriviroc-resis- assay (Monogram Biosciences) (Ab- and they monitored gag and protease tant viruses use drug-bound CCR5 for stract 592). Both tests were performed genes over time. The investigators re- entry. Vicriviroc-resistant virus was also on 4 distinct patient groups: an HIV ported that in 5 of 5 cultures with HIV shown to be cross-resistant to maravi- acute-seroconversion cohort (n = 69), subtype AG, a mutation occurred at the roc and TAK-779. Additionally, the au- an early-treatment-naive cohort (n = NC/p1 cleavage site at gag codon 437. thors showed how vicriviroc-resistant 271), a treatment-naive cohort of The gag 437 mutation corresponds viruses are inhibited by monoclonal participants in ACTG 384 (n = 221), and with a 5- to 7-fold decreased suscepti- antibodies directed against the CCR5 a late-treatment-experienced group

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(n = 587). Compared with the en- grases containing the mutation T97A Of those tested, 58 seroconversions hanced-sensitivity tropism assay, V3 alone or with Y143C/R (Abstract 606). occurred in the placebo group and 33 sequencing showed increasing sen- Site-directed mutagenesis experiments in the emtricitabine/tenofovir (PrEP)- sitivity with disease stage: 18%, 34%, were performed on expression vectors treated group. The majority of HIV 43%, and 62%, respectively, in the 4 harboring the integrase gene, and the subtypes were B. Minor resistance- patient groups. There was also a strong T97A mutation was introduced. Both associated mutations were detected in inverse correlation of average sensitiv- wild-type and mutated integrase genes 2 samples from the placebo group: 1 ity compared with CD4+ cell count were expressed in bacteria and puri- with K65R and the other with M184V. (R2 = −.98; P = .01). The authors con- fied. Strains were studied in the pres- There were no minor variant muta- cluded that V3 sequencing for predic- ence and absence of raltegravir. Virus tions in any of the seroconversions tion of CXCR4 virus in treatment-naive with the T97A mutation alone was as from the treatment group. Most of the individuals is inadequate, given its lack susceptible as wild-type virus, but the seroconversions in the PrEP group did of sensitivity in this group. combination of T97A and Y143C or not have positive PrEP-drug levels, and The role of ultra-deep sequencing in Y143R resulted in severely impaired the 3 subjects with detectable drug had the use of maraviroc was explored by susceptibility to raltegravir compared extremely low levels and did not show Heera and colleagues (Abstract 593). with Y143C or Y143R alone. This find- minor drug-resistant variants. There Ultra-deep sequencing was performed ing is consistent with previous clinical were 3 individuals who were HIV- on specimens from treatment-experi- observations. seronegative at entry but later found to enced patients who participated in the Huang and colleagues also looked be undergoing acute HIV infection, of combined maraviroc-treated groups of at integrase codon 143. Using iso- whom 2 were from the PrEP arm: 1 the MOTIVATE (Maraviroc Versus Opti- lates from virus submitted for drug found to have an M184V mutation and mized Therapy in Viremic Antiretrovi- resistance testing, the authors identi- the other an M184I mutation. In these ral Treatment–Experienced Patients) fied and studied 75 viruses contain- 2 individuals, the mutant subpopula- trials, of whom 674 patients had been ing amino acid substitutions (Abstract tions became undetectable by popu- identified as having R5 virus and 215 607). In addition to the well-known lation sequencing by 9 weeks and 12 as having non-R5 virus by the original Y143R/C mutations, Y143H/G/S muta- weeks after discontinuing PrEP. coreceptor tropism assay (Monogram tions were also identified. Fold-change Biosciences). Both the relative percent- in susceptibility with Y143R was 25 Viral Load Monitoring and Resistance age of X4 virus and the absolute count and fold-changes with any of the other Testing of virus were determined via ultra- substitutions ranged from 2 to 8. Apart deep sequencing. Multivariate analysis from Y143R, all the other substitu- Metzner discussed the current state-of- of predictors of achieving a plasma HIV tions required secondary mutations to the-art and future directions for viral RNA level of less than 50 copies/mL confer large reductions in raltegravir load assays, drug resistance mutations at 48 weeks revealed that baseline susceptibility. testing, and the goal of expanded ac- CD4+ cell count, activity of back- cess to technology for RLS (Abstract 72). ground drugs, and the absolute X4 vi- Preexposure Prophylaxis and With regard to viral load detection, the ral load by ultra-deep sequencing were Resistance increasing sensitivity of commercially independent predictors of long-term available assays to a detection level of maraviroc responses. Patients with PrEP was covered extensively at the 20 copies/mL, or perhaps in the future X4 HIV RNA levels of less than 5300 conference. Resistance in the context to 1 copy/mL, raises questions about copies/mL had a response rate of 65%, of PrEP during the iPrEx (Chemopro- the importance of low-level viremia at which increased to 71% if the CD4+ phylaxis for HIV Prevention in Men) different levels in relation to risk of re- cell count was greater than 70/μL. study was examined by Liegler and sistance, need for antiretroviral drug ad- Other studies of the utility of ultra-deep colleagues (Abstract 97LB). Data were justment, and immune activation. sequencing as well as other assays for presented from the interim iPrEx Session 124 provided insight into predicting CCR5 coreceptor antagonist study’s analysis on the presence of novel HIV quantification methods success were presented in Session 126 resistance mutations in samples from through nucleic acid amplification. (Abstracts 666−671). patients at the time of first evidence Yukl and colleagues explored modifica- of seroconversion, tested using both tion of a well-known commercial real- Raltegravir Resistance bulk sequencing (genotypic or pheno- time PCR assay to detect plasma HIV-1 typic assays) and a novel quantitative RNA levels less than 1 copy/mL (Ab- Session 116 highlighted resistance is- minor variant assay (lower limit of de- stract 656). Investigators reported that sues with the INSTI class. The role of tection, 0.5%) for detection of K65R, mean plasma viral load correlated in- T97A in the presence of Y143C/R was K70E, M184V, and M184I mutations. versely (R = −0.78; P = .028) with total explored by Reigadas and colleagues, There were 100 participants who were duration of viral suppression (plasma who performed in vitro assays com- infected during the study, for whom 91 HIV RNA levels < 40 copies/mL) and paring wild-type integrase with inte- samples were successfully tested. suggested that residual viremia may

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decay slowly over years of treatment sion 125, Abstracts 662−664). activity. Martin and colleagues report- (Abstract 656). ed on the pharmacokinetic profiles in Innovations in genotypic drug resis- Pharmacokinetic Considerations several animal models (Abstract 627). tance testing were also discussed, such There was good bioavailability and a as testing of other areas of the HIV ge- Tenofovir/Emtricitabine for long plasma half-life (approximately nome, or even whole HIV-1 genome Preexposure Prophylaxis 35 hours) in all the species examined. sequencing. At this point, there is no Telaprevir is a nonstructural pro- evidence that whole-genome sequenc- Anderson and colleagues evaluated tein 3 (NS3)/4A protease inhibitor ing is superior to sequencing of prote- drug concentrations in plasma and that was recently approved by the US ase and reverse transcriptase; however, PBMCs in 16 HIV-uninfected adults Food and Drug Administration (FDA) whole-genome sequencing could offer given a single tablet of fixed-dose te- for the treatment of HCV infection. It increased options for combining of nofovir/emtricitabine (Abstract 641). is both a substrate and an inhibitor antiretroviral drugs and enhance cur- They found that the tenofovir diphos- of cytochrome P450 3A (CYP3A). The rent methods of epidemiology. Whole- phate concentrations in PBMCs were current dose is 750 mg every 8 hours. genome sequencing would require ef- approximately 35% of those achieved Garg and colleagues attempted to en- fective algorithms to be developed for in primate models of HIV transmis- hance the pharmacokinetic profile of the prediction of the clinical relevance sion and that the tenofovir diphos- telaprevir by adding ritonavir (Abstract of various mutations. phate concentrations in plasma were 629). Two dosing schemes, telaprevir The role of minority drug resistance similar to those in the primary models. 250 mg/ritonavir 100 mg twice daily mutation assays compared with bulk As expected, concentrations of both and telaprevir 750 mg/ritonavir 100 sequencing was also emphasized. drugs were much lower than steady- mg twice daily, were administered to Metzner described data comparing the state concentrations in HIV-1-infected healthy volunteers, and the pharmaco- presence of minority drug resistance patients receiving long-term therapy. kinetic properties were compared with mutations in the Zurich Primary HIV The authors note that the low concen- those of the standard dose. Neither of Cohort with that of a chronically infect- trations of tenofovir diphosphate are the ritonavir regimens achieved ade- ed group from the Swiss Cohort Study. concerning for episodic administration quate trough levels of telaprevir. More- Results showed that minority variants of tenofovir/emtricitabine as used for over, the addition of ritonavir did not with the K103N mutation were detect- PrEP of HIV-1 transmission. appear to change the pharmacokinetic ed at equal rates in both groups (4%) profile of telaprevir. but that M184V variants were present Raltegravir-Based Antiretroviral Rilpivirine is a NNRTI recently ap- at higher rates in the primary-HIV-in- Therapy proved by the FDA for the treatment of fection cohort (8%) than in the chroni- HIV infection. Crauwels and colleagues cally HIV-infected cohort (2.5%), sug- Miro and colleagues reported on the evaluated the pharmacokinetic pro- gesting that the M184V virus is less fit antiviral and pharmacokinetic proper- files of rilpivirine after switching from and less likely to persist over time. ties of raltegravir-based regimens for efavirenz (Abstract 630). They found The impact of NNRTI-associated mi- HIV-1-infected, solid-organ transplant that rilpivirine concentrations were re- nority resistance variants on virologic recipients (Abstract 644). There were duced after switching from efavirenz success for treatment-naive patients 15 subjects whose regimens were compared with a control period of beginning initial NNRTI-based regi- switched to raltegravir plus tenofovir/ rilpivirine administration before efavi- mens was illustrated in a meta-analysis emtricitabine or abacavir/lamivudine. renz dosing. This effect lessened over of 10 studies and 985 subjects covered All participants had continued virolog- time but was still somewhat apparent by Li and colleagues (Abstract 614). ic control, and this regimen switch al- up to 28 days after efavirenz admin- Patients with baseline NNRTI-associat- lowed for standard dosing of immuno- istration. The authors concluded, how- ed minority resistance variants had a suppressant medications. The authors ever, that none of the observed drug statistically significantly higher risk of found no statistically significant phar- concentrations was low enough to be viral failure, regardless of adherence, macokinetic interactions between concerning for virologic breakthrough than patients without such variants. raltegravir and cyclosporine or myco- and that this switch should be safe in The importance of minority resistance phenolic acid. clinical practice. variants appears to vary by drug class. Further study will be needed to under- Pharmacokinetic Properties of Once-Daily Maraviroc Dosing stand their impact on clinical care. Newly Available and Investigational The design and application of fea- Compounds Taylor and colleagues investigated the sible resistance mutations testing pharmacokinetic profile of maravi- methods for use in RLS is of crucial The compound TBR-652 is an inves- roc dosed once daily with darunavir/r importance. Several abstracts at the tigational antagonist of CCR5 and CC (Abstract 636). They compared the conference illustrated methods for re- chemokine receptor 2 (CCR2) virus maximal concentration and trough sistance mutation analysis in RLS (Ses- that has demonstrated in vivo antiviral concentration of 20 subjects receiv-

95 IAS–USA Topics in Antiviral Medicine

ing maraviroc 300 mg once daily plus Antiretroviral Therapy and Pfizer Inc, ViiV Healthcare, and Quest Diag- once-daily darunavir/r with those of 13 Breast-feeding nostics Inc and has received research support subjects receiving maraviroc 300 mg from Tibotec Therapeutics. Dr Hammer has twice daily plus fixed-dose tenofovir/ Liotta and colleagues presented data served as a scientific advisor for Merck & Co, emtricitabine. They found that maxi- on drug concentrations in infants be- Inc, and Progenics Pharmaceuticals, Inc. mal concentrations (at 2 hours post– ing breast-fed by HIV-1-infected wom- maraviroc dosing in both groups) and en receiving antiretroviral therapy A list of all cited abstracts trough concentrations (at 24 hours and (Abstract 757). They had 38 paired appears on pages 99–106. 12 hours post–maraviroc dosing, re- maternal and infant samples from spectively) were similar in the 2 groups. patients at 1 month to 6 months postpartum. Nevirapine was present at References Neuroleptic Drugs therapeutic concentrations in all infant samples tested. Lamivudine was 1. Wilkin TJ, Goetz MB, Leduc R, et al. Re- analysis of coreceptor tropism in HIV-1- Okulicz and colleagues evaluated the detectable in most infant samples. infected adults using a phenotypic assay virologic outcomes of 21 patients re- Lopinavir, stavudine, and zidovudine with enhanced sensitivity. Clin Infect Dis. ceiving antiepileptic drugs that induce were detected much less commonly. 2011;52:925-928. the CYP3A4 enzymes: phenytoin, car- The authors concluded that direct ad- 2. Mwagomba B, Zachariah R, Massaquoi bamazepine, and phenobarbital (Ab- ministration of nevirapine to infants M, et al. Mortality reduction associated stract 646). Their comparison included during breast-feeding was likely not with HIV/AIDS care and antiretroviral necessary. treatment in rural Malawi: evidence from 85 patients receiving other neuroleptic registers, coffin sales and funerals. PLoS drugs as a control group. The authors One. 2010;5:e10452. found the risk of virologic failure was Rifabutin and Lopinavir/Ritonavir 3. World Health Organization. Antiretroviral much higher for patients receiving the therapy for HIV infection in adults and ad- enzyme-inducing antiepileptic drugs; Naiker and colleagues evaluated 2 dos- olescents: Recommendations for a public 10 of 17 patients (59%) had virologic ing schemes for rifabutin when ad- health approach: 2010 revision. http:// www.who.int/hiv/pub/arv/adult2010/en/ failure compared with 20 of 75 pa- ministered with lopinavir/r (Abstract index.html. Accessed May 20, 2011. tients (27%) taking other neuroleptic 650). They enrolled 16 HIV-1-infected 4. World Health Organization. Antiretroviral drugs. They noted that this difference patients being treated for tuberculo- drugs for treating pregnant women ande has important implications for RLS, sis. All patients received rifabutin 300 preventing HIV infection in infants: Rec- where, in general, only enzyme-induc- mg daily for 4 weeks along with other ommendations for a public health ap- standard initial tuberculosis drugs, af- proach (2010 version). http://www.who. ing antiepileptic drugs are available for int/hiv/pub/mtct/antiretroviral2010/en/. treatment of seizure disorders. ter which a lopinavir/r-based regimen Accessed May 20, 2011. was added. Patients were randomly 5. Granich RM, Gilks CF, Dye C, De Cock Efavirenz in the Second and Third assigned to a reduced dose of rifabu- KM, Williams BG. Universal voluntary Trimesters of Pregnancy tin (either 150 mg daily or 150 mg 3 HIV testing with immediate antiretroviral times per week). Participants receiving therapy as a strategy for elimination of HIV transmission: a mathematical model. Efavirenz is teratogenic when taken 150 mg 3 times weekly had rifabutin Lancet. 2009;373:48-57. early in pregnancy but is recommend- drug levels that were appreciably low- 6. Severe P, Juste MA, Ambroise A, et al. Ear- ed as initial therapy by the WHO for er than levels before the initiation of ly versus standard antiretroviral therapy HIV-1-infected women after the first lopinavr/r. The group receiving rifabu- for HIV-infected adults in Haiti. N Engl J trimester. Cressey and colleagues com- tin 150 mg daily had levels that were Med. 2010;363:257-265. pared the pharmacokinetics of efa- similar to or slightly higher than those 7. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral virenz in HIV-1-infected women dur- observed before lopinavir/r dosing, drugs during tuberculosis therapy. N Engl ing the third trimester of pregnancy and they had peak rifabutin concentra- J Med. 2010;362:697-706. with pharmacokinetics at 6 weeks to tions that were within the therapeutic 8. Holmes CB, Coggin W, Jamieson D, et al. 12 weeks postpartum (Abstract 754). range. There were no safety concerns Use of generic antiretroviral agents and They found slightly higher efavirenz in any of the groups. The authors sug- cost savings in PEPFAR treatment pro- clearance and lower trough concentra- gested that rifabutin should be admin- grams. JAMA. 2010;304:313-320. 9. Pujades-Rodríguez M, Balkan S, Ar- tions during the third trimester than istered at 150 mg daily when dosed nould L, Brinkhof MA, Calmy A. Treat- at the postpartum points. The authors with lopinavir/r, not at the currently ment failure and mortality factors in felt that the magnitude of this change accepted dosage of 150 mg 3 times patients receiving second-line HIV ther- was enough to warrant a change in weekly. apy in resource-limited countries. JAMA. efavirenz dosing during pregnancy. It 2010;304:303-312. 10. Goldie SJ, Yazdanpanah Y, Losina E, et is important to note the majority of Financial Disclosures: Dr Taylor has no rel- al. Cost-effectiveness of HIV treatment in the women in this study were Thai evant financial affiliations to disclose. Dr resource-poor settings—the case of Côte and these results may not generalize Olender has no relevant financial affiliations d'Ivoire. N Engl J Med. 2006;355:1141- to other populations. to disclose. Dr Wilkin is a consultant for 1153.

