In
the United States, an estimated 48,100 new human immunodeficiency virus (HIV)
infections occurred in 2009 (1). Of these, 27% were in heterosexual men and
women who did not inject drugs, and 64% were in men who have sex with men
(MSM), including 3% in MSM who inject drugs. In January 2011, following
publication of evidence of safety and efficacy of daily oral tenofovir
disoproxil fumarate 300 mg (TDF)/emtricitabine 200 mg (FTC) (Truvada, Gilead
Sciences) as antiretroviral preexposure prophylaxis (PrEP) to reduce the risk
for HIV acquisition among MSM in the iPrEx trial, CDC issued interim guidance to
make available information and important initial cautions on the use of PrEP in
this population. Those recommendations remain valid for MSM, including MSM who
also have sex with women (2). Since January 2011, data from studies of PrEP
among heterosexual men and women have become available, and on July 16, 2012,
the Food and Drug Administration (FDA) approved a label indication for
reduction of risk for sexual acquisition of HIV infection among adults,
including both heterosexuals and MSM.* This interim guidance includes
consideration of the new information and addresses pregnancy and safety issues
for heterosexually active adults at very high risk for sexual HIV acquisition
that were not discussed in the previous interim guidance for the use of PrEP in
MSM.
Data
from the four randomized, double-blind, placebo-controlled, clinical trials of
oral PrEP with TDF and FTC that have been conducted in HIV-uninfected,
heterosexually active adults were reviewed. Medical epidemiologists in the
Division of HIV/AIDS Prevention of the National Center for HIV, Viral
Hepatitis, STD, and TB Prevention at CDC developed this interim guidance.
Subject matter experts at other federal health agencies, academic researchers,
health department HIV policy stakeholders, and community representatives have
participated in working groups and consultations to inform content for
comprehensive U.S. Public Health Service (PHS) guidelines for PrEP use
currently in development; those ideas also were used in developing this interim
guidance.
Rationale
and Evidence
The
Partners PrEP trial evaluated a daily dose of a fixed-dose combination of 300
mg TDF and 200 mg FTC, and daily TDF alone (300 mg), for the HIV-uninfected
male or female partner in HIV-discordant couples (where one partner is infected
with HIV and the other is not) in Kenya and Uganda (3). The TDF2 trial
evaluated daily TDF/FTC in adult women and men in Botswana (4), the FEM-PrEP
study evaluated daily TDF/FTC in women in Kenya, South Africa, and Tanzania
(5), and the VOICE trial in women in Uganda, South Africa, and Zimbabwe
included one group to assess daily oral TDF/FTC, a second group to assess daily
oral TDF alone, and a third group to assess daily use of a 1% tenofovir vaginal
gel (6). These four trials compared HIV infection rates in participants
randomized to receive antiretroviral medication compared with rates in
participants randomized to receive placebo pills. All participants in these
four trials received regular risk-reduction counseling, condoms, medication
adherence counseling, and testing for sexually transmitted infections with
treatment as indicated (Table 1).
No
serious toxicities were identified in any of the four trials comparing
participants receiving daily oral TDF/FTC with those receiving placebo pills;
however, in the first 1–2 months on medication, nausea and vomiting were more
common in those receiving TDF/FTC than in those receiving placebo. The Partners
PrEP trial reported 75% efficacy for TDF/FTC (95% confidence interval [CI] =
55%–87%) and 67% efficacy for TDF (CI = 44%–81%), with 97% medication adherence
by returned pill count. In the trial, no statistically significant difference
in efficacy between the two regimens was observed, and efficacy was reported
for both men and women independently (Table 2). The TDF2 trial found 62%
efficacy (CI = 22%–83%) in men and women combined, with 84% medication
adherence by returned pill count. Among persons tested who were assigned to
receive TDF/FTC, the drug was detected in the blood of 81% of persons in
Partners PrEP and 81% of persons in TDF2. In Partners PrEP, within a subgroup
of persons who received TDF/FTC and had plasma drug levels tested, having
measurable TDF concentrations was associated with a 90% risk reduction compared
with placebo.
The
FEM-PrEP trial and the oral TDF portion of the VOICE trial were stopped early
by their data safety monitoring boards when they concluded that no evidence of
efficacy would be found (futility). In the FEM-PrEP trial, researchers reported
very low levels of medication adherence. Frequency of drug detection in in the
blood of FEM-PrEP participants overall was not reported but was <27% among
women who acquired HIV infection and <38% among matched uninfected controls.
No interim analysis data were provided from the VOICE trial because the trial
remains blinded, and the oral TDF/FTC and placebo study groups are continuing,
with final results anticipated in late 2013.
