PrEP: Roadmap to the Real World

Key Questions

As the issues above are addressed, preferably through a consultative process that involves all relevant stakeholders, we need to turn ourselves to the specific questions that must be addressed by the demonstration projects. Although the list is long and possibly complex, it is not unusual in bringing new biomedical advances forward to consider such issues and answer them in clinical settings. These questions include:

1. What are the best criteria for defining the populations most appropriate for a PrEP intervention, and what outreach and recruitment strategies are most effective in reaching them?
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   Given the devastating impact HIV/AIDS has had on G/MSM and transgender communities, the first demonstration projects in the United States should focus on G/MSM and transgender women who have sex with men. There remains variation in HIV incidence and prevalence by race, ethnicity, gender identity, and geography. Therefore, it may be necessary to define and assess risk differently within different demonstration projects. For instance, a history of unprotected receptive anal intercourse might be sufficient to designate some individuals as appropriate for PrEP outreach efforts, while in others this history might need to be accompanied by a documented lack of success with other behavioral interventions.

   Given these differences in how risk is defined, and in how much various groups know about and accept PrEP, a variety of outreach and recruitment strategies will likely be desirable. Demonstration projects should attempt to capture these differences in risk definition, population targeting, and level of community knowledge about and acceptance of PrEP in their determination of the success of outreach and recruitment methods.

2. What characteristics at the individual and population level -- such as race/ethnicity and culture -- define who might need additional support for initiating and maintaining PrEP use? What additional strategies might help to support adherence and riskreduction for these groups?

   Data from iPrEx and other PrEP studies suggest that social and behavioral factors (e.g., alcohol use) might influence the success or failure of PrEP.ix Previous studies of other types of interventions have demonstrated that these factors are also strongly associated with differences in risk perception,¹⁰ attitudes toward health care providers¹¹ and antiretroviral therapy, medication adherence (in people living with HIV),¹² and retention in HIV care. What's more, structural issues (e.g. poverty) and issues related to individual resilience may influence adherence. It will, therefore, be ideal for researchers to measure these factors within demonstration projects, in order to inform the design and implementation of procedures that will encourage individuals at highest HIV risk to take PrEP and to maximize their adherence and risk reduction, while managing drug side effects.

3. What are the optimal health care settings for PrEP delivery to reach those most at risk of HIV infection, and what are the common and unique operational challenges that vary across practice settings?

   A number of factors have resulted in great variation in how HIV testing and prevention services are provided across regions of the United States. Moreover, linkages between HIV prevention providers, STI testing and treatment facilities, and HIV treatment providers add even greater variation and complexity. As such, it would be ideal for demonstration projects to be able to determine how well PrEP provision can be offered effectively and sustainably across different types of service providers, organizations, and provider networks.

   Additionally, data should be sought, both within and outside the projects, through surveys and focus groups on the attitudes toward PrEP among the providers most likely to dispense it, their knowledge of PrEP and HIV prevention in general, their comfort in conducting risk-reduction assessments and frequent monitoring, their professional practice concerns, their ability to integrate this care into operations and payment systems and their capacity for providing support for adherence.

4. What is the optimal PrEP package -- including, for example, screening, assessment of readiness to begin PrEP, STI testing, acceptable frequency of visits for follow-up testing, adherence support, clinical monitoring, and counseling -- and which intervention packages are most likely to lead targeted individuals to increase condom use and other risk-reduction strategies over time?

   Though the screening and follow-up procedures in iPrEx, Partners PrEP, and TDF2 -- along with the package of prevention services and adherence support offered -- resulted in a substantial reduction in new HIV infections, it is not yet clear whether these methods are either sustainable or ideal for every health care system or individual participant. Variations in implementation of PrEP and supportive services -- especially those which seek to reduce costs without sacrificing safety or efficacy -- may be desirable.

