PrEP Cuts HIV Infection by 44% among Gay/Bisexual Men in Worldwide
Pre-exposure prophylaxis (PrEP) using a daily combination
of tenofovir and emtricitabine (the drugs in the
Truvada coformulation) reduced the risk of acquiring
HIV by 44%, according to a large international study
of men who have sex with men. As described in the
23, 2010 advance online edition of the New England
Journal of Medicine, the iPrEx study found
that men who achieved good adherence had more than
a 70% reduction in new infections. The drug combo
was well-tolerated over nearly 3 years of follow-up,
with mostly mild, transient side effects.
recent figures estimating that more that more than 56,000
new HIV infections occur each year in the U.S. -- and some
2.7 million worldwide -- the need for better methods of preventing
transmission remains urgent. Over the past decade, studies
of HIV vaccines, microbicides, and other approaches have largely
produced disappointing results...but the tide has recently
started to turn.
prophylaxis, or PrEP, refers to HIV negative people taking
antiretroviral drugs in an effort to prevent infection. A
number of studies have shown that PrEP using tenofovir
(Viread) plus emtricitabine
(Emtriva) reduces the risk of new infections in non-human
iPrEx study, conducted by an international team of investigators
led by Robert Grant the Gladstone Institute of Virology and
Immunology in San Francisco and Javier Lama from Investigaciones
Medicas en Salud in Lima, Peru, was among the first to evaluate
the effectiveness of PrEP in humans; earlier studies have
shown that the approach appears safe and feasible. iPrEx was
funded by the U.S. National Institutes of Health and the Bill
and Melinda Gates Foundation, and study drugs were provided
by Gilead Sciences (Gilead had no role in designing the study
or collecting or analyzing data).
The study enrolled 2470 men who have sex with men (MSM) and
29 transgender women who have sex with men at 11 sites in
Brazil, Ecuador, Peru, South Africa, Thailand, and the U.S.
(Boston and San Francisco) between July 2007 and December
2009. All participants tested HIV negative at study entry.
They were sexually active and considered to be at high-risk
for infection; the average number of sexual partners during
the past 3 months was 18, and about 60% reported receptive
Participants were randomly assigned to receive either oral
tenofovir/emtricitabine (using the 300mg/200mg Truvada
coformulation) or placebo, both once-daily. Follow-up continued
for a median of 1.2 years, reaching a maximum of 2.8 years.
addition to their daily medication, participants also received
monthly HIV testing, risk-reduction counseling, free condoms,
and diagnosis and treatment of other sexually transmitted
diseases. During these visits they also submitted pill counts
to monitor adherence and participated in adherence counseling.
They were encouraged to maintain safer sex practices and were
told that tenofovir/emtricitabine was not yet proven to prevent
HIV infection and that they might receive the placebo.
total of 100 new HIV infections occurred during 3324 person-years
of follow-up (an additional 10 people were later determined
to have been HIV-infected at enrollment):
new infections among 1251 participants in the tenofovir/emtricitabine
infections among 1248 placebo recipients.
difference represented a 43.8% reduction in HIV incidence
(P = 0.005).
benefit of tenofovir/emtricitabine was greater among participants
who achieved better adherence:
adherence (taking pills at least half the time):
50.2% fewer new infections (P = 0.006);
adherence: 72.8% fewer infections (P = 0.001).
the tenofovir/emtricitabine arm, people with detectable
drug levels had about a 13-fold or 92% lower risk of HIV
acquisition than those with undetectable levels.
analysis of participants who became infected in the tenofovir/emtricitabine
arm found that only 3 people (9%) had detectable plasma
drug levels, and all of these individuals had below average
cellular drug levels.
was no significant difference in degree of protection
based on region, race/ethnicity, age, circumcision status,
education level, or alcohol use.
reduced their risk behavior during the study, including
using condoms more often and having fewer sex partners.