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11. Walensky RP, Ciaranello AL, Park JE, improve adherence to antiretroviral treat- trial. [Abstract 125.] 15th Conference Freedberg KA. Cost-effectiveness of labo- ment in a resource-limited setting: a ran- on Retroviruses and Opportunistic Infec- ratory monitoring in sub-Saharan Africa: domized controlled trial of text message tions (CROI). February 3-6, 2008; Boston, a review of the current literature. Clin In- reminders. AIDS. 2011;25:825-834. MA. fect Dis. 2010;51:85-92. 21. Haberer JE, Kahane J, Kigozi I, et al. 30. Reynolds SJ, Nakigozi G, Newell K, et al. 12. Walensky RP, Wood R, Ciaranello AL, et Real-time adherence monitoring for Failure of immunologic criteria to appro- al. Scaling up the 2010 World Health Or- HIV antiretroviral therapy. AIDS Behav. priately identify antiretroviral treatment ganization HIV treatment guidelines in 2010;14:1340-1346. failure in Uganda. AIDS. 2009;23:697- resource-limited settings: a model-based 22. Parienti JJ, Das-Douglas M, Massari V, et 700. analysis. PLoS Med. 2010;7:e1000382. al. Not all missed doses are the same: 31. Mee P, Fielding KL, Charalambous S, 13. Hirnschall G, Schwartländer B. Treatment sustained NNRTI treatment interruptions Churchyard GJ, Grant AD. Evaluation of 2.0: catalysing the next phase of scale-up predict HIV rebound at low-to-moderate the WHO criteria for antiretroviral treat- [published online ahead of print Febru- adherence levels. PLoS One. 2008;3:e278 ment failure among adults in South Af- ary 24, 2011]. Lancet. 2011;doi:10.1016/ 23. Bisson GP, Gross R, Bellamy S, et al. Phar- rica. AIDS. 2008;22:1971-1977. S0140-6736(11)60247-X. macy refill adherence compared with 32. Chaiwarith R, Wachirakaphan C, Kotara- 14. Hill A, Ananworanich J, Calmy A. Dose CD4 count changes for monitoring HIV- thititum W, Praparatanaphan J, Sirisan- optimisation: a strategy to improve toler- infected adults on antiretroviral therapy. thana T, Supparatpinyo K. Sensitivity and ability and lower antiretroviral drug pric- PLoS Med. 2008;5:e109. specificity of using CD4+ measurement es in low and middle income countries. 24. Geng EH, Bwana MB, Kabakyenga J, et and clinical evaluation to determine anti- Open Infect Dis J. 2010;4:85-91. al. Diminishing availability of publicly retroviral treatment failure in Thailand. 15. Sanne I, Orrell C, Fox MP, et al. Nurse ver- funded slots for antiretroviral initiation Int J Infect Dis. 2007;11:413-416. sus doctor management of HIV-infected among HIV-infected ART-eligible patients 33. Keiser O, MacPhail P, Boulle A, et al. Ac- patients receiving antiretroviral therapy in Uganda. PLoS One. 2010;5:e14098. curacy of WHO CD4 cell count criteria for (CIPRA-SA): a randomised non-inferiority 25. Nachega JB, Leisegang R, Bishai D, et al. virological failure of antiretroviral therapy. trial. Lancet. 2010;376:33-40. Association of antiretroviral therapy ad- Trop Med Int Health. 2009;14:1220-1225. 16. Mills EJ, Nachega JB, Buchan I, et al. Adher- herence and health care costs. Ann Intern 34. Moore DM, Awor A, Downing R, et al. ence to antiretroviral therapy in sub-Sa- Med. 2010;152:18-25. CD4+ T-cell count monitoring does not haran Africa and North America: a meta- 26. Rosen S, Fox MP, Gill CJ. Patient retention accurately identify HIV-infected adults analysis. JAMA. 2006;296:679-690.1 in antiretroviral therapy programs in sub- with virologic failure receiving antiretro- 17. Ware NC, Idoko J, Kaaya S, et al. Explain- Saharan Africa: a systematic review. PLoS viral therapy. JAIDS. 2008;49:477-484. ing adherence success in sub-Saharan Med. 2007;4:e298. 35. Keiser O, Tweya H, Boulle A, et al. Switch- Africa: an ethnographic study. PLoS Med. 27. Coovadia A, Abrams EJ, Stehlau R, et ing to second-line antiretroviral therapy 2009;6:e11. al. Reuse of nevirapine in exposed HIV- in resource-limited settings: comparison 18. Byakika-Tusiime J, Crane J, Oyugi JH, et infected children after protease inhibitor- of programmes with and without viral al. Longitudinal antiretroviral adherence based viral suppression: a randomized load monitoring. AIDS. 2009;23:1867- in HIV+ Ugandan parents and their chil- controlled trial. JAMA. 2010;304:1082- 1874. dren initiating HAART in the MTCT-Plus 1090. 36. Johnson VA, Brun-Vézinet F, Clotet B, et family treatment model: role of depres- 28. Mugyenyi P, Walker AS, Hakim J, et al. al. Update of the drug resistance muta- sion in declining adherence over time. Routine versus clinically driven labora- tions in HIV-1: December 2010. Top HIV AIDS Behav. 2009;13 Suppl 1:82-91. tory monitoring of HIV antiretroviral ther- Med. 2010;18:156-163. 19. Lester RT, Ritvo P, Mills EJ, et al. Effects of apy in Africa (DART): a randomised non- a mobile phone short message service on inferiority trial. Lancet. 2010;375:123- antiretroviral treatment adherence in Ken- 131. ya (WelTel Kenya1): a randomised trial. 29. Coutinho A, Mermin J, Ekwaru J, et al. Lancet. 2010;376:1838-1845. Utility of routine viral load CD4 cell count, 20. Pop-Eleches C, Thirumurthy H, Habyari- and clinical monitoring among HIV-in- Top Antivir Med. 2011;19(2):69–97 mana JP, et al. Mobile phone technologies fected adults in Uganda: a randomized ©2011, IAS–USA

97 IAS–USA Topics in Antiviral Medicine

Educational Programs of the IAS–USA Established in 1992, the IAS–USA is a not-for-profit, viral diseases education organization. The mission of the IAS–USA is to improve the treatment, care, and quality of life for people with HIV or other viral infections through high-quality, relevant, balanced, and needs-oriented education and information for practitioners who are actively involved in medical care for people with viral infections. The organization’s educational activities are particularly intended to bridge clinical research and patient care.

Continuing Medical Education Courses IAS–USA CME course announcements are paperless. Please watch for e-mail updates, and visit the IAS–USA Web site at www.iasusa.org for general course information, agendas, and online registration. Early registration is strongly recommended. These live activities have been approved for AMA PRA Category 1 Credit™.

Improving the Management of HIV Disease® The full-day advanced CME course, now in its 19th year, continues to focus on cutting-edge, scientifically rigorous issues presented by leading experts in the field, providing the latest insights and data on the full spectrum of HIV- and AIDS-related treatment issues. 2011 Full-Day HIV Course Schedule Atlanta, Georgia Los Angeles, California New York, New York Monday, March 14, 2011 Monday, March 28, 2011 Tuesday, April 5, 2011 Renaissance Waverly Hotel California Endowment Center New York Marriott Marquis Washington, DC San Francisco, California Chicago, Illinois Wednesday, May 4, 2011 Monday, May 16, 2011 Monday, June 13, 2011 Capital Hilton Grand Hyatt San Francisco Marriott Chicago Downtown

New York, New York - Fall Friday, October 14, 2011 New York Marriott Marquis

14th Annual Clinical Conference for the Ryan White HIV/AIDS Program Tampa, Florida June 27–29, 2011 Marriott Tampa Waterside Hotel

Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes Part of the new IAS–USA focus on the management of viral hepatitis infection, this effort includes half-day, small-group, intensive CME workshops and a full-day CME course presented by leading experts in viral hepatitis.

2011 Full-Day Viral Hepatitis Course New York, New York Friday, April 15, 2011 Grand Hyatt New York

Educational Resources: CME resources from past live courses are available on the IAS–USA Web site at www.iasusa.org, including Webcasts (available for CME credit), Podcasts, downloadable key slides from lectures, and various handouts from presenters.

For information about any of these programs, please contact the IAS–USA. Phone: (415) 544-9400 • Fax: (415) 544-9402 • E-mail: Registration2011”at”iasusa.org • Web site: www.iasusa.org 98 Conference Highlights—Abstracts Cited Volume 19 Issue 2 May/June 2011

Conference Abstracts Cited in This Issue The full text of all abstracts is available online at www.retroconference.org

6. Global ART Update. Papa Salif Sow. E Hogg, J Anderson, I Sanne, and A5521 Team. Campbell, E Daar, C Yiannoutsos, A Gongvatana, R 17. Viruses and miRNA. Bryan Cullen. 39LB. Optimal Timing of ART during TB Therapy: Cohen, and HIV Neuroimaging Consortium. 18. “The Journey”—HIV/AIDS, Treatment and Pre- Findings of the SAPiT Trial. Salim Abdool Karim, K 57. Higher HIV-1 Genetic Diversity Is Associated vention: Malawi. Anthony Harries. Naidoo, N Padayatchi, A Grobler, C Baxter, S Gen- with AIDS and Neuropsychological Impairment. giah, W El-Sadr, G Friedland, and Q Abdool Karim. 19. The Science and Practice of HIV Prevention in George Hightower, J Wong, S Letendre, A Umlauf, the US. Jonathan Mermin. 40. Adjunctive IFN-gamma Immunotherapy for the R Ellis, C Ignacio, R Heaton, I Grant, D Richman, D Treatment of HIV-associated Cryptococcal Meningi- Smith, and CHARTER Group. 20. Neutralizing Antibody Response to HIV. Michel tis: A Randomized Controlled Trial. Joseph Jarvis, G Nussenzweig. 58. HIV-1 Infection of the Brain. G Schnell, S Jo- Meintjes, K Rebe, N Williams, T Bicanic, A Williams, seph, S Spudich, R Price, and Ronald Swanstrom. 26. Down-regulation of CCR5 by Its Ligands De- C Schutz, L-G Bekker, R Wood, and T Harrison. creases Number of Target Cells for HIV-1 in GBV- 59. SIV-induced Neuronal Injury Correlates with C-infected Individuals. Molly Perkins, J Liebner, D 42. Feasibility, Accuracy, and Acceptability of Using Plasma and Brain Viral Burden and Activated Mono- Himelfarb, H Edward, J Brenchley, J Stapleton, S Oral HIV Test Kits for Supervised Community-level cyte Subsets. Robert Fell, E-M Ratai, M Piatak, J Lif- Rowland-Jones, X Xu, A McMichael, and D Douek. Self-testing in a Resource-poor High-HIV Preva- son, T Burdo, P Autissier, E Masliah, S Westmore- lence Setting: Blantyre, Malawi. Augustine Choko, land, K Williams, and G González. 27. Co-infection with GBV-C Reduces CD4 and CD8 N Desmond, E Webb, K Chavula, S Mavedzenge, S Activation and Proliferation in Subjects with Detect- 60LB. Neuroprotective MVC Monotherapy in Makombe, B Squire, N French, V Mwapasa, and E SIV-infected Macaques. K Kelly, S Beck, K Pate, S able HIV Viral Load. Jack Stapleton, K Chaloner, J Corbet. Zhang, D Klinzman, J Martinson, J Xiang, S Desai, Queen, J Karper, P Tarwater, L Avery, W Hubbard, R and A Landay. 43. Shifting Management of Stable ART Patients Adams, and Joseph Mankowski. from Doctors to Nurses in South Africa: Excellent 61. CSF Proteomic Discovery in HIV Infection 28LB. An Intrinsic Inhibitor of CDK9-mediated Outcomes and Lower Costs. Lawrence Long, A Transcriptional Elongation of HIV-1 in CD4 T Cells Guided by CSF Neopterin Concentrations. T Angel, J Brennan, M Fox, B Ndibongo, I Jaffray, M Maskew, P Jacobs, S Spudich, M Grill, M Gritsenko, D Camp, D from Elite Controllers. J Huang, C Li, T Cung, H MacPhail, I Sanne, and S Rosen. Chen, J Beamon, K Seiss, M Carrington, B Walker, X Fuchs, R Smith, and Richard Price. Yu, and Mathias Lichterfeld. 44. PHPT-3: A Randomized Clinical Trial Comparing 62. Isolation and Characterization of Broadly Neu- CD4 vs Viral Load ART Monitoring/Switching Strate- 29. Factors Associated with HSV-2 Incidence in a tralizing Monoclonal Antibodies to HIV-1. John Mas- gies in Thailand. G Jourdain, N Ngo-Giang-Huong, cola Cohort of HIV-1– Kenyan Men and Women Report- S Le Coeur, P Traisaithit, S Barbier, M Techaporn- 63. Clonal Deletion of MPER Antibodies: Implica- ing High-risk Sexual Behavior. Haile Okuku, E Sand- roong, S Banchongkit, S Buranabanjasatean, G Hal- tions for Vaccine Design. Laurent Verkoczy, Y Chen, ers, J Nyiro, C Ngetsa, E Ohuma, S McClelland, M ue, Marc Lallemant, and PHPT-3 Study Group. Price, and S Graham. H Bouton-Verville, J Hutchinson, R Scearce, M Holl, 45LB. HIV Viral Load, CD4 Cell Count, and Clinical K Hwang, G Kelsoe, and B Haynes. 30. High Protection against Vaginal Infection in Monitoring vs Clinical Monitoring Alone for ART in 64. Quality of B Cell Responses Induced by Sol- Macaques by PEP with Gel Containing RAL. Charles Rural Hospitals in Cameroon: Stratall ANRS 12110/ uble HIV-1 Env Protein Trimers. C Sundling, Y Li, Dobard, S Sharma, U Parikh, D Hanson, J Lipscomb, ESTHER Trial, a Randomized Non-inferiority Trial. N Huynh, S O’Dell, J Mascola, R Wyatt, and Gunilla F Novembre, J Smith, M Hendry, G Garcia-Lerma, Charles Kouanfack, C Laurent, G Laborde-Balen, A Karlsson Hedestam. and W Heneine. Aghokeng, J Tchatchueng-Mbougua, S Boyer, P Car- 31. Complete Protection against Rectal Transmis- rieri, J-P Moatti, S Koulla-Shiro, E Delaporte, and 65. The Search for Antibody Correlates of Protec- sion of an Emtricitabine-resistant SHIV162p3- Stratall ANRS 12110/ESTHER Study Group. tion for HIV-1 Acquisition in RV144: An Update. Je- rome Kim for the RV144 Sci Working Groups and M184V Mutant by Intermittent Prophylaxis with Successful and Persistent Engraftment of ZFN- 46. MOPH-TAVEG Collaboration. Truvada. M-E Cong, A Youngpairoj, Q Zheng, W M-R5-D Autologous CD4 T Cells (SB-728-T) in Avire- Aung, J Mitchell, D Hanson, M Hendry, C Dobard, W mic HIV-infected Subjects on HAART. Jay Lalezari, 66. Adolescents and HIV: Understanding the Com- Heneine, and Gerardo Garcia-Lerma. R Mitsuyasu, S Deeks, S Wang, G Lee, M Holmes, P plexity of Adolescence and Intervening to Foster a 33. Healthy Post-menopausal Women Have Higher Gregory, M Giedlin, W Tang, and D Ando. Safe Transition to Adulthood. Audrey Pettifor. Percentages of CCR5+ Cervical CD4+ T Cells Com- 47. Creating an HIV-resistant Immune System: Us- 67. Responding to Risk in Pregnancy. Grace John- pared to Pre-menopausal Women: Implications for ing CXCR4 ZFN to Edit the Human Genome. Craig Stewart, A Drake, J Kinuthia, J Slyker, A Wagner, and HIV Transmission. Amie Meditz, K Moreau, W Go- Wilen, J Wang, J Tilton, J Miller, S Sherrill-Mix, B Richardson. zansky, K Melander, W Kohrt, M Wierman, and E F Bushman, P Gregory, C June, M Holmes, and R 68. Evaluating and Responding to Risk in MSM in Connick. Doms. Developing Countries. Chris Beyrer. 34LB. RMP-02/MTN-006: A Phase 1 Placebo-con- 49. Pharmacodynamics, Safety, and Pharmacoki- 69. Responding to Risk in US MSM. Gregorio Mil- trolled Trial of Rectally Applied 1% Vaginal TFV Gel netics of BMS-663068: A Potentially First-in-class lett. with Comparison to Oral TDF. Peter Anton, R Crans- Oral HIV Attachment Inhibitor. Richard Nettles, D 72. Cutting Edge Monitoring Tools in HIV Infection. ton, A Carballo-Dieguez, A Kashuba, E Khanukhova, Schurmann, L Zhu, M Stonier, S-P Huang, C Chien, Karin Metzner. J Elliott, L Janocko, W Cumberland, C Mauck, and I M Krystal, M Wind-Rotolo, R Bertz, and D Grasela. McGowan. 74. Cost-effectiveness in HIV Care: Understanding 52. Surveillance of Transmitted and Acquired HIV Value in a World of Limited Resources. Rochelle 35LB. MTN-001: A Phase 2 Cross-over Study of Drug Resistance Using WHO Surveys in Resource- Walensky. Daily Oral and Vaginal TFV in Healthy, Sexually limited Settings. Silvia Bertagnolio, K Kelley, A Saa- 75. The Structure of Retroviral Integrase and the Active Women Results in Significantly Different dani Hassani, Y Obeng-Aduasare, and M Jordan. Product Acceptability and Vaginal Tissue Drug Con- Mechanism of Strand Transfer Inhibitor Action. Pe- centrations. Craig Hendrix, A Minnis, V Guddera, S 53. Routine VLM Reduces the Rate of Accumulated ter Cherepanov. Riddler, R Salata, C Nakabiito, C Hoesley, J Justman, Genotypic Resistance to Commonly Used ART in 76. Decreased Limb Muscle and Increased Central L Soto-Torres, B Richardson, and MTN-001 Study Uganda. Steven Reynolds, H Sendagire, K Newell, Adiposity Are Associated with 5-Year All-cause Mor- Team. B Castelnuovo, A Kiragga, I Namugga, B Namono, T tality in HIV Infection. Rebecca Scherzer, S Heyms- Quinn, Y Munabe, and A Kambugu. 36. Longer-term Effects of Male Circumcision on field, D Lee, W Powderly, P Tien, P Bacchetti, M HIV Incidence and Risk Behaviors during Post-trial 54. HIV Brain Viral and Inflammatory Signature Shlipak, C Grunfeld, and Study of Fat Redistribution Surveillance in Rakai, Uganda. Xiangrong Kong, G during Acute Infection. Victor Valcour, N Sailasuta, T and Metabolic Change in HIV Infection. Kigozi, V Ssempija, D Serwadda, F Nalugoda, F Ma- Chalermchai, M Marovich, S Lerdlum, D Suttichom, 77. Central Fat Accumulation in ART-naïve Subjects kumbi, T Lutalo, S Watya, M Wawer, and R Gray. N Charnnarong, L Jagodzinski, N Michael, J Anan- Randomized to ABC/3TC or TDF/FTC with ATV/r 37LB. Cost Effectiveness of PrEP for HIV Infection woranich, and RV254/SEARCH 010 Study Group. or EFV: ACTG A5224s, a Substudy of ACTG A5202. in South Africa. R Walensky, Ji-Eun Park, R Wood, K 55LB. Injury to the Brain Is Evident Early in HIV Grace McComsey, D Kitch, P Sax, P Tebas, C Tier- Freedberg, C Scott, L-G Bekker, E Losina, K Mayer, G Infection. Ann Ragin, Y Wu, H Du, R Ochs, and L ney, N Jahed, L Myers, K Melbourne, B Ha, and E Seage, and D Paltiel. Epstein. Daar. 38. International Randomized Trial of Immediate 56. A Longitudinal Study of Neurological Injury 78. HAART-induced Immune Reconstitution: A vs Early ART in HIV+ Patients Treated for TB: ACTG in HIV-infected Subjects on Stable ART: The HIV Driving Force Behind Bone Resorption in HIV/AIDS. 5221 STRIDE Study. Diane Havlir, P Ive, M Kendall, Neuroimaging Consortium Cohort Study. Bradford Ighovwerha Ofotokun, N Weitzmann, A Vunnava, A A Luetkemeyer, S Swindells, J Kumwenda, S Qasba, Navia, J Harezlak, G Schifitto, M Taylor, E Singer, T Sheth, F Villinger, J Zhou, E Williams, S Sanford, M 99 IAS–USA Topics in Antiviral Medicine

