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TMC278 Noninferior to Efavirenz in Naive But With More Virologic Failures
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XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
TMC278 (rilpivirine), an experimental nonnucleoside, met noninferiority criteria when compared with efavirenz in a pooled analysis of two 48-week international double-blind trials that enrolled previously untreated people, ECHO and THRIVE [1]. The virologic failure rate was higher with rilpivirine (9.0% versus 4.8%), but there were more discontinuations because of adverse events with efavirenz (7.6% versus 3.4%).
ECHO randomized 690 antiretroviral-naive adults to rilpivirine (25 mg once daily) or efavirenz, both with tenofovir/emtricitabine. In THRIVE 678 people randomized to the same dose of rilpivirine or efavirenz could take tenofovir/emtricitabine, zidovudine/lamivudine, or abacavir/lamivudine. The 1368 people randomized and treated in the two trials had a median pretreatment viral load of 100,000 copies and a median pretreatment CD4 count of 256.
The primary endpoint was the proportion of people with a viral load below 50 copies at week 48 in a time-to-loss-of-virologic-response analysis. By that yardstick 84.3% of people taking rilpivirine and 82.3% taking efavirenz had a week-48 viral load under 50 copies, results that established the noninferiority of rilpivirine to efavirenz. Rilpivirine was also noninferior to efavirenz in an analysis limited to people with a pretreatment viral load above 100,000.
However, 62 of 686 people (9.0%) taking rilpivirine versus 33 of 682 (4.8%) taking efavirenz met virologic failure criteria. The failure rate difference was higher in ECHO (11.0% versus 4.4%) than in THRIVE (7.1% versus 5.3%). The investigators are scrutinizing results to see if they can determine the reasons for this difference.
Among the 62 people with rilpivirine virologic failure, a nonnucleoside mutation developed in 39 (63%) and a nucleoside mutation arose in 42 (68%). Among 28 people genotyped after efavirenz failure, 15 (54%) had a nonnucleoside mutation and 9 (32%) a nucleoside mutation. E138K and M184I were the most frequent nonnucleoside and nucleoside mutations with rilpivirine, while K103N and M184V arose most often with efavirenz.
Study clinicians considered 109 (15.9%) grade 2 to 4 adverse events possibly related to treatment in the rilpivirine arms, versus 212 (31.1%) in the efavirenz arms (P < 0.0001). While 52 adverse events (7.6%) led to discontinuation in the efavirenz group, 23 (3.4%) did so in the rilpivirine groups (P = 0.0005). Serious adverse event rates were 6.6% with rilpivirine and 8.1% with efavirenz, a nonsignificant difference.
Central nervous system side effects and rash all affected significantly more people in the efavirenz group than the rilpivirine groups: psychiatric 22.7% versus 14.9% (P = 0.0002), abnormal dreams 12.8% versus 8.2% (P = 0.0061), neurologic events 37.8% versus 17.1% (P < 0.0001), dizziness 26.2% versus 8.0% (P < 0.0001), and any rash 13.6% versus 3.1% (P < 0.0001). Grade 3 or 4 lipid elevations also affected more people taking efavirenz than rilpivirine: total cholesterol 2.5% versus 0.1%, low-density lipoprotein cholesterol 4.1% versus 0.7%, and triglycerides 2.2% versus 0.3% (P < 0.001 for all).
CD4 counts rose by an average 192 with rilpivirine and 176 with efavirenz.
Reference
1. 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. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract THLBB206.
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