Introduction
Efforts to reduce HIV infection through the use of topical and oral prophylactic antiretrovirals (ARVs) have recently yielded remarkable successes [
1‐
4], with two exceptions. In the FEM-PrEP trial, product adherence was too low to assess the efficacy of daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada) in preventing HIV acquisition in the study population [
5]. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, futility results (the inability to show efficacy for protection from HIV infection) for daily oral tenofovir and vaginal tenofovir gel remain to be explained [
6,
7]. The FDA approval of prophylactic use of Truvada has increased attention on who should be the target group for oral PrEP and how to optimize PrEP adherence to maximize its prevention potential. Even with highly effective ARV-based PrEP drugs, use of the drug is essential to confer protection, and no or low drug use results in no protection [
5,
8]. In both the Iniciativa Prophylaxis (iPrEx) and Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trials, a clear dose response could be delineated with higher levels of protection observed with higher adherence to product use. Enhancing understanding of who will use PrEP and how it will be used is recognized as an important challenge [
9,
10]. In contrast to the large body of literature available with respect to supporting and promoting adherence to ARVs in a therapeutic context, less is known about how to support adherence in the context of prophylactic use of ARVs among healthy, HIV-uninfected individuals [
11,
12]. Despite clear recommendations to support or ‘counsel on’ PrEP adherence among those opting to use it [
13‐
15], to date there are few publications or guidelines on how to operationally and effectively do so.
Evidence-based guidance on how to best support PrEP adherence is starting to emerge [
12], as this area of research has only recently come to life with the identification of effective PrEP products. All blinded trials of PrEP agents have used strategies to support adherence in their study populations, and all are confronted with the challenges of promoting adherence among healthy participants to products of unknown efficacy, incomplete safety profiles, and with equal odds of participants receiving the active agent or a placebo. Despite the limitations of product use in clinical trial settings, lessons learned from the approaches used to support product use in blinded trials can offer concrete guidance for future PrEP efficacy trials, and initial guidance for supporting PrEP use in “real life” contexts.
Here, we offer an overview of the adherence support approaches developed for use in CAPRISA 004, FEM-PrEP, iPrEx, and VOICE (detailed in Table
1). Our aim is to describe the approaches deployed, clarify the strategies leveraged to promote product use in these diverse settings, and share experiences that will likely continue to be relevant in demonstration projects. Within each trial, the adherence support approach was applied as standard practice. Hence, evaluation of adherence intervention efficacy with adequate comparison controls is not possible. Rather, our explorations are based on experiences amassed by study teams and the resulting recommendations that emerge from these for supporting PrEP use in demonstration and efficacy trials.
Table 1
Trials and adherence support programs developed
Product | Tenofovir 1 % gel | TDF/FTC tablet | TDF/FTC tablet | TDF/FTC tablets (ongoing); TDF tablets (stopped); Tenofovir 1 % gel (stopped) |
Regimen | Coital (BAT24) | Daily | Daily | Daily |
Sample size | 889 | 2,120 (3,900 original sample size) | 2,499 | 5,029 |
Location | South Africa | Kenya, South Africa, Tanzania | Peru, Ecuador, South Africa, Brazil, Thailand, United States | Uganda, Zimbabwe, South Africa |
Population (age) | Women (18–40) | Women (18–35) | MSM, TW (18 +) | Women (18–45) |
Months on-study | 12–30 | 14 | ~33 | 12–36 |
Pre-enrollment experiential activities | Product introduction and demonstration | Run-in: with daily vitamin | None | None |
Product counseling; support approach in use at end study | MI; client-centered, options | MI; client-centered | MI; client-centered | MI; client-centered, NSC |
Behavioral theory | IMB | IMB | IMB | IMB |
Launch of support approach | Mid-trial (month 16) | Trial onset | Late-trial (month 34) | Mid-trial (month 20) |
Counseling frequency | Monthly | Monthly | Monthly | Monthly |
Implementers/counselors | Nurse counselors | Nurse counselors, counselors | Mixed (nurses, counselors, clinicians) | Mixed (nurses, counselors, pharmacists) |
