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FDA Approves Stribild, Gilead's 4-in-1 Quad Pill for First-line HIV Treatment

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On August 27, 2012, the U.S. Food and Drug Administration (FDA) approved Stribild, a new single-tablet regimen containing the next-generation integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and tenofovir/emtricitabine (the drugs in Truvada). Stribild is indicated for HIV positive adults starting treatment for the first time.

Stribild is the third once-daily single-tablet regimen for HIV, joining Atripla (efavirenz/tenofovir/emtricitabine) and Complera (rilpivirine/tenofovir/emtricitabine), both also developed by Gilead.

The FDA's Antiviral Drugs Advisory Committee recommended approval of the new coformulation -- formerly known as the Quad -- by a vote of 13-1 this past May. Stribild's regulatory pathway has been unusual in that the combination pill was approved before all of its components were approved as single agents. Gilead requested separate approval of elvitegravir and cobicistat in late June. Unlike the sole approved pharmacoenhancer, ritonavir (Norvir), cobicistat is not itself active against HIV.

Phase 3 studies have shown that Stribild suppresses HIV viral load as effectively as either Atripla or boosted atazanavir (Reyataz), a widely used protease inhibitor. As previously reported, both studies were described in the June 30, 2012, issue of The Lancet.

Gilead's Study 102 (GS-US-236-0102), a head-to-head comparison of Stribild vs Atripla in 700 treatment-naive patients, found that the 2 single-tablet regimens worked equally well at 48 weeks (88% and84%, respectively, with HIV RNA < 50 copies/mL). Similar proportions of patients discontinued treatment prematurely, but fewer in the Stribild arm stopped due to adverse events, especially neuropsychiatric symptoms such as abnormal dreams, insomnia, and dizziness.

Study 103 (GS-US-236-0103) compared Stribild against ritonavir-boosted atazanavir plus tenofovir/emtricitabine in 708 previously untreated patients.Here, 90% of people in the Stribild arm and 87% in the boosted atazanavir arm achieved undetectable HIV RNA at 48 weeks. Both regimens were generally well-tolerated, with similar proportions discontinuing due to adverse events.

Subgroup analyses presented last month at the XIX International AIDS Conference (AIDS 2012) in Washington, DC, showed that Stribild worked as well as either Atripla or boosted atazanavir for people across baseline HIV viral load and CD4 T-cell levels.

"Over the past decade, co-formulated HIV medicines have simplified therapy for many patients and have become standard of care," said Study 102 principal investigator Paul Sax from Brigham and Women’s Hospital in a press release issued by Gilead. "Today’s approval of Stribild will provide physicians and their patients an effective new single tablet treatment option for individuals starting HIV therapy for the first time."

The annual wholesale cost of Stribild will be about $28,500 -- several thousand dollars higher than Atripla. Gilead indicated that it will provide financial assistance to patients without insurance through its Advancing Access program (call 800-226-2056), as well as out-of-pocket co-payment assistance for people with private insurance. 

Earlier this month California legislators asked Gilead to keep down the cost of the new combination pill so as not to burden AIDS Drug Assistance Programs (ADAPs); the company said it will work with the ADAP Crisis Task Force to offer state ADAP discounts. Gilead also indicated that it will allow the HIV Medicines Patent Pool and generic drug companies to produce cheaper versions of the combination pill for use in low-income countries

Side Effect Cautions

In Study 102 and 103, people taking Stribild had larger early increases in serum creatinine -- a marker of possible kidney impairment -- but this stabilized within several weeks and did not progress over time. Investigators explained that cobicistat inhibits kidney tubular secretion, thereby altering estimated but not actual GFR (a measure of kidney function).

This is a concern with Stribild because tenofovir has been linked to kidney problems in a small proportion of patients. While data so far show that cobicistat does not appear to cause kidney toxicity, its effect on estimated GFR may make it harder to detect kidney impairment related to other drugs. The Stribild product label instructs clinicians to monitor estimated creatinine clearance, urine glucose, and urine protein in all patients prior to initiating and during therapy, and to also monitor serum phosphorus in patients with or at risk for kidney impairment.

The Stribild product information also includes a Boxed Warning about lactic acidosis with severe hepatomegaly and steatosis, a potential adverse effect of most NRTIs including tenofovir.

Another warning concerns worsening hepatitis B after Stribild discontinuation. Tenofovir and emtricitabine are active against hepatitis B virus (HBV) as well as HIV. DHHS antiretroviral treatment guidelines recommend that HIV/HBV coinfected people should use a regimen that contains dually active agents, but Stribild has not been approved for treatment of chronic hepatitis B and its safety and efficacy have not yet been established in coinfected patients.

Gilead will conduct additional studies to help further characterize the drug’s safety in women and children, how drug resistance develops, and the possibility of interactions between Stribild and other drugs, according to an FDA press release announcing the approval.

Full U.S. prescribing information for Stribild, including important safety precautions, contraindications, and drug interactions, is available at www.Gilead.com.

8/28/12

Sources

U.S. Food and Drug Administration. FDA Approves New Combination Pill for HIV Treatment for Some Patients. Press release. August 27, 2012.

Gilead Sciences. U.S. FDA Approves Gilead’s Stribild, a Complete Once-Daily Single Tablet Regimen for Treatment-Naïve Adults with HIV-1 Infection. Press release. August 27, 2012.