Raltegravir: The First HIV Integrase Inhibitor

Background: The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment-experienced adult patients with viral resistance. Objective: This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir. Methods: Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (20012007); and European AIDS Conference (2001-2007) were also searched. Results: Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median T-max of similar to 4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase 11 studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450-related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin. Conclusion: Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals. (Clin Ther. 2008; 30:1747-1765) (C) 2008 Excerpta Medica Inc.