Conference Highlights - Advances in Antiretroviral Therapy Volume 15 Issue 2 April/May 2007 Advances in Antiretroviral Therapy Joyce Jones, MD, Barbara Taylor, MD, Timothy J. Wilkin, MD, MPH, and Scott M. Hammer, MD The 14th Conference on Retroviruses and Opportunistic Infections provided line HIV-1 RNA of 4.8 to 4.9 log10 cop- a forum for presentation of state-of-the-art research on antiretroviral ies/mL. The primary endpoint, a reduc- therapy. This year’s conference marked the first public presentation of tion in plasma HIV-1 RNA at 24 weeks, phase III trials of the lead compounds in 2 new drug classes: maraviroc (a was statistically significantly greater in CCR5 inhibitor) and raltegravir (an HIV-1 integrase inhibitor). These agents the once-daily (1.82 log10 copies/mL) are likely to be approved by the US Food and Drug Administration this and twice-daily arms (1.95 log10 cop- year and should provide major new options for treatment-experienced ies/mL) than in the placebo arm (1.03 patients with multidrug resistant virus. Other dominant themes of the log10 copies/mL). Subjects in the once- conference were the impressive number of presentations describing and twice-daily arms were more likely outcomes of antiretroviral therapy programs in resource-limited settings to achieve plasma HIV-1 RNA levels and new information on mechanisms of drug resistance. Among the latter, below 50 copies/mL at week 24 than the importance of drug resistance mutations occurring in the RNase H and subjects in the placebo arm (42% and connection domains of the HIV-1 reverse transcriptase was of special note. 49% vs 25%, respectively), and had a In addition, substantial new information was presented on other new greater increase in CD4+ counts (107 antiretroviral agents, studies in treatment-naive patients, antiretroviral and 111 vs 52 cells/µL, respectively). therapy strategies, prevention of mother-to-child transmission, predictors There were no marked safety issues of clinical response to therapy, and antiretroviral pharmacokinetics. and the rates of adverse events in the Research in antiretroviral therapy remains dynamic and advances in the maraviroc arm were not statistically field continue to improve our ability to maintain long-term control of significantly different from rates in the HIV-1 replication in infected persons. placebo arm, including liver-related adverse events and malignancies. New Antiretrovirals Antiretrovirals in Late-phase In MOTIVATE 2, 464 subjects were Clinical Development enrolled (approximately 85% of sub- A major focus of this year’s conference jects were white and 84% were male). was the presentation of phase III stud- Entry Inhibitors: Maraviroc. Outcomes Across groups the median ranges were ies of entry and integrase inhibitors, of 2 phase IIb/III studies of maravi- baseline CD4+ counts of 174 to 182 which showed good clinical outcomes roc, an investigational CCR5 inhibitor, cells/µL and baseline HIV-1 RNA of 4.8 with acceptable side effect profiles. were presented: MOTIVATE 1 (Abstract to 4.9 log10 copies/mL. The primary (see Table 1) These drugs are likely to 104aLB) and MOTIVATE 2 (Abstract endpoint, reduction in plasma HIV- be approved by the US Food and Drug 104bLB). The studies were of identical 1 RNA at 24 weeks, was significantly Administration (FDA) in 2007 and will design but conducted in different coun- greater in once-daily (1.95 log10 copies/ provide new options for treatment-ex- tries. Eligible subjects were 3-class ex- mL) and twice-daily arms (1.97 log10 perienced patients with multidrug re- perienced patients with plasma HIV-1 copies/mL) than in the placebo arm sistant HIV-1. Studies on antiretrovirals RNA levels above 5000 copies/mL and (0.93 log10 copies/mL). Subjects in the in early-phase and preclinical develop- exclusive use of CCR5 coreceptor for once- and twice-daily arms were more ment highlighted promising drugs that entry as determined by tropism testing. likely to achieve a plasma HIV-1 RNA will hopefully further expand antiret- Subjects were randomized 1:2:2 to pla- level below 50 copies/mL at week 24 roviral regimens available to HIV-sero- cebo, maraviroc 150 mg once daily, and than subjects in the placebo arm (41% positive patients. maraviroc 150 mg twice daily, all given and 46% vs 21%, respectively), and with an optimized background regimen had a greater increase in CD4+ count (OBR) of 3 to 6 antiretrovirals. If subjects (112 and 102 vs 64 cells/µL, respective- Dr Jones is an Instructor of Clinical Medi- were not receiving a ritonavir-boosted ly). There were no marked safety is- cine at Columbia University Medical Center. protease inhibitor (PI), they received sues and rates of adverse events in the Dr Wilkin is an Assistant Professor of Medi- maraviroc 300 mg once or twice daily. maraviroc arm were not statistically cine at Weill Medical College of Cornell Both