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Management of Antiretroviral Therapy International AIDS Society–USA Topics in HIV Medicine Management of Antiretroviral Therapy Timothy J. Wilkin, MD, C. Mhorag Hay, MD, Christine M. Hogan, MD, and Scott M. Hammer, MD As in previous years, the 9th Conference Entry Inhibitors ants (Abstract 2). The drug is not cur- on Retroviruses and Opportunistic rently going forward in clinical develop- Infections provided a forum for a state- The chemokine receptors CCR5 and ment, but proof of principle appears to of-the-art update in antiretroviral thera- CXCR4 are coreceptors used by many have been established. py. Highlights included the status of strains of HIV-1 in addition to CD4 to new antiretroviral agents from both enter cells. Attempts are under way to CCR5 Receptor Blockers. Laughlin pre- existing and new drug classes; presenta- develop antiretroviral agents that inhib- sented the results for the first 12 HIV- tion of trials in antiretroviral-naive and it HIV-1 entry by blocking these requisite infected volunteers treated with SCH-C, antiretroviral-experienced persons; up- coreceptors. an orally bioavailable CCR5 receptor dates on strategic approaches to thera- antagonist with potent in vitro antiviral py, including when to start therapy, CXCR4 Receptor Blockers. AMD-3100 is a activity against a broad range of primary treatment interruptions, and immune- small-molecule CXCR4 receptor blocker HIV-1 isolates (Abstract 1). In this ongo- based therapies; mechanisms and evo- with potent in vitro anti-HIV activity. ing, sequential rising-dose trial, in which lution of viral drug resistance; clinical Results of an open-label dose-escala- there will be 12 subjects per group, HIV- applications of drug resistance testing; tion study to test the safety, pharma- infected volunteers receive 10 days of and therapeutic drug-level monitoring. cokinetics, and antiviral effect of AMD- SCH-C monotherapy with total daily 3100 were presented (Abstract 391-T). doses of 50, 100, and 200 mg. To date, 12 Forty HIV-infected volunteers with plas- HIV-1-infected adults, with CD4+ cell Antiretroviral Chemotherapy: ma HIV-1 RNA levels above 5000 counts above 250/µL, currently not New Investigational Agents copies/mL, on no or stable antiretroviral receiving antiretroviral therapy and with regimens, were enrolled and received 10 a non-SI phenotype, have received SCH- The advent of currently available days of continuous intravenous infusion C 25 mg orally every 12 hours for 10 days antiretroviral medications has substan- of AMD-3100 at a dose escalating from and have undergone intensive pharma- tially reduced HIV-1-related morbidity 2.5 µg/kg/hr up to 160 µg/kg/hr. Presence cokinetic and plasma HIV-1 RNA moni- and mortality. However, the increasing of the syncytium-inducing (SI) pheno- toring. emergence of drug-resistant HIV-1 vari- type (one method for determining pres- SCH-C was well tolerated, although ants as well as short-term and long-term ence of CXCR4-using variants) was not in electrocardiogram testing, subtle pro- toxic effects of these agents limit their part of the inclusion criteria, and only longation of the mean QTc interval was overall effectiveness. Several presenta- 28% of volunteers harbored SI variants. seen over 10 days of the lowest dose. Ten tions at the conference addressed new The study was discontinued early of 12 volunteers experienced at least a antiretroviral agents, including new because of adverse effects and lack of 0.5-log10 reduction in plasma HIV-1 RNA agents in existing classes with more antiviral effect. Adverse experiences, level from baseline during dosing, and 4 favorable resistance or toxicity profiles, particularly gastrointestinal in nature, subjects experienced a 1-log10 or greater as well as agents in new classes with were generally common. Two patients drop in plasma HIV-1 RNA level from non-overlapping resistance mecha- experienced unexpected adverse events baseline. Thus these preliminary proof- nisms compared with currently avail- of premature ventricle contractions, and of-principle data for SCH-C support fur- able classes. some patients in each dose group had ther exploration of the CCR5 receptor as atrial tachycardia. Three volunteers dis- a target for antiretroviral therapy. The Dr Wilkin is Post-Doctoral Research continued the study drug because of clinical future of SCH-C will depend in Fellow and Dr Hay is Instructor in Clinical adverse events. No volunteer harboring part on electrocardiographic findings at Medicine in the Division of Infectious SI virus showed a 1-log10 or higher drop the higher doses. Diseases at Columbia University College in HIV-1 RNA, but 1 patient harboring SI One of the concerns of targeting the of Physicians and Surgeons. Dr Hogan is virus had a 0.9-log10 drop at day 10 of the CCR5 coreceptor is that doing so could Research Associate at the Aaron highest dose. Of note however, through select