NNRTI
Microbicide UC781 Appears Safe for Rectal Use
By
Liz Highleyman  Microbicides
are being studied in large trials as a means of preventing transmission of HIV
to women during vaginal intercourse,
but there is also an urgent need to test these products for rectal safety, since
any approved product will inevitably be used for anal sex by both heterosexual
and homosexual couples.
In
a poster at the 16th Conference on Retroviruses and Opportunistic
Infections (CROI 2009) last month in Montreal, Peter Anton from the University
of California at Los Angeles and colleagues presented the first data from a Phase
1 trial evaluating at the acceptability and rectal safety of a microbicide gel
containing UC781, an investigational non-nucleoside reverse transcriptase inhibitor
(NNRTI). The
study included 36 HIV negative volunteers (26 men, 10 women) who agreed to abstain
from sex during the study. They were randomly assigned to use gel containing either
active UC781 (at concentrations of 0.10% or 0.25%) or placebo, first as a single
dose, and then as once-daily doses for 7 days.
Participants underwent
flexible sigmoidoscopy with stool and rectal fluid sampling at baseline and following
gel exposures. Investigators looked for signs of rectal tissue damage and inflammation
including epithelial sloughing (shedding of cells), histopathology, microflora
changes, mucosal cytokine profile, mucosal immunoglobulins, and fecal calprotectin
indicating inflammation.
In addition, tissue specimens were collected
for direct HIV challenge in an in vitro laboratory study (presented as a separate
poster).
Results
All enrolled participants completed the study.
Reported adherence was high.
UC781 gel was generally well-tolerated, with no severe (grade 3-4) adverse events.
Study participants reported 89 mild-to-moderate (grade 1-2) adverse events.
Symptoms considered possibly related to UC78 were fever, cramps, flatulence and
diarrhea.
Rectal tissue biopsies and biomarker analyses showed that participants who received
UC781 gel had no more evidence of rectal mucosal damage or inflammation than placebo
recipients.
There was also no significant difference between the 0.1% and 0.25% UC781 concentrations.
A majority of participants rated the gel as highly acceptable, both overall and
on specific attributes such as color, smell, and consistency.
In the laboratory study, tissue explant samples exposed to 0.25% UC781 gel demonstrated
significant suppression of HIV infection.
"This
first phase 1 rectal safety trial assessing the vaginal microbicide UC781 showed
the product to be safe and well tolerated," the investigators concluded.
"Participants were highly compliant and all procedures completed. No significant
differences were seen in mucosal injury assays between high dose (0.25%), low
dose (0.1%), or placebo groups."
These findings are reassuring given
the history of nonoxynol-9,
an approved and widely used contraceptive/microbicide gel that was later shown
to cause sloughing of tissue during rectal use or frequent vaginal use.
3/03/09
References
P
Anton, A Adler, E Khanuknova, and others. A Phase 1 Rectal Safety and Acceptability
Study of UC781 Microbicide Gel. 16th Conference on Retroviruses and Opportunistic
Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 1066. P
Anton, J Elliott, K Tanner, and others. Strong Suppression of HIV-1 Infection
of Colorectal Explants following in vivo Rectal Application of UC781 Gel: A Novel
Endpoint in a Phase I Trial. CROI 2009. Abstract 1067. |
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