Over 34 million people across the globe were living with HIV/AIDS at the end of 2011, with an estimated 2.5 million new infections occurring in 2011 alone.1 Although there have been tremendous advances in developing effective treatments for HIV/AIDS, identifying effective HIV prevention strategies remains of paramount importance as the epidemic enters its fourth decade. Antiretrovirals as HIV preexposure prophylaxis (PrEP) may be an important tool in HIV prevention efforts.
Four PrEP trials conducted among individuals with sexual behavior as a primary HIV risk factor have yielded positive results, whereas 2 trials were negative. The heterogeneity of these findings has been largely attributed to differences in adherence.2 The 2 trials that did not show efficacy, Preexposure Prophylaxis Trial for HIV Prevention among African Women (Fem-PrEP)3 and the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trials,4 had low adherence based on tenofovir drug levels. Although adherence support was provided at monthly visits in all trials, data on the efficacy of the approaches are not available. The positive trials include Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004,5 the Chemoprophylaxis for HIV Prevention in Men study (iPrEx) trial,6 the CDC tenofovir disoproxil fumarate (TDF) 2 study,7 and the Partners PrEP Study.8
The Partners PrEP Study was a placebo-controlled trial of oral TDF and emtricitabine (FTC)/TDF among uninfected members of HIV-serodiscordant couples in East Africa. The primary trial demonstrated a 67% HIV risk reduction in the TDF arm and a 75% reduction in the FTC/TDF arm.8 Detection of tenofovir in plasma samples was associated with even higher protection from HIV (86% in the TDF arm and 90% in the FTC/TDF arm).9 Adherence across both arms was high (97%) based on clinic-based pill counts. The Partners PrEP Study included an ancillary adherence study in 1147 participants with objective adherence measures, and an intensive adherence counseling intervention was provided for those participants whose adherence dropped <80%. Median adherence was 99.1% based on unannounced pill counts and 97.2% by medication event monitoring system (MEMS) (Aardex, Switzerland); there were no HIV infections among participants who received active drug in the ancillary adherence study, suggesting 100% PrEP efficacy in this subset [95% confidence interval (CI): 83.7% to 100%, P < 0.001].9
In summary, the preponderance of evidence to date suggests that TDF or FTC/TDF used as PrEP can be an effective biomedical HIV prevention strategy, given sufficient adherence. Although all PrEP efficacy trials included adherence counseling, they were generally designed to support overall adherence to obtain an accurate estimate of PrEP efficacy rather than to specifically evaluate a potential effect of the adherence counseling. There have been no rigorous evaluations of PrEP adherence interventions. The goal of this article is to describe the PrEP adherence intervention delivered in the adherence ancillary study of the Partners PrEP Study and to present data on its usefulness for supporting adherence.
Partners PrEP Study
The Partners PrEP Study was a phase III, randomized, double-blind, placebo-controlled, 3-arm clinical trial of daily oral TDF and FTC/TDF PrEP provided to HIV-uninfected members of 4758 HIV-serodiscordant couples enrolled at 9 clinical research sites in Kenya and Uganda, beginning in July 2008. The design, procedures, and outcomes of the Partners PrEP Study clinical trial are described elsewhere.8 Briefly, HIV-uninfected partners were randomly assigned to once-daily TDF, combination FTC/TDF, or matching placebo and followed monthly for safety assessments and HIV seroconversion for up to 36 months. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. After an interim review of study data by the data safety and monitoring board (University of Washington) revealed that prespecified efficacy bounds had been crossed, efficacy findings were released on July 10, 2011.
Ancillary Adherence Study
Participants were recruited to an ancillary adherence study from 1 urban (Kampala) and 2 rural (Tororo and Kabwohe) Ugandan sites of the Partners PrEP Study. The ancillary adherence study was designed to determine the level, pattern, and predictors of PrEP adherence using objective adherence measures (ie, MEMS, unannounced pill count, and drug levels) and both quantitative and qualitative data collection. Data on drug levels, overall patterns of adherence, and the qualitative study are reported elsewhere.8–10 Another goal was to develop and implement an intervention targeted to HIV-negative participants with low (<80%) unannounced pill count adherence. The threshold value of 80% was chosen based on biologic plausibility based on thresholds for efficacy in macaques11 and is consistent with a level of adherence conferring a high level of protection in the CAPRISA 004 topical tenofovir gel study,5 although the exact level of adherence needed to protect against HIV acquisition is unknown. All participants already enrolled or simultaneously enrolling in the parent trial in these 3 sites were offered participation in the ancillary adherence trial without knowledge of study arm. Participants were asked to complete at least one intervention session with the option to attend additional follow-up sessions. The number of sessions was flexible and determined by the adherence counselor (based on the needs of the participant) and the participants' preferences.
