Gilead's Quad Pill Matches Atripla, New Booster Cobicistat (GS 9350) Looks Good with Atazanavir (Reyataz)

		SUMMARY: Gilead's "Quad" pill -- a coformulation containing the experimental integrase inhibitor elvitegravir, the novel boosting agent cobicistat (GS 9350), tenofovir, and emtricitabine -- was non-inferior to Atripla (the efavirenz/tenofovir/emtricitabine combination pill) in a head-to-head comparison of once-daily all-in-one regimens, researchers reported at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) this week in San Francisco. A related study showed that cobicistat equaled ritonavir (Norvir) as a booster for atazanavir (Reyataz).

By Liz Highleyman

Cal Cohen from the Community Research Initiative of New England reported on 2 studies involving cobicistat, which just received its generic name.

Boosting agents (pharmacoenhancers) interfere with liver enzymes that process other drugs, thereby raising the latter drug's blood concentration. As previously reported, cobicistat has demonstrated good boosting activity in combination with atazanavir and elvitegravir.

Quad vs Atripla

In the first trial, Study 236-0104, a total of 71 treatment-naive participants 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 and no resistance to the 3 earliest antiretroviral drug classes. The average viral load was about 40,000 copies/mL and the mean CD4 cell count was approximately 400 cells/mm3.

Results

	6% of participants in the Quad arm and 13% in the Atripla arm discontinued therapy prematurely.
	At 24 weeks, 90% of participants in the Quad group achieved viral load < 50 copies/mL, compared with 83% in the Atripla group, in an intent-to-treat (ITT) analysis with missing patients counted as failures,
	This result showed that the Quad pill was non-inferior to Atripla, though the study was not designed as a non-inferiority trial.
	In a second ITT analysis with missing patients excluded, 96% in the Quad group and 95% in the Atripla group achieved HIV RNA < 50 copies/mL.
	Median CD4 count increases at week 24 were about equal, 123 cells/mm3 in the Quad arm and 124 cells/mm3 in the Atripla arm.
	35% patients in the Quad arm experienced drug-related adverse events of any severity, compared with 57% in the Atripla arm, largely attributable to fewer efavirenz-associated central nervous system (CNS) side effects.
	No participants in the Quad arm and 1 in the Atripla discontinued early due to adverse events.
	Participants receiving cobicistat showed a greater -- though still small -- increase in serum creatinine (a marker of potential kidney impairment), +0.14 mg/dL versus +0.04 mg/dL in the Atripla arm.
	Mean estimated glomerular filtration rate (eGFR, a calculation of kidney function) was lower (i.e., worse) in the Quad arm at 24 weeks, 111 vs 126 mL/min.

These findings led the investigators to conclude that the Quad pill "met criteria for non-inferiority" to Atripla, with "fewer study drug-related adverse events (particularly CNS)."

"These positive efficacy and safety results indicate that the Quad has the potential to become an important new treatment option in HIV therapy," Cohen said in a press release issued by Gilead Sciences.

At the opening press conference, CROI co-chair John Mellors highlighted once-daily complete regimen combination pills like Atripla and the Quad pill as the future of HIV therapy. Ideally, he said, there will be an "armamentarium" of all-in-one regimens with no overlapping components, meaning no risk of cross-resistance when patients switch from first-line to second-line regimens.

Cobicistat vs Ritonavir

In the second trial, Study 216-0105, a total of 79 previously untreated patients were randomly assigned (again 2:1) to receive 150 mg cobicistat or 100 mg ritonavir, all with once-daily atazanavir plus tenofovir/emtricitabine (Truvada), for 48 weeks. Participant characteristics were similar to those in the previous study, but this group had a higher proportion of non-white patients.

Results

	8% of participants in the cobicistat arm and 10% in the ritonavir group discontinued early.
	The 2 drugs produced statistically similar virological suppression rates.
	At week 24, in an ITT missing=failure analysis, 84% of participants in the cobicistat arm achieved HIV RNA < 50 copies/mL, compared with 86% in the ritonavir arm.
	In an ITT missing=excluded analysis, the corresponding rates were 91% in the cobicistat arm versus 96% in the ritonavir arm.
	Patients taking cobicistat experienced a median CD4 cell gain of 206 cells/mm3 compared with 190 cells/mm in the ritonavir arm.
	Rates of drug-related adverse events were similar overall, at 20% in the cobicistat arm versus 24% in the ritonavir group (although > 80% in both arms had elevated bilirubin associated with atazanavir).
	2 people in the cobicistat arm and 1 in the ritonavir arm discontinued early due to adverse events.
	Again, serum creatinine increased more in patients taking cobicistat, +0.18 mg/dL compared with +0.14 mg/dL in the ritonavir arm.
	Mean eGFR was again lower among cobicistat recipients, 102 vs 111 mL/min.

The researchers concluded that cobicistat and ritonavir had similar efficacy, safety, and tolerability.

The main concern in these studies was the signal of kidney toxicity suggested by elevated elevated serum creatinine and reduced eGFR in people taking cobicistat. Creatinine is one of the factors used to compute eGFR. In discussing the findings, Cohen explained that cobicistat alters estimated but not actual GFR.

Prior studies of healthy HIV negative volunteers suggested cobicistat may inhibit kidney tubular secretion -- leading to elevated creatinine -- but does not seem to cause the type of nephrotoxicity seen with other drugs. Nevertheless, caution may be warranted with a pill that combines cobicistat and tenofovir, which has been linked to kidney impairment.

Based on the favorable results from these studies, Gilead announced that large-scale Phase 3 studies of the Quad pill and cobicistat are expected to start by the middle of 2010.

Community Research Initiative of New England, Boston, MA; Whitman Walker Clinic, Washington, DC; Orlando Immunology Center, Orlando, FL; Gilead Sciences, Foster City, CA.

2/19/10

Reference
C Cohen, D Shamblaw, P Ruane, and others. 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. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 58LB.

Other source
Gilead Sciences. Gilead's Single-tablet "Quad" Regimen for HIV Achieves a High Rate of Virologic Suppression in Phase II study. Press release. February 17, 2010.