Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis.

BACKGROUND: The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. METHODS: We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. RESULTS: The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. DISCUSSION: At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.

Efficacy and safety of DAA in children and adolescents with chronic HCV infection: A systematic review and meta-analysis.

BACKGROUND AND AIMS: We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines. METHODS: We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach. RESULTS: A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%). CONCLUSIONS: All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes. PROSPERO RECORD: CRD42020146752.

Reflex Hepatitis C Virus Viral Load Testing Following an Initial Positive Hepatitis C Virus Antibody Test: A Global Systematic Review and Meta-analysis.

BACKGROUND: Many people who have a positive hepatitis C virus (HCV) antibody (Ab) test never receive a confirmatory HCV RNA viral load (VL) test. Reflex VL testing may help address this problem. We undertook a systematic review to evaluate the effectiveness of reflex VL testing compared with standard nonreflex approaches on outcomes across the HCV care cascade. METHODS: We searched 4 databases for studies that examined laboratory-based reflex or clinic-based reflex VL testing approaches, with or without a nonreflex comparator, and had data on the uptake of HCV RNA VL test and treatment initiation and turnaround time between Ab and VL testing. Both laboratory- and clinic-based reflex VL testing involve only a single clinic visit. Summary estimates were calculated using random-effects meta-analyses. RESULTS: Fifty-one studies were included (32 laboratory-based and 19 clinic-based reflex VL testing). Laboratory-based reflex VL testing increased HCV VL test uptake versus nonreflex testing (RR: 1.35; 95% CI: 1.16-1.58) and may improve linkage to care among people with a positive HCV RNA test (RR: 1.47; 95% CI: .81-2.67) and HCV treatment initiation (RR: 1.03; 95% CI: .46-2.32). The median time between Ab and VL test was <1 day for all laboratory-based reflex studies and 0-5 days for 13 clinic-based reflex testing. CONCLUSIONS: Laboratory-based and clinic-based HCV reflex VL testing increased uptake and reduced time to HCV VL testing and may increase HCV linkage to care. The World Health Organization now recommends reflex VL testing as an additional strategy to promote access to HCV VL testing and treatment. CLINICAL TRIALS REGISTRATION: PROSPERO CRD42021283822.

Training the healthcare workforce to support task-shifting and viral hepatitis elimination: a global review of English language online trainings and in-person workshops for management of hepatitis B and C infection.

BACKGROUND: Achieving World Health Organization (WHO) targets for viral hepatitis elimination will require simplification and decentralisation of care, supported through task-shifting and training of non-specialist frontline healthcare workers. To inform development of national health worker trainings in viral hepatitis, we review and summarise available online and workshop trainings for management of hepatitis B virus (HBV) and hepatitis C virus (HCV). METHODS: We performed a systematic search of PubMed, Embase, Web of Science, conference abstracts, and grey literature using Google to identify online and in-person workshop trainings for health workers focused on HBV and/or HCV. Additional trainings were identified through a WHO regional network. We included online trainings written in English and in-person workshops developed for low-and-middle-income countries (LMICs). Available curricula are summarised together with key operational features (e.g. training length, year developed/updated, developing institution) and programmatic features (e.g. content, mechanism for self-assessment, use of clinical case studies). RESULTS: A total of 30 trainings met our inclusion criteria (10 online trainings; 20 in-person workshops). 50% covered both HBV and HCV, 13% HBV alone and 37% HCV alone. Among online trainings, only 2 (20%) were specifically developed or adapted for LMICs; 70% covered all aspects of hepatitis care, including prevention, assessment, and treatment; 9 (90%) included guidance on when to refer to specialists, and 6 (60%) included modules on management in specific populations (e.g., people who inject drugs [PWID], prisoners, and children). Online trainings used different formats including text-based modules, narrated slide-sets, and interactive web-based modules. Most workshops (95%) were targeted towards non-specialty providers, and 50% were an integral part of a national strategy for viral hepatitis elimination. Workshop length ranged from several hours to multiple sessions over the course of months, and many were part of a blended educational model, which included other opportunities for ongoing learning (e.g., telementorship). CONCLUSION: This compendium of online and in-person workshop trainings for HBV and HCV is a useful resource for national hepatitis programmes developing training curricula for non-specialists. Additional online training curricula are needed for use in LMICs, and additional materials are needed to address management challenges in key populations, such as PWID.