for X4-using strains of HIV-1 that Diamond AIDS Research Center, the use of an entry assay that can identify have been associated with more rapid Rockefeller University, and Instructor in HIV-1 isolates that are X4-, X5-, or dual- CD4+ T-cell count decline and clinical the Division of Infectious Diseases at tropic, investigators observed that 9 of progression. HIV-1 variants resistant to Columbia. Dr Hammer is Professor of 19 patients with dual (X4/R5) or mixed SCH-C were generated by in vitro pas- Medicine at Columbia and Chief of the (X4 and R5) virus at baseline exhibited a saging of HIV-1 strains in peripheral Division of Infectious Diseases at complete loss of X4 virus by day 11 of blood mononuclear cells (PBMCs) in the Columbia Presbyterian Medical Center in treatment. This result suggested the presence of increasing concentrations of New York, New York. ability of the drug to eliminate X4 vari- SCH-C (Abstract 397-T). Characterization 18 Conference Highlights - Antiretroviral Therapy Volume 10 Issue 1 March/April 2002 of the emerging variants with reduced located within either gp41 or the CD4 Tenofovir disoproxil fumarate (teno- sensitivity to SCH-C showed no switch to binding site of gp120. fovir) is a recently approved nucleotide other chemokine receptors including A cautionary note was sounded reverse transcriptase inhibitor for treat- CXCR4. However, it has not been deter- regarding the targeting of the very het- ing HIV infection. Louie and colleagues mined whether this switch occurs in erogeneous HIV-1 envelope protein: assessed the antiviral potency of this vivo. Similar findings in terms of contin- although 20 of 24 subtype-B isolates agent by obtaining frequent measure- ued CCR5 coreceptor use by resistant were inhibited by BMS-806 with an EC50 ments of HIV-1 RNA during the first 3 virus were reported from in vitro serial below 100 nM, 4 outliers had an EC50 as weeks of monotherapy with tenofovir in passaging experiments in the presence high as 10,000 nM. Future studies with 10 HIV-infected patients (Abstract 3). of SCH-D, another potent small- this promising compound will elucidate The decay rate of HIV-1 RNA was calcu- molecule antagonist of CCR5 in preclini- the mechanism of this diminished sus- lated and compared with the decay rates cal development (Abstract 396-T). ceptibility and the potential of this agent from similar previous experiments with PRO 140 is an anti-CCR5 monoclonal to inhibit a wide variety of HIV-1 strains. other agents. They found that tenofovir antibody that potently inhibits HIV-1 monotherapy led to a decay rate similar entry in vitro. Results of a study evaluat- Integrase Inhibitors to that seen in ritonavir monotherapy, ing the antiviral activity of PRO 140 in indicating that this agent has robust vivo in the hu-PBL-SCID mouse model of In vitro data for a new HIV-1 integrase activity against HIV-1. HIV-1 infection were presented (Abstract inhibitor in clinical development were presented by Fujiwara and colleagues 403-T). The mice were infected with the Nonnucleoside Reverse Transcriptase (Abstract 8). S-1360 is an orally available R5 isolate HIV-1 JR-CSF and then treated Inhibitors intraperitoneally with PRO 140 or a con- small-molecule inhibitor of HIV-1 inte- trol antibody. Both single-dose (1 mg) grase, the enzyme essential for the inte- TMC125 is a novel, second-generation and multiple-dose (0.1-1.0 mg every 3 gration of HIV-1 proviral DNA into host- investigational nonnucleoside reverse days for 3 weeks) PRO 140 reduced plas- cell chromosomes. The compound is an transcriptase inhibitor (NNRTI) with ma HIV-1 RNA to levels below detection integrase inhibitor with an EC50 of 28 to equally potent in vitro activity against in all treated animals, with the highest 74 ng/mL in vitro against clinical iso- wild-type HIV-1 and NNRTI-resistant plasma HIV-1 RNA level reduction being lates, and has demonstrated anti-HIV HIV-1 bearing the L100I, K103N, Y181C, activity in a mouse-MT4 in vivo assay. 1.8 log10 copies/mL. Dose-dependent dif- Y188L, or G190A/S mutations. Gazzard ferences were observed in the kinetics of HIV-1 variants resistant to S-1360 have (Abstract 4) presented results of a trial the antiviral response. Further studies of been isolated in vitro and the amino acid evaluating the antiviral activity of this compound in HIV-infected volun- substitutions responsible for drug resis- TMC125 in patients on failing NNRTI- teers are planned. tance have been shown to be in close containing regimens. Sixteen male vol- proximity to the integrase active site (eg, unteers with documented resistance to Novel Entry Inhibitors. Colonno de- T66I). This compound is currently being efavirenz (>10-fold decrease in suscepti- scribed the identification and characteri- investigated in a phase 1/2 study of HIV- bility by VirtualPhenotype and/or Anti- zation of a novel small-molecule in- infected volunteers.
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