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Treatment And Prevention for female Sex workers in South Africa: protocol for the TAPS Demonstration Project
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011595
Article Type: Protocol
Date Submitted by the Author: 19-Feb-2016
Complete List of Authors: Gomez, Gabriela; Amsterdam Institute for Global Health and Development, Eakle, Robyn; University of the Witwatersrand, Wits RHI; London School of Hygiene and Tropical Medicine Mbogua, Judie; University of the Witwatersrand, Wits RHI Akpomiemie, Godspower; University of the Witwatersrand, Wits RHI Venter, WD Francois; University of the Witwatersrand, Wits RHI Rees, Helen; University of the Witwatersrand, Wits RHI
Primary Subject HIV/AIDS Heading:
Secondary Subject Heading: Public health, Health services research, Health economics
HIV Prevention, pre-exposure prophylaxis (PrEP), key populations, Keywords: implementation science, Immediate Treatment http://bmjopen.bmj.com/
on September 26, 2021 by guest. Protected copyright.
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1 2 3 Treatment And Prevention for female Sex workers in South Africa: protocol for the TAPS 4 Demonstration Project 5 6 7 Author Institution Email 8 Gabriela B Gomez‡ Department of Global Health and [email protected] 9 Amsterdam Institute for Global 10 Health and Development, 11 Academic Medical Center, 12 University of Amsterdam, The 13 Netherlands and Department of 14 Global Health and Development, 15 For peerLondon School review of Hygiene and only 16 Tropical Medicine, UK 17 18 Robyn Eakle*‡ Wits Reproductive Health and HIV [email protected] 19 Institute, London School of Hygiene 20 and Tropical Medicine, UK 21 Godspower Akpomiemie Wits Reproductive Health and HIV [email protected] 22 Institute 23 Judie Mbogua Wits Reproductive Health and HIV [email protected] 24 Institute 25 W D Francois Venter Wits Reproductive Health and HIV [email protected] 26 Institute 27 Helen Rees Wits Reproductive Health and HIV [email protected] 28 29 Institute 30 31 ‡ Contributed equally 32 *Corresponding author: 33 Robyn Eakle
34 http://bmjopen.bmj.com/ 35 Wits Reproductive Health & HIV Institute 36 University of the Witwatersrand, 37 Hillbrow Health Precinct, 22 Esselen Street, Hillbrow, 2001, Johannesburg, South Africa 38 t: +27 11 358 5350; e: [email protected] 39 40 41 Word count: abstract – 300 (max 300 words); text – 4575 excluding tables/figures (max 42
recommended: 4000 words) on September 26, 2021 by guest. Protected copyright. 43 Number of tables: 3; Number of figures: 0 (max figures and tables: 5) 44 45 46 47 Key words: HIV prevention, pre-exposure prophylaxis (PrEP), key populations, implementation 48 science, Immediate Treatment. 49 50 51 52 53 54 55 56 57 58 59 60 1
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1 2 3 ABSTRACT 4 Introduction 5 Updated guidelines have been recently published by the World Health Organisation recommending 6 7 antiretroviral treatment for adults with HIV at any CD4 count and daily oral pre-exposure prophylaxis 8 (PrEP) as an additional prevention strategy for people at substantial risk of HIV infection. However, 9 implementation challenges relating to health service capacity, acceptability, financing and resource 10 allocation may hinder the ability of programmes to translate these recommendations into successful 11 12 practice. This demonstration project is the first to integrate PrEP (for HIV-negative) and Immediate 13 Treatment (ITx; for those testing HIV-positive, with a higher CD4 count above national guidelines) for 14 female sex workers (FSWs) in South Africa with the overall aim to answer operational research 15 questions. For peer review only 16 17 18 Methods and Analysis 19 This is a prospective cohort study where the main outcome is retention at 12 months. The study 20 population includes FSWs in two urban sites in South Africa recruited into two arms: 1) PrEP arm 21 22 allowing women to cycle on and off of the medication (n=400); and 2) ITx arm (n=300). We will 23 systematically investigate process and other health indicators. A qualitative research component will 24 aim to better understand the motivations and barriers to uptake and use of PrEP and ITx for both 25 participants and providers. Finally, an economic evaluation will inform a cost-effectiveness analysis 26 27 combined with estimates of impact through epidemiological modelling. 28 29 Ethics and Dissemination 30 The TAPS Project was designed as an implementation study, however, when it was conceived the 31 32 indication for use of the Truvada combination as PrEP was not yet approved in South Africa. 33 Therefore, the requirements for ethical and Medicines Control Council approvals at clinical trial level
34 regulations were followed. At completion, results will be disseminated sequentially: to TAPS http://bmjopen.bmj.com/ 35 participants, local health officials and stakeholders, and other partners. We will aim to disseminate 36 further study results in peer-reviewed journals and conferences. 37 38 39 40 Strengths and Limitations 41 The strengths of this study exist within the design, incorporating a multidisciplinary evaluation within 42 an implementation science paradigm focused on service delivery. We will be able to measure the on September 26, 2021 by guest. Protected copyright. 43 44 success of the study using several outcomes, enabling us to triangulate data to explain findings. The 45 study has also been designed for flexibility so that changes in elements such as CD4 count threshold 46 in current ART guidelines and providers delivering the services can be accommodated as clinical 47 standards shift within South Africa. In this way, we aim to provide data which are relevant and 48 49 supportive of new policy and planning. 50 51 As with any study, there are limitations. As this is an implementation study, there is no comparison 52 arm so we will not be able to measure the effectiveness of any service delivery model, only its 53 54 acceptability and feasibility within current service delivery. Substantial efforts have been made to 55 include the evaluation within a service delivery that is as close to real world as possible. This has 56 meant that data collection points have been reduced to the minimum to avoid interference in 57 service delivery. Finally, we are testing new interventions for a stigmatised population where access 58 59 60 2
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1 2 3 to services is limited. Our resulting sample size is small and might not be representative of the 4 national population of female sex workers. Nevertheless, this study is the first and only ongoing 5 study testing simultaneously the expansion of ARV-related service (ie immediate treatment and 6 7 PrEP) for FSWs in South Africa. 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 43 on September 26, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3
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1 2 3 INTRODUCTION 4 Globally, UNAIDS data have shown a significant and continuous decline (35%) in the number of new 5 HIV infections since 2000 (1). In sub-Saharan Africa, this trend is even more pronounced with a 41% 6 7 decline. However, in this region of the world, where women make up for more than half of all 8 people living with HIV, incidence rates remain high (1). In particular, the HIV epidemic in South Africa 9 continues to be the largest in the world (2). 10 11 12 The South African National Strategic Plan on HIV, STIs, and TB (NSP) for 2012-2016 prioritizes 13 interventions with the aim to reduce new infections on a national level by 50% using combination 14 prevention while scaling up treatment to cover at least 80% of the population. The NSP also 15 identifies key Forpopulations aspeer a major focus ofreview the strategy, which calls only for a multi-faceted approach 16 17 to ending the epidemic. Sex workers are among the key populations identified in the past and 18 current NSP. Globally, female sex workers (FSWs) are 13.5 times more likely to be living with HIV 19 than women in the general population (3). The 2013 South African Key Populations Report estimates 20 that HIV prevalence among FSWs is between 44 and 69% (4–7), with 19.8% of all new infections 21 22 being attributed to sex work, including infections among clients and partners of clients (8). A study 23 conducted in 2008 in a cohort of high risk women in KwaZulu-Natal Province, estimated incidence to 24 be as high as 7.2/100 person-years (7). More recently, an HIV and syphilis prevalence study 25 conducted among populations of sex workers found a 72% prevalence with low treatment uptake in 26 27 Gauteng Province (9). This high vulnerability is rooted in the many structural drivers of HIV risk 28 affecting this population including: restricted access to healthcare, criminalization and lack of legal 29 protection, unsafe working conditions, stigma, and economic hardship (8). As a marginalized 30 population who are stigmatized and criminalized, sex workers require specialized programmes 31 32 sensitive to their needs for interventions in HIV prevention, care, and treatment as well as support 33 to access other health and legal services.
34 http://bmjopen.bmj.com/ 35 Following the positive results of ARV-based prevention studies in reducing both HIV transmission 36 (through Immediate Treatment, ITx) and acquisition (through pre-exposure prophylaxis, PrEP) (10– 37 38 16), global and national authorities updated HIV guidelines to recommend antiretroviral treatment 39 (ART) be initiated at any CD4 count in adults and daily oral PrEP as an additional prevention strategy 40 for people at substantial risk of HIV infection (17,18). While modelling studies have shown that the 41 scaling up of new prevention and treatment tools across the HIV continuum of care could have a 42 43 significant impact on the epidemic (19–21), implementation challenges relating to health service on September 26, 2021 by guest. Protected copyright. 44 capacity, acceptability, and financing and resource allocation may hinder the ability of programmes 45 from making a significant difference to HIV prevalence(22,23). 46
47 48 The evaluation of existing and innovative models of care to implement new technologies for 49 prevention and treatment through demonstration projects is being conducted around the world 50 (24). These projects represent a spectrum of designs from clinical trial-like protocols to ‘real-world’ 51 implementation science studies, yet all have similar goals: to test delivery models of new 52 53 technologies and interventions to inform policy and programming. In particular, projects tend to 54 cater to key populations where acceptability and uptake of technologies such as oral PrEP may be 55 higher and intersect with those populations who might benefit the most initially, such as men who 56 have sex with men (MSM), sex workers, serodiscordant couples, and young women. These 57 58 prevention-focused projects are situated within a landscape of evolving HIV treatment guidelines, as 59 60 4
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1 2 3 treatment is now recognised as the major contributor to prevention, and thus many include 4 treatment components (17,25). 5 6 7 The demonstration project described here is the first to integrate a combination prevention 8 intervention including oral PrEP and ITx (for those with CD4 counts higher than current national 9 guidelines) for FSWs in South Africa. The interventions are being delivered at two clinic-based sites 10 for FSWs in Gauteng Province. Gauteng is the most densely populated province of South Africa, 11 12 home to both the economic and political capitals of the country (26). This implementation study 13 seeks to understand the ‘real-world’ implications of introducing PrEP and ITx into an existing service 14 delivery structure. By combining PrEP and ITx, we aim to leverage, in a novel way, the service 15 delivery areasFor needed to supportpeer these programmes review which primarily only include outreach for testing 16 17 and counselling and clinic services. The overall aim will be to answer operational questions: whether 18 FSWs will accept ITx or combination prevention including PrEP, whether the service delivery 19 mechanism is capable of handling the increase in resource needs these interventions might lead to, 20 and what kind of implications this strategy would have on overall costs and long-term sustainability 21 22 for the health system, should they be considered for scale up. 23 24 METHODS AND ANALYSIS 25 Population and setting 26 27 The study population will be comprised of FSWs (women self-identifying as sex workers, and who 28 have received goods or money in exchange for sex in the past three months), age 18 or above, 29 operating in the areas surrounding two existing clinics providing services for sex workers in Hillbrow, 30 Johannesburg, and the central business district in Pretoria. These clinics are run by Wits 31 32 Reproductive Health and HIV Institute, one of the largest research Institutes of the University of 33 Witswatersrand; since 1994, Wits RHI has pioneered health programmes with a strong community
34 focus. The Hillbrow site is connected to the Esselen Clinic which is home to the well-established Wits http://bmjopen.bmj.com/ 35 RHI Sex Worker Project . The Sex Worker Project is a full reproductive health, HIV and STI prevention 36 and treatment service programme partnered with City of Johannesburg and the South African 37 38 Department of Health (DoH). It provides services such as: HIV counselling and testing and condom 39 distribution, NiMART (nurse-initiated and managed antiretroviral treatment), tuberculosis screening, 40 HPV screening, clinical services for minor ailments, psychosocial support, and referrals to both 41 clinical and legal services. The programme accesses several brothels, with mobile units to serve 42 43 street-based sex workers, and a stationary clinic space. The actual clinic space for the TAPS on September 26, 2021 by guest. Protected copyright. 44 Demonstration Project will be located in the Wits RHI Research and Training Centre, which is 45 adjacent to the Esselen Clinic. 46
47 48 The Pretoria site is located in Sediba Hope Medical Centre, a private non-profit clinic affiliated with 49 the Department of Health, which has been serving the local community in the heart of the inner city 50 of Pretoria. Wits RHI’s Sex Worker Project has now opened a sex worker clinic at Sediba Hope which 51 is also linked to the Community Health Clinic in the same building. 52 53 54 55 56
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1 2 3 Design 4 The study design is a prospective, observational cohort study, with two study arms: 5 6 7 1) A PrEP intervention as part of a combination prevention approach for recently documented 8 HIV-negative FSWs; 9 2) An ITx intervention for HIV-positive ART-naïve FSWs not eligible for ART at the currently 10 implemented CD4-defined standard of care (currently <500 cells/mm3). 11 12 13 The PrEP intervention arm will seek to protect HIV-negative FSWs from acquiring HIV through the 14 use of PrEP and other available prevention options (such as condoms). The ITx intervention arm will 15 seek to link FSWsFor directly topeer care to reduce andreview avoid loss to follow uponly within the treatment cascade. 16 17 Indirectly, it will seek to prevent HIV-positive FSWs from transmitting the virus to clients and other 18 sex partners through the use of ARVs. 19 20 Sample size and eligibility criteria 21 22 Table 1 shows the sample size considerations for both study arms. We aim to enroll 400 FSWs in the 23 PrEP arm of the study. With an expected retention rate of 65% (precision of ±5%) at 12 months, we 24 need 350 participants, which we have increased to 400 to account for variability across the two sites. 25 To achieve this sample size, we aim to screen 1,600 FSWs, of which 800 are expected to be HIV- 26 27 negative (assuming an HIV prevalence of 50%) and we estimate conservatively that 50% accept to 28 participate. For the ITx arm, we aim to enroll 300 FSWs with an expected retention rate of 75% 29 (precision of ±5%) at 12 months, assuming a 25% default rate which reflects recent research on the 30 treatment cascade (23). To achieve this sample size, we aim to screen 3,600 FSWs, of which 1,800 31 32 are expected to be HIV-positive (assuming an HIV prevalence of 50%), one third with CD4 counts 33 over 350 (n= 600) and 50% accept to participate. Note that the original calculations for this study
