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"Quad" Pill Continues to Impress in Week-48 Results; Cobicistat Moves Forward in Battle With Ritonavir

By Myles Helfand

September 14, 2010

The "quad" -- a once-daily, four-drug combination pill -- continues to sail relatively smooth waters on its route through the HIV drug development process. Building off its solid showing at CROI earlier this year, 48-week phase 2 data newly released at ICAAC 2010 show levels of effectiveness and safety that are similar to the drug combo that comprises Atripla (efavirenz/tenofovir/FTC).

The quad pill is a tablet consisting of two already-approved antiretrovirals, Emtriva (emtricitabine, FTC) and Viread (tenofovir), as well as two as-yet unapproved drugs, elvitegravir (an integrase inhibitor) and cobicistat (a novel booster drug previously known as GS 9350). The phase 2 study results presented here involved 71 HIV-positive people who had never before taken antiretroviral therapy and had no resistance to NNRTIs, NRTIs or protease inhibitors. Volunteers were randomized to receive either the quad pill (48 people) or Atripla (23 people).

After 48 weeks of treatment, the quad pill easily proved itself "non-inferior" to Atripla. People in both arms were highly likely to achieve an undetectable viral load: 90 percent of quad recipients versus 83 percent of Atripla recipients, a virtual dead heat due to the small number of people in the study. CD4 count increase trended higher among people taking the quad pill (up 240, on average) than those taking Atripla (up 162).

The rate of adverse events was similar between the two study arms (46 percent of people on the quad versus 57 percent on Atripla). Serious adverse events were very rare, and only one person discontinued treatment as a result (on the Atripla arm, due to thoughts of suicide, a potential side effect of the efavirenz in the pill). The type of adverse event differed a bit between study arms, with central nervous system side effects (such as abnormal dreams, dizziness, headache and trouble sleeping) occurring more frequently on the Atripla arm and rash occurring more frequently on the quad arm. The quad pill also appeared a bit more cholesterol-friendly than Atripla, while Atripla came out a little better on the triglycerides front (although people's cholesterol and triglyceride levels generally increased while on either pill).

The one blip on the quad's radar has been concerns that it may cause kidney impairment in some people. To examine this issue, the study investigators looked at volunteers' serum creatinine levels and estimated glomerular filtration rates (e-GFR), two measurements of kidney function. Creatinine levels leaped quickly at week 2 among quad recipients, but afterward those levels increased at a similar rate to that of people on Atripla. Similarly, the mean change in e-GFR dropped sharply during the first two weeks of therapy on the quad, but slowly stabilized afterward.

Wrapped into a nice little package with the quad-versus-Atripla study was a parallel study that compared cobicistat to Norvir (ritonavir) in a battle of booster drugs. (Both were taken with Reyataz [atazanavir] and Truvada [tenofovir/FTC].) Although I'm mentioning this second within this summary, it's worth noting that the development of cobicistat as a potential alternative to Norvir could ultimately be just as important to the evolution of HIV treatment, if not more so, than the development of the quad pill as an alternative to Atripla.

In short, cobicistat looks good: The cobicistat-containing regimen was just as likely as the Norvir-containing regimen to suppress viral load. The side effect profile is a little more uncertain: Lipid levels were better in the cobicistat arm, but the cobicistat appears to be the driving force behind the sudden creatinine and e-GFR changes among people starting the quad pill. That these changes appear to stabilize after the first couple of weeks is encouraging, but will likely not convince everyone. Phase 3 trials currently underway for the quad pill and cobicistat, thanks to their long duration and higher number of volunteers, should help resolve lingering questions about cobicistat's potential kidney effects.

Myles is the editorial director of TheBody.com and TheBodyPRO.com.


Reference

Elion R, Gathe J, Rashbaum B, et al. The single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF: "Quad") maintains a high rate of virologic suppression, and cobicistat (COBI) is an effective pharmacoenhancer through 48 weeks. In: Program and abstracts of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2010; Boston, Mass. Abstract H-938B.


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