Rivas, and J Lennox. in HIV Co-infected Individuals? Christoph Boesecke, ing Clinical Care in Tanzania, Kenya, and Namibia. 79LB. Change in Vitamin D Levels Smaller and H-J Stellbrink, S Mauss, E Page, M Nelson, S Bha- Pamela Bachanas, A Medley, D Kidder, S Flores, J Risk of Development of Severe Vitamin D Deficien- gani, M Guiguet, C Katlama, M Vogel, J Rockstroh, Zhang, M Sheriff, N Deluca, G Antelman, O Muhen- cy Lower among HIV-1-infected, Treatment-naïve and NEAT Study Group. je, A Wadud, and PwP Study Team. Adults Receiving TMC278 Compared with EFV: 48- 115. BOC Combined with P/R for Treatment-naïve 141LB. Interaction of the V1V2 Loop with a Neigh- Week Results from the Phase III ECHO Trial. David Patients with HCV Genotype-1: SPRINT-2 Final boring gp120 Unit Shield the HIV Envelope Trimer Wohl, M Doroana, C Orkin, JH Pilotto, S Sungkanu- Results. Mark Sulkowski, F Poordad, J McCone, B against Neutralization. P Rusert, A Krarup, C Mag- parph, P Yeni, S Vanveggel, H Deckx, and K Boven. Bacon, S Bruno, M Manns, I Jacobson, R Reddy, J nus, O Brandenberg, J Weber, A-K Ehlert, R Regoes, 85. SIV nef Proteins Antagonize Tetherin by AP-2- Albrecht, and J-P Bronowicki. H Günthard, and Alexandra Trkola. dependent Removal from Sites of Virion Budding. 116. HCV RESPOND-2 Final Results: High Sustained 142. Non-neutralizing Antibodies Provide Ma- Fengwen Zhang, W Landford, M Ng, P Bieniasz, and Virologic Response among Genotype-1 Previous caques Limited or No Protection against Vaginal T Hatziioannou. Non-responders and Relapsers to pegIFN/RBV when SHIV Challenge Compared to a Neutralizing Anti- 87. HIV-1 Engineered to Package SIV vpx Efficiently Re-treated with BOC + PEGINTRON/RBV. Stuart Gor- body. John Moore, D Burton, A Hessel, P Klasse, B Infects Macrophages and Dendritic Cells and Elicits don, B Bacon, E Lawitz, P Marcellin, J Vierling, S Keele, and R Veazey. an Enhanced Innate Immune Response. Nicole Sun- Zeuzem, F Poordad, J Albrecht, and R Esteban. 146LB. Interim Analysis of a Phase 2a Double- seri, M O’Brien, N Bhardwaj, and N Landau. 118. Clinical Pharmacology of BOC: Metabolism, blind Study of TVR in Combination with pegIFN- 88. Signal Transduction by the Cytoplasmic Tail of Excretion, and Drug-Drug Interactions. C Kasserra, alfa2a and RBV in HIV/HCV Co-infected Patients. Gp41 of HIV and SIV. Thomas Postler and R Des- E Hughes, M Treitel, S Gupta, and Edward O’Mara. Mark Sulkowski, D Dieterich, K Sherman, J Rock- rosiers. 119. Pharmacokinetic Interactions between ARV stroh, N Adda, L Mahnke, V Garg, S Gharakhanian, S McCallister, and V Soriano. 89. A Specific Role for Rab11a Family of Interacting Agents and the Investigational HCV Protease Inhibi- Proteins in Directing HIV Envelope Incorporation tor TVR in Healthy Volunteers. Rudolph van Hees- 148LB. A Randomized Open-label Trial of 5-Drug into Virion Particles. Mingli Qi, J-J Wang, H Chu, L wijk, A Vandevoorde, G Boogaerts, T Vangeneug- vs 3-Drug Standard PI-based cART Initiated during Ding, and P Spearman. den, E de Paepe, R Polo, R Van Solingen-Ristea, K Acute and Early HIV-1 Infection: 48-Week Results. de Backer, V Garg, and M Beumont. Martin Markowitz, T Evering, M Caskey, A Figueroa, 90. Reverse Transcription Facilitates HIV Uncoat- K Rodriguez, M La Mar, S Palmer, V Sahi, N Prada, ing. A Hulme, O Perez, and Thomas Hope. 120. Drugs for Prevention—Topical and Systemic PrEP. Connie Celum. and H Mohri. 92. Pre-exposure Chemprophylaxis for Prevention Efficacy and Safety of EFV with either Co- of HIV among Trans-women and MSM: iPREx Study. 121. New Antiviral Therapies in the Management 149LB. formulated 3TC/ZDV or FTC/TDF for Initial Treat- Robert Grant, J Lama, D Glidden, and iPrEx Study of HCV. Stefan Zeuzem. ment of HIV-1-infected Men and Women in Di- Team. 122. Transmission of HIV-1 and CMV during Gesta- verse Multinational Settings: ACTG PEARLS Study. 93. BMD Loss in HIV− Men Participating in a TDF tion and Delivery in the Offspring of HIV+ Mothers. Woottichai Khamduang, G Jourdain, W Sirirungsi, Thomas Campbell, L Smeaton, N Kumarasamy, T PrEP Clinical Trial in San Francisco. Albert Liu, E Vit- Flanigan, J Sanchez, B Grinsztejn, S Tripathy, J Kum- tinghoff, R Irby, K Mulligan, D Sellmeyer, K Mayer, P Layangool, S Kanjanavanit, S Hongsiriwon, T Borkird, M Lallemant, K McIntosh, N Ngo-Giang- wenda, V deGruttola, J Hakim, and ACTG PEARLS M Thompson, R Gvetadze, L Grohskopf, and S Buch- A5175 Study Team. binder. Huong, and Prgm for HIV Prevention and Treat- ment. 150LB. QDMRK, a Phase III Study of the Safety 94LB. Effects of FTC/TDF on Bone Mineral Density and Efficacy of Once Daily vs Twice Daily RAL in in Seronegative Men from 4 Continents: DEXA Re- 123LB. HPTN 046: Efficacy of Extended Daily Infant NVP through Age 6 Months Compared to 6 Combination Therapy for Treatment-naïve HIV-in- sults of the Global iPrEx Study. Kathleen Mulligan, D fected Patients. Joseph Eron, J Rockstroh, J Reynes, J Glidden, P Gonzales, M-E Ramirez-Cardich, A Liu, S Weeks for Postnatal PMTCT of HIV through Breast- feeding. H Coovadia, E Brown, Yvonne Maldonado, Andrade-Villanueva, J Madruga, J Zhao, P Sklar, B-Y Namwongprom, P Chodacki, L Mendonça, V McMa- Nguyen, and QDMRK Study Team. han, R Grant, and iPrEx Study Team. L Mofenson, D Moodley, P Musoke, MG Fowler, K Manji, K George, S Zwerski, and HPTN 046 Protocol 151LB. DTG in Subjects with HIV Exhibiting RAL 95LB. Adherence Indicators and PrEP Drug Levels Team. Resistance: Functional Monotherapy Results of in the iPrEx Study. Rivet Amico, A Liu, V McMahan, 124LB. Phase III Randomized Trial of the Safety VIKING Study Cohort II. Joseph Eron, P Kumar, A P Anderson, J Lama, J Guanira, J-H Zheng, D Glid- Lazzarin, G Richmond, V Soriano, J Huang, C Vavro, den, and R Grant. and Efficacy of 3 Neonatal ARV Regimens for Pre- vention of Intrapartum HIV-1 Transmission: NICHD M Ait-Khaled, S Min, and J Yeo. 96LB. Interpreting Detection Rates of Intracellular HPTN 040/PACTG 1043. Karin Nielsen-Saines, H 152LB. GS-7340 Demonstrates Greater Declines FTC-TP and TFV-DP: The iPrEx Trial. Peter Ander- Watts, V Gonçalves Veloso, Y Bryson, E Joao, JH Pi- in HIV-1 RNA than TDF during 14 Days of Mono- son, J Lama, S Buchbinder, J Guanira, O Montoya, M lotto, G Gray, G Theron, J Bethel, L Mofenson, and therapy in HIV-1-infected Subjects. M Markowitz, Casapia, L Bragg, L Bushman, D Glidden, R Grant, NICHD/HPTN 040 Study Group. Andrew Zolopa, P Ruane, K Squires, L Zhong, B and iPrEx Study Team. 125LB. LPV/r Monotherapy during Pregnancy for Kearney, and W Lee. 97LB. Drug Resistance and Minor Drug Resistant PMTCT of HIV-1: The PRIMEVA/ANRS 135 Random- 154. Genital HIV-1 RNA Levels Predict Risk of Variants in iPrEx. Teri Liegler, M Abdel-Mohsen, R ized Trial, Pregnancy Outcomes. Roland Tubiana, L Heterosexual HIV-1 Transmission. Jared Baeten, E Atchison, M Mehotra, T Schmidt, C Eden, D Glid- Mandelbrot, S Delmas, J Le Chenadec, C Rouzioux, Kahle, J Lingappa, R Coombs, S Delany-Moretlwe, E den, S Buchbinder, J Lama, R Grant, and iPrEx J-M Tréluyer, M-L Chaix, D Ekoukou, S Blanche, J Nakku-Joloba, N Mugo, A Wald, L Corey, C Celum, Study Team. Warszawski, and Primeva Study Group. and Partners in Prevention HSV/HIV Transmission 98LB. Predicting the Impact of ART and PrEP with Long-term Outcomes of Switching Children to Study Team. Overlapping Regimens on HIV Transmission and 128. NVP-based Therapy after Initial Suppression with a 158. Cytolytic CD4+ T Cells in Individuals Spon- Drug Resistance in South Africa. Ume Abbas, R PI-based Regimen. Louise Kuhn, A Coovadia, R Streh- taneously Controlling Viral Replication following Glaubius, A Mubayi, G Hood, and J Mellors. lau, T Meyers, L Martens, G Sherman, G Hunt, W-Y Acute HIV Infection. Damien Soghoian, S Ranas- 99LB. ART or PrEP for HIV Prevention in HIV Sero- Tsai, L Morris, and E Abrams. inghe, S Cutler, K Axten, H Jessen, B Walker, and discordant Partnerships: A Mathematical Modeling New HIV Infections among MSM—US, 2008. H Streeck. Comparison. Timothy Hallett, J Baeten, R Heffron, 130. James Heffelfinger, N Krishna, A Oster, E DiNenno, 161. An RCT Comparing No Treatment with 24 or G De Bruyn, S Delany-Moretlwe, G Gray, L Johnson, A Smith, K Delaney, B Le, and A Lansky. 60 Weeks of Temporary ART during Primary HIV J McIntyre, H Rees, and C Celum. 131LB. Predictors of Being HIV+ Unaware among Infection. Marlous Grijsen, R Steingrover, F Wit, F 105. Regulation of HLA-C Expression by miRNA Black and Latino MSM. Gregorio Millett, G Marks, H de Wolf, J Lange, A Verbon, K Brinkman, M van der and Its Association with HIV Control. Mary Car- Ding, W Jeffries, S Flores, C Murrill, and T Bingham. Ende, H Schuitemaker, and J Prins. rington. 133. HIV Seroadaptation Is a Frequent Sexual Harm 164. CCR5 Knock-out in Hematopoietic Stem Cells. 107. The Impact of TRIM5 Polymorphisms on Vire- Reduction Strategy for MSM. Hong-Ha Truong, Y-H Paula Cannon, N Holt, U Hofer, C Exline, J Wang, P mia in Rhesus Macaques Infected with SIV. Vanessa Chen, F Raymond, B Nguyen, J Mehrtens, G Colfax, Gregory, and M Holmes. Hirsch, F Wu, A Kirmaier, J Morgan, and W Johnson. T Robertson, R Stall, D Levine, and W McFarland. 165. Disruption of CCR5 in Zinc Finger Nucle- 108. ART Optimization: Choices and Strategies. Determinants of Per-act Infectivity of HIV-1 in ase-treated CD4 T Cells: Phase I Trials. P Tebas, B Marco Vitoria. 135. the Partners in Prevention Study. James Hughes, J Levine, G Binder, J Hoxie, R Collman, P Gregory, M 109. Monitoring for Safety and Outcomes. Mina Baeten, J Lingappa, A Magaret, A Wald, G de Bruyn, Holmes, D Ando, and Carl June. Hosseinipour. J Kiarie, M Inambao, C Farquhar, C Celum, and Part- 166. The ART of Treating TB in HIV-infected Per- 111. Perspectives on Adherence and Resistance to ners in Prevention HSV/HIV Transmission Study sons. William Burman. ART. David Bangsberg. Team. 173. The Next 30 Years: The Evolution of the HIV/ 113. Does Baseline HCV Genotype Have an Impact 136. Knowledge of Partner HIV Status and Consis- AIDS Epidemic. John Bongaarts and F Pelletier. upon Treatment Outcome of Acute HCV Infection tent Condom Use among HIV+ Individuals Attend- 174. Double Pseudotyped Particles Expressing R5 100 Conference Highlights—Abstracts Cited Volume 19 Issue 2 May/June 2011