34 were done assuming a national CD4 count initiation threshold of 350, but this has now changed to http://bmjopen.bmj.com/ 35 500. A summary of eligibility criteria is presented in Table 2. 36
37
38 39 Table 1: Sample size considerations. 40 PrEP arm ITx arm 41 Retention at 12mo Precision N Retention at 12mo Precision N 42 43 65% 2.5% 1398 75% 2.5% 1152 on September 26, 2021 by guest. Protected copyright. 44 65% 5.0% 350 75% 5.0% 288 45 65% 7.5% 155 75% 7.5% 128 46 47 65% 10.0% 87 75% 10.0% 72 48 PrEP, pre-exposure prophylaxis; ITx, immediate treatment; mo: months; N, number. 49 50 51 52 53 54 55
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1 2 3 4 Table 2: TAPS Project Eligibility Criteria 5 PrEP arm ITx arm 6 7 18 years or older 18 years or older 8 Creatinine clearance above 60.0 mL/min Creatinine clearance above 60.0 mL/min 9 Negative for hepatitis B CD4 count above national standard for ART 10 initiation 11 Not pregnant Not pregnant 12 Not presenting signs or symptoms of or taking Not presenting signs or symptoms of or taking 13 medication for MDR-TB medication for MDR-TB 14 Not prescribed other drugs contraindicated for Not prescribed other drugs contraindicated for 15 taking with emtricitabineFor andpeer tenofovir reviewtaking with tenofovir only disoproxyl fumarate/ 16 disoproxil fumarate (FTC/TDF) lamivudine/emtricitabine/efavirenz (TDF + 17 18 3TC/FTC + EFV) 19 PrEP, pre-exposure prophylaxis; ITx, immediate treatment; ART, antiretroviral treatment; MDR-TB, 20 multi-drug resistant tuberculosis. 21 22 Intervention 23 24 Recruitment 25 Participants for both arms of the study will be recruited from the local Wits RHI Sex Worker Project 26 clinics as well as the surrounding community, and in particular places of business such as 27 hotels/brothels, bars, and streets. We will leverage the existing peer educator-based outreach 28 29 services currently provided by the Sex Worker Project to reach out and inform them of the study. 30 Each potential participant will complete a DoH HIV counselling and Testing (HCT) consent form first 31 as part of standard HCT practice, to determine HIV status through the point-of-care rapid testing 32 process. Discordant HIV rapid test results will be confirmed using ELISA using standard local 33 algorithms. Once HIV status is established, participants will sign either the PrEP or ITx TAPS study
34 http://bmjopen.bmj.com/ 35 informed consent form according to HIV status. 36 37 We aimed to balance the “real world” aspect of the demonstration project with the consent and 38 39 information gathering needs for research purposes. Therefore, at the screening visit, participants are 40 asked to complete a demographic and behaviour questionnaire, as well as a short medical history for 41 screening purposes. Blood samples will be taken for creatinine levels, hepatitis B, syphilis testing, 42 HIV confirmation with ELISA (if rapid HIV positive), and viral load testing. All participants will also on September 26, 2021 by guest. Protected copyright. 43 44 take a point-of-care pregnancy test as part of eligibility requirements. 45 46 Participants will be asked to return in one week, within a maximum window of up to 30 days if 47 needed, after the screening visit for enrolment if eligible. At the enrolment visit, participants will be 48 49 scheduled for regular study visits to monitor medication adherence and safety. We will also take a 50 clinical history, offer syndromic STI screening and any other clinically indicated assessments such as 51 for cervical cancer as per DoH guidelines. Potential participants will be asked about fertility 52 intentions, however, future pregnancy plans will not form part of study exclusion. Contraception will 53 54 be offered to those requiring a method as per standard of care, but use of a contraceptive is not a 55 requirement for study eligibility. 56 57 58 59 60 7
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1 2 3 The participants will have access to counselling services, as well as all other services provided by the 4 Sex Worker Project as standard of care, including but not limited to reproductive health services, 5 referrals for legal services, substance use and violence counselling and support, and post-rape care. 6 7 Support groups are not currently planned as an official service of this study, however FSWs may 8 elect to form support groups and project staff will make an effort to support this with space if 9 requested. 10 11 12 Medication and adherence 13 HIV-negative participants fulfilling all eligibility criteria will be started on co-formulated emtricitabine 14 and tenofovir disoproxyl fumarate FTC/TDF (Truvada®) in the PrEP arm. The medication for the ITx 15 arm will be tenofovirFor disoproxyl peer fumarate plusreview lamivudine /emtricitabine only plus efavirenz combination 16 17 (TDF + 3TC/FTC + EFV), or Atripla®, as per current guidelines. The drugs for the TAPS study have been 18 donated by Gilead. 19 20 Participants in the PrEP arm will be counselled and informed about adherence and effectiveness of 21 22 PrEP, the need to use condoms with PrEP in order to ensure a high level of protection against HIV 23 infection as well as to prevent STIs and unwanted pregnancies. We will be measuring adherence to 24 PrEP through several modes of self-report as well as plasma drug level testing. Participants in the ITx 25 arm will also be counselled about adhering to their treatment regimens and using condoms. 26 27 Treatment adherence will be measured through self-report and monitoring viral load suppression. 28 29 As adherence support, all participants will have the option to receive SMS messages. Two types of 30 SMS messages may be sent to participants. The first type will be visit reminders, three sent per visit - 31 32 two as reminders before the visit and one to thank the participant for attendance or to remind them 33 to reschedule if they missed a visit. The second type will be aimed at providing information and
34 support on a weekly basis and within the following themes - adherence/side-effects/informational, http://bmjopen.bmj.com/ 35 health education, healthy living, referral services and affirmations. All participants will be offered 36 each type of messaging services and those who are willing to participate will sign an additional 37 38 consent form. Participants will be able to opt out at any time and feedback on the utility of the 39 messages will be solicited throughout the study. 40 41 Management of pregnancy 42 43 Guidance from major organizations, such as the WHO and United States Centers for Disease Control on September 26, 2021 by guest. Protected copyright. 44 (CDC), has made surveillance of PrEP use in pregnancy a priority (27,28). If a participant becomes 45 pregnant during the course of the project in the PrEP group, she will be given the option to remain 46 taking PrEP or discontinue its use. If she decides to discontinue PrEP, she will be given the option to 47 48 remain in the project using other HIV prevention options, but referred for antenatal services or 49 termination of pregnancy (TOP) services as selected. The potential for harm due to unknown risks of 50 taking PrEP while pregnant is noted in the main study informed consent forms. 51
52 53 If a participant in the treatment group becomes pregnant during the course of the project, she will 54 also be given the option to remain in the study and be referred for antenatal services, where 55 participants will continue treatment lifelong as per current guidelines. If the participant decides to 56 discontinue participation in the study, she will be referred to the clinic of her choice for continued 57 58 treatment. 59 60 8
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1 2 3 Follow up visits and loss to follow up 4 Participants will be scheduled for clinic visits on a three-month basis and will receive a prescription 5 refill once a month in both arms. Monitoring visits will include HIV testing (PrEP arm only), CD4 and 6 7 viral load tests (ITx arm only), creatinine levels, syndromic screening and treatment for STIs as 8 required, and adherence counselling. All these services are standard of care for monitoring patients 9 on treatment and are expected to be the minimum monitoring requirement in the upcoming PrEP 10 guidelines. At each scheduled visit, participants will be asked to complete a short questionnaire to 11 12 record any side effects, changes in risk behaviour, fertility intentions, time of last menstrual period 13 and adherence to ARVs. Participants may also request an unscheduled visit to report safety events at 14 any time. 15 For peer review only 16 17 Loss to follow up is defined as a participant missing two consecutive visits with no contact. Efforts 18 will be made to contact participants by phone in both the PrEP and ITx arms to understand reasons 19 for missed visits. However only additional efforts, which may include a home visit, will be made to 20 encourage participants in the ITx arm to return. If participants are contacted in the PrEP group and 21 22 decide not to return, we will ask if they are willing to participate in a brief exit interview to 23 understand reasons for dropout and to ensure there are no safety concerns. 24 25 Final visit and withdrawal from the project 26 27 At the final project visit, all participants will be asked to answer final behavioural, violence, and 28 participant costing questionnaires. Those in the PrEP arm will have creatinine, STI screening and 29 treatment as necessary; while those in the treatment arm will have CD4 and viral load tests, 30 creatinine, STI screening and treatment as necessary, and counselling for continued adherence to 31 32 their treatment regimen. They will be offered a choice to remain at the same clinic for continued 33 care and treatment, or be transferred to another clinic of their choice. All participants will also be
34 informed as to when they can expect a report back of project results. http://bmjopen.bmj.com/ 35 36 Analysis 37 38 The project will be evaluated through a mixed methods approach. This approach will examine the 39 deliverability of the interventions and their integration into a comprehensive prevention and 40 treatment package, and will include quantitative analysis of process and questionnaire data 41 (behaviours, uptake, linkage and retention in care, and adherence), qualitative assessment of 42 43 providers and user feedback on the interventions, and an economic evaluation from a societal on September 26, 2021 by guest. Protected copyright. 44 perspective. 45 46 Quantitative analysis of process and questionnaire data 47 48 The primary outcome for both arms will be the number of women retained at 12 months of follow 49 up (a participant is considered retained at 12 months if she attended a scheduled follow up visit 50 between 10.5 and 13.5 months after enrolment). In the PrEP arm, we note that a participant will be 51 considered retained even if not on PrEP but continuing the combination prevention visits. Secondary 52 53 outcomes for both arms are shown in table 3. 54 55 56
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1 2 3 Table 3: TAPS Project secondary outcomes 4 Variable PrEP arm ITx arm 5 Knowledge Assessment of HIV knowledge Assessment of HIV knowledge 6 including PrEP including ITx 7 8 Uptake and Description of reasons for ineligibility Description of reasons for ineligibility 9 acceptability after first eligibility assessment after first eligibility assessment 10 Proportion of women accepting PrEP Proportion of women accepting ITx 11 at baseline at baseline 12 Comparison demographic Comparison demographic 13 characteristics of women accepting characteristics of women accepting 14 PrEP vs refusing at baseline ITx vs refusing at baseline 15 Retention ForProportion peer of women retainedreview and Proportion only of women retained and 16 adherent to PrEP at 3, 6, 18, 24 mo adherent to ART at 3, 6, 18, 24 mo 17 Patterns of use Proportion of women using PrEP n/a 18 continuously for 12 mo 19 20 Description of length of use and 21 repetitive uptake for women not 22 using PrEP continuously for 12 mo 23 Adherence Proportion of women reporting Proportion of women reporting 24 taking >85% of pills (self-reported) at taking >85% of pills (self-reported) at 25 each routine visit during 12 mo each routine visit during 12 mo 26 Proportion of women with drug level Proportion of women with 27 detectable in plasma at 12 mo undetectable viral load at 12 m 28 Side effects Number (by type) of all side effects Number (by type) of all side effects 29 reported at routine visits for 12mo reported at routine visits for 12 mo 30 31 HIV status Number of sero-conversion cases at Proportion of women with plasma 32 12 mo and description of all HIV-1 RNA level ≥1000 copies/mL at 33 resistance profiles six months or after initial suppression and description of all 34 http://bmjopen.bmj.com/ 35 resistance profiles 36 Pregnancy Pregnancy rates during follow up Pregnancy rates during the duration 37 of follow up 38 Sexual behaviour Comparison of proportion of women Comparison of proportion of women 39 reporting consistent condom use reporting consistent condom use 40 (stable partners, regular/new (stable partners, regular/new 41 clients): baseline vs PrEP use after 12 clients): baseline vs ART use after 12 42 43 mo mo on September 26, 2021 by guest. Protected copyright. 44 Proportion of women presenting Proportion of women presenting 45 with STI symptoms at each routine with STI symptoms at each routine 46 visit during 12 mo during 12 mo 47 Cell phone Proportion of women opting-out of Proportion of women opting-out of 48 technology for SMS reminders at baseline and SMS reminders at baseline and 49 adherence throughout the duration of the throughout the duration of the 50 support project project 51 Cost of Cost per person-year on PrEP (health Cost per person-year on ITx (health 52 intervention service perspective) service perspective) 53 54 cost per person-year on PrEP Cost per person-year on ITx 55 (participant perspective) (participant perspective) 56 PrEP, pre-exposure prophylaxis; ITx, immediate treatment; mo,month; ART, antiretroviral treatment; 57 STI, sexually transmitted infection. 58 59 60 10
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1 2 3 Qualitative research 4 Data from qualitative research conducted during the PrEP efficacy trials indicate multiple and 5 varying reasons for lack of adherence on the part of participants, thus illustrating the imperative to 6 7 understanding how PrEP may be best implemented in a given context from the point of view of 8 potential consumers (29,30). In this regard, we will conduct multi-faceted qualitative research with 9 participants from the two project arms as well as providers at the clinics to gain perspectives on 10 using and implementing PrEP and ITx. Methods will include in-depth interviews (IDIs) with 11 12 participants, waiting-room observations, and provider group discussions. These methods will serve 13 as a means to compare and contrast sources of data to develop a narrative as to the feasibility, and 14 more specifically, the motivations and barriers of implementing PrEP and ITx. We will also be able to 15 compare theseFor qualitative datapeer with data from review the structured questionnaires only to explore different 16 17 aspects of adherence to medication. All data collection tools will be piloted and adjusted as 18 required. 19 20 Participant in-depth interviews 21 22 We will use an adapted social-ecological model as a framework to explore themes related to 23 motivations and barriers to use of PrEP and ITx based on the multiple spheres influencing women’s 24 lives from community, household, work, and clinic settings. A subset of the women from the PrEP 25 and ITx arms will be randomly invited to participate in the qualitative research component in each 26 27 arm (up to 40 for PrEP and up to 30 for ITx). Each participant will be asked to sign a separate consent 28 form and will be reimbursed for her travel costs since this will be outside of regular clinic visit 29 requirements. This will be the only form of participant reimbursement offered since the purpose of 30 the TAPS project is to assess retention in the programme in a ‘real-world’ clinic setting. Interviews 31 32 will be conducted individually with each participant by a research assistant who is conversant in the 33 participant’s languages.
