Antiretroviral Treatment of Adult HIV Infection 2010 Recommendations of the International AIDS Society–USA Panel

REVIEW CLINICIAN’S CORNER

Melanie A. Thompson, MD Context Recent data regarding the consequences of untreated human immunodefi- Judith A. Aberg, MD ciency virus (HIV) infection and the expansion of treatment choices for antiretroviral- Pedro Cahn, MD naive and antiretroviral-experienced patients warrant an update of the International AIDS Society–USA guidelines for the use of antiretroviral therapy in adults with HIV infection. Julio S. G. Montaner, MD Objectives To provide updated recommendations for management of HIV- Giuliano Rizzardini, MD infected adults, using antiretroviral drugs and laboratory monitoring tools available in Amalio Telenti, MD, PhD the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient moni- Jose´ M. Gatell, MD, PhD toring, when to change therapy, and what regimens to use when changing. Huldrych F. Günthard, MD Data Sources and Study Selection A panel with expertise in HIV research and Scott M. Hammer, MD clinical care reviewed relevant data published or presented at selected scientific con- Martin S. Hirsch, MD ferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiret- Donna M. Jacobsen, BS roviral drug manufacturers for updated clinical trials and adverse event data. Peter Reiss, MD, PhD Data Extraction and Synthesis New evidence was reviewed by the panel. Rec- Douglas D. Richman, MD ommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recom- Paul A. Volberding, MD mendations were made by full panel consensus. Patrick Yeni, MD Conclusions Patient readiness for treatment should be confirmed before initiation of Robert T. Schooley, MD antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count Յ500/µL, for all symptomatic patients, and those with specific conditions and UCCESSFUL ANTIRETROVIRAL comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell therapy (ART) is associated with count Ͼ500/µL. Components of the initial and subsequent regimens must be individu- dramatic decreases in AIDS- alized, particularly in the context of concurrent conditions. Patients receiving antiretro- defining conditions and their as- viral treatment should be monitored regularly; treatment failure should be detected and sociatedS mortality. Expansion of treat- managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 ment options and evolving knowledge RNA suppression below commercially available assay quantification limits. require revision of guidelines for the ini- JAMA. 2010;304(3):321-333 www.jama.com tiation and long-term management of ART in adults with HIV infection. Analyses of clinical trials and epide- appointed by International AIDS Society– Since the 2008 International AIDS miologic cohorts have shed light on the USA according to clinical and research Society–USA ART guidelines,1 new data role of ART in mitigating serious non- expertise. Current panel members do not have emerged regarding timing of AIDS events associated with uncon- participate in pharmaceutical market- therapy, optimal regimen choices, and trolled HIV replication. Newer drugs are ing or promotional activities (eg, speak- monitoring. There are also issues of spe- better understood in terms of efficacy, ers’ bureaus, industry satellites) during cial relevance to circumstances such as toxicity, and potential uses. New data tenure on the panel. The current panel pregnancy, hepatitis virus coinfec- also suggest a role for ART in the pre- convened in January 2010 and met tions, kidney disease, cardiovascular vention of HIV transmission. weekly in person or by teleconference. disease, and primary HIV infection. Data published or presented in specific METHODS scientific meetings since the last report1 The panel was convened in 1995 to de- CME available online at velop evidence-based recommenda- Author Affiliations are listed at the end of this article. www.jamaarchivescme.com tions for ART for HIV-infected adults in Corresponding Author: Melanie A. Thompson, MD, and questions on p 357. 131 Ponce de Leon Ave NE, Ste 130, Atlanta, GA developed-world settings.2 Members are 30308 ([email protected]).

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were considered (eFigure, available at ing in end-organ damage and comorbid nized as reasons to initiate ART regard- http://www.jama.com). Data on file and conditions not previously thought to be less of CD4 cell count.1 Older age is also personal communications were not con- associated with HIV infection. Several associated with higher risk of AIDS and sidered except for data and safety moni- studies have shown that the life span of non-AIDS-related deaths. Pregnant toring board reports and US Food and those with HIV infection still falls short women should be treated at least by the Drug Administration alerts. of that of the general population, even second trimester and therapy contin- For identification of evidence, one at higher CD4 cell counts.3-6 This life span ued after birth.5,10,14-18 member (P.A.V.) conducted a PubMed decrease is related to serious, non-AIDS search of reports published since the last events attributed to chronic immune ac- Special Considerations update. Search terms were HIV and an- tivation and the potentially permanent HIV increases the risk of liver-related tiretroviral, limited to humans, clinical immune damage associated with pro- mortality in those with hepatitis B virus trials, meta-analyses, randomized con- longed immune depletion. In several data (HBV).19 Hepatitis B infection should not trolled trials, reviews, English, and adult, sets,3-8 non-AIDS events were associ- be treated with lamivudine or emtricit- and yielded 582 citations. Of those, 194 ated with elevated levels of viral repli- abine alone. If tenofovir is contraindi- citations were selected for review, elimi- cation and markers of immune activa- cated, entecavir should be added.20 The nating those not relevant to adult care in tion and coagulation (including D-dimer, durability of entecavir is compromised resource-rich settings. Section teams interleukin 6, or high-sensitivity C- by previous HBV treatment failure with identified abstracts from scientific con- reactive protein). Mortality from non- regimens including emtricitabine or la- ferences. Drug manufacturers were asked AIDS events now exceeds that of AIDS- mivudine.21 Flares of hepatocellular in- to provide published or presented data defining opportunistic diseases in flammation may occur when therapy on updated clinical trials and adverse individuals receiving effective ART.9-11 with agents active against HBV is dis- events for their products. The strength of evidence support- continued or when HBV resistance to la- Section team leaders (J.A.A., P.C., ing initiation of therapy increases as mivudine or emtricitabine emerges in pa- J.S.G.M., G.R., and A.T.) summarized CD4 cell count decreases. In a cohort tients receiving these agents without section consensus for group review and of 17 517 asymptomatic HIV-infected tenofovir or entecavir.22,23 If ART must discussion. The quality and strength persons, initiating ART at a CD4 cell be interrupted, patients should be closely of the evidence were rated for each count greater than 500/µL decreased monitored for HBV reactivation.24 recommendation (eBox). Final recom- mortality by 94%, and initiating it at a Patients with HIV–hepatitis C virus mendations were by full panel consensus. CD4 cell count between 351 and 500/µL (HCV) coinfection progress to end- decreased mortality by 69%, although stage liver disease more rapidly than do WHEN TO START the numbers of deaths were low in both HCV monoinfected patients.25 Clear- Established HIV-1 Infection groups. The majority of deaths were ance of HCV is associated with regres- Deciding to start ART requires weigh- from non-AIDS conditions.10 In an sion of liver fibrosis and a reduced risk ing the benefits of treatment on mor- analysis of 62 760 persons in 12 co- of ART-related hepatotoxicity.26 In one bidity and mortality against its risks, in- horts, reduction in death was 23% and study, abacavir with ribavirin was as- cluding toxicity, resistance, drug 45% for those beginning therapy with sociated with a reduced rate of sus- interactions, and the costs and incon- a CD4 cell count greater than 500/µL tained HCV virologic response.27 Zido- venience of lifelong treatment. Sus- and 350 to 500/µL, respectively.12 