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Abstract
Introduction Male clients (MCs) are integral to sex work-driven HIV transmission dynamics as sexual partners of female sex worker (FSW). MCs contribute disproportionately to incident HIV globally and in sub-Saharan Africa, with 27% of new infections attributed to MCs of FSW and other partners of key populations. Gaps in coverage of HIV testing and prevention services for men, including MCs, are well-documented, yet research and innovative interventions to improve MC uptake of effective prevention services, including pre-exposure prophylaxis (PrEP), are scarce.
Methods and analysis MPrEP+ is a cohort study designed to assess the feasibility and acceptability of a PrEP-focused HIV prevention strategy providing daily oral tenofovir/emtricitabine (TDF/FTC) in combination with three adherence self-management interventions: (1) use of a validated point-of-care urine drug-level assay with real-time feedback and tailored self-management counselling; (2) frequent HIV self-testing; and (3) weekly one-way text messaging. This package of interventions is being delivered to 120 MCs enrolled in the study in Kisumu, Kenya over a 6-month period. The primary outcome is PrEP adherence at 6 months as measured by PrEP drug levels. Bivariate and multivariable regression models will be used to identify predictors of PrEP adherence. We will also explore associations of sociodemographic characteristics and PrEP beliefs with PrEP adherence.
Ethics and dissemination The study was approved by the Columbia University Irving Medical Center Institutional Review Board and the Maseno University Ethical Review Committee. Study enrolment was initiated in November 2021 with participant follow-up planned through August 2022. Study results will be submitted for publication in peer-reviewed journals. Summaries and infographics of study findings will be developed and distributed to MC, FSW and stakeholders working in HIV prevention and support for people who sell and buy sex, including Kenya’s Ministry of Health.
Trial registration number NCT04898699; Registered on 24 May 2021.
- HIV & AIDS
- international health services
- public health
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Strengths and limitations of this study
The study engages an understudied population vulnerable to HIV infection in a tailored strategy delivering a highly effective biomedical prevention tool, pre-exposure prophylaxis (PrEP).
The use of a novel pharmacologic measure, a point-of-care urine assay, provides objective real-time feedback on PrEP adherence and may reinforce continued PrEP medication-taking.
The study uses an observational design with no comparison group; thus, the design does not control for confounding factors that might affect study outcomes.
The small sample size may limit ability to demonstrate statistical power.
All participants enrolled in the study will receive the same package of adherence self-management interventions and thus we will not be able to determine the effect of individual intervention effects.
Introduction
Globally male clients (MCs) of female sex workers (FSWs) experience a greater burden of HIV compared with men who do not pay for sex1–3 due to a constellation of factors, including number of sexual partners, elevated HIV prevalence among FSW and patterns of condom use with FSWs. A recent meta-analysis of 87 population surveys in 35 sub-Saharan African countries between 2000 and 2020 indicated that paid sexual encounters by men are prevalent: 8% of sexually active men aged 15–54 reported they had ever paid for sex, and this per cent was higher in studies conducted in East Africa (11.3%).3 Based on 52 of these surveys, men who paid for sex were 50% more likely to be living with HIV (prevalence ratio = 1.50; 95% CI: 1.31 to 1.72) compared with men who had not. This meta-analysis also estimated that only 67.5% of men surveyed between 2010 and 2020 reported using a condom during their last paid sex encounter. A second meta-analysis of 44 studies in low-income and middle-income countries conducted between 1989 and 2019 also found an elevated risk of HIV among men who purchased sex (5% pooled HIV prevalence; n=21 studies), and in studies conducted between 2011 and 2019 (2.85%), compared with men who did not purchase sex.1 Thus, an effective response to the elevated HIV vulnerability experienced by MC is essential to controlling the HIV epidemic, particularly in East and Southern Africa, where MC and other sexual partners of key populations, including FSW, accounted for 15% of new infections among those aged 15–49 years in 2019.4 However, data on factors associated with risk of HIV acquisition as well as studies of HIV prevention interventions among this population are limited, likely due to stigma, difficulty in identifying them and varying legality of commercial sex across countries.
Interventions directed to MCs are needed to strengthen the impact of combination prevention strategies.5 Pre-exposure prophylaxis (PrEP) is an efficacious biomedical HIV prevention intervention6–8 and an optimal tool for MC of FSW, given the multiple barriers to condom use in the sex work context.9–11 In Kenya, the site of this study, the 2018 national guidelines recommend PrEP for individuals at substantial risk for HIV, including those engaged in transactional sex.12 HIV prevalence in Kenya in 2018 was estimated at 4.9% (males: 3.1%; females: 6.6%), with 1.3 million people living with HIV; however, in the Lake Victoria region where this study is conducted in Kisumu County, adult prevalence is 17.5%.13 The HIV epidemic in western Kenya is significantly impacted by HIV infection in FSW. In 2013, the most recent year in which HIV surveillance data for key populations are available, national HIV prevalence among FSWs was 29.3%.14 Under Kenya’s national policy guidelines, PrEP is prioritised as part of combination HIV prevention for people who engage in sex work, including MCs.15 However, MCs have not been a focus of national PrEP implementation plans.