34 http://bmjopen.bmj.com/ 35 Interviews will be conducted longitudinally at months 3, 6, and 9 for each participant to explore 36 themes emerging over time(29). Interview questions will seek data related to reasons for 37 38 participating in the study, motivations and barriers to uptake and use of the interventions, 39 acceptability of the SMS technology, perceived gaps in service delivery, and HIV prevention method 40 preferences over time. Interviews will be audio-taped, and later translated into English as needed 41 and transcribed. 42 43 on September 26, 2021 by guest. Protected copyright. 44 Waiting-room observations 45 Informal conversations held by participants in settings such as waiting-rooms have provided 46 invaluable information for the triangulation of qualitative data thus enriching narratives of 47 48 participant behaviour during studies (29). We will conduct waiting-room observations at the two 49 project sites for a period of one week on a quarterly basis. Permission to conduct these observations 50 will be obtained from the clinic managers, and researchers conducting the observations will provide 51 study participants in the waiting-rooms with notification of who they are, what they are doing, and 52 53 for what purpose. The purpose of these observations will be to gather informal data on participants’ 54 perspectives of the study, the interventions, and issues they may be experiencing that influence 55 their interest in the programme and ability to maintain participation. Information will be recorded in 56 the researcher’s field notebook and later uploaded into NVIVO for coding and analysis. 57 58 59 60 11
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1 2 3 Provider group discussions 4 Recent guidance illustrates the importance of service delivery providers as an important target 5 group for promoting and managing the dissemination and uptake of PrEP (31). As such, we will 6 7 convene informal group discussions at each site to explore provider experiences, including primarily 8 the community health workers/counsellors, nurses, pharmacists, coordinators, and medical officers, 9 in delivering PrEP and ITx. All potential provider-participants will be asked to complete the informed 10 consent process and will have the option to decline participation. The research will be conducted by 11 12 an external contractor and will not include evaluation of providers on performance. As themes for 13 discussion may evolve over time, a more structured discussion guide will be used initially and 14 subsequent guides will build on emerging themes. 15 For peer review only 16 17 Analysis 18 All qualitative research components will be analysed using thematic analysis as defined by Braun and 19 Clarke (32). This approach to thematic analysis features a six-phase process: familiarisation with the 20 data, generation of initial codes, searching for themes, reviewing themes, defining and naming 21 22 themes, and finally producing the report. Translated and transcribed transcripts from the IDIs, 23 waiting-room observations, and provider group discussions will be uploaded into NVIVO software 24 and coded according to the coding manual created. Researchers will assemble the coding manual 25 first by developing overarching data categories based on research objectives, then by systematic and 26 27 iterative review of the data to elicit primary and sub-themes. Once all data have been coded, 28 researchers will synthesize findings to explore commonalities and differences across participant 29 perspectives. 30 31 32 Economic evaluation 33 The introduction of an integrated HIV prevention and care service is likely to involve several trade-
34 offs between costs and efficiencies. We will measure empirically the costs for participants and the http://bmjopen.bmj.com/ 35 healthcare providers in the two sites of the TAPS study to then model total costs, impact and cost- 36 effectiveness of this intervention both on our cohort and at a population level. The evaluation will be 37 38 done from a societal perspective. 39 40 Healthcare provider costs 41 All costs will be estimated using an ingredient costing approach to define the cost per person 42 43 receiving each service. Data will be collected through directly observed resource use (observations on September 26, 2021 by guest. Protected copyright. 44 of practice at sites and interviews with the healthcare workers before implementation, at early 45 stages of implementation, and after one year of the interventions being implemented). We will also 46 review clinic costs (such as utility bills) over the duration of the study. We will include capital costs 47 48 (equipment, buildings, non-recurrent training, outreach efforts, and start-up activities), as well as 49 recurrent costs (personnel, supplies, operations, and maintenance of buildings) in our estimates. We 50 will aim to include costs incurred above the direct service level, such as monitoring and evaluation 51 and coordination costs as well as cost incurred during start up activities such as community 52 53 mobilisation and trainings before service delivery starts. 54 55 56
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1 2 3 Participant costs 4 Data will be collected through voluntary questionnaires administered to all participants in the PrEP 5 and ITx cohorts at one visit (follow up at 12 months). The questionnaires will collect general 6 7 information regarding the participant’s household, employment, and income, out-of-pocket 8 expenditures including transportation fees, consultation fees, non-HIV laboratory tests, non-HIV 9 medication (vitamins, antibiotics, and others) and food, any time lost due to PrEP or ITx 10 appointments, including travel time, consultation time, and loss of income: the participant’s time 11 12 and that of her family/friends will be ascertained. Family/friends time will be estimated from the 13 proportion of visits where a family member/friend escorted the participant 14 15 Modelling For peer review only 16 17 A decision analytic economic modelling approach will be used to look at issues of health system 18 capacity and equity (poverty analysis). The direct impact on costs and health gains that the 19 introduction of PrEP and ITx might have had on the study cohorts and the service provided in the 20 clinics will be explored. Insights from this model will help formulate hypotheses and inform a 21 22 transmission model focusing on the estimated impact that the introduction of PrEP and ITx might 23 have, should the intervention be scaled up nationally. A population-level transmission model fitted 24 to the South African epidemic will be used, with a special emphasis on transmission within FSW 25 groups with high mobility. All modelling exercises will be informed by the data collected during the 26 27 TAPS study on behaviour, uptake, linkage, retention, and medication adherence as well as the 28 costing data. Outputs of the models will include cost-effectiveness and budget impact measures. 29 30 ETHICS AND DISSEMINATION 31 32 33 Ethical considerations
34 As an implementation science research study including human subjects and medication, this study http://bmjopen.bmj.com/ 35 has taken all ethical issues into consideration in line with ICH-GCP guidelines. These include the risks 36 and benefits of taking the study medications as well as the participation in the study itself, the 37 38 informed consent process, maintaining confidentiality, and participation reimbursement. This 39 protocol has been reviewed and approved by the Wits Human Research Ethics Committee (HREC – 40 reference number: 140502) and the Medicines Control Council (MCC – reference number: 41 20140740), South Africa. The protocol was initially approved by both committees on 8 September 42 43 2014, and 15 October 2014 respectively. on September 26, 2021 by guest. Protected copyright. 44 45 As this project is not a clinic trial but rather an implementation study, using a product not registered 46 for the relevant indications in South Africa at the time of ethical and MCC applications, the 47 48 requirements for ethical and MCC approvals were unclear. As with other demonstration projects 49 globally, the project was held to clinical trial standards during the course of the review with 50 questions about procedure, monitoring, and participant support throughout the process. In 51 particular, the project is seeking to evaluate the willingness of FSW’s to take up and use PrEP and 52 53 ITx, therefore we were strongly committed to delivering the interventions in a ‘real-world’ context 54 which meant excluding reimbursements for clinic visits. This had to be negotiated with the ethics 55 and MCC committees, where a participant fee was suggested, based on the guarantee of minimal 56 invasive procedures (e.g. nothing outside of what would be done routinely in a public health clinic) 57 58 and limited waiting time spent in the clinics. In the end, it was agreed that participants would not be 59 60 13
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1 2 3 paid given the project was offering new interventions for free on top of routine services, but those 4 participants participating in the IDIs would be reimbursed for transport costs at R50. 5 6 7 Due to the vulnerable nature of this population, confidentiality was an important factor to 8 incorporate into all aspects of the project, but in particular the design of clinic processes. All staff 9 members, whether in contact with participants or not, were trained on how to maintain 10 confidentiality of participants and all patient files, questionnaire data and specimens are being 11 12 labelled and managed in such a way to safeguard identities. 13 14 Dissemination 15 A stakeholderFor engagement peer plan has been implementedreview as part of theonly project which includes the 16 17 formation of a sex worker focused community advisory board (CAB), engagement with officials in 18 the South African health sector both at the national and local levels, engagement with partners and 19 stakeholders at the international level, and continuous community outreach and education including 20 sensitization trainings for community members and Wits RHI staff. The engagement nationally and 21 22 internationally has included participation on WHO guidelines committees, South African DoH 23 guidelines committees for PrEP and ITx, and the new National Sex Worker Plan, as well as plenaries 24 and other presentations at international and local conferences. 25 26 27 The stakeholder engagement plan provides for the dissemination of information about the study 28 through the channels mentioned above, as well as eventual dissemination of results. Once the study 29 has completed, study staff will first disseminate results to TAPS participants. This may be done 30 through meetings or SMS. Results will be presented to local health officials and stakeholders at 31 32 meetings, and then sent out through press releases to other partners. 33
