Sustained Efficacy and Safety of Raltegravir After 5 Years of Combination Antiretroviral Therapy as Initial Treatment of HIV-1 Infection: Final Results of a Randomized, Controlled, Phase II Study (Protocol 004)
Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained <50 copies per milliliter in 68.8% (raltegravir) versus 63.2% (efavirenz), and CD4 increases were 302 versus 276 cells per microliter, respectively. Early HIV-RNA decline predicted later CD4 increases in both groups. Raltegravir resistance was observed in 3 of 10 raltegravir recipients with virologic failure. Few drug-related adverse events were reported after week 48. Raltegravir had minimal effect on laboratory values, including lipids. Raltegravir with tenofovir/lamivudine showed durable efficacy and good tolerability over 5 years.
"This percentage dropped to only 80% by the end of 5 years. Viral load <50 copies/mL was a secondary end point, with 110 (69%) of the patients on RAL compared to 24 (63%) in the efavirenz group achieving this goal at 240 weeks.33,34 "
[Show abstract][Hide abstract] ABSTRACT: Raltegravir is an integrase strand-transfer inhibitor approved for the treatment of HIV infection. It was the first medication in a novel class of antiretroviral agents to be approved for use in the United States in 2007. Raltegravir exhibits potent activity against wild-type HIV-1, but resistance development has been noted through three different pathways. It is metabolized primarily through uridine diphosphate glucuronosyltransferase 1A1 and has a single inactive glucuronide metabolite. Raltegravir is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes and exhibits low potential for drug-drug interactions; however, strong uridine diphosphate glucuronosyltransferase 1A1 inhibitors or inducers can alter the pharmacokinetics of raltegravir. It is well tolerated, and the most commonly reported adverse effects include headache, nausea, and diarrhea. Serious adverse effects with raltegravir are rare but include rhabdomyolysis and severe skin and hypersensitivity reactions. It has been approved for use in both treatment-naïve and treatment-experienced patients and is a preferred first-line agent in both United States and European HIV treatment guidelines. Although initial approval was granted on 48-week data, 5-year clinical data have recently been published. This article reviews the data supporting long-term efficacy and safety of raltegravir in the treatment of HIV infection.
Infection and Drug Resistance 03/2014; 7:73-84. DOI:10.2147/IDR.S40168
[Show abstract][Hide abstract] ABSTRACT: The integrase enzyme facilitates the incorporation of HIV-1 proviral DNA into the host cell genome and catalyses a function vital to viral replication. Inhibitors of this enzyme represent the newest class of antiretroviral drugs in our armamentarium to treat HIV-1 infection. Raltegravir, an integrase strand transfer inhibitor, was the first drug of this class approved by the US FDA; it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance. These qualities have prompted the search for agents with once-daily dosing, a more robust barrier to resistance, and a resistance profile of limited overlap with that of raltegravir. We review a series of integrase inhibitors that are in clinical or advanced pre-clinical studies. Elvitegravir, recently approved by the FDA as part of the elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir. Dolutegravir is the most advanced second-generation integrase inhibitor, and it boasts good tolerability, once-daily dosing with no need for a pharmacological enhancer, and relatively little cross-resistance with raltegravir. S/GSK1265744 has been developed into a long-acting parenteral agent that shows a high barrier to resistance in vitro and the potential for an infrequent dosing schedule. BI 224436 is in early clinical trials, but is unlikely to demonstrate cross-resistance with other integrase inhibitors. The inhibitors of the lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase (LEDGINs) are extremely early in development. Each of these contributes a new benefit to the class and will extend the treatment options for patients with HIV-1 infection.
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