To date, six clinical trials have explored the efficacy of pre-exposure prophylaxis (PrEP) against HIV infection using oral tenofovir and/or emtricitabine/tenofovir [1–6]. Efficacy ranged from 0 to 75% , the variation of which can largely be explained by differences in PrEP adherence . Efficacy data directly correlate with the objective adherence measures in those studies, and efficacy estimates were between 90 and 100% when adherence was consistently high [2,9,10]. PrEP is clearly efficacious when taken as prescribed.
Pre-exposure prophylaxis adherence is, however, complex and should be understood within the context of variable risk for HIV infection and use of other HIV-prevention methods. Different levels of adherence may be needed in different populations to achieve HIV prevention, and the optimal methods for achieving the necessary adherence for both individual and public health benefits are unknown. In moving beyond clinical trials toward demonstration projects (i.e. studies of PrEP delivery methods) and broader implementation in clinical care, guidance for PrEP use must consider these questions to determine if PrEP-based HIV-prevention programs are successful at both the individual and public health level.
In this article, we propose a new paradigm for understanding and measuring PrEP adherence, termed prevention-effective adherence, which incorporates dynamic HIV-acquisition risk behaviors and the use of HIV-alternative prevention strategies. We focus on sexual transmission of HIV, as the role of PrEP in preventing HIV transmission via injection drug use is less well understood. We discuss the need for daily PrEP use only during periods of risk for HIV exposure, describe key issues for measuring and understanding relevant behaviors, review lessons from another health-prevention field (i.e. family planning), and provide guidance for prevention-effective PrEP use. Moreover, we challenge emerging calls for sustained, near-perfect PrEP adherence, regardless of risk exposure, and offer a more practical and public health-focused vision for this prevention intervention.
Understanding pre-exposure prophylaxis adherence
Sustained lifelong high adherence: the paradigm for antiretroviral therapy
The adherence message for antiretroviral therapy (ART) of HIV infection is simple: viral suppression and improved health require indefinite, consistently high adherence following ART initiation . Whereas early regimens required at least 95% adherence , contemporary regimens reliably suppress viral replication at somewhat lower adherence levels (e.g. 80%) [13,14], depending on adherence patterns and prior duration of viral suppression [15,16]. Nevertheless, lifelong sustained adherence is required to stop disease progression. While scheduled intermittent dosing of ART (e.g. planned drug holidays) was suggested to ease the adherence burden, studies of prescribed intermittent ART and unplanned missed doses showed increased rates of viral rebound and worse clinical outcomes [17,18].
Sustained high adherence for the duration of pre-exposure prophylaxis clinical trials
High levels of sustained adherence are also required for the evaluation of efficacy and safety of potential PrEP agents. Thus, in placebo-controlled, randomized clinical trials, one could argue for selecting participants who are motivated to adhere, as well as providing intense adherence support to maintain consistently high adherence regardless of dynamic risk behaviors. This scenario, however, does not generalize to open-label use and uptake of PrEP that is now known to be effective.
Prevention-effective adherence: a novel paradigm
Several differences between ART and PrEP (as used outside of clinical trials) are noted in Table 1, and the type of adherence needed for each setting is presented in Fig. 1. The message for PrEP adherence is not simply 100% adherence for life or the duration of a research study. Because an individual's risk for HIV acquisition changes over time and alternative prevention strategies may be used, the indication for PrEP also changes over time. PrEP use, for example, may not be indicated if sexual activity is restricted to a monogamous relationship with a known HIV-negative partner without other risk exposures, or if another effective HIV-prevention tool (e.g. condoms) is consistently used. Perfect PrEP adherence in the absence of risk confers cost, side effects, and toxicity, but no benefit. Consistently high adherence during periods of exposure, however, is critical when PrEP is being used for effective HIV prevention.
Prevention-effective PrEP adherence means the use of PrEP only during periods of risk exposure such that it leads to effective protection against HIV acquisition. Failure to understand this concept may result in missed opportunities for HIV prevention. For example, individuals who struggle to use PrEP at certain times in their lives (e.g. young women in high HIV-prevalence areas) may be able to use it at others if they are guided through the process of understanding risk and choice of effective prevention options. Moreover, this concept can lead to efficient PrEP use that will limit adverse events and costs, and potentially widen availability in settings of resource scarcity.
