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4-in-1 Pill With Elvitegravir/Cobicistat Versus Atripla or Atazanavir Regimen
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
Two weeks before ICAAC, the FDA announced approval of coformulated elvitegravir/cobicistat plus tenofovir/emtricitabine (QUAD, or Stribild) for antiretroviral-naive adults [1]. At the meeting researchers offered a combined comparison of the three trials that provided the basis for QUAD's approval. These 48-week studies compared QUAD with either coformulated efavirenz/tenofovir/emtricitabine (Atripla) or atazanavir/ritonavir plus tenofovir/emtricitabine in previously untreated adults [2]. With the licensing of QUAD, elvitegravir joins raltegravir among approved integrase inhibitors, and cobicistat becomes the first nonritonavir, nonantiretroviral boosting agent.
QUAD researchers presented combined 48-week results of three double-blind trials comparing QUAD with either Atripla (studies 102 and 104) or the atazanavir/ritonavir (ATV/r) combination (study 103) in antiretroviral-naive adults [2]. The primary endpoint of these studies was the proportion of participants with a viral load below 50 copies in a snapshot analysis, which considers virologic outcomes at a single point.
The studies included 749 people randomized to QUAD, 375 randomized to Atripla, and 355 randomized to ATV/r. Pretreatment characteristics were similar across study arms. Median ages were 37 with QUAD, 38 with Atripla, and 39 with ATV/r. About 90% in all three groups were men, and one third or fewer were nonwhite. Median viral loads and average CD4 counts were 4.78 log10 copies/mL and 377 CD4s in the QUAD group, 4.77 log and 386 CD4s with Atripla, and 4.86 log and 375 CD4s with ATV/r.
Similar proportions in the QUAD, Atripla, and ATV/r arms discontinued treatment (10%, 13%, and 11%). A slightly lower proportion in the QUAD group (3%) than in the comparison groups (5% each) quit because of adverse events, and 1% or fewer quit each group because of lack of efficacy.
Proportions with a viral load below 50 copies at week 48 were 88.8% with QUAD, 84.0% with Atripla, and 86.6% with ATV/r. Differences were 5.1% (95% confidence interval [CI] 0.7 to 9.4) between QUAD and Atripla and 1.9% (95% CI -2.3 to 6.1) between QUAD and ATV/r. These results established the noninferiority of QUAD to the other two regimens--both of which are preferred first-line regimens in the United States--in previously untreated people. QUAD efficacy in these studies proved consistent in analyses of subgroups with different ages, race, gender, baseline viral loads, and baseline CD4 counts.
CD4 gains through 48 weeks averaged 224 with QUAD, 203 with Atripla (P = 0.081 versus QUAD), and 211 with ATV/r (P = 0.24 versus QUAD).
Rates of adverse events leading to discontinuation of study drugs were 3.5% with QUAD, 5.1% with Atripla, and 5.1% with ATV/r, while respective serious adverse event rates were 9.2%, 6.7%, and 8.7% and death rates 0.1%, 0.5% and 0.8%. The FDA approval announcement lists nausea and diarrhea as common QUAD side effects, while the serious side effect list includes new or worsening kidney problems, decreased bone mineral density, fat redistribution, and immune system changes (immune reconstitution syndrome) [1].
Through 48 weeks people randomized to QUAD had significantly fewer neuropsychiatric problems than those randomized to Atripla (42.9% versus 62.1%, P < 0.001) as well as a significantly lower rash rate (17.5% versus 27.7%, P < 0.001) [2]. Median creatinine increased through 48 weeks with QUAD (+0.13 mg/dL) and ATV/r (+0.08 mg/dL) but not with Atripla (+0.01 mg/dL).
QUAD trial researchers noted that creatinine jumps with QUAD appeared as early as treatment week 2 and remained stable through week 48. They suggested that an "early small increase in creatinine that stabilizes is expected with QUAD due to cobicistat's inhibition of renal creatinine tubular secretion." The investigators proposed that a creatinine increase up to 0.4 mg/dL probably represents a gain unlikely to be caused by cobicistat. In this analysis 4 people with proximal tubulopathy in the QUAD arms had creatinine climbs greater than 0.4 mg/dL.
Through 48 weeks, median total cholesterol rose significantly less with QUAD than with Atripla (+10 versus +19 mg/dL, P < 0.001), as did "bad" LDL cholesterol (+10 versus +17 mg/dL, P < 0.001). But "good" HDL cholesterol also rose significantly less through 48 weeks with QUAD than with Atripla (+5 versus +8 mg/dL, P = 0.002). The investigators did not report relative changes to total-to-HDL cholesterol ratio. Median triglycerides rose significantly less through 48 weeks with QUAD than with ATV/r (+8 versus +23 mg/dL, P = 0.006).
The FDA approval notice stresses that QUAD is not licensed to treat chronic hepatitis B virus infection, even though tenofovir and emtricitabine have activity against HBV. The FDA requires Gilead Sciences, maker to QUAD, to conduct additional studies focused on (1) safety in women and children, (2) evolution of resistance to agents in the combination pill, and (3) interactions between QUAD and other drugs.
References
1. FDA. FDA approves new combination pill for HIV treatment for some patients. August 27, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317004.htm.
2. Ward D, Crofoot G, Shamblaw D, et al. Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF from an integrated analysis of phase 2 and 3 clinical trials. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-555.
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