Goals of the Adherence Intervention
The intervention is based on work conducted by Safren et al12,13 on increasing antiretroviral therapy (ART) adherence, specifically the Lifesteps intervention. Lifesteps is a brief adherence intervention that uses general principles of cognitive–behavioral therapy and problem-solving therapy14,15 and was used in 2 large-scale ART as prevention intervention trials.16,17 The intervention manual was developed to (1) standardize the provision of information related to adherence while preserving the flexibility to tailor counseling messages to meet the needs of individual participants; (2) allow for delivery by staff members with various levels of training; and (3) provide a reference for future counseling sessions.
Process of Intervention Development
The intervention was developed over several months using an iterative process. First, 6 study team members (C.P., S.A.S., J.E.H., D.R.B., K.M., E.N.J.) had informal community advisory meetings with 10 participants in the Partners PrEP Study from the Kampala site. Discussions focused on experiences with PrEP use (including beliefs about PrEP and experiences with stigma) and barriers to PrEP adherence, with the goal of learning more about the cultural setting in which PrEP was being used, and ways in which adherence to PrEP may vary from adherence to ART. Second, team members reviewed qualitative data examining reasons for adherence among participants, collected as part of the ancillary adherence study from the Kabwohe site.10 Lastly, feedback from the adherence counselors at all 3 sites was collected as part of monthly supervision calls. This feedback allowed for adaptive intervention design during the first few months of implementation, including the addition of culturally relevant metaphors to explain the concept of adherence, and increasing the counselors' flexibility to skip modules less relevant for individual participants, particularly at follow-up sessions.
The intervention manual was divided into sections, each of which is described below. The counselors, who were lay counselors with the equivalent of a high school education, were trained for 2 days on general counseling skills, the use of cognitive–behavioral therapy strategies in effecting health-related behavior change, and the intervention content. Counselors then participated in supervision calls every 4–6 weeks with a study investigator (C.P.), during which time cases were reviewed in detail and feedback on the intervention was provided. Site visits were also conducted for continued training/supervision and problem-solving issues related to intervention delivery.
Description of Intervention Components
The first intervention session began with information gathering, educational information and rapport building, and later involved motivational interviewing and assistance with specific problem-solving strategies. Because the study population consisted of individuals in HIV-serodiscordant partnerships, the intervention was couple based; the initial portion of the first session was conducted with just the participant taking PrEP and the second part with both members of the dyad when possible. Subsequent counseling sessions began with a review of prior session content; the skills were then used to target additional barriers to adherence and/or plan for anticipated barriers to adherence. A description of each of the intervention components is provided in Table 1.
Adherence to PrEP
Adherence assessment for participants in the adherence ancillary study was performed using 2 validated objective measures.19,20 First, pill counts were unannounced (ie, participants were not informed of the date of the visit) on a randomly selected day every month for the first 6 months and quarterly thereafter. The random nature of the visit was intended to lessen the chance that participants would manipulate pill bottles (ie, dump pills) before the measurement to appear more adherent than they were. Second, MEMS (Aardex) was used to electronically record the date and time of pill bottle openings; data were downloaded monthly. Unannounced pill count was used to trigger the intervention. MEMS data were used to examine adherence relative to the intervention because the daily frequency of the MEMS measurement allowed for closer linkage of behavior with the intervention than would have been possible with the quarterly summary measures obtained through unannounced visits for pill counts.
Adherence Intervention Process Measure
This measure was completed by the counselor after each intervention session. It tracked the duration of sessions, use of specific intervention modules, barriers to PrEP adherence, and the counselor's assessment of how well participants were able to implement their adherence plan (follow-up counseling sessions only).