The paradigm presented here is applicable to both PrEP demonstration project and wider implementation. Unlike in clinical trials, target participants in demonstration projects and implementation are those who are interested in PrEP when they are at risk for HIV exposure, but actual PrEP uptake and time-on-PrEP will vary considerably as needs change over time. Guidelines suggest PrEP should be used in populations at high risk for HIV acquisition [19,20]. PrEP is unlikely to be a preferred or cost-effective HIV-prevention tool for individuals with rare or unpredictable HIV exposure , for whom other prevention options may be more appropriate [e.g. postexposure prophylaxis (PEP) for victims of rape, or condom use for individuals with infrequent sexual encounters who can use condoms effectively].
Measuring prevention-effective combination adherence
Prevention-effective adherence requires measurement of HIV-risk exposure, use of PrEP, and use of other effective HIV-prevention tools. These factors are then combined in the calculation of adherence.
The first step in measuring prevention-effective adherence is the assessment of risk for HIV exposure. Measurement of risk exposure is challenging and largely limited to self-report of behavior or perceived risk, which may be inaccurate due to recall and social desirability biases . Accuracy, however, may increase via short recall periods [23,24] and can be measured concurrently with medication adherence (e.g. 24-h recall by SMS surveys) . Biomarkers of sexual intercourse (e.g. prostate-specific antigen in vaginal secretions) can provide objective evidence of sex; however, they are difficult to obtain and impractical for clinical practice [26,27]. They also do not comment on male sexual activity. Surrogate markers (e.g. incidence of other sexually transmitted infections and pregnancy) may provide some indication of potential HIV exposure, but are generally informative at the population, not individual, level. Risk assessments should aim to identify periods of sustained risk, for which PrEP might be a preferred HIV-prevention option. Ongoing studies (i.e. IPERGAY, HPTN067, and HPTN 069) involve extensive data collection on sexual behavior and risk for HIV exposure, and may provide further insights into optimal measurement strategies.
Use of pre-exposure prophylaxis
The next step in assessing prevention-effective adherence is to quantify PrEP use. No gold standard exists for measuring medication-taking behavior; all have strengths and weaknesses (see Table 2) [28,29]. Because all adherence measures are imperfect, a context-appropriate set of more than one measure is needed to understand adherence behavior. Importantly, self-report did not correlate with drug levels in several PrEP clinical trials and was largely uninformative due to over-reporting of adherence [4,6]. As noted above for self-reported risk behavior, self-reported adherence may be improved through SMS surveys of short recall periods and/or questions that have that been validated with objective PrEP adherence measures. The accuracy of self-report may also improve in the absence of consequences for reporting socially undesired behavior (e.g. burdensome intervention components when condomless sex or nonadherence is reported). Importantly, reporting of nonadherence is more likely to be accurate than reporting of adherence . Pharmacy refill records provide an objective approach that has performed well in predicting viral suppression in ART programs  and may be feasible for routine clinical use with PrEP. While cost limits electronic adherence monitoring to research studies, it is the only method that provides dose-by-dose measurement for assessing adherence patterns, which are critical for understanding prevention-effective adherence . Electronic monitoring in at least a subset of participants in demonstration projects should therefore be considered. Wireless electronic monitoring is also available and can provide data in real time, reduce the risk of data loss, and decrease the human resources needed for data collection in geographically dispersed settings . Drug levels were critical in providing objective documentation of drug ingestion in the PrEP clinical trials; however, they are also impractical for routine use. Stored samples for selective testing offer a less expensive approach that may be appropriate for demonstration projects.
Demonstration projects that involve multiple PrEP adherence measurements will help determine the best measures for prevention-effective PrEP adherence, which can then be compared to assess the most informative, accurate, and affordable measures for use in the less resourced context of implementation. For example, electronic monitoring or drug levels may be used to determine which types of self-report questions best identify individuals with adherence challenges.
