What specific CDC studies are under way or
planned?
CDC is currently sponsoring three separate trials in Thailand, Botswana, and the United States, which together are designed to answer important questions about the safety and efficacy of PrEP for several of the populations now at greatest risk for infection worldwide. In all, these trials will involve
3,600 participants.
- In Thailand, CDC is conducting a trial to determine if once-daily oral
tenofovir is safe and effective in reducing HIV transmission among
injection drug users (IDUs). The trial is being conducted in
collaboration with the Bangkok Metropolitan Administration and the
Thailand Ministry of Public Health.
- In Botswana, CDC is
conducting a trial in collaboration with the Botswana Ministry of Health
to provide data on the safety and efficacy of a once-daily tenofovir
plus emtricitabine pill in reducing transmission among young
heterosexual men and women.
The Botswana research will also provide important information on the
safety of tenofovir alone in this population. Because the trial had
originally planned to study tenofovir alone (before there was evidence to
support initiating trials of tenofovir plus emtricitabine), the study had
already enrolled 71 high-risk men and women. Researchers continued to follow
these participants until the new trial was initiated to obtain data on the
safety of tenofovir alone.
- In the U.S., CDC is
evaluating the safety and tolerability of once-daily tenofovir alone
among men who have sex with men (MSM). This trial will not be large
enough to evaluate the drug’s effectiveness in reducing HIV
transmission. It is being conducted in collaboration with the San
Francisco Department of Public Health, the AIDS Research Consortium
of Atlanta, and Fenway Community Health in Boston. (Note: The
efficacy of a once-daily PrEP regimen among MSM in Peru and Ecuador
is being evaluated independently by the National Institutes of
Health.)
In addition to the three CDC-sponsored trials currently underway, CDC
will also co-manage two trial sites in Uganda as part of the University
of Washington Partners PrEP Study, which is examining the safety and
efficacy of two drug regimens—tenofovir and tenofovir plus emtracitabine—among
heterosexual couples in which one partner is infected and the other is
not.
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What other issues will the trials examine?
CDC trials are also designed to address several issues that will be
critical to the design of future studies, as well as HIV prevention and
treatment programs.
Impact on behavior: Understanding the potential impact of use of a
daily preventive drug on HIV risk behaviors will be critical should any PrEP
drug prove effective in reducing HIV transmission. One of the greatest
risks, as efforts progress to identify new biomedical prevention approaches,
is that persons at risk for HIV infection will reduce their use of proven
behavioral prevention strategies. Because no single prevention strategy will
be 100% effective against HIV transmission, reducing transmission will
require determining how best to integrate all available prevention
strategies—both biomedical and behavioral. During the trials, all
participants will receive state-of-the-art HIV risk-reduction counseling and
other proven HIV prevention interventions.
Adherence and
acceptability: Even if these trials demonstrate that PrEP can reduce HIV
transmission, it is critical to understand whether persons at risk will be
willing and able to maintain consistent use of a daily drug. These trials
will therefore closely examine participants’ adherence to, and acceptance
of, daily oral preventive drug use.
Resistance: A key question about resistance will be addressed during
the trials. Although resistance to tenofovir is uncommon among HIV-infected
persons when used in combination with other drugs, it is unclear how often
resistance may develop if prophylaxis fails and persons become infected
while taking tenofovir alone. Similarly, while the risk of drug-resistant
virus will likely be lower in the tenofovir plus emtricitabine trial, due to
the presence of two drugs, it will be important to assess any resistance to
either drug that emerges.
Several study procedures have been designed to minimize the risk of
resistance among any individuals who become infected despite receiving PrEP.
Regular HIV testing with a rapid HIV test and immediate discontinuation of
study pills if participants become infected will result in a very low risk
of resistant virus emerging. Additionally, HIV resistance testing will be
provided to all persons infected during the trial. These data will provide
important information on the degree to which resistance occurs and will help
guide treatment decisions as infected persons are referred to treatment and
care.