vudine, didanosine, and stavudine have tained viral suppression restores and Data from prospective observational overlapping hematologic and hepatic preserves immunologic function, de- cohorts and clinical trials demonstrate toxicities with current HCV therapy.25 creasing opportunistic diseases and worse outcomes among patients who be- Patients with HCV coinfection are at in- mortality. The patient must be ready gin receiving ART at CD4 cell counts less creased risk of hepatotoxicity, and cer- and willing to adhere to lifelong than 350/µL or who have symptomatic tain ART regimens may require dose ad- therapy. Advances in ART continue to HIV disease.1 Among 24 444 patients justment (see “Monitoring” section). shift the therapeutic risk-benefit bal- from 18 cohorts, there was no addi- Current HCV therapy has a higher ance to earlier treatment. Improve- tional benefit from initiating therapy at probability of sustained HCV viro- ments in potency, toxicity and toler- CD4 cell counts of 451 to 550/µL com- logic response with HCV genotype 2 or ability, and pill burden allow for durable pared with 351 to 450/µL. However, this 3; therefore, for patients with a high viral suppression for most patients. analysis included only persons who be- CD4 cell count and no imperative to be- The risks associated with ART have gan receiving ART at less than 550/ gin ART, HCV treatment before ART decreased, whereas concerns regarding µL.13 A randomized trial addressing the may avoid cumulative drug toxicity and the risks of long-standing untreated vi- timing of initiation of therapy is under drug interactions.28 remia have increased. Uncontrolled HIV way. Indicators of rapid progression of Renal disease ranges from HIV-asso- replication and immune activation lead disease, such as high HIV-1 RNA and ciated nephropathy, to HIV-associated to a chronic inflammatory state, result- rapid CD4 cell count decline, are recog- immune complex kidney disease, to

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thrombotic microangiopathy. In 5 cross- ning tuberculosis treatment decreased is contraindicated (BIIa). Initiation of sectional cohort studies, 5.5% of pa- mortality by 56% compared with initi- therapy is recommended (TABLE 1) for tients had stages 3 to 5 chronic kidney ating ART after completion of TB treat- symptomaticpatientswithestablisheddis- disease (estimated glomerular filtration ment.37 Immune reconstitution inflam- ease, regardless of CD4 cell count (AIa), rate [eGFR] Ͻ60 mL/min for more than matory syndromes occurred more often and for asymptomatic individuals with 3 months). Older patients, blacks, per- with early therapy, but no changes in CD4 cell counts less than or equal to sons with lower CD4 nadirs, and those ART were needed and no deaths were re- 500/µL (AIa for Ͻ350/µL, AIIa for Յ500/ with diabetes or hypertension have a lated to immune reconstitution inflam- µL). Treatment should be considered higher risk of developing chronic kid- matory syndromes. Consideration must for asymptomatic individuals with CD4 ney disease.29,30 Albuminuria and eGFR be given to the potential for drug inter- cell counts greater than 500/µL (CIII). less than 60 mL/min per 1.73 m2 are in- actions among therapies for opportunis- Therapy is recommended regardless of dependently associated with an in- tic infections and ART.38,39 CD4 cell count in the following settings: creased risk of cardiovascular events.31 Patients who present with sympto- increased risk of disease progression as- Tenofovir is associated with a decrease matic primary HIV infection may sociated with a rapid decline in CD4 cell in GFR and tubular dysfunction; both in- progress more rapidly than those who count (ie, Ͼ100/µL per year) or a plasma dinavir (about 4% of patients)32 and present without symptoms.40,41 Anti- HIV-1 RNA level greater than 100 000 atazanavir33 (uncommonly) are associ- retroviral therapy reduces the ex- copies/mL1 (AIIa); older than 60 years ated with nephrolithiasis. All nRTIs ex- tremely high viral loads in primary (BIIa); pregnancy (at least by the second cept abacavir may require dose adjust- infection and may reduce transmis- trimester) (AIa); or chronic HBV or HCV ments according to the GFR. sion.42,43 For patients presenting with coinfection (BIIa), although for patients Uncontrolled HIV infection is asso- asymptomatic primary infection, there with HCV genotype 2 or 3 and high CD4 ciated with increased cardiovascular are insufficient data for a recommen- cell counts, an attempt to eradicate HCV risk.34 In a multivariate analysis involv- dation on whether to treat immedi- may be undertaken before ART is initi- ing 70 357 (487 HIV-infected and ately or defer; however, an analysis of ated(BIII);HIV-associatedkidneydisease 69 870 HIV-uninfected) subjects, el- 3019 seroconverters showed a 78% re- (BIIa), avoiding drugs with potential ad- evated high-sensitivity C-reactive pro- duction in mortality when ART was ini- verse effects on the kidney (tenofovir, in- tein and HIV were independently as- tiated rather than delayed.12 dinavir, atazanavir), if possible (AIIa)53; sociated with acute myocardial Antiretroviral therapy reduces HIV high cardiovascular risk (BIIa), modifi- infarction. With both risk factors, acute transmission.44 Widespread use of ART ableriskfactorsforcardiovasculardisease myocardial infarction risk increased during pregnancy has nearly elimi- shouldbeaggressivelymanaged(AIa);op- greater than 4-fold.35 There were strong nated mother-to-child transmission in portunistic infections, including tubercu- associations between overall mortal- the developed world.45,46 A meta- losis, with attention to drug interactions ity or cardiovascular disease and spe- analysis concluded that ART also de- and the potential for immune reconstitu- cific biomarkers. Although ART re- creases the risk of HIV transmission to tion inflammatory syndromes (AIa); and duces the level of these biomarkers, they uninfected partners in HIV-serodiscor- symptomatic primary HIV infection to remain elevated compared with those dant heterosexual couples,43 and a co- preventrapidprogression,topreserveim- of HIV-uninfected individuals. The hort study of 3381 heterosexual sero- munefunction,andtolimitongoingtrans- clinical utility of these biomarkers for discordant couples showed a 92% mission from this high-risk population initiation or monitoring therapy is reduction in transmission when ART was (BIIa).42 Once initiated, ART should be unknown. Modifiable cardiovascular used by the infected partner.47 Another continued,exceptinthecontextofaclini- risk factors should be aggressively cohort study showed a strong associa- cal trial (AIa). Therapy should be consid- addressed in all persons with HIV tion between increased ART coverage, ered where there is a heightened risk of infection. decreased community plasma viral load, HIVtransmission(ie,HIV-serodiscordant In a randomized controlled trial of and decreased HIV incidence among in- couples) (BIIa), without supplanting tra- when to initiate ART for patients with ac- jection drug users.48 Some mathematic ditional prevention approaches. Risk re- tive opportunistic infections (exclud- models suggest that more aggressive ART duction counseling should be a routine ing tuberculosis [TB]), early initiation coverage could reduce the incidence of part of care at each patient-clinician (median, 12 days after presentation) re- new HIV infections49-51; some field data interaction.54 duced death or AIDS progression by 50% also support this.42,52 compared with beginning ART after the WHAT TO START completion of opportunistic infection Recommendations Selecting an initial regimen has long- treatment.36 A South African random- Patient readiness for treatment is a key standingconsequencesforfuturetherapy. ized controlled trial including patients considerationwhendecidingwhentoini- The initial regimen should be individu- with TB and HIV demonstrated that initiate ART. There is no CD4 cell count alized according to resistance testing re- tiating ART within 2 months of begin- threshold at which initiating therapy sults and predicted virologic efficacy, tox-

