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

AIDS PATIENT CARE and STDs Volume 25, Number 2, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/apc.2010.0222

CLINICAL AND EPIDEMIOLOGIC RESEARCH

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. Currently, 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 prophylactic 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.

non-HIV sexually transmitted diseases to decrease HIV spread.6–9 Because of the improved tolerability, ease of administration (due to coformulation of multiple agents), improved efficacy of highly active antiretroviral therapy (HAART) in humans, as well as animal model data, clinical researchers began to explore other HIV prevention strategies focusing on the use of antiretroviral drugs for prevention, including pre-exposure prophylaxis (PrEP).10,11 PrEP has been used in other contexts, e.g., it is currently used in the prevention of malaria for those traveling to nations where the organisms are endemic.12 In theory, PrEP for HIV prevention can refer to either antiretroviral-based vaginal or rectal gels or oral medication; the gels are often called ‘‘microbicides,’’ and the pills are often called ‘‘PrEP.’’ The goal of both approaches is the prevention of disease transmission.10 Clinical trials of PrEP in humans have thus far studied antiretrovirals (ARVs) usually used to treat HIV, principally either tenofovir disoproxil fumarate (TDF) administered orally alone or with emtricitabine (FTC), or tenofovir gel (TFV). The focus of this review is the issues raised by oral PrEP (non-gel–based interventions), given the recent publication of

Introduction

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 largest number of new infections (53%) being diagnosed among men who have sex with men (MSM).2 Social, cultural, and psychiatric stressors ranging from internalized homophobia leading to depression, as well as substance use, can lead to failure to use condoms consistently and nonadherence to other prevention strategies, resulting in HIV transmission.3–5 Although condoms are effective in preventing HIV transmission if consistently used, after almost three decades of continued HIV transmission, it is evident that access to information and condoms alone has not been sufficient to cause consistent decreases in HIV incidence in most parts of the world.

Unfortunately, until recently, a range of biomedical HIV prevention prevention approaches have not been successful, including vaccines, nonspecific topical microbicides (those not containing an antiretroviral agent) and the treatment of

1

Alpert Medical School of Brown University, Department of Community Health, Providence, Rhode Island.

The Miriam Hospital, Providence, Rhode Island.

Fenway Institute, Boston, Massachusetts.

2 3

63

64 the first-in-humans efficacy data emanating from the iPrEx study given that these drugs are already FDA-approved, and thus could soon be widely available for chemoprophylaxis.13–18 Oral PrEP could involve the use of antiretroviral drugs taken either continuously by high-risk persons or intermittently (before and after a high-risk sex episode).10 Biological Rationale Behind PrEP The idea of PrEP as a viable prevention measure is based on both animal models and clinical studies in humans showing the effectiveness of postexposure prophylaxis (PEP).11 Both PEP and PrEP are intended to prevent HIV infection from establishing infection when a host is exposed, but one approach presumes that exposure is infrequent and unpredictable (PEP), while the other anticipates that the PrEP user may have regular exposures to HIV.19 The biological principle behind PrEP is that by limiting the size of the ‘‘founder population’’ of free virions or infected cells, infection cannot be established. It is thought that antiretroviral drugs block the establishment of this critical founder population by blocking viral replication and allowing innate host immune responses to remove the small inoculum.19 Several drugs, including TDF are highly potent inhibitors of HIV-1 reverse transcriptase and have the ability to terminate the growing DNA viral chain by inhibiting reverse transcriptase.20 Early studies in macaques using a simian immunodeficiency (SIV) model with PMPA (a congener of TDF, which is formulated to enhanced oral bioavailability) and zidovudine (AZT) have shown the efficacy of PEP if dosed daily and continued for 28 days.14 Although this study provided robust initial evidence for the efficacy of PEP, other animal studies have shown less encouraging results. Tsai et al.15 found that treatment was not effective if initiated 48 or 72 h after an exposure and was not effective if continued for just 3–10 days. Another study, which combined AZT, lamivudine (3TC), and indinavir (IDV) initiated 4 h after challenge with SHIV and continued for 28 days failed to protect the animals.16 More recent studies with macaques have tested the administration of PrEP in different animal models. Van Rompay et al.21 found that oral TDF reduced the risk of contracting SHIV via an oral route, which simulates breast-feeding.

