Gates Open Res Gates Open Research 2572-4754 F1000 Research Limited London, UK 10.12688/gatesopenres.14682.1 Study Protocol Articles Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study

[version 1; peer review: 2 approved with reservations]

 Maskew Mhairi Conceptualization Investigation Methodology Project Administration Supervision Validation Writing – Original Draft Preparation Writing – Review & Editing 1 Ntjikelane Vinolia Investigation Project Administration Software Writing – Review & Editing a 1 Juntunen Allison Conceptualization Project Administration Software Writing – Review & Editing 2 Scott Nancy Conceptualization Methodology Project Administration Writing – Original Draft Preparation Writing – Review & Editing 2 Benade Mariet Conceptualization Methodology Project Administration Writing – Original Draft Preparation Writing – Review & Editing 2 Sande Linda Investigation Project Administration Supervision Validation Writing – Original Draft Preparation Writing – Review & Editing 1 Hasweeka Pamfred Investigation Project Administration Writing – Review & Editing 3 Haimbe Prudence Project Administration Writing – Review & Editing 3 Lumano-Mulenga Priscilla Project Administration Writing – Review & Editing 4 Shakewelele Hilda Conceptualization Supervision Writing – Review & Editing 3 Mukumbwa-Mwenechanya Mpande Conceptualization Writing – Review & Editing 5 Rosen Sydney Conceptualization Funding Acquisition Methodology Project Administration Supervision Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-6560-2964 b 1 2 Health Economics and Epidemiology Research Office, Faculty of Health Sciences, University of the Witwatersrand Johannesburg, Johannesburg, Gauteng, South Africa Global Health, Boston University, Boston, MA, 02118, USA CHAI-Zambia, Clinton Health Access Initiative, Lusaka, Zambia MOH Zambia, Ministry of Health, Lusaka, Zambia Center for Infectious Disease Research in Zambia, Lusaka, Lusaka Province, Zambia vntjikelane@heroza.org sbrosen@bu.edu

Competing interests: No competing interests were disclosed. PLM holds a position in a government agency that has supervisory authority over some of the healthcare facilities involved in this study.

 12 9 2023 2023 7 119 8 6 2023 Copyright: © 2023 Maskew M et al. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background 

For patients on HIV treatment in sub-Saharan Africa (SSA), the highest risk for loss from care consistently remains the first six months after antiretroviral (ART) initiation, when patients are not yet eligible for most existing differentiated service delivery (DSD) models. To reduce disengagement from care during this period, we must gain a comprehensive understanding of patients’ needs, concerns, resources, and preferences for service delivery during this period. The PREFER study will use a sequential mixed-methods approach to survey a sample of patients in South Africa and Zambia 0-6 months after ART initiation to develop a detailed profile of patient characteristics and needs.

Protocol 

PREFER is an observational, prospective cohort study of adult patients on ART for ≤6 months at 12 public sector healthcare facilities in Zambia and 18 in South Africa that aims to inform the design of DSD models for the early HIV treatment period. It has four components: 1) survey of clients 0-6 months after ART initiation; 2) follow up through routinely collected medical records for <12 or <24 months after enrollment; 3) focus group discussions to explore specific issues raised in the survey; and 4) in South Africa only, collection of blood samples self-reported naïve participants to assess the prevalence of ARV metabolites indicating prior ART use. Results will include demographic and clinical characteristics of patients, self-reported HIV care histories, preferences for treatment delivery, and predictors of disengagement.

Conclusions 

PREFER aims to understand why the early treatment period is so challenging and how service delivery can be amended to address the obstacles that lead to early disengagement from care and to distinguish the barriers encountered by naïve patients to those facing re-initiators. The information collected by PREFER will help respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward.

 HIV South Africa Zambia antiretroviral therapy retention models of care  Gates Foundation INV-031690 Funding for the study was provided by the Gates Foundation through INV-031690 to Boston University. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction

Rapid, same-day, and community-based initiation of antiretroviral therapy (ART) for HIV has shifted the challenge of achieving optimal outcomes in HIV treatment onto retention in care after a patient has started ART. The highest risk for loss from care consistently remains a patient’s first six months after ART initiation 1 . Dubbed the “early retention” period 2 , this interval accounts for roughly three quarters of all first-year attrition from HIV programs in sub-Saharan Africa 3 . In South Africa, 26% of patients were lost to follow up by 6 months after initiation in a recent trial of a case management intervention 4 , and attrition was 35.6% by 6 months in a recent observational study 5 .

Patient characteristics and service delivery characteristics both contribute to high attrition during the early treatment period 6 . After the World Health Organization (WHO) began recommending universal treatment access in 2016, the median CD4 count of new ART initiates rose substantially, reflecting the much higher proportion of asymptomatic, “healthy” patients than in the past 7 , despite a fairly consistent minority of a quarter to a third continuing to present with very low CD4 counts 8, 9 . The proportion of patients who are re-initiating ART after previously interrupting care is also climbing. A recent modeling exercise estimated that in 2020, fully 58% of those who tested positive for HIV were already aware of their positive status 10 and thus may have declined an earlier opportunity to start or remain on treatment. Two small studies in South Africa identified ARV metabolites—evidence of recent exposure to ARV medications—in 53% and 19% of self-reported naïve ART initiators in Limpopo and KZN provinces, respectively 11, 12 . Individuals who know their HIV-positive status but are not on ART likely face multiple barriers to starting treatment; those who both know their status and have already started and stopped ART at least once (re-initiators) may require additional support to remain in care once they re-initiate care.

