Abacavir May Be Less Effective in HIV Patients With High Viral Load

The controversy about whether use of abacavir (ABC) increases the risk for virologic failure in patients with a high viral load was given center stage in back-to-back late-breaker presentations here at the XVII International AIDS Conference.

Paul Sax, MD, from the Brigham and Women's Hospital, Boston, Massachusetts, presented interim findings from part of the AIDS Clinical Trials Group (ACTG) 5202 trial. The 96-week phase 3B study randomly assigned treatment-naive patients to double-blinded regimens of ABC/lamivudine (3TC) or tenofovir (TDF)/emtricitabine (FTC), with open-label use of efavirenz or atazanavir/ritonavir, and stratified them at entry by HIV RNA levels either lower or higher than 100,000 copies/mL.

In January 2008, the data safety monitoring board (DSMB), during a scheduled review of data, identified "highly significant difference between ABC/3TC and TDF/FTC, with excess virologic failures on the ABC/3TC arm occurring in the >100,000 stratum," Dr. Sax said. The ACTG followed the DSMB recommendation and unblinded the stratum with the higher viral load. Dr. Sax presented an analysis of that group.

This portion of the study included 797 study patients (of a total of 1858 patients enrolled) with a median follow-up of 60 weeks. Baseline genotyping was performed on 43% of patients, and if relevant point mutations were present, the patients were excluded from the study.

Virologic failure was more common in the ABC/3TC group than in the TDF/FTC group (57 vs 26 events; P = .0003; hazard ratio for failure of 2.33). Dr. Sax said, "There is a consistent excess of failures in the ABC/3TC arm regardless of the criteria you use for virologic failure"; either early failure to suppress viral load below 200 copies/mL or later failure in rebounding above that level.

Combining time to virologic failure and time to modification of the nucleoside component of the regimen, the researchers found 114 and 68 events, respectively (P = .0001).

Suspected drug hypersensitivity events occurred in 27 patients (7%) in each group. "Screening for HLA 5701 was only done in a small fraction of the patients in the study, and generally not until the end of it," Dr. Sax said.

One death likely was a result of a hypersensitivity reaction on reinitiation of ABC, despite sites being "extensively educated" about recognition and management of that risk.

Grade 3 and 4 adverse events occurred in 33% and 19% of the ABC/3TC and TDF/FTC groups, respectively. Changes in lipid levels were similar in both groups and were probably not clinically significant.

Dr. Sax concluded, "ABC/3TC was associated with a significantly shorter time to virologic failure...and a shorter time to the first adverse event" in the group of patients with HIV RNA levels higher than 100,000 copies/mL.

These findings differ from what has been seen in earlier clinical trials. Dr. Sax suggested that the larger sample size in ACTG 5202 "may have allowed us to describe differences between the groups with greater precision than with a smaller sample size." The use of a different comparator regimen might also help to explain the differences.

During discussion, Dr. Sax acknowledged that different rates of adherence might have affected outcomes in this study; adherence has not yet been analyzed.