Yet another large study that aims to prevent the spread of HIV by giving uninfected women antiretroviral (ARV) pills has had to redesign the trial
because of startling—and negative—interim results.
The Microbicide Trials Network (MTN), which is funded by the U.S. National Institutes of Health, today announced that it decided to stop one arm of a
study involving more than 5000 women in South Africa, Zimbabwe, and Uganda. The decision followed an
interim review of the ongoing trial by an independent monitoring board, which found that the drug tenofovir when used as pre-exposure prophylaxis
(PrEP) had less effect in protecting women than anticipated. Although the board did not offer any specifics on how many women became infected on the
drug versus placebo, they said continuing with the tenofovir arm was "futile" as it would not yield meaningful results. They didn't give numbers
because parts of the trial are still going on, testing other prevention measures.
Sharon Hillier, who heads the MTN, says her team is "incredibly disappointed" and that she personally is humbled and somewhat flummoxed. "I've got to
quit guessing how studies will turn out," Hillier says. "It breaks your heart."
The study, Vaginal and Oral Interventions to Control the
Epidemic (VOICE), began in September 2009 and is not scheduled to end
until about 1 year from
now. The MTN designed VOICE to compare three different PrEP
strategies: tenofovir pills, tenofovir in a vaginal gel, and Truvada
pills (a combination
of tenofovir and a second antiretroviral, emtricitabine). The
tenofovir gel and Truvada pills arms of the study are still under way.
research is a constant reminder of how much we don't know," says
Mitchell Warren, who heads the AIDS Vaccine Advocacy Coalition, which
closely follows PrEP studies.
The new results particularly baffled people who follow this
promising prevention strategy because there were mixed but encouraging
findings in two
similar studies reported earlier this year. In April, researchers
stopped a study called FEM-PrEP
that evaluated Truvada pills in nearly 2000
uninfected young women in South Africa, Kenya, and Tanzania
after an interim analysis revealed that continuing was futile. But then
in July, an early
look at infections in a study that evaluated taking either
tenofovir or Truvada pills as PrEP found that both worked well in women.
A key difference in
the second trial, called Partners PrEP,
is that it
involved more than 4700 couples in Kenya and Uganda in which one
partner tested positive at the outset, while both VOICE and FEM-PrEP
enrolled young, single women.
Timothy Mastro, who helped lead the truncated FEM-PrEP for FHI
360 in Durham, North Carolina, says teasing out why the same drugs would
fail in one
population and work in another will require analyzing two main
factors: biology and behavior. Studies have shown that small amounts of
drugs taken orally reach the vaginal mucosa. That protection may
have been overwhelmed in VOICE and FEM-PrEP if male partners had higher
levels of HIV
than those in Partners PrEP. Or it could be that women in
Partners PrEP had more motivation to "adhere" to study protocols and
take pills each day as
instructed, given that they knew for certain—unlike women in the
other two trials—that they were having sex with an HIV-infected man.
The infected men
in Partners PrEP may have also encouraged their uninfected
partners to adhere. "It's really important for our two groups to compare
the data and study
populations," Mastro says.
VOICE's Hillier says she's looking forward to Mastro's group
completing their detailed analyses of the factors behind FEM-PrEP's
"There's not going to be a simple answer about who should get
PrEP, and it's very clear that different populations can get different
Hillier emphasizes that these conflicting findings underscore that much
remains to be learned about PrEP, which also worked well in gay men
in yet another large study recently completed. That
analysis needs to be done before public health officials roll
out recommendations for its use. "The data are trying to tell us
important," Hillier says. "People thought ARVs were going to be
magic, and you could sprinkle them out there and people would use them
all time and
they'd prevent all infections. These studies are teaching us
loud and clear that how and when they'll work raises very nuanced
questions. And these
studies are teaching us things we didn't want to know."
VOICE hopes to have results for the other two arms of the study by the end of next year.