Pre-exposure Prophylaxis State of the Science: Empirical Analogies for Research and Implementation

The introduction of new prevention technologies can be a challenging process, as high-risk individuals are often reluctant to adopt prophylactic treatment [6•, 7, 8]. Similar concerns are likely to occur with the adoption of PrEP. In developing strategies to promote PrEP adoption, researchers and practitioners should consider findings from three areas of behavioral and social sciences research: 1) information processing regarding risk and probability; 2) framing effects; and 3) the role of stigma in determining health behavior. Findings from each area provide important insights into the decision making of potential PrEP adopters and their response to potential PrEP information campaigns.

Research on communication of risk and probability information emerges from the disciplines of behavioral economics and social psychology, which study the ways in which people encode, retain, and apply probability information to make choices that involve risk/benefit calculations. In this paradigm, probability information refers to individuals’ understanding of the likelihood of particular outcomes—both positive and negative—associated with a given behavior. Risk refers to individuals’ understanding of the probability of these outcomes, plus the value they ascribe to these outcomes. For example, decision-making around risky sexual behavior involves both probability information (ie, perceived likelihood of contracting HIV or another STD by engaging in this behavior) and risk information (ie, integration of these probabilities with both negative value placed on HIV/STD infection and the positive value placed on having unprotected sex). Effective communication regarding risk and probability will be essential to PrEP adoption because PrEP is unlikely to provide complete protection from HIV infection [9]. Public information and provider-based education about PrEP must effectively communicate information about efficacy in a manner that allows high-risk populations to make informed decisions about its use. In a recent meta-analytic review of empirical findings on communication about risk and probability, Visschers and colleagues [10••] make a series of specific recommendations regarding the most effective methods for presenting probability (eg, that a certain drug might confer only 60% protection) to insure that consumers are able to understand and apply it to their decision-making processes. For example, increasing the personal relevance of risk information by presenting probability estimates tailored to an individual’s specific characteristics and context consistently results in more accurate comprehension and application of risk information. These and other findings from the literature on information processing [11] will be vital to the development of both public information campaigns and tailored personal messages to promote PrEP acceptability and adoption.

In addition to understanding the best strategies for presenting PrEP-related risk and probability information, it is important to understand factors that impact potential users’ ability to comprehend this information and apply it to their decision-making. According to the heuristic-systematic information processing model, individuals process new information either systematically—ie, by conducting a deliberative, in-depth analysis—or heuristically—ie, by using simple inferential rules or shortcuts [12]. When individuals process information heuristically, they are more vulnerable to biases that might impair their decision-making. One of the challenges to the development of effective PrEP communication strategies will be maximizing the likelihood that patients and consumers use more deliberate, systematic decision-making as they consider PrEP adoption—eg, thoughtfully considering the pros and cons of PrEP use and the feasibility of regular self-administration of drugs in their daily lives—rather than more spontaneous, heuristic decision-making. Consistent with evidence from other similar social psychological models of communication and persuasion [13], the likelihood of systematic processing is determined by individuals’ capacity for systematic processing (ie, cognitive capacity, attention, and time) and their motivation to engage in this type of processing (ie, interest, personal relevance). In constructing messages about PrEP adoption, it will be critical to consider ways to facilitate capacity and motivation among potential consumers. For example, providers must insure that PrEP information is presented to patients in a setting in which they have sufficient time and energy to engage with the message, and in a manner that optimizes personal relevance and motivation to attend to the message. Behavioral science also emphasizes characteristics of the messenger or communicator that maximize decision-making within the target or consumer [13]. Accordingly, research must examine health provider characteristics—such as communication style, clarity, and empathy—that facilitate attention and responsiveness among potential PrEP users.

The second major concept that can inform PrEP adoption campaigns involves research on framing effects. Framing effects are a central tenet of Prospect Theory [14], which argues that decision-making is significantly affected by the manner in which choices are presented. Because PrEP may show only partial efficacy in protecting against HIV infection, the communication and framing of the relative merits and limitations of this strategy are crucial. Behavioral science has shown that, when faced with an identical decision (eg, between a pill that protects 60% of the time versus one that fails to protect 40% of the time), individuals react differently when the choice is framed in terms of potential benefits (“gain” frame) compared to potential harm (“loss” frame) [15]. Research in the application of framing effects to decision-making regarding prevention behavior suggests that presentation of PrEP in either a gain frame (eg, “taking PrEP will help protect you against HIV”) or a loss frame (eg, “if you don’t take PrEP, you increase your risk of becoming infected with HIV”) may have significant effects on adoption [16], but it is currently unclear which may be more effective. More research is needed into the application of framing effects to the specific dynamics surrounding PrEP, but a nuanced understanding of framing effects is critical to the presentation of PrEP information to potential consumers.