Formative research we conducted to inform the study protocol indicated that MCs were supportive of and interested in PrEP, and most FSWs and MCs viewed PrEP as life-saving protection for both themselves and their non-commercial sex partners.5 Yet, we are unaware of any published studies offering PrEP to MCs of FSWs. This highlights the need for implementation science research in real-world settings to demonstrate how to engage MCs in PrEP use and to inform national programmes as they expand PrEP to reach key and priority populations. Additionally, as adherence is a critical determinant of PrEP efficacy, research to guide the design and implementation of evidence-based adherence support interventions for MCs is needed to realise PrEP’s individual-level and population-level effectiveness.
Self-management approaches offer a promising and novel framework to improve adherence and engagement in PrEP, whereby persons at substantial risk for HIV initiate PrEP, and proactively adopt and monitor their own behaviours to optimise PrEP effectiveness and safety. Such approaches have been used to manage chronic conditions, for example, cardiovascular disease, creatinine monitoring post-kidney transplant, glycaemic control for diabetes, body weight in obesity and HIV treatment, but are less frequently applied for HIV prevention.16–20 Objective feedback on adherence behaviour to tailor counselling and reinforce successful adherence is a critical component in self-management approaches,21 22 and a potentially impactful support for PrEP adherence.23 24 Therefore, we are implementing MPrEP+, to our knowledge, the first HIV combination prevention strategy that offers oral PrEP with adherence support interventions to increase PrEP use among MCs.
Methods and analysis
Study design
MPrEP+ is a single-arm longitudinal study offering PrEP and adherence support to MC of FSW in Kisumu County, western Kenya. The study assesses adherence, feasibility and acceptability of a PrEP-focused prevention strategy offering daily oral PrEP (tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)) in combination with three adherence self-management interventions: real-time feedback from point of care (POC) urine drug-level assay, HIV self-testing (HIVST) and weekly one-way text message reminders plus standard of care HIV risk-reduction counselling over a 6-month period among MCs in Kisumu, Kenya. All participants receive the same intervention and attend four study visits over a 6-month follow-up period.
Eligibility criteria
Participants are HIV-negative men aged 18 and older who report having exchanged money, goods or services for sex with a woman in the past 3 months, and live or work and intend to stay in Kisumu County for the next 6 months. Other inclusion criteria include ability to provide informed consent and complete study procedures in English, Kiswahili or Dholuo, report no current or recent (within past 3 months) PrEP use and are willing to participate in study procedures, including the study intervention.
Sampling and recruitment
Recruitment is conducted by trained, supervised mobilizers connected to FSW groups active in the study catchment area. Mobilizers conduct outreach and education about the study aims and components in community-based venues such as bars and other social spaces where people sell and buy sex in the Kisumu urban area. Interested individuals are asked for verbal consent to undergo prescreening at the venues. Those providing verbal consent are prescreened with a brief questionnaire to assess initial eligibility (age, residence and intent to stay in Kisumu County for study duration, and having exchanged money, goods or services for sex with a woman in the past 3 months).
Mobilizers invite MCs identified in prescreening as potentially eligible to the study site to complete an enrolment visit, beginning with the informed consent process and study eligibility assessment, including eligibility for PrEP. The recruitment goal is 120 HIV-negative MCs enrolled in the cohort. Study staff document the number of individuals approached by mobilizers; number agreeing to prescreen; number prescreened as potentially eligible who attend scheduled enrolment visits; and number enrolled.
Study procedures
All study procedures, including baseline and follow-up visits, are conducted at the clinical research site managed by Impact Research and Development Organization. This site is located within a low-cost private hospital in Kisumu, Kenya, and has an onsite pharmacy and certified laboratory. The population being served by the hospital comprises both low- and middle-income neighbourhoods.
Baseline visit
Informed consent and locator information
Prior to the initiation of any study activities, participants undergo a written informed consent process. Once consented, trained study staff collect complete locator information from all participants.
