Recommendations and guidance on hepatitis C virus self-testing: web annex C: hepatitis C virus self-testing: systematic review report

RECOMMENDATIONS AND GUIDANCE ON HEPATITIS C VIRUS SELF-TESTING July 2021 Web Annex C. Hepatitis C virus self-testing: systematic review report Virginia A. Fonner, Hunied Kautsar, Ingrid Eshun-Wilson, Katherine McGee, Nandi Siegfried, Muhammad S. Jamil, Niklas Luhmann, Cheryl Johnson, Rachel Baggaley Recommendations and guidance on hepatitis C virus self-testing. Web Annex C. Hepatitis C virus self-testing: systematic review report/ Virginia A Fonner, Hunied Kautsar, Ingrid Eshun-Wilson, Katherine McGee, Nandi Siegfried, Muhammad S Jamil et al. ISBN 978-92-4-003116-6 (electronic version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. 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The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. This publication forms part of the WHO guideline entitled Recommendations and guidance on hepatitis C virus self- testing. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014). 1 Hepatitis C self-testing: A systematic review report Virginia A. Fonner1, Hunied Kautsar2, Ingrid Eshun-Wilson3, Katherine McGee4, Nandi Siegfried5, Muhammad S. Jamil6, Niklas Luhmann6, Cheryl Johnson6, Rachel Baggaley6 1 Medical University of South Carolina, Charleston, SC, USA 2 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 3 University of Washington St. Louis, St. Louis, MO, USA 4 London School of Hygiene and Tropical Medicine, London, UK 5 Independent methodologist, Cape Town, South Africa 6 World Health Organization, Geneva, Switzerland 2 Contents 1. Background ......................................................................................................................................... 4 2. Methods ............................................................................................................................................... 4 2.1 PICO question .................................................................................................................................. 4 2.2 Review outcomes .............................................................................................................................. 5 2.3 Inclusion criteria, search strategy, screening, and data extraction ................................................ 5 2.4 Review of HIV self-testing evidence ................................................................................................. 6 2.5 Values and preferences review ........................................................................................................ 7 2.6 Feasibility and resource needs ........................................................................................................ 7 2.7 Role of independent methodologist .................................................................................................. 8 3. Results ................................................................................................................................................. 8 3.1 HCVST effectiveness review ............................................................................................................ 8 3.2 HIVST systematic review ................................................................................................................. 9 3.2.1 Summary of outcomes from RCTs ........................................................................................ 10 3.2.2 Observational study among PWID ........................................................................................ 10 3.3 Values and preferences – users and providers .............................................................................. 11 3.3.1 Results from HCVST Review ............................................................................................... 11 3.3.2 Community HCVST studies.................................................................................................. 11 3.3.3 Values and preferences review from HIVST ........................................................................ 11 3.4 Feasibility ...................................................................................................................................... 12 3.4.1 Results from HCVST review ................................................................................................ 12 3.4.2 Studies on HCVST usability ................................................................................................. 12 3.5 Resource use and cost effectiveness ............................................................................................... 12 3.6 Equity and human rights ................................................................................................................ 12 3.7 Evidence-to-Decision table ............................................................................................................ 13 3.8 Recommendation ............................................................................................................................ 14 4. Conclusions ....................................................................................................................................... 15 5. Limitations and gaps ........................................................................................................................ 16 6. References ......................................................................................................................................... 17 7. Appendices ........................................................................................................................................ 22 Appendix 1. Published literature search strategy ................................................................................... 22 Appendix 2a. Trial registry search ......................................................................................................... 24 Appendix 2b. Conference abstract search .............................................................................................. 24 Appendix 3. HIVST review results .......................................................................................................... 25 Appendix 4. Ranking of outcomes ........................................................................................................... 51 3 Appendix 5. Characteristics of values and preferences articles for HCVST review .............................. 52 4 1. Background The WHO guidelines on testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) were last updated in February 2017(1) and focused on facility- and community-based testing approaches needed to achieve WHO elimination goals (2). These guidelines highlighted the potential of hepatitis C self-testing (HCVST) to expand hepatitis testing services. Despite recent advances in highly effective and affordable HCV treatment, many people with HCV do not know their status due to limited access and low uptake of testing services. The progress to date has been far from achieving the 2030 coverage targets of 90% diagnosis and 80% treatment for those infected. As of 2021, only 26% of the estimated 58 million people living with HCV knew their status, and approximately 9.4 million people have been treated between 2015-2019 (3). Moreover, some countries that have developed strong national programs aiming to eliminate HCV as a public health threat have seen testing uptake plateau or have faced challenges reaching key populations. Therefore, new and innovative approaches are required to find the remaining people with HCV and link them to treatment. Approaches that can reduce the HCV testing gap are essential to achieving HCV elimination targets and expanding testing and treatment. Self-testing is one such approach. Self-testing is a process whereby an individual collects their own specimen and then performs a simple rapid test and interprets their own result. Those with a reactive HCVST result will need further testing to confirm viremia and clinical assessment before treatment initiation in accordance with the national algorithm. Over the past five years, HIV self-testing (HIVST) has been successfully implemented in a range of settings and has proved effective in reaching populations who would not otherwise test for HIV. In 2016 WHO first recommended HIVST as an additional approach to HIV testing services (4). In 2019, WHO updated the recommendation based on a review of 32 randomized controlled trials (RCTs) and provided guidance and operational considerations on service delivery models (5). Building on the guidance and lessons learned from HIVST implementation, several small studies have explored the acceptability, usability, and feasibility of HCVST in a range of priority settings and populations (6, 7). However, WHO guidance on HCVST is needed to inform national policy decisions and implementation. As seen with HIVST, three times as many countries implemented HIVST between 2017–2020 following the release of WHO guidance. Therefore, in this systematic review, we aimed to address whether HCVST should be offered as an additional testing approach to HCV testing services. 2. Methods 2.1 PICO question Should HCV self-testing be offered as an additional HCV testing approach? P Populations receiving HCV testing services I HCV testing services that include self-testing C Standard facility-based HCV testing services O Listed below Box 1. Prior WHO HIVST recommendations 2016: 5 RCTs HIVST should be offered as an additional approach to HTS (strong recommendation, moderate quality evidence) 2019: 32 RCTs HIVST should be offered as an approach to HTS (strong recommendation, moderate quality evidence) 5 2.2 Review outcomes The following outcomes were selected and ranked in order of relative importance and priority by the Guidelines Development Group (GDG) in consultation with WHO. The ranking used a scale of 1–9 to consider what was most critical to patients or end-users who may be directly affected by the recommendation (1–3 NOT IMPORTANT; 4–6 IMPORTANT; 7–9 CRITICAL). 1. Uptake of HCV testing services: proportion of participants who completed HCV testing among those randomized in a specified time frame (GDG ranking 7.8 – critical) 2. Positivity: proportion of people diagnosed with HCV or proportion of people who had a reactive HCV antibody test (self-test, rapid test or enzyme immunoassay (EIA)) among those randomized (adjusted to exclude people aware of their HCV chronic infection status before testing and/or on treatment) (GDG ranking 6.4 – important) 3. Linkage to additional testing (testing by a trained provider) after reactive HCVST results, including a) additional antibody testing and/or b) viral load (PCR) and/or HCV core Ag testing to confirm chronic infection (GDG ranking 8.0 – critical) 4. Linkage to clinical assessment and/or treatment initiation among those randomized (GDG ranking 8.0 – critical) 5. Number/proportion cured or initiated and completed treatment among those randomized or diagnosed with chronic HCV infection (GDG ranking 7.4 – critical) 6. Misuse related to HCV testing e.g., coercion or forced testing (GDG ranking 5.8 – important) 7. Social harm or adverse events related to HCV testing e.g., relationship breakdown, violence (including intimate-partner violence, violence from family members, or community members, etc.), psycho-social harm, self-harm, economic harm, suicide, stigma, discrimination (GDG ranking 6.4 – important) 8. Device-related issues e.g., test failure, injury, acceptability, etc. (GDG ranking 6.6 – critical) 2.3 Inclusion criteria, search strategy, screening, and data extraction We conducted a comprehensive, systematic search of the published literature, conference abstracts and grey literature regarding studies assessing the effectiveness of HCVST following methods and reporting outlined by PRISMA (8). The protocol was prospectively registered with PROSPERO (CRD42021235825). Inclusion criteria To be included in the review, an article must have met the following criteria: 1. Study design that compares people who received HCV testing using self-tests to people who received testing through standard facility-based testing services. 