Training required/provided | • 1-day workshop • Monthly to quarterly follow-up interactive sessions over course of project • Debriefing sessions | • 4 sessions (8 h) during study training • 2-day follow-up training • Monthly to quarterly counselor discussions | • 1 to 3 day workshops* • Booster on-site visits approximately 3–6 months after trainings (2 h) • Monthly conference calls | • 1-day workshop • Booster on-site visits ~5 months post-workshops (~2 h) • Monthly conference calls |
Tools incorporated | Yes (e.g., clock face, adherence prescription) | Yes (e.g., pill boxes, calendar) | Yes (e.g., pill boxes and other dose-carrying tools) | Limited (calendars) |
Barriers emphasis | Yes | Yes | No | No |
High adherence praised/reinforced | Yes | Yes | No | No |
Use of product doses taken/missed in counseling | Yes—product counts and applicator returns used to alert nurses to potential problems | Informal assessment of product use (separate from the official trial-collected measurement of adherence); one site used product counts to guide counseling | No | No |
Site-level adherence used as performance feedback to site PIs | No | No | No (removed) | No |
FEM-PrEP
Overview
FEM-PrEP was a phase III RCT designed to assess the safety and effectiveness of a daily oral dose of TDF/FTC for HIV prevention among women at higher risk of HIV in Kenya, South Africa, and Tanzania (see Table
1). In April 2011, the FEM-PrEP investigators decided to stop the trial early, because the Independent Data Monitoring Committee recommended that the study would be unlikely to demonstrate the effectiveness of TDF/FTC in preventing HIV infection even if the trial continued to its planned end and all end-points were collected [
5].
Prior to trial initiation, socio-behavioral research was conducted to inform the behavioral components of the trial [
22]. In-depth interviews (IDIs) and focus group discussions (FGDs) were conducted with potential participants, community stakeholders, and men from the community to identify factors that might facilitate or impede daily pill use. These data guided the development of the adherence counseling approach for FEM-PrEP participants, as did adult learning principles, lessons learned from adherence counseling for antiretroviral treatment and contraceptives, the IMB model, and MI [
23‐
30]. In addition, a vitamin run-in period was implemented prior to dispensation of study drug. The vitamin was about the same shape and size as the study tablets. Participants were asked to take one vitamin daily between the screening and enrollment visits. At enrollment, participants were observed swallowing the tablet. Those unable to swallow the tablet could not enroll. Experiences with vitamin adherence were then explored during adherence counseling at enrollment and used to create personal adherence plans for the study drug.
Adherence Support Approach
Participant-centered and goal-oriented adherence counseling was provided by a trained counselor at each monthly study visit in all sites as early as possible in the flow of the visit. Participants developed a personal adherence plan in collaboration with the study counselors, which included strategies to integrate pill-taking into daily routines and social context. Each follow-up adherence counseling session began with participants describing their experience with trying out their previous adherence goal over the past month. Counselors also asked participants how many pills they missed in the past 7 days. Participants described any barriers they faced and how useful the previously identified strategies had been in overcoming those barriers. Counselors tailored the counseling topics and questions to each participant’s situation, although the same steps were followed for each participant regardless of their reported level of adherence. Counselors were trained to remain non-judgmental when instances of non-adherence were reported, and to acknowledge good or improved adherence. Counselors were also trained to assist participants in transforming barriers into goals. For example, if a participant had difficulty taking the pills over the weekend, the participant and counselor would strategize on how the participant might be able to take the pills during those days (e.g., set an alarm, link to an event that occurs on weekends), and the goal would focus on the implementation of that strategy. Counseling ended with participants refining their adherence plans and goals as needed. Table
2 lists specific steps followed at each counseling session.
