You are on page 1of 10

AIDS PATIENT CARE and STDs CLINICAL AND EPIDEMIOLOGIC RESEARCH

Volume 25, Number 2, 2011


ª Mary Ann Liebert, Inc.
DOI: 10.1089/apc.2010.0222

Oral Preexposure Anti-HIV Prophylaxis for High-Risk U.S.


Populations: Current Considerations in Light of New Findings

Gavin M. Myers, M.A.,1 and Kenneth H. Mayer, M.D.1–3

Abstract

This article reviews the status of current research evaluating oral preexposure prophylaxis (PrEP) for prevention
of HIV infection in high-risk populations. In animal model studies, the use of antiretrovirals has been shown to
be effective in preventing HIV acquisition. Early-phase PrEP studies have established safety in humans. Cur-
rently, more than 20,000 men and women will soon be enrolled in studies of oral or topical chemoprophylaxis,
testing a variety of drug delivery methods including tenofovir disoproxil fumarate (TDF) gel applied vaginally
or rectally, as well as oral PrEP using TDF by itself or coformulated with emtricitabine (FTC). The largest global
PrEP trial in men who have sex with men (MSM), known as iPrEx has demonstrated that oral chemoprophylaxis
can decrease HIV incidence in this population. Although TDF/FTC PrEP was generally well tolerated, side
effects such as nausea, as well as mild and reversible renal abnormalities were increased among the men who
received active medication, suggesting that PrEP users will need ongoing PrEP clinical monitoring. The pro-
phylactic benefits of TDF/FTC were substantially attenuated by nonadherence, indicating that effective PrEP
implementation programs will need to focus on this behavioral variable, in addition to safer sex counseling. This
article considers biological, policy, and practical implications of large-scale oral PrEP implementation.

Introduction non-HIV sexually transmitted diseases to decrease HIV


spread.6–9 Because of the improved tolerability, ease of ad-

H IV remains one of the world’s most challenging public


health concerns.1 In the United States, there are more
than 56,000 new cases of HIV diagnosed annually with the
ministration (due to coformulation of multiple agents), im-
proved efficacy of highly active antiretroviral therapy
(HAART) in humans, as well as animal model data, clinical
largest number of new infections (53%) being diagnosed researchers began to explore other HIV prevention strategies
among men who have sex with men (MSM).2 Social, cultural, focusing on the use of antiretroviral drugs for prevention,
and psychiatric stressors ranging from internalized homo- including pre-exposure prophylaxis (PrEP).10,11 PrEP has
phobia leading to depression, as well as substance use, can been used in other contexts, e.g., it is currently used in the
lead to failure to use condoms consistently and nonadherence prevention of malaria for those traveling to nations where the
to other prevention strategies, resulting in HIV transmis- organisms are endemic.12 In theory, PrEP for HIV prevention
sion.3–5 Although condoms are effective in preventing HIV can refer to either antiretroviral-based vaginal or rectal gels or
transmission if consistently used, after almost three decades of oral medication; the gels are often called ‘‘microbicides,’’ and
continued HIV transmission, it is evident that access to in- the pills are often called ‘‘PrEP.’’ The goal of both approaches
formation and condoms alone has not been sufficient to cause is the prevention of disease transmission.10
consistent decreases in HIV incidence in most parts of the Clinical trials of PrEP in humans have thus far studied
world. antiretrovirals (ARVs) usually used to treat HIV, principally
Unfortunately, until recently, a range of biomedical HIV either tenofovir disoproxil fumarate (TDF) administered
prevention prevention approaches have not been successful, orally alone or with emtricitabine (FTC), or tenofovir gel
including vaccines, nonspecific topical microbicides (those (TFV). The focus of this review is the issues raised by oral PrEP
not containing an antiretroviral agent) and the treatment of (non-gel–based interventions), given the recent publication of

1
Alpert Medical School of Brown University, Department of Community Health, Providence, Rhode Island.
2
The Miriam Hospital, Providence, Rhode Island.
3
Fenway Institute, Boston, Massachusetts.