Subbaro et al.17 using repeated low-dose atraumatic rectal challenges found that while TDF resulted in a 60% decrease in per-exposure probability of being infected with SHIV, neither weekly nor daily PrEP ultimately prevented the animals from becoming infected. The researchers noted this could have been due to the relatively high inoculum used in these rectal challenges (approximately 5 times that found in human semen).17 Moreover, these studies did not combine TDF with FTC, which from a theoretical standpoint could be a more convincing model for HIV prevention, since two drugs are used. Garcia-Lerma et al.18 administered TDF/FTC to four separate groups of macaques based on different dosing times and compared them to groups receiving a placebo and determined that intermittent dosing of TDF/FTC could be successful in HIV prevention. That study showed a 15.9-fold reduction of HIV infection transmission in the group of animals receiving a dose of TDF/FTC 22 h before and a second dose 2 h after exposure, but interestingly, even animals that received TDF/FTC just 2 h before and 22 h after expo-

MYERS AND MAYER sure (i.e., PEP) also showed a 3.9 risk reduction relative to placebo.18 In animals that received one dose 2 h after exposure and another dose 26 h after exposure risk reduction was 3.8-fold; 3 of 6 animals remained protected after 14 weekly challenges.18 Another clinical model that shows the power of ARVs in preventing HIV transmission comes from a variety of motherto-child SHIV transmission studies that show reduced rates of HIV transmission to babies from mothers who took ARVs, such as AZT and 3TC for 36 weeks prior to giving birth and for a week after birth; other studies with different time sequences have also shown prevention benefits.22 Another study in which two doses of TDF were given 4 h before and 24 h after oral inoculations protected newborn macaques against SIV.23 Finally, in another study in which the dose of PMPA was reduced by 5-fold to 4 mg/kg of body weight, partial protection against SHIV was maintained, underscoring the possible effects of ARVs in preventing HIV transmission.24 Drug Candidates for PrEP: Are There Alternatives to TDF/FTC? For a variety of reasons, TDF/FTC is considered a prime candidate for PrEP. The nucleoside reverse transcriptase inhibitors (NRTIs) have been an ARV class of choice for PrEP, because they work early in the HIV life cycle, prior to HIV’s DNA integration into the cell’s genome, and they have been used for HIV treatment for more than two decades. Gallant et al. 25 found the TDF/FTC component of a HAART regimen more tolerable than AZT/3TC. Protease inhibitors (PIs) work postviral integration and therefore are not thought to be suitable to prevent transmission.26 Moreover, many PIs have undesirable side effects including hyperlidipedmia, nausea, and gastrointestinal discomfort.27 TDF and FTC are synergistic in their antiretroviral activity, and the transmission or development of resistance to both drugs is much less likely than if a single drug would be used for prophylaxis. Specifically, TDF/FTC has a low rate of side effects relative to placebo, resulting in lower likelihood of inadvertent unblinding in clinical trials.19,28 A Family Health International study (FHI) found that among 859 high-risk African women, there were no increased adverse events among participants receiving daily TDF compared to placebo.10 TDF has a longer half-life in serum (17 h) and in cells ( 60 h) relative to other nucleoside analogues, suggesting the drug could be useful in patients who may miss an occasional dose.26 TDF/FTC also reaches high concentrations in cells in the genital secretions and tissue, suggesting it could be a particularly effective in preventing HIV transmission.29,30 Other agents such as stavudine, abacavir, and efavirenz achieve such low concentrations in the genital tract that they are thought to be suboptimal candidates in a PrEP regimen.29,30 Moreover, the side effects that can occur with these drugs make them undesirable PrEP candidates.32,33 Despite TDF/FTC’s attractiveness as an agent for PrEP, there are some theoretical concerns. Both drugs can have serious side effects in less than 1% of patients; these can include but are not limited to acute renal failure, Fanconi’s syndrome, decreases in bone mineral density, and extremely rarely, lactic acidosis.33 More significantly, if an individual becomes infected with HIV during administration of TDF/FTC as PrEP and

ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS does not routinely get retested to detect new HIV infection as early as possible, their strain of HIV could become resistant to one or both drugs, which could remove these first-line drugs as part of a HAART regimen.33 One other concern about the use of TDF and FTC for PrEP is that they each have activity against hepatitis B, so that intermittent PrEP use or erratic adherence could result in the development of drug resistance in hepatitis B-infected individuals, and potential flares of virologic activity following PrEP discontinuation. Thus, all PrEP candidates should be screened for hepatitis B prior to the initiation of TDF/FTC PrEP. Seronegative patients should receive hepatitis B vaccination prior to PrEP use, and those with chronic hepatitis B should be educated about the potential impact of suboptimal adherence on their liver infection.