Table 2
FEM-PrEP: Adherence counseling topics at the screening, enrollment, and follow-up visits
Introduce counselor and role of adherence counselor | Introduce counselor, if needed |
Review information about study and assess knowledge | Discuss participant’s experience in trying last session’s adherence goal |
Discuss how to take vitamins | Ask about adherence to vitamins (enrollment)/study pill (follow-up) |
Discuss potential barriers to adherence | Discuss barriers faced and usefulness of strategies implemented to overcome barriers in previous month; identify new strategies as needed |
Discuss upcoming travel | Review information about the study and assess knowledge | Assess knowledge and review information about the study (weeks 4–12) and as needed (weeks 16–48) |
Discuss potential tools/strategies for barriers identified, including pill box and calendar demonstration | Discuss how to take study pills | Assess for side effects and provide home management of side effects, if needed |
Assist participant in making an adherence plan for the vitamin regimen: • Strategies to try to overcome potential barriers • Time of day or daily activity to link to taking vitamin • Where to store vitamins • How to maintain confidentiality, if needed • Adherence goal | Discuss potential stigma |
| Discuss upcoming travel and potential impact on adherence |
| Assess and discuss participant’s perception of the importance of taking the study pill and perceived ability to take the study pill daily |
| Assist participant in making an adherence plan (same items found in screening checklist) | Discuss adherence fatigue (starting at week 20) |
| | Discuss partner’s feelings about her participation and support provided; discuss the influence of friends/community perceptions about the trial and whether support is provided |
Adherence counseling checklists were used to facilitate counseling in all sites, and prior to the counseling session the counselors reviewed the checklist from the previous visit in order to contextualize the current counseling session. Various adherence tools were also offered (e.g., pill boxes, calendars), and key messages on adherence were provided at strategic time points over the course of the trial to provide necessary information but to avoid overburdening participants with too much information (e.g., key messages were explained in detail at enrollment, assessed and summarized monthly for the first quarter, and then provided on an as-needed basis thereafter).
Operational guidance was also provided. In some sites, IDIs were conducted quarterly with a 5 % random sample of enrolled participants. Data describing the adherence facilitators, barriers, and experiences with the study product among these participants, as well as summaries of self-reported adherence among all participants, were provided to counselors so that they could explore the content with participants when applicable (e.g., suggestions on facilitators, experience with specific barriers, pill taking fatigue). In addition, in 2010 one site expressed concerns that adherence may be lower than reported, following feedback from various community forums and information obtained from participants during the IDIs. In response, all participants at that site were invited to take part in one of several group meetings to discuss concerns about adherence and rumors about the study product. Participants’ concerns were summarized and provided to counselors; counselors were encouraged to explore with participants in subsequent counseling sessions the possible rumors that may have impeded their pill use.
To reduce socially-desirable responses in the self-report measurement of adherence, the behavioral questionnaires were administered before adherence counseling by different staff from those facilitating adherence counseling in all sites. Counselors did not review these behavioral questionnaires prior to providing counseling.
1
Monitoring and Evaluation
Observations of adherence counseling were conducted by behavioral leadership at some sites. Discussions among counselors took place monthly after trial initiation, and then quarterly to review data summaries, discuss experiences, and make decisions on steps to enhance adherence counseling as appropriate. Data were collected during IDIs with women who seroconverted during the trial on their perceptions of adherence counseling. These data are currently being analyzed.
Primary analyses revealed that adherence was low, despite the substantial adherence counseling support described above. Fewer than 40 % of a representative sub-sample of uninfected women had any evidence of study drug in plasma within 48 h of specimen collection. In contrast, self-reported adherence was high, with 95 % of participants reporting that they ‘usually’ or ‘always’ used the product as recommended over the course of the trial, and pill count data were consistent with participants having used the product on 88 % of days in the trial [
5].
Additional drug level analyses of stored biological specimens are planned in order to characterize adherence among study participants assigned to TDF/FTC. Specifically, intracellular drug level testing will provide a better understanding of adherence in between study visits since tenofovir diphosphate has a half-life measured in days and remains detectable weeks after cessation of dosing. Mixed-method analyses integrating quantitative, qualitative, and drug level data will also provide insight into low adherence, discrepancy between self-report and drug level data, and variations across sites. These analyses will examine the association between HIV risk perception and drug level, facilitators and barriers to adherence among those with various drug levels, population characteristics and relationship dynamics, and motivation to join and remain in the trial.