Training the healthcare workforce: the global experience with telementorship for hepatitis B and hepatitis C.

BACKGROUND: Telementorship has emerged as an innovative strategy to decentralise medical knowledge and increase healthcare capacity across a wide range of disease processes. We report the global experience with telementorship to support healthcare workers delivering hepatitis B virus (HBV) and hepatitis C virus (HCV) care and treatment. METHODS: In early 2020, we conducted a survey of HBV and HCV telementorship programmes, followed by an in-depth interview with programme leads. Programmes were eligible to participate if they were located outside of the United States (U.S.), focused on support to healthcare workers in management of HBV and/or HCV, and were affiliated with or maintained adherence to the Project ECHO model, a telementorship programme pioneered at the University of New Mexico. One programme in the U.S., focused on HCV treatment in the Native American community, was purposively sampled and invited to participate. Surveys were administered online, and all qualitative interviews were performed remotely. Descriptive statistics were calculated for survey responses, and qualitative interviews were assessed for major themes. RESULTS: Eleven of 18 eligible programmes completed the survey and follow up interview. Sixty-four percent of programmes were located at regional academic medical centers. The majority of programmes (64%) were led by hepatologists. Most programmes (82%) addressed both HBV and HCV, and the remainder focused on HCV only. The median number of participating clinical spoke sites per programme was 22, and most spoke site participants were primary care providers. Most ECHO sessions were held monthly (36%) or bimonthly (27%), with sessions ranging from 45 min to 2 h in length. Programme leaders identified collective learning, empowerment and collaboration to be key strengths of their telementorship programme, while insufficient funding and a lack of protected time for telementorship leaders and participants were identified as major barriers to success. CONCLUSION: The Project ECHO model for telementorship can be successfully implemented across high and low-and-middle-income countries to improve provider knowledge and experience in management of viral hepatitis. There is a tremendous opportunity to further expand upon the existing experience with telementorship to support non-specialist healthcare workers and promote elimination of viral hepatitis.

Feasibility and acceptability of integrating hepatitis B care into routine HIV services: a qualitative study among health care providers and patients in West Nile region, Uganda.

BACKGROUND: Despite facing a dual burden of HBV and HIV, Africa lacks experience in offering integrated care for HIV and HBV. To contextualize individual and group-level feasibility and acceptability of an integrated HIV/HBV care model, we explored perspectives of health care providers and care recipients on feasibility and acceptability of integration. METHODS: In two regional hospitals of West Nile region, we performed a demonstration project to assess feasibility and acceptability of merging the care of HBV-monoinfected patients with existing HIV care system. Using interviews with health care providers as key informants, and 6 focus groups discussions with 3 groups of patients, we explored feasibility [(i)whether integration is perceived to fit within the existing healthcare infrastructure, (ii) perceived ease of implementation of HIV/HBV integrated care, and (iii) perceived sustainability of integration] and acceptability [whether the HIV/HBV care model is perceived as (i) suitable, (ii) satisfying and attractive (iii) there is perceived demand, need and intention to recommend its use]. We audio-recorded the interviews and data was analysed using framework analysis. RESULTS: The following themes emerged from the data (i) integrating HBV into HIV care is perceived to be feasible, fit and beneficial, after making requisite adjustments (ii) integration is acceptable due to the need for both free treatment and anticipated collaboration between HIV and HBV clients in terms of peer-support (iii) there are concerns about the likely rise in stigma and the lack of community awareness about integrated care. CONCLUSION: The integrated HIV/HBV care model is feasible and acceptable among both providers and recipients. Necessary adjustments to the existing care system, including training, for community sensitization on the reasons and significance of integration are required.

