The Quad single-tablet regimen, an all-in-one pill containing the experimental integrase inhibitor elvitegravir plus two other antiretroviral drugs and a novel boosting agent, was as effective as the widely used Atripla combination but with fewer neuropsychiatric side-effects, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections last week in Seattle. In a companion study the Quad regimen also matched boosted atazanavir (Reyataz).
Quad vs Atripla
Paul Sax from Brigham and Women's Hospital in Boston reported 48-week primary data from a Phase 3 trial (Study 236-0102) comparing two convenient single-tablet regimens.
The study enrolled 700 participants. Most (about 90%) were men, about two-thirds were white and the average age was 38 years. All were starting their first antiretroviral therapy (ART) regimen. One-third had high baseline HIV viral load (> 100,000 copies/ml). The mean CD4 cell count was about 385 cells/mm3, but about 30% had levels below 350 cells/mm3 and 13% had less than 200 cells/mm3.
Participants were randomly assigned to take one of two all-in-one regimens: Gilead's Quad pill, containing the second-generation integrase inhibitor elvitegravir, the pharmacoenhancer cobicistat, tenofovir and emtricitabine, or else Atripla, containing the NNRTI efavirenz (Sustiva or Stocrin) plus tenofovir and emtricitabine.
Both regimens performed well through 48 weeks, with 88% of participants in the Quad arm and 84% of those on Atripla having undetectable HIV viral load (< 50 copies/ml), not a statistically significant difference. Virological failure was seen in 7% of participants in both arms.
The regimens performed equally well in analyses of demographic subgroups and in people with high baseline viral load (84% vs 82%, respectively), but the Quad appeared to hold an edge among people with CD4 counts above 350 cells/mm3 (91% versus 84%). Patients in the Quad arm had a small but significant advantage in CD4 cell gains, 239 vs 206 cells/mm3 at week 48.
Both single-tablet regimens were generally well-tolerated. Similar proportions of patients discontinued the study prematurely (11% in the Quad arm, 13% in the Atripla arm), but fewer in the Quad group stopped early due to adverse events (12 vs 18 participants); most of the remainder were lost to follow-up or were non-adherent.
Participants in the Quad arm were significantly more likely to report nausea (21% vs 14%), but several other side-effects occurred more often in the Atripla group, including abnormal dreams (15% vs 27%, respectively), insomnia (9% vs 14%), dizziness (7% vs 24%) and skin rash (6% vs 12%).
People in the Quad arm had significantly smaller increases in total, LDL ('bad') and HDL ('good') cholesterol, with similar rises in triglycerides.
Patients receiving the Quad regimen had a larger increase in serum creatinine (a marker of possible kidney damage) early on, but this soon stabilised and did not progress over time. Prior studies have shown that cobicistat affects kidney tubule secretion of creatinine, but it does not appear to cause the type of damage seen with kidney-toxic drugs.
In this study comparing once-daily single-tablet HIV regimens, "Quad demonstrated non-inferior efficacy", the researchers concluded. The Quad regimen was well-tolerated with "similar low rates of treatment discontinuation".
Quad vs atazanavir
Findings from a second parallel trial (Study 236-0103) were presented in a poster by Edwin DeJesus and colleagues. This study compared the Quad to a popular protease inhibitor regimen, ritonavir-boosted atazanavir plus tenofovir and emtricitabine.
In this analysis, which included a similar population of 708 treatment-naive participants, 90% of people in the Quad arm and 87% in the boosted atazanavir arm had undetectable HIV RNA at 48 weeks, again not a significant difference. Among people with high baseline viral load the corresponding rates were 85% vs 82%. Virological failure was uncommon in both arms at 5%. Median CD4 cell gains were also similar (207 vs 211 cells/mm3, respectively).
Here too, both regimens were generally safe and well-tolerated, with similar proportions of particupants discontinuing due to adverse events (4% vs 5%, respectively). As expected, fewer people taking the Quad regimen developed elevated bilirubin, a known side-effect of atazanavir.
Based on these findings, Gilead has submitted Quad for regulatory approval in Europe, the US, Australia and Canada, with a decision from the US Food and Drug Administration expected by August 2012.
At an earlier presentation at the conference, researchers reported that the company is also working on a new Quad formulation that replaces tenofovir with its pro-drug GS-7340, which concentrates in cells and may cause fewer side-effects.
Sax P et al. Elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) has non-inferior efficacy and favorable safety compared to efavirenz/emtricitabine/tenofovir in treatment-naive HIV-1+ subjects. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 101, 2012. The abstract is available on the official conference website.
DeJesus E et al. Week 48 results of an ongoing global phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir (Quad) with atazanavir/ritonavir plus emtricitabine/tenofovir in treatment-naive HIV-1+ subjects showing efficacy, safety, and pharmacokinetics. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 627, 2012. The abstract is available on the official conference website.