The service delivery landscape has transformed at many points in the HIV treatment cascade in recent years, most notably through the introduction of rapid and same-day ART initiation for those not yet on treatment 13 and the development of patient-centred differentiated service delivery (DSD) models for those already established on ART for at least 6 months 14 . Neither same-day initiation nor most current DSD models, however, offer solutions for patients during the first six months after initiation 15 . The model of care for the early treatment period that is offered to most newly-initiating and re-initiating patients has evolved little from its original outlines, though COVID-19 restrictions precipitated some reductions in required numbers of clinic visits and increases in dispensing intervals 16 .

A first step in designing new models of care for the early treatment period is to gain a comprehensive understanding of patients’ needs, concerns, resources, and preferences for service delivery during this period. Treatment and retention in the first 6 months after ART initiation could be improved if patients were triaged to receive more or less support based on a combination of known risks to retention in care and patient preferences for how little or how much interaction, and what kinds of interaction, with the health system are desired.

In the PREFER study, we will use a sequential mixed-methods approach to survey a sample of patients in South Africa and Zambia at various points between months 0 and 6 after ART initiation to develop a detailed profile of different groups of patients who may be best served by different models of care.

 Protocol Overview

PREFER is an observational, prospective cohort study in South Africa and Zambia that aims to inform the design of service delivery models for the early HIV treatment period. It has four components: 1) a survey of clients during the period from 0 to 6 months after ART initiation; 2) follow up through routinely collected medical records for a maximum of 12 or 24 months after study enrollment, depending on the study country; 3) focus group discussions (FGDs) to explore specific issues raised in the survey; and 4) in South Africa only, collection of blood samples from a subsample of self-reported naïve participants who are initiating ART on the day of study enrollment to assess the prevalence of ARV metabolites indicating prior ART use.

PREFER is registered at Clinicaltrials.gov as NCT05454839 (South Africa) and NCT05454852 (Zambia).

 Study sites

PREFER will be conducted at 18 healthcare facilities in South Africa and 12 in Zambia ( Table 1). Study sites represent the facilities participating in the SENTINEL study of the AMBIT Project. For SENTINEL, local study teams first identified provinces and districts that were accessible, had a high burden of HIV, utilized the national electronic medical record system, and jointly provided diversity in setting (rural, urban), facility size, and nongovernmental support partners. Within each district, SENTINEL then selected a set of facilities that represented the desired diversity and were large enough to provide the sample sizes required. These were chosen with engagement from the relevant Departments and Ministries of Health, including national and district government health officials with responsibility for the sites. Further information about SENTINEL and preliminary results can be found at www.sites.bu.edu/ambit.

PREFER study sites.
Facility Setting ART patients as of August, 2021 Average ART initiates per month, 2021
South Africa
West Rand District (Gauteng Province)
   Clinic Urban 1,783 16
   Clinic Rural 1,803 17
   Clinic Urban 1,897 16
   Clinic Urban 2,116 37
   Clinic Rural 2,301 13
   Clinic Urban 2,959 30
Ehlanzeni District (Mpumalanga Province)
   Clinic Urban 6,365 49
   Clinic Rural 3,553 24
   Clinic Rural 1,946 9
   Clinic Rural 3,001 28
   Community Health Centre Urban 5,234 105
   Health Centre Urban 5,523 43
King Cetshwayo District (KZN Province)
   Clinic Rural 1,182 11
   Clinic Rural 1,509 11
   Clinic Rural 2,231 10
   Clinic Rural 3,361 23
   Clinic Rural 5,190 34
   Clinic Urban 7,934 34
Zambia
Lusaka Province
   Urban Health Centre Urban 2,370 21
   Referral Rural Health Centre Rural 4,060 35
   Health Center Peri-urban 3,754 23
   First Level Hospital Urban 10,794 131
   First Level Hospital Urban 13,386 121
   First Level Hospital Urban 6,954 45
Central Province
   District Hospital Rural 3,397 16
   Urban Clinic Urban 6,805 48
   Urban Health Centre Urban 3,753 17
   Urban Health Centre Urban 2,855 21
   Mission Hospital Rural 2,397 17
   District Hospital Rural 4,326 18
Study population and enrollment

We will sequentially recruit adult (≥18 years old) ART patients on treatment for ≤6 months who present at the study sites for ART initiation, routine care, or unscheduled HIV-related care and provide written informed consent. We will exclude anyone who is unable to communicate in any of the languages into which the survey has been translated, is unwilling to take the time required to complete the survey on the day of consent, or who, in the opinion of study staff, is physically, mentally, or emotionally unable to participate in the study. Eligibility will be determined through completion of a survey screening form, which will also allow us to compare the sex and age distribution of the population enrolled in the survey with those of the full potentially eligible population (Extended data - Supplementary file 1).

At the study sites, clinic staff will inform potentially eligible patients that they may be eligible to participate in a research study when the patient checks in at the reception desk. Patients will be recruited consecutively as they arrive at the facility, based on availability of study interviewers, and written informed consent will be sought, covering the survey, medical record review, agreement to be contacted for later focus group participation, and agreement to blood sample testing for prior ARV exposure (Extended data - Supplementary file 2). The consent process and questionnaire will be administered in a confidential space by a trained research assistant in a private location at the clinic during the periods while patients are waiting in queues for facility services (consultations or medication pickups). Participants will be assured that they will not lose their places in the queue as a result of study participation. Patients who start the survey but do not have time to complete it before reaching the front of the queue will be asked to return to the research assistant after receiving services, in order to complete the survey. We anticipate that each interview will last 75 minutes, including the consent process.

