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Cobicistat Booster Is a Safe and Effective Alternative to Ritonavir

The novel pharmacoenhancer cobicistat boosts blood levels of atazanavir (Reyataz) as well as ritonavir (Norvir) and is generally safe and well-tolerated over 48 weeks, according to final study results published in the July 1, 2013, Journal of Infectious Diseases.

Some antiretroviral drugs -- including most HIV protease inhibitors, the integrase inhibitor elvitegravir, and certain direct-acting hepatitis C virus drugs -- have trouble reaching effective levels in the body. Boosters like cobicistat and ritonavir raise concentrations by inhibiting activity of the CYP3A enzyme in the liver, which slows drug processing. Unlike ritonavir, Gilead Sciences' cobicistat is not itself active against HIV.

Joel Gallant from Johns Hopkins University School of Medicine and colleagues conducted a randomized, controlled Phase 3 trial (Study 114; NCT01108510) comparing the safety and efficacy of cobicistat versus ritonavir, both used as part of a first-line antiretroviral regimen with atazanavir and tenofovir disoproxil fumarate/emtricitabine (the drugs in Truvada). Data were previously presented at scientific meetings including the 2012 International AIDS Conference, and final results have now been published.

This international trial included 692 treatment-naive participants. About 80% were men, a majority were white, the average age was about 38 years, and the mean CD4 T-cell count was about 350 cells/mm³. People with impaired kidney function at baseline were excluded, as earlier studies showed cobicistat might affect kidney function; the median baseline estimated glomerular filtration rate (GFR) was about 114 mL/min (Cockcroft-Gault method).

Results

• At 48 weeks, 85% of people taking cobicistat and 87% of those taking ritonavir had HIV viral load < 50 copies/mL in an intent-to-treat "snapshot" analysis.
• The 2% difference in efficacy fell well within the pre-specified 12% non-inferiority margin, indicating that cobicistat was not inferior to ritonavir. 
• Response rates were similar (86% in both arms) for participants with high baseline viral load (>100 000 copies/mL).
• CD4 cell gains at 48 weeks were also similar in both arms.
• Both treatment arms had similar rates of serious adverse events (10% vs 7%) and adverse events leading to treatment discontinuation (7% in both).
• Serum creatinine increased in both arms, by 0.13 mg/dL among cobicistat recipients and by 0.09 mg/dL among ritonavir recipients.
• Elevated bilirubin -- a known side effect of atazanavir -- was common overall, but more so among cobicistat recipients.
• Discontinuation due to kidney-related side effects was infrequent and comparable in both arms.

Based on these findings, the study authors concluded, "Cobicistat was non-inferior to ritonavir in combination with atazanavir plus [tenofovir/emtricitabine] at week 48."

"Both regimens achieved high rates of virologic success," they continued. "Safety and tolerability profiles of the 2 regimens were comparable. Once-daily cobicistat is a safe and effective pharmacoenhancer of the protease inhibitor atazanavir."

In their discussion, the researchers explained that the observed serum creatinine increase is thought to be due to cobicistat's effect on renal tubular secretion, not impaired filtration -- meaning it alters estimated, but not actual, GFR.

Gilead took the unusual step of requesting U.S. Food and Drug Administration(FDA) approval of Stribild, its 4-in-1 combination pill containing cobicistat, elvitegravir, tenofovir, and emtricitabine, before all of the individual components were approved; approval of the quad pill was granted in August 2012. However, the FDA recently declined approval of cobicistat and elvitegravir as stand-alone agents due to "deficiencies in documentation and validation of certain quality testing procedures." No safety issues were raised, and Gilead said it is working with the agency to address these issues and move the applications forward.

5/30/13

Reference

JE Gallant, E Koenig, J Andrade-Villanueva, et al. Cobicistat Versus Ritonavir as a Pharmacoenhancer of Atazanavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-Naive HIV Type 1-Infected Patients: Week 48 Results. Journal of Infectious Diseases 208(1):32-39. July 1, 2013.