Covariates and Descriptive Data
Most enrollment characteristics (eg, age, gender, time to clinic) were collected at enrollment into the ancillary adherence study; data on income, main source of income, marital status, cohabitating status, years cohabitating, years known discordant, and polygamous relationship were collected at parent study enrollment. Socioeconomic status was calculated as a principal components analysis based on the Filmer–Pritchett index. The index involved the presence of running water, a concrete floor, electricity, a metal roof, a television, and 2 or more rooms in the residence.21 Heavy alcohol use was defined as a positive Rapid Alcohol Problems Screen.22
Characteristics of participants who did and did not trigger the intervention were described and compared using Fisher exact test (categorical covariates) or Wilcoxon rank sum test (continuous covariates). To compare adherence before versus after the intervention, intervals were defined as follows: (1) the 28 days immediately preceding the unannounced pill count <80%, (2) the time immediately preceding the first intervention session, defined as up to the last 28 days between the unannounced pill count <80% and the first intervention session (often at the next clinic visit), and (3) the 28 days immediately after the first intervention session. The interval between triggering and receiving the first intervention session could be several months because of the need to process data and participant-related factors (eg, travel and scheduling challenges). Medication adherence was calculated by dividing the number of doses taken by the number of prescribed doses. Adherence before versus after the first intervention session was compared using Wilcoxon rank sum test. Sensitivity analyses were conducted limiting data to the blinded study period (ie, before release of efficacy findings on July 10, 2011).
Adherence after the intervention was calculated by study month for each participant. The relationship between adherence and the intervention was estimated using data from 0 to 12 months post-intervention in a linear mixed model with a random intercept and slope for each participant. Predictors of interest were chosen based on the work of Haberer et al9 and included time since the first intervention session (in months) and the number of adherence sessions completed; linear and nonlinear relationships (eg, log linear, square root) between each of these factors and adherence were considered. Adjustment for confounding was considered for age, gender, sex with study partner in the prior month, polygamy, time on PrEP, and alcohol use at the time of trigger.9 Crude adherence before and up to 12 months post-intervention is presented in a plot. To illustrate model predictions for the 12 months after the intervention, predicted adherence overall by months since the first intervention session was also plotted along with 2 scenarios for number of sessions attended: (1) assuming a session was attended every month and (2) assuming that after the first session additional sessions were only attended on average half of the months. All analyses were conducted using SAS 9.3; P values <0.05 were considered statistically significant.
All study procedures were approved by institutional review boards and ethics committees from Massachusetts General Hospital/Partners Healthcare, the University of Washington, the Centers for Disease Control and Prevention, the Uganda National Council for Science and Technology, and the Uganda Virus Research Institute.
Figure S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A530) depicts the flow of participants through the adherence intervention. One thousand one hundred forty-seven participants were eligible for the current analysis based on an enrollment date before July 10, 2011 (when the preliminary results from the Partners PrEP Study were released); participants were followed until the end of the parent study. A total of 168 (14.6%) participants triggered the intervention because of <80% unannounced pill count adherence; of these, 9 were ineligible for follow-up analysis for the following reasons: taken off drug because of exit from study (n = 1), seroconversion (n = 1), or triggering immediately before unblinding of the placebo arm during the parent study (n = 7). Of the remaining 159, 154 (91.7%) received at least one intervention session and 146 (94.8%) had adequate MEMS data based on the intervals described above to examine adherence after the intervention.
Participant characteristics are depicted in Table 2 and characteristics of the intervention are shown in Table 3. The median number of sessions was 10 [interquartile range (IQR), 5–16]. The length of the intervention sessions varied. The first session was the longest with a median of 40 minutes (IQR, 30–50); session length decreased to a median of 20 minutes (IQR, 15–30) by session 4. Fourteen percent of participants participated in a couple session as part of their first intervention session. As per counselor report, the most frequently endorsed barriers to adherence at session 1 were travel (identified as a barrier for 50% of participants) and forgetting (identified as a barrier for 45% of participants). Although the frequency of identified barriers to adherence decreased over time, travel and forgetting remained among the most commonly endorsed barriers across all sessions.