 PREFER survey

The PREFER survey instrument will be a structured questionnaire designed for primarily quantitative analysis but with some open-ended questions (Extended data - Supplementary file 3). The questionnaire has eight substantive sections, addressing the respondent’s demographics and socio-economic status, HIV testing history, HIV treatment history, current HIV care and treatment experience, other healthcare, preferences for features of treatment delivery, expectations, and costs of seeking care. Questions are designed to elicit information about participants’ past experiences with the healthcare system and identify changes that would potentially improve their future experiences.

As PREFER is a descriptive study that aims to describe participants’ self-reported experiences and preferences, rather than comparing outcomes or testing a hypothesis, sample sizes were chosen to optimize the use of study resources and time availability. Using the expected number of eligible patients at each study site, the number of such patients who are expected to visit the sites during the data collection period, and an anticipated data collection period of 90 days in each country, the study protocols allow a maximum enrollment of 2,500 participants per country. We anticipate that actual enrollment will be somewhat less than this, with a minimum target of an average of 50 participants per study site, or 900 in South Africa and 600 in Zambia; we expect these sample sizes to be sufficient to generate sufficiently precise results to the survey’s quantitative questions.

 Medical record review

Using identifiers collected as part of the structured questionnaire, we will also collect follow up data from routine medical records for the period from each participant’s initial data entry (first presentation for testing or care) to 12 months after study enrollment, with an additional round of medical record data collection up to 24 months after study enrollment in South Africa. Medical record data will be drawn from Tier.Net in South Africa and Smartcare in Zambia, paper records and registers maintained at the study sites, and other databases, such as South Africa’s National Health Laboratory Services database, to ascertain whether patients are retained in care during the first 6 months on ART. We will collect data on HIV treatment history and current engagement, medications dispensed, laboratory tests performed, comorbidities, and other healthcare provided by the site and recorded in the EMR during the study period. We note that the EMRs in both countries are largely limited to HIV care; they may capture data on tuberculosis and other conditions but generally do not contain information about services provided by other departments within the clinics.

 Post-enrollment focus group discussions

Participants will be asked during the consent process for their agreement to be contacted by telephone or e-mail at any time during the 12 months following study enrollment and invited to participate in a FGD. We anticipate inviting up to 300 participants to participate in FGDs of up to 10 participants in each of up to 30 groups, 15 per country. We will purposively select PREFER sites which have sufficient numbers of enrollees and represent a diversity of settings and purposively identify participants who have a record of missed visits or who have expressed concerns about their care in the quantitative survey. Patients will be contacted by telephone or email, depending on their preference stated at enrollment. Study staff conversant in English and the appropriate local language and trained in qualitative research methods and human subjects protection will conduct the FGDs.

Before commencing the FGD, all participants will be briefly screened for eligibility and study staff will proceed with the informed consent process. We will document informed consent with a signature or a thumb-print and capture basic demographic information for each participant to allow linkage to their survey results. FGD leaders, who will be trained study research assistants, will remind all participants that anything said during the discussion must remain private and should not be shared beyond the group. The FGDs will conducted in a private setting in the clinic or community.

To guide the discussion and probe for more in-depth responses, FGD leaders will use an FGD tool developed based on responses to the PREFER survey and focusing on specific issues or concerns that participants raise in the survey. Anticipated topics, which may vary by country, include HIV treatment experience, patient preferences for receiving HIV treatment, and patient expectations of HIV care. The FGD will be audio recorded and the leaders will also take notes during the interview. FGDs should take no longer than two hours.

 Biological sample collection at South African sites

For a subsample of South African study participants who are enrolled on the day of ART initiation or re-initiation who self-report as ART-naïve, a dried blood specimen (DBS) will be collected from PREFER survey participants at some study sites. Blood is drawn routinely as part of the standard of care ART initiation process in South Africa. DBS specimens will be extracted from the routinely collected blood samples drawn by existing clinic staff (nurses or phlebotomists), who are trained in safe and sterile collection techniques. For the study, a sample of 50μml will be extracted from an existing EDTA vacutainer tube with a capillary tube and placed onto a Whatman Protein 903 filter paper. A minimum of 3 dried blood spots will be completed for each patient. Specimens will be allowed to air dry for 2 hours after being taken, or according to assay instructions. Specimens will be covered with glycine weighing paper after drying. Collected, dried specimens will be stored in a -4°C freezer and be shipped in 6-weekly batches via courier to the University of Cape Town Division of Pharmacology, PK Laboratory for analysis. Specimens will be batch-screened for the presence of tenofovir diphosphate. Presence of TDF above 0.02μg/ml will be considered as positive for previous ART use in the previous 3 months or as advised by the laboratory.

Participants who meet the inclusion criteria for this subsample (initiating or re-initiating ART and self-reporting as ART-naïve) will be consecutively enrolled up to a maximum of 200 participants from all participating study sites combined. Consent for biological sample collection is included in the overall survey consent form.

 Data management

A screening register will be kept by the study research assistants to record the consent process and keep track of those who do not consent, to allow us to determine if our sample is biased by patient characteristics due to differential consent. The screening register will not contain any individual identifiers. It will request age category, gender, and months on ART, as needed to determine survey eligibility only.