63
64 MYERS AND MAYER

the first-in-humans efficacy data emanating from the iPrEx sure (i.e., PEP) also showed a 3.9 risk reduction relative to
study given that these drugs are already FDA-approved, and placebo.18 In animals that received one dose 2 h after expo-
thus could soon be widely available for chemoprophy- sure and another dose 26 h after exposure risk reduction was
laxis.13–18 Oral PrEP could involve the use of antiretroviral 3.8-fold; 3 of 6 animals remained protected after 14 weekly
drugs taken either continuously by high-risk persons or in- challenges.18
termittently (before and after a high-risk sex episode).10 Another clinical model that shows the power of ARVs in
preventing HIV transmission comes from a variety of mother-
to-child SHIV transmission studies that show reduced rates of
Biological Rationale Behind PrEP
HIV transmission to babies from mothers who took ARVs,
The idea of PrEP as a viable prevention measure is based on such as AZT and 3TC for 36 weeks prior to giving birth and
both animal models and clinical studies in humans showing for a week after birth; other studies with different time se-
the effectiveness of postexposure prophylaxis (PEP).11 Both quences have also shown prevention benefits.22 Another
PEP and PrEP are intended to prevent HIV infection from study in which two doses of TDF were given 4 h before and
establishing infection when a host is exposed, but one ap- 24 h after oral inoculations protected newborn macaques
proach presumes that exposure is infrequent and unpredict- against SIV.23 Finally, in another study in which the dose of
able (PEP), while the other anticipates that the PrEP user may PMPA was reduced by 5-fold to 4 mg/kg of body weight,
have regular exposures to HIV.19 The biological principle partial protection against SHIV was maintained, under-
behind PrEP is that by limiting the size of the ‘‘founder pop- scoring the possible effects of ARVs in preventing HIV
ulation’’ of free virions or infected cells, infection cannot be transmission.24
established. It is thought that antiretroviral drugs block the
establishment of this critical founder population by blocking
Drug Candidates for PrEP:
viral replication and allowing innate host immune responses
Are There Alternatives to TDF/FTC?
to remove the small inoculum.19
Several drugs, including TDF are highly potent inhibitors For a variety of reasons, TDF/FTC is considered a prime
of HIV-1 reverse transcriptase and have the ability to termi- candidate for PrEP. The nucleoside reverse transcriptase in-
nate the growing DNA viral chain by inhibiting reverse hibitors (NRTIs) have been an ARV class of choice for PrEP,
transcriptase.20 Early studies in macaques using a simian because they work early in the HIV life cycle, prior to HIV’s
immunodeficiency (SIV) model with PMPA (a congener of DNA integration into the cell’s genome, and they have been
TDF, which is formulated to enhanced oral bioavailability) used for HIV treatment for more than two decades. Gallant
and zidovudine (AZT) have shown the efficacy of PEP if et al. 25 found the TDF/FTC component of a HAART regimen
dosed daily and continued for 28 days.14 Although this study more tolerable than AZT/3TC. Protease inhibitors (PIs) work
provided robust initial evidence for the efficacy of PEP, other postviral integration and therefore are not thought to be
animal studies have shown less encouraging results. Tsai suitable to prevent transmission.26 Moreover, many PIs have
et al.15 found that treatment was not effective if initiated 48 or undesirable side effects including hyperlidipedmia, nausea,
72 h after an exposure and was not effective if continued for and gastrointestinal discomfort.27 TDF and FTC are syner-
just 3–10 days. Another study, which combined AZT, gistic in their antiretroviral activity, and the transmission or
lamivudine (3TC), and indinavir (IDV) initiated 4 h after development of resistance to both drugs is much less likely
challenge with SHIV and continued for 28 days failed to pro- than if a single drug would be used for prophylaxis. Specifi-
tect the animals.16 cally, TDF/FTC has a low rate of side effects relative to pla-
More recent studies with macaques have tested the ad- cebo, resulting in lower likelihood of inadvertent unblinding
ministration of PrEP in different animal models. Van Rompay in clinical trials.19,28 A Family Health International study
et al.21 found that oral TDF reduced the risk of contracting (FHI) found that among 859 high-risk African women, there
SHIV via an oral route, which simulates breast-feeding. were no increased adverse events among participants re-
Subbaro et al.17 using repeated low-dose atraumatic rectal ceiving daily TDF compared to placebo.10
challenges found that while TDF resulted in a 60% decrease in TDF has a longer half-life in serum (17 h) and in cells (60 h)
per-exposure probability of being infected with SHIV, neither relative to other nucleoside analogues, suggesting the drug
weekly nor daily PrEP ultimately prevented the animals from could be useful in patients who may miss an occasional
becoming infected. The researchers noted this could have dose.26 TDF/FTC also reaches high concentrations in cells in
been due to the relatively high inoculum used in these rectal the genital secretions and tissue, suggesting it could be a
challenges (approximately 5 times that found in human se- particularly effective in preventing HIV transmission.29,30
men).17 Moreover, these studies did not combine TDF with Other agents such as stavudine, abacavir, and efavirenz
FTC, which from a theoretical standpoint could be a more achieve such low concentrations in the genital tract that they
convincing model for HIV prevention, since two drugs are are thought to be suboptimal candidates in a PrEP regi-
used. Garcia-Lerma et al.18 administered TDF/FTC to four men.29,30 Moreover, the side effects that can occur with these
separate groups of macaques based on different dosing times drugs make them undesirable PrEP candidates.32,33 Despite
and compared them to groups receiving a placebo and de- TDF/FTC’s attractiveness as an agent for PrEP, there are some
termined that intermittent dosing of TDF/FTC could be suc- theoretical concerns. Both drugs can have serious side effects
cessful in HIV prevention. That study showed a 15.9-fold in less than 1% of patients; these can include but are not
reduction of HIV infection transmission in the group of ani- limited to acute renal failure, Fanconi’s syndrome, decreases
mals receiving a dose of TDF/FTC 22 h before and a second in bone mineral density, and extremely rarely, lactic acido-
dose 2 h after exposure, but interestingly, even animals sis.33 More significantly, if an individual becomes infected
that received TDF/FTC just 2 h before and 22 h after expo- with HIV during administration of TDF/FTC as PrEP and
ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS 65

