Recruitment

Participants for both arms of the study are recruited from the local Wits RHI Sex Worker Project clinics as well as the surrounding community, and in particular places of business such as hotels/brothels, bars and streets. We leverage the existing peer educator-based outreach services currently provided by the Sex Worker Project to reach out and inform them of the study. Each potential participant completes a DoH HIV counselling and Testing (HCT) consent form first as part of standard HCT practice, to determine HIV status through the point-of-care rapid testing process. Discordant HIV rapid test results are then confirmed using ELISA using standard local algorithms (ie, algorithm: two rapid tests are performed simultaneously for confirmation. In case of discordant, indeterminate or positive results, blood is drawn for an ELISA).34 Once HIV status is established, participants sign either the PrEP or ITx TAPS study informed consent form according to HIV status. Participants in the PrEP arm are counselled and informed about adherence and effectiveness of PrEP, the need to use condoms with PrEP in order to ensure a high level of protection against HIV infection as well as to prevent STIs and unwanted pregnancies. Participants in the ITx arm are also counselled about adhering to their treatment regimens and using condoms.

We aimed to balance the ‘real world’ aspect of the demonstration project with the consent and information gathering needs for research purposes. Therefore, at the screening visit, participants are asked to complete a demographic and behaviour questionnaire, as well as a short medical history for screening purposes. Blood samples are taken for creatinine levels, hepatitis B, syphilis testing, HIV confirmation with ELISA and viral load testing. All participants also take a point-of-care pregnancy test as part of eligibility requirements.

Participants are asked to return in 1-week, within a maximum window of up to 30 days if needed, after the screening visit for enrolment if eligible. At the enrolment visit, participants are scheduled for regular study visits to monitor medication adherence and safety. We also take a clinical history, offer syndromic STI screening and any other clinically indicated assessments such as for cervical cancer as per DoH guidelines. Potential participants are asked about fertility intentions; however, future pregnancy plans are not a part of study exclusion. Contraception is offered to those requiring a method as per standard of care, but use of a contraceptive is not a requirement for study eligibility.

The participants have access to counselling services, as well as all other services provided by the Sex Worker Project as standard of care, including but not limited to reproductive health services, referrals for legal services, substance use and violence counselling and support and post-rape care. Support groups are not currently planned as an official service of this study; however, FSWs may elect to form support groups and project staff make an effort to support this with space if requested.

Medication and adherence

HIV-negative participants fulfilling all eligibility criteria are started on co-formulated emtricitabine and tenofovir disoproxyl fumarate FTC/TDF (Truvada) in the PrEP arm. The medication for the ITx arm is tenofovir disoproxyl fumarate plus lamivudine/emtricitabine plus efavirenz combination (TDF+ 3TC/FTC+EFV), or Atripla, as per current guidelines. The drugs for the TAPS study have been donated by Gilead.

We measure adherence to PrEP through several modes of self-report as well as plasma drug level testing. Treatment adherence is measured through self-report and monitoring viral load suppression.

As adherence support, all participants have the option to receive SMS. Two types of SMS may be sent to participants. The first type is visit reminders, three sent per visit—two as reminders before the visit and one to thank the participant for attendance or to remind them to reschedule if they missed a visit. The second type is aimed at providing information and support on a weekly basis and within the following themes—adherence/side-effects/informational, health education, healthy living, referral services and affirmations. All participants are offered each type of messaging services and those who are willing to participate sign an additional consent form. Participants are able to opt out at any time and feedback on the utility of the messages is solicited throughout the study.

Management of pregnancy

Guidance from major organisations, such as the WHO and Centers for Disease Control and Prevention (CDC), USA, has made surveillance of PrEP use in pregnancy a priority.35 ,36 If a participant becomes pregnant during the course of the project in the PrEP group, she will be given the option to either continue or discontinue taking PrEP. If she decides to discontinue PrEP, she will be given the option to remain in the project using other HIV prevention options, but is referred for antenatal services or termination of pregnancy services as selected. The potential for harm due to unknown risks of taking PrEP while pregnant is noted in the main study's informed consent forms.

If a participant in the treatment group becomes pregnant during the course of the project, she will also be given the option to remain in the study and be referred for antenatal services, where participants will continue lifelong treatment as per the current guidelines. If the participant decides to discontinue participation in the study, she will be referred to the clinic of her choice for continued treatment.

Follow-up visits and loss to follow-up

Participants are scheduled for clinic visits on a 3-month basis and receive a prescription refill once a month in both arms. Monitoring visits include HIV testing (PrEP arm only), CD4 and viral load tests (ITx arm only), creatinine levels, syndromic screening and treatment for STIs as required, and adherence counselling. All these services are standard of care for monitoring patients on treatment and are the minimum monitoring requirement in the newly published PrEP and ITx guidelines.23 At each scheduled visit, participants are asked to complete a short questionnaire to record any side effects, changes in risk behaviour, fertility intentions, time of last menstrual period and adherence to ARVs. Participants may also request an unscheduled visit to report safety events at any time. We are not collecting quantitative information on diversion of medications (eg, selling or giving ARVs to others), but we are both collecting qualitative information on this important issue as part of the in-depth interviews (IDIs) and providing intensive adherence counselling.