Patient survey responses will be entered live at the time of the interview into an electronic database on Survey CTO (Dobility 2023) using handheld tablets. If there are power failures, data will be entered onto paper study forms and then transcribed into a database at the local study office. Survey data will be converted to SAS, STATA, or R for final cleaning and data analysis. All analytic databases will be password protected with access restricted to the members of the study team. All survey respondents will be assigned a seven-digit, sequential identification number. The study ID number will be used to identify individual subjects in the study databases and to link survey response data to patient retention outcomes data and for all data analysis. Once data are linked, identifiers will be removed from the analysis file and all subjects will be assigned a random study ID, which will be used for all analysis.

FGD audio files will be transcribed verbatim, then transcribed and translated into English for analysis.

 Data analysis and dissemination

We will first create a descriptive summary of the demographic and clinical characteristics of participants enrolled in the study and responses to each question using frequencies and simple proportions for categorical variables and medians with interquartile ranges for continuous variables. We will then stratify these baseline survey responses by site characteristics, time on ART, self-reported naïve v non-naïve treatment status, and/or patient characteristics such as age and sex, as data allow. Data will not be pooled across countries, but differences in results by country will be noted and discussed.

Utilizing follow up data collected from patient medical records, we will conduct a crude analysis reporting simple proportions with 95% confidence intervals of patients disengaging from care, defined as missing a scheduled clinical or medication pickup visit during the first 6 months after treatment initiation by more than 28 days. Next, we will compare the proportions of patient disengaged from care by key variables including age, gender, clinical stage at ART initiation, site characteristics, time on ART, and naïve v non-naïve treatment status.

If enrollment numbers allow, the analysis will include a simple unadjusted comparison of outcome groups (retained or disengaged) with respect to baseline predictors of outcomes. Potential predictors include demographic and clinical variables and geographic and facility-level factors (urban vs rural setting, facility type). Using a log-linear regression model, we will next estimate crude risk ratios and crude risk differences and their corresponding 95% confidence intervals. If any important differences are observed, we will proceed with an adjusted model. Should crude stratification techniques reveal potential effect measure modification, these analyses will not be adjusted but rather reported as stratified output.

For the FGD output, we will conduct a content analysis of the qualitative data using the Framework Method 17 . We will use a combination inductive-deductive approach wherein most codes will be identified a priori, aligned with the FGD guide and literature, but the coding process will allow for additional codes to emerge to form a final analytical framework. Data will be charted, summarized, and quotations will be presented to illustrate key points when appropriate. Results will be presented stratified by country and urbanicity of sites.

The study results will be disseminated in several ways. The primary audiences for the results of this study are the South African National Department of Health and Zambian Ministry of Health and their partners, who will use the findings to improve retention in care during the early treatment period. In addition, we will use the results to inform the design of one or more new models of service delivery, which we expect to implement and evaluate during a later stage of this project. Many of the findings will also likely be of broader interest in South Africa and other countries and will be made as widely available as possible, through journals, websites, and conferences. Only aggregated, stratified data will be presented; it will not be possible to identify any individual patients from any of the results that are presented.

 Limitations

We anticipate that the PREFER study will have a number of limitations. First, the target sample size is small, in terms of both number of study sites and number of participants, and generalizability to districts and provinces not included in the survey will require caution. Second, survey participants will provide responses about their experiences up to 6 months after ART initiation, creating the possibility of recall bias for questions pertaining to HIV testing and other pre-ART events. Third, we will largely rely on participant self-report to determine prior ART use. Several studies have demonstrated underreporting of prior ART use by self-report which could result in exposure misclassification for analyses stratified by prior treatment status. While we plan to do dried blood sampling to measure ART metabolites for prior ART exposure, the subsample who will be tested will be too small to stratify by patient or facility characteristics. Fourth, as we can only enroll participants actively participating in ART care at health facilities, the study will not capture the experiences and perceptions of individuals who have already disengaged from care. While we will be able to observe re-initiators, those who have not returned to the initiating facility will not be enrolled, potentially limiting our understanding of those who have disengaged from care. Fifth, we will utilize routinely collected EMR data to ascertain participant ART retention outcomes at 6 months after ART initiation. While efficient in terms of resources, this approach is limited to data observed at the initiating facility and will not observe participants accessing care at other facilities. Silent transfers such as these may result in outcome misclassification among some classified as disengaged.

 Ethics review

The PREFER study was approved with a separate protocol for each study country by the Boston University Institutional Review Board (South Africa H-42726, May 20, 2022; Zambia H-42903, July 11, 2022) and by the University of the Witwatersrand Human Research Ethics Committee (South Africa M220440, August 23, 2022; Zambia M210342, September 30, 2021). The protocol for South Africa was approved by Provincial Health Research Committees through the National Health Research Database for each study district (August 1, 2022 for West Rand; September 1, 2022 for King Cetshwayo and August 28, 2022 for Ehlanzeni). The protocol for Zambia was approved by the ERES-Converge IRB (2022-June-007, June 24, 2022) and the Zambia National Health Research Authority (NHRA000007/10/07/2022, July 10, 2022).

 Current status of the study

Enrollment in the PREFER survey began on September 7, 2022 in South Africa and September 21, 2022 in Zambia. We anticipate that the quantitative survey will be completed in May 2023 and all data collection by August 2023. At the time of submission of the first version of the manuscript, data collection for the quantitative survey is ongoing; data collection for the medical record review, focus group discussions, and biological samples has not yet started.