does not routinely get retested to detect new HIV infection as As new agents demonstrate fewer side effects, more op-
early as possible, their strain of HIV could become resistant to tions develop for use in PrEP. A recent study investigated the
one or both drugs, which could remove these first-line drugs use of raltegravir (RAL), an integrase inhibitor, in conjunction
as part of a HAART regimen.33 One other concern about the with TDF/FTC for PEP among gay and bisexual men in
use of TDF and FTC for PrEP is that they each have activity Boston, due to its potentially reduced side effect profile rela-
against hepatitis B, so that intermittent PrEP use or erratic tive to PIs.41 The combination was well tolerated, with 97.4%
adherence could result in the development of drug resistance of the 39 men completing the 4-week course, suggesting that
in hepatitis B-infected individuals, and potential flares of RAL could be an option for PrEP if combined with other an-
virologic activity following PrEP discontinuation. Thus, all tiretroviral agents.41 Because PrEP is a preventive measure
PrEP candidates should be screened for hepatitis B prior and is likely to be used in high-risk populations, it seems
to the initiation of TDF/FTC PrEP. Seronegative patients unlikely that regimens that require more than one pill daily
should receive hepatitis B vaccination prior to PrEP use, and would be practical or feasible, so coformulation of future
those with chronic hepatitis B should be educated about PrEP regimens will be highly desirable.
the potential impact of suboptimal adherence on their liver When looking outside the realm of oral PrEP, another
infection. possible agent that could be tested for PrEP is ibalizumab
Another agent that is particularly attractive for PrEP is (TNX-355), a drug in phase II clinical trials for therapeutic
maraviroc (MVC), a novel antagonist of the CCR5 coreceptor indications.42 This type of agent could be a unique prototype
that HIV usually binds when infecting susceptible mononu- of drug for PrEP if found to be safe and effective. This in-
clear cells. MVC is FDA-approved for use in the treatment of vestigational product is a humanized IgG4 monoclonal anti-
HIV in combination with other antiretrovirals. Dumond body administered via intravenous infusion and is being
et al.34 found that MVC maintains high concentrations in tested at either 800 mg every 2 weeks or 2000 mg every 4
cervicovaginal tissue (CVF) and vaginal tissue (VT) in weeks.44 While intravenous administration could be a barrier
HIV-uninfected women. Because MVC works to prevent the to access, it could provide a broader range of protection
earliest point of the HIV life cycle—mononuclear cellular against various HIV tropic strains, theoretically preventing
binding—it remains an attractive candidate for PrEP since viral HIV from binding both CCR5 and CXCR4. Moreover, since
entry could be halted at the earliest stage of HIV infection. the drug can be administered relatively infrequently, it could
While there may be some theoretical concerns about preven- be ideally suited for individuals who would be less compliant
tion against HIV strains that could bind other co-receptors with a daily pill. Since this injection is not a vaccine, like oral
(dual-tropic virus or CXCR4 virus), the vast majority of new PrEP, the drug would have to be taken for as long as indi-
viral infections preferentially binds CCR5.35,36 The theoretical viduals engage in risk-taking behaviors.
concern is that in rare cases if MVC prophylaxis fails, people
who become infected with viruses that preferentially use the
Current State of Topical and Oral PrEP:
CXCR4 receptor have been shown to progress more rapidly
Ongoing Clinical Trials
through CD4 lymphocyte depletion.37–39 While MVC will not
protect against these viruses, if other antiretrovirals are com- There are currently several trials being conducted test-
bined with MVC this approach would theoretically prevent ing oral and topical chemoprophylaxis around the world
these resistant HIV strains. The safety of long-term MVC ad- (Table 1). The first study in the general field of PrEP with
ministration will need to be substantiated before this drug positive results, CAPRISA 004, studied the use of pericoital
could be considered as a possible first-line PrEP regimen. tenofovir gel, which was recently found to be efficacious in
Major questions about the role of MVC for chemoprophy- protecting high-risk South African women against HIV
laxis include: whether it would be advisable to give the drug infection, with an overall protective effect of 39%, which
by itself, or to avoid the development of resistance, would it was greater than 50% among women who were highly
make sense to try to coformulate with other antiretroviral adherent to the regimen (i.e., use of the product for more
drugs that work via a different mechanism. Future PrEP than 50% of sexual exposures).44 These data were the first
regimens could include combinations of FTC or 3TC, or TDF to suggest that antiretroviral chemoprophylaxis is feasible,
alone, or coformulated TDF/FTC plus MVC, or MVC with so over the next few years, the major questions will be
FTC or 3TC. However, because these agents are manu- which mode of antiretroviral drug delivery (e.g., oral
factured and patented by different companies, legal issues, versus mucosal, vaginal versus rectal) may be most effec-
including patent and intellectual property concerns may serve tive for each population.
as roadblocks to these drugs from becoming part of a once- Among trials of oral PrEP, CDC 4323 evaluated the clinical
daily PrEP regimen. However, with the demonstrated effi- safety and potential for behavioral disinhibition of TDF for
cacy of many ARVs combined into one pill (Truvada and PrEP among HIV-uninfected MSM in the United States. The
Atripla, Gilead Sciences, Foster City, CA; Combivir, first data from this trial were presented at the recent Inter-
GlaxoSmithKline: London, UK) for HIV treatment, combina- national AIDS Conference in Vienna and TDF was found to be
tions of MVC and other antiretrovirals may be feasible and safe and well tolerated in the 400 MSM participants, with no
desirable. Support for a strategy of using multiple drugs for increase in nephrotoxicity, other safety laboratory tests, nor
chemoprophylaxis comes from clinical experience, in which any evidence of increased behavioral risk taking among the
during high-risk exposures with known HIV-infected sour- men.45 Although the study was not powered to demonstrate
ces, exposed persons are often placed on not only an NRTI efficacy, none of the men assigned to take tenofovir became
backbone such as TDF/FTC, but also a boosted-PI in order to infected in the study. CDC 4370 is testing the safety and ef-
insure viral replication is adequately suppressed during a PEP ficacy of once-daily oral TDF to prevent HIV infection in in-
regimen.40 travenous drug users in Thailand.
Table 1. Global State of Oral PrEP Clinical Trials

Study name Trial type and phase Location Population Intervention arms(s) Funding source Study status

US Extended Safety Phase II, safety United States 400 MSM (penile-rectal) Daily oral TDF CDC Completed Quarter
Trial (CDC 4323) 3/2010
Bankok Tenofovir Phase II/III, safety Thailand 2400 IDU (parenteral) Daily oral TDF CDC Enrolling Quarter
Study (CDC 4370) and efficacy 4/2010
iPrEx Phase III, safety Brazil, Ecuador, 2499 MSM (penile-rectal) Daily oral TDF/FTC NIH, BMGF Fully enrolled/Quarter
and efficacy Peru, South Africa, 4 2010
Thailand,
United States
TDF2 (CDC 4940) Phase II, safety Botswana 1200 heterosexual men Daily oral TDF/FTC CDC Fully enrolled/Quarter
and adherence and women 4 2010
(penile-vaginal)
Partners PrEP Phase III, safety Kenya, Uganda 4700 serodiscordant Daily oral TDF; daily BMGF Enrolling/2012
and efficacy heterosexual couples oral TDF/FTC
(penile-vaginal)

66
FEM-PrEP Phase III, safety Kenya, Malawi, 3900 heterosexual Daily oral TDF/FTC FHI, USAID, Enrolling/2013
and effectiveness South Africa, women (vagina) BMGF
Tanzania, Zambia
VOICE (MTN 003) Phase IIb, safety Malawi, South Africa, 5000 heterosexual women Daily oral TDF; daily oral MTN, NIH Enrolling/2013
and effectiveness Uganda, Zambia, (vaginal) TDF/FTC; daily topical
Zimbabwe tenofovir gel
IAVI E001 &E002 Phase I/II, safety, Kenya, Uganda 150 serodiscordant couples Daily oral TDF/FTC; IAVI Fully enrolled/Quarter
acceptability, and men and women intermittent 4 2010
adherence (vaginal and penile-rectal) oral TDF/FTC (twice
weeklyþcoital dosing)
PrEP in YMSM Phase II, safety, United States 99 YMSM (penile-rectal) Daily oral TDF/FTC ATN, NICHD Enrolling/2011
(ATN 082) acceptability,
feasibility

