This study is being conducted in the Greater Edendale Area (GEA) and Vulindlela region in KZN, South Africa. The area has a combined population of nearly 400,000 people spanning 20 municipal wards characterized by low population density, few infrastructure and developmental resources, high HIV prevalence (31%), high unemployment and low per capita income (under US$2 per day). The population is primarily black African (99.3%). Nine of the wards fall under the tribal authority of a traditional leader or chief. Health services are provided through seven health facilities – Edendale Hospital, the main referral facility; two primary health clinics and three satellite primary health clinics.
The study combines the best of three strategies (male-focused mobilisation, community-based mobile HTS and a small incentive) to determine if the strategies singly and in combination can result in more men diagnosed with HIV, and more men linked to and maintained in care with undetectable VL. The specific aims are as follows:
Aim 1: To test the hypothesis, in a cluster randomised design, that men-centred mobilisation and testing strategies plus a small incentive will result in a substantially higher proportion of men getting tested for HIV (difference at least 30%).
Aim 2: To test the hypothesis, in an individual randomised design, that POC CD4 testing combined with personalised linkage to care (PLC) will result in a higher proportion of HIV-positive men linked to and maintained in care with undetectable VL than POC alone, and that both will be superior to standard of care.
Aim 3: To integrate the outcomes of the structural and individual level interventions and evaluate the joint effect of the structural and individual-level interventions on the percentage of HIV-positive men who are effectively treated (tested, linked to care and maintained with undetectable VL).
This is a two-stage design of a cluster-randomised trial and an individual randomised trial to test how structural and individual-level interventions address the demand-side factors that affect HIV testing and treatment for hard-to reach, high-risk men. A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) are presented in Figure 1 and Additional file 1.
Cluster Randomised Study
Eight (8) communities of approximately 5,000 persons (4 intervention and 4 control communities) from the GEA and Vulindlela regions will be selected with an equal mix of rural and peri-urban communities to ensure greater generalisability of the intervention in different settings. Each of the communities will be randomised to men-centred mobilisation and testing strategies plus a small incentive, or the control condition. Randomisation will be performed by the statistical centre in a restricted way, so that four communities are assigned to each arm. Randomisation code will be written in R and will use the Mersenne-Twister random number generator with seed derived from current system time.
Individual Randomised Study
A sample of 440 HIV-positive men identified though mobile HTS at baseline will be randomised to either standard-of-care referral to ART or POC CD4 testing combined with personalised linkage to care. Randomisation sequence will be generated in advance by the statistical centre, using the Mersenne-Twister random number generator with seed derived from current system time. Randomization assignments will be placed into sealed tamper-proof numbered envelopes according to the generated sequence and released to study counsellors in small batches. The envelopes will be used in the assigned order to reveal randomization results for individual participants. Lost or misplaced envelopes will be registered and tracked. The randomization sequence will be fully non-predictable.
Due to the nature of the interventions, neither community-randomized nor individual-randomized intervention assignments will be blinded.
Research Ethics Approval and Data Safety Monitoring
The Institutional Review Board of the University of California, Los Angeles (UCLA, 00003962) and the Research Ethics Committee of the Human Sciences Research Council in South Africa (HSRC, REC 3/18/02/15) have approved the study and oversee adherence to the study protocol over time. A six-member Data Safety and Monitoring Board (DSMB), consisting of local and international experts, will monitor the implementation of the trial. National, provincial, district, and municipal health authorities approved the study and its protocol, and set the conditions of the standard care practice.
The DSMB will review the effectiveness and scientific validity of the study. The DSMB will provide their evaluation feedback to the principal investigators and study sponsor assessing interim analyses on enrolment progress, protocol fidelity and participant safety. Concurrently, enrolment progress is reported each trimester directly to the study sponsor. On-going harms and adverse monitoring is overseen by the local institutional research ethics (REC) committee. A Community Advisory Board consisting of community stakeholders, representatives and leaders has been constituted for this study. Quarterly meetings are held with a Community Advisory Board (CAB) consisting of 25 local stakeholders who serve as liaison between research staff and the community, advising on study policies and keeping the community informed of progress. CAB members and study personnel have been trained to identify and report incidents of social harm and adverse events that may occur in the community to the study project manager. Regular feedback meetings are conducted with health authorities. The study project manager is responsible for logging, assessing and actioning any appropriate remedial steps (onward referral, staff re-training, community messaging etc.), reporting to the local REC and maintaining a register of incidents, if any, for the DSMB.
