Jim Kling

March 13, 2012

March 13, 2012 (Seattle, Washington) — In a phase 3 study, a once-daily tablet consisting of 4 antiretroviral agents — elvitegravir, cobicistat, emtricitabine, and tenofovir DF — had a response rate similar to the triple-therapy regimen of efavirenz, emtricitabine, and tenofovir DF.

The new formulation, known as Quad, has a superior adverse-effect profile with respect to central nervous system (CNS) effects, rash, and fasting lipid levels, according to researchers here at the 19th Conference on Retroviruses and Opportunistic Infections.

In a press conference, Paul Sax, MD, clinical director of the division of infectious diseases at Brigham and Women's Hospital, and professor of infectious diseases at Harvard Medical School, in Boston, Massachusetts, reported the 48-week results of a prospective, randomized, double-blind, active-controlled, ongoing phase 3 trial comparing the Quad regimen with the triple-therapy regimen of efavirenz, emtricitabine, and tenofovir DF in treatment-naïve patients with HIV. "We already knew from the phase 2 study that the Quad pill looked comparable to the standard-of-care regimen," Dr. Sax reported at a press conference.

Treatment-naïve HIV-positive subjects were randomized to once-daily Quad or triple therapy. To be eligible, patients had to have an HIV RNA viral load of at least 5000 copies/mL, a creatinine clearance of at least 70 mL/min, and viral sensitivity to the 3 agents comprising the triple therapy. Patients were stratified into 1 of 2 groups: those with an HIV-1 RNA viral load above 100,000 copies/mL, and those with an HIV-1 RNA viral load of 100,000 copies/mL or less. The primary end point was an HIV RNA viral load of 50 copies/mL at week 48.

A total of 700 patients were treated (89% male, 37% nonwhite, 33% with a viral load above 100,000 copies/mL).

Dr. Sax reported that 88% of patients in the Quad group met the end point, compared with 84% of those in the triple-therapy group (difference, 3.6%; 95% confidence interval, –1.6% to +8.8%). For patients with a baseline HIV RNA viral load above 100,000 copies/mL, response rates were similar in the Quad and triple-therapy groups (84% vs 82%).

Both groups had virologic failure rates of 7% at week 48.

At week 48, the mean increase in CD4 cell count was 239 cells/μL in the Quad group and 206 cells/μL in the triple-therapy group (P = .009).

The Quad and triple-therapy regimens had similar discontinuation rates due to adverse events (4% vs 5%). The most significant adverse events in the Quad and triple-therapy groups were nausea (21% vs 14%), dizziness (7% vs 24%), abnormal dreams (15% vs 27%), insomnia (9% vs 14%), and rash (6% vs 12%).

At week 2, a decrease in creatinine clearance was seen in the Quad group; at week 48, the decrease was greater in the Quad than in the triple-therapy group (14.3 vs 3.0 mL/min).

Increases in total cholesterol were lower in the Quad than in the triple-therapy group at week 48 (10 vs 19 mg/dL; P < .001), as were increases in low-density-lipoprotein cholesterol (10 vs 17; P = .001) and high-density-lipoprotein cholesterol (5 vs 8; P = .001). Mean changes in triglycerides were the same in the 2 groups (7 vs 7; P = .44).

"Most of the [outcomes] favored the Quad regimen, although the confidence intervals did cross 0," said Dr. Sax, adding that patients currently on standard-of-care regimens could consider switching to Quad if it is approved.

"There might be patients who are currently taking the triple regimen who would be concerned about switching because it's working well for them. Although this has not been tested in a prospective trial, it looks like a switch would be virologically safe and may be associated with fewer CNS side effects," Dr. Sax noted.

Andrew Carr, MD, PhD, an immunologist at the University of New South Wales in Sydney, Australia, who attended the conference, was impressed by the results.

Both regimens were "pretty effective, and the differences were pretty modest. I think the key advantage for patients is going to be the lack of CNS stimulation. Patients cope with [those adverse effects] because it's one pill a day, but they aren't fond of them. I would be surprised if Quad isn't licensed in the next 6 months, and I think that treatment-naïve patients will take it up and some existing patients may choose to switch to it," Dr. Carr told Medscape Medical News.

Dr. Sax reports serving as a consultant for Abbott, Aileron, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Merck; and receiving research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec. Dr. Carr reports serving as a consultant for Gilead Sciences and speaking at Gilead-sponsored meetings.

19th Conference on Retroviruses and Opportunistic Infections (CROI): Abstract 101. Presented March 7, 2012.

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