Merck reported initial results from the phase III study investigating the efficacy and safety of a treatment regimen including Isentress (raltegravir) tablets once daily in treatment-naïve adult patients infected with HIV-1. Isentress is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults. In the study, although the treatment regimen that included Isentress once daily enabled more than 80 per cent of patients to achieve viral suppression, Isentress once daily did not demonstrate non-inferiority to the treatment regimen that included Isentress twice daily.
Merck said that based on the initial results and following the recommendation of an independent Data Monitoring Committee, Merck will end the study. Merck is notifying clinical investigators of this decision this week and is recommending that patients enrolled in the once-daily dosing arm of the study be switched to Isentress twice daily, the FDA-approved dose. Results from this study will be submitted for presentation at an appropriate scientific meeting in 2011.
This phase III study evaluated the safety and efficacy of an investigational once-daily dose of raltegravir (800 mg once daily) versus the approved twice-daily dose (400 mg twice daily), each given in combination with a once-daily fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate, in adult treatment-naïve HIV-1-infected patients. In this study, 775 patients were randomized, and 770 patients received study drug and are included in the current analyses.
After 48 weeks in the study, 83.2 per cent (n=318/382) of patients receiving the regimen including Isentress once daily achieved undetectable viral levels (HIV-RNA <50 copies/mL), compared to 88.9 per cent (n=343/386) of patients receiving the regimen including Isentress twice daily. The treatment difference between the 800 mg once daily group and 400 mg twice daily group was -5.7 per cent, with an associated 95 percent Confidence Interval (CI) of (-10.7 percent, -0.83 per cent). The difference did not meet the pre-defined statistical criteria for non-inferiority.
The overall treatment difference observed between the once-daily and twice-daily groups was primarily due to results in patients with high viral load. Among patients with more than 100,000 copies/mL of HIV-RNA, 74.3 per cent (n=113/152) of those in the once-daily group achieved viral suppression compared to 84.2 per cent (n=128/152) of those in the twice-daily group. The safety and tolerability profiles of the two regimens were similar in the study, and were consistent with current labelling for Isentress.
Isentress is Merck's integrase inhibitor for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adult patients. Isentress currently is the only approved integrase inhibitor for the treatment of HIV-1. The label for Isentress is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled clinical studies of Isentress Two of these studies were conducted in clinically advanced, three-class antiretroviral (ARV) [non-nucleoside reverse transcriptase inhibitor (NNRTI), Nucleoside Reverse Transcriptase Inhibitor (NRTI), Protease Inhibitor (PI)] treatment-experienced adults and one was conducted in treatment-naïve adults. The safety and efficacy of Isentress have not been established in paediatric patients. The use of other active agents with Isentress is associated with a greater likelihood of treatment response.
Isentress is the first medicine to be approved in a class of antiretroviral drugs called integrase inhibitors. Isentress works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but Isentress is the only approved drug that inhibits the integrase enzyme.
Isentress is now approved in more than 90 countries worldwide. Merck is continuing to move forward with filings in additional countries around the world for use of Isentress in both treatment-experienced and treatment-naïve HIV-infected patients.
Isentress does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with ARV therapy, which may necessitate further evaluation and treatment.
Creatine kinase elevations were observed in subjects who received Isentress. Myopathy and rhabdomyolysis have been reported. Isentress should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.
The most commonly reported drug-related Adverse Event (AE) of moderate to severe intensity that occurred in greater than or equal to 2 percent of patients and at a higher incidence than efavirenz in treatment-naïve patients receiving Isentress was insomnia (4 per cent versus 3 per cent, respectively).
The most commonly reported (greater than or equal to 2 percent in either treatment group) drug-related clinical AE of moderate or severe intensity in treatment-experienced patients receiving Isentress and at a higher rate compared to placebo was headache (2 per cent vs. less than 1 per cent) for Isentress plus Optimized Background Therapy (OBT) and placebo plus OBT, respectively.
In treatment-experienced patients, rash occurred more often in patients taking Isentress and darunavir together than with either drug separately. Rashes were mild to moderate in severity and did not limit therapy. There were no discontinuations due to rash.
Isentress is a single 400 mg tablet taken twice daily without regard to food. The dose of should be increased during co-administration with rifampin to 800 mg twice daily.
Co-administration with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may reduce plasma concentrations of Isentress. Rifampin, a strong inducer of (UGT) 1A1 reduces plasma concentrations of Isentress. Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of Isentress is required when co administered with other ARV agents. Also, preclinical studies show that Isentress is not metabolized by cytochrome P450 enzymes.
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