HIV env and VSV-G Overcome an Entry Restriction als with Normal Cognition Predict Deterioration. C 443. Progressive Atrophy of the Corpus Callosum in Naïve CD4+ T Cells. Matthew Pace, L Agosto, and Anderson, N Sacktor, J McArthur, and Avindra Nath. in HIV-infected Patients on Stable ART. David Tate, U O’Doherty. 408. Lower CSAR Are Associated with Global Neu- J Harezlak, E Daar, M Taylor, G Schifitto, E Singer, 181. Resistance of HIV-1 Virologic Synapse-medi- rocognitive Impairment in Antiretroviral-treated T Campbell, C Yiannoutsos, C Guttmann, and B ated Infection to Neutralization Is Regulated by the People with HIV. Scott Letendre, D Croteau, R Ellis, Navia. gp41 Cytoplasmic Tail. Natasha Durham, P Chen, D Clifford, B Gelman, C Marra, J McArthur, A Mc- 444. Biomarkers of Immune Activation Contribute and B Chen. Cutchan, D Simpson, I Grant, and CHARTER Group. to Patterns of Neural Injury in HIV-infected Patients 182. Efficacy of Virus Entry Inhibitors Is Attenuated 409. Novel Plasma Biomarkers Predict Develop- on Stable ART: An in vivo Proton MRS Study. Scott against Mature Dendritic Cell-mediated HIV-1 Trans- ment of Lentivirus-associated Neurologic Disease. Letendre, J Harezlak, M Taylor, G Schifitto, E Daar, infection. Hisashi Akiyama, A Tsibris, B Etemad, N Kenneth Witwer, S Sarbanes, and J Clements. T Campbell, D Rosario, L Gualtieri, C Yiannoutsos, Ramirez, I Freitas, M Sagar, and R Gummuluru. 410. Initiation of HAART during Acute SIV Infection and B Navia. 191. Residual HIV-1 Replication Is Observed in the Rapidly Controls Virus Replication in the CNS by En- 446. Marked Relationship of MCP-1 with Brain In- Absence of LEDGF/p75 but Remains Sensitive to In- hancing Immune Activity and Preserving Protective jury in HIV Infection. Ann Ragin, Y Wu, R Ochs, H hibition by LEDGIN. Rik Schrijvers, R Gijsbers, J De Immune Responses. D Graham, L Gama, S Queen, Du, C Pardo, L Epstein, and J McArthur. Rijck, B Desimmie, F Christ, K Ronen, F Bushman, M Li, A Brice, K Kelly, J Mankowski, Janice Clements, 448. Clinical Factors Associated with Cerebral and Z Debyser. and C Zink. White Matter Integrity in HIV-infected Individuals. 197. HIV-1 Latency Establishment Is a Function 411. Elevated Intrathecal Inflammation Correlates Assawin Gongvatana, R Cohen, S Correia, K Dev- of Host-gene Transcription Level. Frank Wolschen- with Incidence of Neurological Manifestations dur- lin, J Miles, D Laidlaw, H Ombao, B Navia, and K dorf, A Duverger, A Henderson, F Wagner, J Jones, ing Primary HIV-1 Infection. Evelyn Lee, M Gisslén, Tashima. F Bibollet-Ruche, W Hillen, C Berens, M Davenport, L Hagberg, B Brew, P Cinque, E Ho, I Leppla, F 450. 2D L-COSY of the Brain in HIV Youths by Prof- and O Kutsch. Hecht, R Price, and S Spudich. it Quantitation. R Nagarajan, A Thomas, M Sarma, 198. Potency and Toxicity of HDACi and Other Im- 412. Comparison of Effects of ART Initiation during J Hayes, K Nielsen-Saines, D Michalik, J Church, J mune Activators in Inducing HIV Production Using a Primary vs Chronic HIV-1 Infection on Biomarkers Deville, L Chang, and Margaret Keller. Primary Resting T Cell Model of HIV Latency. Fiona of CNS Disease. Dharushana Muthulingam, E Lee, J 477. Whole Genome Association Study of Viral Wightman, S Ramanayake, S Saleh, A Solomon, A Peterson, K Robertson, C Yiannoutsos, R Price, and Failure with EFV- and/or ABC-containing Regimens Dear, M Shehu-Xhilaga, P Cameron, and S Lewin. S Spudich. in ACTG Studies. Paul McLaren, H Ribaudo, E Daar, 304. No Correlation between Microbial Transloca- 413. Fatigue and CSF Inflammation during Primary G Robbins, R Haubrich, E Acosta, G Morse, P de Bak- tion, Immune Activation, and Low-level HIV Viremia HIV Infection. Marie Grill, J Peterson, E Lee, K Rob- ker, D Haas, and ACTG. in HIV-infected Individuals with Poor CD4+ T Cell ertson, F Hecht, R Price, and S Spudich. 482. Estimating HIV Transmission Rates to Evalu- Recovery Despite Suppressive ART. Damian Purcell, 421. Minocycline Treatment for HAND: Results ate the Impact of Country-level ART Programs in S Lewin, H Byakwaga, M French, A Kelleher, J Amin, from a Multicenter Trial. Ned Sacktor, S Miyahara, Resource-limited Settings. Vimalanand Prabhu, J H Haskelberg, M Kelly, D Cooper, S Emery. L Deng, S Evans, G Schifitto, B Cohen, R Paul, K Grove, J Barker, P Farnham, P Young, S Hersey, and 360. SIVmac239 DNA and Virus Particle Vaccination Robertson, R Coombs, D Clifford, and Adult ACTG. J Blandford. Confers Protection upon Mucosal Challenge with 423. Low Levels of HIV-1 Detected in the CSF of 483. Decreasing Community Infectiousness Is a Heterologous SIVsmE660. George Pavlakis, R Jalah, Suppressed Subjects Enrolled in a RAL Intensifica- Marker for Decreases in New HIV Infections among V Patel, V Kulkarni, A Valentin, C Alicea, A von tion Study and in Elite Controllers. Viktor Dahl, S Dutch Homosexual Men. Ard van Sighem, D Beze- Gegerfelt, N Sardesai, D Montefiori, and B Felber. Spudich, E Lee, E Ho, R Price, and S Palmer. mer, F de Wolf, and C Fraser. 375. Baseline D-dimer Levels Identify a Subset 424. A Pilot Study of the Effect of RAL Intensifi- 484. Decline in Community Viral Load Strongly As- of Patients at Higher Risk of Death following IL-2 cation on CNS Immunoactivation in Virally Sup- sociated with Declining HIV Incidence among IDU. Administration. Clifford Lane and INSIGHT, ESPRIT pressed Subjects. Richard Price, E Lee, I Leppla, E Gregory Kirk, N Galai, J Astemborski, B Linas, D and SILCAAT. Sinclair, J Peterson, E Ho, S Spudich, and D Fuchs. Celentano, S Mehta, and D Vlahov. 390. HLA Influence on HIV-associated Neurocog- 428. A Comparison of Neuropsychological and 488. Near Perfect Early Adherence to Antiretroviral nitive Impairment: Anhui, China. Rachel Schrier, S Neurological Effects of 3 Antiretroviral Regimens in PrEP against HIV Infection among HIV Serodiscor- Gupta, K Riggs, S Letendre, H Jin, Z Wu, KX Hong, S Diverse RLS: ACTG Study A5199, the International dant Couples as Determined by Multiple Measures: Chuan, R Heaton, and HNRC Group. Neurological Study. Kevin Robertson, J Jiang, J Kum- Preliminary Data from the Partners PrEP Study. Jes- 392. Signs of Neural Injury in Asymptomatic HIV wenda, K Supparatpinyo, S Evans, T Campbell, R sica Haberer, J Baeten, C Celum, E Tumwesigye, E Infection Is Mainly Found in Subjects with Very Low Price, S Tripathy, N Kumarasamy, A LaRosa, and Katabira, M Krows, L Kidoguchi, D Donnell, A Muju- CD4 Cell Counts. J Krut, H Zetterberg, D Fuchs, L ACTG 5199. gira, and D Bangsberg. Hagberg, L Rosengren, S Spudich, R Price, and Mag- 429. CSF Neopterin Decay Characteristics after 513. Rapid Reversion Coupled with Complete and nus Gisslén. Initiation of ART. Aylin Yilmaz, R Price, D Fuchs, L Sustained Wild-type Outgrowth at M184V following 402. Increased Neurocognitive Test Scores after 6 Hagberg, C Yiannoutsos, S Spudich, and M Gisslén. Transmitted Drug Resistance. Teri Liegler, M Abdel- Months in the SMART Neurology Substudy Suggest 430. Increased Turnover of Perivascular Macro- Mohsen, V Jain, T Schmidt, G Spotts, W Hartogen- Learning Effect. Birgit Grund, E Wright, K Robert- phages in the CNS of SIV-infected Rhesus Macaques sis, R Grant, and F Hecht. son, B Brew, M Roediger, M Bain, M Vjecha, J Hoy, is Proportional to Disease Severity and Decreased 514. Detection of Minority Resistance during Ear- J Shlay, R Price, and INSIGHT SMART Study Group. Survival Time. Brian Nowlin, T Burdo, C Conerly- ly HIV-1 Infection: Natural Variation and Spurious 403. CV Risk Factors and Carotid IMT Are Corre- Midkiff, X Alvarez, and K Williams. Detection Rather than Transmission and Evolution of Multiple Viral Variants. Sara Gianella, W Delport, lated to Lower Neurocognitive Performance in HIV- 436. HIV Brain Sequence Database. Alexander Hol- M Pacold, J Young, JY Choi, S Little, D Richman, S infected Patients. Massimiliano Fabbiani, N Cicca- man, M Mefford, and D Gabuzda. relli, MC Silveri, M Tana, S Farina, E Baldonero, V Di Kosakovsky Pond, and D Smith. Cristo, R Cauda, P Grima, and S Di Giambenedetto. 437. Increasing Frequency of a Macrophage-tropic 516. Mega-HAART Suppresses HIV Viremia, Reduc- SIV Variant in Longitudinal Lymphoid Tissues 404. LPS May Be a Predictive Factor Even in Mild mac251 es Viral Reservoir, and Restores Immunity in Periph- and Brain of CD8-depleted Macaques with Neuro- Forms of HIV-associated Neurocognitive Impair- eral Blood and Sigmoid Colon of Acute HIV-infected pathology. Rebecca Gray, S Strickland, S Lamers, T ment: Sub-analysis of the Neuradapt Study. H Subjects. Jintanat Ananworanich, A Schuetz, I Sere- Burdo, B Nowlin, X Alvarez, C Midkiff, M Goode- Carsenti-Dellamonica, Matteo Vassallo, C Pradier, J ti, R Rerknimitr, M deSouza, R Dewar, N Chomont, now, K Williams, and M Salemi. Durant, A Harvey-Langton, C Lebrun-Frenay, J Cot- N Phanuphak, P Phanuphak, J Kim, and RV254/ talorda, V Biscay, M Ticchioni, P Dellamonica, and 438. Neurodegeneration during Progressive HIV-1 SEARCH 010 Study Group. Neuradapt Study Group. Infection of Humanized Mice. Prasanta Dash, S 517. ART Initiation during Acute/Early HIV Infec- 405. Plasma-soluble CD14 Is a Strong Predictor of Gorantla, J Knibbe, G Casale, E Makarov, A Epstein, tion Compared to Later ART Initiation Is Associated Impaired Neurocognitive Test Performance in At- H Gelbard, M Boska, H Gendelman, and L Poluek- with Improved Immunologic and Virologic Param- tention and Learning Domains in HIV-infected Sub- tova. eters during Suppressive ART. Vivek Jain, W Harto- jects. Jennifer Lyons, H Uno, P Ancuta, A Kamat, D 441. Regional Cortical Thinning in Virally Sup- gensis, P Bacchetti, P Hunt, L Epling, E Sinclair, T-H Moore, E Singer, S Morgello, and D Gabuzda. pressed HIV-infected Patients with Detectable Lev- Lee, M Busch, F Hecht, and S Deeks. 406. Higher Levels of Phosphorylated Tau in CSF els of PBMC HIV DNA. Kalpana Kallianpur, G Kirk, 518. Antiviral Activity of a New Small Molecule HIV- Are Associated with HIV Infection, Older Age, Anti- N Sailasuta, V Valcour, B Shiramizu, B Nakamoto, E 1 Attachment Inhibitor, BMS-626529, the Parent of retroviral Use, and Worse Prospective Memory. Hannum, and C Shikuma. BMS-663068. B Nowicka-Sans, Y-F Gong, H-T Ho, R Scott Letendre, D Rosario, R Ellis, M Potter, and SP 442. Prolonged HAART Causes Caudate Volume Colonno, P-F Lin, M Wind-Rotolo, J Kadow, N Mean- Woods. Reduction. Mario Ortega, T Lee, J Thomas, P Ho, D well, R Nettles, and Mark Krystal. 407. CSF Neurofilament H Levels in HIV+ Individu- Clifford, F Vaida, and B Ances. 520. GSK2248761 Retains Potency against Many 101 IAS–USA Topics in Antiviral Medicine

NNRTI Resistance Mutants and Is Additive to Syner- in 4 Sub-Saharan HIV Programs. David Maman, M Aga, H Ribaudo, C Wallis, D Katzenstein, W Stevens, gistic in Combination with Other ART. Cindy Vavro, Pujades-Rodriguez, F Subtil, L Pinoges, M Mcguire, M Norton, K Klingman, B Kallungal, N Kumarasamy, R Ferris, M Edelstein, D Standring, and M StClair. R Ecochard, and J-F Etard. and ACTG. 523. Identification of BI-C, a Novel HIV-1 Non- 560. Delayed ART Initiation and Risk of Death. 584. Second-line LPV/r Monotherapy Was Infe- catalytic Site Integrase Inhibitor. Craig Fenwick, R Christopher Hoffmann, J Lewis, S Charalambous, G rior to TDF/3TC/LPV/r in Patients who Failed NNRTI Bethell, P Bonneau, J Duan, A-M Faucher, S Mason, Churchyard, N Martinson, and R Chaisson. Regimen: HIV STAR Study. Torsak Bunupuradah, P M-A Poupart, B Simoneau, Y Tsantrizos, and C Yoa- 561. Long-term Survival of HIV-infected Adults Chetchotisakd, W Munsakul, S Jirajariyavet, P Kanti- kim. Starting HAART in Thailand: Risk Factors for Early pong, W Prasithsirikul, S Sungkanuparph, C Bowon- 534. Long-term Efficacy of DVR/r Monotherapy in and Late Mortality. F Fregonese, I Collins, G Jour- watanuwong, V Klinbuayaem, K Ruxrungtham, and Patients with HIV-1 Viral Suppression in the MONOI- dain, S Le Coeur, T Cressey, N Ngo-Giang-Huong, HIV STAR Study Team. ANRS 136 Study: Results at 96 Weeks. Marc-Antoine S Banchongkit, A Chutanunta, M Techapornroong, 589. Vicriviroc-resistant HIV-1 Clinical Isolates De- Valantin, C Duvivier, S Lambert-Niclot, P Flandre, A Marc Lallemant, and Prgm for HIV Prevention and pend on the Second Extracellular Loop of CCR5 for Cabié, J-M Molina, L Cuzin, L Slama, A-G Marcelin, Treatment Study Group. Entry and Demonstrate Delayed Entry Kinetics that and C Katlama. 562. Service Delivery Site Factors Are Associated Correct in the Presence of Drug. Opass Putcharoen, 537. Efficacy and Safety of Generic NVP-based with ART Cohort Outcomes—Analysis of National T Henrich, S-H Lee, N Lewine, J Vanichanan, S Rao, First-line ART in China, a Prospective Randomized Assessment Data to Inform Public Health Action. N R Gulick, W Greaves, D Kuritzkes, and A Tsibris. Multicenter 100-week Study. Wei Lu, Y Han, F Guo, Do Thi, T Nguyen Thi Minh, H Do Mai, Masaya Kato, 590. MVC-resistant Viruses Continue to Use ECL2 and T Li. T Cao Thi Thanh, V Nguyen Thi Thuy, K Nguyen and N-terminal Domain Regions of CCR5 for Cell 538. ZDV/3TC vs d4T/3TC Outcomes among HIV- Van, D Bui Duc, L Nguyen Thanh, and M Fujita. Entry. B Jubb, Scott Butler, C Craig, and M Westby. 1-infected Adults Receiving First-line Combination 563. Modular HIV Patient Education: Impact of 591. Signature Mutations in V3 and Bridging Sheet ART in Botswana: Results from a Clinical Trial. Wil- Learning Outcomes on ART Failures, Development Domain of HIV-1 gp120 HIV-1 Are Specifically As- liam Wester, M Blevins, H Bussmann, S Moyo, M of Drug Resistance, Prevalence of Non-infectious sociated with Dual Tropism and Modulate the In- Farahani, B Shepherd, J Makhema, M Essex, V de- Co-morbidities, and Mortality. Olusegun Busari, A teraction with CCR5 N-Terminus. Valentina Svicher, Gruttola, and R Marlink. Busari, A Adeyemi, and HIV Study Group. F Mercurio, A Artese, C Alteri, G Costa, F Stazi, R 539. Predictors of Suboptimal CD4 Response 564. Localized Spatial Distribution of Early Vi- Salpini, S Dimonte, S Alcaro, and CF Perno. among Women Achieving Virologic Suppression ral Response to ART in a South African Area with 592. HIV-1 Disease Stage Significantly Correlates in a Randomized ART Trial, Africa. A Asmelash, Y Significant Spatial Clustering of HIV Cases. Portia with Sensitivity of V3 Sequence-based Predictions Zheng, K Wools-Kaloustian, D Shaffer, F Sawe, R Mutevedzi, R Lessells, T de Oliveira, F Tanser, and of CXCR4 Use. Eoin Coakley, E Stawiski, J Toma, Salata, E Stringer, J Currier, M Hughes, and Shahin M-L Newell. M Haddad, L Napolitano, J Whitcomb, R Leduc, G Lockman. 565. Competing Risks: Loss to Follow-up and Mor- Skowron, M Goetz, and W Huang. 541. Second-line Boosted Protease-containing Ther- tality in HIV Cohort Studies in Zambia and Switzer- 593. Predicting MVC Responses According to Ab- apy: Assessing the Impact of Maintaining 3TC land. Franziska Schöni-Affolter, O Keiser, A Mwan- solute Number vs Proportion of CXCR-4 Using Virus vs Switching to ddI in Addition to 2 Drugs from go, B Chi, B Ledergerber, L Mulenga, A Westfall, N among Treatment-experienced Patients. J Heera, R New Classes in a Randomized Comparison. Ivan Chintu, M Egger, and J Stringer. Harrigan, M Lewis, D Chapman, P Biswas, L Swen- Mambule, S Walker, A Reid, F Ssali, P Munderi, H 566. A Global Clinical Comparison of TDF+3TC son, S Portsmouth, and Hernan Valdez. Grosskurth, D Gibb, J Hakim, P Mugyenyi, C Gilks, +NVP vs TDF+3TC+EFV in Resource-constrained 594. Fitness Interactions of RPV and 3TC/FTC Re- and DART Trial Team. Populations. M Etienne-Mesubi, Anthony Amoroso, sistance Mutations—A Possible Explanation for the 548. Trends in HIV Viral Load among Adults in A Edozien, M Obiefune, R Sheneberger, C Bositis, M Association of E138K and M184I in Clinical Trials. Clinical Care in the US and Canada, 1997-2007. Hossain, and R Redfield. Zixin Hu and D Kuritzkes. Keri Althoff, P Rebeiro, J Gill, M Horberg, J Eron, S 567. Income Decline Is Associated with Virologic 595. Predicting NNRTI Resistance: Do Polymor- Napravnik, K Anastos, R Bosch, R Moore, S Gange, Rebound among HIV+ ART-treated Individuals in phisms Matter? Nicola Mackie, L Garvey, AM Geretti, and North American AIDS Cohort Collaboration on Rural Uganda. Marcella Alsan, F Bajurnirwe, S L Harrison, P Tilston, C Sabin, D Dunn, and UK HIV Res and Design. Weiser, A Tsai, N Emenyonu, C Muzoora, P Hunt, J Drug Resistance Database and UK Collaborative 549. Long-term Follow-up of Patients Receiving Martin, and D Bangsberg. HIV Cohort Study. RAL, ETV, and DRV/r in the ANRS 139 TRIO Trial. 568. ARV Drug Prices, Foreign Assistance, and HIV 596. NNRTI Clearance Rates, Drug-resistance Pro- Catherine Fagard, D Descamps, C Colin, A-M Tabu- Treatment Coverage in Africa. Eran Bendavid, E Le- files, and Virologic Outcomes of Patients Stopping ret, J-M Molina, C Katlama, F Raffi, F Jeanblanc, G roux, J Bhattacharya, N Smith, and G Miller. and Restarting NNRTI-based cART in SMART. Anna Chêne, Y Yazdanpanah, and ANRS 139 TRIO Trial 578. Outcomes after Switch from or Interruption to Maria Geretti, Z Fox, J Johnson, A Owen, J Lipscomb, Group. First ART Regimen: The ART Cohort Collaboration. L Stuyver, A Phillips, and INSIGHT Study Group. 551. Results from a Single Arm Study of DRV/r + Sophie Abgrall, R Cornish, M Mugavero, M Saag, M 598. Predictors of Virologic Response to ETR- RAL in Treatment-naïve HIV-1-infected Patients May, J Sterne, and ART-CC. based cART Regimens in a Large European Cohort (ACTG A5262). Babafemi Taiwo, S Zheng, S Gallien, 579. Effect of Fixed-dose Combinations of NRTI of HIV-infected Patients. Alessandro Cozzi-Lepri, R R Matining, D Kuritzkes, C Wilson, B Berzins, E on Regimen Switching during First Year of Ther- Paredes, A Phillips, J Kjær, A Lazzarin, J van Lunzen, Acosta, P Kim, J Eron, and ACTG A5262 Team. apy: Analysis of the CANOC. Mark Hull, D Moore, A Karlsson, M Johnson, J Lundgren, and EuroSIDA 552. Comparison of Durability and Patient Survival K Chan, D Milan, M Klein, M Loutfy, C Cooper, N Study Group. between NVP-based and EFV-based First-line ART Machouf, J Raboud, R Hogg, and Canadian Obser- 599. Non-active Site Mutations Contribute to Drug Regimens in China’s National Free ART Program. vational Cohort Collaboration. Resistance in HIV-1 Protease by Potentially Altering Yao Zhang, Y Ma, R Zhang, Z Dou, Y Zhao, E Geng, 580. Rates and Predictors of Failure of First-line the Dynamics of Substrate Processing. Seema Mittal H Zhu, and F Zhang. ART and Switch to Second-line ART in South Afri- and C Schiffer. 554. Use of Computational Models to Predict HIV ca: the IeDEA Southern Africa Collaboration. Mat- 600. Key Mutations Maintain Protein Stability dur- Treatment Outcomes in Romania. Luminita Ene, D thew Fox, G van Cutsem, J Giddy, C Hoffmann, M ing the Evolution of Drug Resistance in HIV-1 Prote- Duiculescu, A Revell, D Wang, M Youle, A Pozniak, J Maskew, O Keiser, H Prozesky, R Wood, M Hernan, J ase. Max Chang and B Torbett. Montaner, and B Larder. Sterne, and IeDEA-Southern Africa Network. 601. TPV-resistant HIV-1 Lacks both Protease Enzy- 555. Examining the Interaction between Current 581. Is Duration or Magnitude of Viremia at Time matic Inhibition and Dimerization Inhibition Activ- CD4 Cell Count, Current Viral Load Suppression, of Switch Associated with Ability to Achieve Virolog- ity. Manabu Aoki, K Ide, M Danish, Y Koh, H Aoki- and Time on ART and Mortality. Alana Brennan, M ic Suppression on Second-line ART? Victoria John- Ogata, and H Mitsuya. Maskew, P MacPhail, I Sanne, and M Fox. ston, K Fielding, S Charalambous, M Mampho, M 602. Co-evolution of p1-p6 Results in Altered Inter- 557. Hb Levels at 6 Months and Their Association Eisenstein, P Hippner, M Maraisane, G Churchyard, actions with NFV-resistant D30N/N88D HIV-1 Prote- with Subsequent Mortality among Adults on ART in A Phillips, and A Grant. ase. Madhavi Kolli and C Schiffer. Lusaka, Zambia. Mohammed Limbada, M Giganti, A 582. Adherence to Second-line ART and Long-term Genetic Barrier of DRV Is Decreased by Gag Mwango, L Mulenga, C Bolton-Moore, P Mulenga, J Virologic Outcomes in South Africa. Richard Mur- 603. Polymorphisms. Axel Fun, D de Jong, and M Nijhuis. Stringer, and B Chi. phy, H Sunpath, C Castilla, S Ebrahim, R Court, H 558. Differences in Mortality Rates among Treated Nguyen, D Kuritzkes, V Marconi, J Nachega, and 604. Positive Impact of HIV-1 gag CS A431V Muta- Patients According to Geographical Origin and Eth- South Africa Resistance Cohort Study Team. tion on Virologic Response to DRV/r Boosted with nicity/Race: The ART Cohort Collaboration. I Jarrin, 583. A Pilot Study of LPV/r Monotherapy follow- Ritonavir. L Larrouy, S Lambert-Niclot, C Charpen- Julia Del Amo, and ART-CC. ing Virologic Failure of First-line NNRTI-containing tier, M Wirden, C Katlama, P Yeni, F Brun-Vézinet, V Calvez, A-G Marcelin, and Diane Descamps. 559. Gender Differences in Long-term Immune Regimens in Resource-limited Settings: The Week- Response to ART and Mortality: A Cohort Analysis 24 Primary Analysis of ACTG 5230. John Bartlett, E 605. Protease Associated-resistance Mutations 102 Conference Highlights—Abstracts Cited Volume 19 Issue 2 May/June 2011

