Etravirine: A Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Active Against NNRTI-Resistant Strains of HIV

Background: Since 1981, the AIDs epidemic has continued to expand and, at the end of 2007, there were similar to 33 million people worldwide living with HIV, including 1.2 million in North America. Objective: This article provides a comprehensive overview of the nonnucleoside reverse transcriptase inhibitor (NNRTI) etravirine when used in treatment-experienced adult patients with multidrug-resistant HIV Infectious. Methods: Relevant information was gathered through a search of MEDLINE (1966-December 2008) and International Pharmaceutical Abstracts (1970-December 2008) databases, as well as abstracts of the Conference on Retroviruses and Opportunistic Infections (2006-2008) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (20022008). Clinical trial data were limited to human studies that were Phase IIa or higher. The search terms used were etravirine and TMC125. References were also identified through screening, of citations in the gathered. Results: Etravirine is an NNRTI that is able to adapt its binding orientation and overcome common NNRTI resistance associated Mutations (RAMs) such as K103N. It was originally formulated in polyethylene glycol (PEG), but pharmacokinetic studies using an updated tablet formulation identified a more favorable absorption profile that has allowed the study of lower doses (200 mg instead of 900 mg BID). Phase IIa Studies using the PEG formulation of etravirine found that viral loads were reduced in both treatment-naive and treatment-experienced patients with HIV (-1.99 vs -0.86 log(10) copies/mL; P < 0.001). Phase IIb studies expanded on this finding by using various doses of the reformulated tablet to evaluate virologlc efficacy In highly treatment-experienced patients with triple-class (protease Inhibitor, nucleoside/nucleotide reverse transcriptase Inhibitors [NRTI], and NNRTI) resistance. Patients in an open-label, partially blinded, Phase IIb study (N = 199) were randomized to receive an optimized back-round regimen alone or in combination with either 400 or 800 mg of etravirine BID. Regardless of the dose, patients in the etravirine arms had a greater decrease in viral load from baseline (-1.04 and -1.18 log(10) copies/mL, respectively) compared with patients in the placebo arm (-0.19 log(10) copies/mL; P = 0.005 and P < 0.001, respectively). The DUET studies (DUET-1, N = 612; DUET-2, N = 593) are 2 ongoing, international, randomized, double-blind, placebo-controlled, Phase III trials in which patients with preexisting RAMs are treated with darunavir/ritonavir and an optimized NRTI background In combination with etravirine or placebo and the optional use of enfurirtide. According to pooled, 48-week data from these studies, significantly more patients who received etravirine achieved an HIV RNA <50 copies/mL (61% vs 40%; P < 0.001) and had greater virologic (-2.25 vs -1.49 log(10) copies/mL reduction in HIV RNA from baseline; P < 0.001) and immunologic (98 vs 73 cells/mm(3) CD4 cell count change from baseline; P < 0.001) responses compared with placebo. Additionally, the incidence of adverse events, including diarrhea, nausea, and headache, was similar between treatment groups in the DUET studies; rash, however, was significantly more common in the etravirine group (17% vs 9%; P < 0.001). Conclusion: Etravirine is an NNRTI that was reported to be effective when used as part of all optimized, highly active antiretroviral therapy regimen in NNRTI treatment-experienced adult patients with HIV. (Clin Ther. 2009;31:692-704) (C) 2009 Excerpta Medica Inc.