Clinical and laboratory assessments
All consented participants undergo HIV rapid testing and counselling following national guidelines and are assessed for PrEP eligibility using screening procedures detailed in the 2018 Guidelines on Use of Antiretroviral Drugs for Treating and Preventing HIV Infection in Kenya.12 Standard procedures include assessment of behavioural and medical eligibility for PrEP using national tools; symptom-driven assessment for acute HIV infection; and assessment for contraindications for use of TDF/FTC.
A 10 mL blood sample is collected via venipuncture for measurement of creatinine and hepatitis B surface antigen testing as required in the PrEP guidelines. Additionally, a 10 mL urine sample is taken for chlamydia, gonorrhoea and trichomoniasis screening. If a participant is found to have one of these sexually transmitted infections (STIs), he is immediately referred to the study clinician for further management.
Baseline interview
At baseline, all participants complete a baseline interview administered by trained research staff in English, Kiswahili or Dholuo according to preference. Interview domains are guided by the adapted Information-Motivation-Behavioural Skills Model (figure 1), including demographic information; psychosocial characteristics; alcohol and drug use; sexual partnering, including relationships with FSWs; sexual practices and relationship characteristics; history and current experiences of psychological, physical and sexual abuse; social support; HIV-related stigma; HIV-related and prevention-related knowledge, practices, attitudes, including those related to PrEP, and effects of the ongoing COVID-19 pandemic on their lives.25 Details of domains included in the baseline interview are found in table 1.
MPrEP+ adapted IMB model: determinants of PrEP engagement and sexual behaviour among male clients in Kenya.24 IMB, Information–Motivation–Behavioural Skills.
MPrEP+ activities and procedures by time point
Follow-up visits
Follow-up visits are conducted at months 1, 3 and 6 post-enrolment.
Clinical and laboratory assessments
At each follow-up visit, participants undergo HIV rapid testing and counselling following Kenya’s national guidelines and a symptom-driven clinical exam including assessment of symptoms of acute HIV infection or STIs. Participants found to be HIV-positive receive confirmatory testing and appropriate post-test counselling, including assisted referral for immediate HIV treatment initiation at local health facility. There is no further study follow-up for participants who were HIV-positive.
In addition, for all participants, a 10 mL blood sample is collected via venipuncture at months 3 and 6 follow-up visits to assess metabolised tenofovir (TFV) levels.26 Other laboratory tests are conducted when clinically indicated.
Follow-up interview
At follow-up visits, all participants complete a follow-up interview administered by trained research staff in English, Kiswahili or Dholuo according to preference. Follow-up questionnaires are 45–60 min in duration; see table 1 for interview domains at 1-month, 3-month and 6-month follow-ups. The 6-month follow-up interview includes several open-ended questions regarding participants’ experience taking PrEP and with study participation. Participants who express a desire to end study participation at the 3-month visit will be asked to complete the module of open-ended questions during the 3-month interview. Responses to open-ended questions will be transcribed verbatim, and if needed, translated from Kiswahili or Dholuo into English, reviewed for accuracy and completion, deidentified, and entered into a Dedoose database for analysis.
MPrEP+ adherence support intervention components and procedures
The MPrEP+ strategy includes the provision of daily oral PrEP combined with three adherence self-management interventions: (1) use of a validated POC urine TFV assay, UrSure, with real-time feedback and tailored self-management counselling; (2) HIVST; and (3) weekly one-way text messaging.
Daily oral FTC/TDF as PrEP
At enrolment visit, participants eligible for and willing to take PrEP receive a 1 month supply (30 pills) of FTC/TDF as daily oral PrEP and education and counselling about PrEP dosing, signs and symptoms of drug toxicity, acute HIV infection and STIs, importance of daily adherence and need for regular HIV testing. At month 1, a 2-month supply of daily oral FTC/TDF after HIV testing according to national guidelines is provided, along with assessment for acute HIV infection and review of side effects and adherence. At month 3, oral FTC/TDF will be dispensed as a 3-month supply. At month 6, participants receive a referral to local PrEP providers to continue on PrEP.
Urine assay with real-time feedback
This POC assay provides a biomarker of PrEP pill-taking within the past 72 hours, with return of results provided within 15 min.27 28 Sharing this objective measure of recent adherence behaviour with participants during follow-up visits facilitates open discussion of recent PrEP use and allows providers to tailor counselling messages to reinforce each participant’s strengths and address their challenges. Also, real-time feedback based on test results at study visit can assure adherent PrEP users that they are achieving the prerequisite drug level for protection. Study participants are provided with brief interactive counselling tailored to results of their urine assay at their 3-month and 6-month visits.
At enrolment, study staff explain the use of this UrSure kit and how it will be used experimentally to inform PrEP adherence counselling at follow-up visits. At months 3 and 6 follow-up visits, participants are asked to provide a 5 mL urine sample that will be used to perform the UrSure test. Participants receive real-time feedback and self-management counselling, tailored to the results of their urine assay.