Research activities and procedures
Male-Focused Community Outreach and Mobilization (Component 1)
The community outreach team engage traditional leaders and key governmental and local stakeholders to obtain permission to conduct the study in the communities. Information is provided about the study aims and objectives, and the rationale for including men in the intervention. The team identifies formal (e.g. community halls and churches) and informal social venues (e.g. transport hubs and sporting events) in each of the study communities where men are mobilised to participate in the study. At both venues, four community-based mobilisers (CBMs) conduct activities such as dialogues, social games and distribute pamphlets and edutainment to encourage men to test and link to treatment (see Table 1). Through these social networks, early adopters are identified and encouraged to test. Some of the early adopters are invited to be community champions (CC). Community champions work with study staff to identify other men in their networks who are invited to participate in the intervention. These formal spaces are used for mobilisation activities but also as possible spaces where mobile HIV testing is conducted. In addition, men identified through these venues are given information about the mobile HTS schedule and venues.
In addition to recruiting men to testing through formal and informal venues, CBMs go from house to house in the study communities to talk to men about healthy living and the importance of screening for HIV and other diseases. These CBM’s also visit busy road intersections and talk with people who are passing by and distribute study information using pamphlets and appointment cards. In both these instances, men are provided information regarding when testing is likely to happen in their communities.
Male-focused and delivered mobile HTS (Component 2)
The mobile HIV testing services teams coordinate with community mobiliser teams to ensure that testing happens according to the testing schedule. Copies of the testing schedule are distributed to community working groups, community-based outreach volunteers, local police stations, local health centres, and other community centres deemed appropriate by the study team.
Two HTS teams (4 male nurse counsellors and 1 driver per team) deliver easy-to-access mobile HIV testing through two mobile caravans. A mobile HTS team circulates through a range of male-centred locations in the community on a regular schedule of days and times suitable for men. Two teams serve the four intervention communities, with each team being responsible for two intervention communities over the course of the intervention. The team is supervised by a Counsellor Supervisor.
Community mobilisers are stationed in the vicinity of the men-centred spaces and engage men individually and in groups about the study. Mobilizers also inform men that a small incentive of R50 cell phone airtime (approximately US$5) would be received at completion of testing, regardless of HIV status. Other men in the vicinity of the mobile facility, but not necessarily frequenting the venues, are also encouraged to test by study staff. Recruited men are handed over to the study counsellor at the mobile caravan for a fuller explanation of the study, informed consent and completion of the HTS process.
Participants consent for on-site point of care procedures for HIV and non-communicable diseases (NCDs) screening. No specimen are retained for NCDs testing. In the event of a discordant HIV test result, Dry Blood Spot (DBS) specimen will be collected from the participant for a laboratory confirmatory test to confirm serostatus. No specimen are retained for confirmatory tests. Participants who are eligible for enrolment (HIV positive and not on antiretroviral treatment), who consent to enrolment provide a DBS for baseline viral load measures. Consent is provided for participants to be re-contacted at 3 and 6 months for study contact visits, and for an exit visit at 9 months post enrolment where participant exist survey data and end line viral load will be collected. Participants consent for their data to be stored and for secondary use of their data if such use is approved by the REC.
After consent is obtained, the study counsellor completes the utilization form on the mobile phone. The form includes basic socio-demographic information as well information about previous testing behaviour, and engagement in HIV treatment and prevention and related health activities. If the male is not willing to participate, he will still complete the utilization form to allow for comparison of participants with non-participants.
Brief risk-reduction counselling
In our Uganda study we showed that briefer modes of HIV risk-reduction counseling are likely to be equally effective as extended counseling and testing . We adapted this briefer risk-reduction counselling method (between 10-23 minutes) by incorporating appropriate messages into the counselling that would addresses men’s masculinity concerns and gender beliefs about testing and treatment (See Table 2 for a breakdown of each session). The approach is male-friendly: we provide services to men in their social spaces and at their convenience; sessions are shorter and tailored to address their particular concerns; men do not have to wait in long queues and all screening services are offered by male counsellors.