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on either the association or a possible Table 1. Recommendations for Initiating Antiretroviral Therapy (ART) in Treatment-Naive 66 Adults With HIV-1 Infection Who Are Ready to Begin Therapya mechanism. Measure Recommendation Rating Lamivudine and emtricitabine are each Specific conditions ART is recommended regardless well tolerated and select for the M184V of CD4 cell count mutation, which confers high-level re- Symptomatic HIV disease AIa sistance to both drugs but enhances the Pregnant women AIa activity of tenofovir. Both are active HIV-1 RNA Ͼ100 000 copies/mL AIIa against HBV but should only be used in Rapid decline in CD4 cell count, AIIa combination with a second HBV-active Ͼ 100/µL per year drug when treating HIV-HBV coin- Active hepatitis B or C virus coinfection BIIa, AIIa fected patients. The role of zidovudine Active or high risk for cardiovascular BIIa disease in initial regimens is limited by toler- HIV-associated nephropathy BIIa ability issues, as well as increased risk for Symptomatic primary HIV infection BIIa lipodystrophy and hyperlipidemia com- 1 Risk for secondary HIV transmission is BIIa pared with tenofovir. Stavudine and di- high, eg, serodiscordant couples danosine are not recommended for ini- Asymptomatic, CD4 cell count Յ500/µL ART is recommended tial therapy because of increased toxicity CD4 cell count Ͻ350/µL AIa of each.1 Combination regimens includ- CD4 cell count 350-500/µL AIIa ing 3 or 4 nRTIs alone are not recom- Asymptomatic, CD4 cell count Ͼ500/µL ART should be considered, CIII mended because of suboptimal viro- unless patient is an elite 1,67 controller (HIV-1 RNA Ͻ50 logic activity and increased toxicity. copies/mL) or has stable CD4 cell count and low-level Nonnucleoside Reverse viremia in the absence of ART Transcriptase Inhibitors Abbreviation: HIV, human immunodeficiency virus. a Details, cautions, considerations, and supporting data1,3-18,20-52 are described in the text. Ratings are described in the Several studies have shown consis- eBox (http://www.jama.com). tently high and sustained rates of viral suppression with efavirenz in the initial icity and tolerability, pill burden, dosing in PI-based regimens.56-58 Tenofovir is regimen.1,68 Efavirenz was virologically frequency,drug-druginteractions,comor- available in fixed-dose, once-daily for- superior to ritonavir-boosted lopinavir bidities, and patient and practitioner pref- mulations with emtricitabine and with (lopinavir/r)69,70 and comparable to erence. In the absence of overriding con- emtricitabine plus efavirenz. atazanavir/r61,62 and raltegravir.71 In AIDS siderations, cost and affordability should HLA-B*5701 testing identifies persons Clinical Trials Group A5142 and 2 other alsobeconsidered.Currentevidencesup- at high risk for abacavir hypersensitiv- studies, lopinavir/r showed better CD4 ports the combination of 2 nRTIs and a ity.59,60 In the AIDS Clinical Trials Group cell count responses and less drug resis- potent third agent from another class study A5202, inferior virologic responses tance after virologic failure than efavi- (BOX). Fixed-dose formulations and were observed with abacavir plus lamivu- renz.69,72,73 Efavirenz is associated with once-daily regimens are generally pre- dine compared with tenofovir plus em- rash and central nervous system ad- ferred for initial therapy. The eTable tricitabine in subjects with baseline HIV- verse effects and should not be used dur- presents a summary of selected clinical RNA levels greater than 100 000 copies/ ing the first trimester of pregnancy or in trial results in treatment-naive patients. mL. Abacavir plus lamivudine also was women of childbearing age trying to con- associated with more lipid abnormali- ceive or not using effective and consis- Nucleoside and Nucleotide Reverse ties.61,62 The Data Collection on Adverse tent contraception.17 Efavirenz is an in- Transcriptase Inhibitors Events of Anti-HIV Drugs study, a large ducer of cytochrome P450, and potential Tenofovir has activity against both HIV-1 multinationalobservationalcohort,found drug interactions are an important con- and HBV and a long intracellular half- that recent, current, or cumulative use of sideration. Baseline genotypic testing is life. Potent viral suppression and CD4 abacavir predicted an increased risk of important when considering nonnucleo- cell count increases occur when tenofo- myocardial infarction, an association not side reverse transcriptase inhibitor vir and emtricitabine are used with a observed with tenofovir.63,64 This risk was (NNRTI) use. Primary NNRTI resis- third agent. Alternative nRTIs are pre- accentuated in participants who had pre- tance rates vary from approximately 8.1% ferred over dose-adjusted tenofovir for existingcardiovascularriskfactors.Incon- in the United States to 2.3% in patients with renal dysfunction.55 Teno- trast, in a pooled analysis of 52 clinical Europe.74-76 fovir concentrations can be increased by trials involving more than 9500 partici- Nevirapine was noninferior to atazana- some protease inhibitors (PIs), and stud- pantswhoreceivedabacavir,noincreased vir/r (each combined with tenofovir plus ies have suggested a greater risk of re- risk of myocardial infarction was found.65 emtricitabine) in a randomized con- nal dysfunction when tenofovir is used Thus, no consensus has yet been reached trolled trial restricted to women and men

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Box. Recommended Components of the Initial Antiretroviral Regimena Dual nRTI Component cacyinpatientswithtreatmentexperience,andmultidrug- Recommended resistant virus influence choice Tenofovir/emtricitabine Raltegravirc Availableasfixed-dosecombinationaloneandwithefavirenz INSTI class (only 1 FDA approved at present time) Once daily Twice daily Low genetic barrier to resistance (emtricitabine) Low drug interaction potential Renal dysfunction, decreased bone mineral density Rapid decline in HIV-1 RNA slope after initiation associated with tenofovir influence choice Low genetic barrier Alternative Abacavir/lamivudine Limited experience in naive patients, presence of other options in most naive patients, and efficacy in Available as fixed-dose combination treatment-experienced patients with multidrug- Once daily resistant virus influence choice Weaker antiviral efficacy in treatment-naive patients with Alternatives baseline HIV-1 RNA Ͼ100 000 copies/mL than tenofovir/ Lopinavir/r emtricitabine PI/r class Low genetic barrier (lamivudine) Extensive clinical experience Need to screen for HLA-B*5701b to reduce risk of aba- Comparator PI/r in many trials cavir hypersensitivity Only PI coformulated with ritonavir (heat stable) Abacavir may be associated with increased cardiovascular Can be given once daily in naive patients risk Potential for hyperlipidemia and gastrointestinal Key Third Agent adverse effects influences choice Recommended Fosamprenavir/r Efavirenzb PI/r class NNRTI class Profile similar to lopinavir/r Available in fixed-dose combination with tenofovir/ emtricitabine, which has become standard-of-care com- May be useful when other initial PI/r not tolerated parator regimen in most clinical trials Maraviroc Low genetic barrier CCR5 antagonist class Major psychiatric illness, first trimester of pregnancy, or Targets host protein (viral coreceptor) intention to become pregnant influences choice Need to perform viral tropism assay before use b Atazanavir/r Limited clinical experience in treatment-naive patients PI/r class Strategically, may be more useful in treatment- Once daily experienced patients or when primary (transmitted) Widely prescribed when PI/r is chosen for initial therapy drug resistance is present but viral population should be exclusively receptor 5 Leaves options for future regimens Less lipidogenic potential than lopinavir/r Abbreviations: CCR5, CC chemokine receptor 5; FDA, Food and Hyperbilirubinemia, need for acid-reducing agents, and Drug Administration; HIV, human immunodeficiency virus; INSTI, risk of nephrolithiasis influence choice integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; nRTI, nucleoside or nucleotide analogue reverse c Darunavir/r transcriptase inhibitor; PI, protease inhibitor; /r, ritonavir boosted. PI/r class a Details, cautions, considerations, and supporting data1,17,55-105 are described in the text. Once daily in treatment-naive patients b Based on extensive clinical experience. Limited experience in treatment-naive patients, pres- cBased on antiviral efficacy and tolerability comparable to that of key ence of other options in most naive patients, and effi- third agents but more limited experience in treatment-naive patients.