Prevention-effective adherence also requires measurement of PrEP initiation and discontinuation. An objective approach is to determine when medication was picked up via pharmacy refill records. The timing of discontinuation, however, is difficult to know, as individuals may initiate and discontinue PrEP multiple times during a single refill period. Electronic monitors can provide more precise patterns of PrEP initiation and discontinuation. Self-report may be considered as a complementary tool to further define either of these objective measurements. For example, individuals can be asked whether periods of nonadherence were intentional or unintentional. The above-noted limitations of self-reported data, however, should be kept in mind.
A key distinction should be drawn between periodic and intermittent PrEP use. ‘Periodic use’ involves voluntary starting and stopping of daily PrEP use depending on HIV-prevention needs and choices (e.g. while trying to conceive a child within a serodiscordant couple ). Periodic use is based on the once-daily dosing recommendation, and periods of time can be considered as on or off PrEP for as long as PrEP is part of an overall HIV-prevention approach. In contrast, ‘intermittent PrEP’ refers to a prescription of less-than-daily PrEP, as was used in the International AIDS Vaccine Initiative (IAVI) pilot randomized controlled trial [35,36] and is currently being evaluated in IPERGAY and HPTN067. Preliminary data from IPERGAY are promising, although a full understanding of the data is pending . Importantly, adherence to intermittent doses was lower than to fixed doses in the IAVI trial.
Use of other HIV-prevention tools
While measuring use of the other HIV-prevention tools is complex and beyond the scope of this article, it is an important concept in defining prevention-effective adherence. Briefly, condom use and behavior modification (e.g. partner reduction, knowledge of HIV status) typically rely on self-report. Medical male circumcision does not require ongoing adherence measurement; however, a 50% reduction in risk of HIV acquisition is arguably insufficient to recommend it as a sole prevention strategy. ART in the HIV-infected partner of a stable serodiscordant couple can prevent secondary transmission, and adherence may be measured as described above for PrEP, as well as with HIV RNA levels. Other forms of PrEP beyond tablets (e.g. vaginal rings, gels, depo injections) may become available and individuals may choose different formulations at different times. Ongoing assessments of when and how various HIV prevention tools are used are therefore needed.
Execution and persistence of prevention-effective pre-exposure prophylaxis adherence
The above three factors are all required to calculate two types of adherence: execution and persistence. First, execution of prevention-effective PrEP adherence refers to adherence during the time an individual relies upon PrEP for protection against HIV acquisition (Fig. 2). It depends on periods of HIV risk as defined by behavior and/or use of other effective prevention tools, as well as initiation/discontinuation of PrEP. It is not simply lifelong as with ART or for the duration of a clinical trial. Execution of prevention-effective adherence should include the doses needed to achieve effective drug concentrations during PrEP initiation (discussed below), but should not include periods without risk exposure.
For example, a sex worker may engage in unprotected sex for 6 months in an urban setting, but then return home to a rural area for the following 6 months where she does not engage in any sex. If she took PrEP daily for all but the final 2 weeks of the 6 months spent doing sex work, her executed adherence would be 92%. If she stopped sex work a month early, her executed adherence would be 100%. Conversely, if she continued daily PrEP for the full year without sex work in the final six months, her executed prevention-effective adherence would be 200% (thus, a potential misallocation of resources and unnecessary risk for side effects). Both PrEP use and the number of expected dosing events should be censored when HIV-transmission risk approaches zero.
Persistence of prevention-effective PrEP adherence describes the duration of PrEP use before an individual stops it (either temporarily or permanently). End of use should be defined by self-reported intentional cessation or a clear break in use (e.g. 28 days of non-use), as consistent with the concept of periodic PrEP use. Missing a few doses because of temporary lapses still constitutes persistence, albeit with imperfectly executed adherence. With ART, persistence is desired for life, so no denominator is needed. With prevention-effective PrEP adherence, persistence should be considered over the duration of risk based on behavior and/or use alternative HIV-prevention tools. Importantly, the length of the denominator should be noted to reflect the extent of risk.
