Single 4-Drug Pill Shows Positive Results in HIV Trial

September 17, 2010 (Boston, Massachusetts) — A single pill called Quad (Gilead Sciences) that contains 4 drugs used to treat HIV infection — elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate — showed promising results, compared with a single-pill triple-drug formulation called Atripla (efavirenz, emtricitabine, and tenofovir), according to late-breaking phase 2 data released here at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

Quad maintained a high rate of virologic suppression through 48 weeks, and had similar antiviral activity to Atripla, announced investigators from the Quad Study 236-0104. These data extend the 24-week results of this trial presented in February 2010 at the Conference on Retroviruses and Opportunistic Infections.

"The challenge [in treating HIV patients] is to make the treatment simple and compress the number of pills that need to be taken. The bottom line is that our study showed that use of an experimental booster [cobicistat] in this regimen that includes an experimental integrase inhibitor [elvitegravir] achieved similar results to Atripla with improved tolerability," said lead author Richard Elion, MD, from the Whitman Walker Clinic in Washington, DC. "These results suggest that Quad could be an important new option for people with HIV."

Unlike ritonavir, another booster drug used to treat HIV, cobicistat is amenable to coformulation with other antiretroviral drugs, Dr. Elion explained.

At ICAAC, Dr. Elion and coauthors presented the results of 2 phase 2 comparisons. In the first, 48 patients were given Quad and 23 patients were given Atripla in a 2:1 ratio.

Subjects were HIV-infected and treatment-naïve adults with a viral load of 5000 copies/mL or more and CD4 counts greater than 50 cells/mm³ at baseline.

At 48 weeks, 90% of the Quad group and 83% of the Atripla group achieved the primary end point of HIV RNA levels of less than 50 copies/mL. At 48 weeks, patients taking Quad experienced a mean increase in CD4 cells of 240 cells/mm³, compared with 162 cells/mm³ in Atripla patients.

Discontinuation rates and adverse events were similar between the 2 groups. Rates of adverse events were also similar, but fewer central nervous system events were reported in patients taking Quad. The incidence of grades 2 to 4 laboratory abnormalities was similar in the 2 groups.

In the double-blind, multicenter, randomized, active-controlled, 48-week cobicistat Study 216-0105, 50 patients given cobicistat-boosted atazanavir, emtricitabine, and tenofovir were compared with 29 patients given ritonavir-boosted atazanavir in combination with emtricitabine plus tenofovir (Truvada, Gilead Sciences).

At 48 weeks, 82% of those in the cobicistat group and 86% of the ritonavir group met the primary objective of achieving HIV RNA levels of less than 50 copies/mL. At 48 weeks, patients in the cobicistat group had a mean increase in CD4 cell count of 230 cells/mm³, compared with 206 cells/mm³ in the ritonavir group.

Discontinuation rates and laboratory abnormalities were similar in both groups, with the exception of early increases in serum creatinine in the cobicistat group, resulting in decreased creatinine clearance, but that stabilized through week 48 and rates were comparable to the ritonavir group at that time point.

Dr. Elion said that Gilead Sciences now has 3 phase 3 studies of Quad in progress involving a total of 2100 patients (700 in each trial).

Enthusiastic Response to the 4-Drug Pill

"I welcome this single pill that can be taken once a day as an important alternative to the existing single pill now on the market, Atripla, for initial treatment or in cases of toxicity without having to resort to more a complex prescription," said Amalio Telenti, MD, director of the Institute of Microbiology at the University of Lausanne in Switzerland.

"It is also positive," he continued, "to have a [nonnucleoside reverse transcriptase inhibitor] choice if needed, although the field needs a simpler formulation that would allow a [nucleoside reverse transcriptase inhibitor]-free option."

Dr. Telenti told Medscape Medical News that the long-term safety of Gilead's 2 investigational compounds — elvitegravir and cobicistat — has yet to be established. "The decreased creatinine clearance with cobicistat is relevant and could be compounded by the known association between tenofovir and renal and possibly bone metabolism," he noted.

With these caveats, he said, Quad "is a significant advance and I am looking forward to longer follow-up data in a larger population."

Dr. Elion reports receiving financial support from Gilead Sciences Inc. Dr. Telenti reports financial ties with Merck, Boehringer Mannheim, and Abbott.

50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract H-938B. Presented September 13, 2010.