with CD4 cell counts less than 250/µL can women with CD4 cell counts less described within the first several weeks and 400/µL, respectively.77 Nevirapine than 200/µL.78 However, drug discon- of initiation of nevirapine-based therapy was similar virologically to lopinavir/r tinuation because of adverse events was but are less frequent if nevirapine is re- (again, each with tenofovir/emtricita- higher among nevirapine recipi- stricted to pretreatment CD4 cell counts bine) in a randomized trial of 500 Afri- ents.79,80 Serious hepatic events have been less than 250/µL (women) or less than

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400/µL (men).81 Patients who experi- therapy, once-daily and twice-daily lopi- Entry Inhibitors enced CD4 cell count increases to lev- navir/r in combination with tenofovir The CC chemokine receptor 5 (CCR5) els above these thresholds with unde- plus emtricitabine achieved compa- inhibitor maraviroc was compared with tectable viremia as a result of previous rable rates of plasma HIV-1-RNA levels efavirenz, both in combination with zi- ART safely switched to nevirapine less than 50 copies/mL at 48 weeks,91 dovudinepluslamivudine,in633subjects therapy.82 The efficacy in initial therapy with similar rates of moderate to severe with CCR5-tropic virus and no evidence of etravirine, a newer NNRTI, has not yet drug-related diarrhea. Other major ad- of resistance to the study drugs.101 At 48 been reported. verse effects of lopinavir/r include insu- weeks, HIV-1 RNA less than 50 copies/ lin resistance and hyperlipidemia. mL was achieved in 65% and 69% of Protease Inhibitors Twice-dailyfosamprenavir/randlopin- maraviroc and efavirenz recipients, re- Atazanavir/r has greater virologic activ- avir/r, both administered with abacavir spectively. The results did not meet ity than unboosted atazanavir when com- plus lamivudine, had comparable rates of prespecified criteria for noninferiority for bined with 2 nRTIs.83 Once-daily virologic suppression and adverse events maraviroc. Through 48 weeks, more par- atazanavir/r and twice-daily lopina- at48and144weeks.92 Once-dailyvstwice- ticipantsdiscontinuedmaravirocbecause vir/r, both combined with tenofovir plus dailyfosamprenavir/rdidnotdifferinrates of lack of efficacy (11.9% and 4.2%, re- emtricitabine, showed similar virologic of virologic suppression.93 spectively),whereasfewerparticipantsdis- and CD4 cell count responses at 48 and Saquinavir/r was compared with lopi- continued maraviroc because of toxicity 96 weeks.84,85 The hyperbilirubinemia, navir/r, both with tenofovir plus emtri- (4.2% and 13.6%, respectively). Follow- scleral icterus, or frank jaundice associ- citabine, resulting in rates of viral sup- up results at 96 weeks demonstrated du- ated with atazanavir exposure is not ac- pression at 48 weeks of about 65% for rableresponsesinbothgroups.102 Reanaly- companied by hepatic transaminase el- each regimen; however, the statistical sis of the results with a more sensitive tro- evations but is more frequent with power of this study was limited by small pism assay or with a genotype-based ritonavir boosting. Nephrolithiasis has sample size and short length of follow- approach suggested that the differences occurred uncommonly with atazana- up.94 Triglyceride levels were higher in between treatment arms could be attrib- vir, with or without ritonavir,33 and the the lopinavir/r arm. Although this was uted to misclassification of tropism in eGFR may decrease when atazanavir is possibly a class effect, the Food and Drug some patients by the older assay.101,103-105 combined with tenofovir.86 Unboosted Administration has issued a warning of IfonlysubjectswithR5virusatentrywere atazanavir should not be used with te- a potential risk for QT-interval prolon- considered, maraviroc appeared similar nofovir.87 Atazanavir requires acidic gas- gation with saquinavir/r.95 to efavirenz in antiretroviral activity. Ma- tric pH for dissolution. Thus, concomi- Hepatictransaminaseelevationscanoc- ravirochasnotbeenevaluatedextensively tant use of drugs that increase gastric pH, cur with any of the above regimens,96 with other nRTI backbones in initial such as antacids, H2 antagonists, and par- especially in patients with underlying therapy. ticularly proton-pump inhibitors, may liver disease. Cumulative exposure to impair absorption of atazanavir and com- indinavir/r, lopinavir/r, and fosampren- Recommendations promise its activity.88 avir/r (but not saquinavir/r) has also been Fixed-dose combinations are recom- Darunavir/r once daily was compared associated with an increased risk of car- mended when possible for convenience. with standard doses of lopinavir/r (once diovascular events.63,64,97 If possible, these Tenofovir plus emtricitabine is the rec- or twice daily), each in combination with drugs are best avoided in patients with el- ommended nRTI combination in initial tenofovirplusemtricitabine.At48weeks, evated cardiovascular risk. Data concern- therapy (A1a). If tenofovir plus emtricit- darunavir/r was noninferior to lopinavir/ ing cardiovascular risk associated with abine cannot be used, abacavir plus lam- r, but virologic response rates were lower atazanavir/r or darunavir/r are pending. ivudine may be used as an alternative in the lopinavir/r arm among subjects when HLA B*5701 testing results are with baseline HIV-1-RNA levels greater Integrase Strand Transfer Inhibitors negative,keepinginmindabacavir’slower than 100 000 copies/mL. At 96 weeks, Raltegravir and efavirenz, each combined efficacy at high viral loads (AIa) and its darunavir/r was virologically superior to with tenofovir and emtricitabine, showed possible association with increased car- lopinavir/r.89 Grade 2 to 4 adverse events, similar high virologic efficacy during 192 diovascular risk (AIIa). Zidovudine plus primarily diarrhea, were more frequent weeks.71,98,99 Raltegravir is well tolerated lamivudine should be reserved for in- inthelopinavir/rarm.90 Darunavir/riscon- and has a favorable lipid and drug inter- stancesinwhichneithertenofovirnoraba- sidered by many as less attractive in ini- action profile; however, it is dosed twice cavir can be used. Three or 4 nRTIs alone tial therapy because it is particularly use- daily and has a relatively low genetic bar- are not recommended for initial therapy ful for patients with PI-resistant virus. rierforselectionofresistancemutations.100 (AIa). Efavirenz (AIa), atazanavir/r (AIa), Lopinavir/r demonstrates lower viro- Raltegravir is considered by some as less darunavir/r (AIa), or raltegravir (AIa) is logic efficacy but better CD4 response attractive for initial therapy because it is recommended as the third component of and fewer emergent resistance muta- particularly useful for patients with drug- an initial regimen. More evidence is avail- tions than efavirenz.69,72,73 For initial resistant virus. able for efavirenz and atazanavir/r than