During the pre-test counselling session, the counsellor explains the clinical and prevention benefits of testing, the right to refuse, the follow-up services that will be offered, and, in the event of a positive test result, the importance of disclosure to others who may have been exposed to HIV infection. If the patient has never tested for HIV, the counsellor explains why it is important to know one’s HIV status and then offers the test.
Post-test counselling is tailored to the outcome of the test (positive/negative) and retain key messages (e.g., disclosure and partner testing, risk reduction, linkage to care, availability of care). The HIV-positive patient counselling session focuses on emotional support, HIV risk reduction, disclosure of HIV status, follow-up care available and referral; and partner notification and testing. Counselling for the HIV-negative patient focuses on HIV risk reduction, disclosure of HIV status, and partner notification and testing.
HIV testing is conducted using blood collected by finger-stick with a sterile lancet and using a serial testing algorithm for rapid testing according to 2015 South African National HIV Test Services guidelines . All specimens are first tested with one assay (Test 1 or screening test) and specimens that are non-reactive are considered HIV-negative and reported as such. Any specimens that are reactive on the first assay (Test 1) are tested again using a different assay (Test 2 or confirmatory test). For specimens that are reactive on both the first and the second assays, results are reported as HIV-positive. Specimens that are reactive on the first assay but non-reactive on the second assay will receive an ELISA laboratory test and be recorded as discordant. In the case of discordant results, the individual is given the schedule of mobile HTS testing locations and asked to return in seven days  for their HIV results.
Participants are triaged according to their HIV test result. HIV-negative participants will have completed their visit, as they are not eligible for further study participation and if required, referrals to relevant services are made. Study counsellors will explain to HIV-positive men in the intervention communities that they are eligible for the randomization and the next phase of the study, if interested. All HIV-positive participants are asked for locator information (addresses and alternate/additional contact phone numbers) so if randomised into the PLC arm they can be contacted. Permission is obtained to call and/or text the participant to arrange and keep in contact for PLC.
Non-Communicable Disease Screening
In order to destigmatise HIV testing for men, a variety of NCDs screening services are provided alongside the screening for HIV. Procedures for hypertension, diabetes, obesity and STI are explained to interested men, the relevant tests conducted and results provided. Appropriate information on these conditions as well as follow-up referrals are made to nearby health facilities if further care is indicated.
Control communities receive the current standard of care HTS services. All primary health care facilities in South Africa provide client-initiated counselling and testing (CICT) and provider-initiated counselling and testing (PICT). CICT involves individuals or couples/sexual partners actively seeking HIV testing and counselling at a facility that offers these services, while PICT is initiated and recommended by health care providers to all clients attending health care facilities as a standard component of medical care. All counselling includes the provision of pre-test information sessions conducted with groups, couples, or individuals, the HIV test itself, and post-test counselling. The standard of care also involves the promotion of HTS through flyers in clinics, and the service is offered free of charge during office hours, predominantly on weekdays.
Quality assurance of HTS
Rapid, on-site HIV testing has the potential to be a useful and advantageous testing strategy in community-based or outreach settings. The intervention performs HIV testing according to the South African national rapid testing algorithms with on-going external quality assessment (EQA). All staff are fully trained in performing the rapid testing algorithm. CD4 counts are done by POC tests with on-going EQA. Viral load testing are done at a laboratory with EQA participation. Training in rapid testing technology was done as part of the 10-day counselling course for counsellors.
In addition to covering all of the didactic portions of the counselling and testing process, counsellors practice using the test kits themselves with known HIV-positive and HIV-negative sera to ensure that they are performing and reading the tests correctly. Counsellors also practiced with mock patients under the supervision of the counsellor supervisor. Supervisors periodically observe counsellors in the HTS process, using a standardized checklist, to ensure that all parts of the procedure are being followed. Counsellors are recertified bi-annually with panels of HIV-positive and HIV-negative sera. They are expected to achieve 100% correct results; if they fail to do so, the counsellor is taken out of the study, retrained and recertified, and monitored closely to ensure correct adherence to testing protocols. We also conduct daily test kit validation to ensure quality test results. For each mobile unit, we conduct a known positive and known negative validation. We expect perfect concordance of results. If we do not achieve this, the batch is identified and set aside. A new batch of test kits will be validated and used for further testing.