34 Finally, investigators will publish main study results as well as findings from the multiple research http://bmjopen.bmj.com/ 35 components of the study, namely the economic evaluation, qualitative research, and other clinical 36 and process data. Results from the study will also be presented at various conferences. 37 38 39 40 41 42 43 on September 26, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 14
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1 2 3 ACKNOWLEDGEMENTS 4 The authors would like to thank multiple people who helped make this protocol and project a reality. 5 Mohamed Majam provided advice on laboratory support; Pranitha Ramchuran and Anika Naidoo 6 7 provided invaluable support on the submission of this project to the Wits Human Research Ethics 8 Committee and the South African Medicines Control Council; and Eleanor Kaunda provided 9 administrative support for the committee submissions. Maria Sibanyoni and Nyaradzo Mutanha 10 helped with practical and logistical aspects of the design of the project as an addition to the existing 11 12 Sex Worker Project services. The Peer Educators were essential in planning and designing the project 13 and support mechanisms designs. Technical advice on the qualitative research components of this 14 project was given by Adam Bourne, Charlotte Watts, Jonathan Stadler, and Heidi Larson. Clinical 15 advice was givenFor on original peer and revised versions review by Vivian Black and only Michelle Moorhouse. Finally, a 16 17 huge debt of gratitude is owed to the entire TAPS team who has worked tirelessly to implement this 18 project in Hillbrow and Pretoria. 19 20 AUTHOR’S CONTRIBUTIONS 21 22 Conceived and designed the experiments: RE, GBG, WDFV, HR. Performed the experiments: RE, GBG, 23 JM. Analyzed the data: RE, GBG, JM. Contributed reagents/materials/analysis tools: RE, GBG, GA, JM. 24 Wrote the initial draft: RE, GBG. Reviewed the final draft: RE, GBG, GA, JM, WDFV, HR. 25 26 27 FUNDING STATEMENT 28 This work was supported by the Bill and Melinda Gates Foundation [reference number: 29 OPP1084416] and the United States Agency for International Development [reference number: AID- 30 674-A-12-00034]. GBG was partly funded by an AMC ASPASIA overseas grant financed by the 31 32 Netherlands Organisation for Scientific Research (NWO) [reference number 015.009.042]. 33
34 The views and opinions expressed in this paper are those of the authors and not necessarily the http://bmjopen.bmj.com/ 35 views and opinions of the United States Agency for International Development. 36
37 38 COMPETING INTERESTS STATEMENT 39 GBG, RE, GA, and JM declare no competing interests. WDFV has served on Gilead advisory boards; in 40 addition, he is designing a study that requests a donation of a Gilead product. HR was the protocol 41 chair of a microbicide trial involving a Gilead product and is Chair of the SA Medicines Control 42 43 Council, and has been and is the principal investigator for several trials involving donations from on September 26, 2021 by guest. Protected copyright. 44 Gilead products. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15
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1 2 3 REFERENCES 4 5 1. UNAIDS. How AIDS changed everything — MDG6: 15 years, 15 lessons of hope from the AIDS 6 response [Internet]. [cited 2015 Oct 28]. Available from: 7 8 http://www.unaids.org/en/resources/documents/2015/MDG6_15years- 9 15lessonsfromtheAIDSresponse 10 11 2. UNAIDS. AIDS by the numbers [Internet]. [cited 2015 Aug 7]. Available from: 12 http://www.unaids.org/en/resources/documents/2013/JC2571_AIDS_by_the_numbers 13 14 3. Deanna Kerrigan, Andrea Wirtz, Stefan Baral, Michele Decker, Laura Murray, Tonia Poteat, et al. 15 The GlobalFor HIV Epidemics peer among Sex Workers. review The World Bank; only 2012. 16 17 4. Rees H, Beksinska ME, Dickson-Tetteh K, Ballard RC, Htun Y. Commercial sex workers in 18 Johannesburg: risk behaviour and HIV status. South Afr J Sci. 2000 Jun;96:283–4. 19 20 5. Hedden SL HA. Alcohol, Drug and Sexual Risk Behavior Correlates of Recent Transactional Sex 21 Among Female Black South African Drug Users. J Subst Use. 2011;16:57–67. 22 23 6. Dunkle KL BM. Risk factors for HIV infection among sex workers in Johannesburg, South Africa. 24 Int J STD AIDS. 2005;16:256–61. 25 26 7. van Loggerenberg F, Mlisana K, Williamson C, Auld SC, Morris L, Gray CM, et al. Establishing a 27 Cohort at High Risk of HIV Infection in South Africa: Challenges and Experiences of the CAPRISA 28 29 002 Acute Infection Study. PLoS ONE. 2008;3:e1954. 30 31 8. Desmond Tutu HIV Foundation. Key Populations, Key Responses: A Gap Analysis for Key 32 Populations and HIV in South Africa, and Recommendations for the National Strategic Plan for 33 HIV/AIDS, STIs and TB (2012–2016) [Internet]. 2011 [cited 2013 Jan 24]. Available from: http://www.desmondtutuhivfoundation.org.za/documents/Key-Populations-Key-Solutions-
34 http://bmjopen.bmj.com/ 35 report.pdf 36 37 9. Lane T, Sibanyoni M, Manyuchi A, Osmand T, Marr A, Grasso M, et al. High utilization of health 38 services and low ART uptake among female sex workers (FSW) in three South African cities: 39 results from the South African Health Monitoring Study (SAHMS-FSW). In: WEAC0103. 40 Vancouver; 2015. 41 42
10. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention on September 26, 2021 by guest. Protected copyright. 43 of HIV-1 Infection with Early Antiretroviral Therapy. N Engl J Med. 2011 Aug 11;365(6):493–505. 44 45 11. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral 46 Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367:399– 47 48 410. 49 50 12. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure 51 Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 52 2010;363:2587–99. 53 54 13. Thigpen MC KP. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually 55 active young adults in Botswana: results from the TDF2 study. In 2011. 56 57 14. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis 58 to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase 59 60 16
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1 2 3 of a pragmatic open-label randomised trial. The Lancet [Internet]. 2015 Sep [cited 2015 Oct 28]; 4 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673615000562 5 6 15. Molina J-M, Capitant C, Spire B, Pialoux G, Chidiac C, Charreau I, et al. On Demand PrEP With 7 Oral TDF-FTC in MSM: Results of the ANRS Ipergay Trial. In 2015 [cited 2015 Oct 28]. Available 8 from: http://www.croiconference.org/sessions/demand-prep-oral-tdf-ftc-msm-results-anrs- 9 ipergay-trial 10 11 16. Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. 12 Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the 13 Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The 14 15 Lancet. 2013For Jun;381(9883):2083–90. peer review only 16 17 17. World Health Organization. WHO | Consolidated strategic information guidelines for HIV in the 18 health sector [Internet]. WHO. 2015 [cited 2015 Oct 28]. Available from: 19 http://www.who.int/hiv/pub/guidelines/strategic-information-guidelines/en/ 20 21 18. Department of Health, South Africa. Oral Pre-Exposure Prophylaxis (PrEP) and Test and Treat 22 National Guidelines. in preparation. 23 24 19. Eaton JW, Johnson LF, Salomon JA, Bärnighausen T, Bendavid E, Bershteyn A, et al. HIV 25 Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential 26 Impact of Antiretroviral Therapy on HIV Incidence in South Africa. PLoS Med. 2012;9:e1001245. 27 28 20. Dodd PJ, Garnett GP, Hallett TB. Examining the Promise of HIV Elimination by “Test and Treat” in 29 Hyper-Endemic Settings. AIDS Lond Engl. 2010 Mar 13;24(5):729–35. 30 31 21. Cremin I, Alsallaq R, Dybul M, Piot P, Garnett G, Hallett TB. The new role of antiretrovirals in 32 combination HIV prevention: a mathematical modelling analysis. AIDS. 2013 Jan;27(3):447–58. 33
34 http://bmjopen.bmj.com/ 22. International AIDS Society. Sustainable and Transitional Financing and Resource Allocation for 35 36 HIV and AIDS. In: Symposia Session TUSY01. Vancouver; 2015. 37 38 23. Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a 39 systematic review. PLoS Med Public Libr Sci. 2011 Jul;8:e1001056. 40 41 24. AVAC. Ongoing and Planned PrEP Open Label, Demonstration and Implementation Projects, as 42 of October 2015. Available from: http://www.avac.org/sites/default/files/resource- 43 files/PrEP_Trials_and_Demo_Projects_Oct2015.pdf on September 26, 2021 by guest. Protected copyright. 44 45 25. IAPAC. Global HIV Policy Watch. Available from: http://www.hivpolicywatch.org/ 46 47 26. Statistics South Africa. Statistics South Africa. Available from: 48 http://www.statssa.gov.za/?page_id=1859&period=July+2015&page=1 49 50 27. AIDSinfo. What’s New in the Guidelines | Perinatal Guidelines [Internet]. AIDSinfo. [cited 2015 51 Oct 28]. Available from: https://aidsinfo.nih.gov/ 52 53 28. World Health Organization. WHO | Guideline on when to start antiretroviral therapy and on pre- 54 exposure prophylaxis for HIV [Internet]. 2015 [cited 2015 Oct 28]. Available from: 55 http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ 56 57 58 59 60 17
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1 2 3 29. van der Straten A, Stadler J, Montgomery E, Hartmann M, Magazi B, Mathebula F, et al. 4 Women’s Experiences with Oral and Vaginal Pre-Exposure Prophylaxis: The VOICE-C Qualitative 5 Study in Johannesburg, South Africa. PloS One. 2014;9(2):e89118. 6 7 30. Corneli A, Wang M, Agot K, Olang’o L, Makatu S, Lombaard J, et al. The association between risk 8 perception and adherence in the FEM-PrEP clinical trial. In Kuala Lumpur; 2013 [cited 2014 Apr 9 15]. Available from: http://pag.ias2013.org/Abstracts.aspx?AID=3118 10 11 31. Dearing JW, Smith DK, Larson RS, Estabrooks CA. Designing for Diffusion of a Biomedical 12 Intervention. Am J Prev Med. 2013 Jan;44(1):S70–6. 13 14 32. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006 Jan;3(2):77– 15 For peer review only 16 101. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 43 on September 26, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 18
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Treatment And Prevention for female Sex workers in South Africa: protocol for the TAPS Demonstration Project
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011595.R1
Article Type: Protocol
Date Submitted by the Author: 13-Jul-2016
Complete List of Authors: Gomez, Gabriela; University of the Witwatersrand, Wits RHI; Amsterdam Institute for Global Health and Development Eakle, Robyn; University of the Witwatersrand, Wits RHI; London School of Hygiene and Tropical Medicine Mbogua, Judie; University of the Witwatersrand, Wits RHI Akpomiemie, Godspower; University of the Witwatersrand, Wits RHI Venter, WD Francois; University of the Witwatersrand, Wits RHI Rees, Helen; University of the Witwatersrand, Wits RHI
Primary Subject HIV/AIDS Heading:
Secondary Subject Heading: Public health, Health services research, Health economics
HIV Prevention, pre-exposure prophylaxis (PrEP), key populations, Keywords: implementation science, Immediate Treatment http://bmjopen.bmj.com/
on September 26, 2021 by guest. Protected copyright.
