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Quad Not Inferior to Efavirenz Combo at 48 Weeks in Phase 3 Trial
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
Quad, the 4-in-1 once-daily pill including the integrase inhibitor elvitegravir, proved virologically noninferior to Atripla in the first phase 3 trial comparing two single-pill combination antiretrovirals [1]. Toxicity profiles differed with the two coformulated drugs in this study of antiretroviral-naive people, but dropouts due to side effects were similar.
Besides elvitegravir, Quad contains the boosting agent cobicistat, tenofovir, and emtricitabine. Atripla melds the latter two drugs with the nonnucleoside efavirenz. Conducted in the United States and Puerto Rico, this trial compared the two convenient regimens in 700 antiretroviral-naive people with any CD4 count.
Study participants averaged 38 years in age, about 90% were men, and almost two thirds were white. Pretreatment CD4 counts averaged 391 in the QUAD arm and 382 in the Atripla arm. Both groups had a median pretreatment viral load around 4.75 log10 copies/mL (about 55,000 copies). Thirty-seven of 348 people (11%) discontinued treatment in the Quad arm, 12 because of adverse events and 5 for lack of efficacy. Forty-six of 352 people (13%) quit in the Atripla arm, 18 because of adverse events and 4 for lack of efficacy.
In the primary endpoint (snapshot) analysis, 88% in the Quad group and 84% in the Atripla group had a week-48 viral load below 50 copies, a result establishing the noninferiority of Quad to Atripla in treatment-naive people. Virologic nonsuppression rates were 7% in both arms. Other analyses, such as time to loss of virologic response (TLOVR) and virologic failure, yielded similar results.
Week-48 virologic response rates did not differ between the two regimens among people who started therapy with a viral load above 100,000 (84% with Quad, 82% with Atripla) or a CD4 count below 350 (83% with Quad, 84% with Atripla). Among people who began therapy with more than 350 CD4s, Quad held a significant advantage in 50-copy response rate (91% versus 84%). Forty-eight-week CD4 gains were significantly greater with Quad than Atripla (+239 versus +206, P = 0.009).
Among 14 people taking Quad who met resistance analysis criteria, 8 had detectable mutations, including 7 E92Q integrase mutations, 8 M184V/I emtricitabine mutations, and 3 K65R tenofovir mutations. Among 17 people taking Atripla who met resistance analysis criteria, 8 had detectable mutations, all of them with a major nonnucleoside mutation, 2 with M184V/I, and 2 with K65R.
Similar low proportions in each group had to discontinue study drugs because of side effects--4% in the Quad group (renal abnormalities in 1.4%) and 5% in the Atripla group (rash in 1.4%). Nausea proved more frequent with Quad than Atripla (21% versus 14%, P < 0.05), while familiar nonnucleoside side effects were more frequent with Atripla: abnormal dreams (27% versus 15%, P < 0.05), insomnia (14% versus 9%, P < 0.05), dizziness (24% versus 7%, P < 0.001), and rash (12% versus 6%, P = 0.009).
Serum creatinine climbed in the early weeks of Quad therapy, then leveled off. At week 48 median creatinine changes were +0.14 mg/dL in the Quad arm and +0.01 mg/dL in the Atripla arm (P < 0.001).
Total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol all rose significantly more through 48 weeks with Atripla than with Quad. But the total-to-HDL cholesterol ratio did not differ between the two groups at week 48; neither did triglycerides.
Results of a parallel trial comparing Quad with atazanavir/ritonavir plus tenofovir/emtricitabine will be presented at this conference tomorrow.
Reference
1. Sax P, DeJesus E, Mills A, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate has non-inferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1+ subjects. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 101.
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