Personalised Linkage to Care (Component 3)
In this third component of the intervention, HIV-positive men are randomised into two arms: 1) standard of care HIV follow-up 2) versus POC CD4 testing with male-centred PLC.
POC CD4 testing with male-centred PLC
HIV positive participants randomised into the PLC phase of the study receive POC CD4 testing. The study nurse conducts same-day CD4 testing by taking a small blood sample obtained from the participant’s fingertip by a lancet. The date of the HIV and CD4 test and symptoms reported by the participant are provided in a one-page letter to the clinic to facilitate ART initiation. At the end of the counselling session, the nurse counsellor schedules a follow-up visit for the participant and their study assigned PLC clinic-based champion (CBC). The clinic-based champion coordinates schedules with the participant and visits the HIV clinic with the participant within 2 weeks of enrolment. PLC services are tailored for individual clients and include pro-active case-management counselling to discuss and reduce barriers to linkage to care, adherence and the importance of disclosure. It also comprises clinic champion accompaniment of the participant to help them navigate the health systems, and extended hours access to the ART clinic.
Accompaniment to the HIV clinic by the clinic-based champion
The PLC clinic-based champion discusses with the participant the usual means of travel to the clinic and encourages the participant to attend the clinic. As appropriate, the champion may travel with the participant to the clinic by public transport or meet the participant at the clinic. At the clinic accompaniment visit, clinic-based champions answer questions and provide support for HIV care. If several accompaniment visits are required before linking to care, the CBC may make these visits with the participant.
Extended Clinic Hours for Men (Happy Hour)
The PLC team leader negotiates with health services to ensure that extended hours of operation for obtaining ART and services are made available to PLC participants who have conflicting engagements during regular HIV clinic hours. This service (called happy hour) is already provided to young people by the Department of Health. A sample of clinics are opened once a week during 17h00-20h00 especially to cater for men. This male only HIV service allows the PLC participants to feel more comfortable in accessing services and discussing their questions and concerns more freely with the staff at the after-hours HIV clinic. The after-hours HIV clinic will offer all services normally available at a standard HIC clinic during regular work hours including HIV testing, counselling, ART medicines.
Regular follow-ups by the clinic-based champion
Further follow-up visits may be scheduled for 3 and 6 months after the initial visit, if the participant has not established care at an HIV clinic. At the follow-up visits, clinic-based champions answer questions about barriers to care, difficulties with adherence and provide support for HIV care. Participants complete a questionnaire on their experience accessing care, including barriers to care, risk behaviour, HIV clinical care and knowledge of HIV treatment and prevention. Examination of HIV care documentation (e.g., registration card from HIV care clinic) and recording of medications (e.g., HIV care medications and ART) takes place.
CBC also link men to appropriate referrals and support, including arranging opportunities for men to come together for support groups with other men to talk about and discuss issues of disclosure, adherence and retention in care.
HIV standard of care
HIV positive men randomized into the standard of care arm are referred to the study counsellor. All participants who get assigned to standard of care receive HIV and NCDs testing results slip that is used as referral letter with all testing outcomes written on it. The lay counsellor provides information about HIV treatment and encourages the participant to visit the nearest clinic or any health care service of their choice for further clinical attention. Participants get information about being contacted telephonically at 3 and 6 months in preparation for the 9-month follow-up visit. The telephonic contact at 3 and 6 months is for tracking purposes to maintain contact with the participant. At 9 months, participant is invited to participate in another short survey and a DBS specimen collection again. Another consent process with participant is solicited at this point.
Aim 1: Outcome measures focusing on men-centred mobilisation and testing strategies in intervention communities to control communities.
- Proportion of men getting tested for HIV in the last 12 months
Men who have been tested for HIV in the last 12 months.
Measurement of Aim 1 outcomes
Conduct post-intervention assessments in intervention and control communities (n=1600, 8 communities x 200).
- Post-intervention random survey data (focusing on self-reported testing history, other wellness related data, health-seeking indicators etc.); and
- Specimen samples from men living in the study communities. We will be able to look at reported HIV status vs actual status.
Aim 2: Outcome measures comparing enrolled participants assigned to PLC to those in standard care during the intervention.
