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TMC-278 Phase 3 ECHO/THRIVE Studies Resistance Profile
Rilpivirine
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Noninferior to Efavirenz, But With More Virologic Failures and Better Safety/Discontinuation Profile
50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
Rilpivirine (TMC278) was noninferior to efavirenz through 48 weeks in previously untreated people enrolled in the phase 3 ECHO and THRIVE trials [1]. As reported in Vienna a higher proportion of pooled trial participants taking rilpivirine, a nonnucleoside (NNRTI), met protocol-defined criteria for virologic failure (9.0% vs 4.8%). And among people with virologic failure, resistance mutation rates were higher with rilpivirine than with efavirenz. More people taking efavirenz stopped treatment because of adverse events and other reasons, a result explaining the noninferiority of rilpivirine.
This pooled analysis of the ECHO and THRIVE trials involved 686 people randomized to rilpivirine (25 mg once daily) and 682 randomized to efavirenz. Everyone also took tenofovir/emtricitabine in ECHO, while in THRIVE study clinicians picked the nucleosides (60% picked tenofovir/emtricitabine, 30% zidovudine/lamivudine, and 10% abacavir/lamivudine). No one had nonnucleoside-related mutations when they entered the study, and everyone had virus susceptible to nucleosides. (from Jules: patients with NNRTI baseline resistance were excluded from the study).
The primary endpoint of both trials was the percentage of patients with a viral load below 50 copies in a week-48 time-to-loss-of-virologic-response analysis. That analysis determined response rates of 84.3% for rilpivirine and 82.3% for efavirenz, a result that established the noninferiority of rilpivirine to efavirenz. Proportions responding to rilpivirine and efavirenz were also equivalent among people starting therapy with more than 100,000 copies (77% and 81%, difference -3.6, 95% confidence interval [CI] -9.8 to 2.5).
However, 72 of 686 rilpivirine recipients (10%) met the definition of virologic failure, compared with 39 of 682 people (6%) taking efavirenz. The trials defined failure as (1) never achieving two consecutive viral loads below 50 copies and having at least a 0.5-log rise from the lowest viral load or (2) reaching consecutive viral loads below 50 copies, followed by two consecutive loads above 50 copies, or one above 50 copies if it was the last load measured. The investigators successfully genotyped virus from 62 people (86%) in whom rilpivirine failed and from 28 (72%) in whom efavirenz failed.
Among successfully genotyped patients, 68% taking rilpivirine and 32% taking efavirenz had nucleoside/nucleotide mutations that emerged during treatment. The most frequent NRTI mutation with rilpivirine was M184I, the lamivudine/emtricitabine mutation that often precedes and is replaced by M184V.
Rates of emerging NNRTI-related mutations were more balanced between the two groups. The most frequent NNRTI mutation to emerge upon rilpivirine failure was E138K, which has been associated with resistance to etravirine, efavirenz, and nevirapine in vitro [2]. Investigator Joseph Eron noted that E138K is a rare mutation, with a prevalence of only 0.6% in the database of Monogram Biosciences. Other mutations seen upon rilpivirine failure were K101E and H221Y. The nonnucleoside mutation K103N emerged most often upon efavirenz failure. The investigators documented phenotypic resistance to nonnucleosides in 50% of patients in whom rilpivirine failed and in 43% of efavirenz failures. Mutations that confer resistance to rilpivirine in studies so far are substitutions at position E138, K101, and Y181, along with H221Y.
Eron presented data showing that suboptimal adherence and/or higher pretreatment viral load largely explained virologic failures in both study arms. But the impact was greater in the rilpivirine arm. In contrast, people taking rilpivirine discontinued treatment less often for adverse events and other reasons than people taking efavirenz.
Through a median treatment duration of 56 weeks, 31% taking efavirenz versus 16% taking rilpivirine had a grade 2 to 4 adverse event at least possibly related to study drugs (P < 0.0001). While 8% taking efavirenz dropped out because of adverse events, 3% stopped rilpivirine for that reason (P = 0.0005). Rash and central nervous system side effects such as dizziness and abnormal dreams were all significantly more frequent with efavirenz than with rilpivirine.
ECHO and THRIVE were rilpivirine registrational trials. The nonnucleoside is being developed as a stand-alone agent and as part of a fixed-dose combination with tenofovir and emtricitabine.
References
1. Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the phase 3 studies ECHO and THRIVE. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-1810.
2. Asahchop E, Tremblay C, Brenner B, et al. Selection in vitro of a novel etravirine associated resistance mutation in B and non-B HIV-1 subtypes. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. Abstract 552. http://www.retroconference.org/2010/PDFs/552.pdf
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