Loss to follow-up is defined as a participant missing two consecutive visits with no contact. Efforts will be made to contact participants by phone in the PrEP and ITx arms to understand the reasons for missed visits. However, only additional efforts, which may include a home visit, will be made to encourage participants in the ITx arm to return. If participants are contacted in the PrEP group and decide not to return, we will ask if they are willing to participate in a brief exit interview to understand the reasons for dropout and to ensure there are no safety concerns.

Final visit and withdrawal from the project

At the final project visit, all participants will be asked to answer final behavioural, violence and participant costing questionnaires. Those in the PrEP arm will have creatinine test, STI screening and treatment as necessary; while those in the treatment arm will have CD4 and viral load tests, creatinine test, STI screening and treatment as necessary, and counselling for continued adherence to their treatment regimen. They will be offered a choice to remain at the same clinic for continued care and treatment, or be transferred to another clinic of their choice. If a participant in the PrEP arm sero-converts, we will offer a full resistance testing. The participant will not be rolled on to the ITx arm but will be offered a choice to remain at the same clinic for continued care and treatment, or be transferred to another clinic of their choice. All participants will also be informed as to when they can expect a report of the project's results.

As of 1 June 2016, PrEP and the test and treat approach has been prioritised for sex workers. As a result, we are now able to transition all of the women in our study to PrEP and HIV treatment services in our Sex Worker Programme or to other clinics of their choosing offering these services, either at the end of the study or should they choose to leave the study early for any reason.

For ease of reference, we mapped all events and provided a visit schedule for both PrEP arm and ITx arm in the online supplementary appendix.

Quantitative analysis of process and questionnaire data

The primary outcome for both arms is the number of women retained at 12 months of follow-up (a participant is considered retained at 12 months if she attended a scheduled follow-up visit between 10.5 and 13.5 months after enrolment). In the PrEP arm, we note that a participant is considered retained even if not on PrEP but continuing the combination prevention visits. Secondary outcomes for both arms are shown in table 3.

We can expect three types of bias in cohort studies: selection bias, information bias and misclassification bias. It is possible that participants ‘auto-select’ (ie, a selection bias), meaning that those FSWs feeling most vulnerable will be most likely to enrol and continue participation. Since this is a demonstration project, we expect participants to decide whether to participate based on their risk perception and we will aim to document these motivations and perceptions as much as possible through qualitative research. We do not expect an information bias to be present as we are collecting the same information for all participants. Finally, misclassification could arise from a participant being considered not retained in care as per her participation in our study; however, she might be in care at another clinic. We will aim to ascertain if this is a potential bias while contacting by phone those participants missing two consecutive clinic visits in either the PrEP or the ITx arm to understand the reasons for missed visits.

Qualitative research

Data from qualitative research conducted during the PrEP efficacy trials indicate multiple and varying reasons for lack of adherence on the part of participants, thus illustrating the imperative to understand how PrEP may be best implemented in a given context from the point of view of potential consumers.37 ,38 In this regard, we are conducting a multifaceted qualitative research with participants from the two project arms as well as providers at the clinics to gain perspectives on using and implementing PrEP and ITx. Methods include IDIs with participants, waiting-room observations and provider group discussions. These methods will serve as a means to compare and contrast sources of data to develop a narrative as to the feasibility, and more specifically, the motivations and barriers of implementing PrEP and ITx. We will also be able to compare these qualitative data with data from the structured questionnaires to explore different aspects of adherence to medication. All data collection tools have been piloted and adjusted as required.

Participant IDIs

We use an adapted socioecological model as a framework to explore themes related to motivations and barriers to the use of PrEP and ITx based on the multiple spheres influencing women's lives from community, household, work and clinic settings. A subset of women from the PrEP and ITx arms are being randomly invited to participate in the qualitative research component in each arm (up to 40 for PrEP and up to 30 for ITx). Each participant is asked to sign a separate consent form and is reimbursed for her travel costs since this will be outside of regular clinic visit requirements. This is the only form of participant reimbursement offered since the purpose of the TAPS project is to assess retention in the programme in a ‘real-world’ clinic setting. Interviews are conducted individually with each participant by a research assistant who is conversant in the participant's language.

Interviews will be conducted longitudinally at months 3, 6 and 9 for each participant in order to explore themes emerging over time.37 Interview questions will seek data related to reasons for participating in the study, motivations and barriers to uptake and use of the interventions, acceptability of the SMS technology, perceived gaps in service delivery and HIV prevention method preferences over time. Interviews will be audio taped, and later translated into English, as needed, and transcribed.

