A new formulation that combines three antiretroviral drugs plus a novel boosting agent in a single once-daily pill was highly effective in a Phase 2 trial of previously untreated participants, researchers reported at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) taking place this week in San Francisco.
A second study showed that the booster, now named cobicistat (GS 9350), worked as well as ritonavir in a combination regimen.
Calvin Cohen and colleagues conducted two prospective Phase 2 studies featuring cobicistat. In the first trial (Study 236-0104), 71 participants were randomly assigned to take one of two complete regimens in a single once-daily pill.
A total of 48 received the new 'Quad' pill, containing the experimental integrase inhibitor elvitegravir with cobicistat as a booster, plus tenofovir (Viread) and emtricitabine (Emtriva). In the other arm, 23 received the Atripla pill containing efavirenz (Sustiva, Stocrin) plus tenofovir and emtricitabine.
The second trial (Study 216-0105) compared 150mg cobicistat against 100mg ritonavir (Norvir) – the sole currently approved boosting agent, or pharmacoenhancer – when combined with tenofovir/emtricitabine (Truvada) and the protease inhibitor atazanavir (Reyataz); 50 people took cobicistat and 29 took ritonavir.
As previously reported, pharmacoenhancers like cobicistat and ritonavir work by interfering with liver enzymes that process drugs such as elvitegravir and many protease inhibitors, allowing them to rise to higher concentrations in the body. Unlike ritonavir, however, cobicistat does not have its own anti-HIV activity.
In both trials, about 90% of participants were men, the average age was about 35 years, and a majority were white. At study entry, all had a viral load of at least 5000 copies/ml and no resistance to the three original antiretroviral drug classes. The average viral load was about 40,000 copies/ml and the approximate mean CD4 cell count range was 350 to 450 cells/mm3.
In the first trial, after 24 weeks, 90% of participants in the Quad group and 83% in the Atripla group reached a viral load below 50 copies/ml, according to an intent-to-treat analysis in which people who dropped out of the study early (6% in the Quad arm, 13% in the Atripla arm) were counted as "failures".
Although not designed to be a non-inferiority trial, the study did show that the Quad pill was non-inferior to Atripla.
In the second study, using the same type of analysis at 24 weeks, 84% of people taking cobicistat and 86% of those taking ritonavir saw their viral load fall to below 50 copies/ml, showing that cobicistat boosted atazanavir just as well as ritonavir. A similar proportion of people in both arms dropped out early (8% vs 10%, respectively).
In both trials, people in the two arms experienced similar CD4 cell count increases. In the first study, those taking the Quad pill gained 123 cells/mm3 by week 24, whilst those taking Atripla gained 124 cells/mm3. Increases in the second study were somewhat larger, 206 cells/mm3 in the cobicistat arm and 190 cells/mm3 in the ritonavir arm.
Looking at the first trial, people taking the Quad pill experienced fewer drug-related adverse events overall than those taking Atripla – 35% vs 57%, respectively – which was largely attributable to the lower frequency of central nervous system side-effects associated with efavirenz. No participants in the Quad arm and only one in the Atripla arm left the study early due to adverse events.
In the second trial, rates of drug-related adverse events were similar, 20% in the cobicistat arm and 24% in the ritonavir group. Here, two people taking cobicistat dropped out early, as did one ritonavir recipient.
The major point of concern with cobicistat was a small increase in blood creatinine levels, a sign of possible kidney impairment. Creatinine rose by 0.14 mg/dl with the Quad pill vs 0.04 mg/dl with Atripla in the first trial, and by 0.18 mg/dl with cobicistat vs 0.14 mg/dl with ritonavir in the second trial.
Because creatinine is one of the factors used to compute estimated glomerular filtration rate (eGFR), the eGFR level was lower – suggesting worse kidney function – in the Quad and cobicistat arms.
However, Dr Cohen explained that early studies of cobicistat in healthy HIV-negative volunteers showed that the drug did not affect actual GFR, only the estimated value. This suggests that whilst cobicistat slightly inhibits kidney tubule secretion of creatinine, it does not cause the type of damage usually seen with kidney-toxic drugs.
Based on the favourable results from these studies, Gilead Sciences expects to move into Phase 3 trials of cobicistat and the Quad pill later this year.
Cohen C et al. The single-tablet, fixed-dose regimen of elvitegravir/GS-9350/emtricitabine/tenofovir DF (Quad) achieves a high rate of virologic suppression and GS-9350 is an effective booster. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 58LB, San Francisco, 2010.