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Dapivirine vaginal ring safe and effective in tissue study, but maraviroc component doesn't work
Liz Highleyman, 2014-03-20 08:30:00
Vaginal rings containing the experimental NNRTI
dapivirine were well tolerated and blocked HIV infection of cervical tissue
samples, but rings containing maraviroc did not produce adequate drug
concentrations, researchers reported at the 21st Conference on Retroviruses and
Opportunistic Infections (CROI) this month in Boston.
The area of biomedical prevention – using
antiretroviral drugs or other medical rather than behavioural approaches to
prevent HIV transmission – has produced some of the major gains in the HIV
field in recent years. Studies have demonstrated the effectiveness of treatment as prevention and oral pre-exposure prophylaxis (PrEP), but
researchers are also looking at other methods including long-acting injectables and microbicide gels and rings. Vaginal rings release
drugs slowly over time, which could help with adherence.
Beatrice Chen of the University of Pittsburgh
presented findings from a phase 1 clinical trial (MTN-013/IPM 026) evaluating the safety,
pharmacokinetics and pharmacodynamics of vaginal rings containing the investigational non-nucleoside reverse
transcriptase inhibitor (NNRTI) dapivirine (formerly TMC120) alone, the CCR5 co-receptor blocker maraviroc (Celsentri) alone, both drugs in one ring or a placebo
The dapivirine-only ring is currently in phase 3 trials. The combination
ring – being tested for the first time in a human trial – contains 25mg
dapivirine plus 100mg maraviroc. All rings are made
of a silicone elastomer measuring 56mm in diameter and 7.7mm thick.
This double-blind, randomised, placebo-controlled trial included 48 sexually
abstinent HIV-negative women in Pittsburgh, Boston and Birmingham,
Alabama. Half the women were
white, about 40% were black and the average age was approximately 30 years.
The researchers measured dapivirine and maraviroc levels in blood plasma
and vaginal fluid and collected information about adverse events. Adherence was
assessed by self-report and residual drug levels in returned rings. After
wearing the rings for 28 days, participants underwent cervical biopsies to
collect tissue samples which were then exposed to HIV in the laboratory (known
as an ex vivo challenge).
Almost all participants completed the study and more than 90% reported
full adherence, which was confirmed by residual drug levels in used rings. Most women wore the ring continuously for 28 days, though
nearly one in five said they would prefer not to do so during menstruation.
All the vaginal rings were generally safe and
well-tolerated. Participants reported a total of 167 adverse events, most of
which were mild (88%) or moderate (10%), and a majority of which (71%) were
deemed unrelated to the study products. There were no significant differences
in frequency of genitourinary side-effects or moderate or worse adverse events
across the treatment and placebo arms.
Maximum plasma concentrations (Cmax) of dapivirine were
similar in women using the dapivirine-only and combination rings (272 vs 294
pg/ml, respectively). Plasma concentrations of maraviroc, however, were below
limits of quantification.
At day 28, mean dapivirine levels in vaginal fluid were 14.9 and 10.0
mcg/ml, respectively, in women who used the dapivirine-only and combination
rings. The mean maraviroc level in vaginal fluid reached 6.7 mcg/ml with the
maraviroc-only ring, but only 1.1 mcg/ml with the combination ring.
Levels of dapivirine in cervical tissue samples were 0.6 and 1.6 mcg/ml,
respectively, with the dapivirine-only and combination rings. However, only 4
of the 24 women who used the maraviroc-only or combination rings had cervical
tissue levels of maraviroc above the limit of quantification.
Cervical tissue samples from women using dapivirine and combination
rings showed a significant inverse linear relationship between HIV replication
and tissue dapivirine levels – that is, higher levels were associated with
reduced viral replication. There was no observed relationship with maraviroc
levels, which in most cases were undetectable.
“Dapivirine but not maraviroc delivered by a vaginal ring for 28 days
blocked HIV-1 infection in cervical tissue,” the researchers concluded. “There
was a linear correlation between dapivirine levels in tissue and protective
effect. These data suggest that delivery of NNRTIs via vaginal rings is a viable
approach for HIV prevention.”
“It's encouraging that both drugs were safe, and that
most women didn't mind wearing the ring,” Chen said in a press release issued
by the Microbicide Trials Network, which ran the trial. “However,
we found maraviroc wasn't getting absorbed in tissue like dapivirine was and it
didn't work as well as dapivirine in our laboratory studies looking at activity
Zeda Rosenberg from
the International Partnership for Microbicides said that the non-profit organisation
is doing additional development work to try to increase the amount of maraviroc
that gets into cervical tissue and is planning a second safety study for 2015.