Another agent that is particularly attractive for PrEP is maraviroc (MVC), a novel antagonist of the CCR5 coreceptor that HIV usually binds when infecting susceptible mononuclear cells. MVC is FDA-approved for use in the treatment of HIV in combination with other antiretrovirals. Dumond et al.34 found that MVC maintains high concentrations in cervicovaginal tissue (CVF) and vaginal tissue (VT) in HIV-uninfected women. Because MVC works to prevent the earliest point of the HIV life cycle—mononuclear cellular binding—it remains an attractive candidate for PrEP since viral entry could be halted at the earliest stage of HIV infection.

While there may be some theoretical concerns about prevention against HIV strains that could bind other co-receptors (dual-tropic virus or CXCR4 virus), the vast majority of new viral infections preferentially binds CCR5.35,36 The theoretical concern is that in rare cases if MVC prophylaxis fails, people who become infected with viruses that preferentially use the CXCR4 receptor have been shown to progress more rapidly through CD4 lymphocyte depletion.37–39 While MVC will not protect against these viruses, if other antiretrovirals are combined with MVC this approach would theoretically prevent these resistant HIV strains. The safety of long-term MVC administration will need to be substantiated before this drug could be considered as a possible first-line PrEP regimen.

Major questions about the role of MVC for chemoprophylaxis include: whether it would be advisable to give the drug by itself, or to avoid the development of resistance, would it make sense to try to coformulate with other antiretroviral drugs that work via a different mechanism. Future PrEP regimens could include combinations of FTC or 3TC, or TDF alone, or coformulated TDF/FTC plus MVC, or MVC with FTC or 3TC. However, because these agents are manufactured and patented by different companies, legal issues, including patent and intellectual property concerns may serve as roadblocks to these drugs from becoming part of a oncedaily PrEP regimen. However, with the demonstrated efficacy of many ARVs combined into one pill (Truvada and Atripla , Gilead Sciences, Foster City, CA; Combivir , GlaxoSmithKline: London, UK) for HIV treatment, combinations of MVC and other antiretrovirals may be feasible and desirable. Support for a strategy of using multiple drugs for chemoprophylaxis comes from clinical experience, in which during high-risk exposures with known HIV-infected sources, exposed persons are often placed on not only an NRTI backbone such as TDF/FTC, but also a boosted-PI in order to insure viral replication is adequately suppressed during a PEP regimen.40

65 As new agents demonstrate fewer side effects, more options develop for use in PrEP. A recent study investigated the use of raltegravir (RAL), an integrase inhibitor, in conjunction with TDF/FTC for PEP among gay and bisexual men in Boston, due to its potentially reduced side effect profile relative to PIs.41 The combination was well tolerated, with 97.4% of the 39 men completing the 4-week course, suggesting that RAL could be an option for PrEP if combined with other antiretroviral agents.41 Because PrEP is a preventive measure and is likely to be used in high-risk populations, it seems unlikely that regimens that require more than one pill daily would be practical or feasible, so coformulation of future PrEP regimens will be highly desirable.

When looking outside the realm of oral PrEP, another possible agent that could be tested for PrEP is ibalizumab (TNX-355), a drug in phase II clinical trials for therapeutic indications.42 This type of agent could be a unique prototype of drug for PrEP if found to be safe and effective. This investigational product is a humanized IgG4 monoclonal antibody administered via intravenous infusion and is being tested at either 800 mg every 2 weeks or 2000 mg every 4 weeks.44 While intravenous administration could be a barrier to access, it could provide a broader range of protection against various HIV tropic strains, theoretically preventing HIV from binding both CCR5 and CXCR4. Moreover, since the drug can be administered relatively infrequently, it could be ideally suited for individuals who would be less compliant with a daily pill. Since this injection is not a vaccine, like oral PrEP, the drug would have to be taken for as long as individuals engage in risk-taking behaviors.