in HIV-1 Group O. Agnès Depatureaux, M Leoz, C TMC278 following Administration of EFV in Healthy of Disagreement. Eduardo Seclén, V Soriano, MD Charpentier, A Vessière, D Rousset, J Ladner, J-C Volunteers. Herta Crauwels, J Vingerhoets, R Ryan, J González, S Gomez, A Thielen, and E Poveda. Plantier, and RESO. Witek, and D Anderson. 671. Molecular Determinants of HIV-2 R5/X4 Tro- 606. Integrase Mutation T97A and Resistance to 636. MVC 300 mg Once Daily + DRV/RTV 800/100 pism in the V3 Loop: Development of a New Geno- RAL. S Reigadas, Bernard Masquelier, C Calmels, E mg Once Daily Provides MVC Trough Concentra- typic Tool. B Visseaux, M Hurtado-Nedelec, C Char- Lazaro, M-A Vandenhende, D Neau, H Fleury, and tions Comparable to Trough Concentrations in HIV-1 pentier, G Collin, A Storto, S Matheron, L Larrouy, M-L Andréola. Patients Taking MVC 300 mg Twice Daily + TVD: F Damond, F Brun-Vézinet, Diane Descamps, and 607. Identification of Alternative Amino Acid Sub- Implications for Phase 3 Studies. Stephen Taylor, N ANRS CO 05 HIV-2 Cohort. stitutions at HIV-1 Integrase Codon 143 that Confer Dufty, J Watson, D White, G Gilleran, S Barrett, C 675. Cost Comparison of CD4 vs Viral Load Moni- Reduced Susceptibility to RAL. Wei Huang, S Fran- Robertson, K Gandhi, and E Smit. toring Strategies in Nigeria: A Markov Model. Holly sen, A Frantzell, and C Petropoulos. 641. Single-dose Pharmacokinetic Profile of In- Rawizza, B Chaplin, S Meloni, J-L Sankale, D Hamel, 614. Minority HIV-1 Drug Resistance Mutations and tracellular TFV-DP and FTC-TP in HIV- Volunteers. G Eisen, K Darin, K Scarsi, P Kanki, and APIN the Risk of Initial ART Failure: A Systematic Review Peter Anderson, A Meditz, J Kiser, J-H Zheng, J Pred- PEPFAR Team. and Pooled Analysis. Jonathan Li, R Paredes, H Rib- homme, E Gardner, J Rower, B Klein, C Fernandez, 676. A Single CD4 Test with Threshold >250 Cells/ audo, D Kuritzkes, and Minority Resistance Variants and L Bushman. mm3 Can Markedly Reduce Switching to Second- Working Group. 644. Combination of RAL + 3TC or FTC+ ABV or line ART in African Patients Managed without CD4 618. Rapid Accumulation of Thymidine-analog Mu- TDF Is Safe, Effective, and Prevents Pharmacoki- or Viral Monitoring. Charles Gilks, S Walker, P Mun- tations and Virologic Implications in the Absence of netic Interactions with Immunosuppressive Drugs deri, C Kityo, A Reid, E Katabira, H Grosskurth, P Viral Load Monitoring. Ravindra Gupta, D Pillay, M in HIV-1-infected Solid Organ Transplant Recipients. Mugyenyi, D Gibb, J Hakim, and DART Trial Team. Ranopa, C Kityo, P Munderi, F Lyagoba, N Ndembi, J Miro, Christian Manzardo, M Brunet, F Cofan, A 677. High Rates of Virologic Suppression among C Gilks, T Pattery, P Kaleebu, and DART Virology Rimola, F Pérez-Villa, C Cervera, M Tuset, M La- Patients Not Receiving Routine Virologic Monitoring Group. guno, A Moreno, and Hosp Clin SOT-HIV Working after 5 Years of First-line ART. Cissy Kityo, D Dunn, 619. Global Surveillance of Transmitted HIV-1 Drug Group. R Kasirye, I Mambule, R Goodall, P Kaleebu, D Pil- Resistance in PEPFAR-supported Countries Using a 646. Co-administered HAART and CYP450 EI-AED: lay, C Gilks, D Gibb, P Mugyenyi, and DART Trial Broadly Sensitive Genotyping Assay. Chunfu Yang, Implications for HIV/Epilepsy Treatment in Re- Team. BD Nguyen, E Bile, L Marum, N Wagar, and J Nken- source-limited Settings. Jason Okulicz, G Grandits, 678. Immunological Response and Mortality in gasong. J French, D Simpson, J George, A Weintrob, A Ga- ART Programs with and without Routine Viral Load 620. NVP and 3TC-resistant HIV-1 Detected in nesan, M Bavaro, T Lalani, M Landrum, and IDCRP Monitoring in Southern Africa. Olivia Keiser, B Chi, Antiretroviral-naïve Kenyans Initiating NNRTI-based HIV Working Group. T Gsponer, A Boulle, C Orrell, S Phiri, A Westfall, M ART. Sandra Dross, M Chung, J Kiarie, G John-Stew- 650. Pharmacokinetic Evaluation of Different Ri- Maskew, H Prozesky, M Egger, and IeDEA Southern art, J Overbaugh, S Sakr, and L Frenkel. fabutin Dosing Strategies in African TB Patients Africa. 621. Increasing Primary HIV-1 Drug Resistance on Lopinavir/ritonavir-based ART. Suhashni Naiker, 680. Predictive Value of CD4 Count for the among Recently Infected Persons in Uganda, East C Conolly, L Weisner, D Phillips, A Harries, C Lien- 12-month Risk of Death among Untreated HIV-1+ Africa. Nicaise Ndembi, R Hamers, K Sigaloff, C Wa- hardt, H McIlleron, and A Pym. Children: Abidjan, Côte d’Ivoire. K Malateste, E Aka, tera, B Nanteza, F Lyagoba, M Van Vugt, P Kaleebu, 656. Modification of the Abbott Real Time PCR S Desmonde, C Amani-Bosse, F Dabis, P Toure, A T Rinke de Wit, on behalf of PharmAccess African Assay to Detect HIV-1 Plasma RNA Viral Loads Alioum, F-E Tanoh, and Valériane Leroy. Studies to Evaluate Resistance. <1 Copy/mL. Steven Yukl, P Li, K Fujimoto, S 681. Serious Morbidity, Mortality, and Loss to Fol- 622. HIV-1 Drug Resistance in ARV-naïve Individu- Deeks, T Liegler, M Pandori, D Havlir, and J Wong. low-up of Untreated HIV+ Children in a Pediatric als in Sub-Saharan Africa Is Associated with Time 662. A Simplified Universal Assay for HIV-1 Drug Care Program: Abidjan, Côte d’Ivoire, 2004 to 2009. since Scale-up of ART. Raph Hamers, C Wallis, C Resistance Genotyping in Africa. Susan Aitken, M Sophie Desmonde, P Coffie, E Aka, C Bosse, E Mes- Kityo, M Siwale, F Conradie, K Mandaliya, K Si- Bronze, S Balinda, C Kityo, C Wallis, T Rinke de Wit, sou, X Anglaret, F Dabis, A Alioum, A Ciaranello, galoff, R Schuurman, W Stevens, T Rinke de Wit, K Steegen, and R Schuurman. and V Leroy. and PharmAccess African Studies to Evaluate Re- 663. Low-cost Detection of HIV Drug Resistance 682. Virologic Response among ARV-experienced sistance. in West African Subtypes by Multiplex Ligation- Ugandan Children on NNRTI-based First-line Thera- 623. National Prevalence and Trends of HIV Trans- amplification PCR-based Method. Nzovu Ulenga, B py Enrolled in ART Programs Using Clinical and Im- mitted Drug Resistance in Mexico. Santiago Avila- Chaplin, and P Kanki. munologic Criteria to Assess Response to Therapy. Rios, C Ormsby, C Garcia-Morales, D Garrido-Rodri- 664. National HIV Drug Resistance Surveillance Us- Linda Barlow-Mosha, P Mudiope, W Massavon, D guez, J Andrade-Villanueva, L Gonzalez-Hernandez, ing Tagged Pooled Pyrosequencing. Hezhao Ji, Y Li, Bagenda, M Etima, D Wabwire, MG Fowler, M Nan- I Torres-Escobar, S Navarro-Alvarez, L Ceja-Barrera, M Graham, B Liang, S Tyler, S Tyson, G Peters, H yonga, C Giaquinto, and P Musoke. G Reyes-Teran, and Mexican HIV Molecular Epi Proj- Merks, P Sandstrom, and J Brooks. 684. Wamepotea [They have become lost]: Out- ect Group. 666. Relative Performance of ESTA, Trofile, 454 comes of HIV-infected and HIV-exposed Children 624. Prevalence of Transmitted HIV-1 Antiretroviral Deep Sequencing, and “Reflex” Testing for HIV Lost to Follow-up from a Large HIV Treatment Pro- Resistance among Patients Initiating ART in Brazil: Tropism in the MOTIVATE Screening Population of gram in Western Kenya. Paula Braitstein, J Songok, A Surveillance Using Dried Blood Spots. C Soares, T Therapy-experienced Patients. Chanson Brumme, T R Vreeman, K Wools-Kaloustian, S Ayaya, W Nyan- Vergara, MC Sucupira, C Brites, D Urbaez, F Pereira, Wilkin, Z Su, J Schapiro, R Kagan, D Chapman, J diko, C Yiannoutsos, and IeDEA East Africa Con- M Caseiro, C Correa, S Komninakis, Ricardo Diaz, Heera, H Valdez, and R Harrigan. sortium. and HIV-1 RESPRI Study Group. 667. Geno2Pheno False Positive Rate of Standard 685. Outcomes and Outpatient Costs of Pediatric ART in Zambia and South Africa. G Meyer-Rath, K HIV-1 Drug Resistance in Antiretroviral-naïve V3 Population Sequencing Predicts Burden of X4 625. McCoy, B Ndibongo, M Nalubamba-Phiri, A Bren- Patients with HIV-associated Tuberculous Meningi- Quasi-species. Valentina Svicher, V Cento, G Rozera, nan, L Long, C Bolton-Moore, K Technau, A Coova- tis in Ho Chi Minh City, Vietnam. Thao Vu, T Le, E I Abbate, G Palamara, G Rizzardini, L Sarmati, F dia, and Sydney Rosen. Török, Y Nguyen, C Tran, S Jurriaans, R Doorn, M de Ceccherini-Silberstein, MR Capobianchi, and CF Jong, J Farrar, and S Dunstan. Perno. 690. Behavioral, Biological, and Demographic Risk 668. Genotypic Analysis of Cellular HIV V3 DNA Factors for New HIV Infections among Youth: Rakai 626. Monitoring ART: Clinic and Program Perfor- to Predict Virologic Response to Maraviroc: Perfor- District, Uganda, 1999 to 2008. John Santelli, M mance Using WHO HIV Drug Resistance Early mance of Population-based and 454 Deep V3 Se- Orr, Y Wei, S Mathur, F Nalugoda, T Lutalo, R Gray, J Warning Indicators in 21 Countries. Michael Jordan, quencing. Luke Swenson, R McGovern, I James, J Higgins, M Wawer, and D Serwadda. K Kelley, A Saadani Hassani, Y Obeng-Aduasare, Demarest, D Chapman, S Ellery, J Heera, H Valdez, Starting Late and Stopping Early: Disparities and S Bertagnolio. 692. R Harrigan, and A Poon. in HAART Utilization for Behaviorally HIV-infected 627. TBR-652 Absorption, Distribution, Metabo- 669. Plasma and PBMC Viruses Provide Equivalent Youth. Allison Agwu, R Rutstein, A Gaur, S Spector, lism, and Excretion Profile in Rats, Dogs, Monkeys, Genetic Information for Genotypic Tropism Testing: R Warford, K Gebo, and HIV Res Network. and Humans. David Martin, M Kawase, S Asahi, Analysis Using Quantitative Deep HIV-1 Sequenc- 693. Status of Vertically-acquired HIV-infected Y Tagawa, T Kondo, A Morohasi, M Nishihara, H ing. Christian Pou, F Codoñer, A Thielen, R Bellido, Children at the Time of their Transfer to an Adult Yamasaki, R Ogden, and S Palleja. M Schiaulini, S Pérez-Álvarez, E Coakley, M Däumer, Clinic. Jesus Saavedra-Lozano, M Navarro, P Rojo, I 629. Low-dose RTV and the Pharmacokinetics of B Clotet, R Paredes, and Barcelona Tropism Study Gonzalez-Granado, I De Jose, S Jimenez de Ory, M the Investigational HCV Protease Inhibitor TVR in Group. Mellado, MA Muñoz-Fernández, J Ramos, and Ma- Healthy Volunteers. Varun Garg, X Luo, L McNair, R 670. High Concordance between PSSM and Geno- drid Cohort of HIV-infected Children van Heeswijk, and R Kauffman. 2Pheno Algorithms for Genotypic Interpretation 694. Clinical Outcomes of HIV-1+ Adolescents and 630. Pharmacokinetic Parameters of Once-daily of HIV-1 Tropism—V3 Length as the Major Cause Young Adults in Adult-oriented Care. Patrick Ryscav- 103 IAS–USA Topics in Antiviral Medicine

