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New HIV NNRTI Lersivirine Matches Efavirenz in Phase 2b Trial

The investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) lersivirine suppressed HIV viral load as well as efavirenz (Sustiva) in a 48-week trial, but with a different and side effect profile, researchers reported in the February 1, 2013, Journal of Acquired Immune Deficiency Syndromes.

[Editor's note: On February 5, 2013, ViiV told HIV treatment writers that the company has decided to stop the development program investigating lersivirine after determining that it "would not provide an improvement over existing medicines in the NNRTI class."]

Pfizer's Lersivirine (formerly UK-453,061), being developed by ViiV Healthcare, has a novel binding pattern to HIV's reverse transcriptase enzyme, which enables it to remain active against HIV with certain first-generation NNRTI resistance mutations.

Pietro Vernazza from Cantonal Hospital in St. Gallen, Switzerland, and colleaguesconducted an exploratory 96-week Phase 2b clinical trial (Study A5271015) to evaluate the safety and antiviral activity of lersivirine for treatment-naive patients. 48-week results were previously presented at the 2011International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome.

This multinational study included 193 previously untreated participants in 9 countries who had no reverse transcriptase resistance mutations evident at baseline. Approximately three-quarters were men, about 60% were white, about 33% were black, the average age was 36 years, and the median baseline CD4 T-cell count was about 320 cells/mm³. Participants were stratified by baseline viral load (above or below 10,000 copies/mL) and geographic region; about one-third were in South Africa, with the rest in Europe, North and South America, and Australia.

Participants were randomly assigned to receive once-daily 500 mg lersivirine, 750 mg lersivirine, or 600 mg efavirenz, all in combination with tenofovir/emtricitabine (the drugs in Truvada). The primary endpoint was the proportion of patients with HIV RNA < 50 copies/mL at week 48 (missing/discontinuation = failure); follow-up continued through week 96.

Results

• In an intent-to-treat analysis at 48 weeks, 79% of participants in both lersivirine dose groups achieved viral load < 50 copies/mL, compared with 86% in the efavirenz arm, not a significant difference.
• While all 3 regimens worked similarly for people with low baseline viral load, lersivirine did not work as well for people with higher viral load:

o   < 100,000 copies/mL: 80% with 500 mg lersivirine, 86% with 750 mg lersivirine, 88% with efavirenz;

o   >100,000 copies/mL: 75%, 62%, and 82%, respectively.

• 22% of participants in both lersivirine groups experienced treatment failure, compared with 15% in the efavirenz group.
• Among those eligible for assessment, the observed pattern of resistance mutations was distinct from that seen with first-generation NNRTIs.
• CD4 cell gains from baseline were similar in all groups, at just under 200 cells/mm³ at week 48.
• Overall frequency of treatment-related adverse events was "slightly lower" with lersivirine than with efavirenz
• Serious adverse events, however, occurred at similar rates across all treatment groups.
• 5% of patients in both lersivirine groups discontinued due to adverse events, compared with 8% of people taking efavirenz.
• Participants receiving lersivirine experienced more nausea but fewer neuropsychiatric side effects compared with efavirenz recipients:

o   Nausea: 23% with 500 mg lersivirine, 42% with 750 mg lersivirine, and 13% with efavirenz;

o   Dizziness: 8%, 6%, and 21%, respectively;

o   Abnormal dreams: 8%, 8%, and 19%, respectively.

• Lersivirine had a "neutral effect" on lipids, while larger increases were seen in the efavirenz group.

Based on these findings, the study authors concluded, "Both lersivirine doses showed broadly comparable efficacy to efavirenz over 48 weeks in treatment-naive patients, with different adverse event profiles from efavirenz."

"With the current safety and efficacy profile observed in this small Phase IIb estimation study, lersivirine may have the potential to provide an alternative to efavirenz where neuropsychiatric events or pharmacokinetic interactions are a concern," they added.

2/1/13

Reference

P Vernazza, C Wang, A Pozniak, et al. Efficacy and Safety of Lersivirine (UK-453,061) Versus Efavirenz in Antiretroviral Treatment–Naive HIV-1–Infected Patients: Week 48 Primary Analysis Results From an Ongoing, Multicenter, Randomized, Double-Blind, Phase IIb Trial. Journal of Acquired Immune Deficiency Syndromes 62(2):171-179. February 1, 2013.