Tenofovir for Prevention of HIV Infection in Women
The
HIV epidemic is continuing to expand worldwide. Use of condoms is recommended
for prevention of sexually
transmitted HIV, but often women
are unable to negotiate condom use with their male partners. Safe, effective,
and easy to use methods of HIV prevention are urgently needed, especially for
women.
One potential new approach is the use of pre-exposure
prophylaxis (PrEP) with selected antiretrovirals. However, it is not yet known
if use of antiretrovirals can prevent infection of HIV in humans.
The nucleotide
analogue tenofovir (TDF; Viread) was selected for clinical development
as a treatment for HIV infection because of its (1) potency against wild-type
HIV and some nucleoside-resistant strains of HIV; (2) low potential of selecting
for TDF-resistant mutants; (3) low likelihood of metabolic/mitochondrial toxicity;
and (4) pharmacologic profile supporting daily dosing. The US Food and Drug Administration
(FDA) licensed TDF for the treatment of established HIV-1 infection 2001.
The
objective of the present study, published online May 25, 2007 in PLoS Clinical Trials, was to investigate the safety and preliminary
effectiveness of a daily dose of 300 mg of TDF versus placebo in preventing HIV
infection in women.
This
was a phase 2, randomized, double-blind, placebo-controlled trial that enrolled
936 HIV-negative women at high risk of HIV infection. The study was conducted
between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.
Participants
were randomized 1:1 to once daily use of 300 mg of TDF or placebo.
The
primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0
mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine
aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or
4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection
with HIV-1 or HIV-2.
Results
Study
participants contributed 428 person-years of laboratory testing to the primary
safety analysis.
No
significant differences emerged between treatment groups in clinical or laboratory
safety outcomes.
Study
participants contributed 476 person-years of HIV testing to the primary effectiveness
analysis, during which time eight seroconversions occurred.
Two
were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and
six in participants receiving placebo (2.48 per 100 person-years), yielding a
rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve
statistical significance.
Owing
to premature closures of the Cameroon
and Nigeria
study sites, the planned person-years of follow-up and study power could not be
achieved.
In
conclusion, the study authors write, “Daily oral use of TDF in HIV-uninfected
women was not associated with increased clinical or laboratory adverse events.
Effectiveness could not be conclusively evaluated because of the small number
of HIV infections observed during the study.”
Discussion
The
data obtained from this trial provide an encouraging rationale for additional
research to evaluate oral antiretroviral drugs as prophylaxis against HIV infection.
No significant differences in safety patterns occurred among participants receiving
daily oral TDF compared with those
receiving placebo, consistent with results seen in previous treatment studies.
The
premature stopping of the study in Cameroon
and Nigeria limited
the amount of follow-up safety and effectiveness data obtained in this study.
Furthermore, adverse events (AEs) and laboratory abnormalities in the TDF group
may have been diluted by lower than expected product use due to missed visits,
drug stoppage due to pregnancy, and other reasons for non-use of study drug.
No
flares of ALT or AST were observed among those with HBV infection in this study,
although the analysis was limited to 23 TDF-treated women with reactive tests
for HBsAg.
As
a new HIV prevention approach, prophylactic use of TDF could be used with other
prevention strategies such as condoms to reduce the number of people who become infected with HIV.
Larger
phase 3 studies to conclusively determine the safety, effectiveness, and feasibility
of using TDF (either alone or in combination
with other antiretrovirals) as chemoprophylaxis against HIV infection in both
women and men are needed.
Commentary
The
following editorial commentary was
written by the Public Library of Science (PLoS) staff, based on the reports of the
academic editors and peer reviewers.
Unfortunately,
this trial was not completed as planned.
Two sites (Nigeria and Cameroon)
were closed either before the planned number of participants had been recruited
or before all participants had completed
full follow-up. Therefore, not enough data were available from this trial to determine
whether tenofovir reduced the risk of HIV infection.
The
researchers did not see any statistically significant differences in the safety
endpoints between participants taking tenofovir and those taking placebo. There
were also no statistically significant differences between the treatment groups
in the number of AEs.
The
main efficacy analysis found two new HIV infections in the tenofovir group and
six in the placebo group. Because only eight effectiveness endpoints were observed
during this study, the difference in HIV incidence between these groups was not
statistically significant.
A strength of this trial is that it was correctly designed to address
the original objectives of the study, involving appropriate concealment of randomization
and blinding of participants and study staff to treatment assignment. The main
limitation of this study was the closure of two study sites, which meant that
the study did not have sufficient power to assess differences between trial arms
in the primary efficacy analysis.
At
the time this trial was completed, there was no other evidence from randomized
studies that evaluated antiretroviral drugs for prevention of HIV infection.
This
trial cannot, however, definitively address whether tenofovir reduces the risk
of HIV infection among at-risk women or not. Ongoing and future trials are essential
in order to answer this question.
The
safety data reported in this trial are encouraging and suggest that tenofovir
use is not associated with increased adverse events as compared
to placebo.
The
HIV epidemic is continuing to expand worldwide. Use of condoms is re