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for darunavir/r or raltegravir. Lopinavir/r, weeksapartshouldpromptacarefulevalu- The prevalence of transmitted drug fosamprenavir/r, and maraviroc are alter- ation of regimen tolerability, drug-drug resistance varies in resource-rich soci- native third-component choices (AIa). interactions, and patient adherence. eties from 8% to 16%.75,76,114 Baseline ge- Neither saquinavir/r nor unboosted PIs, including atazanavir, are recommended Table 2. Initial Antiretroviral Therapy (ART) and Considerations in Patients With Specific Conditionsa forinitialtherapy(BIa).Nevirapineshould Regimen Components be used as an alternative initial therapy only with pretreatment CD4 cell counts Possible Condition Backbone Drugs Third Agent Considerations less than 250/µL (women) or less than High athero- Emtricitabine, lamivu- Efavirenz, Initiation of ART, regardless of CD4 cell 400/µL(men)(BI).Considerationsforini- sclerotic dine, tenofovir nevirapine, count, is recommended.34 cardio- atazanavir/r, If possible avoid abacavir, fosamprenavir/r tial therapy in patients with specific con- vascular raltegravir indinavir/r, lopinavir/r because of an ditions are summarized in TABLE 2. risk associated increased risk of cardiovascular events.63,97 Chronic kid- Abacavir,b emtricita- Efavirenz, Initiate ART regardless of CD4 cell count MONITORING ney dis- bine, lamivudine; raltegravir, (BIIa). ease avoid tenofovir nevirapine, Avoid potentially nephrotoxic drugs (AIIa).53 Effectivetherapyshouldresultinsuppres- (glomerular and maraviroc, When potentially nephrotoxic drugs must sion to less than 50 copies/mL (poly- tubular toxicity), PI/r be used, monitor renal function closely. atazanavir, For patients with reduced estimated glo- merase chain reaction) or 75 copies/µL and indinavir merular filtration rate, dose adjustment (branched DNA) by 24 weeks, regardless (nephrolithiasis) for drugs with renal metabolism (emtricitabine, lamivudine, tenofovir, of previous treatment experience. Fre- maraviroc) should be considered. quent HIV-1 RNA monitoring is recom- Chronic HBV Emtricitabine, lamivu- Efavirenz, ART that includes tenofovir/emtricitabine infection dine, tenofovir. Use raltegravir, PI/r should be used irrespective of CD4 mended during the first year of ART to 2 HBV-active should be moni- cell count20 (BIIa). detect failure.106 Testing of HIV-1 RNA drugs. Do not use tored for hepa- Monitor alanine aminotransferase after abacavir or totoxicity. ART initiation and after withdrawal of should be repeated 2 to 8 weeks after abacavir/ Avoid nevirapine suppressive therapy.22-24 initiation, every 4 to 8 weeks until sup- lamivudine alone except for In patients with moderate to severe liver for treatment of women with impairment, dose adjustment for pressed, and then every 3 to 4 months for HBV in coinfected CD4 Ͻ250/µL drugs metabolized by the liver should at least the first year. CD4 cell counts patients. and men with be considered. Ͻ400/µL. Alcohol should be avoided. should be monitored at least every 3 to 4 Maraviroc should be months after initiation of therapy, espe- used with caution in ciallyamongpatientswithcountslessthan patients with liver 200/µL,todeterminetheneedforcontinu- disease. Chronic HCV Emtricitabine, lamivu- Efavirenz, raltegravir, ART should generally be initiated first in all ing opportunistic infection prophy- infection dine, tenofovir PI/r should be patients with HCV coinfection regard- laxis.107,108 In a EuroSIDA study, patients requiring monitored for less of CD4 cell count to slow liver dis- therapy hepatotoxicity. ease progression (BIIa), except possi- who maintained stable and fully suppres- Avoid nevirapine ex- bly in patients with HCV genotype 2 or sive ART for 1 year had a low chance of cept for women 3 infection and a high CD4 cell count, with CD4 Ͻ250/ for whom current HCV therapy has a experiencing treatment failure in the en- µL and men with higher probability of a sustained viro- suingmonths.109 Therefore,onceviralrep- Ͻ400/µL. logic response26,28 (BIII). Maraviroc should be Avoid zidovudine, didanosine, zalcitabine, lication is suppressed, monitoring inter- used with cau- and stavudine, as well as abacavir. 25,27 tion in patients Alcohol should be avoided by all coin- valsmaybeextendeduptoevery6months with liver disease. fected patients. among patients who remain virologically Pregnant Complete recommendations for the use of ART is recommended to prevent the suppressed and have CD4 cell counts women antiviral therapy in pregnant women are transmission of the virus to the fetus available at http://www.aidsinfo.nih.gov or infant (AIa). greater than 350/µL. More frequent mon- /ContentFiles/PerinatalGL.pdf, and http: Efavirenz should generally be avoided, itoring is required for patients who have //www.europeanaidsclinicalsociety.org especially in the first trimester of preg- /guidelines.asp.17,18 nancy (teratogenic effect). changed therapy because of virologic Opportunistic Any, according to the Choice of agent will ART should be initiated as soon as pos- failure.110 infections, “What to Start” be influenced by sible in patients with opportunistic including section drug interac- infections, including tuberculosis, with Changes in assay methodology may re- tubercu- tions, especially attention to drug interactions and the sult in detectable viral load in individu- losis with rifampin potential for immune reconstitution and rifabutin. inflammatory syndromes (AIa).36,37 Drug als with previously undetectable vire- interactions likely to require dose ad- mia.111,112 Detectionartifactshavealsobeen justments; consult drug interaction dosing references (http://www.hiv attributed to specific plasma processing -druginteractions.org, and http: practices.113 Newassaysmaysoonbeavail- //hivinsite.ucsf.edu/insite?page =ar-00-02.38,39 able with a lower limit of 20 copies/mL; Abbreviations: ART, antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; PI, protease inhibitor; /r, ritonavir however, the clinical implications of vi- boosted. aDetails, cautions, considerations, and supporting data are described in the text. Levels of evidence are described in the remia between 20 and 50 copies/mL are eBox (available at http://www.jama.com). not yet clear. Confirmed viral load re- bIn HLA B*5701–negative patients; has been associated with increased risk of myocardial infarction. Lower efficacy in patients with Ͼ100 000 copies/mL of HIV RNA at baseline (see text). bound on 2 separate tests at least 2 to 4

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notypic testing is recommended for all should be assessed by available tools. The achievable, even in most patients with treatment-naive patients.81 For con- Framingham risk algorithm may be the multiregimen failure.130-132 Reasons for vi- firmed virologic failure, resistance test- most appropriate but may underestimate ral rebound after complete suppres- ing is essential and should be per- cardiovascular disease risk in the setting sion, such as poor adherence, drug- formed while the patient is receiving the ofHIVinfection.128 Guidelinesforthepre- drug interactions, concurrent infections, failing regimen, when possible. If the vention and management of metabolic and recent vaccinations, should be con- trajectory of HIV-1 RNA reduction is complications and noninfectious comor- sidered before the regimen is changed. not optimal after a new regimen, ar- biditiesinHIVinfectionareavailable.108,121 Testing for an isolated detectable viral chived mutations or minority variants Therapeutic drug monitoring re- load should be repeated to exclude mea- may emerge. Minority variants not de- mains controversial.129 When assays are surement error or self-resolving low- tected by current resistance testing have performed by a quality-assured labora- level viremia.1 Stage of HIV disease, been associated with an increased risk tory, monitoring of PI and NNRTI lev- nadir and current CD4 cell count, co- of virologic failure; however, the as- els may