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Lersivirine, a New NNRTI, Versus Efavirenz as First-Line Therapy: 48 Weeks
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Virologic response at 48 weeks proved similar with lersivirine, an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI), and efavirenz in an ongoing phase 2b trial of previously untreated people [1]. The new NNRTI caused central nervous system side effects or rash less often than efavirenz, but nausea was more common with lersivirine.
Earlier cell studies found that lersivirine inhibited more than 60% of viruses bearing critical reverse transcriptase mutations at 50% effective concentrations within 10-fold of those for wild-type (nonmutant) virus [2]. In particular, lersivirine retains activity against virus with mutations at position Y181, which confer resistance to efavirenz, etravirine, and nevirapine.
The new study is a phase 2b international, double-blind trial testing two once-daily doses of lersivirine (500 or 750 mg) against standard-dose efavirenz in previously untreated people. The 191 study participants also took tenofovir/emtricitabine. This phase 2b trial is not powered to demonstrate noninferiority of lersivirine to efavirenz.
Anton Pozniak (Chelsea and Westminster Hospital, London) and colleagues randomized 66 people to 500 mg of lersivirine, 66 to 750 mg of lersivirine, and 63 to efavirenz. One person in each of the lersivirine arms did not begin treatment. Age averaged 36 to 37 across the three treatment arms, viral load 4.7 log (about 50,000 copies), and pretreatment CD4 count around 320. Sixty-four study participants (33% of those randomized and treated) live in South Africa and have subtype C HIV-1. Whites made up about 60% of the study group.
Through 48 weeks, 12 of 65 people (18%) in the 500-mg lersivirine arm discontinued treatment, 5 for "insufficient clinical response" and 3 because of adverse events. Twelve (18% of 65) also dropped out of the 750-mg lersivirine arm, 4 because of "insufficient clinical response" and 3 with side effects. Nine people (14% of 63) quit the efavirenz group, only 1 because of "insufficient clinical response" and 5 because of adverse events.
In a noncompleter-equals-failure analysis, 48-week sub-50 copy rates were 79% with 500 mg of lersivirine, 79% with 750 mg of lersivirine, and 86% with efavirenz. When the investigators split this response analysis into people with pretreatment viral loads above and below 100,000 copies, results were similar in the three treatment arms in the lower viral load group. But among people who began treatment with a viral load above 100,000 copies, at 48 weeks sub-50-copy noncompleter-equals-failure rates were 75% with 500 mg of lersivirine, 62% with 750 mg of lersivirine, and 82% with efavirenz.
These lower response rates with lersivirine could reflect the relatively high proportions of South Africans who started treatment with a viral load above 100,000 copies, and their slightly worse response to lersivirine: Sub-50 response rates among South Africans were 72% with 500 mg of lersivirine, 68% with 750 mg, and 83% with efavirenz (83%), though the numbers in this analysis are small (18, 22, and 24). The investigators are analyzing NNRTI plasma concentrations and adherence results to shed more light on these response rates. (from Jules: I recall Posniak said it was due to nonadherence in most of the So African patients)
Among people whose virus could be genotyped after virologic failure, the familiar K103N NNRTI mutation arose with efavirenz, but never with lersivirine. NNRTI mutations in 4 people with lersivirine failure were (1) K101E, V108I, H221H/Y, (2) Y188Y/H, F227F/L, L234L/I, (3) F227C, and (4) V106M, F227L.
In a week 48 last-observation-carried-forward analysis, average CD4-cell gains were also similar in the three study arm: 191 with 500 mg of lersivirine, 195 with 750 mg of lersivirine, and 188 with efavirenz.
Serious adverse events rose in 4 people (6%) taking 500 mg of lersivirine, 5 (8%) taking 750 mg of lersivirine, and 4 (6%) taking efavirenz. Three people (5%) in each of the lersivirine arms dropped out because of adverse events, compared with 5 (8%) taking efavirenz.
The most common adverse events were abnormal dreams (19% with efavirenz, 8% in either lersivirine group), dizziness (21% with efavirenz, 8% with 500 mg of lersivirine, 6% with 750 mg of lersivirine), nausea (13% with efavirenz, 23% with 500 mg of lersivirine, 42% with 750 mg of lersivirine), and headache (14% with efavirenz, 23% with 500 mg of lersivirine, 17% with 750 mg of lersivirine). Rash arose more often with efavirenz than with 500 or 750 mg of lersivirine (11%, 5%, 2%), as did any grade 3 or 4 adverse event (22%, 6%, 14%).
Any grade 3 or 4 lab abnormality arose in 13% taking efavirenz, 3% taking 500 mg of lersivirine, and 5% taking 750 mg of lersivirine. Lipid changes at week 48 were more favorable with 500 or 750 mg of lersivirine than with efavirenz: total cholesterol (+0.9 mg/dL, -4.2 mg/dL, +15.5 mg/dL), low-density lipoprotein cholesterol (-1.7 mg/dL, -4.6 mg/dL, +4.0 mg/dL), and triglycerides (-1.5 mg/dL, -3.1 mg/dL, +10.6 mg/dL).
When asked what niche lersivirine might fill in an increasingly well-stocked NNRTI larder, Pozniak suggested it may prove particularly useful for people with a position Y181 mutation. Its once-daily dosing, he added, makes it a reasonable candidate for coformulation with other antiretrovirals.
References
1. Vernazza P, Wang C, Pozniak A, et al. Efficacy and safety of lersivirine (UK-453,061) vs. efavirenz in antiretroviral treatment-na•ve HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study A5271015). 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract TUAB0101.
2. Corbau R, Mori J, Phillips C, et al. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2010;54:4451-4463. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944613/?tool=pubmed.
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