Current State of Topical and Oral PrEP: Ongoing Clinical Trials There are currently several trials being conducted testing oral and topical chemoprophylaxis around the world (Table 1). The first study in the general field of PrEP with positive results, CAPRISA 004, studied the use of pericoital tenofovir gel, which was recently found to be efficacious in protecting high-risk South African women against HIV infection, with an overall protective effect of 39%, which was greater than 50% among women who were highly adherent to the regimen (i.e., use of the product for more than 50% of sexual exposures).44 These data were the first to suggest that antiretroviral chemoprophylaxis is feasible, so over the next few years, the major questions will be which mode of antiretroviral drug delivery (e.g., oral versus mucosal, vaginal versus rectal) may be most effective for each population.

Among trials of oral PrEP, CDC 4323 evaluated the clinical safety and potential for behavioral disinhibition of TDF for PrEP among HIV-uninfected MSM in the United States. The first data from this trial were presented at the recent International AIDS Conference in Vienna and TDF was found to be safe and well tolerated in the 400 MSM participants, with no increase in nephrotoxicity, other safety laboratory tests, nor any evidence of increased behavioral risk taking among the men.45 Although the study was not powered to demonstrate efficacy, none of the men assigned to take tenofovir became infected in the study. CDC 4370 is testing the safety and efficacy of once-daily oral TDF to prevent HIV infection in intravenous drug users in Thailand.

66

Phase IIb, safety and effectiveness

Phase I/II, safety, acceptability, adherence

Phase II, safety, acceptability, feasibility

VOICE (MTN 003)

IAVI E001 &E002

PrEP in YMSM (ATN 082)

United States

Kenya, Malawi, South Africa, Tanzania, Zambia Malawi, South Africa, Uganda, Zambia, Zimbabwe Kenya, Uganda

Kenya, Uganda

99 YMSM (penile-rectal)

150 serodiscordant couples and men and women (vaginal and penile-rectal)

5000 heterosexual women (vaginal)

1200 heterosexual men and women (penile-vaginal) 4700 serodiscordant heterosexual couples (penile-vaginal) 3900 heterosexual women (vagina)

Daily oral TDF; daily oral TDF/FTC; daily topical tenofovir gel Daily oral TDF/FTC; intermittent oral TDF/FTC (twice weeklyĂžcoital dosing) Daily oral TDF/FTC

Daily oral TDF/FTC

Daily oral TDF; daily oral TDF/FTC

Daily oral TDF/FTC

Fully enrolled/Quarter 4 2010

IAVI

Enrolling/2011

Enrolling/2013

MTN, NIH

ATN, NICHD

Enrolling/2013

Enrolling/2012

Fully enrolled/Quarter 4 2010

Completed Quarter 3/2010 Enrolling Quarter 4/2010 Fully enrolled/Quarter 4 2010

Study status

FHI, USAID, BMGF

BMGF

CDC

NIH, BMGF

CDC

CDC

Funding source

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.

Phase III, safety and effectiveness

Phase III, safety and efficacy

Partners PrEP

FEM-PrEP

Phase II, safety and adherence

Daily oral TDF/FTC

2499 MSM (penile-rectal)

Brazil, Ecuador, Peru, South Africa, Thailand, United States Botswana

TDF2 (CDC 4940)

Daily oral TDF

2400 IDU (parenteral)

Thailand

Daily oral TDF

Phase II/III, safety and efficacy Phase III, safety and efficacy

400 MSM (penile-rectal)

United States

Intervention arms(s)