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When did the
trials begin and how are they designed?
The Thailand and U.S. trials of tenofovir began in 2005 and the Botswana
trial of tenofovir plus emtricitabine began in early 2007. All three trials
are randomized, doubleblind, placebo-controlled trials. In each trial, all
participants receive risk-reduction counseling and other prevention
services, including condoms. In addition, half of the participants are
assigned by chance to receive one antiretroviral pill daily (either
tenofovir alone or tenofovir plus emtricitabine, depending on the trial
site), and the other half are assigned by chance to take one daily placebo
pill (a similar pill without active medication). Neither researchers nor
participants know a participant’s group assignment. This design allows the
researchers to determine in a scientifically valid way whether the risks for
side effects and HIV infection are different for persons taking the study
drug versus persons taking the placebo.
Botswana and Thailand
The trials in Botswana and Thailand are safety and efficacy trials. The
Botswana trial is examining the safety and efficacy of tenofovir plus
emtricitabine, and the Thailand trial is examining the safety and efficacy
of tenofovir.
Botswana: The Botswana trial is being conducted in
collaboration with the Botswana government and is enrolling 1,200
HIV-negative heterosexual men and women, aged 18–39, in the nation’s two
largest cities, Gaborone and Francistown. Participants are being recruited
at a number of venues, including HIV voluntary counseling and testing
centers, sexually transmitted disease and family planning clinics, youth
organizations, and community events.
Thailand: The Thailand trial is being conducted in
collaboration with the Bangkok Metropolitan Administration and the Thailand
Ministry of Public Health and is enrolling 2,400 HIV-negative injection drug
users (IDUs) at 17 drug-treatment clinics in Bangkok. Participants are being
recruited at the drug treatment clinics, at community outreach sites, and
through a peer referral program.
United States
The U.S. trial is designed to assess the clinical and behavioral safety
of once-daily tenofovir among HIV-negative men who have sex with men (MSM).
The trial is being conducted at three sites in collaboration with the San
Francisco Department of Public Health, the AIDS Research Consortium of
Atlanta, and Fenway Community Health in Boston. A variety of previously
successful recruitment techniques, including outreach and referrals through
clinician and community-based service organizations, were used to enroll 400
HIV-negative MSM who reported having had anal intercourse during the prior
12 months. To reflect the demographics of the U.S. HIV epidemic, a
substantial proportion of participants will be MSM of color.
Participants are randomly assigned to one of four study groups. Two
groups receive either tenofovir or placebo immediately; the other two groups
receive either tenofovir or placebo 9 months after enrollment. This design
allows researchers to compare risk behaviors among persons who are and
persons who are not taking a daily pill. This analysis is critical to
understanding the potential impact of a daily drug regimen on HIV
risk behavior.
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Why have these
populations been selected to take part in the trials?
It is critical to evaluate new prevention methods among the populations
who most urgently need them. These and other studies of PrEP will determine
if the strategy is safe and effective in reducing transmission among
individuals at highest risk for HIV infection around the world.
Botswana has one of the most widespread HIV epidemics in the world: an
estimated 24 percent of the population 15–49 years of age is infected.
Despite the fact that recent data suggest that new infections are
stabilizing among young heterosexual men and women, it is estimated that 26
percent of women aged 20-24 are infected with HIV and that 41 percent of
those aged 25–29 are infected. Among men, 9 percent of men aged 20–24 and 23
percent of men aged 25–29 are believed to be HIV infected. These data
suggest very high incidence among young men and women.
In Thailand, HIV prevalence is high among injection drug users (IDUs): an
estimated 40 percent of IDUs are already infected. As a result of the
extensive risk reduction counseling and other prevention services provided,
HIV incidence among IDUs participating in research trials in the Bangkok
drug treatment clinics has declined by over 50% since 1996. Still, a recent
study found that HIV incidence among Thai IDUs was over 3% per year. Given
estimates of the number of IDUs in Bangkok, this means that approximately
750 men and women in the city become infected through this transmission
route every year.