 Conclusions/Discussion

Many sub-Saharan African countries have achieved the first and third of the “three 90s” 18 —HIV testing and viral suppression among those remaining on treatment--that represented global targets for HIV programs during most of the decade of the 2010s. The second of the 90s—initiating and maintaining at least 90% of known HIV-positive people on ART—has remained out of reach for countries like South Africa and Zambia, in part due to high rates of disengagement from care after treatment initiation. For some countries, improving retention in care may be the only effective option for achieving current targets 19 , which have been revised to the “three 95s” 20 . To do this, attrition from care during the early treatment period—patients’ first six months on ART—must be reduced.

The PREFER study aims to understand what is happening during the early treatment period on the ground, as individual healthcare facilities interpret and implement national guidelines and healthcare workers and clients adapt to new medication regimens and new models of service delivery. PREFER was designed to understand why the early treatment period is so challenging for many patients and how service delivery can be amended to address the obstacles that lead to early disengagement from care, be they out-of-pocket costs, fear of disclosure, poor provider relations, or other concerns, and to distinguish the barriers encountered by naïve patients to those facing re-initiators. The information collected by PREFER will help policy makers and program managers respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward.

 Data availability statement Underlying data

No data are associated with this article.

 Extended data

OpenBU. Study protocol and supplementary files for protocol manuscript in Gates Open Research. DOI: https://hdl.handle.net/2144/46276.

This project contains the following data:

Supplementary file 1. Screening form.

Supplementary file 2. PREFER consent information sheet and signature form.

Supplementary file 3. PREFER survey form.

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

 Rosen S Grimsrud A Ehrenkranz P : Models of service delivery for optimizing a patient's first six months on antiretroviral therapy for HIV: an applied research agenda. Gates Open Res. 2020;4:116. 32875281 10.12688/gatesopenres.13159.1 7445417 Fox MP Rosen S : A new cascade of HIV care for the era of "treat all". PLoS Med. 2017;14(4):e1002268. 28399160 10.1371/journal.pmed.1002268 5388465 Fox MP Rosen S : Retention of adult patients on antiretroviral therapy in low- and middle-income countries: systematic review and meta-analysis 2008-2013. J Acquir Immune Defic Syndr. 2015;69(1):98–108. 25942461 10.1097/QAI.0000000000000553 4422218 Aurum Institute: Case Management: Preliminary outcomes.Johannesburg: 2020. Lilian RR Rees K McIntyre JA : Same-day antiretroviral therapy initiation for HIV-infected adults in South Africa: Analysis of routine data. PLoS One. 2020;15(1):e0227572. 31935240 10.1371/journal.pone.0227572 6959580 Rosen S Grimsrud A Ehrenkranz P : Models of service delivery for optimizing a patient's first six months on antiretroviral therapy for HIV: an applied research agenda [version 1 ; awaiting peer review]. Gates Open Res. 2020;4:116. 32875281 10.12688/gatesopenres.13159.1 7445417 Matare T Shewade HD Ncube RT : Anti-retroviral therapy after “Treat All” in Harare, Zimbabwe: What are the changes in uptake, time to initiation and retention? [version 2; peer review: 2 approved, 1 approved with reservations]. F1000Res. 2020;9:287. 32934801 10.12688/f1000research.23417.2 7475956 Lilian RR Rees K Mabitsi M : Baseline CD4 and mortality trends in the South African human immunodeficiency virus programme: Analysis of routine data. South Afr J HIV Med. 2019;20(1):963. 31392037 10.4102/sajhivmed.v20i1.963 6676982 Zaniewski E Dao Ostinelli CH Chammartin F : Trends in CD4 and viral load testing 2005 to 2018: multi-cohort study of people living with HIV in Southern Africa. J Int AIDS Soc. 2020;23(7):e25546. 32640106 10.1002/jia2.25546 7343336 Giguère K Eaton JW Marsh K : Trends in knowledge of HIV status and efficiency of HIV testing services in sub-Saharan Africa, 2000-20: a modelling study using survey and HIV testing programme data. Lancet HIV. 2021;8(5):e284–e293. 33667411 10.1016/S2352-3018(20)30315-5 8097636 Sithole N Gunda R Koole O : Undisclosed antiretroviral therapy use at primary health care clinics in Rural KwaZulu Natal South Africa: A DO-ART trial sub-study. AIDS Behav. 2021;25(11):3695–3703. 34097208 10.1007/s10461-021-03319-4 8560667 Mavhandu-Ramarumo LG Tambe LAM Matume ND : Undisclosed exposure to antiretrovirals prior to treatment initiation: An exploratory analysis. South Afr J HIV Med. 2021;22(1):1200. 33936791 10.4102/sajhivmed.v22i1.1200 8063556 Ford N Migone C Calmy A : Benefits and risks of rapid initiation of antiretroviral therapy. AIDS. 2017;32(1):17–23. 29112073 10.1097/QAD.0000000000001671 5732637 Ehrenkranz P Grimsrud A Rabkin M : Differentiated service delivery: Navigating the path to scale. Curr Opin HIV AIDS. 2019;14(1):60–65. 30394947 10.1097/COH.0000000000000509 International AIDS Society: DSD Dashboard: Time on ART before eligible for DSD for HIV treatment.In: 2022[cited 18 Apr 2023]. Reference Source Grimsrud A Wilkinson L : Acceleration of differentiated service delivery for HIV treatment in sub-Saharan Africa during COVID-19. J Int AIDS Soc. 2021;24(6):e25704. 34105884 10.1002/jia2.25704 8188395 Gale NK Heath G Cameron E : Using the framework method for the analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol. 2013;13:117. 24047204 10.1186/1471-2288-13-117 3848812 UNAIDS: 90-90-90 An ambitious treatment target to help end the AIDS epidemic. 2014. Reference Source Meyer-Rath G Jamieson L Johnson LF : When the only intervention left to optimise is retention: Comparing the 2021 and 2016 South African HIV Investment Cases.2022. Reference Source Ehrenkranz P Rosen S Boulle A : The revolving door of HIV care: Revising the service delivery cascade to achieve the UNAIDS 95-95-95 goals. PLoS Med. 2021;18(5):e1003651. 34029346 10.1371/journal.pmed.1003651 8186775 10.21956/gatesopenres.16006.r35302 Reviewer response for version 1 Engler Kim 1 Referee https://orcid.org/0000-0001-8364-7421 Center for Outcomes Research and Evaluation, McGill University, Montreal, Québec, Canada