2. Measures one or more of the outcomes of interest (described above). 3. Published in a peer-reviewed journal or conference abstract, or part of an ongoing trial with unpublished results. 6 Exclusion criteria Review articles, editorials, commentaries, opinion pieces and other articles not including primary data were excluded. Relevant review articles were retained as background material. The reference lists of these articles were screened to identify relevant citations. No restrictions were placed based on location of the intervention, and no language restrictions were used on the search. Search strategy The search strategies for HIVST from prior WHO systematic reviews were adapted for HCVST, and search terms were refined by an information specialist (Appendix 1). The following electronic databases were searched from January 1, 2010 through to December 16, 2020: PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO and Scopus (includes EMBASE and Medline). We also searched 20 global, regional, and national trial registries to identify ongoing studies (Appendix 2a), and we searched for conference abstracts from 13 global and regional conferences (Appendix 2b). Search terms used for trial registries and conference abstract searches contained a simple string of terms, such as “hepatitis C” and “self-test” due to limited search feature in these platforms. Further, we contacted experts in the field to identify additional articles, unpublished or ongoing studies that were not identified through other search methods. Screening and data extraction Titles, abstracts, citation information, and descriptor terms of citations identified through the search strategy were screened by one member of the senior study staff. Full-text articles were obtained of all selected citations and two independent reviewers assessed full-text articles for eligibility; differences were resolved through consensus. Data were to be extracted using standardized data extraction forms, with risk of bias for RCTs assessed through the Cochrane Collaboration’s risk of bias tool (9) and the ROBINS-I tool used to assess risk of bias within non-randomized studies (10). 2.4 Review of HIV self-testing evidence A decision was made a priori in consultation with the Guidelines Steering Committee and the GDG to include data from the HIVST evidence base to inform the HCVST review, given its relevance to HCVST and the rigorous systematic review procedures that were established for HIVST for the 2019 WHO guidelines on HIV testing services (5). Given that the review methods for HIVST were set up as a living review (11, 12), results were updated through June 2020. The methods for this review are described in more detail elsewhere (11), in brief the review assessed for risk of bias using the Cochrane Collaboration’s risk-of-bias tool for randomized studies (9), and outcomes were synthesized using random effects meta-analysis. A GRADE profile was created for each outcome using GRADE Pro Software, and the GDG and an independent methodologist were consulted regarding all certainty assessments. In order to maximize relevance between the HIVST and HCVST, comparable outcomes included in both reviews were identified (Table 1), including uptake, positivity, linkage to additional testing, linkage to care/treatment, misuse of self-testing, and harms (including social harms and adverse events). Stratified outcomes by population type (general and key populations1 were analyzed and presented, as both population groups are at heightened risk for HCV in different settings, including people who inject drugs (PWID), men who have sex with men (MSM), and the general population in certain high prevalence settings. In addition to randomized studies that were focus of the HIVST review, observational 1 Key populations include men who have sex with men, people who inject drugs, people in prisons and closed settings, sex workers and transgender people. 7 studies were searched to identify any HIVST studies that were conducted among PWID as this was identified as a priority population for HCV. Table 1. Comparable outcomes included in HCVST and HIVST reviews HCVST outcomes HIVST Outcomes Uptake of testing services Uptake of testing services Positivity Positivity Linkage to additional testing Linkage to additional testing Linkage to clinical assessment and/or treatment initiation Linkage to clinical assessment and treatment initiation Number/proportion cured (or who completed treatment) Not applicable to HIV Misuse related to HCV testing (e.g., coercion or forced testing) Misuse of self-tests Social harm or adverse events related to HCV testing Social harm or adverse events related to HIV self-testing (includes device-related issues) Device related issues (e.g., test failure, injury, etc.) Condom use or condomless sex 2.5 Values and preferences review Data for the values and preferences review were identified through three sources: 1. HCVST systematic review: The same search terms described above for the HCVST review were used to identify studies to be included in the values and preferences review. Studies identified during the search that did not meet the inclusion criteria for the effectiveness review but did include primary data—qualitative or quantitative—related to the acceptability of HCVST were included. These included studies that involved participants using HCVST or those that asked hypothetical question(s) about interest in HCVST or HCVST use. Studies were also included if they discussed the acceptability of aspects relevant to HCVST (e.g., self-sampling, use of oral fluid-based tests, and community-based testing using rapid diagnostic tests), regardless of whether self-testing was performed. Studies relevant to values and preferences were catalogued and coded using a coding form collecting data on study location, population, study design, results, and whether participants performed HCVST. 2. Community-based studies: We also reviewed and summarized unpublished studies from community organizations and networks relevant to HCVST values and preferences, including conference abstracts and data from commissioned studies led by Foundation for Innovative Diagnostics (FIND). 3. HIVST systematic review: We reviewed the values and preferences literature identified as part of the HIVST review and summarized the relevant data. 2.6 Feasibility and resource needs We summarized data related to HCVST feasibility studies, as well as those related to relevant aspects of self-testing, such as self-sampling, use of oral fluid-based tests, and community-based rapid testing. For cost and resource needs, we summarized findings from a commissioned HCVST cost-effectiveness study. The full reports on feasibility and resource needs are presented as separate web annexes (see Annexes C and E). 8 2.7 Role of independent methodologist The WHO and review team were supported by an independent methodologist contracted by WHO. The methodologist advised the review team on analytical decisions, and synthesis and grading of evidence. The methodologist also facilitated the GDG discussion and formulation of recommendations. 3. Results 3.1 HCVST effectiveness review The databases and grey literature search yielded 1039 unique citations. The full text of fifty-seven articles was assessed for eligibility, but no articles met the inclusion criteria (Figure 1). Figure 1. Flowchart of study inclusion for HCVST systematic review Records identified through database searching (n=1110) Additional records identified through conference abstracts and grey literature searching (n=1) Records screened (n=1039) Records after duplicates removed (n=1039) Full text articles assessed for eligibility (n=57) Records excluded (n=983) Studies included in quantitative synthesis (n=0) Full-text articles excluded (n=57) because: • Did not involve self-testing (n=20) • No intervention (n=8) • No primary data (editorial or commentary) (n=4) • Not relevant to HCV testing (n=3) • No relevant comparator (n=2) • Ineligible but included as background: o Relevant review (n=12) o Values and preferences (n=5) o Cost-effectiveness (n=2) Id en ti fi ca ti o n Sc re en in g El ig ib ili ty In cl u d ed 9 3.2 HIVST systematic review Twenty-seven RCTs were included that compared HIVST to standard (i.e., facility-based) testing (Figure 2) (13-39). Results from HIVST review that were included in GDG discussion are presented in Appendix 3, including summary of study characteristics, forest plots and GRADE evidence profiles. The included studies comprised a large body of evidence representing diverse settings, populations, and delivery models of HIVST. Key populations represented in the studies included MSM and transgender people (n=7) (only a small proportion of sample were transgender people), and female sex workers (n=3). Summary of results from the HIVST review that are comparable to prioritized HCVST outcomes are presented below. The GDG ranking of outcomes is presented in Appendix 4. No RCTs were conducted among PWID, we identified one observational study from Ukraine pertaining to HIVST among PWID (40). Figure 2. Flowchart of study inclusion for HIVST systematic review 10 3.2.1 Summary of outcomes from RCTs Uptake of testing was reported in 26 RCTs, including 10 among the general population and 16 among key populations. The pooled-effect size across studies showed greater testing uptake overall with HIVST as compared to facility-based testing (relative risk (RR)= 1.77, 95% confidence interval (CI): 1.55–2.01; moderate certainty of evidence). The uptake was slightly higher among the general population. Positivity (confirmed HIV-positive diagnosis was preferentially used but included unconfirmed or self- reported diagnosis if not available) was reported in 18 RCTs, including nine among general populations and nine among key populations. Overall, HIVST compared to facility-based testing found higher rates of HIV positivity (RR=1.70, 95% CI: 1.13–2.56; moderate certainty of evidence). The results were consistent for the general population and MSM/TGW but there was no difference in positivity rate for female sex workers. Linkage to additional or confirmatory testing after reactive HIVST results were synthesized across individuals randomized to HIVST only. Results were used from the 2019 systematic review as this outcome was not updated in 2020. This outcome was reported within seven trials. A pooled estimate from these seven trials showed 65% (25–76%) of those with reactive HIVST results reported confirmatory testing within two weeks to 5 months. (There was low certainty of evidence.) Linkage to ART initiation or clinical assessment was reported in 12 studies (six among general populations and six among key populations). Overall, there was no difference in linkage rate comparing HIVST to standard testing (RR=1.22, 95% CI: 0.81–1.84; moderate certainty of evidence). Results were largely similar across populations. Regarding the misuse of HIV self-tests, synthesized results from the 2019 review (the outcome was not updated in 2020) among two studies found very few instances of test misuse. Four instances of coercion were reported out of 13 267 participants in one study (41), and no reports of coercion were reported in the other study with 1063 participants (42). Regarding adverse events, the occurrence of intimate partner violence (IPV) was pooled across nine studies as this was most commonly reported in included RCTs and was suitable for meta-analysis. There was no difference in IPV comparing HIVST to standard testing (RR=0.92, 95% CI: 0.60-1.12; moderate certainty evidence). The overall number of adverse events reported was small. Other reported harms included separation between couples and discrimination by family members. Social harms were often exacerbated by pre-existing conditions within a couple, such as alcohol abuse and a history of gender- based violence. Many events were of a temporary nature (for example temporary separation between couples) and resolved. There were no reports of suicide across all studies. 