be useful in pregnant women, morbidities, treatment history, current say thresholds that identify patients at children, and patients with renal or liver and previous drug resistance tests, and greatest risk of experiencing poor out- impairment to minimize overexposure concomitant medications with poten- comes have not been defined.40,115-119 and adverse effects, manage potential tial for interactions should be consid- Tropism testing before use of a CCR5 drug-drug interactions, or evaluate vi- ered when the new regimen is de- antagonist is essential because this class rologic failure in the absence of resis- signed. Ideally 3, but at least 2, fully active has no activity against CX chemokine tance. As stated, HLA-B*5701 screen- drugs should be included and drugs from receptor 4 or dual-tropic viruses.101 Im- ing can identify patients at risk for new classes should be considered. The provement in tropism assay method- abacavir-associated hypersensitivity.59 toxicities of stavudine, didanosine, and ology may further facilitate the clini- to a lesser extent zidovudine make their cal use of CCR5 antagonists.101,120 Recommendations use problematic, and they should be used The frequency of monitoring for ART PlasmaHIV-1RNAlevelsshouldbemoni- only when options are limited. toxicity depends on the known toxici- tored frequently when treatment is initi- Initial Failure of NNRTI-Based ties of specific drugs and underlying co- atedorchangedforvirologicfailure(AIIa) Regimens. Once failure has been con- morbidities. Monitoring may occur every until they decrease below detection lim- firmed, an NNRTI-containing regimen 2 to 8 weeks after initiation of therapy, its and regularly thereafter (BIII). Once shouldbediscontinuedassoonaspossible decreasing to every 6 to 12 months af- the viral load is suppressed for a year and tominimizetheselectionofadditionalmu- ter stabilization of HIV disease.108,121 CD4 cell counts are stable at 350/µL or tations. Initial NNRTI failures tradition- Assessment of renal function should greater,viralloadandCD4cellcountscan ally have been treated with 2 active nRTIs occur before initiation and during ART, bemonitoredatintervalsofupto6months plus a PI/r, but raltegravir, maraviroc, in particular when tenofovir is used, al- in patients with dependable adherence and etravirine now provide additional op- lowing avoidance, dose modification, or (CIII). Baseline genotypic testing for re- tions. According to potency and high ge- timely substitution of another drug when sistance should be performed in all netic barrier,the inclusion of a PI/r should appropriate. treatment-naive patients (AIIa) and in be considered whenever possible, but The recommendations and algorithms cases of confirmed virologic failure (AIa). when not possible, an agent from a new of the National Osteoporosis Founda- HLA-B*5701haplotypescreeningshould class should be considered. Treatment- tion122 and the World Health Organiza- beperformedinanypatientforwhomaba- experienced patients receiving etravirine tion fracture risk assessment tool123,124 are cavir is considered (AIa). Assessment of and darunavir/r plus an optimized back- useful for the assessment of risk and pre- viraltropismisrecommendedbeforeusing ground regimen had better virologic re- vention of osteoporotic fractures; how- maraviroc (AIa). Therapeutic drug moni- sponses than those receiving placebo plus ever,thesetoolshavenotbeenspecifically toringisnotrecommendedinroutinecare; background regimen, with comparable validated in the HIV-infected population. however, selected patients might benefit tolerability at 48 weeks.133 Vitamin D deficiency is common in the from this intervention (CIII). Initial Failure of PI/r Regimens. Re- setting of HIV infection and may be as- sistance to the PI/r component does not sociated with ART use.125 Monitoring of WHEN TO CHANGE always emerge when regimen failure is vitamin D levels may be of benefit.125-127 AND WHAT TO CHANGE detected, allowing the same drug or an- Hepatic,cardiovascular,andrenalcom- Changing for Virologic Failure other in the PI class to be used in the next plications may be associated with uncon- The virologic goal of treatment for first- regimen. For early failures, strategic se- trolled HIV replication. Clinical and labo- and multiple-regimen failure is to achieve quencing of PIs should be considered. If ratory assessment of relevant comorbid a plasma HIV-1 RNA level below the limit some degree of PI resistance exists, da- conditions should be performed before of detection of the most sensitive assays runavir/r is likely to be preferred over initiation of treatment and during follow- available. With the availability of new lopinavir/r or tipranavir/r because of its up.108,121 Cardiovascular disease risk drugs and regimens, this goal now is superior tolerability and toxicity pro-

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file, as well as problematic drug interac- oftoxicity/tolerability.Delayingswitches mens. Virologic failure of an initial regi- tions associated with tipranavir/r.1 If not when adverse effects persist may affect men (confirmed measurable viremia) previously used, an NNRTI may be in- adherence and facilitate the emergence should be identified and treated as early cluded, provided that potential drug in- of resistance. as possible with at least 2 fully active teractions are considered. Whenever pos- drugs (AIa) to avoid the accumulation sible, a new antiretroviral regimen should Simplification of resistance mutations. For NNRTI fail- contain at least 2 fully active drugs. It may be desirable to switch to an equally ures, the new combination usually Multidrug (Including PI and NNRTI) effective regimen with fewer drugs or should include a PI/r or an agent from a Resistance. In this setting, 3 active drugs, lower pill burden. Not all switches, even new class (AIa) if a PI/r is not possible. including new classes of agents (inte- with a drug from a new class, are success- Etravirine may be a useful component of grase strand transfer inhibitors or entry ful because the activity of the accompa- a new regimen for NNRTI failure but inhibitors), should be used. Individuals nying drugs in the regimen is a key must be supported by a potent combi- with multidrug-resistant virus usually determinant of outcome. Continuing nation including a PI/r (AIa). Depend- benefit from a PI/r with activity against lopinavir/r was virologically better than ing on the resistance profile and op- resistant strains, such as darunavir/r or switching to raltegravir in patients with tions available, inclusion of agents from tipranavir/r. Etravirine can be paired with extensiveprevious3-classARTexperience new drug classes (raltegravir or maravi- darunavir/r (but not tipranavir/r) and and pre-existing nRTI resistance.140 With roc) should be considered (BIIb). Mono- may be of value, depending on the num- raltegravir, it is important to maintain a therapy with a PI/r should be avoided un- ber of NNRTI mutations present. Enfu- strong ART backbone, usually including less other drugs cannot be considered for virtide may be an option if no other new a PI/r. Two smaller studies found that ral- reasons of toxicity/tolerability (AIa). class can be used, despite the inconve- tegravir was safe, well tolerated, and vi- Design of a new regimen should con- nience of subcutaneous injection and in- rologically similar when substituted for sider previous drug exposure, previ- jection site