Effective combination antiretroviral therapies have transformed HIV infection from a death sentence to a chronic condition. But the protease inhibitors are seen as the weak link. Cobicistat\'s improved physicochemical properties enable it to be co-formulated with antiretroviral drugs and it also causes fewer side-effects
Effective combination antiretroviral therapies have transformed HIV infection from a death sentence to a chronic condition. These drug cocktails contain agents that act via different mechanisms and on different stages of the virus’s lifecycle. But the protease inhibitors are seen as the weak link because they tend to be metabolised rapidly by the cytochrome P450 3A enzyme. This can be counteracted to some extent by giving the antiviral drug ritonavir alongside them, as this inhibits CYP3A. However, ritonavir is plagued by side-effects, and an alternative is being developed by Gilead.
Cobicistat has no antiviral activity of its own, but its improved physicochemical properties enable it to be co-formulated with antiretroviral drugs – unlike ritonavir – and it also causes fewer side-effects. Indeed, it was tested in a study alongside the CYP3A substrate midazolam, and in both single and multiple dose escalations it gave a very significant increase in exposure to midazolam.1
Several trials have been carried out on anti-HIV regimens that have been co-formulated with cobicistat. In one randomised, partially placebo-controlled, double blind Phase II trial, antiretroviral naïve patients with HIV were given placebo-blinded cobicistat (100mg) or ritonavir (150mg) once a day alongside open label atazanavir and a fixed dose emtricitabine and tenofovir combination.2 In total 84% of those given cobicistat and 86% of the ritonavir group had viral suppression to below 50 copies/ml after 24 weeks, with similar levels after 48 weeks. Treatment-related adverse events were lower in the cobicistat group: 36% versus 48%.
In another Phase II randomised, double blind, double dummy trial, a single tablet regimen of elvitegravir (a CYP3A substrate), cobicistat, emtricitabine and tenofovir was compared with single tablets of efavirenz, emtricitabine and tenofovir.3 A total of 72 adults with HIV infection who had not previously received antiretroviral therapy were given one of the fixed dose combinations for 48 weeks. Those given the dosage including cobicistat had a more rapid decline in HIV-1 RNA, and a greater proportion had a viral load suppression to below 50 copies/ml than in the control group. There were also fewer central nervous system and psychiatric adverse events in the cobicistat group.
1. A.A. Mathias et al. Clin. Pharmacol. Ther. 2010, 87, 322
2. R. Elion et al. AIDS 2011, 25, 1881
3. C. Cohen et al. AIDS 2011, 25 (6), F7