HIV self-testing
The MPrEP+ intervention conceptualises HIVST29 as a self-management tool allowing participants control over combination HIV prevention, including regular testing. Several studies have found HIVST to be acceptable and feasible in Kenya,30–32 including among MC.33 34 The enormous strain on health systems wrought by the ongoing COVID-19 pandemic brought into sharp relief the potential of HIVST to ensure access to essential testing resources outside of clinical settings.35–37 At each study visit, participants are given two HIVST kits for self-testing between study visits. They receive detailed, interactive training on HIVST with pictorial elements, including instructions in the three study languages to contact study staff immediately in event of a positive test for confirmation as per national guidelines.
Weekly SMS text messaging
On completion of the baseline visit, all participants begin receiving discrete weekly SMS text messages (or voice message in the case of low literacy) to support PrEP adherence, encourage healthy behaviours, use of HIVST and study engagement. Message content is selected by the participant and does not include information identifying the participant as part of a study or study details, for example, ‘Remember to look after yourself today. See you tomorrow’.
Reimbursement for participant time and transport
After completion of each study visit, participants receive the equivalent of about US$13 in Kenya shillings for their time and effort. This amount is specified in the consent form. Refreshments are also provided during participation in study procedures.
Retention procedures
At enrolment, participants are asked to provide detailed locator information (for example, name, address, email or social media details, telephone number, usual hangouts and at least one alternative contact address and phone number). This information is updated at each follow-up visit. Participants also receive reminder calls or text messages the day prior to their scheduled visit and contacted immediately in the case of missed visits.
Patient and public involvement
The study team collected extensive formative data among MCs in Kisumu, which informed the development of the study protocol, specifically in relation to the study design, recruitment methods and intervention components.5 Findings were presented to national stakeholders in advance of protocol finalisation for feedback.38 39 We will draw on experience with previous research dissemination activities, including those related to our formative work, as well as other types of events (participant appreciation events) to inform how best to convey findings to larger groups of MCs in Kisumu. The study has an active advisory group composed of local stakeholders, including advocates and representatives of FSWs, and the advisory group will be involved in planning dissemination to local and national audiences.
Data analysis plan
Sample size justification
The study sample size was determined to be 120 MCs based on feasibility concerns for conducting a convenience sample of this population. An estimate of the precision of the 95% CI of our primary outcome of 6-month adherence (described below) was obtained using the methodology applied by Cornfield and assuming a Design Effect of 2.40 A Design Effect is a simple number that estimates how much less efficient a non-random sample is compared with a simple random sample; a Design Effect of 2 implies that a non-random sample would need twice the number of individuals as a simple random sample to obtain the same-precision estimates .41
With 120 participants enrolled, and treating those lost to follow-up as ‘not adherent’ (as in the primary analysis), this sample size will result in a reasonably precise estimate of adherence at 6 months. For example, assuming 70% adherence at 6 months, our powered 95% CI will be 58.4%–81.6%% (11.6% precision). Similarly, conducting a ‘complete case’ analysis (as in the secondary analysis) restricted to those with complete outcome ascertainment and assuming loss-to-follow-up of 10%, our powered 95% CI will be marginally wider at 57.8%–82.2% (12.2% precision).41 With 120 participants, our precision will be similar across a range of measured adherence proportions at 6 months (table 2).
Width of 95% CI for estimating adherence at 6 months, assuming a sample size of 120 and a design effect of 2
Quantitative data analysis will be conducted using SAS V.9.4 (Cary, North Carolina, USA). An overview of primary and secondary outcomes and their definitions follows.
Primary outcome
Adherence to PrEP
The primary outcome is recent PrEP adherence measured at 6 months. Recent adherence will be operationalised as a dichotomous variable based on measured presence of plasma TFV at or above the test level of detection of 10 ng/mL.26 To estimate this outcome, we will calculate the proportion of participants who are adherent with daily oral PrEP (FTC/TDF) at 6 months as measured through plasma TFV. For the primary analysis we will conservatively assume those participants lost to follow-up or discontinuing PrEP for any reason were ‘non-adherent’. In a secondary analysis, a ‘complete case’ analysis will be performed, restricted to those not lost to follow-up and otherwise adhering to the intervention protocol. Sensitivity analyses will also explore multiple imputing likely 6-month adherence status among those lost to follow-up assuming a missing at random, conditioned on covariates and mechanism of missingness.