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1 2 3 Treatment And Prevention for female Sex workers in South Africa: protocol for the TAPS 4 Demonstration Project 5 6 7 Author Institution Email 8 Gabriela B Gomez‡ Wits Reproductive Health and HIV [email protected] 9 Institute 10 Department of Global Health and 11 Amsterdam Institute for Global 12 Health and Development, 13 Academic Medical Center, 14 University of Amsterdam, The 15 For peerNetherlands review only 16 Robyn Eakle*‡ Wits Reproductive Health and HIV [email protected] 17 18 Institute, London School of Hygiene 19 and Tropical Medicine, UK 20 Judie Mbogua Wits Reproductive Health and HIV [email protected] 21 Institute 22 Godspower Akpomiemie Wits Reproductive Health and HIV [email protected] 23 Institute 24 W D Francois Venter Wits Reproductive Health and HIV [email protected] 25 Institute 26 Helen Rees Wits Reproductive Health and HIV [email protected] 27 Institute 28 29 30 ‡ Contributed equally 31 *Corresponding author: 32 Robyn Eakle 33 Wits Reproductive Health & HIV Institute
34 http://bmjopen.bmj.com/ 35 University of the Witwatersrand, 36 Hillbrow Health Precinct, 22 Esselen Street, Hillbrow, 2001, Johannesburg, South Africa 37 t: +27 11 358 5350; e: [email protected] 38 39 40 Word count: abstract – 298 (max 300 words); text – 4575 excluding tables/figures (max 41 recommended: 4000 words) 42 Number of tables: 3; Number of figures: 0 (max figures and tables: 5) on September 26, 2021 by guest. Protected copyright. 43 44 45 46 Key words: HIV prevention, pre-exposure prophylaxis (PrEP), key populations, implementation 47 science, Immediate Treatment. 48
49 50 51 52 53 54 55 56 57 58 59 60 1
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1 2 3 ABSTRACT 4 Introduction 5 Updated guidelines from the World Health Organisation recommend antiretroviral treatment for 6 7 adults with HIV at any CD4 count and daily oral pre-exposure prophylaxis (PrEP) for people at 8 substantial risk of HIV infection. However, implementation challenges may hinder the ability of 9 programmes to translate these recommendations into successful practice. This demonstration 10 project is the first to integrate PrEP and Immediate Treatment (ITx) for female sex workers (FSWs) in 11 12 South Africa to answer operational research questions. 13 14 Methods and Analysis 15 This is a prospectiveFor cohort peer study where the review main outcome is retention only at 12 months. The study 16 17 population is recruited into two arms across two urban sites: 1) PrEP for HIV-negative FSWs (n=400); 18 and 2) ITx for HIV-positive FSWs with a CD4 > national guidelines (n=300). We investigate process 19 and other health indicators, uptake and use of PrEP and ITx through qualitative research, and 20 evaluate cost-effectiveness analysis combined with estimates of impact through epidemiological 21 22 modelling. 23 24 Ethics and Dissemination 25 The TAPS Project was designed as an implementation study before emtricitabine/tenofovir 26 27 disoproxil fumarate was licensed as an indication for PrEP in South Africa. Therefore, clinical trial 28 requirements for ethical and South African Medicines Control Council approvals were followed. 29 Results will be disseminated to participants, local health officials, and other stakeholders, as well as 30 in peer-reviewed journals and at conferences. 31 32 33 Strengths and Limitations
34 - The TAPS study incorporates a multidisciplinary service delivery evaluation within an http://bmjopen.bmj.com/ 35 implementation science paradigm. 36 - Success will be measured using several outcomes enabling triangulation of data. 37 38 - The study was designed to adapt to shifts in South African ART guidelines and clinical 39 standards. 40 - The study will not measure the effectiveness of any service delivery model as there is no 41 comparison arm. 42 43 - Our sample size is relatively small and might not be representative of the national on September 26, 2021 by guest. Protected copyright. 44 population of FSWs. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2
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1 2 3 INTRODUCTION 4 Globally, UNAIDS data have shown a significant and continuous decline (35%) in the number of new 5 HIV infections since 2000 (1). In sub-Saharan Africa, this trend is even more pronounced with a 41% 6 7 decline. However, in this region of the world, where women make up for more than half of all 8 people living with HIV, incidence rates remain high (1). In particular, the HIV epidemic in South Africa 9 continues to be the largest in the world, based on both HIV incidence (with a currently estimated 10 rate of up to 4 per 100 women-years (2,3)) and total number of people living with HIV (6.8 million 11 12 estimated in 2014(4)(5). 13 14 The South African National Strategic Plan on HIV, STIs, and TB for 2012-2016 (6) prioritizes 15 interventionsFor with the aim peerto reduce new infectionsreview on a national levelonly by 50% using combination 16 17 prevention while scaling up treatment to cover at least 80% of the population. It also identifies key 18 populations as a major focus of the strategy, which calls for a multi-faceted approach to ending the 19 epidemic. Sex workers are among the key populations identified in the past and current National 20 Strategic Plans. Globally, female sex workers (FSWs) are 13.5 times more likely to be living with HIV 21 22 than women in the general population (7). The 2013 South African Key Populations Report estimates 23 that HIV prevalence among FSWs is between 44 and 69% (8–11), with 19.8% of all new infections 24 being attributed to sex work, including infections among clients and partners of clients (12). A study 25 conducted in 2008 in a cohort of high risk women in KwaZulu-Natal Province, estimated incidence to 26 27 be as high as 7.2/100 person-years (11). More recently, a prevalence study conducted among 28 populations of sex workers found a 72% HIV prevalence with low treatment uptake in Gauteng 29 Province(13). This high vulnerability is rooted in the many structural drivers of HIV risk affecting this 30 population including: restricted access to healthcare, criminalization and lack of legal protection, 31 32 unsafe working conditions, stigma, and economic hardship (12). As a marginalized population who 33 are stigmatized and criminalized, sex workers require specialized programmes sensitive to their
34 needs for interventions in HIV prevention, care, and treatment as well as support to access other http://bmjopen.bmj.com/ 35 health and legal services. 36
37 38 Following the positive results of ARV-based prevention studies in reducing both HIV transmission 39 (through Immediate Treatment, ITx) and acquisition (through pre-exposure prophylaxis, PrEP) (14– 40 20), global and national authorities updated HIV guidelines to recommend antiretroviral treatment 41 (ART) be initiated at any CD4 count in adults and daily oral PrEP as an additional prevention strategy 42 43 for people at substantial risk of HIV infection (21–23). While modelling studies have shown that the on September 26, 2021 by guest. Protected copyright. 44 scaling up of new prevention and treatment tools across the HIV continuum of care could have a 45 significant impact on the epidemic (24–26), implementation challenges relating to health service 46 capacity, acceptability, and financing and resource allocation may hinder the ability of programmes 47 48 from making a significant difference to the HIV epidemic (27,28). 49 50 The evaluation of existing and innovative models of care to implement new technologies for 51 prevention and treatment through demonstration projects is being conducted around the world 52 53 (29). These projects represent a spectrum of designs from clinical trial-like protocols to ‘real-world’ 54 implementation science studies, yet all have similar goals: to test delivery models of new 55 technologies and interventions to inform policy and programming. In particular, projects tend to 56 cater to key populations where acceptability and uptake of technologies such as oral PrEP may be 57 58 higher and intersect with those populations who might benefit the most initially, such as men who 59 60 3
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1 2 3 have sex with men, sex workers, serodiscordant couples, and young women. These prevention- 4 focused projects are situated within a landscape of evolving HIV treatment guidelines, as treatment 5 is now recognised as the major contributor to prevention, and thus many include treatment 6 7 components (21,30). 8 9 The demonstration project described here is the first to integrate a combination prevention 10 intervention including oral PrEP and ITx (for those with CD4 counts higher than current national 11 1 12 guidelines) for FSWs in South Africa . The interventions are being delivered at two clinic-based sites 13 for FSWs in Gauteng Province. Gauteng is the most densely populated province of South Africa, also 14 home to both the economic and political capitals of the country (31). This implementation study 15 seeks to understandFor the ‘real-world’ peer implications review of introducing PrEP only and ITx into an existing service 16 17 delivery structure. By combining PrEP and ITx, we aim to leverage, in a novel way, the service 18 delivery areas needed to support these programmes which primarily include outreach for testing 19 and counselling and clinic services. The overall aim will be to answer operational questions: whether 20 FSWs will accept ITx or combination prevention including PrEP, whether the service delivery 21 22 mechanism is capable of handling the increase in resource needs these interventions might lead to, 23 and what kind of implications this strategy would have on overall costs , should they be considered 24 for scale up. 25 26 27 METHODS AND ANALYSIS 28 Population and setting 29 Female sex workers are the study population defined as women self-identifying as sex workers, and 30 who have received goods or money in exchange for sex in the past three months, age 18 or above, 31 32 operating in the areas surrounding two existing clinics providing services for sex workers in Hillbrow, 33 Johannesburg, and the central business district in Pretoria. These clinics are run by Wits
34 Reproductive Health and HIV Institute, one of the largest research Institutes of the University of http://bmjopen.bmj.com/ 35 Witswatersrand; since 1994, Wits RHI has pioneered health programmes with a strong community 36 focus. The Hillbrow site is connected to the Esselen Clinic which is home to the well-established Wits 37 38 RHI Sex Worker Project (32). The Sex Worker Project is a full reproductive health, HIV and STI 39 prevention and treatment service programme partnered with City of Johannesburg and the South 40 African Department of Health (DoH). It provides services such as: HIV counselling and testing and 41 condom distribution, NiMART (nurse-initiated and managed antiretroviral treatment), tuberculosis 42 43 screening, HPV screening, clinical services for minor ailments, psychosocial support, and referrals to on September 26, 2021 by guest. Protected copyright. 44 both clinical and legal services. The programme accesses several brothels, with mobile units to serve 45 street-based sex workers, and a stationary clinic space. The actual clinic space for the TAPS 46 Demonstration Project is located in the Wits RHI Research and Training Centre, which is adjacent to 47 48 the Esselen Clinic. At the time we initiated the study, renovations at the Esselen Clinic had begun and 49 the building was closed which is the reason for housing the TAPS Project in the Research Centre. 50 51 The Pretoria site is located in Sediba Hope Medical Centre, a private non-profit clinic affiliated with 52 53 the Department of Health, which has been serving the local community in the heart of the inner city 54 55 1 Recently (June 2016), the NDoH started the piloting at 10 sites of new National guidelines for treatment, 56 where all people infected with HIV independent of their CD4 count are eligible and PrEP is available for FSWs. 57 This demonstration project is informing the roll out pilot directly. 58 59 60 4
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1 2 3 of Pretoria. Wits RHI’s Sex Worker Project has now opened a sex worker clinic at Sediba Hope which 4 is also linked to the Community Health Clinic in the same building. 5 6 7 Design 8 The study design is a prospective, observational cohort study, with two study arms: 9 10 1) A PrEP intervention as part of a combination prevention approach for recently documented 11 12 HIV-negative FSWs; 13 2) An ITx intervention for HIV-positive ART-naïve FSWs not eligible for ART at the currently 14 implemented CD4-defined standard of care. 15 For peer review only 16 17 The PrEP intervention arm will seek to protect HIV-negative FSWs from acquiring HIV through the 18 use of PrEP and other available prevention options (such as condoms). The ITx intervention arm will 19 seek to link FSWs directly to care to reduce and avoid loss to follow up within the treatment cascade. 20 Indirectly, it will seek to prevent HIV-positive FSWs from transmitting the virus to clients and other 21 22 sex partners through the use of ARVs. 23 24 Sample size and eligibility criteria 25 Table 1 shows the sample size considerations for both study arms. We aim to enroll 400 FSWs in the 26 27 PrEP arm of the study. With an expected retention rate of 65% (precision of ±5%) at 12 months, we 28 need 350 participants, which we have increased to 400 to account for variability across the two sites. 29 To achieve this sample size, we should aim to screen 1,600 FSWs, of which 800 are expected to be 30 HIV-negative (assuming an HIV prevalence of 50%) and we estimate conservatively that 50% accept 31 32 to participate. For the ITx arm, we aim to enroll 300 FSWs with an expected retention rate of 75% 33 (precision of ±5%) at 12 months, assuming a 25% default rate which reflects recent research on the
34 treatment cascade (33). To achieve this sample size, we should aim to screen 3,600 FSWs, of which http://bmjopen.bmj.com/ 35 1,800 are expected to be HIV-positive (assuming an HIV prevalence of 50%), one third with CD4 36 counts over 350 (n= 600) and 50% accept to participate. In practice, the screening process is a joint 37 38 step in the recruitment of both the PrEP and the ITx arms. As such, we will aim to screen 3,600 FSWs 39 to be able to achieve the required sample sizes. PrEP enrolment will stop as soon as the required 40 sample size is achieved. Note that the original calculations for this study were done assuming a 41 national CD4 count initiation threshold of 350. 42 43 on September 26, 2021 by guest. Protected copyright. 44 A summary of eligibility criteria is presented in table 2. We exclude patients at risk of documented 45 serious side effects of the regimes used. This includes patients with abnormal kidney function (e.g. a 46 creatinine clearance rate above 60.0 mL/min), taking medication for multi-drug resistant 47 48 tuberculosis, testing positive for hepatitis B (PrEP only), or being prescribed any other drugs 49 contraindicated for taking with any of the drug regimens prescribed in the study. Patients are also 50 excluded at clinician’s discretion according to their assessment of the patient’s safety. We also 51 exclude FSWs pregnant at enrolment. All pregnant women are referred to ante-natal care, where 52 53 HIV-positive FSWs are started on ART as per guidelines and HIV-negative FSWs counselled. 54 55 56 Table 1: Sample size considerations. 57 PrEP arm ITx arm 58 59 60 5
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1 2 3 Retention at 12mo Precision N Retention at 12mo Precision N 4 65% 2.5% 1398 75% 2.5% 1152 5 6 65% 5.0% 350 75% 5.0% 288 7 65% 7.5% 155 75% 7.5% 128 8 65% 10.0% 87 75% 10.0% 72 9 10 PrEP, pre-exposure prophylaxis; ITx, immediate treatment; mo: months; N, number. 11 12 13 Table 2: TAPS Project Eligibility Criteria 14 15 PrEP arm For peer reviewITx arm only 16 18 years or older 18 years or older 17 Creatinine clearance above 60.0 mL/min Creatinine clearance above 60.0 mL/min 18 Negative for hepatitis B CD4 count above national standard for ART 19 initiation 20 Not pregnant Not pregnant 21 Not presenting signs or symptoms of or taking Not presenting signs or symptoms of or taking 22 medication for MDR-TB medication for MDR-TB 23 24 Not prescribed other drugs contraindicated for Not prescribed other drugs contraindicated for 25 taking with emtricitabine and tenofovir taking with tenofovir disoproxyl fumarate/ 26 disoproxil fumarate (FTC/TDF) lamivudine/emtricitabine/efavirenz (TDF + 27 3TC/FTC + EFV) 28 PrEP, pre-exposure prophylaxis; ITx, immediate treatment; ART, antiretroviral treatment; MDR-TB, 29 multi-drug resistant tuberculosis. 30 31 32 Intervention 33 Recruitment