The
findings in this report are subject to at least three limitations. First, the
assessment of adherence by drug-level testing currently is incomplete in trials
with heterosexually active adults and is likely to provide important additional
information regarding the relationship of efficacy to medication adherence that
will need to be addressed in clinical practice. Second, women who became
pregnant during the PrEP trials described in this report were discontinued
promptly from medication, so the safety of chronic fetal exposure could not be
assessed adequately. Therefore, decisions to continue PrEP during pregnancy require
additional consideration. Both TDF and FTC have been used among HIV-infected
pregnant women to prevent perinatal transmission, have been studied for use by
discordant couples attempting conception, and have been examined in
antiretroviral treatment trials that included HIV-infected women who continued
therapy during their pregnancies. Data from these sources and the
Antiretroviral Use in Pregnancy Registry† indicate no evidence of adverse
effects among fetuses exposed to TDF or FTC (7). In addition, the higher risk
for HIV transmission to uninfected women during pregnancy (compared with
uninfected women who are not pregnant) might indicate an added value to
continuing PrEP during pregnancy (8). Finally, sexual risk behaviors and
adherence to PrEP medications among persons taking TDF/FTC for PrEP in clinical
practice, when users are made aware of trial results, might be different from
adherence by heterosexually active adults in PrEP trials who were unaware of
their assignment to active drug or placebo and could not know the impact of
adherence on efficacy.
Recommendation
for Clinicians
Daily
oral TDF/FTC use in two studies has been shown to be safe in reducing the risk
for sexual HIV acquisition by heterosexual women and men when consistently
used. In a third study with heterosexual women, PrEP was not found to be
effective, and results are pending in a fourth study. The conflicting trial
results for efficacy of TDF/FTC in heterosexual women can be partially
explained by the low medication adherence in FEM-PrEP compared with the higher
adherence in Partners PrEP and TDF2. As yet unidentified factors also might
have influenced the results.
Until
comprehensive PHS guidelines are available, CDC's January 2011 interim
recommendations should help guide the use of PrEP in MSM (2). On the basis of
the new data regarding PrEP use in heterosexually active adults, CDC now
provides the following interim guidance for clinicians considering the use of
PrEP for adults at very high risk for HIV acquisition through heterosexual sex
(e.g., those with partners known to have HIV infection): 1) TDF/FTC is
contraindicated for PrEP in persons with unknown or positive HIV status; 2) in
women and men at very high risk for acquiring HIV from penile-vaginal sex,
daily doses of TDF/FTC can be safe and effective in reducing the risk of HIV
infection; 3) PrEP use may be one of several options (9,10) to help protect the
HIV-negative partner in discordant couples during attempts to conceive; and 4)
women of reproductive age should have a documented pregnancy test before
beginning PrEP and if not pregnant at initiation, at regular intervals while
being prescribed PrEP. If women are either pregnant before initiating PrEP or
become pregnant while being prescribed PrEP, health-care providers should
discuss currently available information regarding potential risks and benefits
of continuing PrEP so that an informed decision can be made. If a woman takes
PrEP while pregnant, providers are encouraged to prospectively and anonymously
submit information about the pregnancy to the Antiretroviral Use in Pregnancy
Registry.
Health-care
providers should be aware, and should inform their patients that 1) the
efficacy of TDF/FTC for HIV prevention is highly dependent on adherence to
daily doses of medication, and 2) its long-term safety in HIV-uninfected adults
or following fetal exposure is not yet determined. Health-care providers should
report any serious adverse events resulting from prescribed TDF/FTC for PrEP to
the FDA's MedWatch.§
CDC
and other PHS agencies are developing PHS guidelines on the use of PrEP as part
of a comprehensive set of HIV prevention services that will include specific
recommendations for use with MSM and heterosexually active adults at very high
risk for HIV acquisition. The guidelines will be updated as information about
factors affecting efficacy and safety for all transmission risk groups becomes
available from additional studies.
Important
Reminders
PrEP
has the potential to contribute to safe and effective HIV prevention for
heterosexually active adults as well as MSM. CDC advises clinicians and
patients to use this interim guidance as a basis to prescribe or use PrEP for
heterosexually active patients until full PHS guidelines are available (Box).
When PrEP is used by heterosexually active adults, it is important to ensure
that 1) PrEP is targeted to persons at very high risk for HIV acquisition (11),
especially uninfected persons whose regular sexual partners are known to have
HIV infection; 2) the importance of adherence to daily medication and its
influence on efficacy is clearly discussed; 3) couples understand that although
no adverse effects have been found among infants exposed to TDF/FTC during
pregnancy and breastfeeding, these data are incomplete for women in
HIV-discordant couples using TDF/FTC to prevent acquisition of HIV; 4) PrEP is delivered
as part of a comprehensive set of prevention services, including
risk-reduction, PrEP medication adherence counseling, and ready access to
condoms; 5) sexually transmitted infection treatment is provided when indicated
by laboratory screening tests conducted at least every 6 months, and 6) PrEP is
accompanied by monitoring of HIV status, pregnancy status, side effects,
adherence, and risk behaviors at each quarterly follow-up visit.
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