studies had similar participant significantly different from rates in the University. Dr Taylor is a Fellow at Columbia baseline characteristics. University Medical Center, New York Pres- placebo arm, including liver-related byterian Hospital. Dr Hammer is Professor In MOTIVATE 1, 585 subjects were en- adverse events and malignancies. of Medicine at the Columbia University Col- rolled (approximately 82% were white The combined analysis from these 2 lege of Physicians and Surgeons and Chief and 90% were male). Across groups the trials showed that 56% of subjects who of the Division of Infectious Diseases at Co- median ranges were baseline CD4+ screened for this study had HIV-1 that lumbia Presbyterian Medical Center. counts of 150 to 168 cells/µL and base- utilized only the CCR5 coreceptor for 48 International AIDS Society–USA Topics in HIV Medicine Table 1. Selected Trials of Investigational Antiretroviral Drugs in Treatment-experienced Patients Study Name Regimen(s) Population Baseline CD4+ Log10 Copies HIV Follow-up HIV-1 RNA Response Comments Abstract No. (No. Patients) cells/μL RNA/mL Time Description MOTIVATE-1 Best available regimen 3-class experienced; plasma 150-168 (median) 4.8-4.9 (mean) 24 weeks –1.03 vs –1.82 and –1.95 log10 Abstract 104aLB (PIs, nRTIs, +/– enfuvirtide) HIV-1 RNA >5000 copies/ copies/mL (n=118) mL; CCR5-using virus Phase IIb/III randomized, double- 25% vs 42% and 49% <50 vs blind trial of maraviroc, an copies/mL Combined analyses: investigational CCR5 inhibitor maraviroc 150 mg qd (n=232) or maraviroc 150 The qd and bid dosing groups mg bid (n=235) appeared no different when having 1 or more active drugs in OBR; in MOTIVATE-2 Best available regimen 1 or more major PI 174-182 (median) 4.8-4.9 (mean) 24 weeks –0.93 vs –1.95 and –1.97 log10 31/49 subjects in whom maraviroc Abstract 104bLB (PIs, nRTIs +/– enfuvirtide) mutations, 3-class copies/mL failed, there was a change in (n=91) experience coreceptor usage Phase IIb/III randomized, double- 21% vs 46% and 41% <50 vs blind trial of maraviroc copies/mL maraviroc 150 mg qd (n=182) or maraviroc 150 mg bid (n=191) BENCHMRK-1 Raltegravir 400 mg bid Genotypic or phenotypic 153-156 (mean) 4.5-4.6 (mean) 16 weeks 77% vs 41% <400 copies/mL Abstract 105aLB (n=232) resistance to at least 1 drug 61% vs 33% <50 copies/mL or from all 3 current classes, Phase III, randomized, placebo- plasma HIV-1 RNA >1000 Combined analyses: controlled trial of raltegravir placebo with OBR (n=118) copies/mL 32/41 subjects in whom raltegravir (MK0518), an investigational failed had mutations in integrase; integrase inhibitor 98% of subjects receiving raltegravir and enfuvirtide for the BENCHMRK-2 Raltegravir 400 mg bid Genotypic or phenotypic 146-163 (mean) 4.5-4.6 (mean) 16 weeks 77% vs 43% <400 copies/mL first time had <400 HIV-1 RNA Abstract 105bLB (n=230) evidence of resistance to 62% vs 36% <50 copies/mL copies/mL at week 16 or at least 1 drug from all 3 Phase III, randomized, placebo- placebo with OBR (n=119) current classes, plasma HIV-1 controlled trial of raltegravir RNA >1000 copies/mL The HIV Integrase Inhibitor Elvitegravir (20 mg, 50 mg, 1 or more PI mutations, 157-243 (median) 4.5-4.7 (median) 16 weeks 50-mg arm, –1.5 log10 copies/mL GS-9137 Demonstrates Potent or 125 mg) + ritonavir 100 plasma HIV-1 RNA >1000 Elvitegravir led to rapid declines in 125-mg arm, –1.7 log10 copies/mL ARV Activity in Treatment- mg qd or best available copies/mL plasma HIV-1 RNA at week 2 that vs experienced Patients control PI given with OBR were sustained only if there were Abstract 143LB (n=278) control arm, –1.2 log10 copies/mL other active drugs in the OBR Phase II, dose-finding study 20-mg arm stopped early for of elvitegravir (GS9137), an virologic failure investigational integrase inhibitor PI indicates protease inhibitor; nRTI, nucleoside analogue reverse transcriptase inhibitor; OBR, optimized background regimen; qd, once-daily; bid, twice daily. entry (R5 HIV). Eight percent of subjects tive drugs in the OBR was found to be a in the OBR, indicating that difference in who had R5 HIV at screening had dual predictor of suppression to less than 50 viral load outcomes between once- and or mixed HIV-1 populations that utilized HIV-1 RNA copies/mL and baseline HIV-1 twice-daily maraviroc was apparent only both CCR5 and CXCR4 coreceptors for RNA viral load was not related. The pro- among patients with no active drugs in entry at baseline, prior to receiving mara- portion of patients achieving HIV-1 RNA the OBR. viroc. The dual or mixed HIV subjects below 50 copies/mL in the once- and Among patients with virologic fail- who received maraviroc had a poorer twice-daily arms were 18% and 29%, re- ure, change in coreceptor usage from virologic response than R5 HIV subjects spectively, among patients with no active R5 HIV to dual or mixed HIV was noted who received maraviroc.