For example, an individual using PrEP for the first 5 of 6 months with HIV risk behavior and no other effective prevention tools has a persistence of 83% over 6 months. Another individual using PrEP for the first 10 of 12 months with risk and no alternative effective prevention tools also has a persistence of 83% over 12 months. Although the percentage of persistence is the same, the overall risk for the latter individual is higher, given the potential for exposure during 1 month more than the former individual. This time-dependent nature of risk is important in considering the overall effectiveness of a given level of persistence. Additionally, it is important to note that someone may have high persistence and still not achieve prevention-effective adherence, if the execution of adherence during that time is inadequate.
The effectiveness aspect of prevention-effective adherence requires HIV testing. Current guidelines recommend testing prior to initiation of PrEP and periodic testing during use [19,20], although the optimal schedule for periodic testing is not clear. Both clinic-based and home-based approaches are being explored in demonstration projects . Given the lack of evidence on the optimal interval for retesting, adherence to HIV testing at a given interval should not preclude PrEP use. However, testing prior to re-initiation of PrEP after a period of nonuse is critical to avoid drug resistance due to ongoing use during acute infection. Underappreciation of risk could result in exposure without PrEP use, making such testing particularly important when targeting prevention-effective adherence.
Interpretation of pre-exposure prophylaxis adherence by route of infection
When putting PrEP adherence in the context of risk exposure, two additional factors must be considered to discern if a given PrEP adherence pattern will provide the anticipated effectiveness: steady-state drug concentration and drug level at the time of exposure. These factors differ with the route of exposure and are critical for knowing how much PrEP is enough.
Steady-state drug concentration
Efficacy in most oral PrEP trials has been associated with blood concentrations of tenofovir [1–3,5]. Most estimates indicate that approximately seven daily oral doses will result in steady-state drug concentrations in blood mononuclear cells [39,40]. Fewer data are available to guide when steady-state concentrations are achieved in vaginal and rectal tissue , but data generally parallel concentrations in blood , thus providing a reasonable evidence-based recommendation for 7 days of PrEP use prior to achieving protection. The impact of missed doses on efficacy may have more serious implications when steady state has not yet been achieved (i.e. there is likely less ‘forgiveness’ for missed doses). Given that PrEP use may be periodic, these factors must be considered throughout PrEP use, not just at initiation.
Drug level at the time of exposure
To provide protection, the adherence pattern must result in a drug level at the time of risk exposure that is adequate to prevent HIV replication. In modeling studies based on MSM, two doses per week on average may provide 76% efficacy, four doses per week 96% protection, and seven doses per week 99% efficacy . However, tenofovir concentrations are much higher in rectal compared to vaginal tissue; therefore, vaginal tissue may require more frequent oral dosing to maintain drug levels in a protective range [41,43].
Additionally, the precise timing as to when risk from an exposure has passed is unclear because it is unknown how long HIV takes to be completely cleared from the body. Practical guidance can be drawn from PEP, for which recommendations indicate 28 days of continued use after exposure . PrEP differs from PEP in that early replication is presumably blocked by PrEP from ongoing use, and 28 days of postexposure dosing without further risk may be challenging for some individuals. However, 28 days of continued dosing allows ample time for adopting alternative HIV-prevention tools. Additional research in this area is needed.
Guidance in achieving prevention-effective adherence for individual and public health benefits
The paradigm of prevention-effective adherence will be new for at-risk individuals, as well as researchers, clinicians, and policy makers. In efficacy trials, at-risk individuals are typically given one or more HIV-prevention tools and are expected to consistently adhere to all prevention strategies regardless of need or preference. In demonstration projects and implementation, a menu of prevention options is more likely to reflect how individuals will achieve personal HIV prevention. Specific guidance is needed in the provision of HIV-prevention options and associated counseling messages.
Lessons from family planning
Although conception and HIV infection are clearly very different conditions, both occur via sex and multiple strategies exist for prevention; lessons learned from family planning may therefore be useful for PrEP . Studies have shown that women frequently move among contraceptive options . A woman may use oral contraceptive pills (OCPs) for some time, but stop when she no longer has a sexual partner. She may choose depo injection, OCPs, or some other female-controlled method if her partner does not want to reliably use condoms. After missing several OCPs, she may switch to condoms as an effective alternative for contraception with future exposures. Women can adapt and change their choice of contraception to fit their needs, perceptions, and preferences. A similar approach could be used for HIV prevention, and measurement of adherence to each method will then determine if the individual has achieved prevention-effective adherence. Of note, even after long-acting injectables or rings are available for PrEP, pill-based options will still make sense for some people at certain times in their lives.