new drug-resistance mutations were detected in participants
who were newly infected during the study; however, 3 people
who were actually HIV positive at the start of the study
developed emtricitabine resistance.
was generally well-tolerated:
in the tenofovir/emtricitabine group were significantly
more likely than those in the placebo group to report
moderate nausea during the first 4 weeks of treatment
(22 vs 10 events, respectively), but this typically
resolved over time.
groups had similar rates of serious adverse events.
of participants in the tenofovir/emtricitabine group
and 1% in the placebo group experienced elevated
serum creatinine, a marker of impaired kidney function.
cases of creatinine elevation were transient, but
7 patients taking tenofovir/emtricitabine and 3
taking placebo discontinued therapy for this reason.
on these findings, the investigators concluded, "Oral
[tenofovir/emtricitabine] provided protection against the
acquisition of HIV infection among the subjects. Detectable
blood levels strongly correlated with the prophylactic effect."
"The iPrEx results are extremely important and provide
strong evidence that PrEP can reduce HIV acquisition among
a segment of society disproportionately affected by HIV/AIDS,"
said National Institute of Allergy and Infectious Diseases
Director Anthony Fauci during a media conference call on Monday.
Robert Grant, the iPrEx Protocol Chair, noted that this study
"provides the first proof that oral PrEP works in people,
and the first proof of any biomedical intervention to prevent
infection in gay and bisexual men."
Interestingly, data from the CAPRISA
004 trial, presented at this summer's International AIDS
Conference (AIDS 2010) in Vienna, showed that a vaginal gel
microbicide containing 1% tenofovir used before and after
sex lowered women's risk of HIV acquisition by 39%, offering
about the same degree of protection as daily oral tenofovir/emtricitabine.
and Grant both emphasized that the latest results come from
a single study in a specific population. While the number
of participants was large enough to show a real protective
effect -- rather than just differences due to chance -- it
is not yet known whether tenofovir/emtricitabine PrEP will
work for women, heterosexual men, or injection drug users.
Studies looking at other populations, and at intermittent
tenofovir/emtricitabine taken on a less frequent schedule
or before and after having sex, are now or soon will be underway.
study findings suggest that one commonly expressed concern
surrounding biomedical prevention -- that people who believe
they are protected will relax safer sex practices, known as
"behavioral disinhibition" or "risk compensation"
-- was not a problem, given that participants actually used
condoms more often during the study.
pills everyday, however, proved to be a challenge -- as it
is with all diseases. Participants' reported adherence (around
90% or better) was higher than that indicated by drug level
measurements. The researchers suggested that inexpensive methods
for measuring long-term drug exposure, for example hair analysis,
might be useful. In addition, Grant suggested that adherence
might be better in a real-world setting where people know
they are taking the active drug and know that it works to
reduce the risk of HIV infection.
The emergence of resistance among 3 participants who were
mistakenly identified as uninfected at study entry -- meaning
they were, in effect, treating HIV with NRTI-only dual therapy
-- underscores the importance of ensuring HIV is not already
present when starting PrEP, even if an individual has not
yet produced enough antibodies to show up on a standard screening
test. Grant noted that a majority of participants who became
infected showed non-specific symptoms of acute viral infection,
and suggested that symptomatic individuals should not start
area of concern relates to cost-effectiveness and access to
PrEP drugs, especially in resource-limited settings where
even HIV positive people who require treatment are not always
able to get the drugs they need. But Grant suggested that,
"by preventing new infections, the burden on treatment
programs will eventually decrease." It remains to be
seen whether private insurance or public benefits programs
will see fit to cover the cost or PrEP.
about at-risk individuals who might wish to start using tenofovir/emtricitabine
PrEP on an off-label basis right away, Fauci said, "I
won't recommend one way or the other to them, but they should
make sure they understand the caveats. This has been shown
in MSM, so it's one demographic group, there is a clear possibility
of long-range toxicities of the drugs, that it should not
be used in a vacuum, but should be used with other comprehensive
also said it was impossible to give a time frame for when
antiretroviral guidelines might be changed or the Food and
Drug Administration (FDA) might approve an additional PrEP
indication for tenofovir/emtricitabine.
