Preexposure Prophylaxis for HIV: Title and subTitle BreakUnproven Promise and Potential Pitfalls

An estimated 11 000 new human immunodeficiency virus (HIV) infections occur worldwide per day and approximately 4 million individuals are infected with HIV per year.¹ Although behavior change has likely led to substantial reductions in HIV incidence in some populations and risk-reduction counseling will likely remain the cornerstone of HIV prevention programs, new HIV prevention strategies are urgently needed to further reduce incident infections. Preexposure chemoprophylaxis (PrEP) has emerged as a promising new biomedical strategy for preventing HIV infection,² and clinical trials are planned or under way³ to evaluate the safety and efficacy of this approach. Because many antiretroviral drugs are licensed in the United States, PrEP could become available for use as a prevention tool more quickly than other experimental prevention strategies, such as an HIV vaccine.

Recent interest in PrEP as a prevention strategy has been based in part on encouraging preclinical data on combination PrEP⁴ and also on an announcement from the Centers for Disease Control and Prevention (CDC)^{5 - 6} about a switch in antiretroviral agent for the PrEP trial in Botswana from single agent tenofovir to combination emtricitabine/tenofovir (FTC/TDF). This attention⁵ appears to have created increased interest in PrEP, as well as potential confusion in community laypersons and clinicians about how PrEP is different from postexposure prophylaxis (PEP) and which antiretroviral medications are being evaluated in the current PrEP trials. Meanwhile, there have been anecdotal reports of off-label and unapproved PrEP use occurring in the community outside clinical trials. The current interest in PrEP could result in increased use of this strategy despite the lack of proven safety and efficacy for preventing HIV infection.

This commentary will provide background on and context for the recent developments in the PrEP field by clarifying the concept of PrEP by distinguishing PEP from PrEP, providing an update on the current PrEP clinical trials and implications of recent changes in the trials, discussing anecdotal reports of off-label PrEP use and potential individual and community harms associated with this practice, and providing recommendations to clinicians for discussing PrEP with their patients.

Unlike PEP, which is a 28-day course of antiretroviral therapy taken shortly after a high-risk exposure, PrEP refers to HIV-negative individuals taking a daily dose of antiretroviral therapy started before HIV exposure and continuing throughout periods of risk. PrEP has several theoretical advantages over PEP as a prevention tool. Although both PEP and PrEP have prevented simian immunodeficiency virus acquisition in nonhuman primate models,^{7 - 10} data from animal studies suggest that higher levels of protection may be achieved when antiretroviral medications are given before exposure (PrEP) rather than after exposure (PEP). In addition, PEP may be challenging to implement effectively in humans because of the difficulty individuals have in accurately self-identifying high-risk exposures¹¹ and the numerous operational challenges in providing PEP to patients as soon as possible after high-risk exposure.¹²

In contrast to PEP, PrEP dosing is unlinked to sexual practice, does not require individuals to identify high-risk exposures, and does not need to be initiated within a critical period after exposure. Because many seroconverting individuals have multiple risk episodes during periods of risk,¹³ PrEP taken continuously may be a more successful strategy than PEP in reducing infection rates globally, if proven both safe and effective.

Several clinical trials are under way to evaluate daily oral tenofovir disoproxil fumarate (TDF) as PrEP in various HIV-negative populations. These first-generation PrEP studies are randomized, double-blind, placebo-controlled trials designed to evaluate the safety and efficacy of PrEP in high-risk heterosexual men and women in Botswana and injection drug users in Thailand and the biological and behavioral safety of PrEP in men who have sex with men in the United States (San Francisco and Atlanta).³ One of the authors (R.M.G.) is the principal investigator of a planned National Institutes of Health–funded efficacy trial of PrEP involving men who have sex with men in Peru.³ These studies will also collect data on antiretroviral resistance in seroconverting individuals, adherence patterns, and whether taking PrEP affects risk behavior. Although data from these trials will not be available for the next few years, preliminary data may be reported later this year from a recently completed PrEP trial in 400 high-risk women in Africa.³ Waiting for results from the full complement of PrEP trials before recommending its use is important because this single study will not provide definitive efficacy data. Also, extrapolating from one population to another will be difficult because patterns of PrEP use, tolerability, and toxicity; route and patterns of HIV exposure; and drug levels in target tissues may be different across different risk groups.

Questions have been raised about the need for combination PrEP, arising in part from recently presented data⁴ involving an evaluation of a daily combination of FTC/TDF in macaques. Although promising, these data do not provide direct comparisons of the safety, tolerability, or efficacy of single vs combination therapy. More important, data from small numbers of animals in an artificial challenge system cannot be used to predict human experience with chemoprophylaxis. In response to emerging information, the recently initiated Botswana study and the planned Peru study will involve evaluation of the FTC/TDF combination, whereas the US and Thailand studies, which are further along in enrollment, will continue with TDF alone. This complement of clinical trials will provide an evaluation of the safety and efficacy of both regimens and may help determine the optimal number of drugs needed for PrEP. Similar to the strategy for tuberculosis, the number of drugs needed for HIV chemoprophylaxis may be less than that needed for effective treatment.

