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JAMA
March 1, 2016
Soon after the AIDS epidemic first was recognized in 1981, it became clear that penile-anal and penile-vaginal sex were primary causes of HIV spread and that safer sex practices (ie, abstinence, monogamy, consistent condom use, and substitution of less risky behaviors, such as oral sex) were protective against human immunodeficiency virus (HIV). These prevention approaches seemed effective as new HIV infections decreased from more than 100 000 per year in the 1980s to approximately 50 000 per year by the mid-1990s.1 Although early mortality among sexually active individuals infected with HIV explained some of the decrease, increased condom use clearly played a role.
However, despite 2 decades of highly active antiretroviral therapy (HAART), HIV infection rates globally remain high (about 2 million new infections annually),2 even though HIV transmission is substantially attenuated when individuals use antiretroviral therapy.3 Among at-risk persons who are uninfected, decreases in protective behaviors may be due to “therapeutic optimism,” the belief that HIV is no longer a serious illness. Among HIV-infected persons, new transmissions occur because some are unaware of their infection1 and others are not stably engaged in care (ie, not following up regularly with their primary care physician) and are not virologically suppressed, which can enable them to infect new partners.3
If HIV spread is to be halted, individuals at greatest risk of acquisition need to be engaged in new ways. Antiretroviral preexposure prophylaxis (PrEP) is tailored for individuals who have a recurring risk of being infected with HIV. Taking tenofovir daily, with or without emtricitabine, was shown to be protective in trials involving heterosexual HIV-discordant African couples, men who have sex with men, transgender women, and injecting drug users.4 Although 3 studies involving young African women did not demonstrate efficacy, plasma drug levels suggested that participant adherence to taking the prophylactic was insufficient to provide protection.4 Individuals who consistently used the medication had high rates of protection (exceeding 85% in the most recent studies). Among men who have sex with men, no incident infections were detected among those whose plasma drug levels suggested that they took at least 4 pills per week.5Unlike men, women may need to adhere more stringently to their treatment regimens because of relatively lower drug concentrations in cervicovaginal tissues, but women whose plasma tenofovir levels suggested that they were using PrEP daily were highly protected.
Some have questioned the wisdom of providing expensive medication that could enable people to engage in condomless sex and that could cause adverse effects in otherwise healthy persons. Although tenofovir can be nephrotoxic, no evidence of permanent renal insufficiency was seen among participants taking the medication during clinical trials,4 whose inclusion criteria required participants to have normal renal function. Tenofovir has been associated with a statistically significant, but not clinically significant, decrease in bone mineral density, which is leading to further evaluation of these medications in persons younger than 25 years.
However, in the absence of significant clinical toxic effects, the question for clinicians is whether the wider use of PrEP will result in net societal benefit or whether it could incur net social harms. Although the medication regimen is expensive in the United States, with annual retail costs exceeding $12 000, PrEP appears to be cost-effective,6 and ultimately cost saving7 if those at greatest risk of acquiring HIV use it. Optimal dissemination of this new approach will require significant efforts to educate clinicians and the general public. Furthermore, in the era of health care cost containment and increasing use of prospective budgeting, payers will need to adjust baseline budgets in legacy contracts, such as Medicare, Medicaid, and private insurers, to reflect the up-front costs of these new, expensive, but ultimately cost-effective, preventive technologies. This is especially true for clinicians who disproportionately care for those at risk of acquiring HIV.
Recent trials and initial demonstration projects suggest that most PrEP adopters tend to be adherent to the medical regimen.8 However, many PrEP users continue to engage in condomless sex, raising some concern that PrEP may prevent these individuals from adopting safer sexual practices. Others suggest that concerns about the abandonment of safer sex practices are ignoring the reality that many people who are not motivated to use condoms regularly may be willing to use a medication to protect themselves from acquiring HIV. In the ideal circumstance, PrEP candidates, some of whom would otherwise not seek health services, would be in contact with clinicians to access medication. These encounters could allow the clinician to assess the patient’s recent behaviors, which could lead to discussions about other prevention options, such as condoms or other behavioral changes. Monitoring visits could also include discussions about medication adherence and about screening for HIV, treatable bacterial sexually transmitted infections, or both. These regular clinical visits could decrease the amount of time between a high-risk person’s acquiring HIV or a sexually transmitted infection and transmitting that infection to other partners because asymptomatic infections could be more promptly diagnosed and treated.
PrEP in 2016 is not what PrEP will be in the future. To obviate the need for daily treatment, studies have been under way to evaluate pericoital, event-driven PrEP and to assess other modes of antiretroviral prophylaxis, such as vaginal rings, injectable medications, and new topical gel formulations. Each of these approaches might offer advantages for specific subsets of individuals. The evolution of PrEP is similar to that of hormonal contraception. When the initial contraceptive studies were undertaken, critics raised questions about moral hazard and potential toxic effects on otherwise healthy individuals. The first-generation medications had more adverse effects, but new modalities and safer formulations have been developed.
Antiretroviral PrEP will also undergo iterations. Eventually clinicians will be able to match the prophylactic modality with their patients’ social and behavioral patterns. Clinicians must play a key role if PrEP is to stop HIV spread. Sexual identity and sexual activity are intrinsic human attributes. Knowledgeable clinicians who ask patients appropriate questions about specific behaviors and provide nonjudgmental counseling may positively influence their patients. Although some clinicians may have misgivings about PrEP, it is important that primary care practitioners are educated about these issues because of their potential public health significance. The Centers for Disease Control and Prevention estimate that 1.2 million persons in the United States are at substantial risk of HIV acquisition, including 1 in 4 sexually active men who have sex with men,9 so many primary care clinicians are likely to encounter individuals who could benefit from PrEP.
Comprehensive primary care involves solicitation of information about behaviors that may not be congruent with clinicians’ personal beliefs. Because most adults are sexually active, it behooves primary care physicians to ask their patients about their sexual and drug activities to determine their risk for HIV and STDs. Clinicians should be able to offer counseling and testing to rule out these infections and consider those individuals appropriate for triage to PrEP and more frequent STD screening. Antiretroviral chemoprophylaxis is not a panacea, but it has been proven to decrease HIV transmission for diverse groups of high-risk persons and could increase engagement in sexual health care. PrEP provision should be incorporated into the compendium of evidence-based prevention interventions used in primary care.