The mean adherence in the 28 days before the intervention trigger unannounced pill count was 64.6% and increased significantly to 75.7% (P < 0.001) in the time immediately before the intervention (Table 4). Adherence after the intervention increased by an additional 8.4% compared with adherence immediately before the intervention (75.7% versus 84.1%, P < 0.001). Seventy-five percent (n = 110) of participants achieved adherence ≥80% at the study visit immediately after the first intervention session. As per sensitivity analyses, results after the intervention were very similar when limited to the blinded period of the study (data not shown). Results of the regression analysis of adherence over time after the first intervention session indicate that mean adherence increased by 8.1% in the first month after the intervention, followed by a log-linear decline corresponding to a decline of 3.6% in the second month post-intervention, 0.9% by 6 months post-intervention, and 0.5% by 12 months post-intervention. The overall decline was 0.05 log per month (95% CI: 0.03 to 0.07, P < 0.001), which was composed of a decrease of 0.18 log per month associated over time (95% CI: 0.10 to 0.25, P < 0.001) and an increase of 0.14 log (95% CI: 0.06 to 0.22, P < 0.01) for every session attended. These associations correspond to a steeper predicted decline for those attending only some sessions versus attending a session each month (Fig. 1). Crude mean adherence at 12 months post-intervention remained higher than at the time of trigger, but not compared with the time immediately before the intervention. Crude mean adherence reached the level seen immediately before the intervention at 5 months post-intervention.
This adherence substudy within the context of a PrEP efficacy trial among HIV-serodiscordant couples in Uganda found that a PrEP adherence intervention delivered was associated with a temporal improvement in electronically monitored adherence to daily PrEP pill taking. Adapting an evidence-based behavioral ART treatment intervention to support PrEP adherence in a trial of HIV-serodiscordant couples was also feasible. Most participants who triggered the intervention completed at least one intervention session, and nearly all participants completed additional sessions. Travel and forgetting were the most frequently addressed barriers. Men, younger persons, those with higher income, and those who identified themselves as laborers or employed in trade/sales reached the <80% adherence trigger more frequently than women, older persons, those with lower income, or those employed in other occupations, such as farming. This is consistent with findings from Haberer et al9 and may indicate work- or travel-associated adherence barriers, such as forgetting pills during travel or seasonal planting or that individuals perceive themselves at less risk while traveling for occupational reasons.
Some improvement in adherence was noted in between the time the intervention was triggered and the first intervention session was delivered. This improvement may be because of the resolution of time-limited barriers, such as unanticipated travel for work or burials that resolved independently of the intervention. However, a problem solving–based adherence intervention may help individuals anticipate these events and minimize their impact on adherence. This approach is especially beneficial if periods of travel represent times of sexual risk, such as acquiring new partners while away from home. Such strategies are particularly important in sub-Saharan Africa, where travel to secure employment is common.23 In this study population, 26% of participants who triggered the intervention were classified as “laborers” and 21% identified their source of income as trade or sales.
Adherence increased from a mean of 75.8% to a mean of 84.1% in the period after the first intervention session. The level of PrEP adherence necessary to confer maximum benefit is currently unknown; current guidelines indicate that PrEP should be taken daily. Recent modeling data from a sample of men who have sex with men suggest that 4 doses of PrEP per week confer greater than 97% protection from HIV.24 Thus, adherence interventions may be best targeted to those who are unable to meet this threshold of approximately 57% adherence or 4 doses per week. However, these findings may not apply to heterosexual serodiscordant couples as concentrations of tenofovir diphosphate are higher in rectal tissue than vaginal tissue25 and more frequent dosing may be required to reach protective drug levels. Prior studies have shown a strong association between adherence and efficacy, thus supporting the use of adherence interventions.8,9 Alternatively, the increase in adherence observed directly after the trigger could be explained by natural regression back to the mean after observing low adherence or that the pill count may have raised participants' awareness of recent adherence lapses and had an effect on increasing adherence.