In the United States, MSM continue to be at the greatest risk for HIV
infection. Recent data from the 33 states with long-standing HIV reporting
systems indicate that in 2006, MSM accounted for 50 percent of new HIV
diagnoses. Of the roughly one million people living with HIV in the U.S., an
estimated 45% are MSM. Additionally, a five-city CDC study of HIV prevalence
among MSM found that 25% of MSM overall, and 46% of black MSM, were infected
in those cities.
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Who is eligible to participate in the PrEP trials?
Because the trials are designed to determine the safety and efficacy of
PrEP as an HIV prevention strategy, all participants will be healthy and
HIV-negative. To protect the health of participants and ensure that trial
data are accurate, several conditions would render some persons ineligible
for participation. These include the ongoing use of prescription medication,
pregnancy or breast feeding, a history of kidney or bone disease, and
participation in any other HIV clinical trial. Additional conditions,
including active, untreated syphilis, hypertension, and alcohol or substance
use, may also prevent some MSM from participating in the U.S. trial.
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What is the University of Washington Partners PrEP
Study and how is CDC involved?
The University of Washington is working with collaborators in Kenya
and Uganda to conduct the Partners PrEP Study, which is examining
the safety and efficacy of two different PrEP regimens —once-daily
tenofovir and once-daily tenofovir plus emtricitabine—among
heterosexual couples. CDC will co-manage two trial sites in Uganda,
in conjunction with The AIDS Support Organization (TASO), the
largest indigenous non-governmental organization providing HIV care
in Uganda.
This randomized, double-blind, placebo-controlled study will operate at
eight trial sites in Kenya and Uganda and include 3,900 serodiscordant
couples (couples in which one person is HIV-infected and the other is not).
Stable serodiscordant couples are the largest risk group for HIV infection
in Africa, and this trial will provide important data on whether PrEP could
be used to prevent new HIV infections among this population. HIV-uninfected
partners will be assigned to three groups: one group will receive tenofovir,
a second group will receive tenofovir plus emtracitabine, and the third
group will receive a placebo. All participants will receive ongoing risk
reduction counseling and HIV testing, and volunteers’ safety will be
monitored by the study’s independent data and safety monitoring board (DSMB)
and local institutional review boards, or IRBs. HIV-infected members of the
discordant couples will receive ongoing HIV care.
The trial is the first to test the safety and efficacy of both tenofovir
and tenofovir plus emtricitabine in the same population and will allow
investigators to simultaneously evaluate the two drugs as candidates for use
as PrEP.
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Are similar trials being conducted
else where?
Yes. In 2006, Family Health International, with funding from the
Bill and Melinda Gates Foundation, completed a similar trial of
tenofovir for HIV prevention among young women in Ghana. The study
provided the first data showing PrEP with tenofovir to be both safe
and acceptable for use by HIV negative individuals, but did not
indicate if it was effective in preventing new infections.
The National Institutes of Health (NIH) is currently evaluating the
safety and efficacy of PrEP among MSM in Peru, Ecuador, South Africa and the
U.S. and plans to expand its trial to additional countries. Additional
trials investigating PrEP among women in Africa are scheduled to be launched
by FHI and the Microbicide Trials Network (MTN) within the next year.
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Why are there so many different trials currently
ongoing?
A PrEP regimen that is proven effective in reducing HIV transmission in
one population may not necessarily work in other at-risk populations.
Because of this, CDC and other researchers are conducting trials in
population groups representing multiple routes of HIV transmission,
including heterosexuals, MSM, and IDUs. These trials will help inform the
development of public health guidance for different populations.
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What
is the cost of the CDC studies of PrEP?
CDC estimates that its total contribution for the CDC-sponsored PrEP
trials will be $53 million over 7 years. For the Botswana trial, CDC will
provide approximately $26 million in support. In Thailand, CDC’s
contribution is estimated to be $16 million, and in the United States, CDC
will provide $11 million in support of the three institutions conducting the
trial.
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