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Early Virologic Failure with Tenofovir/FTC + Nevirapine as Initial Therapy

Investigators stopped a clinical study when three of seven patients receiving tenofovir/FTC + nevirapine experienced early virologic rebound; each had evidence of multiclass viral resistance.

The combination of tenofovir, FTC (or 3TC), and nevirapine is listed in several guidelines as a preferred or alternative regimen for initial HIV treatment. However, this combination has never been studied in a fully powered, prospective clinical trial. Now, results from a small study raise concerns about its antiviral efficacy.

In this open-label clinical trial, treatment-naive patients were randomized to receive once-daily tenofovir/FTC plus either nevirapine (200 mg twice daily) or ritonavir-boosted atazanavir. The primary purpose of the study was to evaluate changes in plasma lipid levels. However, in April 2007, investigators decided to conduct an interim analysis of efficacy, after data from the DAUFIN study showed early virologic failures with once-daily tenofovir, 3TC, and nevirapine (ACC Apr 2 2007).

Seven patients were enrolled in each arm at the time of the interim analysis. Despite only 12 weeks of therapy, three patients in the nevirapine arm experienced virologic failure versus none in the boosted-atazanavir arm. All three patients had resistance mutations detected at 12 weeks that were not present at baseline — K65R, Y181C, and G190A in patient 1; T69N, K101E, Y181C, and M184V in patient 2; and K103N, Y181C, and M184V in patient 3. The three patients had good self-reported adherence and appropriate nevirapine trough concentrations (>3 mg/dL); before starting therapy, each had a high viral load (>100,000 copies/mL) and a low CD4 count (<200 cells/mm³). Based on these findings, the trial was stopped early.

Comment: Data on the combined use of tenofovir, FTC (or 3TC), and nevirapine are decidedly mixed, with worrisome reports of early virologic failure coming from at least two small prospective clinical trials. These results have particularly important implications in resource-limited settings, where nevirapine use is much more widespread and where d4T toxicity has led some treatment programs to substitute tenofovir for d4T. A fully powered, industry-sponsored trial is currently underway to evaluate tenofovir/FTC plus either once- or twice-daily nevirapine (with boosted atazanavir used in the control arm). Until results are available, clinicians should refrain from using tenofovir/FTC plus nevirapine as initial therapy.

— Paul E. Sax, MD

Published in AIDS Clinical Care April 14, 2008

Citation(s):

Lapadula G et al. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy–naive HIV-infected patients. Clin Infect Dis 2008 Apr 1; 46:1127.

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