Competing interests: No competing interests were disclosed.

 28 11 2023 Copyright: © 2023 Engler K 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

Thank you for the opportunity to review the research protocol manuscript submitted by Maskey and colleagues which described the PREFER study protocol. My comments are presented below, section by section.

Title/abstract: The background’s first 2 1/2 lines could be synthesized to provide space to explain the role or significance of the differentiated service delivery models in patient retention, for those not familiar with them. The rationale and objectives are clear. A word is missing in the protocol section: “…collection of blood samples [from] self-reported naïve participants.” Also in the protocol section, perhaps the precise objective for each component of the study could be systematically provided. This will help us better understand, for instance, the significance of looking at the prevalence of ARV metabolites indicating prior ART use. Similarly, in the conclusions, should this: “to distinguish the barriers encountered by naïve patients to those facing re-initiators” be formally a part of the study objectives or rationale, instead of in the conclusions?

Introduction: The introduction is extremely well written and logical. The study appears highly relevant and well justified. The study design seems appropriate. However, as previously suggested, I think the introduction could benefit by ending with a list of specific objectives (beyond the general overarching goals mentioned), that would better contextualize and prepare the reader for the data collection and planned analyses sections. There are hints of these interspersed throughout the text and their consolidation in one location would be helpful. Indeed, the different data collection methods and analyses could be headed by their respective objective, as a guide.

Protocol: Some questions about study methodology could be addressed, for instance, is patient compensation for study participation provided? More could also be said about the origins and construction of the PREFER survey. How was the content developed or chosen -who was involved? Were instruments with evidence of validity used? Were patients involved in piloting or choosing the survey content?

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Not applicable

Reviewer Expertise:

HIV, patient-reported outcome measures, qualitative methods, antiretroviral therapy adherence and its barriers, stakeholder engagement, implementation research

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Rosen Sydney

Competing interests: None.

 27 12 2023

Response to Reviewer 2 of “Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study [version 1; peer review: 2 approved with reservations]”

APPROVED WITH RESERVATIONS

Thank you for the opportunity to review the research protocol manuscript submitted by Maskew and colleagues which described the PREFER study protocol. My comments are presented below, section by section.

1. Title/abstract: The background’s first 2 1/2 lines could be synthesized to provide space to explain the role or significance of the differentiated service delivery models in patient retention, for those not familiar with them. The rationale and objectives are clear. A word is missing in the protocol section: “…collection of blood samples [from] self-reported naïve participants.” Also in the protocol section, perhaps the precise objective for each component of the study could be systematically provided. This will help us better understand, for instance, the significance of looking at the prevalence of ARV metabolites indicating prior ART use. Similarly, in the conclusions, should this: “to distinguish the barriers encountered by naïve patients to those facing re-initiators” be formally a part of the study objectives or rationale, instead of in the conclusions?

Response: Thank you for these suggestions. We have added a brief note about the purpose of DSD models We have added the missing word—thank you for catching that error. We have added objectives for each component of the study to the abstract to the extent possible within length limits. We have also now explained the objectives of the different components in the manuscript text, in the sections in which each component is described. We also agree that the line regarding distinguish differences between naïve and re-initiating patients belongs a part of the objectives and have moved it accordingly.

2. Introduction: The introduction is extremely well written and logical. The study appears highly relevant and well justified. The study design seems appropriate. However, as previously suggested, I think the introduction could benefit by ending with a list of specific objectives (beyond the general overarching goals mentioned), that would better contextualize and prepare the reader for the data collection and planned analyses sections. There are hints of these interspersed throughout the text and their consolidation in one location would be helpful. Indeed, the different data collection methods and analyses could be headed by their respective objective, as a guide.

Response: Thank you for the positive comments about the introduction and study. We have added the following sentence to the end of the introduction:

“The specific objectives of the study include describing the characteristics and preferences of new and re-initiating ART clients, exploring their concerns in depth through focus groups, identifying associations between client characteristics and early treatment outcomes, and assessing differences between naïve and non-naïve treatment initiators.”

In addition, we have made the section titles more descriptive, as you suggest.

3. Protocol: Some questions about study methodology could be addressed, for instance, is patient compensation for study participation provided? More could also be said about the origins and construction of the PREFER survey. How was the content developed or chosen -who was involved? Were instruments with evidence of validity used? Were patients involved in piloting or choosing the survey content?