Determining the lower limit of detection required for HCV viral load assay for test of cure following direct-acting antiviral-based treatment regimens: Evidence from a global data set.

Achieving global elimination of hepatitis C virus requires a substantial scale-up of testing. Point-of-care HCV viral load assays are available as an alternative to laboratory-based assays to promote access in hard to reach or marginalized populations. The diagnostic performance and lower limit of detection are important attributes of these new assays for both diagnosis and test of cure. Therefore, our objective was to determine an acceptable LLoD for detectable HCV viraemia as a test for cure, 12 weeks post-treatment (SVR12). We assembled a global data set of patients with detectable viraemia at SVR12 from observational databases from 9 countries (Egypt, the United States, United Kingdom, Georgia, Ukraine, Myanmar, Cambodia, Pakistan, Mozambique) and two pharmaceutical-sponsored clinical trial registries. We examined the distribution of HCV viral load at SVR12 and presented the 90th, 95th, 97th and 99th percentiles. We used logistic regression to assess characteristics associated with low-level virological treatment failure (defined as <1000 IU/mL). There were 5973 cases of detectable viraemia at SVR12 from the combined data set. Median detectable HCV RNA at SVR12 was 287,986 IU/mL. The level of detection for the 95th percentile was 227 IU/mL (95% CI 170-276). Females and those with minimal fibrosis were more likely to experience low-level viraemia at SVR12 compared to men (adjusted odds ratio AOR = 1.60 95% confidence interval [CI] 1.30-1.97 and those with cirrhosis (AOR = 1.49 95% CI 1.15-1.93). In conclusion, an assay with a level of detection of 1000 IU/mL or greater may miss a proportion of those with low-level treatment failure.

Feasibility and effectiveness of HCV viraemia testing at harm reduction sites in Georgia: A prospective three-arm study.

BACKGROUND AND AIMS: In 2015, Georgia began a hepatitis C virus (HCV) elimination programme. Although screening programmes have been decentralized for high-risk groups, viraemic testing remains a bottleneck for people who inject drugs. Here, we describe two models of viraemic testing that aimed to address this gap. METHODS: We assigned eight harm reduction sites (HRS) to one of three arms (2,1:1): Xpert HCV viral load testing on-site, blood draw on-site with centralized HCV core antigen testing (HCVcAg), or standard-of-care (SOC) referral with viremia testing performed at treatment centres. RESULTS: 1671 HCV-seropositive participants were enrolled (Xpert, 37.1%; HCVcAg, 29.1%; referral, 33.8%). Participants were predominantly male (95.4%), mean age (IQR) 43 (37, 50) years and 1290 (77.2%) were currently injecting drugs. Significantly higher proportions of participants in the Xpert (100%) and HCVcAg (99.8%) arms received viraemia testing compared with the referral arm (91.3%) (Xpert vs referral, p < 0.0001; HCVcAg vs referral, p < 0.0001). Among viraemic participants, treatment uptake was similar (Xpert, 84.0%; HCVcAg, 79.5%; referral, 88.4%). The time between screening and sample collection for viraemia testing was significantly longer in the referral arm compared with both Xpert and HCVcAg arms (median 1 day compared with 0 days respectively), and the overall time between screening to treatment initiation was longer for the referral arm (median 67 days) compared with both Xpert and HCVcAg arms (median 57 and 50 days respectively). CONCLUSIONS: Point-of-care viraemia testing and blood drawn on-site for HCVcAg testing yielded more HCV-seropositive patients receiving viraemic testing within a shorter timeframe compared with referrals.

Feasibility, effectiveness and cost of a decentralized HCV care model among the general population in Delhi, India.