PrEP, preexposure prophylaxis; ATN, Adolescent Trial Foundation; BMGF, Bill and Melinda Gates Foundation; CAPRISA, Centre for the AIDS Programme of Research in South Africa; CDC, US
Centers for Disease Control and Prevention; FHI, Family Health International; IAVI, International AIDS Vaccine Initiative; MTN, Microbicide Trials Network; NICHD, National Institute of Child Health
and Human Development; NIH, National Institutes of Health; USAID, United States Agency for International Development; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine.
Source: AVAC, Global Advocacy for HIV Prevention.
ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS 67

The iPrEx study was an efficacy trial that demonstrated the pill would work. The response of MSM in a world where
that once-daily TDF/FTC decreased the likelihood of HIV PrEP would be shown to be highly protective could be very
infection by 44% among 2499 high-risk MSM recruited in different. Moreover, it is certainly feasible that if PrEP efficacy
Brazil, Ecuador, Peru, South Africa, Thailand, and the United is not 100%, that a certain level of risk compensation could
States.13 Among men with greater levels of adherence, the undermine PrEP’s benefit. For example, if PrEP use in a
protective effect was much greater: based on self-report and community sample of MSM decreased the likelihood of
pill counts, men who took at least 90% of the regimen had a transmission by 45% (similar to the change seen in iPrEx) and
greater than 70% level of protection, and when drug levels individuals who felt protected increased their risk taking by
were examined, men who had detectable TDF or FTC in their 75%, then a paradoxical increase in new infections could re-
plasma or blood leukocytes experienced a greater than 90% sult. On the other hand, if PrEP plus intensive adherence
protective effect. Although the regimen was generally well counseling produces a much higher ‘‘real world’’ efficacy, it is
tolerated, and adherence levels in the active arm were com- unlikely that the level of risk compensation could result in an
parable to placebo, men taking TDF/FTC were more likely to increase HIV incidence, but suboptimal adherence could
report mild nausea and experience weight loss in the first few further erode protective benefits. Researchers will need to
weeks, and had a trend towards reversible changes in renal study PrEP’s long-term impact on behavior among high-risk
function. All of these findings were infrequent (occurring in populations if initial trials suggest efficacy, if this is going to
2% or fewer of the participants) and were either self-limited or be a successful intervention. If approved by the FDA for use in
responded to holding medication but underscore the impor- high-risk subgroups of the population, public health mes-
tance of ongoing clinical monitoring of individuals who are sages at the community level will need to be carefully de-
using TDF/FTC for PrEP. signed to prevent PrEP’s clinical effectiveness as being
PrEP is continuing to be studied in other at-risk popula- ‘‘overstated.’’ Therefore, it must be emphasized in public
tions. Among the larger global studies, the Partners PrEP health campaigns that the use of PrEP may be most appro-
study in Kenya and Uganda seeks to test TDF/FTC compared priate for the highest risk groups (individuals unwilling or
to TDF or placebo among 3900 serodiscordant couples. The unable to use condoms). Although PrEP is being tested in
FEMPrEP study will enroll 3900 high-risk women in South clinical trials as a once-daily regimen, intermittent PrEP use
Africa, Kenya, Malawi, and Tanzania using once-daily TDF/ may be possible since in a recent animal-model study, Garcia-
FTC.46 The VOICE study is testing daily oral TDF, daily oral Lerma et al.18 found that intermittent dosing was effective at
TDF/FTC, and daily topical TFV gel among 5000 heterosex- HIV prevention.
ual women and will be the first study to demonstrate whether Currently, while PrEP is not well known to many high-risk
oral or topical PrEP is more protective in a specific high-risk MSM, in one study, many men who were asked about PrEP
population. PCS 082, funded by NICHD and being conducted expressed interest in its use, although almost none had ever
in the Adolescent Trials Network, is novel in that it is testing used it.50 In another study, while 47% of men reported PEP
daily oral TDF/FTC among 99 high-risk young men who awareness, only 16% reported PrEP awareness and less than
have sex with men (YMSM). Finally, intermittent dosing of 1% of men had used PrEP, and two thirds of these men said
PrEP with TDF/FTC is being tested in the IAVI E001 and E002 they would be willing to take a daily PrEP regimen if it proved
studies in Kenya and Uganda among 150 serodiscordant safe and effective against HIV-1 transmission.51
couples and at-risk men and women.47 Other intermittent While Mimiaga et al.50 found that only 19% of men in a
PrEP studies are being planned by the HIV Prevention Trials cohort of MSM in Boston had heard of PrEP, 74% of men
Network (www.hptn.org) to assess optimal pharmacology indicated an interest in using PrEP, especially if it was given at
and acceptability of coitally dependent versus fixed interval no cost and associated with a low incidence of side effects.
dosing of PrEP.47 Interestingly, intent-to-use PrEP in the future was associated
with less education and moderate income, suggesting that
public health PrEP programs may need to develop materials
If PrEP Works: Will Risk-Taking Increase?
tailored to less educated individuals and will need to antici-
Because PrEP is not expected to be 100% effective against pate the costs of program implementation if access for at-risk
HIV-1 transmission even with optimal utilization, public persons is to be ensured.50
policy must determine how to best implement access for At present, there is no consensus about what would con-
specific high-risk groups. Concerns have been raised as to stitute appropriate provision of PrEP at the population level.
whether PrEP could result in increased risky sexual practices The Centers for Disease Control and Prevention (CDC) and
through behavioral disinhibition, also known as risk com- the World Health Organization (WHO) are actively engaging
pensation. It is theoretically possible that individuals may feel stakeholders in discussions as to which individuals are at
‘‘biologically protected’’ and decide to abandon condom use, highest risk and therefore would benefit the most from PrEP.
underscoring the importance of implementing behavioral Policy directives will only become available once firm PrEP
modification and encouraging continued condom use if PrEP efficacy data become available, which will take several years
is to be a successful public health intervention. Several studies before the results of all currently active trials are known.
suggest that the provision of PEP does not increase high-risk Policy recommendations will invariably be tempered by
behavior.13,48,49 TDF/FTC’s high cost in the developed world. The cost of the
The recent data from the CDC MSM and the iPrEx studies drugs alone in the United States is estimated to be more than
provide evidence that risk compensation is not inevitable. But $10,000 per year, and medical monitoring would add to the
the results must be interpreted with caution, since all partic- costs.52 Paltiel et al.52 suggested PrEP may be cost effective in
ipants signed an informed consent telling them they had a 50- young, high-risk MSM populations based on a mathematical
50 chance of receiving a placebo and that it was not known if analysis conservatively assuming the intervention resulted in
68 MYERS AND MAYER

