1. Home>
2. Specialties>
3. HIV/AIDS Clinical Care>
4. Meeting Report

Report from the 2008 Joint ICAAC/IDSA Meeting

The most important HIV-related findings from this year’s meeting

For the first time in several years, the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America hosted a joint annual meeting, attracting some 13,000 infectious disease (ID) specialists to Washington, DC. As expected, the meeting provided myriad opportunities to catch up on general ID medicine, but it also included some important presentations specifically on HIV.

Early ART and Overall Survival

For nearly 2 decades, we have been debating when to start antiretroviral therapy (ART) in asymptomatic HIV-infected patients. The most recent guidelines from both the U.S. Department of Health and Human Services and the International AIDS Society–USA recommend starting ART when CD4 counts fall below 350 cells/mm³. Now, data from the NA-ACCORD study, presented by Mari Kitahata, support starting treatment even earlier [Abstract H-896b].

This prospective cohort analysis involved more than 8000 HIV-infected patients in North America who, at study entry (1996–2006), were treatment-naive and had CD4 counts between 351 and 500 cells/mm³. During follow-up, the risk for all-cause mortality was 43% lower among patients who started ART at CD4 counts between 351 and 500 cells/mm³ (about 30% of the cohort) than among those who deferred therapy. An important methodological advantage of this study was that patients who delayed starting therapy for more than 1.5 years after crossing the "deferred" threshold of 350 cells/mm³ were censored, hence excluding those who never began treatment. Notably, rates of virologic suppression did not differ significantly between the deferred and initiation groups, implying comparable levels of medication adherence and possibly other, unmeasurable confounders. An analysis of patients who started ART at CD4 counts >500 cells/mm³ is under way and is expected to be presented soon.

— Paul E. Sax, MD

Raltegravir vs. Efavirenz in Treatment-Naive Patients

Efavirenz (plus 2 NRTIs) is essentially the current gold standard for initial therapy, but the integrase inhibitor raltegravir might not be far behind. In a phase III, double-blind, industry-supported study conducted by Jeffrey Lennox and colleagues, 563 treatment-naive patients with no evidence of antiretroviral resistance were randomized to receive tenofovir/FTC plus either raltegravir or efavirenz [Abstract H-896a]. At week 48, rates of virologic suppression were 86% for raltegravir and 82% for efavirenz, meeting protocol-specified criteria for noninferiority. Patients in the raltegravir arm had significantly shorter times to virologic suppression, greater CD4-cell increases (mean, 189 vs. 163 cells/mm³), lower rates of drug-related adverse events overall (44% vs. 77%), and lower rates of protocol-specified central nervous system toxicity (10% vs. 18%). Although raltegravir is not yet approved for use in treatment-naive patients, these results reassure us that, at least in the short term, raltegravir is just as effective as our standard-of-care approaches are.

— Paul E. Sax, MD

More on Raltegravir: Resistance and Mechanisms of Action

The ongoing industry-sponsored BENCHMRK studies confirmed the efficacy of adding raltegravir to a new optimized background regimen in patients with triple-class resistance (JW Infect Dis Jul 23 2008). Now, for the first time, investigators have presented resistance details from that study and, more important, a likely mechanism of action for the drug [Abstract H-898].

Daria Hazuda and colleagues analyzed genotypes from 64 study participants who developed new resistance mutations to raltegravir during virologic failure with the drug. Three signature mutations — at positions N155, Q148, and Y143 — were confirmed in most patients with virologic failure. Resistance, however, evolved over time, with high-level resistant viruses replacing low-level resistant mutants. For instance, on the first genotypes obtained, 30% of viruses had one mutation, 44% had two, and 27% had more than two. In contrast, on follow-up genotypes, only 8% of viruses had one mutation, 45% had two, and 47% had more than two. Q148H was the dominant resistance-conferring mutation, often replacing N155H. Alone, Q148H and N155H had similar effects on resistance to raltegravir, but secondary mutations increased resistance substantially more with Q148 mutations (several hundredfold) than with N155H mutations (100-fold) and had less influence on viral fitness.

Hazuda and colleagues also offered a potential explanation for why raltegravir is associated with a much more rapid reduction in viral loads than its competitors in treatment-naive patients and why raltegravir has performed much better than anticipated, even in patients with limited options who had subtherapeutic serum levels. New in vitro studies showed that the binding of raltegravir to the preintegration complex is essentially irreversible, because the "off rate" (the rate at which the drug dissociates from this complex) is longer than the half-life of the complex. Once binding to the preintegration complex occurs, removing the remaining raltegravir from culture does not diminish efficacy. Interestingly, N155 and Q148 mutations primarily affect the off rate and not the binding of raltegravir.

