Experimental Pharmacoenhancer Cobicistat Matches Ritonavir as Booster

The novel boosting agent cobicistat (formerly GS 9350) -- which does not have anti-HIV activity itself -- performed as well as the sole available pharmacoenhancer, ritonavir (Norvir), when combined with atazanavir (Reyataz) plus tenofovir/emtricitabine (the drugs in Truvada), researchers reported in the August 1, 2011, advance online edition of AIDS.

Richard Elion from the Whitman Walker Clinic and fellow investigators with the Gilead Study 216-0105 team assessed the safety and efficacy of cobicistat versus ritonavir as pharmacoenhancers for atazanavir in people starting HIV treatment for the first time.

Like ritonavir, cobicistat works by interfering with the CYP450 system that metabolizes drugs in the liver. These agents inhibit enzyme activity and slow processing of other drugs that use the same pathway -- for example, protease inhibitors -- thereby keeping concentrations of the other drug higher for a longer period.

In this partially placebo-controlled multicenter study, 85 treatment-naive participants were randomly assigned (2:1) to receive either cobicistat or ritonavir as part of a combination antiretroviral regimen with atazanavir and tenofovir/emtricitabine; 6 never received treatment, so the intent-to-treat analysis included 79 people.

Most participants (about 90%) were men, the mean age was about 35 years, and about half were white. The mean CD4 count was right around the treatment initiation threshold of 350 cells/mm³.

Safety and efficacy were assessed at weeks 24 and 48. Week 24 results were previously reported at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010); the AIDSreport extends those findings to week 48.

Results

• At 24 weeks, 84% of patients receiving cobicistat and 86% receiving ritonavir achieved undetectable viral load (<50 copies/ mL), demonstrating non-inferiority.
• The 2 boosters continued to show similar efficacy at 48 weeks, with viral suppression rates of 82% and 86%, respectively.
• Average CD4 cell gains were also similar: 203 vs 199 cells/mm³ at 24 weeks, and 208 vs 177 cells/mm³ at 48 weeks, respectively.
• Overall, treatment-related adverse events were less common in the cobicistat arm compared with the ritonavir arm, 36% vs 48%, respectively.
• Frequency of treatment discontinuation due to adverse events, however, was comparable through 48 weeks, 4% with cobicistat and 3% with ritonavir.
• Almost all patients (96% on cobicistat and 100% on ritonavir) developed hyperbilirubinemia, or elevated bilirubin, a known side effect of atazanavir.
• Similar proportions, 14% and 17%, respectively, had bilirubin high enough to cause jaundice or ocular icterus (yellowing of the skin or eyes).
• The mean estimated glomerular filtration rate (eGFR; Cockcroft-Gault) decreased in both treatment groups, with changes apparent by week 2 but stabilizing thereafter:
  • Week 2: -8% with cobicistat vs -3% with ritonavir;
  • Week 24: -13% vs -11%, respectively;
  • Week 48: -12% vs -11%; respectively.

Based on these findings, the study authors concluded, "Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with emtricitabine/[tenofovir] achieved comparable rates of virologic suppression and CD4 count increase with satisfactory safety profiles."

The kidney safety signal reflected in the larger 2-week decrease in eGFR in the cobicistat arm was no longer significantly different by week 24, and remained stable through week 48.

The results of this Phase 2 study helped guide the design of an ongoing 96-week Phase 3 randomized trial to further evaluate the safety and efficacy of atazanavir/cobicistat vs atazanavir/ritonavir, again both with tenofovir/emtricitabine. Cobicistat is also being tested in Gilead's 4-drug single-tablet regimen known as the "Quad" (elvitegravir/cobicistat/tenofovir/emtricitabine).

Investigator affiliations; Whitman Walker Clinic, Washington, DC; Community Research Initiative of New England, Boston, MA; Therapeutic Concepts, P.A., Houston, TX; TribalMed, Seattle, WA; Southwest C.A.R.E. Center, Santa Fe, NM; Gilead Sciences, Inc., Foster City, CA.

8/5/11

Reference

R Elion, C Cohen, J Gathe, et al (for the GS-US-216–0105 Study Team). Phase 2 Study of Cobicistat versus Ritonavir each with Atazanavir plus Fixed-Dose Emtricitabine/Tenofovir DF in the Initial Treatment of HIV Infection. AIDS (abstract). August 1, 2011 (Epub ahead of print).