- Proportion linking to care for first clinic visit in the last 9 months
Enrolled men who access health care during the intervention.
- Proportion who remained in care in the last 9 months
Enrolled men who have completed scheduled clinic visits during the intervention.
- Proportion with undetectable viral load at exit
Enrolled men with suppressed viral load at exit.
Measurement of Aim 2 outcomes
Using information collected at 9 month exit interview:
- Conduct facility level chart abstraction to confirm linkage to care for those enrolled in the study; and
- Laboratory DBS viral load assessment to establish viral suppression.
Our combination prevention intervention is informed by the social-ecological framework which demonstrates how effective intervention can effectively address individual, socio-cultural, and program or health facility factors that influence individual health decisions. At the individual level, men’s testing and treatment decisions require careful balancing of perceived benefits against constraints of adopting these health behaviours. Men report testing decisions as comprising a struggle between fears of the consequences of not testing (illness and death) and fears of the consequences of HIV testing (stigma and loss of status as a man). For men, there may also be fears that testing exposes their hidden sexual activities [1, 2]. Social-cultural factors affect men’s decisions regarding health care . Prevalent gender norms are important determinants of both decisions to undergo HTC for men and of subsequent progression through the HIV care pathway.
Social networks create powerful conduits for both support and discouragement for men on this pathway. The influences of other men in the social network regarding testing and treatment and how this feeds into ideas of masculinity as well as the influence of sexual partners, family members, and friends also factor into men’s decisions regarding testing and treatment. Health facility factors also shape the individuals cost-benefit analysis of seeking and sustaining testing and treatment. The distance to medical services, financial and opportunity costs of travel, and the quality of care, such as waiting time and the attitude of providers, are all important factors in testing uptake and treatment compliance for men. Men thus formulate personal options and behavioural intentions while negotiating the social environment and the parameters of testing and treatment programs, and they do so against a broader structural environment that in much of sub-Saharan Africa includes entrenched poverty, food security, and weakened health systems . Our multi-level intervention attempts to address all three levels that affect men’s decision-making regarding testing and engagement in care.
Data management and adverse event reporting
The assessments in the study are administered using electronic mobile data capture. The mobile data collection platform allows for offline data collection. Collected data is uploaded to the server once network connection is re-established. Checks are placed to ensure correct information has been entered. Data from laboratory testing (i.e. plasma HIV VL) is collected by participant ID number and merged into the database. Information from the questionnaires collected via the mobile phone is uploaded to a secured server. The de facto standard for securing network traffic is Secure Sockets Layering (SSL). This technology is fully supported by the handsets used in this study and ensures that all data transferred between the device and the server is encrypted.
Similarly, when reviewing, exporting or managing data all communications between browser and server are encrypted. All data is encrypted. Servers are secured by firewalls to prevent unauthorized access and denial of service attacks. Data is protected from virus threats using antivirus technology. The study database is backed up regularly. All personal identifying data will be destroyed 5 years after the study is completed, in compliance with the regulatory requirements of the study funder. The team is committed to ensuring that identifying data, including GPS, are secure until the time of destruction.
To assure data accuracy and completeness, the mobile data collection platform is programmed to require data submission on all data fields. Skip patterns and logic branches are programmed to ensure that valid data is collected. Range checks are programmed on key fields to ensure data consistency. Operational data is collected for cross-check, data tracing and validation purposes. To assure data security, all hard-copy data is stored in locked cabinets in a locked office, and all electronic data is password protected and stored on a secure server in a secure facility. To ensure protocol compliance, the Project Director conducts periodic observations of study procedures [e.g., observing the informed consent process, a face-to-face interview, or HIV test counselling], conducts periodic “retraining” on key study procedures using role-plays during staff meetings, and produces a regular quality assurance report for the PI.
Aim 1: Cluster-Randomised Component. We will test the hypothesis that the community-wide proportion of men who were tested for HIV in the past year is at least by 10 percentage points [on an absolute scale] larger in communities randomised to the active intervention compared to the standard-of-care arm. The analysis will be based on testing reports provided by men included in the post-intervention assessment. Empirical proportions of tested participants will be calculated for each community and compared between the study arms by a two-sample Welch t-test. We will test the hypothesis that the difference in proportions is less than or equal to 0.1 against the alternative that the difference is larger than 0.1 at the one-sided level of 0.05.