3.2.2 Observational study among PWID In addition to the RCT data, one observational study specific to PWID compared routine program data across three waves of HIV testing (n= 378 425 PWID with a total of 844 837 HIV tests conducted)(40). The first wave of HIV testing (2013–2014) involved standard testing performed by trained health workers at NGO service delivery points close to PWID communities. The second wave (2015–2017) involved directly assisted self-testing and “task-shifting” from the previous approach that involved testing done by social workers, often peers. The third wave (2016–2017) involved optimized HIV case finding in which PWID were made active partners in the recruitment mechanism for HIV testing by incorporating financial incentives in partner recruitment for testing. The study found that HIV testing more than tripled after engagement of PWID and their peers, specifically after implementation of directly assisted self-testing and optimized HIV case finding. 11 3.3 Values and preferences – users and providers 3.3.1 Results from HCVST Review Five studies were identified in the HCVST review containing findings relevant to values and preferences (Appendix 5). Of these one was published in 2021 after our search was performed and was identified through expert recommendation. Four took place in Europe involving populations including people who use drugs, hepatology/infectious disease outpatient clinic, youth offenders (7, 43-45); one study took place among the general population in South Africa (46). Two studies described the acceptability of self-sampling for HCV testing, including having participants self-collect blood specimens and prepare dried blood spot specimens (43, 45). One study involved oral- fluid based testing for HCV conducted by trained nurses (44). These studies found that self-sampling and oral fluid-based tests were both feasible and acceptable. The remaining two studies assessed the acceptability of HCVST (7, 46). These studies showed that populations, including members of the general population in South Africa (46), current or former drug users in England, and key stakeholders involved in HCV testing delivery (7), found HCVST valuable. Participants appreciated the immediacy of results, ability to conduct the test in private, ease of use, and the ability to make autonomous decisions about care. There were some concerns about confusing test instructions, ensuring supported pathways to care, and how to manage an uncertain result. 3.3.2 Community HCVST studies FIND conducted a multi-country, community-based rapid qualitative assessment to understand values and preferences for HCVST among various priority population groups for HCV (see Annex D). These studies took place across 11 countries and involved individual and group interviews and participatory action research with approximately 1000 potential users (PWID, MSM, general population) and healthcare workers (6). Participants felt that there was an overall lack of knowledge regarding HCV and that governments were perceived as not investing enough in HCV treatment. Participants felt HCVST was an innovative tool that could help raise awareness, motivate end-users to access confirmatory testing, demand treatment, and modify risk-related behaviors. Participants also felt that implementation of HCVST should be accompanied by HCV awareness campaigns. The main perceived benefits of HCVST included: ability to test in private, confidential results, and ability to make autonomous decisions on further treatment decisions. The main perceived barriers included: the need to seek confirmatory testing (although this is true with any initial HCV test), the lack of established HCV care and supportive testing pathways overall, possibility of performance errors, and the lack of pre/post counseling given the potential risk for psychosocial harms. Healthcare workers felt HCVST could be a safe way to increase early diagnosis and access to HCV treatment. Participants felt that the test should be available free of cost and that distribution and marketing should be tailored and context-specific, with an emphasis on avoiding stigma for marginalized groups. 3.3.3 Values and preferences review from HIVST Results from the HIVST values and preferences review were largely consistent and complementary to the aforementioned results specific to HCVST (5, 47). In the HIVST literature, there is a preference for kits with clear and simple instructions with discreet packaging, particularly among key populations. There is also a desire for choice in service delivery models, as well as a desire for high-quality kits. There was no clear preference for oral fluid-based or blood-based self-tests. 12 3.4 Feasibility 3.4.1 Results from HCVST review Several identified articles in the HCVST review have demonstrated that critical aspects of HCVST are feasible. These include: (1) ability of people to self-collect specimens for testing, such as through the self- preparation of dried blood spots (45, 48-50); (2) acceptability and feasibility of using oral fluid-based tests (44, 51, 52), and (3) feasibility of conducting rapid, point-of-care HCV tests in community-based settings (53-63). 3.4.2 Studies on HCVST usability FIND conducted observational studies to assess HCVST usability in five countries among 775 participants: Egypt (general population); China (MSM); Kenya (PWID); Viet Nam and Georgia (PWID and MSM)(64). The studies used a prototype HCVST kit that contained the oral fluid OraQuick® HCV Rapid Antibody Test with instructions for use that had been adapted for self-testing by the manufacturer. There was generally high acceptability, with four sites reporting >90% of participants would recommend HCVST to friends and family. Usability was also high, with errors most commonly observed in sample collection. While most participants were able to successfully complete all steps when conducting the test independently, the majority of PWID from Viet Nam and Kenya required assistance in performing HCVST. The proportion of participants who found HIVST very easy or easy to conduct ranged from between 55% to 66% in Egypt and Kenya, respectively, and was more than 80% in the other sites (see Annex C)(64). 3.5 Resource use and cost effectiveness A cost-effectiveness study was conducted using a decision-analysis model with a one-year time horizon to examine drivers of cost of diagnosis or cure with the introduction of HCVST in four settings: China: MSM, HCV antibody prevalence 1%; Georgia: men aged 40–49 years, prevalence 23%; Viet Nam: PWID, prevalence 60%; and Kenya: PWID, prevalence 13%. The cost of HCVST was assumed to be US$5/test for oral-fluid and US$1.50/test for blood-based tests. Facility-based testing costs ranged between US$2 and US$21 in different settings. Results showed that HCVST increased the number of people tested, diagnosed, and cured, but at higher cost. The study also found that the cost per diagnosis using HCVST was more expensive than standard of care. The incremental cost per diagnosis was US$104 in Viet Nam, US$163 in Georgia, US$587 in Kenya, and US$2647 in China, with variations driven by differences in prevalence in each setting. Variations in incremental cost per cure were driven by differences in treatment costs across the four settings. In summary, the cost per HCV diagnosis and cure was higher using self-testing, but more people were diagnosed. HCVST is likely to be more cost-effective in high-prevalence settings (see Annex E) (65). 3.6 Equity and human rights The GDG discussed the potential of HCVST to increase equity by reaching those who prefer self-testing or have difficulties accessing standard testing services. It was particularly noted that HCVST could reach people who are missed by existing approaches, such as key populations who are disproportionality affected by HCV and yet often have low testing and treatment coverage. The potential impact HCVST can have on maintaining essential services during COVID-19 services during restrictions was also noted as an important benefit and strategy to improve equitable access. Drawing from lessons learned and experiences from HIVST, the GDG concluded that HCVST can likely improve equity and reach those who may not otherwise test. 13 3.7 Evidence-to-Decision table Table 2a. Evidence-to-Decision table summary Question Judgement 1. Is the problem a priority? Yes 2. How substantial are the benefits? Moderate to large, but varies across populations 3. How substantial are the harms? Trivial or small 4. What is the overall certainty of the evidence? Moderate (downgraded for ROB, noted to be indirect from HIVST but sufficiently similar not to downgrade) 5. What is the balance between benefits and harms? Favours HCVST 6. How do people value HCVST? Possibly important 7. How large are the resource requirements (costs)? Moderate to large costs, but varies by setting 8. What is the certainty of the evidence for the costs? Not assessed 9. Is HCVST cost-effective? Favors or probably favors HCVST 10. What would the impact be on health equity? Increased 11. Is HCVST acceptable to all stakeholders? Probably yes 12. Is HCVST feasible to implement? Yes Table 2. Evidence-to-Decision table, detailed Factor Explanation/Evidence Judgement/ certainty Benefits and harms • No direct evidence for benefits/harms specific to HCVST. • HIVST evidence from 27 RCTs demonstrate: • Greater uptake of testing and increased positivity with HIVST overall and among general population and some key populations (uptake: RR=1.77, 95% CI: 1.55–2.01; positivity: RR=1.70, 95% CI: 1.13– 2.56). • No difference in linkage to treatment/care (RR=1.22, 95% CI: 0.81–1.84; low certainty). • Overall greater absolute number of people were diagnosed and linked to care with HIVST. • No difference in adverse events (harms). Harms were rare, often temporary. No suicide reported. • No evidence available related to the number/proportion cured of HCV. • One observational study among PWID found increased testing following assisted self- testing/peer engagement. Moderate to large benefits, but varies across populations Harms are small or trivial Balance between benefits and harms favors HCVST Overall moderate certainty of evidence Values and preferences • Findings complementary from community-based studies, HCVST review, and HIVST review: • Disparate populations across settings see value in self-testing for HCV. • Advantages: Ease of use, private, immediate results, confidential, autonomous decisions, potential to increase HCV awareness, education and treatment demand. Intended users and providers value HCVST Minor variability 14 • Potential drawbacks: Need