reactions. Dual-boosted PIs enfuvirtide in patients with multidrug- ous resistance profile, drug interac- are not recommended.134 Lamivudine or resistant HIV-1.141,142 tions, and history of intolerance/ emtricitabine is sometimes included to Once-dailydarunavir800mg/ritonavir toxicity (CIII). Treatment interruptions maintain the M184V mutation and de- 100 mg was noninferior to twice-daily da- should be avoided, except in the con- crease viral fitness, but there is no new runavir 600 mg/ritonavir 100 mg in an text of controlled clinical trials (AIa). evidence to support this approach. An- open-labelstudyintreatment-experienced Elective treatment interruptions should other theoretically beneficial strategy is patients.143 Dual therapy strategies in- consider the different half-lives of the to use zidovudine to prevent the emer- tended to take advantage of drug interac- regimen components, with stopping the gence of the K65R mutation in the pres- tions such as the combination of un- drugs in a staggered manner when an ence of thymidine analogue mutations boosted atazanavir and raltegravir are still NNRTI is a component (CIII). when using tenofovir in patients in experimental and are not recommended whom nRTI-containing regimens are fail- for clinical practice. For patients with vi- CONCLUSIONS AND ing. However, no clinical benefit has been rologic suppression who were receiving FUTURE DIRECTIONS shown for this approach.135 aboostedorunboostedPI-basedregimen, Increasing evidence that insidious dam- switchingtoaonce-dailyregimencontain- age occurs during “asymptomatic” HIV Changes for Toxicity, Tolerability, ing atazanavir provided better mainte- infection underscores the potential ben- or Convenience nance of virologic suppression, compa- efit of ART, even when the risk of tradi- Single-agent switches to decrease tox- rable safety, and improved lipids through tional AIDS-defining diseases is relatively icity, avoid drug interactions, or improve 48 weeks compared with continued un- low. The prominence of non-AIDS events convenience and adherence are possible, modified therapy.144 as a major cause of morbidity and mor- provided the potency of the regimen is Treatment interruptions should be tality in those with ongoing HIV replica- maintained and drug interactions are avoided.1 Interruptions, such as those for tionsuggeststhatearlyARTinitiationmay managed. Although some studies have planned surgeries or severe toxicities in further improve the quality and length of shownmaintenanceofvirologicsuppres- patients without options for switching, life for persons living with HIV. The stra- sion with PI/r monotherapy as a simpli- should consider the different half-lives of tegic use of newer drugs can improve tol- fication strategy,136 other studies have the regimen components; drugs should erability, as well as provide durable and shown higher rates of failure, especially bediscontinuedinastaggeredmanner(or potentviralsuppressionininitialandsub- in the central nervous system,137 than a PI/r temporarily substituted) when an sequent therapy. with a combination including 2 nRTI NNRTI is a component.145 However, far too many HIV-infected plus a PI/r.138,139 Therefore, PI/r mono- persons present for medical care with ad- therapy is not recommended, except in Recommendations vanced disease, both in wealthy and exceptional circumstances when other Maintenance of regimen potency is the resource-limited settings. Universal vol- drugs cannot be considered for reasons objective when switching ART regi- untary HIV testing, comprehensive pre-

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vention services, and early linkage to care scientific advisory boards or as a clinical trial design cals. Dr Richman reported being a consultant to Ana- consultant for Chimerix, GeoVax, GlaxoSmithKline, dys Pharmaceuticals, Biota, Boehringer Ingelheim Phar- andtreatmentarenecessarytoensurethat Panacos Pharmaceuticals, Progenics Pharmaceuti- maceuticals, Bristol-Myers Squibb, Chimerix, Gen- advances in ART are made available dur- cals, and Tibotec Therapeutics; has received hono- Probe, Gilead Sciences, Idenix Pharmaceuticals, Koronis raria for scientific lectures from GlaxoSmithKline and Pharmaceuticals, Merck, Monogram Biosciences, ingearlierdiseasestages.AdvancesinART Serono; and has served on data and safety monitor- Myriad Genetics, Pfizer, Roche, Theraclone Sciences, haveshownthatAIDS,astraditionallyde- ing boards for Tibotec Therapeutics. Dr Aberg reported and Tobira Therapeutics; has served on an endpoint fined, can be prevented. One of the great- serving as a scientific advisor to Abbott Laboratories, adjudication committee for Schering-Plough; has been Boehringer Ingelheim Pharmaceutical, Gilead Sci- the recipient of a research grant from Merck; and has est challenges is that full implementation ences, GlaxoSmithKline, Merck, Pfizer, Theratech- been a stock options holder of Chimerix and Idenix of these guidelines will require address- nologies, Tibotec Therapeutics, and ViiV Healthcare; Pharmaceuticals. Dr Volberding reported serving on has received grants and research support from Gilead data and safety monitoring boards for Merck and ing social and structural barriers to diag- Sciences, GlaxoSmithKline, Merck, Pfizer, Schering- TaiMed Biologics and on an endpoint adjudication com- nosis and care, as well as the pervasive Plough, Theratechnologies, Tibotec Therapeutics, Virco mittee for Schering-Plough; has provided paid expert stigmaanddiscriminationassociatedwith Lab, and Wyeth; and has received honoraria from testimony for commercial firms; has served on scien- Abbott Laboratories, Bristol-Myers Squibb, and Gilead tific or clinical advisory boards for Bristol-Myers Squibb, an HIV diagnosis. Sciences. Dr Cahn reported serving on the advisory Gilead Sciences, GlaxoSmithKline, Pfizer, and Tobira boards for Avexa, Gilead Sciences, GlaxoSmithKline, Therapeutics; and has been the recipient of service Author Affiliations: AIDS Research Consortium of At- Myriad Genetics, Merck, Pfizer, Pharmasset, Schering- grants for, or held contracts from, GlaxoSmithKline Italy. lanta, Atlanta, Georgia (Dr Thompson); University of Plough, and Tibotec Therapeutics; has served as an Dr Yeni reported receiving scientific grants from Abbott California San Diego, La Jolla (Dr Schooley); New York investigator for Avexa, Boehringer Ingelheim Phar- Laboratories, Bristol-Myers Squibb, Gilead Sciences, University School of Medicine, New York (Dr Aberg); maceuticals, Gilead Sciences, GlaxoSmithKline, Merck, GlaxoSmithKline, Pfizer, Merck, and Roche Labora- Hospital Juan Fernandez/University of Buenos Aires Pfizer, Pharmasset, Roche Laboratories, Schering- tories. Dr Schooley reported serving as a consultant Medical School and Fundacion Huesped, Argentina Plough, and Tibotec Therapeutics; and has received to Achillion Pharmaceuticals, Anadys Pharmaceuticals, (Dr Cahn); Hospital Clinic-IDIBAPS, University of honoraria for speaking engagements from Abbott Ardea Biosciences, Gilead Sciences, GlaxoSmithKline, Barcelona, Barcelona, Spain (Dr Gatell); University Laboratories, Bristol-Myers Squibb, Boehringer Ingel- Inhibitex, iTherX, Johnson & Johnson, LabCorp, Hospital Zurich, Division of Infectious Diseases and heim, GlaxoSmithKline, Merck, Pfizer, and Tibotec Merck, Myriad Biosciences, Pfizer, TaiMed Biologics, Hospital Epidemiology, University of Zurich, Zurich, Therapeutics. Dr Montaner reported receiving research Tanox, Tobira