BACKGROUND AND AIMS: India has a significant burden of hepatitis C virus (HCV) infection and has committed to achieving national elimination by 2030. This will require a substantial scale-up in testing and treatment. The "HEAD-Start Project Delhi" aimed to enhance HCV diagnosis and treatment pathways among the general population. METHODS: A prospective study was conducted at 5 district hospitals (Arm 1: one-stop shop), 15 polyclinics (Arm 2: referral for viral load (VL) testing and treatment) and 62 screening camps (Arm 3: referral for treatment). HCV prevalence, retention in the HCV care cascade, and turn-around time were measured. RESULTS: Between January and September 2019, 37 425 participants were screened for HCV. The median (IQR) age of participants was 35 (26-48) years, with 50.4% male and 49.6% female. A significantly higher proportion of participants in Arm 1 (93.7%) and Arm 3 (90.3%) received a VL test compared with Arm 2 (52.5%, P < .001). Of those confirmed positive, treatment was initiated at significantly higher rates for participants in both Arms 1 (85.6%) and 2 (73.7%) compared to Arm 3 (41.8%, P < .001). Arm 1 was found to be a cost-saving strategy compared to Arm 2, Arm 3, and no action. CONCLUSIONS: Delivery of all services at a single site (district hospitals) resulted in a higher yield of HCV seropositive cases and retention compared with sites where participants were referred elsewhere for VL testing and/or treatment. The highest level of retention in the care cascade was also associated with the shortest turn-around times.

Usability and acceptability of oral fluid hepatitis C self-testing among people who inject drugs in Coastal Kenya: a cross-sectional pilot study.

BACKGROUND: People who inject drugs (PWID) are disproportionally affected by hepatitis C virus (HCV) infection and many remain undiagnosed. HCV self-testing (HCVST) may be an effective approach to increase testing uptake, but has rarely been used among PWID. We assessed the usability and acceptability of HCVST among PWID in Kenya. METHODS: We conducted a cross-sectional study nested within a cohort study between August and December 2020 on Kenya's North Coast region. Participants were handed a prototype oral fluid HCVST kit and asked to conduct the test relying on the instructions for use. Usability was assessed by documenting errors made and difficulties faced by participants. Acceptability was assessed using an interviewer-administered semi-structured questionnaire. RESULTS: Among 150 participants, 19% were female and 65.3% had primary level education or lower. 71.3% made at least one error, 56.7% experienced some difficulty during at least one step, and the majority of participants (78%) required assistance during at least one step of the procedure. Most common errors occurred when placing the tube into the stand (18%), collecting the oral fluid sample (24%) and timing of reading results (53%). There was a strong association between presence of symptoms of opiate withdrawals and observed errors (94% vs 62%; p = 0.016) in a sub-group of 74 participants assessed. Inter-reader and inter-operator concordance were 97.7% (kappa: 0.92) and 99.2% (kappa: 0.95), respectively. Acceptability assessed by asking whether participants would choose to use HCVST prior to and after conducting HCVST was 98% and 95%, respectively. CONCLUSIONS: We found a high acceptability of oral fluid HCVST among PWID. User errors were common and were associated with the presence of withdrawal symptoms among users. Despite errors, most participants were able to obtain and interpret results correctly. These findings suggest that this group of users may benefit from greater messaging and education including options to receive direct assistance when self-testing for HCV.

Usability and acceptability of oral-based HCV self-testing among key populations: a mixed-methods evaluation in Tbilisi, Georgia.