for confirmatory testing, potential for misinterpretation, concerns related to accuracy. • Preferences: Need for clear/easy to understand instructions, supportive pathway to care, free of charge, non-stigmatizing delivery models, not using a “one size fits all” approach, and choice in delivery models and support tools. • HCWs support HCVST introduction but some concerns. Feasibility • Pilot studies suggest high usability and acceptability for HCVST. • Results from HCVST review found studies have successfully implemented testing modalities somewhat related to self- testing (e.g., self-collection for DBS, community-based testing using RDTs, oral-fluid tests). • HIVST experience demonstrates rapid expansion in self- testing policies and programs. HCVST is feasible to implement and is probably acceptable to stakeholders Resource use • Unit cost of HCVST varied and estimated to be US$2-US$6. • Cost-effectiveness analysis suggests HCVST costs more than standard testing but reaches more people. • Costs are driven by background HCV prevalence as well as referral pathway. Resource requirements vary, ranging from moderate to large Cost-effectiveness favors or probably favors HCVST Equity • HCVST has the potential to increase equity by reaching those who have no other access to testing services HCVST has potential to increase equity Recommendation Yes In favor of HCVST (by consensus) Strength Strong (by consensus) 3.8 Recommendation Based on this review, as well as additional evidence reviewed by the GDG, the following recommendation was formulated. The GDG then assessed the evidence from effectiveness reviews and determined it to be of moderate certainty. By consensus, the GDG decided to unanimously recommend HCVST with additional remarks to address critical implementation considerations (see Box 2). Box 2. WHO recommendation on HCV self-testing (HCVST) NEW RECOMMENDATION HCV self-testing should be offered as an additional approach to HCV testing services. (Strong recommendation, moderate certainty evidence) Remarks • HCVST needs to be followed by linkage to appropriate post-test services, including confirmation of viraemic infection, treatment, care and referral services, according to national standards. • It is desirable to adapt HCVST service delivery and support options to the national and local context, which includes community preferences. • Communities, including networks of key and vulnerable populations and peer-led organizations, need to be meaningfully and effectively engaged in developing, adapting, implementing and monitoring HCVST programmes. 15 Rationale for certainty of evidence decision Considering the evidence on effectiveness of HCVST, its acceptability, feasibility to implement the intervention, and potential for cost-effectiveness and improving equity, the GDG deemed that overall benefits of HCVST outweigh the potential harms and risks. The certainty of evidence was determined through the GRADE approach (66) and in consultation with the GDG. Because HIVST evidence was reviewed, the GDG reached consensus that HIVST evidence should not be downgraded for indirectness as it was deemed sufficiently similar to HCVST in terms of the intervention, outcomes and populations. Offering HCVST as an additional testing option within HCV testing services was assessed to have moderate to large benefits with minimal potential for harm. The GDG noted large gaps in existing HCV testing coverage. As to implementation considerations, the GDG considered this intervention feasible and adaptable for effective delivery in priority populations and settings. 4. Conclusions Benefits and harms Although no direct evidence regarding the benefits and harms of HCVST was identified, evidence from the HIVST systematic review found that across 27 RCTs, HIVST increased uptake of testing and overall positivity as compared with standard testing. There was no difference in rates of linkage to additional testing, linkage to care/treatment or adverse events comparing HIVST to standard testing. Occurrences of test misuse and adverse events were rare. There certainty of evidence was moderate overall, and the GDG decided not to downgrade the evidence for indirectness. Values and preferences Complementary and supportive findings were identified through HCVST review, the HIVST review, and community-based studies. Results suggest that HCVST holds value for diverse populations and stakeholders in various settings. Overall participants valued ability to test in private, confidential results, autonomous decisions regarding next steps, and increased opportunities for education and demanding treatment. Potential drawbacks included the need for confirmatory testing, the possibility of misinterpretation of results, and doubts on test accuracy. Participants emphasized the need to deliver the tests in a non-stigmatizing manner and provide clear, supportive pathways to care. Feasibility Pilot HCVST suggest high usability and acceptability and feasibility to implement across diverse populations and settings. Several relevant aspects of self-testing from other studies, including the ability of people to collect their own samples for HCV testing, the successful use of oral fluid-based tests, and the feasibility of peer-led, rapid-testing in community-based settings were also noted. Cost-effectiveness The cost-effectiveness analysis suggests HCVST costs more than standard testing but reaches more people. As more people are diagnosed, HCVST is likely to be more cost-effective in high prevalence settings. 16 Equity HCVST has the potential to increase equity by reaching those who prefer self-testing or have difficulties accessing standard testing services. It presents one additional option for testing that could be used in diverse settings and populations. 5. Limitations and gaps This systematic review has certain limitations. The findings were drawn primarily from HIVST evidence which was determined to be sufficiently similar to HCVST in terms of intervention and populations. There are certain differences between HIVST and HCVST – of note – effective treatment is available for HCVST, whereas there is no cure for HIV, thus no evidence was available for this outcome. There is no RCT evidence of HIVST/HCVST use among PWID, an important risk group for HCV. Observational study data on acceptability and usability of HCVST is however available and was reviewed. Our search was comprehensive involving published literature, conference abstracts, and trial registries, possibility of missing some studies can not be ruled out. 17 6. References 1. Guidelines on hepatitis B and C testing. Geneva: World Health Organization; 2017. 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Published literature search strategy PubMed search strategy: ("Hepatitis C"(Mesh) OR hepatitis c(tw) OR "Hepacivirus"(Mesh) OR hepacivirus(tw) OR “Hepatitis, Chronic”(Mesh) OR “Hepatitis, Viral, Human”(Mesh) OR HCV(tw) OR "non-A"(tiab) OR "non-B"(tiab) OR (hepatitis(ti) AND c(ti))) AND (home test*(tw) OR home sampl*(tw) OR home specimen(tw) OR home collection(tw) OR remote test*(tw) OR remote sampl*(tw) OR remote specimen(tw) OR remote collection(tw) OR self-collect(tw) OR self-collected(tw) OR self-collection(tw) OR self-test(tw) OR self- testing(tw) OR HCVST(tw) OR mail test*(tw) OR mail sampl*(tw) OR mail specimen(tw) OR mail kit(tw) OR mail collect*(tw) OR “Dried Blood Spot Testing”(Mesh) OR dried blood spot*(tw) OR “Point-of-Care Systems”(Majr) OR “point-of-care”(tw) OR self-administered(ti) OR “alternative test”(tw) OR “alternative testing”(tw) OR “internet-based testing”(tw)) • Filters/limits: none • Date searched: December 16, 2020 • # of records identified: 689 Scopus search strategy: (hepatitis OR hepacivirus OR HCV OR "non-A” OR "non-B") AND (“alternative test” OR “alternative testing” OR “outside the clinic” OR “internet-based testing” OR (home W/3 "dried blood spot") OR (mail W/3 “dried blood spot”) OR (home W/3 “point of care”) OR (home W/3 collect*) OR (home W/3 sampl*) OR (home W/3 specimen*) OR (home W/3 test*) OR (home W/3 kit) OR (self W/3 collect*) OR (self W/3 sampl*) OR (self W/3 specimen*) OR (self W/3 test*) OR (self W/3 kit) OR (mail W/3 collect*) OR (mail W/3 sampl*) OR (mail W/3 specimen*) OR (mail W/3 test*) OR (mail W/3 kit) OR (remote W/3 collect*) OR (remote W/3 sampl*) OR (remote W/3 specimen*) OR (remote W/3 test*) OR (remote W/3 kit)) • Filters/limits: none • Date searched: December 16, 2020 • # of records identified: 368 Scopus Cut and paste into Advanced Search box: ( TITLE-ABS-KEY ( hepatitis OR hepacivirus OR hcv OR "non-A" OR "non-B" ) ) AND ( ( TITLE-ABS-KEY ( "alternative test" OR "alternative testing" OR "outside the clinic" OR "internet- based testing" ) OR TITLE-ABS-KEY ( ( home W/3 "dried blood spot" ) OR ( mail W/3 "dried blood spot" ) OR ( home W/3 "point of care" ) ) OR TITLE-ABS-KEY ( ( home W/3 collect* ) OR ( home W/3 sampl* ) OR ( home W/3 specimen* ) OR ( home W/3 test* ) OR ( home W/3 kit ) ) OR TITLE-ABS-KEY ( ( self W/3 collect* ) OR ( self W/3 sampl* ) OR ( self W/3 specimen* ) OR ( self W/3 test* ) OR ( self W/3 kit ) ) OR TITLE-ABS-KEY ( ( mail W/3 collect* ) OR ( mail W/3 sampl* ) OR ( mail W/3 specimen* ) OR ( mail W/3 test* ) OR ( mail W/3 kit ) ) OR TITLE-ABS-KEY ( ( remote W/3 collect* ) OR ( remote W/3 sampl* ) OR ( remote W/3 specimen* ) OR ( remote W/3 test* ) OR ( remote W/3 kit ) ) ) ) PsycINFO search strategy: (hepatitis OR hepacivirus) AND (home test* OR self-collect* OR self-test* OR self-sampl* OR HCVST OR mail test*) • Filters/limits: none • Date searched: December 16, 2020 • # of records identified: 14 23 CINAHL search strategy: (hepatitis OR hepacivirus) AND (home test* OR self-collect* OR self-test* OR self-sampl* OR HCVST OR mail test*) • Filters/limits: none • Date searched: December 16, 2020 • # of records identified: 39 24 Appendix 2a. Trial registry search The following trial registries were searched in January 2021: Trial registry Website Clinicaltrials https://clinicaltrials.gov/ WHO ICTRP https://apps.who.int/trialsearch/ PACTR http://www.pactr.org/ ANZCTR https://www.anzctr.org.au/ Cochrane Library https://www.cochranelibrary.com/search Brazilian Clinical Trials Registry (ReBec) https://ensaiosclinicos.gov.br Chinese Clinical Trial Registry (ChiCTR) http://www.chictr.org.cn/index.aspx Clinical Research Information Service (CRiS), Republic of Korea https://cris.nih.go.kr/cris/en/use_guide/cris_introduce.j sp Clinical Trials Registry - India (CTRI) http://ctri.nic.in/ Cuban Public Registry of Clinical Trials (RPCEC) http://registroclinico.sld.cu/en/home EU Clinical Trials Register (EU-CTR) https://www.clinicaltrialsregister.eu/ctr-search/search German Clinical Trials Register (DRKS) http://www.germanctr.de/ Iranian Registry of Clinical Trials (IRCT) http://www.irct.ir/ ISRCTN http://www.isrctn.org/ Japan Primary Registries Network (JPRN) https://rctportal.niph.go.jp/en/ Lebanese Clinical Trials Registry (LBCTR) https://lbctr.moph.gov.lb/ Thai Clinical Trials Registry (TCTR) http://www.clinicaltrials.in.th/ The Netherlands National Trial Register http://www.trialregister.nl/ Peruvian Clinical Trial Registry (REPEC) https://ensayosclinicos-repec.ins.gob.pe/en/ Sri Lanka Clinical Trials Registry https://www.slctr.lk/ Appendix 2b. Conference abstract search Abstracts from the following conferences were searched from January 2010 to December 2020 (availability of data varied by conference): Conference HIV/Viral Hepatitis Co Infection Meeting (sponsored by the International AIDS Society), International Symposium of Viral Hepatitis, African Society for Laboratory Medicine (ASLM). Interest EASL (European