Waiting-room observations

Informal conversations held by participants in settings such as waiting-rooms have provided invaluable information for the triangulation of qualitative data thus enriching narratives of participant behaviour during studies.37 We are conducting waiting-room observations at the two project sites for a period of 1-week on a quarterly basis. Permission to conduct these observations is obtained from the clinic managers, and researchers conducting the observations provide study participants in the waiting-rooms with notification of who they are, what they are doing and for what purpose. The purpose of these observations is to gather informal data on participants' perspectives of the study, the interventions and issues they may be experiencing that influence their interest in the programme and ability to maintain participation. Information will be recorded in the researcher's field notebook and later uploaded into NVIVO for coding and analysis.

Provider group discussions

A recent guidance illustrates the importance of service delivery providers as an important target group for promoting and managing the dissemination and uptake of PrEP.39 As such, we are convening informal group discussions at each site in order to explore provider experiences, including primarily the community health workers/counsellors, nurses, pharmacists, coordinators and medical officers, in delivering PrEP and ITx. All potential provider-participants are asked to complete the informed consent process and have the option to decline participation. The research is being conducted by an external contractor and does not include evaluation of providers on performance. As themes for discussion may evolve over time, a more structured discussion guide is being used initially and subsequent guides will build on emerging themes.

Analysis

All qualitative research components will be analysed using thematic analysis as defined by Braun and Clarke.40 This approach to thematic analysis features a six-phase process: familiarisation with the data, generation of initial codes, searching for themes, reviewing themes, defining and naming themes, and finally producing the report. Translated and transcribed transcripts from the IDIs, waiting-room observations and provider group discussions will be uploaded into NVIVO software and coded according to the coding manual created. Researchers will assemble the coding manual first by developing overarching data categories based on research objectives, then by systematic and iterative review of the data to elicit primary and subthemes. We will aim to have at least two coders per transcript. Any discrepancies in coding will be discussed between the coders with input from the senior investigator to gain consensus. Once all the data have been coded, researchers will synthesise the findings to explore commonalities and differences across participant perspectives.

Economic evaluation

The introduction of an integrated HIV prevention and care service is likely to involve several trade-offs between costs and efficiencies. We are measuring empirically the costs for participants and the healthcare providers in the two sites of the TAPS study to then model total costs, impact and cost-effectiveness of this intervention both in our cohort and at a population level. The evaluation is carried out from a societal perspective.

Healthcare provider costs

All costs will be estimated using an ingredient costing approach to define the cost per person receiving each service. Data are collected through directly observed resource use (observations of practice at sites and interviews with the healthcare workers before implementation, at early stages of implementation and 1-year after the interventions are implemented). We also review clinic costs (such as utility bills) over the duration of the study. We include capital costs (equipment, buildings, non-recurrent training), as well as recurring costs (personnel, supplies, operations and maintenance of buildings) in our estimates. We aim to include costs incurred above the direct service level, such as monitoring and evaluation and coordination costs as well as cost incurred during start up activities such as community mobilisation and training before the service delivery starts. The current micro costing approach allows us to record in detail all processes happening at each visit and their purpose (for research or service delivery). The unit cost will then be reported disaggregating research-related costs.

Participant costs

Data are collected through voluntary questionnaires administered to all participants in the PrEP and ITx cohorts at one visit (follow-up at 12 months). In the questionnaires, we collect general information regarding the participant's household, employment and income, out-of-pocket expenditures including transportation fees, consultation fees, non-HIV laboratory tests, non-HIV medication (vitamins, antibiotics and others) and food, any time lost due to PrEP or ITx appointments, including travel time, consultation time and loss of income: the participant's time and that of her family/friends will be ascertained. Family/friends time will be estimated from the proportion of visits where a family member/friend escorted the participant.

Modelling

All modelling exercises will be informed from the data collected during the TAPS study on behaviour, uptake, linkage, retention and medication adherence as well as the costing data. A decision analytic economic modelling approach will be used to look at issues of health system capacity (staff constraints) and equity (poverty analysis using patient-related costs within the cohort). The direct impact on costs and health gains that the introduction of PrEP and ITx might have had on the study cohorts and the service provided in the clinics will be explored.

A population-level transmission model fitted to the South African epidemic will be used, with a special emphasis on transmission within FSW groups with high mobility model focusing on the estimated impact that the introduction of PrEP and ITx might have, should the intervention be scaled up nationally. Population-level data will be gathered from the literature. Outputs of the transmission model will include cost-effectiveness and budget impact measures. A series of scenario analyses might be needed to reflect the different strategies for scale up that policymakers might consider. We will consult all stakeholders (both users and policymakers) during the process of defining the scenarios for scale up to ensure that the most realistic scenarios are tested. We will aim to estimate the reduction in health costs of implementing both interventions. Therefore, we expect savings from infections averted while on PrEP and from less ‘other’ HIV care if treatment is started early.