Antiretrovirals

Gilead Initiates Phase III Clinical Program Evaluating Single-Tablet, Once-Daily "Quad" Regimen for HIV

"We are pleased to announce that the Quad Phase III clinical program is underway," said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. "Efficacy and safety results from the Phase II study suggest that the Quad may represent an important new option for patients with HIV. We look forward to further defining the clinical profile of the Quad in a larger number of patients in the Phase III trials."

Gilead is also examining cobicistat as a stand-alone boosting agent for other antiretrovirals, in particular protease inhibitors. Later this quarter, Gilead plans to initiate a Phase III clinical trial evaluating the efficacy, safety and tolerability of cobicistat-boosted atazanavir compared to ritonavir-boosted atazanavir, each in combination with Truvada® (emtricitabine and tenofovir disoproxil fumarate). Study Design Study 102 is a randomized, double-blind clinical trial that will compare the efficacy, safety and tolerability of the Quad versus Atripla® (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) over a 96-week period at 130 study sites in the United States and Puerto Rico. Eligible participants will be HIV-infected treatment-naive adults with HIV RNA levels greater than or equal to 5,000 copies/mL. Approximately 700 trial participants will be randomized (1:1) to receive a once-daily tablet containing elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (n=350) or Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (n=350).

Study 103 is a randomized, double-blind clinical trial that will compare the efficacy, safety and tolerability of the Quad versus ritonavir-boosted atazanavir and Truvada over a 96-week period at more than 200 study sites in North America, South America, Europe and Asia Pacific. Eligible participants will be HIV-infected treatment-naive adults with HIV RNA levels greater than or equal to 5,000 copies/mL. Approximately 700 trial participants will be randomized (1:1) to receive a once-daily tablet containing elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (n=350) or ritonavir 100 mg and atazanavir 300 mg and emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (n=350).

The primary endpoint of both trials will be the proportion of patients achieving HIV RNA levels of less than 50 copies/mL at 48 weeks of treatment. Secondary objectives will evaluate the efficacy, safety and tolerability of the treatment regimens through 96 weeks of treatment.

After week 96, subjects will continue to take their blinded study drug until treatment assignments have been unblinded, at which point all subjects will be given the option to participate in an open-label rollover extension and receive the Quad single-tablet regimen. About Elvitegravir Elvitegravir is an HIV integrase inhibitor. Unlike other classes of antiretroviral agents, integrase inhibitors interfere with HIV replication by blocking the ability of the virus to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead's agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights. About Cobicistat Cobicistat is Gilead's proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. In addition to studying the agent as part of an integrase-based fixed-dose regimen, Gilead is also examining cobicistat's potential stand-alone role in boosting commercially available HIV protease inhibitors, which are used in many HIV treatment regimens.

The fixed-dose single-tablet "Quad" regimen, elvitegravir and cobicistat are investigational products and have not yet been determined safe or efficacious in humans. Important Product Safety Information About Truvada and Atripla Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals including Viread (tenofovir disoproxil fumarate), a component of Atripla and Truvada. Atripla and Truvada are not approved for the treatment of chronic hepatitis B virus (HBV) infection and their safety and efficacy have not been established in patients co-infected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients co-infected with HIV-1 and HBV who have discontinued Atripla or Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HBV and HIV-1 and discontinue Atripla or Truvada. If appropriate, initiation of anti-hepatitis B treatment may be warranted. It is important for patients to be aware that anti-HIV medicines including Atripla and Truvada do not cure HIV infection or AIDS and do not reduce the risk of transmitting HIV to others. Additional Important Information About Truvada Truvada is a fixed-dose combination tablet containing 200 mg of emtricitabine (Emtriva) and 300 mg of tenofovir disoproxil fumarate (Viread). In the United States, Truvada is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

Truvada should not be coadministered with Atripla, Emtriva, Viread or lamivudine-containing products, including Combivir® (lamivudine/zidovudine), Epivir® or Epivir-HBV® (lamivudine), Epzicom® (abacavir sulfate/lamivudine) or Trizivir® (abacavir sulfate/lamivudine/zidovudine). In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.

Emtricitabine and tenofovir are principally eliminated by the kidneys. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of Viread. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy with Truvada and as clinically appropriate during therapy. Routine monitoring of calculated creatinine clearance and serum phosphorous should be performed in patients at risk for renal impairment including patients who have previously experienced renal events while receiving Hepsera® (adefovir dipivoxil). Dosing interval adjustment and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 ml/min. Truvada should be avoided with concurrent or recent use of a nephrotoxic agent. Truvada should not be administered with Hepsera.

Coadministration of Truvada and didanosine should be undertaken with caution. Patients should be monitored closely for didanosine-associated adverse events and didanosine should be discontinued if these occur. Dose reduction of didanosine should be considered, if warranted. Patients on atazanavir and lopinavir/ritonavir plus Truvada should be monitored for Truvada-associated adverse events and Truvada should be discontinued if these occur. When co-administered with Truvada, it is recommended that atazanavir be boosted with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with Truvada.

Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The effect on long-term bone health and future fracture risk is unknown. BMD monitoring should be considered in patients with a history of pathologic fractures or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

Changes in body fat have been observed in patients taking anti-HIV medicines. Immune Reconstitution Syndrome has been reported in patients treated with combination therapy, including Viread and Emtriva, and may necessitate further evaluation and treatment.

Most common adverse reactions (incidence =10 percent) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

The parent compound of Viread was discovered through a collaborative research effort between Dr. Antonin Holy, Institute for Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for Medical Research, Katholic University in Leuven, Belgium. The inventors of Viread have agreed to waive their right to a royalty on sales of Viread and Truvada in the Gilead Access Program countries to ensure the product can be offered at a no-profit price in parts of the world where the epidemic has hit the hardest.

For complete prescribing information for Truvada, visit www.Truvada.com. Additional Important Information About Atripla In the United States, Atripla is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

Keywords: AIDS, AIDS/HIV, Adverse Drug Effect, Adverse Drug Event, Adverse Drug Reaction, Anti-HIV, Antivirals, Asia, Atazanavir, Biochemistry, Biotechnology, Biotechnology Business, Biotechnology Company, Chemicals, Chemistry, China, Clinical Trial Research, Clinical Trials, Drugs, Efavirenz, Emtricitabine, Enzymes, Gastroenterology, Gilead Sciences, HBV, Health, Hepatitis B Virus, Hepatology, Hepatomegaly, Hospitals, Integrase, Japan, Lactic Acidosis, Nucleoside Analog, Nucleoside and Nucleotide Reverse Transcriptase InhibitorsAntiretroviral, Organic Chemistry, Pharmaceutical, Pharmaceuticals, Protease Inhibitors, Ritonavir, Steatosis, Tenofovir, Tenofovir Disoproxil Fumarate, Therapy, Treatment, Truvada, Viread, Virology, Gilead Sciences Inc.

This article was prepared by Anti-Infectives Week editors from staff and other reports. Copyright 2010, Anti-Infectives Week via NewsRx.com.