FDA Approves Etravirine for Multidrug-Resistant HIV
By Yael Waknine
Medscape Medical News
November 30, 2009 — The US Food and Drug Administration (FDA) has granted traditional approval for etravirine 100-mg tablets (Intelence, Tibotec Therapeutics) with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.
"With its efficacy and tolerability demonstrated in 48-week studies, etravirine has become an important option for many treatment-experienced patients with resistance to NNRTIs or other antiretrovirals," said clinical investigator Charles Hicks, MD, associate professor of medicine at Duke University's Division of Infectious Diseases in Durham, North Carolina, in a company news release.
Prior accelerated approval from the FDA was based on a priority review of pooled 24-week data from two 24-week, ongoing, double-blind, placebo-controlled phase 3 studies (Duet-1 and Duet-2) of 1203 patients aged 16 years and older with clinically advanced, highly antiretroviral treatment–experienced HIV-1 infection who had documented resistance to at least 1 NNRTI, nucleotide reverse transcriptase inhibitor (N(t)RTI), and protease inhibitor.
New 48-week data supported earlier findings, showing that the addition of twice-daily etravirine to background therapy (darunavir/ritonavir plus 2 N(t)RTIs with or without enfuvirtide) yielded viral loads of fewer than 50 copies/mL in 60% of patients vs 38% of those receiving optimized background therapy alone (P < .0001).
The most commonly reported adverse events in patients receiving etravirine therapy were rash (10% vs 3% for background therapy alone) and peripheral neuropathy (4% vs 2%).
In the studies, K103N was the most prevalent NNRTI substitution at baseline and did not affect response to etravirine. However, baseline substitutions V179D, V179F, V179T, Y181V, or G190S and the presence of 3 or more International AIDS Society-USA–defined NNRTI substitutions were linked to decreased virologic response.
Patients in whom therapy failed most commonly had V179F, V179I, Y181C, and Y181I substitutions that usually emerged in a background of multiple other NNRTI resistance–associated substitutions. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen.
Etravirine should be administered as a 200-mg dose (2 tablets) twice daily after a meal. Its safety and efficacy have not been studied in patients younger than 16 years and in pregnant women. Caution is advised in patients with severe hepatic impairment (Child-Pugh Class C).
The FDA warns that severe and potentially life-threatening skin reactions have been reported with etravirine therapy, including cases of Stevens-Johnson syndrome, hypersensitivity reactions, toxic epidermal necrolysis, and erythema multiforme. Treatment should be immediately discontinued for signs of severe hypersensitivity, severe rash, or rash with systemic symptoms or liver transaminase elevations.
Etravirine should not be coadministered with NNRTIs, protease inhibitors given without ritonavir, or ritonavir-boosted tipranavir, fosamprenavir, or atazanavir. Ritonavir-boosted lopinavir should be used with caution.
Concomitant use of etravirine with drugs that are substrates of cytochrome P 450 isoenzyme 3A (CYP 3A), CYP 2C9, and/or CYP 2C19 may alter its therapeutic effect or adverse event profile, the FDA said. Coadministration of carbamazepine, phenobarbital, phenytoin, rifampin, rifapentin, rifapentin (with ritonavir-boosted protease inhibitors), or St. John's wort is contraindicated.