- Category: Experimental HIV Drugs
- Published on Friday, 29 June 2012 00:00
- Written by Liz Highleyman
Gilead's investigational Quad pill, a 4-in-1 coformulation containing the second-generation integrase inhibitor elvitegravir and a new boosting agent, performed as well as either the 3-in-1 Atripla coformulation or the popular protease inhibitor atazanavir (Reyataz) in Phase 3 studies, researchers reported in the June 30, 2012, issue of The Lancet.
The Quad is a once-daily single-tablet regimen containing elvitegravir, the novel pharmacoenhancer cobicistat (a CYP3A4 inhibitor thatboosts levels of other drugs but has no antiviral activity itself), and tenofovir/emtricitabine (the drugs in Truvada).
On May 11, 2012, the U.S. Food and Drug Administration's Antiviral Drugs Advisory Committee voted 13 to 1 to recommend approval of the Quad for treatment-naive patients; a final decision in expected by late summer. The recommendation was based on data from 2 pivotal Phase 3 trials comparing the Quad to 2 widely used regimens from different antiretroviral drug classes that are considered "preferred" in the latest U.S. HIV treatment guidelines.
Quad vs Atripla
The first study (GS-US-236-0102), funded by Gilead, compared the Quad versus Atripla (efavirenz/tenofovir/emtricitabine, also made by Gilead). The trial enrolled 700 North American participants starting their first antiretroviral regimen.
Most (about 90%) were men, about two-thirds were white, and the average age was 38 years. The mean CD4 T-cell count was nearly 400 cells/mm3 and a third had high baseline HIV viral load (> 100,000 copies/mL).
Participants were randomly assigned to receive either the Quad or Atripla. The primary endpoint was HIV RNA < 50 copies/mL at week 48 of treatment.
- The Quad was found to be non-inferior to Atripla at 48 weeks.
- 87.6% of participants in the Quad arm and 84.1% in the Atripla arm achieved undetectable HIV viral load, not a statistically significant difference.
- 7% of participants in both arms experienced virological failure.
- Both single-tablet regimens were generally safe and well-tolerated.
- Similar proportions of patients discontinued therapy due to adverse events, 3.7% in the Quad arm vs 5.1 in the Atripla arm.
- Nausea was significantly more common in the Quad arm (20.6% vs 13.6%).
- Quad recipients, however, were less likely to experience neuropsychiatric side effects including dizziness (6.6% vs 24.4%), abnormal dreams (15.2% vs 26.9%), and insomnia (8.6% vs 13.9%), as well as rash (6.3% vs 12.2%, respectively).
- Serum creatinine increased more by week 48 in the Quad arm than in the Atripla arm, a signal of potential kidney impairment (median 13 vs 1 mcmol/L, respectively).
The researchers concluded that the Quad is comparable to Atripla in efficacy and safety, with both having similar low rates of treatment discontinuation.
"If regulatory approval is given, elvitegravir/cobicistat/emtricitabine/tenofovir would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection," they wrote.
Quad vs Atazanavir
The second study (GS-236-0103), also funded by Gilead, compared the Quad versus ritonavir-boosted atazanavir for initial HIV treatment.
This trial included 708 treatment-naive participants with baseline characteristics similar to those in the Atripla study. They were randomly assigned to receive the Quad or atazanavir/ritonavir plus tenofovir/emtricitabine. Again the primary endpoint was HIV RNA < 50 copies/mL at 48 weeks.
- Here too, the Quad was found to be non-inferior to the comparator regimen at 48 weeks.
- 89.5% of participants in the Quad arm and 86.8% in the boosted atazanavir arm had undetectable viral load, again not a significant difference.
- Virological failure was uncommon in both arms, at 5%.
- Both regimens were generally safe and well-tolerated.
- Rates of discontinuation due to adverse events were again similar, 3.7% in the Quad arm vs 5.1% in the atazanavir arm.
- Patients in the Quad arm had smaller increases in fasting triglyceride levels (median 90 vs 260 mcmol/L).
- Quad recipients had fewer abnormal liver function tests than atazanavir recipients and were less likely to develop elevated bilirubin leading to jaundice and yellowing of the eyes (a known atazanavir side effect).
- Both study arms saw small increases in serum creatinine with accompanying decreases in estimated glomerular filtration rate (GFR) by week 2, but these generally stabilized by week 8 and did not change up to week 48 (median change of 11 vs 7 mcmol/L).
Again, the investigators concluded that the Quad is comparable in safety and efficacy to the boosted atazanavir regimen.
Regarding the kidney signal in both trials, earlier studies showed that cobicistat affects kidney tubule secretion of creatinine, causing changes in estimated but not actual GFR; it does not appear to cause the type of damage seen with kidney-toxic drugs. However, tenofovir can cause kidney problems in a small proportion of susceptible patients, and people taking the Quad should have their kidney function monitored regularly. Both studies excluded people with pre-existing kidney impairment, and if approved the product label is likely to recommend against Quad use in this population.
In an accompanying editorial, Rik Schrijvers and Zeger Debyser from the Catholic University of Leuven in Belgium said the Quad would provide an additional convenient once-daily alternative for treatment-naive patients, but they noted the absence of long-term safety data for the Quad -- especially related to kidney toxicity -- as well as the small proportion of women in the trials.
P Sax, E DeJesus, A Mills, et al (GS-US-236-0102 study team). Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 379(9835):2439-2448. June 30, 2012.
E DeJesus, JK Rockstroh, K Henry, et al (GS-US-236-0103 study team). Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 379(9835):2429-2438. June 30, 2012.
R Schrijvers and Z Debyser. Quad's in it for antiretroviral therapy? (Commentary) Lancet 379(9835):2403-2405. June 30, 2012.