SUMMARY: Gilead Science's experimental "Quad" pill -- a once-daily single-tablet coformulation containing the new integrase inhibitor elvitegravir, the novel boosting agent cobicistat (GS 9350), and tenofovir plus emtricitabine (the drugs in the Truvada pill) -- continued to demonstrate potent antiviral activity and good tolerability at 48 weeks, according to data presented this week at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). In a second comparison, cobicistat worked as well as ritonavir as a booster for atazanavir, with similar changes in kidney function.

By Liz Highleyman

If approved, elvitegravir will be the second integrase inhibitor to enter the market. Unlike raltegravir, it requires a pharmacoenhancer, or boosting agent, to reach optimal levels in the body. Cobicistat interferes with liver enzymes that process other drugs, thereby raising the latter drug's concentration in the blood. In contrast with ritonavir (Norvir), the only currently approved booster, cobicistat has no anti-HIV activity of is own.

Results at week 24 from studies of the Quad pill and of cobicistat as a booster for the protease inhibitor atazanavir were presented this past February at the Conference on Retroviruses and Opportunistic Infections (CROI 2010).

At ICAAC, Rick Elion from the Whitman Walker Clinic and colleagues presented 48 week findings from Study 236-0104, a Phase 2 trial comparing the elvitegravir/cobicistat/tenofovir/emtricitabine Quad coformulation versus efavirenz/tenofovir/emtricitabine (Atripla) in previously untreated HIV patients. They also presented data from a comparison of atazanavir boosted with either cobicistat or ritonavir.

Quad vs Atripla

Study 236-0104 included 71 treatment-naive participants who were randomly assigned (2:1) to take the Quad pill or Atripla once-daily for 48 weeks. Most participants (about 90%) were men, the average age was about 35 years, and about 75% were white. All had a baseline viral load of > 5000 copies/mL (mean of about 40,000 copies/mL) and no resistance to NRTIs, NNRTIs, or protease inhibitors. The average CD4 count was approximately 400 cells/mm3.

Results

	In an intent-to-treat (missing = failure) analysis at 48 weeks, 90% of participants in the Quad group achieved viral load < 50 copies/mL, compared with 83% in the Atripla group, showing that the Quad pill was non-inferior to Atripla.
	In an analysis with missing patients excluded, 96% in the Quad group and 95% in the Atripla group achieved undetectable viral load.
	Median CD4 count gains (which had been similar at week 24) were now greater in the Quad arm compared with the Atripla arm (240 vs 162 cells/mm3, respectively).
	3 participants in each arm discontinued their study drug early due; none in the Quad arm and 1 in the Atripla arm did so due to adverse events.
	46% patients in the Quad arm experienced drug-related adverse events of any severity, compared with 57% in the Atripla arm.
	This difference was largely attributable to fewer central nervous system (CNS) side effects in the Quad arm.
	Mean estimated glomerular filtration rate (eGFR, a calculation of kidney function) was worse in the Quad arm than in the Atripla arm at 48 weeks (change of -20 mL/min or -14% vs -6 mL/min or -4%, respectively).

These findings led the investigators to conclude that the Quad pill "was well tolerated and maintained a high rate of virologic suppression (90%) that was non-inferior to [Atripla] (83%)."

Study 102, a large 96-week Phase 3 trial of the Quad pill versus Atripla, is currently underway at more than 130 study sites in the United States and Puerto Rico.

Cobicistat vs Ritonavir

The second trial, Study 216-0105, included 79 treatment-naive participants who were randomly assigned (again 2:1) to receive 150 mg cobicistat or 100 mg ritonavir, all with once-daily atazanavir plus tenofovir/emtricitabine for 48 weeks. Patient characteristics were similar to those in the previous study, except this trial included a higher proportion of people of color.

Results

	In an intent-to-treat (missing = failure) analysis at 48 weeks, 82% of participants in the cobicistat arm and 86% in the ritonavir arm achieved HIV RNA < 50 copies/mL, not a significant difference.
	In an analysis with missing patients excluded, viral suppression rates were 91% vs 96%, respectively.
	Participants taking cobicistat experienced a median CD4 cell gain of 230 cells/mm3 vs 206 cells/mm in the ritonavir arm, again not significantly different.
	2 people in the cobicistat arm and 1 in the ritonavir arm discontinued early due to adverse events.
	36% of patients in the cobicistat arm and 48% in the ritonavir group experienced any drug-related adverse events (mostly elevated bilirubin associated with atazanavir).
	At 48 weeks, mean eGFR decreased by about the same amount in the cobicistat and Atripla arms (-13 mL/min or -12% vs -14 mL/min or -11%, respectively).

Based on these findings, the researchers concluded that cobicistat-boosted atazanavir plus tenofovir/emtricitabine was safe and had efficacy similar to ritonavir-boosted atazanavir plus tenofovir/emtricitabine through 48 weeks.

Elevated serum creatinine and reduced eGFR observed at week 24 in people taking cobicistat raised concern about potential kidney toxicity. Prior studies of HIV negative volunteers showed that cobicistat may inhibit kidney tubular secretion -- leading to elevated creatinine -- but does not seem to cause significant nephrotoxicity. Caution is warranted, however, especially when combining cobicistat with tenofovir, which has been linked to kidney impairment.

Since creatinine is one of the factors in the equation used to compute eGFR, researchers at CROI said that cobicistat alters estimated but not actual GFR. At 48 weeks, the early changes in eGFR seen through week 24 were stable, and in the booster comparison, eGFR decreases were similar in the cobicistat and ritonavir arms.

Investigator affiliations: Whitman Walker Clinic, Washington, DC; Therapeutic Concepts, P.A., Houston, TX; Capital Med. Associates, PC, Washington, DC; Peter Shalit, MD, Seattle, WA; Southwest CARE Ctr., Santa Fe, NM; Gilead Sciences, Inc, Foster City, CA.

9/14/10

Reference
R Elion, J Gathe, B Rashbaum, and others. The Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF; Quad) Maintains a High Rate of Virologic Suppression, and Cobicistat (COBI) is an Effective Pharmacoenhancer Through 48 Weeks. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010.

Other Source
Gilead Sciences. Gilead's Single-Tablet "Quad" HIV Regimen Maintains High Viral Suppression Through 48 Weeks in Phase II Study. Press release. September 13, 2010.