Association for the Study of the Liver) Conference AASLD (American Association for the Study of Liver Diseases) Conference INHSU (International Network on Hepatitis in substance users) Conference COLDA (Conference on Liver Disease in Africa) International Symposium of Viral Hepatitis International Viral Hepatitis Elimination Meeting (IVHEM) The Asian Pacific Association for the Study of the Liver (APASL) United European Gastroenterology (UEG week) Indian National Association of Study of the Liver (INASL) 25 Appendix 3. HIVST review results Table 3a. Characteristics of included studies Study/Year Country Sample size HIVST distribution strategy Population Study design Chanda 2017 Zambia 965 HCW facility / peer in community FSW Cluster RCT Choko 2019a Malawi 2349 Partner distribution Male partners of ANC Cluster RCT Choko 2019b* Malawi 12 868 Partner distribution Male partners of ANC, Partners of HIV positive Cluster RCT Dovel 2019* Malawi 484 Partner distribution Partners of HIV positive RCT Dovel 2020* Malawi 5885 HCW at health facility General population Cluster RCT Gichangi 2018 Kenya 1410 Partner distribution Male partners of ANC RCT Indravudh 2018* Malawi 3457 HCW in community General population Cluster RCT Indravudh 2021 Malawi 5490 HCW in community General population Cluster RCT Jamil 2017 Australia 362 HCW at health facility MSM & TGW RCT Katz 2018 USA 230 HCW at health facility MSM & TGW RCT Kelvin 2018 Kenya 549 HCW at health facility Migrant/mobile men RCT Kelvin 2019a Kenya 2262 HCW at health facility Migrant/mobile men RCT Kelvin 2019b Kenya 2196 HCW at health facility FSW RCT Kim 2020 USA 100 HCW in community ER non-reactive HIV test RCT Korte 2020 Uganda 1514 Partner distribution Male partners of ANC Cluster RCT MacGowan 2019 USA 2665 Online ordering & mail MSM & TGW RCT Marwa 2019 Kenya 1410 Partner distribution Male partners of ANC RCT Masters 2016 Kenya 600 Partner distribution Male partners of ANC RCT Merchant 2018 USA 425 Online ordering & mail MSM (18–24yrs) RCT Neuman 2021 Zambia 5005 HCW in community General population Cluster RCT Nichols 2019* Zambia 12 081 HCW in community General population Cluster RCT 26 Ortblad 2017 Uganda 960 HCW facility / peer in community FSW Cluster RCT Patel 2018 USA 100 HCW at health facility ER HIV test decliners RCT Pettifor 2018* South Africa 284 HCW at health facility Women (18–24yrs) RCT Tang 2018 China 1381 Online ordering & mail MSM & TGW Cluster RCT Wang 2017 Hong Kong, SAR China 430 Online ordering & mail MSM & TGW RCT Wray 2018 USA 65 Online ordering & mail MSM & TGW RCT Table 3b. Summary of distribution and support models for included studies Study/Year HIVST delivery method Who distributed HIVST Where HIVST delivered How HIVST delivered Who administered HIVST Testing choice offered? Testing support Additional intervention components Comparison Chanda 2017 Facility & secondary by peer HCW or peer Facility and community/ home In person Participant No Group demonstration 2 HIVST arms: HIVST coupon for facility testing or HIVST delivered to participants by peer Routine facility-based HIV testing Choko 2019a Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No Instruction enhancement, video or study hotline 5 HIVST arms: HIVST only; HIVST+$3; HIVST +$10; HIVST + reminder; HIVST +lottery (Incentives were given to the men) Routine facility-based HIV testing Choko 2019b Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No Instruction enhancement, video or study hotline 2 HIVST arms: HIVST only; HIVST+$10 incentive (Incentives were given to the men, Routine facility-based HIV testing 27 conditional on attendance of HIV treatment or prevention services within 28 days.) Dovel 2019 Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No Instruction enhancement, video or study hotline Passive referral slips for confirmatory testing at facility; disclosure counseling; map to nearest facility Routine facility-based HIV testing Dovel 2020 Facility- based HCW Clinic outpatient waiting room In-person Participant or assisted by HCW No Group demonstration Trained counselor available for post-test counselling. Group test demonstration in waiting room. Routine facility-based HIV testing Gichangi 2018 Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No Instruction enhancement, video or study hotline Advise on partner negotiation and communication Invitation card to partner to attend health services for routine or HIV care Indravudh 2018 Community- based Community volunteers In community door-to- door In-person Participant No In-person demonstration or training HIVST distributers remunerated per HIVST distributed; post- test support provided Routine facility-based HIV testing Indravudh 2021 HCW community- based Community volunteers In community door-to- door In-person Participant No In-person demonstration or training Community participation (village health committees and community Routine facility-based HIV testing 28 volunteers) in leading and developing 7-day HIVST campaign Jamil 2017 Facility- based HCW/ Researcher Health facility/ Research unit In-person Participant No Instruction enhancement, video or study hotline Supported confirmatory testing and counselling for HIV +ve Routine facility-based HIV testing Katz 2018 Facility- based HCW/ Researcher Health facility/ Research unit In-person Participant No In-person demonstration or training Pre- and post-test counseling materials, a list of local HIV- related resources and condoms Routine facility- based HIV testing Kelvin 2018 Facility- based HCW/ Researcher Roadside wellness clinics at transit hubs In-person Participant or assisted by HCW Yes: Routine test / supervised or unsupervised HIVST In-person observation or supervision Pre and post-test counselling (phone); remuneration for completing baseline and post-test questionnaires Routine provider administered rapid HIVT Kelvin 2019a Facility- based HCW/ Researcher Roadside wellness clinics at transit hubs In-person Participant or assisted by HCW Yes: Routine test / supervised or unsupervised HIVST In-person observation or supervision Text messages weekly x 3 informing of HIVST availability; post- test counselling and follow-up of those taking kit home Routine facility-based HIV testing Kelvin 2019b Facility- based HCW/ Researcher Roadside wellness clinics at transit hubs In-person Participant or assisted by HCW Yes: Routine test / supervised or unsupervised HIVST In-person observation or supervision Text messages weekly x 3 informing of HIVST availability; post- test counselling and follow-up of Routine facility-based HIV testing 29 those taking kit home Study/Year HIVST delivery method Who distributed HIVST Where HIVST delivered How HIVST delivered Who administered HIVST Testing choice offered? Testing support Additional intervention components Comparison Kim 2020 Facility- based HCW/ Researcher Health facility/ Research unit In-person Participant No Instruction enhancement, video or study hotline Supported confirmatory testing and counselling for HIV +ve; encouraged to report results on internet based STIs/HIV testing website Pamphlet with routine HIV testing information and local venues Korte 2020 Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No In-person demonstration or training Advise on partner communication; phone counselor; pre- and post-test information and follow-up of those taking kits home Encouraged to invite partner to attend health services for HIV testing MacGowan 2019 Online & mail Website NA Mail Participant No Instruction enhancement, video or study hotline Phone counselor & mental health counselling; online instructional video; remuneration for study activities Website with routine HIV testing information Marwa 2019 Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No In-person demonstration or training Advise on partner communication; linkage to care/counselling for HIV +ve; report use of tests through mobile phones; follow-up of all participants 2 comparison arms: Invitation card for partner to attend clinic to learn about health of wife/partner; Invitation card to partner to 30 attend health services for HIV testing Masters 2016 Secondary HCW to ANC client to partner Facility and community/ home In-person Participant No Instruction enhancement, video or study hotline Advise on partner negotiation and communication Invitation card to partner to attend health services for HIV testing Merchant 2018 Online & mail Website/ study app NA Mail Participant No No or basic support Remuneration for survey completion Routine facility-based HIV testing Nichols 2019 Community- based HCW/ researcher Facility and community In-person Participant No In-person demonstration or training Clinic referral card or escort to health care facility if positive Routine facility-based HIV testing Neuman 2021 Community- based Community volunteers In community door-to- door and from distributor home In-person Participant No In-person demonstration or training CBDAs visit clients after distributing kit to enquire whether the kit has been used, collect the sealed questionnaire and used kit, and provide advice on referral to additional care if the client discloses a reactive HIVST result. Clients also drop used kits in locked boxes within each community Routine facility-based HIV testing Ortblad 2017 Facility & secondary by peer HCW or peer Facility and community/ home In-person Participant No Group demonstration 2 HIVST arms: HIVST coupon for facility testing or HIVST delivered to participants by peer Routine facility-based HIV testing Patel 2018 Facility- based HCW/ researcher Emergency room In-person Participant No No or basic support Results reported on internet-based STIs/HIV testing recruitment. Also Routine HIV testing information pamphlet 31 received five referral cards to give to their peers. Pettifor 2018 Facility- based* HCW/ researcher Health facility/ Research unit In-person Participant Yes: Routine test / HIVST No or basis support Women were given 5 invitations to test for free at local clinics. Routine facility-based HIV testing Tang 2018 Online & mail Social networking mobile phone app NA Mail Participant No Instruction enhancement, video or study hotline Crowdsourcing community mobilization initiative in study cities for intervention design. Additional HIV self-testing promotional text messages Routine facility-based HIV testing Wang 2017 Online & mail HCW/ researcher NA Mail Participant No Online promotional video with virtual real- time supervision Health promotion videos; remuneration for survey completion; live chat application used for supervision Routine facility-based HIV testing with health promotion video Wray 2018 Online & mail Website/ study app NA Mail Participant No No or basic support Monitoring of kit opening with associated counselor follow up in one arm; remuneration for study activities Letter with routine HIV testing information 32 Forest plots Plot 1. Uptake of HIV testing among randomized, HIVST vs standard of care, by population CI: confidence internal; e: number with events; HIVST: HIV self-testing; MSM: men who have sex with men; n: number randomized; RR: rate ratio; SOC: standard of care; TGW: transgender women. 33 Plot 2. HIV positivity rate among randomized, HIVST vs standard of care, by population CI: confidence internal; e: number with events; HIVST: HIV self-testing; MSM: men who have sex with men; n: number randomized; RR: rate ratio; SOC: standard of care; TGW: transgender women. 34 Plot 3. Proportion linked to confirmatory testing after reactive HIVST results – HIVST arm only 35 Plot 4. Linkage to ART initiation or HIV care, HIVST vs standard of care, by population CI: confidence internal; e: number with events; HIVST: HIV self-testing; MSM: men who have sex with men; n: number randomized; RR: rate ratio; SOC: standard of care; TGW: transgender women. 