These findings have potentially game-changing implications. The serum levels of raltegravir are likely irrelevant as long as all intracellular preintegration complexes are bound. As the binding is essentially irreversible, the drug can likely be given once daily or at even longer dosing intervals. The extremely long off rate should arrest viral replication more thoroughly and thereby protect concurrent antivirals.

— Helmut Albrecht, MD

Darunavir and Atazanavir: 96-Week Data from ARTEMIS and CASTLE

In a 48-week analysis from the industry-sponsored ARTEMIS study, ritonavir-boosted darunavir was found to be noninferior to lopinavir/ritonavir in treatment-naive patients (AIDS Clin Care Aug 11 2008). Now, 96-week results presented by Tony Mills suggest that boosted darunavir is actually superior [Abstract H-1250c]. Compared with patients in the lopinavir/r arm, those in the boosted-darunavir arm had significantly greater rates of virologic suppression (79% vs. 71%) and fewer virologic failures. Stratified analyses further demonstrated the potency of the drug, with results significantly favoring boosted darunavir among patients with baseline CD4 counts <200 cells/mm³ or baseline viral loads 100,000 copies/mL. These results bolster the FDA’s recent decision to approve the use of darunavir in treatment-naive patients (AIDS Clin Care Oct 27 2008).

A 96-week analysis was also presented from the industry-sponsored CASTLE study, by Jean-Michel Molina [Abstract H-1250d]. Consistent with the 48-week analysis (AIDS Clin Care Aug 25 2008), ritonavir-boosted atazanavir remained noninferior to lopinavir/r, with virologic suppression rates of 74% and 68%, respectively.

Notably, in both studies, the lipid results were more favorable — and the occurrence of gastrointestinal side effects less frequent — in the non-lopinavir/r arms than in the lopinavir/r arms. Given the results of these studies, the remaining advantages to lopinavir/r include coformulation and lower cost, because both efficacy and tolerability are better with ritonavir-boosted atazanavir and ritonavir-boosted darunavir.

— Paul E. Sax, MD

Maraviroc vs. Efavirenz: A Reanalysis of MERIT

Initial reports from the industry-sponsored MERIT study indicated that the CCR5 inhibitor maraviroc did not meet criteria for noninferiority when compared with efavirenz among 721 treatment-naive patients with CCR5-tropic virus (AIDS Clin Care Sep 10 2007). However, Michael Saag and colleagues have since reanalyzed the MERIT data using the new enhanced-sensitivity tropism assay that is currently available through Monogram Biosciences [Abstract H-1232a]. By using this assay, they were able to reclassify 107 patients in the study who, in fact, harbored CXCR4-using virus and hence would have been excluded from enrollment had the test been available at study outset. When these patients were excluded from analysis, virologic responses at week 48 were virtually identical between the maraviroc and efavirenz groups (68.5% and 68.3%, respectively), with maraviroc now meeting the criteria for noninferiority. Although these results are encouraging, clinicians are unlikely to use maraviroc much in treatment-naive patients, because tropism testing is not performed routinely in this population, and numerous other effective options already exist.

— Paul E. Sax, MD

More Data on Abacavir/3TC

Results from ACTG 5202 have raised questions about the virologic efficacy of abacavir/3TC in initial treatment regimens, particularly among patients with high viral loads (AIDS Clin Care Sep 15 2008). Two studies presented at ICAAC/IDSA add to the controversy. In the industry-supported ARIES study, 515 patients (all HLA B5701–negative) initiated ART with abacavir/3TC plus ritonavir-boosted atazanavir [Squires K et al. Abstract H-1250a]. At a planned 36-week analysis, a high percentage (80%) of patients had achieved virologic suppression, including 76% of those with high baseline viral loads. On a less encouraging note, a meta-analysis of 12 clinical trials revealed lower rates of virologic suppression with PI-based regimens containing abacavir/3TC than with those containing tenofovir/FTC — especially in the largest group, patients treated with lopinavir/r [Hill A et al. Abstract H-1254].

— Paul E. Sax, MD

Bevirimat: Predictors of Response

Bevirimat is the first maturation inhibitor in development for HIV treatment, and therefore one would expect all patients to respond to it. However, in a phase II, industry-sponsored, dose-finding study presented by Jacob Lalezari [Abstract H-891], only some of the 88 study participants responded to treatment: Those patients with adequate trough concentrations of the drug experienced a maximal viral-load decline of 1.26 log copies/mL after 7 days of monotherapy. Further analysis showed that nonresponders harbored a polymorphism in the Gag region of HIV, making their viruses effectively resistant to the drug. Given that this polymorphism is present in approximately 40% of clade B viruses, a substantial proportion of patients will not be candidates for bevirimat. Nonetheless, a phase III study of the drug is planned, incorporating pretreatment screening for the polymorphism and using a new tablet formulation.

— Paul E. Sax, MD

Published in Journal Watch HIV/AIDS Clinical Care November 10, 2008

2011 Year in Review