   Also, in all of the trials conducted thus far, self-reported condom use actually increased in study participants. This is an encouraging finding and lends weight to the argument that PrEP could be a short- or medium-term intervention that allows individuals a "bridge" to new risk-reduction behaviors and to address structural barriers to sexual health. It will therefore be ideal to determine, to the degree possible, which prevention packages and health care settings are most likely to lead PrEP users to more rapidly adopt other risk-reduction strategies.

5. What is the longer-term safety and tolerability of TDF/FTC when used for PrEP, and what is the likelihood of a person developing drug resistance to either or both drugs should they become infected while taking PrEP?

   Though data on long-term use of TDF/FTC are available for people living with HIV, little is known about their long-term safety of using these drugs in HIV-negative individuals, beyond that observed in the iPrEx trial, which has safety data collected over the longest period of time. So far the data are encouraging that the balance of safety and efficacy in HIV-negative individuals can be managed and monitored to produce a desirable benefit in the time period when use of oral PrEP is most needed. However, while there have been no documented cases of drug resistance in people who became infected after starting PrEP, this could occur. Demonstration projects should prioritize safety, tolerability, and the assessment of drug resistance. They should also document the ability, in real-world settings, of providers to handle issues of safety and tolerability when they arise and to link individuals to appropriate care.

6. What are the optimal methods for predicting, measuring, and supporting adherence and engagement with care providers?

   Although self-reported adherence was moderately predictive of efficacy in iPrEx, there was a substantial difference between stated and actual adherence as determined by the subgroup in which researchers monitored TDF and FTC blood levels.¹³ While it will not likely be cost-effective or practical to conduct blood level monitoring in real-world settings, it will be critical to utilize this method within the demonstration projects to verify which adherence support measures appear to be most successful for a given population and health care setting. Efforts should also be made to test adherence support methods -- including e-health strategies and other new technologies -- that are designed with both social and behavioral risk factors in mind.

   Additionally, it will be helpful to validate less costly and invasive adherence validation procedures, such as testing TDF in hair samples.¹⁴ According to an unpublished analysis by iPrEx researchers, one explanation for non-adherence in some participants may have been lack of sexual activity. In other cases, reasons for non-adherence were unclear. Therefore, demonstration projects should seek to understand the multiple reasons for non-adherence (both intermittent adherence problems and decisions to stop taking PrEP altogether).

7. What is the likelihood of risk compensation (the possible increase in sexual risk behavior due to perceived protection conferred by PrEP) across social and behavioral characteristics, and which practices best counter risk compensation?

   There have been no signs from the clinical trials that receiving PrEP led people to increase their HIV risk behaviors (sometimes referred to as "risk compensation"). In fact, participants in each study actually increased their condom use within the study period. In iPrEx, participants also reduced their number of sex partners. Since these findings are in the context of placebo-controlled trials, we don't yet know how people will use PrEP when they: a) know they are getting an active drug; and b) know its degree of efficacy as determined by clinical trials. For these reasons, surveys should be conducted to determine sexual behavior and perceptions of risk prior to initiating PrEP and during its use.

8. What is the total cost of delivering PrEP in various settings, and which strategies for PrEP delivery appear to be comparatively effective in terms of success in recruitment, participant adherence, HIV/STD screening, retention in care, and minimization of risk compensation?

   Given that efficacy cannot be measured within the demonstration projects (there will be no placebo against which to measure the drug's efficacy), true cost-effectiveness can't be determined. It should be possible, however, to determine which PrEP-delivery strategies offer the best responses for the variables listed above (e.g. initial uptake, adherence, retention in care, risk compensation, etc.) at the lowest cost.

9. Which types of providers or programs are most likely to ensure linkage to HIV care for those found to be HIV-positive during screening and those who seroconvert during PrEP use?

   Though the demonstration projects will not all necessarily be designed to look at linkage to care for participants found to be HIV positive, many in the field do envision PrEP falling well within a greater, comprehensive TLC+ effort. For this reason, it will be desirable to determine whether a participant who tests positive during a demonstration project (at screening or during care) is successfully linked to a health care provider for HIV care. It will also be ideal to determine how effectively PrEP provision can be added to TLC+ programs that are underway or planned.