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  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
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QUAD Four-in-One Pill as Strong as Atripla, But a Kidney Concern Arises
  17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
A once-daily antiretroviral combining the integrase inhibitor elvitegravir with a non-ritonavir booster (GS-9350), tenofovir (TDF), and emtricitabine (FTC) proved as potent at Atripla (efavirenz plus TDF/FTC) after 24 weeks in previously untreated people [1].
This small double-blind, double-dummy phase 2 trial found substantially fewer overall side effects with the four-in-one pill (called Quad) than with Atripla. But presenter Calvin Cohen devoted a goodly number of slides to addressing potential concerns about nephrotoxicity with GS-9350. Kidney trouble with GS-9350 would be a blow to Quad development because of TDF's well-known effect on creatinine clearance. But Cohen maintained the impact of GS-9350 on creatinine approximates that of an over-the-counter ulcer drug.
A separate phase 2 study by the same investigators found GS-9350 (now called cobicistat) equivalent to ritonavir in boosting the protease inhibitor atazanavir with TDF/FTC in previously untreated people. No one in either study had virus resistant to nucleosides, nonnucleosides, or protease inhibitors when the trials began.
The Quad-versus-Atripla trial involved 48 antiretroviral-naive people randomized to Quad and 23 randomized to Atripla. Most were men and about three quarters were white. Age averaged 36 in the Quad group and 35 in the Atripla group. Both groups had an average viral load around 40,000 copies. Median pretreatment CD4 count stood at 354 in the Quad group and 438 in the Atripla group. Fewer than 10% in either arm had AIDS.
After 24 weeks 90% taking Quad and 83% taking Atripla had a viral load under 50 copies in a missing-data-equal-failure analysis. In an intent-to-treat analysis that excluded missing data, 96% taking Quad and 95% taking Atripla had a sub-50 load at 24 weeks. CD4 counts climbed an average of 161 in the Quad group and 113 in the Atripla group.
Overall safety results favored Quad, with 37% having a study drug-related adverse event on Quad versus 57% on Atripla. The only two grade 3/4 safety problems occurred in the Atripla arm. However, by week 24 average serum creatinine rose 0.14 mg/dL with Quad and 0.04 with Atripla. Glomerular filtration rate estimated by the Cockcroft-Gault method was -18 mL/min with Quad versus -7 mL/min with Atripla. Estimated glomerular filtration rate at week 24 averaged 111 mL/min with Quad and 126 mL/min with Atripla.
Further analysis of a study of healthy volunteers suggested GS-9350 has no effect on actual glomerular filtration rate, even though it lowers the estimated rate. Cohen explained that creatinine is excreted primarily by glomerular filtration, but about 10% to 15% is eliminated by active tubular secretion. Thus he hypothesized that GS-9350 may inhibit tubular secretion of creatinine, as does the over-the-counter H2-receptor antagonist cimetidine. Certainly GS-9350 researchers will analyze these issues closely as clinical development of Quad proceeds.
Pretreatment characteristics in the trial comparing GS-9350 with ritonavir as an atazanavir booster were equivalent to those in the Quad-versus-Atripla study. This second trial randomized 50 people to GS-9350 and 29 to ritonavir. Two people dropped out of the GS-9350 group because of adverse events, compared with 1 dropout in the ritonavir arm. Two people taking GS-9350 had study drug-related adverse events, compared with none taking ritonavir.
By two intent-to-treat analyses, equivalent high proportions in both arms had a sub-50 viral load at week 24. CD4 gains averaged 200 in both groups.
1. Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 58LB.