Early community response to the study findings was generally
"Today marks a major step forward in our quest to combat
HIV among MSM and other populations," said amfAR CEO
Kevin Robert Frost. "These results suggest that PrEP
could be a very important prevention tool for gay men and
MSM when used in combination with other prevention interventions
"This discovery alters the HIV prevention landscape forever,"
concurred Jim Pickett of the AIDS Foundation of Chicago and
International Rectal Microbicide Advocates. "While this
level of efficacy is relatively strong, PrEP is not quite
ready for prime time and work remains before this strategy
is rolled out. However, we are thrilled to have a new prevention
option beyond male and female condoms visible on the horizon."
"These important results add to the evidence that antiretrovirals
can block sexual transmission of HIV," said Treatment
Action Group (TAG) Executive Director Mark Harrington. "[H]owever,
they also raise questions about the acceptability of daily
PrEP, because the data suggest that consistent daily use of
the regimen was problematic for many of the study participants."
San Francisco-based advocacy organization Project Inform issued
a statement saying the new data "represents the most
promising development in HIV/AIDS since the introduction of
triple combination drug therapy in 1996."
Nevertheless, Project Inform "strongly urges gay and
bisexual men and trans females not to attempt PrEP
on their own at this time," the statement continued.
"We stress that iPrEx data are based on taking [tenofovir/emtricitabine]
daily along with participation in behavioral counseling, condom
use, medication adherence counselling, and clinical monitoring.
There are no data whatsoever to suggest that using PrEP episodically
or around the time of sex is at all effective."
affiliations: Gladstone Institute of Virology and Immunology,
San Francisco, CA; University of California, San Francisco,
CA; HIV Research Section, San Francisco Department of Public
Health, San Francisco, CA; Investigaciones Medicas en Salud,
Lima, Peru; Asociación Civil Impacta Salud y Educación,
Lima, Peru; Asociación Civil Selva Amazónica,
Iquitos, Peru; University of Colorado, Denver, CO; Fundación
Ecuatoriana Equidad, Guayaquil, Ecuador; Instituto de Pesquisa
Clinica Evandro Chagas-Fundação Oswaldo Cruz,
Rio de Janeiro, Brazil; Projeto Praça Onze, Hospital
Escola São Francisco de Assis, Universidade Federal
do Rio de Janeiro Rio de Janeiro, Brazil; Brown University,
Providence, RI; Fenway Institute, Fenway Health, Boston, MA;
Division of Clinical Immunology and Allergy, School of Medicine,
University of São Paulo, Brazil; Instituto de Investigação
em Imunologia, São Paulo, Brazil; Research Institute
for Health Sciences, Chiang Mai University, Chiang Mai, Thailand;
Desmond Tutu HIV Centre and Department of Medicine, University
of Cape Town, South Africa; Division of AIDS, National Institute
of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD; Gilead Sciences, Foster City, CA; DF/Net
Research, Seattle, WA; Applied Health Research, Brighton,
MI; Center for Health, Intervention, and Prevention, University
of Connecticut, Storrs, CT.
Grant, JR Lama, PL Anderson, and others. Preexposure Chemoprophylaxis
for HIV Prevention in Men Who Have Sex with Men. New England
Journal of Medicine (Abstract).
November 23, 2010.
amfAR Welcomes iPrEx Study Results, Calls for Additional Research
and Demonstration Projects. Press release. November 23, 2010.
Rectal Microbicide Advocates. AIDS Drug Shown to Prevent HIV
in Multinational Trial of HIV-Negative Gay Men. Press release.
November 23, 2010.
Action Group. Pre-Exposure Prophylaxis Proves Effective in
Preventing HIV Infection. Press release. November 23, 2010.
by Project Inform on iPrEx findings. November 23, 2010. Available