Phase II, safety

Population

US Extended Safety Trial (CDC 4323) Bankok Tenofovir Study (CDC 4370) iPrEx

Location

Trial type and phase

Study name

Table 1. Global State of Oral PrEP Clinical Trials

ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS The iPrEx study was an efficacy trial that demonstrated that once-daily TDF/FTC decreased the likelihood of HIV infection by 44% among 2499 high-risk MSM recruited in Brazil, Ecuador, Peru, South Africa, Thailand, and the United States.13 Among men with greater levels of adherence, the protective effect was much greater: based on self-report and pill counts, men who took at least 90% of the regimen had a greater than 70% level of protection, and when drug levels were examined, men who had detectable TDF or FTC in their plasma or blood leukocytes experienced a greater than 90% protective effect. Although the regimen was generally well tolerated, and adherence levels in the active arm were comparable to placebo, men taking TDF/FTC were more likely to report mild nausea and experience weight loss in the first few weeks, and had a trend towards reversible changes in renal function. All of these findings were infrequent (occurring in 2% or fewer of the participants) and were either self-limited or responded to holding medication but underscore the importance of ongoing clinical monitoring of individuals who are using TDF/FTC for PrEP. PrEP is continuing to be studied in other at-risk populations. Among the larger global studies, the Partners PrEP study in Kenya and Uganda seeks to test TDF/FTC compared to TDF or placebo among 3900 serodiscordant couples. The FEMPrEP study will enroll 3900 high-risk women in South Africa, Kenya, Malawi, and Tanzania using once-daily TDF/ FTC.46 The VOICE study is testing daily oral TDF, daily oral TDF/FTC, and daily topical TFV gel among 5000 heterosexual women and will be the first study to demonstrate whether oral or topical PrEP is more protective in a specific high-risk population. PCS 082, funded by NICHD and being conducted in the Adolescent Trials Network, is novel in that it is testing daily oral TDF/FTC among 99 high-risk young men who have sex with men (YMSM). Finally, intermittent dosing of PrEP with TDF/FTC is being tested in the IAVI E001 and E002 studies in Kenya and Uganda among 150 serodiscordant couples and at-risk men and women.47 Other intermittent PrEP studies are being planned by the HIV Prevention Trials Network (www.hptn.org) to assess optimal pharmacology and acceptability of coitally dependent versus fixed interval dosing of PrEP.47 If PrEP Works: Will Risk-Taking Increase?

Because PrEP is not expected to be 100% effective against HIV-1 transmission even with optimal utilization, public policy must determine how to best implement access for specific high-risk groups. Concerns have been raised as to whether PrEP could result in increased risky sexual practices through behavioral disinhibition, also known as risk compensation. It is theoretically possible that individuals may feel ‘‘biologically protected’’ and decide to abandon condom use, underscoring the importance of implementing behavioral modification and encouraging continued condom use if PrEP is to be a successful public health intervention. Several studies suggest that the provision of PEP does not increase high-risk behavior.13,48,49 The recent data from the CDC MSM and the iPrEx studies provide evidence that risk compensation is not inevitable. But the results must be interpreted with caution, since all participants signed an informed consent telling them they had a 5050 chance of receiving a placebo and that it was not known if

67 the pill would work. The response of MSM in a world where PrEP would be shown to be highly protective could be very different. Moreover, it is certainly feasible that if PrEP efficacy is not 100%, that a certain level of risk compensation could undermine PrEP’s benefit. For example, if PrEP use in a community sample of MSM decreased the likelihood of transmission by 45% (similar to the change seen in iPrEx) and individuals who felt protected increased their risk taking by 75%, then a paradoxical increase in new infections could result. On the other hand, if PrEP plus intensive adherence counseling produces a much higher ‘‘real world’’ efficacy, it is unlikely that the level of risk compensation could result in an increase HIV incidence, but suboptimal adherence could further erode protective benefits. Researchers will need to study PrEP’s long-term impact on behavior among high-risk populations if initial trials suggest efficacy, if this is going to be a successful intervention. If approved by the FDA for use in high-risk subgroups of the population, public health messages at the community level will need to be carefully designed to prevent PrEP’s clinical effectiveness as being ‘‘overstated.’’ Therefore, it must be emphasized in public health campaigns that the use of PrEP may be most appropriate for the highest risk groups (individuals unwilling or unable to use condoms). Although PrEP is being tested in clinical trials as a once-daily regimen, intermittent PrEP use may be possible since in a recent animal-model study, GarciaLerma et al.18 found that intermittent dosing was effective at HIV prevention.

Currently, while PrEP is not well known to many high-risk MSM, in one study, many men who were asked about PrEP expressed interest in its use, although almost none had ever used it.50 In another study, while 47% of men reported PEP awareness, only 16% reported PrEP awareness and less than 1% of men had used PrEP, and two thirds of these men said they would be willing to take a daily PrEP regimen if it proved safe and effective against HIV-1 transmission.51 While Mimiaga et al.50 found that only 19% of men in a cohort of MSM in Boston had heard of PrEP, 74% of men indicated an interest in using PrEP, especially if it was given at no cost and associated with a low incidence of side effects.

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 tailored to less educated individuals and will need to anticipate the costs of program implementation if access for at-risk persons is to be ensured.50 At present, there is no consensus about what would constitute appropriate provision of PrEP at the population level.

The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) are actively engaging stakeholders in discussions as to which individuals are at highest risk and therefore would benefit the most from PrEP. Policy directives will only become available once firm PrEP efficacy data become available, which will take several years before the results of all currently active trials are known.

