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CROI 2012: 4-in-1 Elvitegravir Quad Pill Matches Efavirenz and Atazanavir Combos

The Quad single-tablet regimen, an all-in-one pill containing the experimental integrase inhibitor elvitegravir plus 2 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 (CROI 2012) this week in Seattle. In a companion study the Quad 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 2 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 regimen. One-third had high baseline HIV viral load (> 100,000 copies/mL). The mean CD4 T-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 1 of 2 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) plus tenofovir and emtricitabine.

Results

• Both regimens performed well through 48 weeks.
• 88% of participants in the Quad arm and 84% of those on Atripla had undetectable HIV viral load (< 50 copies/mL), not a statistically significant difference.
• Virological failure was seen in 7% of patients in both arms.
• The regimens performed equally well in analyses of demographic subgroups.
• The regimens were similarly effective 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%).
• The Quad arm had a small but significant advantage in CD4 cell gains, 239 vs 206 cells/mm³.
• Both single-tablet regimens were generally safe and 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).
• Participants in the Quad arm were significantly more likely to report nausea (21% vs 14%).
• 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 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.

In this first fully-powered study comparing once-daily single-tablet HIV regimens, "Quad demonstrated non-inferior efficacy", the researchers concluded. The Quad was well-tolerated with "similar low rates of treatment discontinuation".

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.

Coinvestigator Cal Cohen explained in an interview that it will be important for people taking the Quad to have their laboratory values monitored regularly to detect signs of kidney problems, which occur in about 1% of patients. "This is not the kind of drug where you can come in once a year," he said. "We need to find the few people with problems and get them on another drug."

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.

This analysis included 708 treatment-naive participants with baseline characteristics similar to those of the population in the Atripla study.

Results

• Both regimens performed well through 48 weeks.
• 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).
• Again, both regimens were generally safe and well-tolerated, with similar proportions discontinuing due to adverse events (4% vs 5%, respectively).
• As expected, fewer people taking the Quad developed elevated bilirubin, a known side effect of atazanavir.

"Quad demonstrated non-inferior efficacy and was well tolerated at 48 weeks in this Phase 3 blinded active-controlled study in treatment-naive HIV-infected subjects," the researchers concluded. "These data support the use of Quad as a potential new [single-tablet regimen] option for initial HIV treatment."

Based on these findings, Gilead has submitted the 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. 

Investigator affiliations:

Study 0102: Brigham and Women's Hosp, Harvard Med School, Boston, MA; Orlando Immunology Ctr, Orlando, FL; Anthony Mills MD, Inc, Los Angeles, CA; Stanford University, Palo Alto, CA; Community Res Initiative of New England, Boston, MA; Univ of North Carolina, Chapel Hill, NA; Johns Hopkins Univ School of Medicine, Baltimore, MD; Gilead Sciences, Foster City, CA.

Study 0103: Orlando Immunology Ctr, Orlando, FL; Univ of Bonn, Germany; Hennepin County Med Ctr, Minneapolis, MN; Saint Louis Hosp, Paris, France; Therapeutic Concepts PA, Houston, TX; Gilead Sciences, Foster City, CA, US

 3/13/12

References

P Sax, E DeJesus, A Mills, 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 (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 101.

E DeJesus, J Rockstroh, K Henry, 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 (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 627.

Other Sources

Gilead Sciences. Gilead’s Quad Single Tablet Regimen for HIV Non-Inferior to Atripla in Pivotal Phase 3 Study. Press release. March 7, 2012.

Gilead Sciences. Data Show Gilead’s Quad Regimen for HIV Non-Inferior to Protease-Based Regimen at 48 Weeks in Second Pivotal Phase 3 Study. Press release. March 7, 2012.