34 Participants for both arms of the study are recruited from the local Wits RHI Sex Worker Project http://bmjopen.bmj.com/ 35 clinics as well as the surrounding community, and in particular places of business such as 36 37 hotels/brothels, bars, and streets. We leverage the existing peer educator-based outreach services 38 currently provided by the Sex Worker Project to reach out and inform them of the study. Each 39 potential participant completes a DoH HIV counselling and Testing (HCT) consent form first as part of 40 standard HCT practice, to determine HIV status through the point-of-care rapid testing process. 41 42 Discordant HIV rapid test results are then confirmed using ELISA using standard local algorithms (i.e. 43 algorithm: two rapid tests are done simultaneously for confirmation. In case of discordant, on September 26, 2021 by guest. Protected copyright. 44 indeterminate or positive results, blood is drawn for an ELISA) (34). Once HIV status is established, 45 participants sign either the PrEP or ITx TAPS study informed consent form according to HIV status. 46 47 Participants in the PrEP arm are counselled and informed about adherence and effectiveness of 48 PrEP, the need to use condoms with PrEP in order to ensure a high level of protection against HIV 49 infection as well as to prevent STIs and unwanted pregnancies. Participants in the ITx arm are also 50 counselled about adhering to their treatment regimens and using condoms. 51 52 53 We aimed to balance the “real world” aspect of the demonstration project with the consent and 54 information gathering needs for research purposes. Therefore, at the screening visit, participants are 55 asked to complete a demographic and behaviour questionnaire, as well as a short medical history for 56 screening purposes. Blood samples are taken for creatinine levels, hepatitis B, syphilis testing, HIV 57 58 59 60 6
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1 2 3 confirmation with ELISA, and viral load testing. All participants also take a point-of-care pregnancy 4 test as part of eligibility requirements. 5 6 7 Participants are asked to return in one week, within a maximum window of up to 30 days if needed, 8 after the screening visit for enrolment if eligible. At the enrolment visit, participants are scheduled 9 for regular study visits to monitor medication adherence and safety. We also take a clinical history, 10 offer syndromic STI screening and any other clinically indicated assessments such as for cervical 11 12 cancer as per DoH guidelines. Potential participants are asked about fertility intentions, however, 13 future pregnancy plans are not form part of study exclusion. Contraception is offered to those 14 requiring a method as per standard of care, but use of a contraceptive is not a requirement for study 15 eligibility. For peer review only 16 17 18 The participants have access to counselling services, as well as all other services provided by the Sex 19 Worker Project as standard of care, including but not limited to reproductive health services, 20 referrals for legal services, substance use and violence counselling and support, and post-rape care. 21 22 Support groups are not currently planned as an official service of this study, however FSWs may 23 elect to form support groups and project staff make an effort to support this with space if requested. 24 25 Medication and adherence 26 27 HIV-negative participants fulfilling all eligibility criteria are started on co-formulated emtricitabine 28 and tenofovir disoproxyl fumarate FTC/TDF (Truvada®) in the PrEP arm. The medication for the ITx 29 arm is tenofovir disoproxyl fumarate plus lamivudine /emtricitabine plus efavirenz combination (TDF 30 + 3TC/FTC + EFV), or Atripla®, as per current guidelines. The drugs for the TAPS study have been 31 32 donated by Gilead. 33
34 We measure adherence to PrEP through several modes of self-report as well as plasma drug level http://bmjopen.bmj.com/ 35 testing. Treatment adherence is measured through self-report and monitoring viral load 36 suppression. 37 38 39 As adherence support, all participants have the option to receive SMS messages. Two types of SMS 40 messages may be sent to participants. The first type is visit reminders, three sent per visit - two as 41 reminders before the visit and one to thank the participant for attendance or to remind them to 42 43 reschedule if they missed a visit. The second type is aimed at providing information and support on a on September 26, 2021 by guest. Protected copyright. 44 weekly basis and within the following themes - adherence/side-effects/informational, health 45 education, healthy living, referral services and affirmations. All participants are offered each type of 46 messaging services and those who are willing to participate sign an additional consent form. 47 48 Participants are able to opt out at any time and feedback on the utility of the messages is solicited 49 throughout the study. 50 51 Management of pregnancy 52 53 Guidance from major organizations, such as the WHO and United States Centers for Disease Control 54 (CDC), has made surveillance of PrEP use in pregnancy a priority (35,36). If a participant becomes 55 pregnant during the course of the project in the PrEP group, she will be given the option to remain 56 taking PrEP or discontinue its use. If she decides to discontinue PrEP, she will be given the option to 57 58 remain in the project using other HIV prevention options, but referred for antenatal services or 59 60 7
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1 2 3 termination of pregnancy (TOP) services as selected. The potential for harm due to unknown risks of 4 taking PrEP while pregnant is noted in the main study informed consent forms. 5 6 7 If a participant in the treatment group becomes pregnant during the course of the project, she will 8 also be given the option to remain in the study and be referred for antenatal services, where 9 participants will continue lifelong treatment as per current guidelines. If the participant decides to 10 discontinue participation in the study, she will be referred to the clinic of her choice for continued 11 12 treatment. 13 14 Follow up visits and loss to follow up 15 Participants areFor scheduled peerfor clinic visits on review a three-month basis and only receive a prescription refill 16 17 once a month in both arms. Monitoring visits include HIV testing (PrEP arm only), CD4 and viral load 18 tests (ITx arm only), creatinine levels, syndromic screening and treatment for STIs as required, and 19 adherence counselling. All these services are standard of care for monitoring patients on treatment 20 and are the minimum monitoring requirement in the newly published PrEP and ITx guidelines (23). 21 22 At each scheduled visit, participants are asked to complete a short questionnaire to record any side 23 effects, changes in risk behaviour, fertility intentions, time of last menstrual period and adherence to 24 ARVs. Participants may also request an unscheduled visit to report safety events at any time. We are 25 not collecting quantititave information on diversion of medications (e.g., selling or giving ARVs to 26 27 others), but we are both collecting qualitative information on this important issue as part of the in- 28 depth interviews and providing intensive adherence counselling. 29 30 Loss to follow up is defined as a participant missing two consecutive visits with no contact. Efforts 31 32 will be made to contact participants by phone in both the PrEP and ITx arms to understand reasons 33 for missed visits. However only additional efforts, which may include a home visit, will be made to
34 encourage participants in the ITx arm to return. If participants are contacted in the PrEP group and http://bmjopen.bmj.com/ 35 decide not to return, we will ask if they are willing to participate in a brief exit interview to 36 understand reasons for dropout and to ensure there are no safety concerns. 37 38 39 Final visit and withdrawal from the project 40 At the final project visit, all participants will be asked to answer final behavioural, violence, and 41 participant costing questionnaires. Those in the PrEP arm will have creatinine, STI screening and 42 43 treatment as necessary; while those in the treatment arm will have CD4 and viral load tests, on September 26, 2021 by guest. Protected copyright. 44 creatinine, STI screening and treatment as necessary, and counselling for continued adherence to 45 their treatment regimen. They will be offered a choice to remain at the same clinic for continued 46 care and treatment, or be transferred to another clinic of their choice. If a participant in the PrEP 47 48 arm sero-converts, we will offer a full resistance testing. The participant will not be rolled on to the 49 ITx arm but will be offered a choice to remain at the same clinic for continued care and treatment, or 50 be transferred to another clinic of their choice. All participants will also be informed as to when they 51 can expect a report back of project results. 52 53 54 As of June 1st 2016, PrEP and the test and treat approach has been prioritized for sex workers. As a 55 result, we are now able to transition all of the women in our study to PrEP and HIV treatment 56 services in our Sex Worker Programme or to other clinics of their choosing offering these services, 57 58 either at the end of the study or should they choose to leave the study early for any reason. 59 60 8
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1 2 3 4 For ease of reference, we map all events and provide a visit schedule for both PrEP arm and ITx arm 5 in appendix. 6 7 8 Analysis 9 The project is being evaluated through a mixed methods approach. This approach examines the 10 deliverability of the interventions and their integration into a comprehensive prevention and 11 12 treatment package, and includes quantitative analysis of process and questionnaire data 13 (behaviours, uptake, linkage and retention in care, and adherence), qualitative assessment of 14 providers and user feedback on the interventions, and an economic evaluation from a societal 15 perspective. For peer review only 16 17 18 Quantitative analysis of process and questionnaire data 19 The primary outcome for both arms is the number of women retained at 12 months of follow up (a 20 participant is considered retained at 12 months if she attended a scheduled follow up visit between 21 22 10.5 and 13.5 months after enrolment). In the PrEP arm, we note that a participant is considered 23 retained even if not on PrEP but continuing the combination prevention visits. Secondary outcomes 24 for both arms are shown in table 3. 25 26 27 Table 3: TAPS Project secondary outcomes 28 Variable PrEP arm ITx arm Type of data 29 Knowledge Assessment of HIV Assessment of HIV Qualitative data 30 knowledge including PrEP knowledge including ITx (IDIs) and 31 questionnaire data 32 Uptake and Description of reasons for Description of reasons for Questionnaire data, 33 acceptability ineligibility after first ineligibility after first complemented by
34 http://bmjopen.bmj.com/ eligibility assessment eligibility assessment qualitative data 35 36 Proportion of women Proportion of women Programme data, 37 accepting PrEP at baseline accepting ITx at baseline complemented by 38 qualitative data 39 Comparison demographic Comparison demographic Questionnaire data 40 characteristics of women characteristics of women 41 accepting PrEP vs refusing at accepting ITx vs refusing at 42 baseline baseline on September 26, 2021 by guest. Protected copyright. 43 Retention Proportion of women Proportion of women Programme data 44 retained and adherent to retained and adherent to 45 PrEP at 3, 6, 18, 24 mo ART at 3, 6, 18, 24 mo 46 Patterns of Proportion of women using n/a Programme data 47 48 use PrEP continuously for 12 mo 49 Description of length of use Programme data 50 and repetitive uptake for and IDIs 51 women not using PrEP 52 continuously for 12 mo 53 Adherence Proportion of women Proportion of women Questionnaire data 54 reporting taking >85% of pills reporting taking >85% of 55 (self-reported) at each pills (self-reported) at each 56 routine visit during 12 mo routine visit during 12 mo 57 Proportion of women with Proportion of women with Clinical (lab) data 58 59 60 9
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1 2 3 drug level detectable in undetectable viral load at and IDIs 4 plasma at 12 mo 12 m 5 Side effects Number (by type) of all side Number (by type) of all Clinical data, IDIs 6 effects reported at routine side effects reported at and clinic 7 visits for 12mo routine visits for 12 mo observations 8 HIV status Number of sero-conversion Proportion of women with Clinical (lab) data 9 10 cases at 12 mo and plasma HIV-1 RNA level 11 description of all resistance ≥1000 copies/mL at six 12 profiles months or after initial 13 suppression and 14 description of all 15 For peer reviewresistance profiles only 16 Pregnancy Pregnancy rates during Pregnancy rates during Clinical data 17 follow up follow up 18 Sexual Comparison of proportion of Comparison of proportion Questionnaire data 19 behaviour women reporting consistent of women reporting and IDIs 20 condom use (stable partners, consistent condom use 21 regular/new clients): (stable partners, 22 23 baseline vs PrEP use after 12 regular/new clients): 24 mo baseline vs ART use after 25 12 mo 26 Proportion of women Proportion of women Questionnaire data 27 presenting with STI presenting with STI 28 symptoms at each routine symptoms at each routine 29 visit during 12 mo during 12 mo 30 Cell phone Proportion of women opting- Proportion of women Programme data 31 technology out of SMS reminders at opting-out of SMS and IDIs 32 for baseline and throughout the reminders at baseline and 33 adherence duration of the project throughout the duration of
34 http://bmjopen.bmj.com/ 35 support the project 36 Cost of Cost per person-year on PrEP Cost per person-year on Costing data 37 intervention (health service perspective) ITx (health service 38 perspective) 39 Cost per person-year on PrEP Cost per person-year on Costing 40 (participant perspective) ITx (participant questionnaire data 41 perspective) 42
PrEP, pre-exposure prophylaxis; ITx, immediate treatment; mo, month; IDIs, in depth interviews; on September 26, 2021 by guest. Protected copyright. 43 ART, antiretroviral treatment; STI, sexually transmitted infection. 44 45 46 We can expect three types of bias in cohort studies: selection bias, information bias, and 47 misclassification bias. It is possible that participants ‘auto-select’ (ie a selection bias), meaning that 48 those FSWs feeling most vulnerable will be most likely to enrol and continue participation. Because 49 50 this is a demonstration project, we expect participants to decide whether to participate based on 51 their risk perception and we will aim to document these motivations and perceptions as much as 52 possible through qualitative research. We do not expect an information bias to be present as we are 53 collecting the same information for all participants. Finally, misclassification could arise from a 54 55 participant being considered not retained in care as per her participation in our study, however she 56 might be in care at another clinic. We will aim to ascertain if this is a potential bias while contacting 57 58 59 60 10
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1 2 3 by phone participants missing two consecutive clinic visits in either the PrEP or the ITx arm to 4 understand reasons for missed visits. 5
6 7 Qualitative research 8 Data from qualitative research conducted during the PrEP efficacy trials indicate multiple and 9 varying reasons for lack of adherence on the part of participants, thus illustrating the imperative to 10 understanding how PrEP may be best implemented in a given context from the point of view of 11 12 potential consumers (37,38). In this regard, we are conducting multi-faceted qualitative research 13 with participants from the two project arms as well as providers at the clinics to gain perspectives on 14 using and implementing PrEP and ITx. Methods include in-depth interviews (IDIs) with participants, 15 waiting-roomFor observations, peer and provider group review discussions. These methodsonly will serve as a means to 16 17 compare and contrast sources of data to develop a narrative as to the feasibility, and more 18 specifically, the motivations and barriers of implementing PrEP and ITx. We will also be able to 19 compare these qualitative data with data from the structured questionnaires to explore different 20 aspects of adherence to medication. All data collection tools have been piloted and adjusted as 21 22 required. 23 24 Participant in-depth interviews 25 We use an adapted social-ecological model as a framework to explore themes related to motivations 26 27 and barriers to use of PrEP and ITx based on the multiple spheres influencing women’s lives from 28 community, household, work, and clinic settings. A subset of the women from the PrEP and ITx arms 29 are being randomly invited to participate in the qualitative research component in each arm (up to 30 40 for PrEP and up to 30 for ITx). Each participant is asked to sign a separate consent form and is 31 32 reimbursed for her travel costs since this will be outside of regular clinic visit requirements. This is 33 the only form of participant reimbursement offered since the purpose of the TAPS project is to