Response:  Thank you for these helpful suggestions, which identify previous oversights in the manuscript. We have added the following sentence about compensation (page 6):

“Participants will be offered light refreshments during the study, and will be given a token valued at approximately US$10 to thank them for their time and participation.”

The PREFER survey was created by the manuscript’s authors on this manuscript, based on prior experience in creating tools asking about patient experiences in seeking care. No validated tool was used, but many individual questions were drawn from our own prior studies on ART clients’ experiences, characteristics, costs, and other topics. We have now noted that the PREFER survey instrument was developed from previous AMBIT project tools and have cited a number of previous studies relevant to this topic.

 10.21956/gatesopenres.16006.r35301 Reviewer response for version 1 Muwonge Timothy R 1 Referee https://orcid.org/0000-0002-8478-9234 Infectious Diseases Institute, Makerere University, Kampala, Uganda

Competing interests: No competing interests were disclosed.

 1 11 2023 Copyright: © 2023 Muwonge TR 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

Title and Abstract: The title and abstract should provide a clear and concise overview of the study. The title of the manuscript is informative. In the abstract, it would be helpful to briefly mention the key objectives and expected outcomes of the study.

Introduction: The manuscript effectively highlights the importance of the research question by describing the challenges of patient retention during the early phase of ART. It also emphasizes the significance of understanding patient preferences during this period.

Methods: The manuscript provides a comprehensive overview of the study methods. However, it would be beneficial to clarify the sampling strategy in more detail, including how sites and participants were selected. Additionally, it might be useful to include a flowchart or diagram to illustrate the study design and data collection process.

Data Collection: The methods section mentions that a dried blood specimen will be collected from a subsample of South African participants. It would be helpful to specify how this subsample will be selected and how the blood samples will be used in the analysis. 

Potential Improvements

The research protocol could employ Focus Group Discussions (FGDs) to understand the reasons behind loss from care in the first six months after antiretroviral (ART) initiation, this comes along with quite a number of limitations of FGDS;                                       

Proposed research questions.

a) Why is the early treatment period (first six months of ART initiation) challenging?

b) How can service delivery be amended to address the obstacles that lead to early disengagement from care?

c) What are the patient's preferences for healthcare services during the initial six months of ART treatment.?

d) What are the barriers encountered by naïve patients to those facing re-initiators? The information collected by PREFER will help respond to patients’ needs design better strategies for service delivery and improve resource allocation going forward.

Ethical Considerations: While the manuscript mentions that the study was approved by relevant ethics committees, it would be beneficial to provide more information about the informed consent process, including how participants were informed about the study and their rights as participants.

Data Management: The manuscript briefly discusses data management but does not mention data security and privacy. It would be important to highlight the steps taken to protect the confidentiality and privacy of participants' data.

Data Analysis: The manuscript outlines the planned data analysis, including both quantitative and qualitative components. However, it would be helpful to mention specific statistical methods that will be used for data analysis.

Conclusion: The conclusion section effectively summarizes the study's objectives and potential impact on improving retention in HIV care. The manuscript could elaborate on the broader implications of the study's findings for HIV programs in sub-Saharan Africa.

Tables and Figures: It would be beneficial to include tables or figures to visually represent key information, such as the study sites, participant demographics, or the data collection process.

References: Unable to comment on the references as the journal review guidelines do not mention the type of referencing required.

 Overall, the manuscript provides a well-structured and informative research protocol. Addressing the above points will enhance the clarity and completeness of the manuscript.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Yes

Reviewer Expertise:

Infectious diseases, Epidemiology, clinical trials, global health, refugee health, HIV prevention, implementation science.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Rosen Sydney

Competing interests: None.

 27 12 2023

Response to Reviewer 1 of “Preferences for services in a patient’s first six months on antiretroviral therapy for HIV in South Africa and Zambia (PREFER): research protocol for a prospective observational cohort study [version 1; peer review: 2 approved with reservations]”

APPROVED WITH RESERVATIONS

Title and Abstract: The title and abstract should provide a clear and concise overview of the study. The title of the manuscript is informative. In the abstract, it would be helpful to briefly mention the key objectives and expected outcomes of the study.

Response: We have added to the abstract a more explicit statement of the primary objective of the study, as follows:

“Its primary objective is to describe and understand the needs and preferences of initiating and re-initiating ART clients in order to inform the design of DSD models for the early HIV treatment period and improve early treatment outcomes.”

Because of length constraints for the abstract, we could not describe outcomes explicitly, but we believe that the outcomes are clear from the rest of the abstract text.

Introduction: The manuscript effectively highlights the importance of the research question by describing the challenges of patient retention during the early phase of ART. It also emphasizes the significance of understanding patient preferences during this period.

Response: Thank you, we are glad that the Introduction section is clear.

Methods:

1. The manuscript provides a comprehensive overview of the study methods. However, it would be beneficial to clarify the sampling strategy in more detail, including how sites and participants were selected. Additionally, it might be useful to include a flowchart or diagram to illustrate the study design and data collection process.

Response: We would be glad to provide clarification where we can. The description of the selection of study sites on page 5 (and of the sites themselves in Table 1) seems complete; we do not know what other information we could add to clarify it further. In the interval since we originally submitted this manuscript, however, a paper about the SENTINEL survey, for which the PREFER sites were originally chosen, has been published and explains the selection process in a bit more detail. We now cite that paper to provide further information for readers.