age, S Sutton, E Anderson, B Armbruster, and B K Powis, S Moyo, J Makhema, M Essex, and Mma 791. Initiation of cART for HIV Infection and the Taiwo. Bana Study Team. Risk of Non-AIDS Diseases. Shuangjie Zhang, A van 695. Psychosocial Distress, Age at Initiation, and 749. Risk Associated with First Trimester Exposure Sighem, L Gras, J Prins, R Kauffmann, C Richter, P Treatment Failure in HIV+ African Youth. Eliza- to NVP. S Storfer and Peter Piliero. Reiss, F de Wolf, and ATHENA Natl Observational beth Lowenthal, K Lawler, N Harari, E Seloilwe, B 750. Higher Mitochondrial DNA Content Compen- Cohort. Matome, M Masedi, L Moamogwe, J Masunge, and sates for Lower Mitochondrial-encoded Complex 797. Untreated HIV Infection Is Associated with R Gross. IV Activity in ARV-exposed Healthy Infants. Antoni Decreased Thrombin Generation and Increased 705. Low Bone Mass in Behaviorally HIV+ Young Noguera-Julian, N Rovira, C Morén, G Garrabou, M Thrombin Inhibition. Priscilla Hsue, E Weiss, R Men on ART: ATN 021b. Kathleen Mulligan, R Har- Nicolás, F Cardellach, E Sánchez, Ó Miró, and C Scherzer, S Nordstrom, L Kohl, V Selby, A Schnell, J ris, P Emmanuel, R Fielding, D Hardin, C Worrell, Fortuny. Martin, P Hunt, and S Deeks. B Kapogiannis, D Monte, J Sleasman, G Aldrovandi, 751. Association of in utero ARV Exposure with 798. D-Dimer Levels Correlate with Inflammatory and ATN 021b Study Team. Late Language Emergence in HIV− Children Born and Endothelial Activation Markers in HIV+ Adults. 706. Bone Mineral Density, Vitamin D Status, Di- to HIV+ Mothers. Paige Williams, A Buchanan, T Caryn Morse, M McLaughlin, A Rupert, R Stevens, etary Consumption, and Body Composition in Peri- Frederick, R Smith, K Malee, M Purswani, P Sirois, A Jichlinski, A Cullinane, K Ngheim, M Proschan, J natally HIV-infected Adolescents: Associations with G Siberry, H Hoffman, M Rice, and Pediatric HIV/ Lozier, and J Kovacs. Longitudinal Changes in Bone Mineral Content. An- AIDS Cohort Study. 799. Circulating Markers of Coagulation, Endotheli- nie Schtscherbyna, L Mendonça, C Gouveia, R Luiz, 753. Maternal HIV Disease Progression after the al Dysfunction, and Tissue Fibrosis Prior to Incident F Pinheiro, ML Farias, and E Machado. Interruption of Triple ARV or Short-course ARV Venous Thromboembolism in Patients with HIV 707. 2-Year Bone Mass Accrual in HIV+ Children Prophylaxis to Prevent MTCT: MTCT-Plus. Koumavi Infection. Laura Musselwhite, V Sheikh, T Norton, and Adolescents after Bi-monthly Supplementation Ekouevi, R Carter, N Phanuphak, M Schlesinger, and A Rupert, B Porter, S Penzak, J Skinner, J Mican, C with Oral Cholecalciferol and Calcium. Stephen Ar- E Abrams. Hadigan, and I Sereti. padi, D McMahon, E Abrams, B Mahrukh, M Pur- 754. EFV Pharmacokinetics during the Third Tri- 801. Mortality and Length of Stay for HIV+ Persons swani, E Engelson, M Horlick, and E Shane. mester of Pregnancy and Postpartum. Tim Cressey, Admitted for Acute Coronary Syndrome. M Lee, P 735. Extremely Low Risk of MTCT of HIV in Wom- A Stek, E Capparelli, C Bowonwatanuwong, S Prom- Trivedi, Angelique Tjen-A-Looi, L Hannan, P Kumar, en Starting HAART before Pregnancy: French Peri- mas, Y Huo, J Read, E Smith, B Best, M Mirochnick, and J Timpone.. natal Cohort, ANRS EPF CO1/11. Roland Tubiana, and IMPAACT P1026s Team. 802. Accelerated Vascular Aging with HIV-1 Infec- S Matheron, J Le Chenadec, C Dollfus, A Faye, S 757. Drug Concentrations in Breastfeeding Infants tions Regardless of ART Status. Kyle Diehl, E Con- Blanche, C Rouzioux, V Benhammou, L Mandelbrot, of Women Receiving ARV for the Prevention of Post- nick, B Stauffer, and C DeSouza. J Warszawski, and ANRS CO1/CO11. natal Transmission in Malawi. G Liotta, M Pirillo, M 804. Association of Müllerian Inhibiting Substance, 736. Are Sequential Pregnancies in HIV+ Women Andreotti, J-B Sagno, A Doro Altan, E Marchei, MC a Marker of Ovarian Reserve, with Surrogates of Ath- Associated with an Increased Risk of MTCT? Clare Marazzi, S Vella, L Palombi, and Marina Giuliano. erosclerosis in HIV+ Women. Christopher LaCross, French, C Thorne, M Cortina-Borja, and P Tookey. 758. Incidence of HIV-1 Resistance Mutations fol- C Wanke, S Cu-Uvin, S Skinner, and A Mangili. 737. Women Identified as Recently Infected at the lowing Triple-ARV Prophylaxis for the Prevention 805. Epicardial Adipose Tissue Volume Is an In- Time of Delivery Using a Multi-assay Algorithm for of MTCT in the Kesho Bora Randomized Controlled dependent Risk Factor of CVD in HIV-infected Pa- HIV Incidence Had a Higher Rate of in utero HIV Trial, Burkina Faso. V Foulongne, I de Vincenzi, J tients. S Zona, P Raggi, G Orlando, F Carli, G Liga- Transmission: PEPI-Malawi Trial. Susan Eshleman, N’Gou, F Rouet, M Segondy, N Meda, T Farley, bue, R Scaglioni, G Besutti, R Rossi, MG Modena, M James, D Hoover, J Sun, O Laeyendecker, C Mul- Philippe Van de Perre, and Kesho Bora Study Group. and Giovanni Guaraldi. lis, L Mofenson, A Taylor, N Kumwenda, and T Taha. 759. Suppression of NVP Resistance with 7- vs 21- 806. Associations between Visceral and Subcutane- 739. What Will It Take to Eliminate Pediatric HIV? day ARV Regimens after Single-dose NVP: Results ous Fat Depots with Total and Calcified Coronary Reaching “Virtual Elimination” Targets for Preven- of A5207. Deborah McMahon, F Noel, L Zheng, J Plaque: The MACS. Frank Palella, X Li, L Jacobson, tion of MTCT: Zimbabwe. Andrea Ciaranello, F Per- Kabanda, E Halvas, F Taulo, N Kumarasamy, C Wal- T Brown, L Kingsley, M Witt, M Budoff, and W Post. ez, J Keatinge, J-E Park, B Englesmann, M Maruva, lis, M Hughes, J Mellors, and A5207 Study Team. 807. Prognostic Value of Apolipoprotein B/A1 Ra- R Walensky, F Dabis, A Mushavi, and K Freedberg. 760. Efficacy of 1-Week ZDV+3TC Post-partum to tio, Total Cholesterol/HDL Ratio, and Small LDL/ 740. Effectiveness of Maternal HAART vs ZDV to Prevent NVP-resistance Mutations in Non-immuno- HDL Particle Concentrations for CHD in HIV+ Par- Prevent MTCT in a Programmatic Setting: Botswa- compromised Women Who Received Standard ZDV ticipants in the SMART Study: A Nested Case-con- na. Scott Dryden-Peterson, O Jayeoba, H Jibril, K Prophylaxis + Intrapartum sdNVP for PMTCT. Nicole trol Study. D Duprez, Jacqueline Neuhaus, J Baker, Keapoletswe, J Tlale, A Asmelash, S Moyo, J Makhe- Ngo-Giang-Huong, G Jourdain, P Kanjanavikai, W and INSIGHT SMART Study Group. ma, R Shapiro, and S Lockman. Suwankornsakul, T Jarupanich, A Limtrakul, S Sang- 808. No Association of Myocardial Infarction with 742. Efficacy and Safety of Maternal Triple-drug sawang, T Siriwachirachai, S Mahattanan, M Lalle- ABC Use: An FDA Meta-analysis. X Ding, E Andraca- ARV Regimens: Thai Red Cross PMTCT Program, mant, and PHPT-5 Study Team. Carrera, C Cooper, P Miele, C Kornegay, M Soukup, 2004 to 2010. Nittaya Phanuphak, S Teeratakul- 761. Initiation of ART in Women after Delivery and Kendall Marcus. pisarn, A Chinmahun, J Ooprasithiwong, P Matha- Can Induce Multi-class Drug Resistance in Breast- 809. HIV Is Associated with Clinically Confirmed jittiphun, K Jittarach, W Pima, S Intarasuk, S Lim- feeding HIV-infected Infants: PEPI-Malawi Trial. Jes- Myocardial Infarction after Adjustment for Smok- pongsanurak, and P Phanuphak. sica Fogel, Q Li, T Taha, D Hoover, N Kumwenda, ing and Other Risk Factors. Matthew Freiberg, K 743. Large Increase in Prematurity between 1990 L Mofenson, J Kumwenda, MG Fowler, M Thigpen, McGinnis, A Butt, M Goetz, S Brown, KA Oursler, M and 2009 in HIV-infected Women in the National and S Eshleman. Rodriguez-Barradas, C Gibert, D Rimland, A Justice, ANRS French Perinatal Cohort: Does Ritonavir 762. Baseline Seroprevalence of HPV Vaccine and Veterans Aging Cohort Study and VA IHD Qual- Boost Play a Role? Jeanne Sibiude, J Warszawski, R Types 6, 11, 16, and 18 in HIV+ Women Receiv- ity Enhancement Res Initiative. Tubiana, C Dollfus, A Faye, C Rouzioux, J-P Teglas, D ing the Quadrivalent Vaccine in the AIDS Clinical Trials Group Study A5240. Erna Kojic, M Cespedes, 810. Contribution of Immunodeficiency to CHD: Ekoukou, S Blanche, L Mandelbrot, and ANRS CO1/ Cohort Study of HIV+ and HIV− Kaiser Permanente CO11. T Umbleja, M Kang, J Aberg, R Allen, C Godfrey, S Cu-Uvin, and ACTG A5240 Team. Members. Daniel Klein, W Leyden, L Xu, C Chao, M 744. Risk Factors of Preterm Delivery and Low Birth Horberg, W Towner, L Hurley, C Quesenberry, and Weight in a Multicenter Cohort of HIV+ Pregnant 763. Seroprevalence of HPV Vaccine Types 6, 11, M Silverberg. Women. Maria Isabel González-Tomé, I Cuadrado, E 16 and 18 in HIV+ Women from South Africa, Bra- 813. sCD163, a Novel Marker of Activated Macro- Muñoz, L Prieto, B Soto, B Fraile, T del Rosal, M de zil, and Botswana. Cynthia Firnhaber, D Evans, R phages, Is Associated with Noncalcified Coronary Matías, J Ramos, M Fernandez Ibieta, and Spanish Khalili Friedman, S Williams, K Mallhagela, C West- Plaque in HIV Patients. T Burdo, Janet Lo, J Wei, S Cohort for the Study of HIV MTCT. er, B Grinsztejn, and S Lockman. Abbara, F Preffer, E Rosenberg, K Williams, and S 746. Protease Inhibitor-based ART Was Associated 789. Changing Patterns of Causes of Death: SHCS, Grinspoon. with Preterm Delivery, but Not Adverse Infant Out- 2005 to 2009. M Ruppik, B Ledergerber, M Ricken- comes, in a Randomized MTCT Prevention Study bach, H Furrer, M Battegay, M Cavassini, B Hirschel, 815. ABC Induces Leukocyte Adhesion in Arteri- in Botswana. Kathleen Powis, D Kitch, A Ogwu, M E Bernasconi, M Flepp, Rainer Weber, and Swiss oles. C de Pablo, S Orden, N Apostolova, J Esplu- Hughes, S Lockman, J Leidner, E van Widenfelt, J HIV Cohort Study. gues, and Angeles Alvarez. Makhema, M Essex, and R Shapiro. 790. Risk of Cause-specific Deaths over Calendar 822. Vitamin D Deficiency in Chicago Women: 747. Increased Maternal and Infant Mortality fol- Time and According to Cumulative Exposure to When Sunlight Is Not Enough. Mariam Aziz, O Ad- lowing Completion of HAART and Breastfeeding at cART. Justyna Kowalska, A Mocroft, J Reekie, A Phil- eyemi, D Agniel, K Weber, A French, and M Cohen. 6 Months Postpartum in a Randomized PMTCT Tri- lips, P Reiss, B Ledergerber, J Gatell, A d’Arminio 823. Low Vitamin D Levels and Bone Density al: Botswana, the Mma Bana Study. Roger Shapiro, Monforte, J Lundgren, O Kirk, for EuroSIDA Study Changes in Young HIV+ Israeli Women. Eduardo D Kitch, M Hughes, A Ogwu, S Lockman, S Souda, Group. Shahar, G Hassoun, E Kedem, and S Pollack. 104 Conference Highlights—Abstracts Cited Volume 19 Issue 2 May/June 2011

