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 ~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 infections. 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 (2002-2008). 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 articles 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 log10 copies/mL; P < 0.001). Phase IIb studies expanded on this finding by using various doses of the reformulated tablet to evaluate virologic 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 background 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 log10 copies/mL, respectively) compared with patients in the placebo arm (-0.19 log10 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 enfuvirtide. 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 log10 copies/mL reduction in HIV RNA from baseline; P < 0.001) and immuno-logic (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 an optimized, highly active antiretroviral therapy regimen in NNRTI treatment-experienced adult patients with HIV. [References: 49]


Schiller DS, Youssef-Bessler M.




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