Selection of participants is described on page 6. We have tried to clarify the steps and added additional information about the consent process. We thank the Reviewer for the suggestion of a flowchart, which we have now added to the Methods section as Figure 1.

2. Data Collection: The methods section mentions that a dried blood specimen will be collected from a subsample of South African participants. It would be helpful to specify how this subsample will be selected and how the blood samples will be used in the analysis. 

Response: We apologize that the previous version did not clearly state how we would select the subsample. We identified 3 sites (one in each province) within our 18 participating facilities that had providers who were willing to attend training and create DBS using the venous samples they collected as part of the routine blood test performed at ART initiation. Clients enrolling at these facilities who meet the inclusion criteria for PREFER and enroll on their day of ART initiation after the necessary supplies to create DBS specimens are procured and facility staff have been trained will be enrolled consecutively. We have added language to clarify this (page 8) and to describe how we will use the data to estimate the proportion who have evidence of recent ART usage (page 9).

3. Potential Improvements. The research protocol could employ Focus Group Discussions (FGDs) to understand the reasons behind loss from care in the first six months after antiretroviral (ART) initiation, this comes along with quite a number of limitations of FGDS;                                       

Proposed research questions.

 

a) Why is the early treatment period (first six months of ART initiation) challenging?

b) How can service delivery be amended to address the obstacles that lead to early disengagement from care?

c) What are the patient's preferences for healthcare services during the initial six months of ART treatment.?

d) What are the barriers encountered by naïve patients to those facing re-initiators? The information collected by PREFER will help respond to patients’ needs design better strategies for service delivery and improve resource allocation going forward.

Response: Thank you for this suggestion. The research protocol does employ FGDs, as described on page 7. Your suggested research questions are similar to those in our FGD guide, which we have now added as a supplemental file. In addition, after submitting the original version of this manuscript for review, we decided to include a brief discrete choice experiment for focus group participants. This is now described in detail in the same section of the manuscript.

4. Ethical Considerations: While the manuscript mentions that the study was approved by relevant ethics committees, it would be beneficial to provide more information about the informed consent process, including how participants were informed about the study and their rights as participants.

Response: The informed consent process is described on page 6. To provide the additional information requested, we have now added the following sentences:

“Participants will also be informed of the risks or discomforts that may come from study participation, their rights as participants, data security and confidentiality, and information to contact the study team if questions or concerns arise.”

“Participants will be offered light refreshments during the study and will be given a token valued at approximately US$10 to thank them for their time and participation.”

5. Data Management: The manuscript briefly discusses data management but does not mention data security and privacy. It would be important to highlight the steps taken to protect the confidentiality and privacy of participants' data.

Response: Thank you for this suggestion. We have added the following paragraph to the data management section (page 9):

“Data for this study will be accessible only by key study personnel. Study ID numbers will be used in place of names or identifying information to safeguard participants’ privacy. All physical consent forms, questionnaires, and notes will be stored in locked cabinets, with access restricted to study personnel. All data will be collected on encrypted devices and stored on secure drives, with access restricted to study personnel. A fully anonymized data set may be posted to a public data repository when the protocol has been closed, if required by the funder and journal.”

6. Data Analysis: The manuscript outlines the planned data analysis, including both quantitative and qualitative components. However, it would be helpful to mention specific statistical methods that will be used for data analysis.

Response: Page 9 of the manuscript lays out the analysis plan, including proposed general methods. More specific statistical methods will depend to some extent on the data, and in particular our success in linking survey data and medical records for each participant. As is described in the manuscript, we expect to perform crude and adjusted log-linear regressions. Other methods may be used as deemed relevant by the study team once data have been cleaned and descriptive statistics generated. 

7. Conclusion: The conclusion section effectively summarizes the study's objectives and potential impact on improving retention in HIV care. The manuscript could elaborate on the broader implications of the study's findings for HIV programs in sub-Saharan Africa.

Response: Thank you for this suggestion. We did describe our plan to disseminate findings from this work (page 10). It is difficult to discuss the implications of the research before we know the results. To better explain the potential implications, though, we have outlined how we plan to engage local stakeholders with our findings prior to moving to phase 2 of the Retain6 project, as follows:

“Once the analysis has been completed, we expect to disseminate the findings from this research as broadly as possible in countries facing similar challenges with early treatment outcomes as those faced by South Africa and Zambia. Findings will be reported at project transition workshops held for local stakeholders in each country, including recipients of care, Ministries of Health, implementing partners and research organizations. Policy briefs will also be available on the Retain6 website. Within Retain6, we expect to use the information collected by PREFER to inform the second phase of the project, during which we will evaluate interventions to improve early treatment outcomes. The information collected by PREFER will also help policy makers and program managers respond to patients’ needs and design better strategies for service delivery and improve resource allocation going forward.”

8. Tables and Figures: It would be beneficial to include tables or figures to visually represent key information, such as the study sites, participant demographics, or the data collection process.

 

Response: Thank you. Table 1 describes the study sites. We do not yet have information about participant demographics, as this is a protocol for prospective enrollment. We have added a figure to visually represent the data collection process (Figure 1) and hope that this will improve the clarity of our manuscript.

9. References: Unable to comment on the references as the journal review guidelines do not mention the type of referencing required.

Response: None needed

10. Overall, the manuscript provides a well-structured and informative research protocol.

Response: We thank the Reviewer for this summary.