825. TDF Therapy Is Independently Associated to Associated with All-cause Mortality among HIV+ Hentig, I Wieters, P Khaykin, G Nisius, A Haberl, C Hyperparathyroidism in HIV-infected Treated Pa- Persons with Cancer: HOPS during the HAART Era. Stephan, H Doerr, R Allwinn, and HR Brodt. tients. D Pocaterra, L Carenzi, E Ricci, D Minisci, M P Patel, J Brooks, C Armon, K Buchacz, J Chmiel, K 907. A Randomized Trial to Compare the Immu- Schiavini, P Meraviglia, M Campaniello, M Bevilac- Wood, and Richard Novak. nogenicity and Efficacy of Adjuvanted Pandemic qua, G Rizzardini, and Paolo Bonfanti. 868. Mortality Remains High in HIV-associated H1N12009 Vaccine with or without Booster in 827. Vitamin D3 Supplementation Decreases the Lung Cancer. Christian Hoffmann, M Sabranski, C HIV+ Adults. Curtis Cooper, M Klein, S Walmsley, D Risk of Diabetes Mellitus among Patients with HIV Wyen, A Baumgarten, M Hensel, J Bogner, B Schaaf, Hasse, D Scheifele, and Publ Hlth Agency of Canada- Infection. G Guaraldi, S Zona, Gabriella Orlando, F R Pauli, F Kohrs, and H Jäger. Canadian Inst of Hlth Res Influenza Res Network. Carli, G Ligabue, C Stentarelli, M Menozzi, E Gar- 870. Clinical Characteristics and Outcome of HIV+ 909. Durability of the Immune Response after lassi, C Giovanardi, and P Tebas. Patients with Invasive Anal Cancer. Christian Hoff- Vaccination with 2 Doses of Influenza A H1N1v 829. Vitamin D Supplementation and Endothelial mann, M Sabranski, C Wyen, A Baumgarten, J Rock- 2009 Vaccine Formulated with and without AS03A- Function among Vitamin D-deficient HIV-infected stroh, J Bogner, H Jäger, A Jessen, S Hansen, and S adjuvant in HIV+ Adults: ANRS 151 Randomized Persons: A Randomized Placebo-controlled Trial. Esser. HIFLUVAC Trial. C Durier, C Desaint, N Colin de Chris Longenecker, C Hileman, T Carman, A Ross, 871. 24 Months of cART Is Not Associated with Verdière, P-M Girard, Y Lévy, D Rey, C Jacomet, F V Tangpricha, S Seydafkan, T Brown, D Labbato, N a Reduction of Anal HPV Infection in HIV+ MSM. Lucht, J-P Aboulker, Odile Launay, and ANRS 151 Storer, and G McComsey. Christophe Piketty, A Si-Mohamed, E Lanoy, S Tra- Study Group and REIVAC Network. 830. Incidence and Predictors of Fracture in HIV- belsi, R Tubiana, C Rouzioux, E Tartour, P-M Girard, 910. Immunogenicity to an H1N1 Adjuvanted In- infected Individuals: ALLRT. Michael Yin, M Kendall, L Weiss, D Costagliola, and Valparaiso Study Group. fluenza Vaccine in HIV-infected Adults: 2 Single vs 2 X Wu, K Tassiopoulos, J Huang, E Shane, M Hoch- 872. High-grade Anal Intraepithelial Neoplasia and Double Doses: The VIP-H1N1 Study. Marilia Santini- berg, and G McComsey. High-risk HPV Infection among HIV+ and HIV− Oliveira, L Camacho, T Souza, M Siqueira, C Gia- 832. Bone Effects of Rosi in HIV+ Patients with Thai MSM. Nittaya Phanuphak, N Teeratakulpisarn, coia-Gripp, E Nunes, A Lemos, R Ismério Moreira, V Lipoatrophy. Allison Ross, T Brown, C Hileman, N S Kerr, S Triratanachat, S Keelawat, T Pankam, A Gonçalves Veloso, and B Grinsztejn. Rizk, D El Bejjani, M Tungsiripat, N Storer, D Lab- Sukjitpaiboonphol, P Phanuphak, J Ananworanich, 912. Frequent HCV Re-infection in HIV+ MSM. X bato, and G McComsey. and J Palefsky. Thomas, R Molenkamp, J Roozendaal, M de Jong, M 833. Changes in Bone Biomarkers in ARV-naïve 877. Performance of QuantiFERON-TB Gold for De- Prins, Jan van der Meer, and J Schinkel. HIV+ Men Randomized to NVP/LPV/r or AZT/3TC/ tecting TB in HIV+ Adults in Sub-Saharan Africa. M 914. HIV/HCV Co-infection Increases Fracture LPV/r Help Explain Limited Loss of Bone Mineral Kabran, A Inwoley, RD Moh, A Badje, J Lecarrou, F Risk Compared to HCV Mono-infected, HIV Mono- Density over the First 12 Months after ART Initia- Bohoussou, D Gabillard, S Eholié, X Anglaret, and infected, and Uninfected Patients. J Volk, R Localio, tion. M van Vonderen, Patrick Mallon, B Murray, P Christine Danel. C Newcomb, Y-X Yang, S Hennessy, J Kostman, P Doran, M van Agtmael, S Danner, P Lips, P Reiss, for 878. Performance of Urine LAM Testing for Screen- Tebas, M Leonar, and Vincent Lo Re III. MEDICLAS Study Group. ing Ambulatory HIV+ Persons for TB. Celine 921. Long-term Liver Fibrosis Progression in HIV/ 834. Effects of Tesamorelin, a Growth Hormone- Gounder, T Kufa, S Charalambous, N Wada, Y Hani- HCV Co-infected Patients with F0-F2 Baseline Histo- releasing Factor Analogue, on Bone Turnover Mark- fa, K Fielding, A Grant, S Dorman, R Chaisson, and logical Stage. Cristina Tural, A Jou, N Pérez-Álvarez, ers in HIV+ Patients with Excess Abdominal Fat. J-C G Churchyard. R Sanmartin, B Revollo, J Tor, R Muga, A Sanvisens, Mamputu, G Soulban, J Falutz, MH Pham, C Marso- 879. High Yield, Sensitivity, and Specificity of E Martinez, and B Clotet. lais, H Assaad, and Steven Grinspoon. Xpert MTB/RIF for M. tuberculosis Detection in Fine 925. LDL Level as a Prognostic Tool for Liver 835. Association of Regional Body Composition Needle Aspirates from HIV-Infected TB Suspects. Disease Progression in HIV/HCV Co-infection. M with Bone Mineral Density in HIV-infected and Annelies Van Rie, C Menezes, L Scott, K Mellet, N Habayeb, Adefowope Odueyungbo, K Rollet, S -uninfected Women: Women’s Interagency HIV Gous, M-A John, M Mkhwanazi, L Page-Shipp, W Saeed, S Walmsley, N Pick, B Conway, J Cox, M Hull, Study. A Sharma, F Tian, M Yin, M Keller, M Cohen, Stevens, and I Sanne. M Klein, and Canadian Co-infection Cohort Study S Gange, and Phyllis Tien. 881. Effect of cART Timing on Survival in HIV/TB CTN222. 836. Baseline Renal Function as Predictor of Mor- Co-infection: Western Kenya. Ann Mwangi, J Ho- 936. Role of Immune Activation and Microbial tality and Renal Disease Progression in HIV-infected gan, R Kantor, J Carter, and A Siika. Translocation in Liver Disease Progression in HIV/ Patients. F Ibrahim, L Hamzah, R Jones, D Nitsch, C 882. Timing of ART Initiation during TB Treat- HCV Co-infected ARV-naïve Patients with High Sabin, Frank Post, and UK CHIC/CKD Study Group. ment and Early HIV RNA and CD4 T Lymphocyte CD4+ Count. G Marchetti, A Cozzi-Lepri, Giusi 837. Predictors of Chronic Kidney Disease: SMART Responses. Simbarashe Takuva, M Maskew, D West- Maria Bellistrì, E Merlini, F Ceccherini-Silberstein, trial. J Neuhaus, A Mocroft, C Wyatt, Michael Ross, reich, L Mcnamara, I Sanne, and L Page-Shipp. A De Luca, A Antinori, A Castagna, M Puoti, and and INSIGHT SMART Study Group. 886. TB Treatment Completion Rates in an HIV/TB A d’Arminio Monforte, for the Icona Fndn Study Group. 838. Renal Insufficiency Risk among HIV+, ART- Treatment Program: Durban, South Africa. Ingrid naïve Individuals in Lilongwe, Malawi: Implications Bassett, B Wang, S Chetty, M Mazibuko, J Giddy, Z 937. LPS, Immune Activation, and Liver Disease in for TDF Use in ART and PMTCT Programs. Derek Lu, R Walensky, K Freedberg, and E Losina. HIV/HBV Co-infection and the Effects of HBV-active Johnson, C Chasela, M Maliwichi, A Mwafongo, A 887. Risk Factors and Timing of Mortality in HIV+ HAART. M Crane, R Rajasuriar, Anchalee Avihing- Akinkuotu, A Moses, D Jamieson, A Kourtis, C van Smear-negative TB Suspects: 12-Month Cohort sanon, G Matthews, N Skinner, P Tangkitvanich, G der Horst, and M Hosseinipour. Study in Harare, Zimbabwe. Peter MacPherson, M Dore, K Visvanathan, K Ruxrungtham, and S Lewin. 839. Lipid Particle Concentrations and Markers Dimairo, T Bandason, A Zezai, S Munyati, S Mun- 939. Plasma Soluble CD14 Levels Are Associated of Renal Disease: SMART. Alison Bormann, J Neu- gofa, S Rusikaniko, K Fielding, P Mason, and E Cor- with Severity of Liver Disease and Predict Clinical haus, M Ross, D Duprez, and INSIGHT SMART Study bett. Outcome in Hepatitis B and C Infections. Netanya Group. 890. TB and HIV Service Integration within a South Sandler, A Roque, C Koh, J Eccleston, S Deeks, J Li- ang, T Heller, and D Douek. 841. Small but Significant and Non-progressive African Primary Health Care Setting Reduces the Decline in GFR Observed in Therapy-naïve HIV+ Time to ART Initiation without Negatively Impact- 943. IL28B (rs12979860) Allelic Variant in HIV+ Subjects Commencing r/ATV, Compared to either ing TB Outcomes. Colin Brown, B Kerschberger, A Patients with Acute Hepatitis C. Jacob Nattermann, EFV or ZDV/ABC with TDF/FTC after 48 Weeks: A Boulle, D Coetzee, F Post, V Azevedo, E Goemaere, P Ingiliz, A Baumgarten, S Mauss, M Danta, U Nau- Randomized Controlled Study. C Dazo, P Fahey, K Hilderbrand, M Rangaka, and G van Cutsem. mann, C Boesecke, U Spengler, V Soriano, J Rock- Rebekah Puls, A Winston, C Boesecke, A Avihing- 893. Comparison of the Early Fungicidal Activity of stroh, and NEAT Study Group. sanon, J Amin, J Rooney, D Cooper, S Emery, and High-dose 5-FC, Voriconazole, and Flucytosine, as 944. Estimating the Net Contribution of IL28B Vari- Altair Study Group. Second Drugs Given in Combination with Ampho- ation to Spontaneous HCV Clearance. Julia di Iulio, 845. Changes in Body Composition after Switching tericin B, to Treatment of HIV-associated Cryptococ- K Fitzmaurice, D Kelleher, M Rotger, J Fellay, H Gün- from PI/r to RAL in Virologically Suppressed HIV-1+ cal Meningitis. Angela Loyse, D Wilson, G Meintjes, thard, M Battegay, P Klenerman, A Telenti, A Rauch, Patients: SPIRAL LIP Substudy. Adria Curran, M J Jarvis, T Bicanic, L Bishop, K Rebe, L-G Bekker, R and Swiss HIV Cohort Study. Saumoy, E Martinez, M Larrousse, D Podzamczer, Wood, and T Harrison. 945. IL-28B GT Influences Chronification of Hepati- I Ocaña, M Lonca, J Gatell, E Ribera, and SPIRAL 894. Short-course AmB with High-dose Flucon- tis C in HIV/HCV GT 1/4 Co-infected Patients and Ef- Study Group. azole for HIV-associated Cryptococcal Meningitis. ficiently Predicts Response to Hepatitis C Treatment 846. Switching ZDV to TDF Improves Subcutane- Conrad Muzoora, T Kabanda, G Ortu, J Ssentamu, when Combined with Viral GT and Baseline Plasma ous Adipose Tissue Volume and mtDNA Content. P Hearn, J Mwesigye, N Longley, J Jarvis, S Jaffar, HCV-RNA Load in the Co-infected Population. Karin Eoin Feeney, S Vrouenraets, F Wit, K Brinkman, E and T Harrison. Neukam, J Nattermann, N Rallón, A Rivero, A Ca- Capel, P Domingo, F Villaroya, J Capeau, P Reiss, 906. Immune Response after 2 Doses of the Novel ruz, J Macías, J Rockstroh, J Benito, V Soriano, and P Mallon, on behalf of the PREPARE Study Group. Split Virion, Adjuvanted Pandemic H1N1 Influenza J Pineda. 867. Survival after Cancer Diagnosis and Factors A Vaccine in HIV-1+ Patients. Markus Bickel, N von 946. Impact of IL28B Polymorphisms on Sustained 105 IAS–USA Topics in Antiviral Medicine

Virologic Response of HCV/HIV Co-infected Pa- mer Vaginal Rings as Potential Microbicide Delivery Community Viral Load, and Fewer New HIV In- tients. H Bachmann, W Siffert, A Skaletz-Rorowski, Method in African Women. Annalene Nel, K Young, fections, 2004 to 2009. Moupali Das, P Chu, G-M K Jansen, A Moll, S Dupke, S Köppe, T Harrer, M J Romano, C Woodsong, E Montgomery, G Masen- Santos, S Scheer, W McFarland, E Vittinghoff, and Rausch, Norbert Brockmeyer, and Competence Net- ga, H Rees, L-G Bekker, and S Ganesh, G Colfax. work for HIV/AIDS. 1005. Neonatal Male Circumcision in Gaborone, 1023. Community Viral Load as a Population-based 947. Association between IL28B Genotypes and Botswana, and Surrounding Areas: Uptake and Out- Biomarker of HIV, Washington, DC, 2004 to 2008. Plasma HCV RNA Levels in a Large Cohort of HIV/ comes. Rebeca Plank, N Ndubuka, J Mwambona, J Amanda Castel, M Befus, T West-Ojo, A Griffin, S HCV Co-infected Patients in Spain. Pablo Labarga, F Makhema, M Mmalane, F Hussein, C Lesetedi, D Hader, N Kamanu-Elias, and A Greenberg. Di Lello, E Poveda, A Caruz, V Soriano, J Del Rom- Halperin, R Shapiro, and S Lockma. 1024. Disparities in Community Viral Load among ero, F Vidal, E Bernal, J Pineda, on behalf of CoRIS. 1006. An Efficient Campaign for Rapid Scale-up of HIV-infected Persons in New York City. Fabienne 958. High Incidence Rate of HCV Reinfection after Safe Male Circumcision Services in a High HIV Prev- Laraque, H Mavronicolas, H Gortakowski, and A Treatment of Acute HCV Infection in HIV+ MSM: alence Region, Tanzania. Kelly Curran, H Mahler, B Terzian. Amsterdam. Femke Lambers, M Prins, X Thomas, R Kileo, A Hellar, S Nyabenda, M Plotkin, M Machaku, 1025. Characterizing HIV Viral Load Trajectories Molenkamp, J van der Meer, and J Schinkel. S Koshuma, M Lukobo-Durrell1, and T Adamu Ash- among HIV-infected New Yorkers, 2006 to 2007. 959. Kinetically Guided pegIFN and RBV Therapy engo. Arpi Terzian, S Bodach, E Wiewel, S Braunstein, K for HIV+ Adults Co-infected with Acute HCV. B Hare, 1007. Safety and Efficacy Study of the PrePex Sepkowitz, V Peters, and C Shepard. Kristen Marks, A Luetkemeyer, E Charlebois, G Clo- System for Male Circumcision. Jean Paul Bitega, 1028. HSV and HIV Prevalence and Incidence herty, M Glesby, A Talal, D Havlir, and M Peters. ML Ngeruka, T Hategekimana, A Asiimwe, and A among Young Men and Women in Zimbabwe in the 968. Liver-related Mortality Risk Is Greater from Binagwaho. NIMH CPOL Study. Kathryn McClellan, R Patel, G Chronic HBV than from Chronic HCV: MACS. Oluwa- 1008. Circumcision of HIV+ Men and HPV Trans- Woelk, W Pequanat, A Green, K Mayer, and D Kat- seun Falade-Nwulia, E Seaberg, C Rinaldo, S Badri, mission to Female Partners: A Randomized Trial, zenstein. M Witt, and C Thio. Rakai, Uganda. Aaron Tobian, X Kong, M Wawer, G 1030. Age-mixing in Sexual Relationships in Rural 971. Vaccination Schedule with 4 Doses against Kigozi, P Gravitt, D Serwadda, K Eaton, F Nalugoda, KwaZulu-Natal: Seeing Beyond “Sugar Daddies”. M HBV Increases Response Rates and Antibody Titers T Quinn, R Gray, and Rakai Hlth Sci Prgm. Ott, Till Bärnighausen, F Tanser, M Lurie, and M-L in HIV+ Adults Subjects. D Potsch, S Tuboi, L Villar, J 1014. Not All Are Lost: Early Death, Care Interrup- Newell. Miguel, C Ginuino, E Silva, R Mendonça, R Moreira, tion, and Loss to Follow-up in a Large South African 1037. Differential Impact of Serosorting by Race L Camacho, and Paulo Barroso. Community Treatment Program. Aima Ahonkhai, F among MSM. Matthew Golden, J Dombrowski, and 977. Significant Liver Fibrosis Is an Independent Noubary, A Munro, R Stark, M Wilke, K Freedberg, J Stekler. Risk Factor of Renal Impairment in HIV/HBV Co- R Wood, and E Losina. 1039. HIV Serostatus Disclosure Does Not Predict infected Patients Treated with TDF: Results of a 1015. Retaining Adults in HIV Care: Impact of Safer Sexual Behavior among HIV+ MSM in Bang- 3-Year Cohort Study. K Lacombe, Anders Boyd, E Key Program Characteristics on Patient Loss kok. Nneka Edwards-Jackson, N Phanuphak, H Van Lasnier, J Bottero, C Lascoux-Combe, P Miailhes, M to Follow-up among Adult Patients Receiving Tieu, N Chomchey, N Teeratakulpisarn, W Sathien- Lemoine, J-L Meynard, and P-M Girard. cART in the IeDEA East Africa Consortium. Pau- thammawit, C Pakam, N Pharachetsakul, M So- 979. Oral TFV Does Not Decrease HSV-2 Shedding la Braitstein, J Daggy, P Easterbrook, C Cohen, bieszczyk, and J Ananworanich. in HIV-infected Individuals. Darrell Tan, R Kaul, J S Braithwaite, E Geng, A Kambugu, M Bwana, 1040. Sexual Behavior and HIV-1 Risk for HIV-1- Raboud, and S Walmsley. K Wools-Kaloustian, C Yiannoutsos, and IeDEA uninfected Partners in African HIV-1 Serodiscordant 983. TFV Gel Reformulation Results in Improved East Africa Consortium. Partnerships. Patrick Ndase, C Celum, K Thomas, Product Safety for Rectal Application. Charlene Dez- 1016. Efficacy of Using Peer Counselors and Nurses D Donnell, E Bukusi, K Fife, S Delany-Moretlwe, J zutti, L Rohan, J Lynam, L Wang, and D Friend. to Support Adherence to HAART among HIV-1-in- Baeten, and Partners in Prevention HSV/HIV Trans- 992. ARV for HIV Prevention: DRV+ Low-dose RTV fected Patients at the Prevention of MTCT Program, mission Study Team. and ETR Exposure in the Rectal Tissue and Seminal Mulago Hospital, Kampala, Uganda: A Randomized 1041. ART Is Not Associated with Reduced Male Plasma of Healthy Male Volunteers after Single and Non-inferiority Interventional Trial. Flavia Matovu, Condom Use among HIV Serodiscordant Couples Multiple Dosing. Kevin Brown, K Patterson, S Jen- D Wabwire, J Nakibuuka, M Mubiru, D Bagenda, P in Uganda. M Ngolobe, W Zhang, K Shannon, S nings, N Shaheen, H Prince, M Spacek, M Cohen, Musoke, and MG Fowler. Khanakwa, J Birungi, S Alinga, K Muldoon, M Nyo- and A Kashuba. 1017. Failure to Initiate ART, Loss to Follow-up and nyintono, R King, and David Moore. 993. Comparison of 3 Rectal Douches as Safe, Pre- Mortality among HIV-infected Patients during the 1042. Risk Factors for HIV-1 Infection among MSM ferred Delivery Vehicle for Rectal Microbicides. F Pre-ART Period in Uganda: Understanding Engage- in Coastal Kenya. Eduard Sanders, H Okuku, M Leyva, E Fuchs, A Ventuneac, A Carballo-Dieguez, L ment in Care in Resource-limited Settings. Elvin Mwangome, G Fegan, N Peshu, E van der Elst, M Lee, M Torbenson, L Li, and Craig Hendrix. Geng, W Muyindike, D Glidden, M Bwana, C Yi- Price, S McClelland, A Smith, and S Graham. annoutsos, P Braitstein, N Musinguzi, D Bangsberg, 995. Validating Hair as a Biological Marker of TFV J Martin, and EA-IeDEA. 1044. Network Analysis among HIV-infected Young Drug Exposure in HIV PrEP. Albert Liu, M Gandhi, P Black MSM Demonstrates High Connectedness 1018. Free CTX Substantially Improves Retention Bacchetti, Y Huang, P Anderson, K Goggin, S Buch- around Few Venues: Jackson, Mississippi. Alexandra among ART-ineligible Clients in a Kenyan HIV Treat- binder, R Grant, and R Greenblatt. Oster, L Mena, C Wejnert, and J Heffelfinger. ment Program. Pamela Kohler, M Chung, S Benki- 1000. Knowledge, Attitudes, and Beliefs of Massa- Nugent, C McGrath, M Attwa, S Sakr, and G John- 1046. Distinct Patterns of Onward Spread of the chusetts Physicians Regarding Topical and Oral Anti- Stewart. Montreal MSM Epidemic. Bluma Brenner, D Ste- retroviral Chemoprophylaxis. Kenneth Mayer, M phens, J Wainberg, M Roger, B Spira, D Moisi, I Mimiaga, J White, D Krakower, and R Vanderwarker. 1019. 24-Month Outcomes for Adults in Tanzania’s National ART Program from 2004 to 2009: Success Hardy, J-P Routy, J Koopman, M Wainberg, and 1001. Pharmacokinetic and Safety Assessment of Maintained during Scale-up, but Should Services Be Montreal PHI and SPOT Cohorts. Monthly Anti-HIV DPV Vaginal Microbicide Rings More Youth Friendly? Geoffrey Somi, G Arthur, R 1048. Adherence to HIV Testing Guidelines among with Multiple Dosing. Annalene Nel, S Habibi, S Gongo, K Senkoro, T Kellogg, J O’Donnell, J Grove, MSM: US, 2008. Alexandra Oster, B Le, and E Smythe, J Nuttall, and P Lloyd. R Swai, A Khatib, J Vertefeuille, and Tanzania Natl DiNenno. 1002. Oral TDF and Its Impact in HSV-2 Acquisition ART Outcomes Study Team. 1052. Assessing HIV Testing in Community Phar- and Clinical Expression. Javier Lama, K Mayer, M 1020. Evaluation of Methods to Promote Adher- macies as a Complementary Community Site to Schechter, E Kallas, L-G Bekker, S Chariyalertsak, S ence at an HIV Treatment Center in Central Kenya. an HIV Testing and Counseling Program Based in Shiboski, R Grant, and iPrEx Study Team. Loice Achieng, H Musangi, S Ong’uti, E Ombegoh, L a New York City Emergency Department. Yvette 1003. An EVA Vaginal Ring Containing the NNRTI Bryant, J Mwiindi, N Smith, and P Keiser. Calderon, E Cowan, F Molano, J Velloza, F Korich, E MIV-150 Protects against SHIV-RT Infection in vivo. 1021. The Impact of Pregnancy on Adherence to McLoughlin, C Brusalis, and J Leider. Rachel Singer, N Derby, P Mawson, J Lifson, M Pi- and Default from ART. Rory Leisegang, J Nachega, 1075. Accuracy and User-acceptability of HIV Self- atak, J Fernandez-Romero, T Zydowsky, A Gettie, J M Hislop, and G Maartens. testing Using an Oral Fluid HIV Rapid Test. Oon Tek Blanchard, and M Robbiani. 1022. Success of Test and Treat in San Francisco? Ng, A Chow, V Lee, M Chen, L Lin, A Chua, HH Tan, 1004. Safety and Acceptability of Silicone Elasto- Reduced Time to Virologic Suppression, Decreased KW Mar, O Laeyendecker, and YS Leo.