34 assess retention in the programme in a ‘real-world’ clinic setting. Interviews are conducted http://bmjopen.bmj.com/ 35 individually with each participant by a research assistant who is conversant in the participant’s 36 languages. 37 38 39 Interviews will be conducted longitudinally at months 3, 6, and 9 for each participant to explore 40 themes emerging over time(37). Interview questions will seek data related to reasons for 41 participating in the study, motivations and barriers to uptake and use of the interventions, 42 43 acceptability of the SMS technology, perceived gaps in service delivery, and HIV prevention method on September 26, 2021 by guest. Protected copyright. 44 preferences over time. Interviews will be audio-taped, and later translated into English as needed 45 and transcribed. 46
47 48 Waiting-room observations 49 Informal conversations held by participants in settings such as waiting-rooms have provided 50 invaluable information for the triangulation of qualitative data thus enriching narratives of 51 participant behaviour during studies (37). We are conducting waiting-room observations at the two 52 53 project sites for a period of one week on a quarterly basis. Permission to conduct these observations 54 is obtained from the clinic managers, and researchers conducting the observations provide study 55 participants in the waiting-rooms with notification of who they are, what they are doing, and for 56 what purpose. The purpose of these observations is to gather informal data on participants’ 57 58 perspectives of the study, the interventions, and issues they may be experiencing that influence 59 60 11
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1 2 3 their interest in the programme and ability to maintain participation. Information will be recorded in 4 the researcher’s field notebook and later uploaded into NVIVO for coding and analysis. 5 6 7 Provider group discussions 8 Recent guidance illustrates the importance of service delivery providers as an important target 9 group for promoting and managing the dissemination and uptake of PrEP (39). As such, we are 10 convening informal group discussions at each site to explore provider experiences, including 11 12 primarily the community health workers/counsellors, nurses, pharmacists, coordinators, and 13 medical officers, in delivering PrEP and ITx. All potential provider-participants are asked to complete 14 the informed consent process and have the option to decline participation. The research is being 15 conducted byFor an external contractorpeer and does review not include evaluation only of providers on performance. 16 17 As themes for discussion may evolve over time, a more structured discussion guide is being used 18 initially and subsequent guides will build on emerging themes. 19 20 Analysis 21 22 All qualitative research components will be analysed using thematic analysis as defined by Braun and 23 Clarke (40). This approach to thematic analysis features a six-phase process: familiarisation with the 24 data, generation of initial codes, searching for themes, reviewing themes, defining and naming 25 themes, and finally producing the report. Translated and transcribed transcripts from the IDIs, 26 27 waiting-room observations, and provider group discussions will be uploaded into NVIVO software 28 and coded according to the coding manual created. Researchers will assemble the coding manual 29 first by developing overarching data categories based on research objectives, then by systematic and 30 iterative review of the data to elicit primary and sub-themes. We will aim to have at least two coders 31 32 per transcript. Any discrepancies in coding will be discussed between the coders with input from the 33 senior investigator to gain consensus. Once all data have been coded, researchers will synthesize
34 findings to explore commonalities and differences across participant perspectives. http://bmjopen.bmj.com/ 35 36 Economic evaluation 37 38 The introduction of an integrated HIV prevention and care service is likely to involve several trade- 39 offs between costs and efficiencies. We are measuring empirically the costs for participants and the 40 healthcare providers in the two sites of the TAPS study to then model total costs, impact and cost- 41 effectiveness of this intervention both on our cohort and at a population level. The evaluation is 42 43 done from a societal perspective. on September 26, 2021 by guest. Protected copyright. 44 45 Healthcare provider costs 46 All costs will be estimated using an ingredient costing approach to define the cost per person 47 48 receiving each service. Data are collected through directly observed resource use (observations of 49 practice at sites and interviews with the healthcare workers before implementation, at early stages 50 of implementation, and after one year of the interventions being implemented). We also review 51 clinic costs (such as utility bills) over the duration of the study. We include capital costs (equipment, 52 53 buildings, non-recurrent training), as well as recurrent costs (personnel, supplies, operations, and 54 maintenance of buildings) in our estimates. We aim to include costs incurred above the direct 55 service level, such as monitoring and evaluation and coordination costs as well as cost incurred 56 during start up activities such as community mobilisation and trainings before service delivery starts. 57 58 The current micro costing approach allows us to record in detail all processes happening at each visit 59 60 12
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1 2 3 – and their purpose (for research or service delivery). The unit cost will then be reported 4 disaggregating research-related costs. 5 6 7 Participant costs 8 Data are collected through voluntary questionnaires administered to all participants in the PrEP and 9 ITx cohorts at one visit (follow up at 12 months). In the questionnaires, we collect general 10 information regarding the participant’s household, employment, and income, out-of-pocket 11 12 expenditures including transportation fees, consultation fees, non-HIV laboratory tests, non-HIV 13 medication (vitamins, antibiotics, and others) and food, any time lost due to PrEP or ITx 14 appointments, including travel time, consultation time, and loss of income: the participant’s time 15 and that of herFor family/friends peer will be ascertained. review Family/friends time only will be estimated from the 16 17 proportion of visits where a family member/friend escorted the participant 18 19 Modelling 20 All modelling exercises will be informed by the data collected during the TAPS study on behaviour, 21 22 uptake, linkage, retention, and medication adherence as well as the costing data. A decision analytic 23 economic modelling approach will be used to look at issues of health system capacity (staff 24 constraints) and equity (poverty analysis using patient-related costs within the cohort). The direct 25 impact on costs and health gains that the introduction of PrEP and ITx might have had on the study 26 27 cohorts and the service provided in the clinics will be explored. . 28 29 A population-level transmission model fitted to the South African epidemic will be used, with a 30 special emphasis on transmission within FSW groups with high mobility model focusing on the 31 32 estimated impact that the introduction of PrEP and ITx might have, should the intervention be scaled 33 up nationally. Population-level data will be gathered from the literature. Outputs of the transmission
34 model will include cost-effectiveness and budget impact measures. A series of scenario analyses http://bmjopen.bmj.com/ 35 might be needed to reflect the different strategies for scale up that policy makers might consider. 36 We will consult stakeholders (both users and policy makers) during the process of defining the 37 38 scenarios for scale up to ensure the most realistic scenarios are tested. We will aim to estimate the 39 reduction in health costs of implementing both interventions. Therefore, we expect savings from 40 infections averted while on PrEP and from less ‘other’ HIV care if treatment is started early. 41
42 43 on September 26, 2021 by guest. Protected copyright. 44 ETHICS AND DISSEMINATION 45 46 Ethical considerations 47 48 As an implementation science research study including human subjects and medication, this study 49 has taken all ethical issues into consideration in line with ICH-GCP guidelines. These include the risks 50 and benefits of taking the study medications as well as the participation in the study itself, the 51 informed consent process, maintaining confidentiality, and participation reimbursement. This 52 53 protocol has been reviewed and approved by the Wits Human Research Ethics Committee (HREC – 54 reference number: 140502) and the Medicines Control Council (MCC – reference number: 55 20140740), South Africa. The protocol was initially approved by both committees on 8 September 56 2014, and 15 October 2014 respectively. An amendment was approved subsequently (16 March 57 58 59 60 13
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1 2 3 2016) following MCC approval of new indication for FTC/TDF and changes in DoH treatment 4 eligibility criteria. 5
6 7 As this project is not a clinic trial but rather an implementation study, using a product not registered 8 for the relevant indications in South Africa at the time of ethical and MCC applications, the 9 requirements for ethical and MCC approvals were unclear. As with other demonstration projects 10 globally, the project was held to clinical trial standards during the course of the review with 11 12 questions about procedure, monitoring, and participant support throughout the process. In 13 particular, the project is seeking to evaluate the willingness of FSW’s to take up and use PrEP and 14 ITx, therefore we were strongly committed to delivering the interventions in a ‘real-world’ context 15 which meant Forexcluding reimbursements peer for reviewclinic visits. This had to beonly negotiated with the ethics 16 17 and MCC committees, where a participant fee was suggested, based on the guarantee of minimal 18 invasive procedures (e.g. nothing outside of what would be done routinely in a public health clinic) 19 and limited waiting time spent in the clinics. In the end, it was agreed that participants would not be 20 paid given the project was offering new interventions for free on top of routine services, but those 21 22 participants participating in the IDIs would be reimbursed for transport costs at R50. 23 24 Due to the vulnerable nature of this population, confidentiality was an important factor to 25 incorporate into all aspects of the project, but in particular the design of clinic processes. All staff 26 27 members, whether in contact with participants or not, were trained on how to maintain 28 confidentiality of participants and all patient files, questionnaire data and specimens are being 29 labelled and managed in such a way to safeguard identities. 30 31 32 Dissemination 33 A stakeholder engagement plan has been implemented as part of the project which includes the
34 formation of a sex worker focused community advisory board (CAB), engagement with officials in http://bmjopen.bmj.com/ 35 the South African health sector both at the national and local levels, engagement with partners and 36 stakeholders at the international level, and continuous community outreach and education including 37 38 sensitization trainings for community members and Wits RHI staff. The engagement nationally and 39 internationally has included participation on WHO guidelines committees, South African DoH 40 guidelines committees for PrEP and ITx and the new National Sex Worker Plan, as well as plenaries 41 and other presentations at international and local conferences. 42 43 on September 26, 2021 by guest. Protected copyright. 44 The stakeholder engagement plan also includes the dissemination of information about the study as 45 it progresses through the channels mentioned above, as well as eventual dissemination of results. 46 Once the study has completed, study staff will first disseminate results to TAPS participants. This 47 48 may be done through meetings or SMS. Results will be presented to local health officials and 49 stakeholders at meetings, and then sent out through press releases to other partners. 50 51 Finally, investigators will publish main study results as well as findings from the multiple research 52 53 components of the study, namely the economic evaluation, qualitative research, and other clinical 54 and process data. Results from the study will also be presented at various conferences. We will aim 55 to follow STROBE guidelines in the presentation of results; these guidelines were followed in 56 developing the protocol (41). 57 58 59 60 14
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 43 on September 26, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15
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1 2 3 ACKNOWLEDGEMENTS 4 The authors would like to thank many people who helped make this protocol and project a reality. 5 Mohamed Majam provided advice on laboratory support; Pranitha Ramchuran and Anika Naidoo 6 7 provided invaluable support on the submission of this project to the Wits Human Research Ethics 8 Committee and the South African Medicines Control Council; and Eleanor Kaunda provided 9 administrative support for the committee submissions. Maria Sibanyoni and Nyaradzo Mutanha 10 helped with practical and logistical aspects of the design of the project as an addition to the existing 11 12 Sex Worker Project services. The Peer Educators were essential in planning and designing the project 13 and support mechanisms designs. Technical advice on the qualitative research components of this 14 project was given by Adam Bourne, Charlotte Watts, Jonathan Stadler, and Heidi Larson. Clinical 15 advice was givenFor on original peer and revised versions review by Vivian Black and only Michelle Moorhouse. Finally, a 16 17 huge debt of gratitude is owed to the entire TAPS team who has worked tirelessly to implement this 18 project in Hillbrow and Pretoria. 19 20 AUTHOR’S CONTRIBUTIONS 21 22 Conceived and designed the experiments: RE, GBG, WDFV, HR. Performed the experiments: RE, GBG, 23 JM. Analyzed the data: RE, GBG, JM. Contributed reagents/materials/analysis tools: RE, GBG, GA, JM. 24 Wrote the initial draft: RE, GBG. Reviewed the final draft: RE, GBG, GA, JM, WDFV, HR. 25 26 27 FUNDING STATEMENT 28 This work was supported by the Bill and Melinda Gates Foundation [reference number: 29 OPP1084416] and the United States Agency for International Development [reference number: AID- 30 674-A-12-00034]. GBG was partly funded by an AMC ASPASIA overseas grant financed by the 31 32 Netherlands Organisation for Scientific Research (NWO) [reference number 015.009.042]. 33
34 The views and opinions expressed in this paper are those of the authors and not necessarily the http://bmjopen.bmj.com/ 35 views and opinions of the United States Agency for International Development. 36
37 38 COMPETING INTERESTS STATEMENT 39 GBG, RE, GA, and JM declare no competing interests. WDFV has served on Gilead advisory boards; in 40 addition, he is designing a study that requests a donation of a Gilead product. HR was the protocol 41 chair of a microbicide trial involving a Gilead product and has been and is the principal investigator 42 43 for several trials involving study drug donations from Gilead. on September 26, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 16
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1 2 3 REFERENCES 4 5 1. UNAIDS. How AIDS changed everything — MDG6: 15 years, 15 lessons of hope from the AIDS 6 response [Internet]. [cited 2015 Oct 28]. Available from: 7 8 http://www.unaids.org/en/resources/documents/2015/MDG6_15years- 9 15lessonsfromtheAIDSresponse 10 11 2. Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, et al. Use of a 12 Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women. N Engl J Med. 2016 Feb 13 22;0(0):null. 14 15 3. Rees H, Delany-MoretlweFor peer S, Lombard C,review Baron D, Panchia R, Myer only L, et al. FACTS 001 Phase III 16 Trial of Pericoital Tenofovir 1% Gel for HIV Prevention in Women. In Seattle, WA; [cited 2016 Jun 17 21]. Available from: http://www.croiconference.org/sessions/facts-001-phase-iii-trial-pericoital- 18 tenofovir-1-gel-hiv-prevention-women 19 20 4. South Africa | UNAIDS [Internet]. [cited 2016 Jun 21]. Available from: 21 http://www.unaids.org/en/regionscountries/countries/southafrica 22 23 5. UNAIDS. AIDS by the numbers [Internet]. [cited 2015 Aug 7]. Available from: 24 http://www.unaids.org/en/resources/documents/2013/JC2571_AIDS_by_the_numbers 25 26 6. South African National AIDS Council. Strategic Plan on HIV, STIs and TB 2012 – 2016. 2012; 27 28 Available from: 29 http://www.sanac.org.za/files/uploaded/NSP%2027Jan2012%20Full%20APPROVED%2010Feb20 30 12%20Web.pdf 31 32 7. Deanna Kerrigan, Andrea Wirtz, Stefan Baral, Michele Decker, Laura Murray, Tonia Poteat, et al. 33 The Global HIV Epidemics among Sex Workers. The World Bank; 2012.