It has been suggested that PrEP use may be occurring outside clinical trials.^{14 - 15} These reports describe physicians prescribing off-label PrEP to selected high-risk HIV-negative patients and describe use of tenofovir at circuit parties, sex clubs, or bathhouses in combination with “club drugs” such as ecstasy and sildenafil.^{14 - 15} Studies are needed to rigorously evaluate the prevalence of community PrEP use and to monitor patterns and trends in use.

As investigators of the TDF PrEP trial in San Francisco, which began enrollment in February 2005 and is under way, we are concerned about possible off-label or unmonitored PrEP use in the community. The currently available information is not sufficient to recommend PrEP use. Physicians should become familiar with the objectives and limitations of the current PrEP trials and be prepared to discuss with patients the risks of unmonitored use of this unproven practice.

The use of PrEP could result in an increase in the frequency or types of risk behavior in individuals who believe that PrEP is protecting them, despite the lack of efficacy data. In PrEP clinical trials, study participants receive proven prevention interventions, including condoms and risk-reduction counseling, and are told that PrEP's efficacy is unknown. Trial participants also do not know whether they are receiving placebo (which has no protective benefit) or TDF (which has no known protective benefit). If PrEP use is unblinded and unlinked to other prevention strategies in clinical practice, PrEP may be used as a justification for increasing the frequency or types of risk-taking behaviors, which could result in higher rates of sexually transmitted infections and fuel HIV transmission. Findings from the current generation of research are essential for determining how best to counsel PrEP users about risks and benefits. Additional research designed to optimize risk-reduction counseling for PrEP users will be needed if safety and efficacy are demonstrated.

PrEP use could also lead to antiretroviral resistance on the individual and community level, especially if antiretroviral agents are continued after infection occurs. This may be a particular problem if PrEP is taken episodically or even as a single-dose “evening before” or “morning after” pill, resulting in suboptimal plasma and intracellular concentrations. Rapid emergence of drug-resistant simian immunodeficiency virus with the K65R mutation has been documented in macaques with high viral loads early after treatment with tenofovir monotherapy.¹⁶ In addition, drug resistance has occurred when PEP was given to an individual who had a detectable viral load at baseline.¹⁷

Although the frequency and patterns of resistance in the setting of PrEP failure are unknown and will be evaluated in current PrEP trials, infection with acquired or transmitted virus harboring the K65R or M184V mutations could limit treatment options. In these situations, treatment may require use of drugs with greater potential for toxicity or more difficult dosing schedules. For example, the use of the soon-to-be-approved single-pill regimen containing TDF, FTC, and efavirenz would not be appropriate for patients with these mutations. To minimize the risk of drug resistance in PrEP clinical trials, HIV testing is performed frequently to minimize the risk that PrEP therapy will be started for individuals who are already infected and to help ensure that PrEP therapy is promptly stopped for those who may become infected. Such frequent monitoring for HIV infection is not typically available in current clinical practice.

In addition, unmonitored antiretroviral use could result in serious adverse events for HIV-negative individuals. Although uncommon, nephrotoxicity has occurred with use of TDF when combined with other antiretroviral medications in some HIV-infected patients, and renal function should be closely monitored with use.^{18 - 20} Although also potentially uncommon when used only sporadically, small losses in bone mineral density have also been observed during TDF therapy in individuals with HIV infection, although early bone loss may stabilize and no associated fractures have been reported.²¹ Further, TDF and FTC are active against hepatitis B virus,^{22 - 23} and hepatitis B flares have occurred after drug use is discontinued.^{24 - 25} Individuals who begin or stop taking these drugs should have liver function and hepatitis B status monitored. In addition, little is known about potential interaction between antiretroviral drugs and recreational drugs, if taken simultaneously. Drugs acquired from nonprescription sources may also harm individuals taking the drugs because quality control cannot be ensured if drugs are purchased illicitly. Furthermore, if drugs are obtained through drug sharing from HIV-positive individuals, this practice may result in suboptimal dosing and possible regimen failure in HIV-positive individuals. Many of these important safety issues in HIV-negative individuals will be evaluated in current clinical trials.

PrEP is an unproven but promising new HIV prevention strategy that is being evaluated in clinical trials. Off-label PrEP use may be occurring and could lead to individual and community harm. Treatment and research communities can work together to mitigate these potentially harmful effects of unmonitored PrEP use. First, physicians and other health professionals should be aware that PrEP use is not recommended, because insufficient information on safety and efficacy of this strategy is available. The CDC has issued recommendations for nonoccupational PEP to be used in certain situations, and clinicians should provide patient education about the availability of PEP after high-risk exposures.²⁶ In engaging patients in discussions about PrEP, the importance of using standard prevention strategies for HIV infection should be emphasized, and appropriate linkages to prevention services should be provided. Clinicians, health departments, and community-based organizations can develop educational campaigns to inform community members about the current status of clinical trials and potential harms associated with PrEP use. Community forums have been held in several US cities, including one organized by the Community HIV/AIDS Mobilization Project.²⁷

PrEP clinical trials should proceed quickly to provide the evidence required for informed counseling about PrEP. While the results of these trials are eagerly awaited, optimism for the future should not replace currently available and proven prevention strategies.