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
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
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.
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
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.
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.
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
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.