Policy recommendations will invariably be tempered by TDF/FTC’s high cost in the developed world. The cost of the drugs alone in the United States is estimated to be more than $10,000 per year, and medical monitoring would add to the costs.52 Paltiel et al.52 suggested PrEP may be cost effective in young, high-risk MSM populations based on a mathematical analysis conservatively assuming the intervention resulted in

68 a 50% reduction in HIV incidence. It is unclear whether private insurers would pay for once-daily PrEP for individuals self-identifying as high-risk MSM. If the CDC recommended widespread PrEP use, it is also unknown the extent to which primary care or infectious disease specialists would be willing to prescribe TDF/FTC to their patients. No data exist to describe current provider attitudes or experience regarding prescribing antiretrovirals for prevention, which will presumably require medical follow-up including HIV testing, screening for sexually transmitted infections (STIs), and standardized monitoring of liver and kidney function.

More research must be done to survey physicians to determine their knowledge, comfort level, and current prescribing habits of PrEP. It seems that PrEP would be most cost effective if intermittent PrEP proves equally efficacious to once-daily PrEP. Over time, if FTC/TDF becomes available as generic medication, it may be available at a more affordable cost to all parties involved.53 PrEP and Antiretroviral Drug Resistance: Is it a Concern?

If widespread PrEP use becomes common, concerns about drug resistance become more prominent. At present, the K65R mutation that confers TDF resistance is not common, so the majority of individuals exposed to HIV-infected partners would not be likely to develop primary infection with a resistant strain.54 However, in one cell culture study evaluating time to development of TDF resistance, the K65R mutation was shown to emerge faster among HIV-1 subtype C.55 Thus, caution in the use of TDF for PrEP could be considered in areas with endemic HIV-1 subtype C, i.e., many parts of Africa, as well as India. Additionally, with discordant couples, if the HIV-infected partner is known to be on a TDF-based regimen, consideration of other drugs for PrEP may be warranted.

One of the most encouraging aspects of the iPrEx study was the lack of selection for TDF resistance among those who became infected despite being assigned to the TDF/FTC arm of the study.13 However, given that active medication was only found in 3 of 34 men who became HIV-infected in the TDF/FTC group, it is possible that the lack of medication in tissues around the time of acute infection, prevented selection for the evolution of resistance. Because of the possibility of continued selection for resistance after seroconversion frequent HIV testing (e.g., monthly) of PrEP users will be important.

PrEP Implementation Issues As it currently stands, PrEP may be most useful in several specific high-risk subgroups in the U.S. population. MSM engaging in unprotected anal sex would be one of the priority populations for PrEP, given that they account for more than half of new HIV infections in the US. Other groups that may benefit from PrEP include female and male sex workers who may not have control over their partners and may be unable to ask their partners to use condoms or know their partner’s HIV status. In fact, Shannon and colleagues found that among 205 female sex workers, 25% reported having been pressured by clients into not using a condom for sexual intercourse, which increases the risk for HIV risk transmission.56,57 The use of a once-daily or intermittent pill to prevent HIV could give these people the power to continue their work knowing they are at

MYERS AND MAYER less risk for contracting HIV. The intervention could be useful in homosexual, as well as heterosexual serodiscordant couples where intimacy prevents both members from wanting to use condoms on a regular basis.

Because substance abuse is a major risk factor for HIV acquisition through increased sexual risk-taking behavior, PrEP programs will need to be tailored for those who regularly abuse substances such as alcohol and illegal drugs, and may require a focus on enhancing adherence.58–62 The feasibility of PrEP as an intervention will also need to be culturally adapted for use by African American MSM, where HIV incidence rates are among the highest with more than 10,000 annual cases (35% of the total), despite the fact African Americans represent only 13% of the U.S. population.63,64 Several studies have shown that black MSM have significantly higher HIV prevalence and incidence rates than MSM of all other races and ethnic backgrounds.63–68 Because of alienation from the health care system, stemming from perceptions of institutionalized racism (e.g., the Tuskegee syphilis experiment), PrEP education for black MSM may need to address underlying mistrust of the medical care system in the United States.

