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Rilpivirine (TMC278) vs Efavirenz at 96 Weeks in Antiretroviral Naive
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Rilpivirine, a nonnucleoside (NNRTI), proved noninferior to efavirenz at 96 weeks in two phase 3 trials (THRIVE and ECHO) that enrolled previously untreated people [1-3]. The virologic failure rate was twice higher with rilpivirine than with efavirenz, but twice as many people dropped out of the efavirenz arm because of side effects.
For these double-blind, double-dummy trials, researchers in North America, Latin America, Europe, Australia, Asia, and South Africa enrolled 1368 previously untreated people and randomized them to 25 mg of rilpivirine once daily or to standard-dose efavirenz once daily. People in THRIVE took could take tenofovir/emtricitabine, zidovudine/lamivudine, or abacavir/lamivudine with the NNRTI, while everyone in ECHO took tenofovir/emtricitabine. Phenotyping established that study participants had virus susceptible to these backbone drugs.
In the week 96 time-to-loss-of-virologic-response analysis pooling results of the two trials, precisely the same proportion in the rilpivirine arm and the efavirenz arm--77.6%--had a viral load below 50 copies. CD4 gains were similar in the two groups--227.5 with rilpivirine and 219.5 with efavirenz. Virologic failure accounted for the lion's share of failures in the rilpivirine group, while dropouts related to side effects explained most efavirenz failures.
At the 96-week point, 96 people (14%) randomized to rilpivirine had virologic failure, compared with 52 (8%) randomized to efavirenz. Viral rebound accounted for 52 failures (8%) in the rilpivirine group and 34 (5%) in the efavirenz group. While 44 people (6%) taking rilpivirine never reached a viral load below 50 copies, 18 (3%) taking efavirenz never had an undetectable load.
Among people with virologic failure and genotyped virus, 46 of 86 (53%) taking rilpivirine and 20 of 42 (48%) taking efavirenz had NNRTI-related resistance mutations at week 96. However, a higher proportion in whom rilpivirine failed had detectable nucleoside/nucleotide mutations--48 of 86 (56%) versus 11 of 42 (26%) taking efavirenz. NNRTI mutation patterns differed between the two treatment groups. At week 48 in both ECHO and THRIVE [2,3], the most common NNRTI mutation upon rilpivirine failure was E138K, while no one with rilpivirine failure had K103N. When efavirenz failed, K103N was the most frequent NNRTI mutation, and no one failed with E138K.
Pooled safety profiles at 96 weeks favored rilpivirine. At that point 116 people taking rilpivirine (16.9%) had grade 2 to 4 adverse events possibly related to study drugs, compared with 226 (33.1%) taking efavirenz (P < 0.0001). Similarly, about half as many people taking rilpivirine (28, 4.1%) versus efavirenz (58, 8.5%) dropped out of the study because of adverse events. Abnormal dreams were significantly less frequent with rilpivirine (8.3% versus 13.2%, P = 0.0039), as were dizziness (8.0% versus 26.7%, P < 0.0001) and rash (4.2% versus 15.1%, P < 0.0001).
Lipid changes generally favored rilpivirine over efavirenz. At week 48 in ECHO [3], triglycerides fell an average of 0.10 mmol/L with rilpivirine while rising 0.16 mmol/L with efavirenz (P = 0.01). Triglyceride changes were similar in THRIVE [2], with an average drop of 0.07 mmol/L in the rilpivirine group and a gain of 0.14 mmol/L in the efavirenz group (P < 0.0001).
Total-to-high-density-lipoprotein (HDL) cholesterol ratio improved more with rilpivirine than with efavirenz in both trials at week 48, but these differences were not statistically significant (P = 0.25 in both trials). The nonsignificant difference in total-to-HDL ratio persisted through week 96.
References
1. Cohen C, Molina JM, Cassett I, et al. Pooled week 96 efficacy, resistance and safety results from the double-blind, randomised, phase III trials comparing rilpivirine (RPV) versus efavirenz (EFV) in treatment-naive, HIV-1-infected adults. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TULBPE032.
2. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378:229-237.
3. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378:238-246.
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