Therapeutics, Vertex Pharmaceuticals, Switzerland (Dr Günthard); Columbia University Col- grants from, and served as an ad hoc advisor or con- and Vical; has received grants from Gilead Sciences lege of Physicians and Surgeons, New York, New York sultant to, Abbott Laboratories, Argos Therapeutics, and Pfizer; and has stock options for Achillion Phar- (Dr Hammer); Harvard Medical School, Boston, Mas- Boehringer Ingelheim Pharmaceuticals, Bristol-Myers maceuticals. sachusetts (Dr Hirsch); International AIDS Society– Squibb, Cato Research Canada, ConjuChem Biotech, Funding/Support: This work was funded by the In- USA, San Francisco, California (Ms Jacobsen); BC- Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, ternational AIDS Society–USA. Panel members serve Centre for Excellence in HIV/AIDS, Providence Health Johnson & Johnson, Merck Canada, Merck Frosst Labo- in volunteer capacities (ie, are not compensated). No Care and University of British Columbia, Vancouver, ratories, Pfizer Canada, Serono, Theratechnologies, and private sector or government funding was used to sup- Canada (Dr Montaner); Academic Medical Center, Uni- Tibotec Pharmaceuticals and has served on an end- port the effort. The International AIDS Society–USA versity of Amsterdam, Amsterdam, the Netherlands has received grants for selected CME activities (un- point adjudication committee for Schering-Plough. Dr (Dr Reiss); University of California San Diego and Vet- related to guidelines development) from Abbott Rizzardini reported receiving research grants from erans Affairs San Diego Healthcare System (Dr Rich- Laboratories, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences and Merck Sharp & Dohme. Dr Telenti man); Luigi Sacco Hospital, Milan, Italy (Dr Riz- Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, reported receiving research grants or honoraria for lec- zardini); University Hospital of Lausanne, Lausanne, Merck, Pfizer, Roche Laboratories, Tibotec Therapeu- tures from Abbott Laboratories, Boehringer Ingel- Switzerland (Dr Telenti); University of California San tics, and ViiV Healthcare. Grants are pooled such that heim Pharmaceuticals, Bristol-Myers Squibb, and Francisco and San Francisco Veterans Affairs Medical no single company supports any single effort. GlaxoSmithKline. Dr Gatell reported receiving research Center (Dr Volberding); and Hoˆ pital Bichat-Claude Ber- Role of the Sponsor: The International AIDS Society– grants or honoraria for serving on advisory boards or nard and Xavier Bichat Medical School, Paris, France USA determined the need for updated recommenda- for lectures from Abbott Laboratories, Boehringer Ingel- (Dr Yeni). tions, selected the panel members, and provided ad- heim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sci- Author Contributions: Study concept and design: ministrative oversight and financial support. Thompson, Aberg, Cahn, Rizzardini, Telenti, Gatell, ences, Janssen, Merck Sharpe & Dohme, Pfizer, Online-Only Material: The eTable, eBox, and eFig- Günthard, Hammer, Hirsch, Jacobsen, Reiss, Richman, GlaxoSmithKline, Roche Laboratories, Theratechnolo- ure are available at http://www.jama.com. Volberding, Yeni, Schooley. gies, Tibotec Therapeutics, Tobira Therapeutics, and Additional Contributions: We thank Michelle Tayag Acquisition of data: Thompson, Aberg, Cahn, Virco Lab. Dr Günthard reported serving as a consul- Valderama, BS, who was compensated as an em- Rizzardini, Telenti, Hammer, Volberding, Schooley. tant and medical advisor for Abbott Laboratories, ployee of the International AIDS Society–USA, for ad- Analysis and interpretation of data: Thompson, Aberg, Bristol-Myers Squibb, Boehringer Ingelheim Pharma- ministrative support. Cahn, Montaner, Rizzardini, Telenti, Gatell, Günthard, ceuticals, Gilead Sciences, GlaxoSmithKline, Pfizer, Hammer, Hirsch, Reiss, Richman, Volberding, Yeni, Tibotec Therapeutics, and ViiV Healthcare and has Schooley. received unrestricted research and educational grants REFERENCES Drafting of the manuscript: Thompson, Aberg, Cahn, from Abbott Laboratories, Bristol-Myers Squibb, Gilead Rizzardini, Telenti, Günthard, Hirsch, Jacobsen, Reiss, Sciences, Merck Sharp & Dohme, and Pfizer. Dr Ham- 1. Hammer SM, Eron JJ Jr, Reiss P, et al; International Richman, Volberding, Schooley. mer reported serving on a scientific or clinical advi- AIDS Society-USA. Antiretroviral treatment of adult HIV Critical revision of the manuscript for important in- sory boards for Merck, Progenics Pharmaceuticals, infection: 2008 recommendations of the International tellectual content: Thompson, Aberg, Cahn, Montaner, TaiMed Biologics, Tibotec Therapeutics, and Wyeth; AIDS Society-USA panel. JAMA. 2008;300(5):555- Rizzardini, Telenti, Gatell, Günthard, Hammer, Hirsch, has received clinical research contracts from Merck; 570. Reiss, Richman, Volberding, Yeni, Schooley. and has served on data and safety monitoring boards 2. Carpenter CCJ, Fischl MA, Hammer SM, et al; Inter- Obtained funding: Jacobsen, Volberding. and committees for Bristol-Myers Squibb and on the national AIDS Society-USA. Antiretroviral therapy for HIV Administrative, technical, or material support: board of directors of SIGA Pharmaceuticals. Dr Hirsch infection in 1996. JAMA. 1996;276(2):146-154. Montaner, Günthard, Hammer, Jacobsen, Volberding. reported serving on data and safety monitoring boards 3. Harrison KM, Song R, Zhang X. Life expectancy af- Study supervision: Thompson, Cahn, Telenti, Hammer, for Merck and TaiMed Biologics. Dr Reiss reported serv- ter HIV diagnosis based on national HIV surveillance data Hirsch, Jacobsen, Schooley. ing as a scientific advisor to Boehringer Ingelheim Phar- from 25 states, United States. J Acquir Immune Defic Financial Disclosures: Dr Thompson reported receiving maceuticals, Bristol-Myers Squibb, Gilead Sciences, Syndr. 2010;53(1):124-130. research grants awarded to AIDS Research Consor- GlaxoSmithKline, Merck, Theratechnologies, Tibotec 4. Lohse N, Hansen AB, Pedersen G, et al. Survival of tium of Atlanta from Abbott Laboratories, Avexa, Therapeutics, and Tobira Therapeutics; has served on persons with and without HIV infection in Denmark, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers data and safety monitoring boards and endpoint adju- 1995-2005. Ann Intern Med. 2007;146(2):87-95. Squibb, GlaxoSmithKline, Gilead Sciences, GeoVax, Kat- dication committees for Tibotec Therapeutics; has 5. Bhaskaran K, Hamouda O, Sannes M, et al; CASCADE ketsuken, Koronis Pharmaceuticals, Merck Research received honoraria for speaking engagements at sci- Collaboration. Changes in the risk of death after HIV Laboratories, Myriad, Ora-Sure, Panacos Pharmaceu- entific conferences from Boehringer Ingelheim Phar- seroconversion compared with mortality in the general ticals (now Myriad), Pfizer, Progenics Pharmaceuti- maceuticals, Bristol-Myers Squibb, Gilead Sciences, population. JAMA. 2008;300(1):51-59. cals, Roche Laboratories, Roche Molecular Systems, GlaxoSmithKline, and Theratechnologies; and has 6. Antiretroviral Therapy Cohort Collaboration. Life ex- Serono, Theratechnologies Tibotec Therapeutics, Tobira received research support from Gilead Sciences, ViiV pectancy of individuals on combination antiretroviral Therapeutics, Trimeris, and VaxGen; has served on the Healthcare, and Boehringer Ingelheim Pharmaceuti- therapy in high-income countries: a collaborative analy-

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