Summary and Recommendations
Across the approaches reviewed in the four oral and microbicide gel PrEP trials, the critical role of adherence was recognized from study onset, with promotion and monitoring strategies in place from the start. However, few trials have fully appreciated the more nuanced impact of social, individual, and clinic-related factors that would ultimately influence product-use and the accurate reporting of it. Rather, in many cases trials started with a strong emphasis on education, information, and use of persuasion (praise, reinforcement, accountability) to promote “perfect” adherence. Modifications to varying degrees were made in several of the trials to move beyond information-provision and optimize adherence support using well-established health behavior models and intervention strategies. All four approaches converged in regard to underlying health behavior theory, trainings deployed on approach, implementation at study visits, use of motivation-enhancement strategies, and brevity of adherence-support conversations.
Despite considerable consistency in the approaches used in these four different trials, estimated product use (where available) varied considerably and was generally lower than desired. Without an experimental design, it is not possible to evaluate if the enhanced adherence support approaches implemented had any effect on actual product adherence. Because several trials changed approaches to supporting and/or monitoring adherence mid-trial or later, evaluation of the effect of these changes is particularly complicated. Any attempt to evaluate the impact of the adherence approach or subsequent changes would have to account for multiple sources of bias (e.g., dropping of specific arms in a study, release of CAPRISA 004 results for participants in other studies, increasing length of time on study, etc.) and this cannot be done without a non-adherence intervention comparison group. As such, the added benefit of any given approach will be difficult to conclusively evaluate. Qualitative data collected in the context of these trials are under evaluation, which will provide much needed guidance on the role of socio-cultural and community based factors as contributors to (non)-adherence. Diversity in participant populations, risk-perception, culture, community, structures promoting and inhibiting product use, and the culture of sites themselves may likely explain a large part of the variability reported in product use across trials, sites, and participants. These social-cultural dynamics need targeted exploration and research to fully appreciate the context in which regimens are presented, “prescribed,” executed, and maintained. A more thorough exploration of these dynamics can take place through implementation of high quality behavioral research in the context of PrEP demonstration projects, including examination of the models developed to guide the intervention approaches (e.g., what are the main drivers of adherence to PrEP or to product use, how do they interrelate, and what proportion of variability in adherence do they reliably explain), as well as through randomized controlled trials of specific behavioral intervention strategies to promote PrEP or product use.
While most trials reviewed here documented to some extent the implementation of adherence support approaches and exploration of general acceptability and feasibility of the approaches, none used fidelity and implementation monitoring strategies commonly adopted in trials of behavioral interventions (e.g., video or audio review or evaluation of counseling sessions). Fidelity of implementation was often captured only at the most basic level, through collection of checklists or worksheets of steps implemented completed by counselors, leaving many questions concerning actual implementation unanswered. Even if adherence support approaches are well-matched to the participants and their socio-cultural surroundings, intervention drift, adaptation and modification will likely occur to varying degrees (cf., [
39]). Indeed, allocation of resources and competing trial priorities limited the feasibility of intensive monitoring of implementation in any of the trials discussed here. While each trial can speak to what was recommended and how adherence support staff were trained, the fidelity of what was actually implemented and the extent to which it modeled participant-centered approaches versus instruction and persuasion is not clear. Research employing methods to fully characterize implementation and fidelity of adherence support approaches (e.g., use of systematic evaluation of implementation through observation, audio or visual recording, and content, process, or discourse analyses) is needed.