a 50% reduction in HIV incidence. It is unclear whether pri- less risk for contracting HIV. The intervention could be useful
vate insurers would pay for once-daily PrEP for individuals in homosexual, as well as heterosexual serodiscordant cou-
self-identifying as high-risk MSM. If the CDC recommended ples where intimacy prevents both members from wanting to
widespread PrEP use, it is also unknown the extent to which use condoms on a regular basis.
primary care or infectious disease specialists would be willing Because substance abuse is a major risk factor for HIV ac-
to prescribe TDF/FTC to their patients. No data exist to de- quisition through increased sexual risk-taking behavior, PrEP
scribe current provider attitudes or experience regarding programs will need to be tailored for those who regularly
prescribing antiretrovirals for prevention, which will pre- abuse substances such as alcohol and illegal drugs, and may
sumably require medical follow-up including HIV testing, require a focus on enhancing adherence.58–62 The feasibility of
screening for sexually transmitted infections (STIs), and PrEP as an intervention will also need to be culturally adapted
standardized monitoring of liver and kidney function. for use by African American MSM, where HIV incidence
More research must be done to survey physicians to de- rates are among the highest with more than 10,000 annual
termine their knowledge, comfort level, and current pre- cases (35% of the total), despite the fact African Americans
scribing habits of PrEP. It seems that PrEP would be most cost represent only 13% of the U.S. population.63,64 Several studies
effective if intermittent PrEP proves equally efficacious to have shown that black MSM have significantly higher HIV
once-daily PrEP. Over time, if FTC/TDF becomes available as prevalence and incidence rates than MSM of all other races
generic medication, it may be available at a more affordable and ethnic backgrounds.63–68 Because of alienation from the
cost to all parties involved.53 health care system, stemming from perceptions of institu-
tionalized racism (e.g., the Tuskegee syphilis experiment),
PrEP and Antiretroviral Drug Resistance: PrEP education for black MSM may need to address under-
Is it a Concern? lying mistrust of the medical care system in the United States.
The feasibility of PrEP as a means to lower HIV transmis-
If widespread PrEP use becomes common, concerns about
sion in this population therefore must be systematically
drug resistance become more prominent. At present, the K65R
evaluated because it could face unique challenges. Among
mutation that confers TDF resistance is not common, so the
black MSM, many men do not identify as gay or bisexual or
majority of individuals exposed to HIV-infected partners
disclose their sexual behavior to others.69 Even so, the pro-
would not be likely to develop primary infection with a resis-
vision of PrEP to non-gay identifying black MSM may present
tant strain.54 However, in one cell culture study evaluating time
unique cultural challenges, since in one study 66.7% of black
to development of TDF resistance, the K65R mutation was
MSM identified as either straight or bisexual.70 PrEP inter-
shown to emerge faster among HIV-1 subtype C.55 Thus,
ventions that do not implicate gay identity, therefore, may be
caution in the use of TDF for PrEP could be considered in areas
crucial to effectively reach this population. Experiences such
with endemic HIV-1 subtype C, i.e., many parts of Africa, as
as forced sexual intercourse, incarceration, contact with the
well as India. Additionally, with discordant couples, if the
criminal justice system, and unique familial obligations in the
HIV-infected partner is known to be on a TDF-based regimen,
African American community make creating culturally tai-
consideration of other drugs for PrEP may be warranted.
lored interventions of PrEP challenging, given the diversity of
One of the most encouraging aspects of the iPrEx study was
black MSM.70
the lack of selection for TDF resistance among those who
The decision of to whom clinicians should offer PrEP could
became infected despite being assigned to the TDF/FTC arm
be, in part, based on the incorporation of a ‘‘risk score’’ pre-
of the study.13 However, given that active medication was
diction model into primary care clinic visits, similar to the
only found in 3 of 34 men who became HIV-infected in the
Framingham risk score. Menza et al.71 developed a novel
TDF/FTC group, it is possible that the lack of medication in
prediction model for HIV acquisition in MSM populations
tissues around the time of acute infection, prevented selec-
that calculates risk based on sociodemographic characteris-
tion for the evolution of resistance. Because of the possibility
tics, STI infection diagnosis or history, substance use, and
of continued selection for resistance after seroconversion
sexual risk. If the primary care physician determines his or her
frequent HIV testing (e.g., monthly) of PrEP users will be
patient is at high risk for HIV, the patient could be offered
important.
PrEP. However, like any risk prediction model, clinician
judgment will play the largest role in dispensing PrEP.
PrEP Implementation Issues
Because oral PrEP is a complex biomedical intervention
As it currently stands, PrEP may be most useful in several that requires periodic medical monitoring, patients electing to
specific high-risk subgroups in the U.S. population. MSM take oral PrEP will need to receive continual educational
engaging in unprotected anal sex would be one of the priority training about both their own risk factors for HIV, ways to
populations for PrEP, given that they account for more than reduce these risks, and finally the appropriate use of this
half of new HIV infections in the US. Other groups that may potentially life-saving intervention. Providers will need to
benefit from PrEP include female and male sex workers who monitor renal function and HIV serostatus on a regular basis,
may not have control over their partners and may be unable to and will need to know their patients’ Hepatitis B infection
ask their partners to use condoms or know their partner’s HIV status before initiating PrEP. Moreover, they will need to be
status. In fact, Shannon and colleagues found that among 205 able to counsel patients about potential side effects, such as
female sex workers, 25% reported having been pressured by nausea, the need for adherence, as well as risk reduction and
clients into not using a condom for sexual intercourse, which safer sex. Unlike condoms, because oral PrEP is a biomedical
increases the risk for HIV risk transmission.56,57 The use of a intervention, only physicians will be able to provide treat-
once-daily or intermittent pill to prevent HIV could give these ment initially, potentially limiting its widespread use. Thus,
people the power to continue their work knowing they are at specialized gay men’s health clinics, family planning clinics,
ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS 69