Despite the many existing contraceptive options, unwanted pregnancies still occur. Correspondingly, HIV infections will still likely occur despite the availability of PrEP and other prevention tools. Nevertheless, more HIV will be prevented with these tools than without them, just as family planning programs implemented in real world settings globally have prevented many unplanned pregnancies, in spite of imperfect risk assessment and use of contraception. Further research on understanding and supporting prevention-effective adherence is therefore needed to optimize outcomes.
Counseling for prevention-effective pre-exposure prophylaxis adherence
To understand prevention-effective PrEP adherence, individuals will need guidance in making decisions about prevention options. Considerations include their preferences, abilities, risks, and behaviors, as well as the timing of potential exposures . Key adherence information for PrEP users is listed in Table 3; additional information for general PrEP use and adherence should be obtained through other sources, such as governmental and other guidelines, and may need targeting the specific needs of each population [19,20].
For instance, daily PrEP may be useful as a short-acting bridge while an HIV-infected partner accesses and becomes virally suppressed on ART, as is being investigated in the Partners Demonstration Project. Frequent use of PEP may suggest the need for the more proactive strategy of PrEP. If depo injections of long-acting PrEP become available, daily PrEP may be a good option initially to see if side effects develop. Adherence to longer-acting agents will require unique messages directed at infrequent events (e.g. getting depo injections), which has been shown to be challenging for multistage vaccines . Both execution and persistence of adherence can help individuals determine if PrEP will be an effective prevention tool for them. Those who vacillate between PrEP and condoms, for example, are unlikely to achieve prevention-effective adherence with PrEP and should consider focusing on condoms alone or another strategy. Adherence counseling should also address the current recommendation for seven daily doses to achieve protective levels of drug, as well as risk for infection after an exposure, as discussed above.
Using prevention-effective adherence to define programmatic success
Success for HIV-prevention programs should not depend on consistently high PrEP adherence every day for life, as is the standard for ART programs and clinical trials under the old adherence paradigm. Rather, success may be better defined as providing access to multiple prevention tools for the people most at risk for HIV infection, with high adherence to at least one tool at any given time. This approach may be conceptualized as prevention coverage. To what extent is the population covered? To what extent does PrEP increase that coverage and at what cost? Within the iPrEx study, men using PrEP were not the same individuals who were using condoms at baseline ; PrEP filled a prevention gap.
In conclusion, adherence is critical for PrEP effectiveness. Rather than viewing PrEP as a daily pill taken indefinitely, however, it should be seen through the lens of prevention-effective adherence, which takes into account multiple prevention strategies and dynamic risk for HIV acquisition. Measurement of PrEP adherence must include an individual's choice of tools, the timing of those choices, and the pattern of risk behaviors. Although further research is needed on the best measures for both PrEP use and HIV risk, the concept of prevention-effective adherence should be considered as programs explore PrEP for HIV prevention. Discontinuation of PrEP does not necessarily equal failure. Rather, it may be a strategic, effective, and efficient choice for a given individual. HIV-prevention programs may be able to learn from other prevention efforts, such as family planning, so they can supply the access and support needed to successfully guide individuals through a menu of HIV prevention options.
The authors would like to thank the WHO, and Bill and Melinda Gates Foundation for convening a meeting of the authors to discuss key issues in PrEP adherence in June 2014.
Funding: Bill and Melinda Gates Foundation (OPP1056051), US National Institutes of Health (R01MH098744, R01MH095507, U01AI106499), WHO, and the President's Emergency Plan for AIDS Relief
Contributions of authors: All authors contributed to the development of the ideas contained in this manuscript. J.E.H. wrote the first draft of the manuscript, which all other authors edited significantly.
Conflicts of interest
There are no conflicts of interest.
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