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Virologic Failure with Abacavir — ACTG 5202 and the GSK Response

This year’s International AIDS Conference delivered conflicting information about the virologic efficacy of abacavir/3TC.

ACTG 5202 is an important ongoing study of initial treatment strategies for HIV infection; it includes a blinded comparison of fixed-dose tenofovir/FTC versus abacavir/3TC, each together with efavirenz or boosted atazanavir. At this year’s International AIDS Conference, Paul Sax presented results of the NRTI comparison among 797 study participants who had baseline viral loads 100,000 copies/mL; median follow-up was 60 weeks [Abstract THAB0303]. Although these results were described in a press release earlier this year (AIDS Clin Care Mar 10 2008), this is the first time they have been presented in detail.

Among persons with viral loads 100,000 copies/mL at screening, time to virologic failure was significantly shorter among those randomized to abacavir/3TC than among those randomized to tenofovir/FTC (hazard ratio in an intent-to-treat analysis, 2.33; 95% confidence interval, 1.46–3.72). A total of 57 failures occurred in the abacavir/3TC group, compared with 26 in the tenofovir group. Abacavir/3TC recipients also had a shorter time to adverse events (HR, 1.87; 95% CI, 1.43–2.43), defined as a first grade 3 or 4 sign or symptom or a laboratory abnormality one grade higher than baseline. These differences were not explained by hypersensitivity reaction rates, which were comparable in the two groups. The excess virologic failures led the Data and Safety Monitoring Board to recommend unblinding the NRTIs and stopping the comparison between abacavir/3TC and tenofovir/FTC among patients with baseline viral loads 100,000 copies/mL.

In response to these findings, Keith Pappa and colleagues from GlaxoSmithKline (the maker of abacavir) reanalyzed data from 2490 patients who participated in industry-sponsored studies of abacavir/3TC [Abstract THAB0304]. They used the same endpoints and statistical methods as in the ACTG 5202 analysis, stratifying study subjects by baseline viral loads above or below 100,000 copies/mL. No differences were seen between abacavir/3TC arms and control arms in time to loss of virologic response or to presence of grade 3 or 4 adverse events. This analysis was not done as a formal meta-analysis and included a variety of dosing schedules and companion drugs; nonetheless, it provides an important contrast to the ACTG data.

Clearly, more information is needed to sort out the appropriate role of this fixed-dose combination in antiretroviral regimens. While awaiting further data, clinicians should reserve use of abacavir/3TC among treatment-naive HIV-infected persons with high viral loads to those who clearly should avoid tenofovir (e.g., those with clinically significant preexisting renal insufficiency).

— Charles B. Hicks, MD

Published in Journal Watch HIV/AIDS Clinical Care September 15, 2008

2011 Year in Review