Third, efforts to maximize PrEP adoption can be informed by research from social and health psychology on the impact of perceived stigma on health behavior [17•]. Research suggests that individuals may act in ways that might undermine their objective self-interests in order to reduce their association with a stigmatized condition [18]. For example, in order to differentiate themselves from high-risk groups, some individuals might underestimate their risk of having contracted a stigmatized illness, particularly HIV or other sexually transmitted diseases [19]. This underestimate of risk often translates into lower rates of testing and treatment for stigmatized conditions, and poses a significant barrier to uptake of vaccines or other prophylaxis [20]. Issues of HIV-related stigma are particularly relevant for PrEP adoption, as individuals may see taking PrEP as an admission that they are engaging in behaviors that put them at risk for infection. Normalization of testing or prophylactic treatment through opt-out policies, and carefully delivered PrEP education counseling, may lessen the negative impacts of stigma on potential user initiation of PrEP [21]. The success of PrEP as a prevention strategy will be impacted by ongoing structural and societal efforts to reduce HIV stigma, but the role of stigma must be considered in the development of strategies to encourage PrEP adoption.

Following adoption of PrEP, it will be critical to develop strategies to improve and support adherence to PrEP regimens. Nonadherence to prescribed regimens continues to be one of the most significant challenges to successful HIV treatment [22]. Suboptimal adherence is common among patients prescribed prophylactic regimens, and has been documented in other types of HIV-related prophylaxis [23, 24]. In recent PrEP trials, adherence rates approached only 70% [25, 26].

The most important analogies that provide lessons for PrEP adherence can be drawn from investigations of other types of drug treatment, including anti-malarial prophylaxis, treatment for latent tuberculosis infection (LTBI), and daily oral contraceptive pills (OCP), as well as the extensive literature on adherence to HIV medications themselves. Although the research is vast, three consistent findings emerge across almost all adherence investigations: 1) the importance of complete and detailed patient education at regimen initiation; 2) the role of structural issues in determining adherence behavior; and 3) the need for comprehensive approaches to adherence support. Each of these findings will be critical to the development of supportive interventions for PrEP users.

In multiple studies across prophylactic technologies, adherence is strongly associated with patients’ understanding of drug information [24, 27]. At the most basic level, PrEP adherence will be dependent on clear and comprehensive messages regarding proper administration and mechanisms of action. In a large-scale review of factors affecting adherence to treatment for LTBI [6], perceived severity of TB, perceived susceptibility to TB, and perceived accuracy of LTBI diagnosis were all identified as correlates of LTBI adherence. While perceived severity of and susceptibility to HIV infection will be critical determinants of PrEP adoption, these factors must also be addressed as motivators of sustained adherence to a PrEP regimen. For example, if high-risk individuals taking PrEP for a relatively brief time remain HIV-negative at subsequent testing, they might perceive themselves at low personal susceptibility for HIV infection and, consequently, discontinue PrEP use. In the absence of continued reminders of personal susceptibility for and severity of HIV infection, target users may question the appropriateness of PrEP prescription and need for adherence. Lessons from the LTBI literature indicate that patient education regarding PrEP must address these issues directly, ensuring that patients have an accurate assessment of the severity of HIV infection, their personal risk for transmission, and the potential of PrEP to reduce this risk.

Drug-related toxicity and side effects have also been identified as critical factors in nonadherence across medications, including both prophylactic regimens [6•] and treatment of chronic illnesses [28]. Research suggests two factors are critical to patient education at drug initiation. First, providers should distinguish between particular side effects that a particular patient is willing to tolerate and those that he or she is not. Research indicates that patients often have a specific intolerable side effect that varies by individual [29], and this information can be used to select a particular PrEP regimen or to strategize about medication to mitigate specific effects. Second, providers should help patients think through specific action plans that can be initiated in the event that intolerable side effects are experienced, including strategizing about over-the-counter medication that could mitigate side effects in the time it takes to make a medical appointment, or discussing the importance of condom use in the event that PrEP is suspended.

