New NNRTI lersivirine matches efavirenz in phase 2 study

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Lersivirine, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), lowered HIV viral load about as well as efavirenz (Sustiva, Stocrin) for people starting antiretroviral therapy for the first time, researchers reported at the International AIDS Society Conference (IAS 2011) this week in Rome.

Lersivirine (formerly known as UK-453,061), being developed by ViiV Healthcare, has a unique binding pattern to HIV's reverse transcriptase enzyme, enabling it to remain active against HIV with certain NNRTI resistance mutations (including Y181 changes).

Anton Pozniak from Chelsea and Westminster Hospital in London reported findings from a Phase 2b trial (Study A5271015) comparing lersivirine against efavirenz for first-line therapy.



A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 


Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.


The term for the different sub-types of HIV.

secondary endpoints

Endpoints in a trial that provide supportive evidence to the primary endpoint.

This multinational study included 195 treatment-naive participants with no reverse transcriptase resistance mutations evident at baseline. About three-quarters were men, about 60% were white (though this varied across sites) and the average age was 36 years. The median baseline CD4 cell count was approximately 320 cells/mm3.

Participants were stratified according to viral load (above or below 100,000 copies/mL) and geographic region. About one-third lived in South Africa, with the rest in Europe, North and South America, and Australia; a corresponding proportion had HIV Clade C, whilst most of the rest had Clade B.

Participants were randomly assigned to received 500mg lersivirine, 750mg lersivirine, or efavirenz once-daily, in combination with tenofovir/emtricitabine (Truvada).

In an overall intent-to-treat analysis at 48 weeks, 79% of participants in both lersivirine dose groups achieved viral load below 50 copies/mL, compared with 89% of those taking efavirenz; the difference was not statistically significant. CD4 gains were good in all arms at about 100 cells/mm3 in the first month, rising to around +190 cells/mm3 by week 48.

Although lersivirine and efavirenz performed similarly overall, a breakdown of the results showed that both doses of lersivirine performed much less well than efavirenz in people with high viral load (50% vs 38% vs 78%, respectively) in South Africa compared to participants in other regions. Further analysis found that the viral load difference was only significant among the South Africans.

Twelve participants in each of the lersivirine arms and nine in the efavirenz arm discontinued treatment early, usually due to insufficient response or adverse events.

Lersivirne was somewhat better tolerated than efavirenz overall, though serious adverse events and discontinuations for this reason were uncommon and frequency was similar across arms. People taking lersivirine experienced fewer neuropsychiatric side effects, as expected, but had more nausea (usually mild).

Looking at the secondary endpoint of changes in blood lipids, participants taking lersivirine had lesser increases in total cholesterol and triglycerides, and a greater increase in HDL "good" cholesterol; however, the ratio of total-to-HDL cholesterol remained the same in all arms. Overall, Pozniak described lersivirine as "lipid neutral".

Among participants who experienced virological failure, emergence of resistance mutations occurred more often in the 500mg lersivirine arm than the higher-dose lersivirine or efavirenz groups. The K103N NNRTI mutation was not seen in anyone taking lersivirine and one patient taking efavirenz.

In discussing these findings, Pozniak explained that the apparently slightly worse virological suppression with lersivirine was driven by people with high viral load in South Africa. Whether this was attributable to adherence or to other factors remains to be explained.  Although lersivirine looks promising, he stressed that this analysis was not designed to determine superiority or non-inferiority, and Phase 3 studies are planned.



Vernazza P et al. Efficacy and safety of lersivirine (UK­453,061) vs efavirenz in antiretroviral treatment­naive HIV­1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study  A5271015). Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, TUAB0101, Rome, 2011.

View abstract on the conference website.

View the presentation slides, with audio, on the conference website.