The feasibility of PrEP as a means to lower HIV transmission in this population therefore must be systematically evaluated because it could face unique challenges. Among black MSM, many men do not identify as gay or bisexual or disclose their sexual behavior to others.69 Even so, the provision of PrEP to non-gay identifying black MSM may present unique cultural challenges, since in one study 66.7% of black MSM identified as either straight or bisexual.70 PrEP interventions that do not implicate gay identity, therefore, may be crucial to effectively reach this population. Experiences such as forced sexual intercourse, incarceration, contact with the criminal justice system, and unique familial obligations in the African American community make creating culturally tailored interventions of PrEP challenging, given the diversity of black MSM.70 The decision of to whom clinicians should offer PrEP could be, in part, based on the incorporation of a ‘‘risk score’’ prediction model into primary care clinic visits, similar to the Framingham risk score. Menza et al.71 developed a novel prediction model for HIV acquisition in MSM populations that calculates risk based on sociodemographic characteristics, STI infection diagnosis or history, substance use, and sexual risk. If the primary care physician determines his or her patient is at high risk for HIV, the patient could be offered PrEP. However, like any risk prediction model, clinician judgment will play the largest role in dispensing PrEP. Because oral PrEP is a complex biomedical intervention that requires periodic medical monitoring, patients electing to take oral PrEP will need to receive continual educational training about both their own risk factors for HIV, ways to reduce these risks, and finally the appropriate use of this potentially life-saving intervention. Providers will need to monitor renal function and HIV serostatus on a regular basis, and will need to know their patients’ Hepatitis B infection status before initiating PrEP. Moreover, they will need to be able to counsel patients about potential side effects, such as nausea, the need for adherence, as well as risk reduction and safer sex. Unlike condoms, because oral PrEP is a biomedical intervention, only physicians will be able to provide treatment initially, potentially limiting its widespread use. Thus, specialized gay men’s health clinics, family planning clinics,

ORAL PREEXPOSURE ANTI-HIV PROPHYLAXIS and primary care physicians who care for high-risk populations may become the initial providers of PrEP. However, as health care reform becomes a reality in the United States and more Americans begin seeing primary care physicians on a regular basis, potential PrEP consumers may become more dispersed.

With the introduction of PrEP there also will likely be individuals who are at low risk for contracting HIV (condoms consistently used for anal intercourse and unprotected oral sex) who may request PrEP as an adjunct to condom use. In these populations, the evidence for PrEP use is far less clear and will have to be worked out an individual basis. Given that prior studies suggest that the risk of contracting HIV from unprotected oral sex is on the order of one in 10,000 for the individual giving oral sex and on the order of 1 in 20,000 for the individual receiving oral sex from an HIV-positive individual, the use of PrEP for individuals whose sole risk are these practices may not be indicated.40,72,73 Since all PrEP trials are currently testing the efficacy of a once-daily drug, future clinical trials must consider the appropriateness of intermittent dosing since animal studies have shown its effectiveness.18 Intermittent dosing, if effective, is an especially desirable goal since it would minimize exposure to the drugs, minimizing side effects. However, such a study design will require a substantially larger study size.11 Costs to insurers, governments, and individuals would also be substantially less if intermittent PrEP proves effectiveness.

If a clear population benefit for PrEP can be determined— either intermittently or daily—withholding it would be unethical. Thus, it will be the responsibility of normative bodies including the CDC and WHO to work with funders to ensure that individuals who would benefit from PrEP would have access to it. Moreover, it would be in the interests of national governments to find the resources to provide PrEP to key populations, if as some of the early work has suggested, it could be cost effective.51 Those considerations in mind, from a global health perspective, and in an era of constrained resources, it will also be critical for normative bodies like the CDC and WHO to work with national governments and international donor organizations to ensure that the promise of PrEP does not compromise access to treatment for those who are infected and whose clinical and laboratory parameters meet standards for the initiation of therapy.

As we await the results of pivotal trials, we can only hope that the implementation of PrEP will be a major prevention breakthrough, leading to arresting the epidemic’s spread.

Prevention education and reliance on behavior change programs alone have been insufficient. As ARVs drop in price due to the release of generic formulations, and as new drugs show fewer short and long-term side effects, PrEP today could become a reality in the next few years, although many issues will need to be resolved in order to optimize implementation.

Acknowledgments Gavin Myers has equity and stock holdings in Pfizer, Inc. and Merck and Co. Author Disclosure Statement Kenneth Mayer, M.D. has received research grants from Gilead Sciences, Inc. Merck, Inc. and Bristol-Myers-Squibb, Inc.

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Address correspondence to: Kenneth Mayer, M.D. The Miriam Hospital 164 Summit Avenue Providence, RI 02906 E-mail: Kenneth_Mayer@brown.edu