A third finding relevant to patient education around PrEP initiation is the importance of discussing when, where, and how patients will take the new medication. In a large retrospective study of OCP compliance in the United States and Europe, integrating pill-taking into a regular routine was the strongest single factor associated with adherence [27]. Similar findings have been identified in the adherence literature across illnesses [28]. Sustained adherence to PrEP regimens will be possible only to the extent that high-risk individuals are able to incorporate the prophylactic treatment into their everyday lives. Adherence promotion strategies may need to differentiate between daily versus intermittent PrEP dosage regimes should both be proven effective, as each dosage regimen may be associated with unique adherence challenges.

In addition to these shared insights about patient education, a second set of findings from the larger adherence literature is the emphasis on structural—ie, societal and social—factors that influence adherence. Access to affordable, convenient, and culturally competent medical care emerges consistently as one of the most important determinants of medication adherence [30••]. Other structural issues, such as housing stability and access to mental health services for depression or substance use, are also critical factors that enable sustained adherence. These structural issues are important considerations for users in resource-deprived settings, where access to clinics and private places to store and administer pills may be lacking. As discussed above, stigma associated with HIV infection may negatively impact PrEP adoption, but even once adopted, HIV-related stigma may act as a structural barrier to adherence. Individuals with HIV and other stigmatized conditions report needing to hide medications and not wanting to take pills in front of other people, as well as difficulties managing or explaining side effects [31]. Stigma concerns will be important in deciding how broadly to target PrEP; if PrEP is offered only to the highest-risk individuals, there is a potential for stigmatizing PrEP use itself. Providing systems that support PrEP adopters in managing societal and social factors must be considered in the promotion of PrEP adherence on a large scale.

Finally, adherence research has seen a call for a more integrated and comprehensive approach to intervention development. Recent reviews of advances in HIV medication adherence strategies for HIV [22, 30••] and LTBI [6•] emphasize the need for a multidisciplinary, multi-method, and multi-behavioral focus in adherence intervention development [32]. In addition, recent reviews draw attention to a mismatch between the relatively brief duration of most behavioral interventions versus the long-term timeframe in which patients are expected to maintain target behaviors. To provide ongoing reinforcement to PrEP users, behavioral supports and adherence counseling could be integrated into regular clinic visits that become standard of care for PrEP users. Underhill and colleagues (in this issue) argue for an expanded “implementation appropriate” definition of PrEP as a prevention strategy, including not only distribution of antiretroviral medications, but also provision of ongoing HIV testing, behavioral intervention, and integration of PrEP into an overall care platform. Similar to OCPs, PrEP is a prevention method that is not coitally dependent, as in the case of condom use, and has the potential to be sustained significantly longer than other prophylactic regimens such as LTBI or anti-malarial treatment. In developing supportive interventions for PrEP users over time, clinicians and researchers must consider the unique challenges of a prevention method that must be integrated into everyday life rather than associated with a specific sexual act. For example, women often report sporadic OCP use during periods of decreased sexual activity [27]. Although trials of intermittent PrEP are underway, little is currently known about the efficacy of periodic or selective PrEP use, and the potential consequences of PrEP discontinuation or “holidays,” as observed in the HAART literature. If PrEP is proven efficacious in clinical trial settings future research on periodic use will be essential, as it is almost certain to occur.

The third and perhaps most important behavior related to PrEP effectiveness is sustained sexual risk reduction among its users. Both clinicians and researchers have expressed concern about detrimental effects of PrEP adoption on other sexual risk reduction practices, due in part to increased HIV complacency and reduced perceptions of risk [33]. One ongoing concern in PrEP discussions is the potential for risk compensation, or an increase in HIV risk behavior following PrEP initiation due to the perception that one is less susceptible to infection. Indeed, a behavioral economics analysis has shown that, at the population level, prevalence of sexual risk behaviors tends to increase following the introduction of new HIV prevention technologies [34]. Cost-effectiveness models conclude that the positive impact of PrEP may be offset by even modest increases in risk behavior [1, 2, 35]. For this reason, any positive long-term impacts of PrEP will be dependent on the delivery of behavioral interventions that support high-risk individuals in combining PrEP use with sustained risk reduction practices—including condom use, partner reduction, serostatus discussion, and repeat HIV testing.