36 Plot 5. Adverse events (intimate partner violence), HIVST vs standard of care, by population CI: confidence internal; e: number with events; HIVST: HIV self-testing; n: number randomized; RR: rate ratio; SOC: standard of care. 37 Risk of bias assessment for included studies, by outcome Table 1: Risk of bias – Uptake Study Sequence Gen Allocation Concealment Blinding Participant/ Personnel (Performance bias) Blinding Outcome Assessment (Detection bias) Attrition Bias Selective Reporting Other Bias Cluster: Recruitment Bias Cluster: Baseline Imbalance Cluster: Loss of clusters Cluster: Incorrect Analysis Overall ROB Chanda 2017 Low risk Low risk High risk Unclear risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Choko 2019a Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Low risk Low Risk Low risk High risk Choko 2019b Low risk Low risk High risk High risk Unclear risk Low risk Low risk High risk Low risk Unclear Risk Unclear risk High risk Dovel 2019 Unclear risk Unclear risk High risk High risk Low risk Low risk Unclear risk High risk Dovel 2020 Low risk Unclear risk High risk High risk Low risk Unclear risk Low risk High risk Unclear risk Low Risk Low risk High risk Gichangi 2018 Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Indravudh 2018 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Unclear risk Low Risk Low risk High risk Indravudh 2021 Low risk Low risk Unclear risk High risk High risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Jamil 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Katz 2018 Low risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kelvin 2018 Unclear risk Low risk High risk Low risk Low risk Low risk Low risk High risk Kelvin 2019a Unclear risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kelvin 2019b Unclear risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kim 2020 Unclear risk Unclear risk Unclear risk Unclear risk High risk Low risk Low risk Some concerns Korte 2020 Low risk High Risk High Risk High risk low risk High risk Low risk High risk Low risk Low Risk Low risk High risk MacGowan 2019 Low risk Low risk High risk High risk High risk Low risk Unclear risk High risk Marwa 2019 Low risk Low risk High risk High risk High risk High risk Unclear risk High risk Masters 2016 Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Merchant 2018 Low risk Unclear risk High risk High risk High risk Low risk Low risk High risk Neuman 2021 Low risk Unclear risk High risk High risk Low risk Low risk Unclear risk Low risk Low risk Low Risk Low risk High risk Ortblad 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk 38 Study Sequence Gen Allocation Concealment Blinding Participant/ Personnel (Performance bias) Blinding Outcome Assessment (Detection bias) Attrition Bias Selective Reporting Other Bias Cluster: Recruitment Bias Cluster: Baseline Imbalance Cluster: Loss of clusters Cluster: Incorrect Analysis Overall ROB Patel 2019 Unclear risk Low risk High risk High risk High risk Low risk Low risk High risk Pettifor 2018 Unclear risk Unclear risk High risk Unclear risk Low risk Unclear risk Low risk High risk Tang 2018 Low risk Unclear risk High risk Low risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Wang 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Wray 2018 Low risk Low risk High risk High risk Low risk Low risk Unclear risk High risk Table 2: Risk of bias – Positivity Study Sequence Gen Allocation Concealment Blinding Participant/ Personnel (Performance bias) Blinding Outcome Assessment (Detection bias) Attrition Bias Selective Reporting Other Bias Cluster: Recruitment Bias Cluster: Baseline Imbalance Cluster: Loss of clusters Cluster: Incorrect Analysis Overall ROB Chanda 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Choko 2019a Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Low risk Low Risk Low risk High risk Choko 2019b Low risk Low risk High risk Low risk Unclear risk Low risk Low risk High risk Low risk Unclear Risk Unclear risk High risk Dovel 2019 Unclear risk Unclear risk High risk High risk Low risk Low risk Unclear risk High risk Dovel 2020 Low risk Unclear risk High risk High risk Low risk Unclear risk Low risk High risk Unclear risk Low Risk Low risk High risk Jamil 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Katz 2018 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Kelvin 2018 Unclear risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kelvin 2019a Unclear risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kelvin 2019b Unclear risk Low risk High risk Unclear risk Low risk Low risk Low risk High risk Kim 2020 Unclear risk Unclear risk Unclear risk Unclear risk High risk Low risk Low risk Some concerns Korte 2020 Low risk High Risk High Risk High risk low risk High risk Low risk High risk Low risk Low Risk Low risk High risk 39 MacGowan 2019 Low risk Low risk High risk Low risk High risk Low risk Unclear risk High risk Masters 2016 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Merchant 2018 Low risk Unclear risk High risk High risk High risk Low risk Low risk High risk Ortblad 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Wang 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Wray 2018 Low risk Low risk High risk High risk Low risk Low risk Unclear risk High risk Table 3: Risk of bias – Linkage Study Sequence Gen Allocation Concealment Blinding Participant/ Personnel (Performance bias) Blinding Outcome Assessment (Detection bias) Attrition Bias Selective Reporting Other Bias Cluster: Recruitment Bias Cluster: Baseline Imbalance Cluster: Loss of clusters Cluster: Incorrect Analysis Overall ROB Chanda 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Choko 2019a Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Low risk Low Risk Low risk High risk Choko 2019b Low risk Low risk High risk Low risk Unclear risk Low risk Low risk High risk Low risk Unclear Risk Unclear risk High risk Dovel 2019 Unclear risk Unclear risk High risk Low risk Low risk Low risk Unclear risk High risk Dovel 2020 Low risk Unclear risk High risk Low risk Low risk Unclear risk Low risk High risk Unclear risk Low Risk Low risk High risk Jamil 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Katz 2018 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Korte 2020 Low risk High Risk High Risk High risk low risk High risk Low risk High risk Low risk Low Risk Low risk High risk 40 MacGowan 2019 Low risk Low risk High risk Low risk High risk Low risk Unclear risk High risk Masters 2016 Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Ortblad 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Wang 2017 Low risk Low risk High risk Low risk Low risk Low risk Low risk High risk Table 4: Risk of bias – Adverse events (intimate partner violence) Study Sequence Gen Allocation Concealment Blinding Participant/ Personnel (Performance bias) Blinding Outcome Assessment (Detection bias) Attrition Bias Selective Reporting Other Bias Cluster: Recruitment Bias Cluster: Baseline Imbalance Cluster: Loss of clusters Cluster: Incorrect Analysis Overall ROB Chanda 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk Choko 2019a Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Low risk Low Risk Low risk High risk Choko 2019b Low risk Low risk High risk High risk Unclear risk Low risk Low risk High risk Low risk Unclear Risk Unclear risk High risk Dovel 2019 Unclear risk Unclear risk High risk High risk Low risk Low risk Unclear risk High risk Korte 2020 Low risk High Risk High Risk High risk low risk Low risk Low risk High risk Low risk Low Risk Low risk High risk Marwa 2019 Low risk Low risk High risk High risk High risk High risk Unclear risk High risk Masters 2016 Low risk Low risk High risk High risk Low risk Low risk Low risk High risk Neuman 2021 Low risk Unclear risk High risk High risk Low risk Low risk Unclear risk Low risk Low risk Low Risk Low risk High risk 41 Ortblad 2017 Low risk Low risk High risk High risk Low risk Low risk Low risk Low risk Low risk Low Risk Low risk High risk GRADE evidence to decision profiles, by outcome Certainty assessment № of patients Effect Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HIVST SOC Relative (95% CI) Absolute (95% CI) Uptake of HIV testing among randomized (overall) 26 a randomised trials b serious c not serious d not serious e not serious none 17670/25507 (69.3%) f 9756/25507 (38.2%) f RR 1.77 (1.55 to 2.01) 295 more per 1,000 (from 210 more to 386 more) ⨁⨁⨁◯ MODERATE CRITICAL Uptake of HIV testing among randomized (general population) 16 g randomised trials h serious i not serious j not serious k not serious none 14030/20076 (69.9%) l 7747/20020 (38.7%) l RR 2.13 (1.75 to 2.59) 437 more per 1,000 (from 290 more to 615 more) ⨁⨁⨁◯ MODERATE CRITICAL Uptake of HIV testing among randomized (men who have sex with men) 7 m randomised trials n serious o not serious p not serious q not serious none 2460/3404 (72.3%) r 1432/3393 (42.2%) r RR 1.38 (1.19 to 1.59) 160 more per 1,000 (from 80 more to 249 more) ⨁⨁⨁◯ MODERATE CRITICAL 42 Certainty assessment № of patients Effect Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HIVST SOC Relative (95% CI) Absolute (95% CI) Uptake of HIV testing among randomized (female sex workers) 3 s randomised trials t serious u not serious v not serious w not serious none 1180/2027 (58.2%) x 577/2094 (27.6%) x RR 1.42 (1.04 to 1.94) 116 more per 1,000 (from 11 more to 259 more) ⨁⨁⨁◯ MODERATE CRITICAL HIV positivity rate among tested (overall) 19 y randomised trials z serious aa not serious ab not serious ac not serious none 413/14023 (2.9%) ad 333/9642 (3.5%) ad RR 0.94 (0.76 to 1.15) 2 fewer per 1,000 (from 8 fewer to 5 more) ⨁⨁⨁◯ MODERATE IMPORTANT HIV positivity rate among randomized (overall) 18 ae randomised trials af serious ag not serious ah not serious ai not serious none 422/13962 (3.0%) aj 151/9487 (1.6%) aj RR 1.70 (1.13 to 2.56) ak 11 more per 1,000 (from 2 more to 25 more) ⨁⨁⨁◯ MODERATE IMPORTANT HIV positivity rate among randomized (general population) 9 al randomised trials am serious an not serious ao not serious ap not serious none 206/9912 (2.1%) aq 39/6131 (0.6%) aq RR 2.34 (1.38 to 3.97) 9 more per 1,000 (from 2 more to 19 more) ⨁⨁⨁◯ MODERATE IMPORTANT 43 Certainty assessment № of patients Effect Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HIVST SOC Relative (95% CI) Absolute (95% CI) HIV positivity rate among randomized (men who have sex with men) 6 ar randomised trials as serious at not serious au not serious av not serious none 33/2023 (1.6%) aw 14/2012 (0.7%) aw RR 2.14 (1.17 to 3.91) 8 more per 1,000 (from 1 more to 20 more) ⨁⨁⨁◯ MODERATE IMPORTANT HIV positivity rate among randomized (female sex workers) 3 ax randomised trials ay serious az serious ba not serious bb not serious none 280/1265 (22.1%) bc 137/1265 (10.8%) bc RR 1.08 (0.50 to 2.34) 9 more per 1,000 (from 54 fewer to 145 more) ⨁⨁◯◯ LOW IMPORTANT Linkage to additional or confirmatory HIV testing (HIVST arm only) 7 bd randomised trials be serious bf serious bg not serious bh not serious none A pooled estimated from 7 studies showed 65% (52% - 78%) of those with a reactive HIVST result (n=497) had confirmatory HIV testing (n=332). ⨁⨁◯◯ LOW CRITICAL Linkage to ART initiation or HIV care among HIV positive (Overall) 12 bi randomised trials bj serious bk serious bl not serious bm not serious none 205/411 (49.9%) bn 80/144 (55.6%) bn RR 0.77 (0.61 to 0.96) 128 fewer per 1,000 (from 217 fewer to 22 fewer) ⨁⨁◯◯ LOW CRITICAL 44 Certainty