Counseling sessions subsequent to the initial session were conducted at the discretion of the counselor, and many individuals received multiple sessions. However, the data suggest that the majority of the benefit was seen after the first session. Although the data imply that those who continued to attend monthly sessions had higher adherence than those who attended sessions less frequently, participants who attended a greater number sessions may also inherently be more adherent. In the absence of a control group, the effect of subsequent sessions remains uncertain. In either scenario, these sessions seemed to serve as relatively brief check-ins for many participants and may have reflected the value of time with counselors. In implementation settings, it may be possible to deliver one-on-one counseling to PrEP users as presented in this intervention with fewer sessions, especially if adherence monitoring can identify those with particular need for support. Additionally, participants receiving the intervention can transition to other types of adherence support, such as groups or peer-based interventions, which are less resource intensive once barriers to adherence have resolved.
Sub-Saharan Africa bears a substantial amount of the global HIV burden. PrEP has the potential to fill an important gap in HIV prevention. Although treating HIV-positive persons with ART is also an important HIV prevention strategy,16 not all HIV-positive persons are able to access treatment, want to initiate early treatment,26 and are able to adhere at the level that confers the maximum benefit needed for HIV prevention.27 PrEP use offers direct control of HIV prevention to uninfected individuals. In addition, individuals may have multiple partners and could benefit from PrEP even if their main partner is on effective HIV treatment. In this sample, 17% of participants reported an outside partner.9 In support of the need for HIV prevention, in recent studies of HIV-serodiscordant couples, 25%–30% of HIV transmissions were determined to be from an outside partner, based on genetic linkage of transmitted viruses.16,28
The current study had several strengths, including an iterative process of intervention development based on an evidence-based ART adherence intervention and rigorous adherence measurement. Because of the absence of a control group, inferences about the effect of the intervention on adherence are limited, though important information can still be generated when randomized designs are not possible.29 An additional limitation to the interpretation of the data results from the fact that the intervention was delivered in the context of a clinical trial conducted among individuals in heterosexual serodiscordant couples. Thus, results may not be fully generalizable to populations of other PrEP users. Lastly, interim trial results were announced in July 2011, after which time participants knew they were taking active drug. Knowledge that participants were taking an active compound may have also affected adherence after unblinding, although we found that the change in adherence at the time of the first intervention session was similar when limited to the period before unblinding.
In summary, PrEP, given sufficient adherence, is a promising biomedical intervention strategy for HIV-negative people to prevent infection. Nonadherence is one of the biggest threats to successful PrEP implementation. Based on the findings from PrEP trials, it is likely that at least some subset of PrEP users will require adherence support. The World Health Organization stresses the importance of providing PrEP in contexts that support high adherence.30 Thus, future research must elucidate how to best identify PrEP users with low adherence for timely intervention and determine optimal duration of interventions to maximize PrEP effectiveness. Methods to identify PrEP users with low adherence need to be cost effective and accurate, as it is unlikely that electronic monitoring18 will be available outside the clinical trial setting in the near future. Randomized controlled trials of PrEP interventions are also needed and need to be conducted among various populations of PrEP users. Effective interventions may be feasible, even in busy clinical practices, if targeted to those in need. In some cases, those who stand to benefit the most from PrEP may also experience circumstances that negatively affect adherence, such as poverty, stigma, and psychiatric comorbidities. Such barriers to PrEP adherence require further study. Moving forward, biomedical agents for the prevention of HIV should be used in conjunction with behavioral interventions to maximize their biologic effectiveness.
The authors would like to thank the study participants, DF/Net for data coordination, Dr Stephen Becker from the Bill and Melinda Gates Foundation, and the study sites: Tororo (Dr Aloysious Kakia and other team members), Kampala (Dr Edith Nakku-Joloba and other team members), and Kabwohe (Dr Stephen Asiimwe, Deo Agaba, Dr Rogers Twesigye, and other team members).
2. Van der Straten A, Van Damme L, Haberer JE, et al.. Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention
. AIDS. 2012;26:F13–F19.
3. Microbicide Trials Network. MTN-003-VOICE. 2013. Available at: http://www.mtnstopshiv.org/news/studies/mtn003
4. Marrazzo J, Ramjee G, Nair G, et al.. Pre–exposure prophylaxis for HIV in Women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 26LB.
5. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al.. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168–1174.
6. Grant RM, Lama JR, Anderson PL, et al.. Preexposure chemoprophylaxis for HIV prevention
in men who have sex with men. N Engl J Med. 2010;363:2587–2599.
7. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423–434.
8. Baeten JM, Donnell D, Ndase P, et al.. Antiretroviral prophylaxis for HIV prevention
in heterosexual men and women. N Engl J Med. 2012;367:399–410.
9. Haberer JE, Baeten JM, Campbell J, et al.. Adherence to antiretroviral prophylaxis for HIV prevention
: a substudy cohort within a clinical trial of serodiscordant couples in East Africa. PLoS Med. 2013;10:e1001511.
10. Ware NC, Wyatt MA, Haberer JE, et al.. What's love got to do with it? Explaining adherence to oral antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples. J Acquir Immune Defic Syndr. 2012;59:463–468.
11. García-Lerma JG, Otten RA, Qari SH, et al.. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008;5:e28.
12. Safren SA, Otto MW, Worth JL. Life-steps: applying cognitive behavioral therapy to HIV medication adherence. Cogn Behav Pract. 1999;6:332–341.
13. Safren SA, O'Cleirigh C, Tan JY, et al.. A randomized controlled trial of cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV-infected individuals. Health Psychol. 2009;28:1–10.
14. D'Zurilla TJ. Problem-Solving Therapy: A Social Competence Approach to Clinical Intervention. New York: Springer; 1986.
15. Nezu A, D'Zurilla T. Social problem solving and negative affective conditions. In: Kendall P, Watson D, eds. Anxiety and Depression: Distinctive and Overlapping Features. New York, NY: Academic Press; 1989:285–315.
16. Cohen MS, Chen YQ, McCauley M, et al.. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505.
17. Campbell MS, Mullins JI, Hughes JP, et al.. Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial. PLoS One. 2011;6:e16986.
18. Haberer JE, Kahane J, Kigozi I, et al.. Real-time adherence monitoring for HIV antiretroviral therapy. AIDS Behav. 2010;14:1340–1346.
19. Bangsberg DR, Hecht FM, Charlebois ED, et al.. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14:357–366
20. Oyugi JH, Byakika-Tusiime J, Charlebois ED, et al.. Multiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr. 2004;36:1100–1102.
21. Filmer D, Pritchett LH. Estimating wealth effects without expenditure data-or tears: an application to educational enrollments in states of India. Demography. 2001;38:115.
22. Cherpitel CJ, Ye Y, Bond J, et al.. Cross-national performance of the RAPS4/RAPS4-QF for tolerance and heavy drinking: data from 13 countries. J Stud Alcohol. 2005;66:428–432.
23. Lurie MN, Williams BG, Zuma K, et al.. The impact of migration on HIV-1 transmission in South Africa: a study of migrant and nonmigrant men and their partners. Sex Transm Dis. 2003;30:149–156.
24. Anderson PL, Glidden DV, Liu A, et al.. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4:151ra125.
25. Louissaint NA, Cao Y-J, Skipper PL, et al.. Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue. AIDS Res Hum Retroviruses. 2013;29:1443–1450.
26. Heffron R, Ngure K, Mugo N, et al.. Willingness of Kenyan HIV-1 serodiscordant couples to use antiretroviral-based HIV-1 prevention strategies. J Acquir Immune Defic Syndr. 2012;61:116–119.
27. Adakun SA, Siedner MJ, Muzoora C, et al.. Higher baseline CD4 cell count predicts treatment interruptions and persistent viremia in patients initiating ARVs in rural Uganda. J Acquir Immune Defic Syndr. 2013;62:317–321.
28. Celum C, Wald A, Lingappa JR, et al.. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. N Engl J Med. 2010;362:427–439.
29. West SG, Duan N, Pequegnat W, et al.. Alternatives to the randomized controlled trial. Am J Public Health. 2008;98:1359–1366.
30. Guidance on Pre-exposure Oral Prophylaxis (PrEP) for Serodiscordant Couples, Men and Transgender Women Who Have Sex with Men at High Risk of HIV: Recommendations for Use in the Context of Demonstration Projects. Geneva, Switzerland: World Health Organization; 2012. Available at: http://www.ncbi.nlm.nih.gov/books/NBK132003/
. Accessed November 7, 2013.