The state of the science best applied to PrEP-focused behavioral interventions begins with over three decades of HIV prevention research and intervention development. Recent reviews of efficacious HIV and STI prevention interventions [36‐38] and over 30 theories of behavior change that have most often guided intervention development [39••] can provide an important framework within which to develop PrEP-specific interventions and integrate PrEP into existing prevention efforts. In addition, it is important to consider findings regarding the association between beliefs about reduced infectiousness and increased risk behavior among HIV-positive individuals on HAART [40, 41]. These findings and the dynamics they uncover relate directly to PrEP use, both because of the number of PrEP adopters who may be in serodiscordant relationships with partners already taking HAART, and also because beliefs about reduced infectiousness may lead to behavioral disinhibition among PrEP users more broadly. In addition to lessons from HIV itself, two areas of research across behavioral sciences provide important empirical analogies to guide the development of PrEP-focused risk-reduction interventions: 1) research on dynamics of risk perception; and 2) examinations of the role of identity in intention and behavior.

Many theories of behavior change used to develop HIV prevention interventions begin with the idea that individuals need accurate information in order to make choices that will reduce health risks. However, few interventions have integrated empirical research on dynamics of risk perception into the creation of their informational components. Risk perception is likely to play a pivotal role in decisions about condom use on PrEP [42]. Research on mechanisms and processes of risk perception emerges from decision sciences and behavioral economics, focusing on the ways in which individuals understand both personal and societal-level risks and use this information to guide decision-making. According to Fuzzy Trace Theory (FTT), judgment and decision-making rely primarily on “gist” rather than “verbatim” representations of information [43•]. Gist representations are qualitative (eg, that PrEP is “good”); they capture the gut-level meaning of information (eg, that PrEP protects against HIV), but are impacted heavily by emotion, past experience, culture, and level of development (eg, that using PrEP is similar to using ART). This reliance on gist representations is often associated with inaccurate risk perception [43•], because it minimizes the important nuances, probabilities, and outcomes associated with the information. However, an overemphasis on verbatim, or quantitative, risk perception (eg, specific effect sizes from a PrEP trial) can also lead to inaccuracies. For example, individuals underestimate personal risk when they weigh the objective risks and benefits associated with a single act of unprotected sex, rather than focusing on gist perceptions that are linked to the cumulative risk of repeated unprotected acts [44].

Relatedly, PrEP intervention development may benefit from emerging research on the role of affect in risk perception and risky decision-making. Social psychological theories of emotion regard affect as a primary and dominant influence on attitudes, judgments, and behavior, often overriding or shaping cognition [45]. Other models focus on factors that determine the relative strength of “cold” cognitive systems and “hot” emotional systems in self-regulation and delay of gratification [46]. Cognitive neuro-economics provides a model describing the roles of emotion and cognition specifically in decision-making under risk, and integrates external factors (eg, physical environment, culture, group norms) and temporal focus (ie, short-term vs long-term orientation) to explain the relationship between emotion, cognition, perceived risk, and behavior [47••]. Managing conflicting emotions and affective cues will be critical to sustained sexual risk reduction on PrEP, and these models may contribute to a better understanding of the mechanisms through which PrEP availability and/or adoption impacts risk perception and behavior.

Finally, intervention development related to sustained condom use on PrEP may be well informed by research on the role of identity in predicting behavior, particularly habitual health-related behavior. For example, repeated behavior (eg, leafleting weekly for Greenpeace) may represent or signify an identifiable role (eg, volunteer; environmental activist), thereby becoming incorporated into self-concept as both an exemplar and reinforcer of a particular role-identity [48]. In many cases, role-identity has an effect on behavior that is stronger than, and independent of, an individual’s attitudes or perceived social norms. In empirical investigations, the more salient or central a particular role-identity is to an individual, the more predictive it is of both behavioral intentions [49, 50] and actual behavior [48]. Previous investigations in the field of HIV prevention have focused almost exclusively on the negative impact of role-identity on behavior, as evinced in the focus on the role of a “barebacker” identity in predicting unprotected sex among men who have sex with men. PrEP provides an opportunity to capitalize on the positive impact of role-identity on behavior. Individuals who adopt PrEP may be able to see this behavior as reinforcing an identity as a “preventionist,” ie, “the type of person who cares about reducing my risk of HIV infection.” Construing PrEP as a reflection of a risk-reducing role-identity might have a positive impact on sustained risk reduction by replacing fatalistic attitudes associated with prevention fatigue with a new emphasis on prevention activism [4].