and primary care physicians who care for high-risk popula- References
tions may become the initial providers of PrEP. However, as
1. Centers for Disease Control and Prevention. Cases of HIV
health care reform becomes a reality in the United States and
infection and AIDS in the United States and dependent ar-
more Americans begin seeing primary care physicians on a eas, 2006. U.S. Department of Health and Human Services.
regular basis, potential PrEP consumers may become more Volume 18. Atlanta, GA: U.S. Department of Health and
dispersed. Human Services, Centers for Disease Control and Preven-
With the introduction of PrEP there also will likely be in- tion, 2008.
dividuals who are at low risk for contracting HIV (condoms 2. Hall HI, Song R, Rhodes P, et al. Estimation of HIV In-
consistently used for anal intercourse and unprotected oral cidence in the United States. JAMA 2008;300:520–5299.
sex) who may request PrEP as an adjunct to condom use. In 3. Herek GM, Garnets LD. Sexual orientation and mental
these populations, the evidence for PrEP use is far less clear health. Annu Rev Clin Psychol. 2007;3:353–275.
and will have to be worked out an individual basis. Given that 4. Alvy LM, McKirnan DJ, Mansergh G, et al. Depression is
prior studies suggest that the risk of contracting HIV from associated with sexual risk among men who have sex with
unprotected oral sex is on the order of one in 10,000 for the men, but is mediated by cognitive escape and self-efficacy.
individual giving oral sex and on the order of 1 in 20,000 for AIDS Behav (in press).
the individual receiving oral sex from an HIV-positive indi- 5. Safren SA, Thomas BE, Mimiaga MJ, et al. Depressive
vidual, the use of PrEP for individuals whose sole risk are symptoms and human immunodeficiency virus risk behav-
these practices may not be indicated.40,72,73 Since all PrEP ior among men who have sex with men in Chennai, India.
trials are currently testing the efficacy of a once-daily drug, Psychol Health Med 2009;14:705–715.
future clinical trials must consider the appropriateness of in- 6. Moore JP, Klasse PJ, Dolan MJ, Ahuja SK. 2008. AIDS/HIV:
A STEP into darkness or light? Science 2008;320:753–755
termittent dosing since animal studies have shown its effec-
7. Hillier SL, Moench T, Shattock R, et al. In vitro and in vivo:
tiveness.18 Intermittent dosing, if effective, is an especially
The story of nonoxynol 9. J Acquir Immune Defic Syndr
desirable goal since it would minimize exposure to the drugs,
2005;39:1–8.
minimizing side effects. However, such a study design will
8. Celum C, Wald A, Hughes J, et al. Effect of acyclovir on HIV-
require a substantially larger study size.11 Costs to insurers, 1 acquisition in herpes simplex virus 2 seropositive women
governments, and individuals would also be substantially and men who have sex with men: A randomized, double-
less if intermittent PrEP proves effectiveness. blind, placebo-controlled trial. Lancet 2008;371:2109–2119.
If a clear population benefit for PrEP can be determined— 9. Gray RH, Wawer MJ. Randomized trials of HIV prevention.
either intermittently or daily—withholding it would be un- Lancet 2007;370:200–201.
ethical. Thus, it will be the responsibility of normative bodies 10. Liu AY, Grant RM, Buchbinder SP. Preexposure prophylaxis
including the CDC and WHO to work with funders to ensure for HIV: Unproven promise and potential pitfalls. JAMA
that individuals who would benefit from PrEP would have 2006;296:863–865.
access to it. Moreover, it would be in the interests of national 11. Padian NS, Buvé A, Balkus J, Serwadda D, Cates W Jr.
governments to find the resources to provide PrEP to key Biomedical interventions to prevent HIV infection: Evidence,
populations, if as some of the early work has suggested, it challenges, and way forward. Lancet 2008;372:585–5899.
could be cost effective.51 Those considerations in mind, from a 12. Magill AJ. The prevention of malaria. Prim Care 2002;29:
global health perspective, and in an era of constrained re- 815–842, v–vi.
sources, it will also be critical for normative bodies like the 13. Grant RM, Lama JR, Anderson PL, et al. Preexposure che-
CDC and WHO to work with national governments and in- moprophylaxis for HIV prevention in men who have sex
ternational donor organizations to ensure that the promise of with men. N Engl J Med 2010;363:2587–2599.
PrEP does not compromise access to treatment for those who 14. Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV Infection
in Macaques by (R)-9-(2-Phosphonylmethoxypropyl)ade-
are infected and whose clinical and laboratory parameters
nine. Science 1995;270:1197–1199.
meet standards for the initiation of therapy.
15. Tsai CC, Emau P, Follis KE, et al. Effectiveness of postinoc-
As we await the results of pivotal trials, we can only hope
ulation (R)-9-(2-phosphonylmethoxypropyl) adenine treat-
that the implementation of PrEP will be a major prevention
ment for prevention of persistent simian immunodeficiency
breakthrough, leading to arresting the epidemic’s spread. virus SIVmne infection depends critically on timing of initi-
Prevention education and reliance on behavior change pro- ation and duration of treatment. J Virol 1998;72:4265–4273.
grams alone have been insufficient. As ARVs drop in price 16. Le Grand R, Vaslin B, Larghero J, et al. Post-exposure pro-
due to the release of generic formulations, and as new drugs phylaxis with highly active antiretroviral therapy could not
show fewer short and long-term side effects, PrEP today could protect macaques from infection with SIV/HIV chimera.
become a reality in the next few years, although many issues AIDS 2000;14:1864–1866.
will need to be resolved in order to optimize implementation. 17. Subbarao S, Otten RA, Ramos A, et al. Chemoprophylaxis
with tenofovir disoproxil fumarate provided partial protec-
Acknowledgments tion against infection with simian human immunodeficiency
Gavin Myers has equity and stock holdings in Pfizer, Inc. virus in macaques given multiple virus challenges. J Infect
Dis 2006;194:904–911.
and Merck and Co.
18. Garcia-Lerma G, Cong ME, Mitchell J, et al. Intermittent
Author Disclosure Statement prophylaxis with oral truvada protects macaques from rectal
SHIV infection. Sci Transl Med 2010:2:14.
Kenneth Mayer, M.D. has received research grants from 19. Garcı́a-Lerma JG, Paxton L, Kilmarx PH, Heneine W. Oral
Gilead Sciences, Inc. Merck, Inc. and Bristol-Myers-Squibb, pre-exposure prophylaxis for HIV prevention. Trends
Inc. Pharmacol Sci 2010;31:74–81.
70 MYERS AND MAYER

20. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fu- 38. Scarlatti G, Tresoldi E, Bjorndal A, et al. In vivo evolution of
marate. Clin Pharmacol Pharmacokinet 2004;43:595–612. HIV-1 co-receptor usage and sensitivity to chemokine-me-
21. Van Rompay KK, Kearney BP, Sexton JJ, et al. Evaluation of diated suppression. Nat Med 1997;3:1259–1265.
oral tenofovir disoproxil fumarate and topical tenofovir 39. Connor RI, Sheridan KE, Ceradini D, et al. Change in cor-
GS-7340 to protect infant macaques against repeated oral eceptor use coreceptor use correlates with disease progression
challenges with virulent simian immunodeficiency virus. in HIV-1-infected individuals. J Exp Med 1997;185:621–628.
J Acquir Immune Defic Syndr 2006;43:6–14. 40. Landovitz RJ. Occupational and nonoccupational postex-
22. Volmink J, Siegfried N, van der Merwe L, Brocklehurst P. posure prophylaxis for HIV in 2009. Top HIV Med 2009;
Antiretrovirals for reducing the risk of mother-to-child 17:104–108.
transmission of HIV infection. Cochrane Database of Sys- 41. Mayer K, Mimiaga M, Gelman M, et al. Tenofovir DF/
tematic Reviews 2007, Issue 1. Art. No.: CD003510. DOI: emtricitabine/ raltegravir (TDF/FTC/RAL) appears safe
10.1002/14651858.CD003510.pub2. and well-tolerated for non-occupational post-exposure pro-
23. Van Rompay KK, McChesney MB, Aguirre NL, et al. Two phylaxis (NPEP) [Abstract WEAC104]. 5th International
doses of PMPA protect newborn macaques against oral AIDS Society Conference on HIV Pathogenesis, Treatment,
simian immunodeficiency virus infection. AIDS 1998;12: and Prevention (IAS 2009). Cape Town, South Africa: July
F79–83. 19–22, 2009.
24. Van Rompay KK, McChesney MB, Aguirre NL, Schmidt KA, 42. www.aegis.com/default.asp?req¼http://www.aegis.com/
Bischofberger N, Marthas ML. Two low doses of tenofovir news/pr/2006/PR060501.html (Last accessed July 15, 2010).
protect newborn macaques against oral simian immunode- 43. http://clinicaltrials.gov/ct2/show/NCT00784147?term¼
ficiency virus infection. J Infect Dis 2001;184:429–438. ibalizumab&rank¼1 (Last accessed July 15, 2010).
25. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, em- 44. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Ef-
tricitabine, and efavirenz vs. zidovudine, lamivudine, and fectiveness and safety of tenofovir gel, an antiretroviral mi-
efavirenz for HIV. N Eng J Med 2006;354:253–260. crobicide, for the prevention of HIV infection in women.
26. Youle M, Wainberg MA. Pre-exposure chemoprophylaxis Science 2010;329:1168–1174.
(PREP) as an HIV prevention strategy. J Int Assoc Physicians 45. Grohskopf L, Gvetadze R, Pathak S, et al. Preliminary
AIDS Care 2003;2:102–105. analysis of biomedical data from the phase II clinical safety
27. Lee LM, Henderson DK. Tolerability of postexposure anti- trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-
retroviral prophylaxis for occupational exposures to HIV. exposure prophylaxis (PrEP) among U.S. men who have sex
Drug Saf 2001;24:587–597. with men (MSM) [oral]. XVIII International AIDS Con-
28. Pruvost A, Negredo E, Benech H, et al. Measurement of ference, Vienna, Austria: July 18–23, 2010.
intracellular didanosine and tenofovir phosphorylated me- 46. Px Wire. A Quarterly Update on HIV Prevention Research.
tabolites and possible interaction of the two drugs in human January 2009, posted. HIV Prevention Research: A Com-
immunodeficiency virus-infected patients. Antimicrobiol prehensive Timeline of Efficacy Trial Results.
Clin Chemother 2005;49:1907–1914. 47. www.hptn.org (HPTN 066, HPTN 077). (Last accessed July
29. Vourvahis M, Tappouni HL, Patterson KB, et al. The phar- 15, 2010).
macokinetics and viral activity of tenofovir in the male 48. Schechter M, do Lago RF, Mendelsohn AB, Moreira RI,
genital tract. J Acquir Immune Defic Syndr 2008;47:329–333. Moulton LH, Harrison LH. Behavioral impact, accessibility,
30. Dumond JB, Yeh RF, Patterson KB, et al. Antiretroviral drug and hiv incidence among homosexual men with access to
exposure in the female genital tract: Implications for oral pre- postexposure chemoprophylaxis for HIV. J Acquir Immune
and post-exposure prophylaxis. AIDS 2007;21:1899–1907. Defic Syndr 2004;35:519–525.
31. Rihs TA, Begley K, Smith DE, et al. Efavirenz and chronic 49. Martin JN, Roland ME, Neilands TB, et al. Use of postex-
neuropsychiatric symptoms: A cross-sectional case control posure prophylaxis against HIV infection following sexual
study. HIV Med 2006;7:544–548. exposure does not lead to increases in high-risk behavior.
32. Worm SW, Sabin C, Weber R, et al. Risk of myocardial in- AIDS 2004;18:787–792.
farction in patients with HIV infection exposed to specific 50. Mimiaga MJ, Case P, Johnson CV, Safren SA, Mayer KH.
individual antiretroviral drugs from the 3 major drug clas- Preexposure antiretroviral prophylaxis attitudes in high-risk
ses: The data collection on adverse events of anti-HIV drugs boston area men who report having sex with men: Limited
(D:A:D) study. J Infect Dis 2010;201:318–330. knowledge and experience but potential for increased utili-
33. Paxton LA, Hope T, Jaffe HW. Pre-exposure prophylaxis for zation after education. J Acquir Immune Defic Syndr
HIV infection: What if it works? Lancet 2007;370:89–93. 2009;50:77–83.
34. Dumond JB, Patterson KB, Pecha AL, et al. MVC concen- 51. Liu AY, Kittredge PV, Vittinghoff E, et al. Limited knowl-
trates in the cervicovaginal fluid and vaginal tissue of HIV- edge and use of HIV post- and pre-exposure prophylaxis
negative women. J Acquir Immune Defic Syndr 2009;51: among bay and bisexual men. J Acquir Immune Defic Syndr
546–553. 2008;47:241–247.
35. Moyle GJ, Wildfire A, Mandalia S, et al. Epidemiology and 52. Paltiel AD, Freedberg KA, Scott CA, et al. HIV preexposure
predictive factors for chemokine receptor use in HIV-1 in- prophylaxis in the United States: Impact on lifetime infection
fection. J Infect Dis 2005;191:866–872. risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis
36. Zhu T, Mo H, Wang N, et al. Genotypic and phenotypic 2009;15;48:806–815.
characterization of HIV-1 patients with primary infection. 53. Klein R, Struble K. Tentative approval emtricitabine and
Science 1993;261:1179–1181. tenofovir disoproxil fumarate tablets, 200 mg/300 mg. FDA
37. Shankarappa R, Margolick JB, Gange SJ, et al. Consistent HIV/AIDS Update. March 31, 2009.
viral evolutionary changes associated with the progression 54. Brenner BG, Coutsinos D. The K65R mutation in HIV-1 re-
of human immunodeficiency virus type 1 infection. J Virol verse transcriptase: Genetic barriers, resistance profile and
1999;73:10489–10502. clinical implications. HIV Ther 2009;3:583–594.
ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS 71