106 Volume 19 Issue 2 May/June 2011 Continuing Medical Education Activity Posttest and Evaluation Form, Volume 19.2

8. In extended follow-up from the iPrEx (Chemoprophylaxis for HIV Posttest Questions Prevention in Men) study of oral preexposure prophylaxis (PrEP) with emtricitabine/tenofovir, overall efficacy (ie, reduction in new HIV Check the box next to the single best answer to each question infections) was: below from information presented in this issue. To earn CME credit,  A. 92% you must receive a passing score of 80% or more correct.  B. 72%  C. 42% 1. MicroRNAs regulate gene expression by:  D. No efficacy was observed with extended follow-up  A. Introducing double-stranded breaks into the DNA  B. Promoting proteasomal degradation of the protein 9. In the iPrEx PrEP study, participants receiving tenofovir/emtricitabine product were statistically significantly more likely than placebo recipients to experience:  C. Impairing messenger RNA translation and stability  A. Nausea  D. Preventing splicing of the RNA transcript  B. Bone fractures 2. Tetherin/BST2 inhibits HIV-1 replication by:  C. Renal failure  A. Preventing virion detachment from the infected cell  D. Tenofovir-resistant HIV infection  B. Inhibiting reverse transcription of viral RNA 10. HIV-associated neurocognitive disorder (HAND) is defined based  C. Inhibiting processing of viral Gag polyproteins primarily on:  D. Preventing interaction of the viral envelope with  A. Patient symptoms and signs from neurologic history and coreceptor molecules examination 3. Aberrant immune activation in patients with HIV-1 infection  B. Neuropsychological testing performance reflects:  C. Laboratory markers derived from blood and cerebrospinal  A. Stimulation of cell activation following binding of the virus fluid (CSF) testing to the cell surface  D. Brain-imaging results  B. Damage to mucosal integrity and translocation of 11. Which of the following biomarkers has been found in association microbial products such as lipopolysaccharide with early HIV infection?  C. Adverse effects of antiretroviral drugs on the immune  system A. Relatively low levels of plasma HIV-1 RNA   D. Destruction of T cells by virus replication B. An increase in CSF chemokine ligand 2/monocyte chemo- tactic protein 1 level 4. HIV-specific neutralizing antibodies:  C. A decrease in basal ganglia choline:creatine ratios  A. Are found in the acute phase of infection  D. Consistent absence of CSF HIV-1 RNA until the stage of  B. Take more than 2 years to develop and require extensive chronic infection hypermutation 12. All of the following biomarkers have been associated with HAND  C. Do not protect monkeys from simian human immunodefi- except: ciency virus infection  A. CSF level of hyperphosphorylated Tau protein (pTau)  D. Can easily be induced by vaccination  B. CSF level of neurofilament protein 5. Cytolytic CD4+ T cells against HIV:  C. Neurofibrillary tangles in the brain  A. Are found during the acute phase and may be involved in  D. Increased carotid intima media thickness control of HIV replication 13. Compared with HIV-uninfected control subjects, individuals  B. Likely do not play a role in controlling HIV replication with untreated HIV infection may have brain-imaging results  C. Are mostly directed against Env characterized by:  D. Select for viral variation in the acute phase  A. Elevations in levels or ratios of the neuronal integrity 6. According to data from 1990–2006, one risk group in the United cerebral metabolite marker N-acetyl acetate (NAA) States had increasing HIV infection rates; rates for other groups  B. Enlarged caudate volume even in the early stages of were level or decreasing. Which risk group had increased rates? infection  A. Women  C. Decreases in white matter integrity as measured by  B. Injection drug users diffusion tensor imaging  C. Men who have sex with men (MSM)  D. No association between CSF inflammatory markers and magnetic resonance spectroscopy markers of  D. Heterosexuals with HIV-seropositive partners inflammation 7. Rates of HIV infection in black MSM are higher than in other sub- 14. The new oral hepatitis C virus (HCV) protease inhibitors, telaprevir groups of MSM. According to recent data, an explanation for the and boceprevir, may have drug-drug interactions with antiretroviral difference is that: medications based on their roles as:  A. Higher levels of sexual risk-taking behavior are present in  A. Cytochrome P450 (CYP450) inducers black MSM than white MSM  B. CYP450 inhibitors and CYP450 substrates  White MSM have lower rates of drug use than black B.  C. P-glycoprotein inhibitors MSM  D. Inhibitors of gastric acid production  C. The reasons for the differences are unclear  D. White MSM have higher HIV testing rates than black MSM Continued on next page

107 IAS–USA Topics in Antiviral Medicine Continuing Medical Education Activity Posttest and Evaluation Form, Volume 19.2, continued

15. Increased visceral fat was associated with all of the following 19. Data on laboratory monitoring in resource-limited settings from except: the DART (Development of Antiretroviral Therapy in Africa) trial  A. Subclinical atherosclerotic plaque showed:  B. Increased mortality  A. A mortality benefit for immunologic (CD4+ cell count)  C. Initiation of antiretroviral therapy with efavirenz and monitoring compared with clinical monitoring atazanavir/ritonavir  B. A mortality benefit for virologic monitoring compared  D. Vitamin D deficiency with immunologic monitoring in resource-limited settings  C. No difference among the 3 monitoring strategies tested 16. Treatment of HCV infection during the first year of infection (acute  HCV infection) is associated with what rate of sustained virologic D. A mortality benefit for virologic monitoring compared response (cure)? with immunologic monitoring for participants with pre– antiretroviral treatment CD4+ cell counts above 200/µL  A. 15% 20. Data from the HIV Prevention Trials Network 046 study of mother-  B. 40% to-child transmission of HIV showed that:  C. 65%  A. The rate of HIV transmission from HIV-infected mothers to  D. 90% their breast-feeding infants was not associated with 17. Beginning antiretroviral therapy within 2 weeks to 4 weeks of maternal antiretroviral therapy status tuberculosis (TB) treatment initiation was associated with decreased  B. Breast-feeding infants of HIV-infected mothers who mortality and AIDS progression for HIV/TB-coinfected patients with received an extended course (through age 6 months) of CD4+ cells counts below: daily nevirapine had more serious adverse events than  A. 50/µL infants who stopped receiving daily nevirapine at 6 weeks  B. 200/µL postpartum  C. 350/µL  C. The rate of HIV infection was statistically significantly lower at 6 months in infants receiving extended daily  D. 500/µL nevirapine than in infants receiving 6 weeks of nevirapine 18. Compared with twice-daily dosing, once-daily raltegravir dosing postpartum was associated with:  D. Mortality was higher in the infants receiving nevirapine for  A. Increased resistance to raltegravir 6 weeks postpartum than in infants receiving nevirapine  B. Fewer adverse events for 6 months postpartum  C. Higher proportions of participants with plasma HIV-1 RNA levels below 50 copies/mL  D. Decreased adherence

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Please list 3 specific measurable changes you will make in your Other comments (please feel free to comment on any aspect of practice based on the information presented in this issue of TAM: Topics in Antiviral Medicine): 1. ______2. ______3. ______108 Volume 19 Issue 2 May/June 2011

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To receive CME credit, please complete the posttest, participant in- The amount of time (in hours) I spent on reading the articles, re- formation, and evaluation forms and return all to the IAS–USA along viewing the references, reflecting on how the information might be with payment of $35. applied to the practice, and taking the posttest was: Number of CME credits I am claiming (maximum 8): ____  ≤3  4  5  6  7  8  ≥9  other _____

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______Fax or mail this page along with the Degree or License (MD, RN, PA, none, etc) completed posttest and payment of $35 to: ______IAS–USA Institution or Organization 425 California Street, Suite 1450 San Francisco, CA 94104-2120 ______Telephone ( ___Home ___Work) Facsimile Fax: (415) 544-9401 or ______e-mail a PDF of all to: E-mail address to receive CME certificate ( ___Home ___Work) topics2011 “at” iasusa.org

109 IAS–USA Topics in Antiviral Medicine

110 Volume 19 Issue 2 May/June 2011  Topics in Subscription Request ® Antiviral Medicine Address Change

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 111 Guidelines for Authors and Contributors Volume 17 Issue 3 July/August 2009

Guidelines for Authors and Contributors

The IAS–USA publishes Topics in Antiviral Med- Cases From the Field. Topics in Antiviral Receipt of submitted manuscripts will be icine as a resource for physicians and other Medicine invites submission of case reports ac- acknowledged by editorial staff, and submis- health care practitioners who are actively in- companied by a scholarly literature review of sions will be reviewed by peer reviewers. volved in the care of patients with HIV or other the topic. Each case report should be 1500 to Acceptance for publication is based on the viral infections. The journal is indexed in Index 3000 words (excluding references, tables, and quality and relevance of the work.Copyright Medicus/MEDLINE and is distributed to ap- figures), include numbered references and a proximately 12,000 national and international brief summary sentence, and seek to teach an Copyright subscribers. important lesson for HIV or hepatitis virus care Copyright to manuscripts published in Topics in practitioners. The following guidelines describe the types Antiviral Medicine is owned by the IAS–USA. All of articles and contributions published in Stories. Stories for the Telling Stories column authors and contributors of manuscripts accept- the journal, outline its policies, and provide share the experiences of those involved in the ed for publication, with the exception of US fed- instructions for authors. For further informa- care of people infected with HIV or other virus- eral government employees, must sign a copy- tion, contact Topics in Antiviral Medicine at es. Stories may be approximately 800 to 3500 right transfer form as a condition of publication. topics2011“at”iasusa.org. words; unsolicited submissions are welcome. Authorship Requirements Categories of Articles Commentaries. Discussion on a current issue in the management of viral diseases is wel- Topics in Antiviral Medicine uses the defini- Perspectives. Perspective articles are summa- come as a Commentary. Commentaries should tion of authorship formulated by the Interna- ries of selected talks given at IAS–USA continu- be 500 to 1500 words and include numbered tional Committee of Medical Journal Editors ing medical education courses. An IAS–USA references as appropriate. Commentaries may and published in its Uniform Requirements for medical writer prepares a summary manu- be invited by the editors; unsolicited submis- Manuscripts Submitted to Biomedical Journals.1 script from a transcript of the talk. The man- sions are also welcome for consideration. This definition states: “Authorship credit should be based on (1) substantial contributions to uscript is reviewed and edited by the specific Letters to the Editor. Letters to the editor conception and design, acquisition of data, or course presenter and the journal’s appointed are welcome and should be sent to the address analysis and interpretation of data; (2) drafting peer reviewers. listed below. Limit 300 words. the article or revising it critically for important Reviews. Topics in Antiviral Medicine welcomes Special Issues. Topics in Antiviral Medicine intellectual content; and (3) final approval of the original review articles on current issues related publishes 1 or 2 issues each year with a spe- version to be published. Authors should meet to infection with HIV or other viruses. Topics cial focus, such as reports from recent scientific conditions 1, 2, and 3....Acquisition of funding, in Antiviral Medicine does not publish original meetings and summaries of special IAS–USA collection of data, or general supervision of the research. Manuscripts should be 3000 to 6000 continuing medical education courses. research group alone does not constitute au- words (excluding references, tables, and figures) thorship.” Topics in Antiviral Medicine will not and should include numbered references and Online Articles: Occasional articles appear consider ghostwritten articles for publication. a brief introductory abstract of approximately online only. They are easily distinguished from 100 to 200 words. Original, adapted, or reprinted articles by pagination beginning with “e.” Financial Disclosure printed figures and tables may be included and should be cited in the text and accompanied Reprints. Reprints of articles by expert panels It is the policy of the IAS–USA to ensure balance, by a brief title. Adapted and reprinted work re- convened by the IAS–USA are included periodi- independence, objectivity, and scientific rigor in quires proof of permission obtained from the cally in Topics in Antiviral Medicine. all of its educational programs. To that end, all original publishers and authors. Authors inter- authors and contributors of articles published in ested in submitting unsolicited manuscripts are Submission of Manuscripts Topics in Antiviral Medicine are required to dis- encouraged to submit an outline or abstract of close to readers any financial interest or other the proposed manuscript first; please contact Manuscripts should be submitted via mail or relationship with any organization having finan- the editor for further information. e-mail to the address below. Each manuscript cial interest in the content of the manuscript. author should complete an Authorship Form, Financial interests include employment, con- Editorials. Topics in Antiviral Medicine and its which is available online at http://www.iasusa. sultancy, honorarium, grant/research support, editors invite submission of editorials. Editori- org/pub or may be obtained by contacting the stock ownership, and membership in a speak- als should be approximately 500 to 1500 words editor at the address below. Outlines or ab- ers bureau. The complete financial disclosure (excluding references) and should include num- stracts of proposed manuscripts are welcome statements for all authors and contributors are bered references. and may be sent via mail or e-mail. published with the articles. Editor, Topics in Antiviral Medicine Special Contributions. A special contribution IAS–USA 1. International Committee of Medical Journal Ed- article often represents the unique contribution 425 California Street, Suite 1450 itors. Uniform requirements for manuscripts sub- San Francisco, CA 94104-2120 mitted to biomedical journals. Updated October (such as a consensus statement) of an author or 2008. Available at http://www.icmje.org. Accessed group of authors. E-mail: topics2011“at”iasusa.org May 23, 2011. International AIDS Society–USA Topics in HIV Medicine

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