Power Calculations for Aim 1. We assumed 30% annual testing rates in the standard arm [similar to testing rates observed in Project ACCEPT in the community-based HTS arm in Vulindlela site] and between-community variance in testing rates 0.007 (estimated from Project ACCEPT’s Vulindlela data). Then the sample size of 4 communities per arm, with 200 men sampled from each community, provides the following power for detecting intervention effects: power 0.05 for 10% difference (30% vs 40%, null hypothesis); power 0.36 for 20% difference (30% vs. 50%); power 0.86 for 30% difference (30% vs. 60%); power 0.95 for 35% difference (30% vs 65%). Thus the study is powered to detect differences in testing rates that are substantially larger than 20% and therefore likely to be of practical significance. The power for detecting differences of 30% or more is large enough to be reasonably certain that such effects are not missed.
Aim 2: Individually-Randomised Component. We will test the hypothesis that the proportion of HIV-positive men who were linked to care and maintained with undetectable VL 9 months after enrolment will be the same in the POC + PLC arm as in the standard-of-care arm. The analysis will be based on men who were randomised and who completed the follow-up visit. We will use asymptotic tests for log odds ratios performed at the two-sided level of 0.05. Confidence intervals will be obtained by the same method.
Power Calculations for Aim 2.
Assuming that the rates of linkage to care and undetectable VL are 33% in the standard arm and 50% in the POC + PLC arm (odds ratio 2.0), the sample size of 175 subjects per arm yields 88% power to detect the effect of POC + PLC over standard of care. Adjusting for 20% attrition yields the sample size of 220 per arm.
Secondary Analyses for Aim 2
We will carefully investigate the effect on attrition on the primary analysis of Aim 2. We will compare the men who do and do not present for the final visit to assess potential bias in the analysis of the primary endpoint of Aim 2. We will evaluate the attrition effect by multiple imputation of missing data using baseline characteristics of the subjects. We will compare HIV-positive men identified in Aim 1 who do and do not enrol in the Aim 2 study.
Aim 3: Integrating the outcomes of the structural and individual level interventions
We will estimate the joint effect of the structural and individual-level interventions on the percentage of HIV-positive men who are effectively treated (tested, linked to care and maintained with undetectable VL) by estimating the percentage of HIV-positive men who have been tested in male-centred mobile HTS vs. control arms using data on HIV testing and HIV status of the post-intervention assessment participants from Aim 1, and estimating success rates of undetectable VL in SOC and POC + PLC arms in Aim 2 (adjusted for attrition if needed). These estimates will be multiplied to estimate overall success rates of undetectable VL among HIV-positive men in all four combinations of the two interventions. Confidence intervals will be also calculated. We will assume that the interventions do not interact with each other since each targets a different stage in the process leading to successful HIV treatment of HIV-positive men. Given population size and HIV prevalence, we will be able to estimate the number of men who would be identified, treated, and maintained on treatment under each of the possible intervention combinations. A sensitivity analysis will be performed to evaluate the impact of potential non-independence of intervention effects.
A full factorial design is not feasible because one of the interventions is applied at the community level and the other at the individual level, and success at the first of the interventions (being tested) is a condition of enrolment into the other intervention. This brings bias into the randomization of the community-level intervention. This design could only be conducted by randomizing whole communities to the four combinations of the interventions, but that would be too costly.
We will examine effectiveness in terms of: (1) behavioural changes resulting from HIV testing and counselling (which reduces HIV transmission and acquisition), (2) increases in life-expectancy and quality of life from engagement and retention in care, and (3) reductions in HIV transmission, and thus morbidity and mortality from downstream infections, derived from reduced HIV infectivity of those on ART. We will contrast standard of care versus exposure to (1) male-centred mobilization + mobile HTC and (2) combined POC CD4 + Personalized linkage to care. For each, we will use Bernoulli-Process models for HIV transmission, extension of life, and enhancement of quality of life.
We use Monte Carlo and Latin Hypercube simulations with @Risk™ software for sensitivity analyses. Confidence intervals and point estimates from study data will be fitted to distribution functions. Convergence will occur when the addition of model iterations changes the average and standard deviation of the output by less than 1.5%. Correlations between model parameters will be identified to better fit the model.