55. Brenner BG, Oliveira M, Doualla-Bell F, et al. HIV-1 subtype 66. Lemp GF, Hirozawa AM, Givertz D, et al. Seroprevalence of
C viruses rapidly develop K65R resistance to tenofovir in HIV and risk behaviors among young homosexual and bi-
cell culture. AIDS 2006;20:F9–13. sexual men. The San Francisco/Berkeley Young Men’s Sur-
56. Albert AE, Warner DL, Hatcher RA, Trussell J, Bennet C. vey. JAMA 1994;272:449–454.
Condom use among female commercial sex workers in Ne- 67. Torian LV, Makki HA, Menzies IB, Murrill CS, Weisfuse IB.
vada’s legal brothels. Am J Public Health 1995;85:1514–1520. HIV infection in men who have sex with men, New York
57. Shannon K, Strathdee SA, Shoveller J, Rusch M, Kerr T, City Department of Health sexually transmitted disease
Tyndall MW. Structural and environmental barriers to con- clinics, 1990–1999: A decade of serosurveillance finds that
dom use negotiation with clients among female sex workers: racial disparities and associations between HIV and gonor-
Implications for HIV-prevention strategies and policy. Am J rhea persist. Sex Transm Dis 2002;29:73–78.
Public Health 2009;99:659–665. 68. Millett GA Peterson JL, Wolitski RJ, Stall R. Greater risk for
58. Darrow WW, Biersteker S, Geiss T, et al. Risky sexual be- HIV infection of black men who have sex with men: A critical
haviors associated with recreational drug use among men literature review. Am J Public Health 2006;96:1007–1019.
who have sex with men in an international resort area: 69. Bond L, Wheeler DP, Millett GA, LaPollo AB, Carson LF,
Challenges and opportunities. J Urban Health 2005;82: Liau A. Black men who have sex with men and the associ-
601–609. ation of down-low identity with HIV risk behavior. Am J
59. Forrest DW, Metsch LR, Lalota M, Cardenas G, Beck DW, Public Health 2009;99(Suppl 1):S92–95.
Jeanty Y. Crystal methamphetamine use and sexual risk 70. Wheeler DP, Lauby JL, Liu KL, Van Sluytman LG, Murrill C.
behaviors among HIV-positive and HIV-negative men who A comparative analysis of sexual risk characteristics of black
have sex with men in South Florida. J Urban Health men who have sex with men or with men and women. Arch
2010;87:480–485. Sex Behav 2008;37:697–707.
60. Mackesy-Amiti ME, Fendrich M, Johnson TP. Symptoms of 71. Menza TW, Hughes JP, Celum CL, Golden MW. Prediction
substance dependence and risky sexual behavior in a prob- of HIV acquisition among men who have sex with men. Sex
ability sample of HIV-negative men who have sex with men Transm Dis 2009;36:547–555.
in Chicago. Drug Alcohol Depend 2010;110:38–43. 72. Varghese B, Maher JE, Peterman TA, Branson BM, Steketee
61. Celentano DD, Valleroy LA, Sifakis F, et al. Associations RW. Reducing the risk of sexual HIV transmission: Quanti-
between substance use and sexual risk among very young fying the per-act risk for HIV on the basis of choice of
men who have sex with men. Sex Transm Dis 2006;33: partner, sex act, and condom use. Sex Transm Dis 2002;
265–271. 29:38–43.
62. Colfax G, Vittinghoff E, Husnik MJ, et al. Substance use and 73. European Study Group on Heterosexual Transmission of
sexual risk: a participant- and episode level analysis among HIV. Comparison of female to male and male to female
a cohort of men who have sex with men. Am J Epidemiol transmission of HIV in 563 stable couples. BMJ 1992;304:
2004;159:1002–1012. 809–813.
63. www.cdc.gov/hiv/surveillance/incidence/sote/msm-race-age
.htm#Black (Last accessed July 15, 2010).
64. Valleroy LA, MacKellar DA, Karon JM, HIV prevalence and Address correspondence to:
associated risks in young men who have sex with men. Kenneth Mayer, M.D.
JAMA 2000;284:198–204. The Miriam Hospital
65. Easterbrook PJ, Chmiel JS, Hoover DR, et al. Racial and 164 Summit Avenue
ethnic differences in human immunodeficiency virus type 1
Providence, RI 02906
(HIV-1) seroprevalence among homosexual and bisexual
men. Am J Epidemiol 1993;138:415–429. E-mail: Kenneth_Mayer@brown.edu