For both the primary and secondary measurement of PrEP adherence, bivariate and multivariable regression models will be used to identify predictors of PrEP adherence. Specifically, we will explore the association between sociodemographic factors (for example, age, socioeconomic indicators, religious affiliation, number of children), PrEP knowledge, perception, beliefs and concerns, and adverse events during study participation, and PrEP adherence at 3 and 6 months.
Secondary outcomes
Acceptability of daily oral PrEP
Participants will be asked about their satisfaction using PrEP during the 1-month, 3-month and 6-month follow-up interviews. Similar to the analyses described for PrEP retention, bivariate analyses will examine associations between participant sociodemographic and clinical characteristics and acceptability.
Acceptability of HIVST
Participants will be asked about perceived benefits and dislikes of HIVST, reasons for not self-testing, and likelihood of recommending self-testing to a family member or a friend during the 1-month, 3-month and 6-month follow-up interviews. Similar to the analyses described for PrEP retention, bivariate analyses will examine associations between participant sociodemographic and clinical characteristics and acceptability.
Adverse events
Adverse events will be measured in two ways: the proportion of participants who discontinue PrEP due to adverse events and the proportion of individuals reporting social harms due to adverse events (based on self-report). Overall frequency of these outcomes will be tabulated, along with bivariate comparison between.
Validity of self-report, pill count and metabolite measures for PrEP adherence
Taking measures of PrEP drug concentration in plasma as the objective gold standard measure for PrEP adherence, we will compute the sensitivity, specificity and predictive value of (1) urine metabolite classification, (2) pill count classification and (3) self-report against classification into ‘adherent’ or ‘not adherent’ groupings. Additionally, we will compare the correlation between metabolite levels and pill count classification and self-reporting of days adherent using correlation coefficients.
Association of PrEP adherence with sexual behavior
Across and within-study arms, we will compare changes in sexual behaviours between participants classified as ‘adherent’ and ‘not adherent’ to PrEP. Sexual behaviour will be categorised based on number of sexual partners reported during follow-up as well as self-report of condom use at last sexual encounter, separately for paying and non-paying sexual partners. Wilcoxon rank-sum tests will be used to assess whether the median change in number of sexual partners (overall and stratified by paying and non-paying partners) at 6 months differs between participants classified as adherent versus not adherent to PrEP. Second, changes in the proportion reporting condom use at at last sexual encounter across follow-up time points will be estimated using repeated measures generalised estimating equations, allowing for repeated measurements over the time period of interest.
Experience taking PrEP and study participation experience
Open-ended questions in the 6-month follow-up interview will be analysed with content analysis for categorising and eliciting meaning from the content of the textual responses.42
Ethics and dissemination
The MPrEP+ study is registered at clinicaltrials.gov: NCT04898699 (24 May 2021). The study was approved by the Columbia University Irving Medical Center Institutional Review Board (Protocol# AAAT6103, approved 24 May 2021) and the Maseno University Ethical Review Committee (MUERC) (Protocol# MUERC/00932/21, approved 31 March 2021). Key to our approach is the monitoring of social harms related to PrEP use and trial participation at all follow-up visits. All assessments, consent forms and other relevant forms have been translated into the local languages, Dholuo and Kiswahili, and translations were verified for accuracy and received ethics approval.
Study findings and lessons learnt from study implementation will be disseminated through peer-reviewed journals, national and international conference presentations to key policymakers and implementers, meetings with national and county-level Ministry of Health leadership, other stakeholders and study participants and through social and mainstream media outlets such as list-servs, websites of non-governmental organisation stakeholders who work with sex workers, and local newspapers.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors JEM, JF, MRL, WME-S and KA led the process of study conceptualisation. JEM, JF, AZ, DO, ML, DN, WME-S and KA developed the study protocol and associated data collection tools and informed consent forms. AZ and DO facilitated receipt of all required ethics committee and IRB approvals for the protocol. KA and DO are overseeing day-to-day study implementation, including subject recruitment and enrolment and data collection activities. ML, MRL and DMR are leading the development of the statistical plan and planned data analysis. All authors reviewed and edited this manuscript. All authors read and approved the final version of the manuscript.
Funding This study was made possible through the support of the United States National Institute of Mental Health (NIMH), R01MH11051-04S1, Wafaa M El-Sadr, MD, MPH, MPA and Kawango Agot, PhD, Co-Principal Investigators. Joanne E Mantell was also supported by a center grant from the National Institute of Mental Health (NIMH) to the HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute and Columbia University Irving Medical Center (P30-MH43520; Robert H Remien, PhD, Principal Investigator). Domonique M Reed was also supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number T32AI114398. Its contents are the responsibility of the authors and do not necessarily reflect the views of NIMH or the US Government.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.