assessment № of patients Effect Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HIVST SOC Relative (95% CI) Absolute (95% CI) Linkage to ART initiation or HIV care among randomized (Overall) 12 bo randomised trials bp serious bq not serious br not serious bs not serious none 205/12077 (1.7%) bt 80/7661 (1.0%) bt RR 1.22 (0.81 to 1.84) 2 more per 1,000 (from 2 fewer to 9 more) ⨁⨁⨁◯ MODERATE CRITICAL Linkage to ART initiation or HIV care among randomized (general population) 6 bu randomised trials bv serious bw not serious bx not serious by not serious none 139/8962 (1.6%) bz 28/5164 (0.5%) bz RR 1.47 (0.76 to 2.83) 3 more per 1,000 (from 1 fewer to 10 more) ⨁⨁⨁◯ MODERATE CRITICAL Linkage to ART initiation or HIV care among randomized (men who have sex with men) 4 randomised trials ca serious cb not serious cc not serious cd not serious none 23/1838 (1.3%) ce 12/1849 (0.6%) ce RR 1.77 (0.90 to 3.51) 5 more per 1,000 (from 1 fewer to 16 more) ⨁⨁⨁◯ MODERATE CRITICAL Linkage to ART initiation or HIV care among randomized (female sex workers) 2 cf randomised trials cg serious ch serious ci not serious cj not serious none 43/1277 (3.4%) ck 40/648 (6.2%) ck RR 0.56 (0.21 to 1.51) 27 fewer per 1,000 (from 49 fewer to 31 more) ⨁⨁◯◯ LOW CRITICAL 45 Certainty assessment № of patients Effect Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations HIVST SOC Relative (95% CI) Absolute (95% CI) Coercion or misuse of HIVST kits (HIVST arm only) 2 cl randomised trials cm serious cn not serious co not serious cp serious cq none One trial reported 4 instances of coercion or forced to test among 13267 participants. The other trial reported 0 instances of coercion to test or disclose results among 1063 participants. ⨁⨁◯◯ LOW IMPORTANT Adverse events (intimate partner violence) among randomized 9 cr randomised trials cs serious ct not serious cu not serious cv not serious none 80/9223 (0.9%) cw 84/7221 (1.2%) cw RR 0.82 (0.60 to 1.12) 2 fewer per 1,000 (from 5 fewer to 1 more) ⨁⨁⨁◯ MODERATE CRITICAL CI: Confidence interval; RR: Risk ratio 46 Explanations a. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b, Ortblad, 2019 and Wray, 2018 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta- analysis for cluster randomized trials. b. 16 individual randomized trials, 10 cluster randomized trials. c. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in 22 trials and attrition bias in 6 trials (Indravudh, 2021: 23% LTFU in the intervention arm and 21% LTFU in the control arm; Kim, 2020: 56% LTFU in the intervention arm and 46% in the control arm; MacGowan, 2017: 27.1% LTFU in the intervention arm and 28.5% in the control arm; Marwa, 2019: 13–22%, 17–25%, 11–18%, LTFU in three study arms; Merchant, 2018: 38.4% LTFU overall, 26% in the intervention 50% in the control arm; Patel, 2018: 36% LTFU overall, 44% in the intervention and 27% in the control arm). Three cluster randomized trials were subject to recruitment bias. Some risk of bias domains were unclear risk due to lack of information provided. d. There was high statistical heterogeneity (Heterogeneity: Tau² = 0.097; Chi² = 585.62, df = 25, p < 0.01; I² = 96%, 95–97%). Sub-group analyses by population did not fully explain heterogeneity. Study effects from individual RCTs were consistently beneficial and no major difference was observed in other critical outcomes. We did not downgrade. e. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. f. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. g. Meta-analysis: Choko, 2019a and Choko, 2019b had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. h. 9 individual randomized trials and 7 cluster randomized trials i. We downgraded twice. This was due to potential for performance bias (lack of blinding - HIV self-testing intervention) in all trials, detection bias (self-reported or non-validated outcomes) in 15 trials and attrition bias in four trials (Indravudh, 2021: 23% LTFU in the intervention arm and 21% LTFU in the control arm; Kim, 2020: 56% LTFU in the intervention arm and 46% in the control arm; Marwa, 2019: 13-22%, 17-25%, 11-18%, LTFU in three study arms; Patel, 2018: 36% LTFU overall, 44% in the intervention and 27% in the control arm). Four cluster randomized trials were subject to recruitment bias. Some risk of bias domains were unclear risk due to lack of information provided. j. There was a high statistical heterogeneity (Heterogeneity: Tau² = 0.142; Chi² = 273.73, df = 15, p < 0.01; I² = 96%, 95–97%). Study effects from individual RCTs were consistently beneficial and no major difference was observed in other critical outcomes. We did not downgrade. k. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. We noted that all but one trial were conducted in sub-Saharan Africa. This is expected as most countries with generalized epidemics are in this region. l. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. m. Meta-analysis: Wray, 2018 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. n. 6 individual randomized trials and one cluster randomized trial. o. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in three trials and attrition bias in 2 trials (MacGowan, 2017: 27.1% LTFU in the intervention arm and 28.5% in the control arm; Merchant, 2018: 38.4% LTFU overall, 26% in the intervention 50% in the control arm). Some risk of bias domains were unclear risk due to lack of information provided. p. There was high statistical heterogeneity (Heterogeneity: Tau² = 0.069; Chi² = 50.91, df = 6, p < 0.01; I² = 88%, 78–94%). Study effects from individual RCTs were consistently beneficial and no major difference was observed in other critical outcomes. We did not downgrade. q. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. r. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. s. Meta-analysis: Chanda, 2017 and Ortblad, 2017 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. t. One individual randomized trial and 2 cluster randomized trials. u. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials and detection bias (self-reported or non-validated outcomes) in one trial and unclear risk in two trials. Some risk of bias domains were unclear due to insufficient information provided. 47 v. There was high statistical heterogeneity (Heterogeneity: Tau² = 0.069; Chi² = 49.58, df = 2, p < 0.01 ; I² = 96%, 91–98%). Study effects from individual RCTs were consistently beneficial and no major difference was observed in other critical outcomes. We did not downgrade. w. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. x. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. y. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b, Ortblad, 2019 and Wray, 2018 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta- analysis for cluster randomized trials. z. 13 individual randomized and 6 were cluster randomized trials. aa. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in 7 trials or unclear risk of detection bias in 4 trials, and attrition bias in three trials (Kim, 2020: 56% LTFU in the intervention arm and 46% in the control arm; MacGowan, 2017: 27.1% LTFU in the intervention arm and 28.5% in the control arm; Merchant, 2018: 38.4% LTFU overall, 26% in the intervention 50% in the control arm). Three cluster randomized trials were subject to potential recruitment bias. Some risk of bias domains were unclear risk due to lack of information provided. ab. There was low statistical heterogeneity (Heterogeneity: Tau² = 0.024; Chi² = 18.17, df = 18, p = 0.444; I² = 1%, 0–49%). We did not downgrade but noted that outcome definition was not consistent across trials (ranged from HIV positivity defined as confirmed HIV diagnosis, self-reported reactive HIVST result, self-reported positivity or unclear definition). The results were largely similar across individual trials but strength of effect varied and number of events were small. ac. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. ad. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. ae. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b, Ortblad, 2017 and Wray, 2018 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta- analysis for cluster randomized trials. af. 12 individual randomized and 6 were cluster randomized trials. ag. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in seven trials or unclear risk of detection bias in four trials, and attrition bias in two trials (Kim, 2020: 56% LTFU in the intervention arm and 46% in the control arm; Merchant, 2018: 38.4% LTFU overall, 26% in the intervention 50% in the control arm). Four cluster randomized trials were subject to potential recruitment bias. Several risk of bias domains were unclear risk due to insufficient information provided. ah. There was low statistical heterogeneity (Heterogeneity: Tau² = 0.178; Chi² = 24.08, df = 17, p = 0.117; I² = 29%, 0–60%). We did not downgrade but noted that outcome definition was not consistent across trials (ranged from HIV positivity defined as confirmed HIV diagnosis, self-reported reactive HIVST result, self-reported positivity or unclear definition). The results were largely similar across individual trials but noted strength of effect varied and that the direction of effect favored standard of care in four trials. ai. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. aj. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. ak. RR for HIV positivity among randomized: 1.06 (0.76–1.48). al. Meta-analysis: Choko, 2019a and Choko, 2019b had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. am. 5 individual randomized trials and 4 cluster randomized trials. an. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in three trials and attrition bias in one trial (Kim, 2020: 56% LTFU in the intervention arm and 46% in the control arm). Some risk of bias domains were unclear due to insufficient information provided. ao. There was low statistical heterogeneity (Heterogeneity: Tau² = 0.043; Chi² = 8.49, df = 8, p = 0.39; I² = 6%, 0– 67%). We did not downgrade but noted that outcome definition was not consistent across trials (ranged from HIV positivity defined as confirmed HIV diagnosis, self-reported reactive HIVST result, self-reported positivity or unclear definition). The results were largely similar across individual trials but noted strength of effect varied and that the direction of effect favored standard of care in two trials. ap. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. aq. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. 48 ar. Meta-analysis: Chanda, 2017, Ortblad, 2019 and Wray, 2018 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. as. 6 individual randomized trials. at. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in two trials and attrition bias in two trials (MacGowan, 2017: 27.1% LTFU in the intervention arm and 28.5% in the control arm; Marwa, 2019: 13–22%, 17– 25%, 11–18%, LTFU in three study arms; Merchant, 2018: 38.4% LTFU overall, 26% in the intervention 50% in the control arm). Some risk of bias domains were unclear due to insufficient information provided. au. There was low statistical heterogeneity (Heterogeneity: Tau² = 0; Chi² = 1.66, df = 5, p = 0.89; I² = 0%, 0–24%). We did not downgrade but noted that outcome definition was not consistent across trials (ranged from HIV positivity defined as confirmed HIV diagnosis, self-reported reactive HIVST result, self-reported positivity or unclear definition). The results were largely similar across individual trials but noted strength of effect varied and that the direction of effect favored standard of care in one trial. av. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. aw. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. ax. Meta-analysis: Chanda, 2017 and Ortblad, 2017 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. ay. 1individual randomized and 2 cluster randomized trials. az. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, detection bias (self-reported or non-validated outcomes) in two trials or unclear risk of detection bias in one trial. Some risk of bias domains were unclear due to insufficient information provided. ba. There was moderate statistical heterogeneity (Heterogeneity: Tau² = 0.473; Chi² = 4.23, df = 3, p = 0.12; I² = 53%, 0–86%). The direction and strength of effect varied across trials. We downgraded once. bb. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. bc. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. bd. This outcome is only relevant for intervention (HIVST) arm and reported in 9 trials. Results from 7 trials were pooled and reported as pooled percentage. The remaining two trials did not report data usable for pooled analysis. be. Three individual randomized trials and 6 cluster randomized trials. bf. We downgraded once. This was due to potential for performance bias (lack of blinding) in 8 trials, detection bias (self-reported or non-validated outcomes) in 3 trials and attrition bias in one trial. Two cluster randomized trials were subject to recruitment bias and one loss of clusters. Some risk of bias domains were unclear risk due to lack of information from unpublished reports or conference abstracts. bg. There was high statistical heterogeneity (Heterogeneity: I² = 77%, p < 0.01). The measurement time-point varied (range: 2 weeks–5 months) and point estimate from individual studies also varied (25–76%). We downgraded once. bh. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. bi. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b and Ortblad, 2017 had more than one intervention arm, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. bj. 6 individual randomized and 6 cluster randomized trials. bk. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, and detection bias (self-reported or non-validated outcomes) in 4 trials. Four cluster randomized trials were subject to recruitment bias. Some risk of bias domains were unclear risk due to lack of information provided. bl. There was moderate statistical heterogeneity (Heterogeneity: Tau² = 0.061; Chi² = 23.09, df = 11, p = 0.02; I² = 52%, 8–75%). The outcome definition varied across trials (linkage to ART initiation vs. linkage to any HIV care). The results from individual trials varied. We downgraded once. bm. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. bn. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. bo. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b and Ortblad, 2017 had more than one intervention arm, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. bp. 6 individual randomized and 6 cluster randomized trials. bq. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) in all trials, and detection bias (self-reported or non-validated outcomes) in 4 trials. Four cluster randomized trials were subject to recruitment bias. Some risk of bias domains were unclear risk due to lack of information provided. br. There was low statistical heterogeneity (Heterogeneity: Tau² = 0.011; Chi² = 15.71, df = 13, p = 0.51; I² = 0%, 0– 55%). We did not downgrade but noted that outcome definition was not consistent across trials (linkage to ART 49 initiation vs. linkage to any HIV care). The results were largely similar across individual trials but noted that the direction of effect in one trial favored standard of care. The number of events were small. bs. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. bt. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. bu. Meta-analysis: Chanda, 2017, Choko, 2019a, Choko, 2019b, Ortblad, 2017 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. bv. 2 individual randomized trials and 4 cluster randomized trials bw. We downgraded once. This was due to potential for performance bias (lack of blinding - HIV self-testing intervention) in all trials and detection bias (self-reported or non-validated outcomes) in two trials. Four cluster randomized trials were subject to recruitment bias. Some other risk of bias domains were unclear risk due to lack of information provided. bx. There was low statistical heterogeneity (Heterogeneity: Tau² = 0; Chi² = 2.58, df = 5, p = 0.76; I² = 0%, 0– 51%). We did not downgrade but noted that the outcome definition was not consistent across trials (linkage to ART initiation vs. linkage to any HIV care). The results were largely similar across individual trials but noted small number of events. by. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. bz. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. ca. 4 individual randomized trials. cb. We downgraded once. This was due to potential for performance bias (lack of blinding) in all trials and risk of attrition bias in one trial (MacGowan, 2017: 27.1% LTFU in the intervention arm and 28.5% in the control arm). cc. There was low statistical heterogeneity (Heterogeneity: Tau² = 0; Chi² = 1.01, df = 3, p = 0.80; I² = 0%, 0–55%). Results were largely similar across individual trials and noted small number of events. We did not downgrade. cd. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. ce. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. cf. Meta-analysis: Chanda, 2017 and Ortblad, 2017 had more than one intervention arm which included HIVST, we combined arms. Cluster-adjusted analysis was included in meta-analysis for cluster randomized trials. cg. 2 cluster randomized trials. ch. We downgraded once. This was due to potential for performance bias (lack of blinding) and detection bias (self- reported or non-validated outcomes) in both trials. ci. There was low statistical heterogeneity (Heterogeneity: Tau² = 0.152; Chi² = 1.40, df = 1, p = 0.24; I² = 29%). The direction of effect varied between two trials, we downgraded once. cj. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. ck. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. cl. Two trials reported this outcome which is only relevant to the intervention (HIVST) arm. cm. Two cluster randomized trials. cn. We downgraded once. This was due to potential for performance bias (lack of blinding - HIVST intervention) and detection bias (self-reported or non-validated outcomes) in both trials. One cluster randomized trials was subject to recruitment bias. Some risk of bias domains were unclear risk due to insufficient information provided. co. The outcomes were not pooled therefore inconsistency cannot be evaluated. Similar outcomes were reported from both included trials. cp. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. cq. The results are based on very few events so caution is needed when interpreting. We downgraded once. cr. Four trials involved HIVST distribution by women to their male partners (Choko, 2019a, Korte, 2020, Marwa, 2019, Masters, 2016), one involved HIVST distribution by HIV-positive clients to their partners (Dovel, 2019), one involved HIVST distribution by both women to their male partners and HIV-positive clients to their partners (Choko, 2019b), and two involved distribution of HIVST kits or coupons by female sex workers to their peers (Chanda, 2017, Ortblad, 2017). cs. 3 individual randomized and 6 cluster randomized trials. ct. We downgraded once. This was due to potential for performance bias (lack of blinding - HIV self-testing intervention) and detection bias (self-reported or non-validated outcomes) in all trials. Three cluster randomized trials were subject to recruitment bias. Some risk of bias domains were unclear risk due to insufficient information provided. 50 cu. There was low statistical heterogeneity (Heterogeneity: Tau² = 0; Chi² = 6.96, df = 8, p = 0.541; I² = 0%, 0– 60%). We did not downgrade but noted that type of harms or adverse events reported varied across trials and included intimate partner violence, relationship breakdown and verbal abuse. Results were largely similar across individual trials but noted that the direction of effect favored HIV self-testing in the largest trial. Overall number of events were small. cv. As all trials focused on HIV self-testing. The GDG determined downgrading for indirectness was not necessary as intervention and populations are sufficiently similar with HCVST. cw. Original sample size, does not represent effective cluster adjusted sample size in the meta-analysis. 51 Appendix 4. Ranking of outcomes Outcome Score Rank Linkage to additional testing 8.0 Critical Linkage to clinical assessment and/or treatment initiation 8.0 Critical Uptake of HCV testing services 7.8 Critical Number/proportion cured among those diagnosed with chronic HCV infection (or who completed treatment) 7.4 Critical Device related issues e.g., test failure, etc. 6.6 Important Positivity 6.4 Important Social harm or adverse events 6.4 Important Misuse related to HCV testing e.g., coercion 5.8 Important 52 Appendix 5. Characteristics of values and preferences articles for HCVST review Citation Location Population Type of testing (e.g., self- sampling for DBS, oral fluid-based test conducted by peers, etc.) Study design Main results (can be copied & pasted) Abou-Saleh et al., 2013 England Community drug teams /services in London, the County of Surrey, and the local prison 556 drug users over 12-month period (Data collected and testing offered at baseline, 6, and 12 months) Participants offered self- administered DBS, or if refused, key worker/ researcher-led DBS preparation. Cohort Compares results between DBS testing (self and researcher- administered DBS) and “routine” testing carried out in the places of recruitment - Initially self-test packs were not accepted. However, the rate of uptake of self-tests increased from 0.4% at time 1 to 51.7% at time 2. - The use of self-testing packs was successful for retesting clients, especially those who had disengaged from services. Candfield 2017 England the Feltham Young Offender Institution 107 self-identified heterosexual male attendees Participants offered saliva test administered by nurse. Cross-sectional - The saliva test was acceptable to all participants and all tested for HCV. One attendee answered that he would have declined HCV testing had the test been a blood fingerprick test. Guise 2018 England London 22 people (≥18 years) with current/past drug use or chemsex experience; 5 stakeholders Researchers provide examples of HCV self- sampling (inactive prototypes) and HCV self- testing options for illustrative purposes to the FGD participants. Qualitative rapid assessment using FGD and key informant interviews - Main themes reported: choice and control, ease of use, embedding testing in appropriate care pathways, and managing an uncertain result. - Self-testing seen as beneficial in terms of the immediacy, simplicity of operation and use of saliva rather than blood Majam et al., 2021 South Africa Johannesburg 171 members of the general population Participants given one of the three HCVST kits with only instructions for use and asked to perform the test in front of a professional Observational cross-sectional study - Participants liked that self-testing was fast, private and convenient. There was some confusion with instructional steps and pictures, finger-pricking, collecting blood, and transferring the sample to the buffer Prinsenberg 2020 Netherlands Hepatology and ID outpatient departments 39 viremic patients Self-sampling DBS Cross-sectional - 97% of participants found paper instructions to be helpful. - 93% found the experience easy or very easy.