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Int J STD AIDS. 2005;16:256–61. on September 26, 2021 by guest. Protected copyright. 43 44 11. van Loggerenberg F, Mlisana K, Williamson C, Auld SC, Morris L, Gray CM, et al. Establishing a 45 Cohort at High Risk of HIV Infection in South Africa: Challenges and Experiences of the CAPRISA 46 002 Acute Infection Study. PLoS ONE. 2008;3:e1954. 47 48 12. Desmond Tutu HIV Foundation. Key Populations, Key Responses: A Gap Analysis for Key 49 50 Populations and HIV in South Africa, and Recommendations for the National Strategic Plan for 51 HIV/AIDS, STIs and TB (2012–2016) [Internet]. 2011 [cited 2013 Jan 24]. Available from: 52 http://www.desmondtutuhivfoundation.org.za/documents/Key-Populations-Key-Solutions- 53 report.pdf 54 55 13. UCSF, Anova Health Institute, Wits RHI. South African Health Monitoring Survey (SAHMS): An 56 Integrated Biological and Behavioural Survey among Female Sex Workers, South Africa 2013 – 57 2014. San Francisco: UCSF; 2015. 58 59 60 17
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1 2 3 14. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention 4 of HIV-1 Infection with Early Antiretroviral Therapy. N Engl J Med. 2011 Aug 11;365(6):493–505. 5 6 15. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral 7 Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012;367:399– 8 410. 9 10 16. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure 11 Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 12 2010;363:2587–99. 13 14 17. Thigpen MC KP. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually 15 For peer review only 16 active young adults in Botswana: results from the TDF2 study. In 2011. 17 18 18. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis 19 to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase 20 of a pragmatic open-label randomised trial. The Lancet [Internet]. 2015 Sep [cited 2015 Oct 28]; 21 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0140673615000562 22 23 19. Molina J-M, Capitant C, Spire B, Pialoux G, Chidiac C, Charreau I, et al. On Demand PrEP With 24 Oral TDF-FTC in MSM: Results of the ANRS Ipergay Trial. In 2015 [cited 2015 Oct 28]. Available 25 from: http://www.croiconference.org/sessions/demand-prep-oral-tdf-ftc-msm-results-anrs- 26 ipergay-trial 27 28 20. Choopanya K, Martin M, Suntharasamai P, Sangkum U, Mock PA, Leethochawalit M, et al. 29 Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the 30 Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The 31 Lancet. 2013 Jun;381(9883):2083–90. 32 33 21. World Health Organization. WHO | Consolidated strategic information guidelines for HIV in the
34 http://bmjopen.bmj.com/ 35 health sector [Internet]. WHO. 2015 [cited 2015 Oct 28]. Available from: 36 http://www.who.int/hiv/pub/guidelines/strategic-information-guidelines/en/ 37 38 22. SANAC. The South African National Sex Worker HIV Plan, 2016-2019. Pretoria, South Africa; 39 2016. 40 41 23. Department of Health, South Africa. Guidelines for Expanding Combination Prevention and 42 Treatment Options for Sex Workers: Oral Pre-Exposure Prophylaxis (PrEP) and Test and Treat 43 (T&T). 2016. on September 26, 2021 by guest. Protected copyright. 44 45 24. Eaton JW, Johnson LF, Salomon JA, Bärnighausen T, Bendavid E, Bershteyn A, et al. HIV 46 Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential 47 Impact of Antiretroviral Therapy on HIV Incidence in South Africa. PLoS Med. 2012;9:e1001245. 48 49 25. Dodd PJ, Garnett GP, Hallett TB. Examining the Promise of HIV Elimination by “Test and Treat” in 50 Hyper-Endemic Settings. AIDS Lond Engl. 2010 Mar 13;24(5):729–35. 51 52 26. Cremin I, Alsallaq R, Dybul M, Piot P, Garnett G, Hallett TB. The new role of antiretrovirals in 53 combination HIV prevention: a mathematical modelling analysis. AIDS. 2013 Jan;27(3):447–58. 54 55 27. International AIDS Society. Sustainable and Transitional Financing and Resource Allocation for 56 57 HIV and AIDS. In: Symposia Session TUSY01. Vancouver; 2015. 58 59 60 18
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1 2 3 28. Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a 4 systematic review. PLoS Med Public Libr Sci. 2011 Jul;8:e1001056. 5 6 29. AVAC. Ongoing and Planned PrEP Open Label, Demonstration and Implementation Projects, as 7 of October 2015. Available from: http://www.avac.org/sites/default/files/resource- 8 files/PrEP_Trials_and_Demo_Projects_Oct2015.pdf 9 10 30. IAPAC. Global HIV Policy Watch. Available from: http://www.hivpolicywatch.org/ 11 12 31. Statistics South Africa. Statistics South Africa. Available from: 13 http://www.statssa.gov.za/?page_id=1859&period=July+2015&page=1 14 15 32. SibanyoniFor M. Sex in the peer Cities: Comprehensive review healthcare for sex only workers. In 2015. Available 16 from: 17 18 http://www.saaids.co.za/Presentations2/Wednesday%2010%20June%202015/Hall%206/Setellit 19 e%20session%2014h00_Wits%20RHI/pdf/SWMC%20SAAIDS%20Presentation.pdf 20 21 33. Fox MP, Rosen S. Patient retention in antiretroviral therapy programs up to three years on 22 treatment in sub-Saharan Africa, 2007–2009: systematic review. Trop Med Int Health. 2010 23 Jun;15(s1):1–15. 24 25 34. Department of Health, South Africa. National HIV Counselling and Testing Policy Guidelines 26 [Internet]. 2015 [cited 2016 Jun 21]. Available from: https://www.health-e.org.za/wp- 27 content/uploads/2015/07/HCT-Guidelines-2015.pdf 28 29 35. AIDSinfo. What’s New in the Guidelines | Perinatal Guidelines [Internet]. AIDSinfo. [cited 2015 30 Oct 28]. Available from: https://aidsinfo.nih.gov/ 31 32 36. World Health Organization. WHO | Guideline on when to start antiretroviral therapy and on pre- 33 exposure prophylaxis for HIV [Internet]. 2015 [cited 2015 Oct 28]. Available from:
34 http://bmjopen.bmj.com/ http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ 35 36 37. van der Straten A, Stadler J, Montgomery E, Hartmann M, Magazi B, Mathebula F, et al. 37 38 Women’s Experiences with Oral and Vaginal Pre-Exposure Prophylaxis: The VOICE-C Qualitative 39 Study in Johannesburg, South Africa. PloS One. 2014;9(2):e89118. 40 41 38. Corneli A, Wang M, Agot K, Olang’o L, Makatu S, Lombaard J, et al. The association between risk 42 perception and adherence in the FEM-PrEP clinical trial. In Kuala Lumpur; 2013 [cited 2014 Apr 43 15]. Available from: http://pag.ias2013.org/Abstracts.aspx?AID=3118 on September 26, 2021 by guest. Protected copyright. 44 45 39. Dearing JW, Smith DK, Larson RS, Estabrooks CA. Designing for Diffusion of a Biomedical 46 Intervention. Am J Prev Med. 2013 Jan;44(1):S70–6. 47 48 40. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006 Jan;3(2):77– 49 101. 50 51 41. Elm E von, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. Strengthening the 52 reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting 53 observational studies. BMJ. 2007 Oct 18;335(7624):806–8. 54 55 56 57 58 59 60 19
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1 2 3 4
5 Schedule of Events – Combination Prevention Arm (PrEP) BMJ Open: first published as 10.1136/bmjopen-2016-011595 on 26 September 2016. Downloaded from 6 PICT PICT V26 7 Study Visit V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 (a) (b) EOS 8 Study Month -1 M0 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17 M18 M19 M20 M21 M22 M23 M24 9 10 HCT (by RAPID test) X X X X X X X X X X 11 Invitation to participate X 12 Provide study information X 13 Decline study participation SoC 14 X 15 Informed consent process 16 TB assessment X X X X X X X X X 17 Syphyllis test X 18 STI assessment (+ as indicated) X 19 20 Pregnancy assessment (+ as indicated) X . 21 Vitals X 22 For peer review only Medical History X 23 Physical examination (+ as indicated) X 24 Pap Smear (+ as indicated) 25 a 26 Confirmation of HIV ELISA (+ as indicated) 27 Hepatitis B antigen X 28 X X X X X X X X X X 29 Creatinine clearance (Cockcroft-Gault formula) 30 Full Blood Count (+ as indicated) 31 Plasma storage (drug level + resistance) X X X X X X X X X 32 b 33 Behavioural Questionnaire X X X X X X X X X 34 Eligibility assessment X 35 Confirmation of eligibility X 36 Adherence Counselling X X X X X X X X X 37 Study medications dispensed X X X X X X X X X X X X X X X X X X X X X X X X X 38 X X X X X X X X X 39 Adverse event monitoring (+ as indicated) 40 Study medications accountability X X X X X X X X X X X X X X X X X X X X X X X X X http://bmjopen.bmj.com/ 41 a HIV Elisa will be performed to confirm HIV status and for quality control 42 b Expanded questionnaire at 6mo, 12mo, 18mo and 24mo 43 44 Note: PICT (a) refers to HIV testing and consent, (b) refers to screening, history, and questionnaire; pregnancy screening includes test if indicated 45 46 47 48
49 on September 26, 2021 by guest. Protected copyright. 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 5 Schedule of Events – Immediate Treatment Arm (ITx) PICT PICT V26 6 Study Visit V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 7 (a) (b) EOS 8 Study Month -1 0 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17 M18 M19 M20 M21 M22 M23 M24 9 HCT (by RAPID test) X 10 X 11 Invitation to participate 12 Provide study information X 13 Decline study participation SoC 14 Informed consent process X 15 16 TB assessment X 17 STI assessment (+ as indicated) X 18 Syphyllis test X For peer review only 19 Pregnancy assessment (+ as indicated) X 20 Vitals X 21 Medical History X 22 23 Physical examination (+ as indicated) X 24 Pap smear (+ as indicated) 25 Confirmation of HIV ELISA X 26 Hepatitis B antigen X 27 28 Creatinine clearance (Cockcroft-Gault formula) X X X X X 29 a 30 Plasma HIV-1 RNA (viral load) X X X X 31 CD4 cell count X X X 32 Full Blood Count (+ as indicated) 33
34 Plasma storage (resistance) X X X X X http://bmjopen.bmj.com/ X X X X 35 Behavioural Questionnaireb X X X X X X X X X 36 Eligibility assessment X 37 38 Confirmation of eligibility X 39 Adherence Counselling X X X X X X X X X 40 Study medications dispensed X X X X X X X X X X X X X X X X X X X X X X X X X 41 Adverse event monitoring (+ as indicated) X X X X X X X X X
42 on September 26, 2021 by guest. Protected copyright. 43 Study medications accountability X X X X X X X X X X X X X X X X X X X X X X X X X 44 aexpanded questionnaire at 6mo, 12mo, 18mo and 24mo 45 bViral load monitoring may increase if viral increases, consult current national guidelines. Final viral load will be done at exit or M24, whichever comes first. 46 47 Note: PICT (a) refers to HIV testing and consent, (b) refers to screening, history, and questionnaire; pregnancy screening includes test if indicated 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml