Two parallel randomized controlled Phase 3 noninferiority studies (ECHO and THRIVE) evaluated the efficacy and safety of rilpivirine (TMC278), an investigational NNRTI, in treatment-naive individuals. Nearly 1,400 subjects with HIV susceptible to NRTIs and NNRTIs were randomized to take either rilpivirine (25 mg) or efavirenz once daily. They also were given tenofovir/emtricitabine (in the ECHO study) or 2 NRTIs selected by investigators (in the THRIVE study; 60% were treated with tenofovir/emtricitabine). The median baseline HIV RNA level was 5.0 log10 copies/mL, and about 50% of subjects had HIV RNA levels of >100,000 copies/mL. The median baseline CD4 count was 255 cells/µL.
At 48 weeks, by intention-to-treat analysis of pooled data from the two studies, 84% of rilpivirine recipients and 82% of efavirenz recipients had HIV RNA levels of <50 copies/mL; these results met the criteria of noninferiority. In subjects with baseline HIV RNA levels of <100,000 copies/mL, a higher proportion of rilpivirine recipients achieved HIV RNA levels of <50 copies/mL (90%, vs 84% of efavirenz recipients; confidence interval [CI], 1.6-11.5), but in those with baseline HIV RNA levels of >100,000 copies/mL, rilpivirine recipients (primarily in the ECHO study) were less likely to attain virologic suppression (77%, vs 81% for the efavirenz group; CI, -9.8 to 2.5). Mean CD4 count increases were 192 cells/µL in the rilpivirine group and 176 cells/µL in the efavirenz group.
Evaluation of the causes of treatment failure showed that more subjects in the rilpivirine group experienced virologic failure (9%, vs 4.8% in the efavirenz group) whereas more subjects in the efavirenz group discontinued their regimens because of adverse events (2% of the rilpivirine group vs 6.7% of the efavirenz group). Among the rilpivirine subjects with virologic failure, mutations associated with NNRTI resistance were found in 63% (primarily E138K) and mutations associated with NRTI resistance were found in 68% (primarily M184I); in >90% of subjects with resistance to rilpivirine, cross-resistance to etravirine was found on phenotypic testing. Emergent resistance mutations were less frequent in the efavirenz group. Neuropsychiatric adverse effects and rash were significantly more common in the efavirenz group, as were lipid and transaminase elevations.
Clinical Bottom Line
This study demonstrates that treatment with rilpivirine avoids some of the adverse effects of efavirenz but carries a greater risk of virologic failure (and of resistance), perhaps particularly in patients with high pretreatment HIV RNA levels. Further study will be important in helping to characterize patients who are likely to be treated successfully with rilpivirine. The manufacturer of rilpivirine plans to coformulate rilpivirine with tenofovir/emtricitabine, potentially offering (if FDA approval is granted) the possibility of another single-pill, once-daily regimen for initial therapy.
- Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 versus efavirenz in treatment-naive, HIV-1-infected patients. In: Program and abstracts of the XVIII International AIDS Conference; July 18-23, 2010; Vienna. Abstract THLBB206.