With these limitations in mind, it is critical to add rigorous behavioral research to the agenda for PrEP demonstration and on-going efficacy trials. Partners PrEP [
2], a phase III double-blind, placebo controlled, clinical trial of safety and efficacy of oral PrEP (TDF alone or in combination with FTC) among serodiscordant couples in Kenya and Uganda, is one of the only studies completed to date that specifically included a structured adherence intervention as a sub-study. The sub-study involved over a thousand sero-discordant couples at three of the nine parent study sites and used objective measures of product-use to both trigger and evaluate intervention [
40]. Results from this sub-study in terms of effects on product use are expected in 2013 and will provide guidance on the use of targeting adherence support (e.g., providing support when product-use is identified as sub-optimal) and the adaption of a demonstrated treatment intervention to support PrEP adherence (LifeSteps, described in [
41]). Results supporting near-perfect adherence among Partners PrEP participants have already been reported [
2,
40], as have the potentially unique motivations for product use within sero-discordant partnerships [
42]. Of particular importance, Partners PrEP demonstrates the feasibility of clinical trial designs that include comprehensive monitoring of product use and implementation of rigorous behavioral interventions. The Partners PrEP example shows that these designs are not only feasible, but also generate interpretable results and provide a better understanding of the relative contribution of the behavioral and biomedical components of PrEP trials to the overall study findings.
Shifting from a biomedical to a bio-behavioral, or rather a bio-psycho-social, framework will help build the evidence base for effective PrEP adherence interventions. As we enter a new era with oral PrEP now available in some locations [
43], shifting attention to support open label PrEP use among those who seek out and adopt this prevention strategy will offer new insights and opportunities to carefully consider the role of the individual, partners, community, care providers, health systems, and the dosing regimen in the ultimate success of PrEP.
Acknowledgments
This manuscript greatly benefited from the editorial and content contributions from Quarraisha Abdool Karim. We also wish to acknowledge the valuable reviews from Vanessa McMahan, iPrEx RCT, and reviewers from MTN. All four study teams would like first and foremost to pay tribute to the women and men who participated in these trials, their dedication and commitment made these studies possible.
CAPRISA 004: The CAPRISA 004 tenofovir gel trial was supported by the Centre for the AIDS Program of Research in South Africa (CAPRISA), the United States Agency for International Development (USAID), FHI (co operative agreement # GPO-A-00-05-00022-00, contract # 132119), and LIFElab, a biotechnology centre of the South African Department of Science and Technology. Support from CONRAD for the product manufacturing and packaging as well as support from Gilead Sciences for the tenofovir used in the production of gel is gratefully acknowledged. We thank the US National Institutes for Health’s Comprehensive International Program of Research on AIDS (CIPRA grant # AI51794) and the Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP grant # D43TW00231) for the research infrastructure and training that made this trial possible.
FEM-
PrEP: The FEM-PrEP team would like to acknowledge and thank Judith Harkins for developing the adherence counseling session program and materials. FEM-PrEP was a partnership between FHI 360 in the U.S. and local scientists and project staff at the Impact Research and Development Organization (Kenya), Setshaba Research Centre (Pretoria, South Africa), Josha Research (Bloemfontein, South Africa), and Kilimanjaro Christian Medical Center (Tanzania). FEM-PrEP Investigators included Drs. Lut Van Damme (Clinical PI), Amy Corneli (Behavioral PI), Kawango Agot (Bondo Site Investigator), Khatija Ahmed (Pretoria Site Investigator), Johan Lombaard (Bloemfontein Site Investigator), and Rachel Manongi (Arusha Site Investigator). The study was funded by the U.S. Agency for International Development (USAID), and it also received early support from the Bill & Melinda Gates Foundation.
iPrEx: The contributions of the Adherence Working Group, Ed Wolf, and the study site team members are acknowledged as critical factors in the development and implementation of NSC and NA. The full iPrEx study team can be viewed at
http://iprexole.com/. The iPrEx RCT was funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.
VOICE: The contributions of the MTN Behavioral Research Working Group, the VOICE leadership, the VOICE Adherence Working Group, Ashley Mayo of FHI360, Ed Wolf, and the study site investigators and team members are acknowledged as critical factors in the development and implementation of VASP. MTN is funded by NIAID (5UM1AI068633), NICHD and NIMH, all of the U.S. National Institutes of Health. The full VOICE study team can be viewed at
http://www.mtnstopshiv.org/news/studies/mtn003.