BACKGROUND: Hepatitis C virus self-testing (HCVST) is an additional approach that may expand access to HCV testing. We conducted a mixed-methods cross-sectional observational study to assess the usability and acceptability of HCVST among people who inject drugs (PWID), men who have sex with men (MSM) and transgender (TG) people in Tbilisi, Georgia. METHODS: The study was conducted from December 2019 to June 2020 among PWID at one harm reduction site and among MSM/TG at one community-based organization. We used a convergent parallel mixed-methods design. Usability was assessed by observing errors made and difficulties faced by participants. Acceptability was assessed using an interviewer-administered semi-structured questionnaire. A subset of participants participated in cognitive and in-depth interviews. RESULTS: A total of 90 PWID, 84 MSM and 6 TG were observed performing HCVST. PWID were older (median age 35 vs 24) and had a lower level of education compared to MSM/TG (27% vs 59%). The proportion of participants who completed all steps successfully without assistance was 60% among PWID and 80% among MSM/TG. The most common error was in sample collection and this was observed more often among PWID than MSM/TG (21% vs 6%; p = 0.002). More PWID requested assistance during HCVST compared to MSM/TG (22% vs 8%; p = 0.011). Acceptability was high in both groups (98% vs 96%; p = 0.407). Inter-reader agreement was 97% among PWID and 99% among MSM/TG. Qualitative data from cognitive (n = 20) and in-depth interviews (n = 20) was consistent with the quantitative data confirming a high usability and acceptability. CONCLUSIONS: HCVST was highly acceptable among key populations in Georgia of relatively high educational level, and most participants performed HCVST correctly. A significant difference in usability was observed among PWID compared to MSM/TG, indicating that PWID may benefit from improved messaging and education as well as options to receive direct assistance when self-testing for HCV.

A training for health care workers to integrate hepatitis B care and treatment into routine HIV care in a high HBV burden, poorly resourced region of Uganda: the '2for1' project.

INTRODUCTION: The "2for1" project is a demonstration project to examine the feasibility and effectiveness of HBV care integrated into an HIV clinic and service. An initial phase in implementation of this project was the development of a specific training program. Our objective was to describe key features of this integrated training curriculum and evaluation of its impact in the initial cohort of health care workers (HCWs). METHODS: A training curriculum was designed by experts through literature review and expert opinion. Key distinctive features of this training program (compared to standard HBV training provided in the Government program) were; (i) Comparison of commonalities between HIV and HBV (ii) Available clinic- and community-level infrastructure, and the need to strengthen HBV care through integration (iii) Planning and coordination of sustained service integration. The training was aided by a power-point guided presentation, question and answer session and discussion, facilitated by physicians and hepatologists with expertise in viral hepatitis. Assessment approach used a self-administered questionnaire among a cohort of HCWs from 2 health facilities to answer questions on demographic information, knowledge and attitudes related to HBV and its prevention, before and after the training. Knowledge scores were generated and compared using paired t- tests. RESULTS: A training curriculum was developed and delivered to a cohort of 44 HCWs including medical and nursing staff from the two project sites. Of the 44 participants, 20 (45.5%) were male, average age (SD) was 34.3 (8.3) with an age range of 22-58 years. More than half (24, 54.5%) had been in service for fewer than 5 years. Mean correct knowledge scores increased across three knowledge domains (HBV epidemiology and transmission, natural history and treatment) post-intervention. However, knowledge related to diagnosis and prevention of HBV did not change. CONCLUSION: A structured HBV education intervention conducted as part of an HIV/HBV care integration training for health care workers yielded improved knowledge on HBV and identified aspects that require further training. This approach may be replicated in other settings, as a public health strategy to heighten HBV elimination efforts.

Reduced incidence of hepatitis C in 9 villages in rural Egypt: Progress towards national elimination goals.

BACKGROUND & AIMS: Egypt has a major HCV burden and a well established treatment programme, with an ambitious goal of HCV elimination. Our aim was to assess the impact of a comprehensive HCV prevention, test and treat programme on the incidence of new HCV infections in 9 villages in rural Egypt. METHODS: An HCV "educate, test and treat" project was implemented in 73 villages across 7 governorates in Egypt between 06/2015 and 06/2018. In 2018, in 9 of the villages we re-tested individuals who originally tested HCV antibody (HCV-Ab) and HBsAg negative using rapid diagnostic tests (RDTs); confirmatory HCV RNA testing was performed for positive cases. The incidence rate per 1,000 person-years (py) was calculated, and risk factors for incident HCV infections assessed through an interviewer-administered questionnaire in 1:3 age- and gender-matched cases and controls. RESULTS: Out of 20,490 individuals who originally tested HCV-Ab negative in the 9 villages during the 2015-2016 implementation of the "educate, test and treat" programme, 19,816 (96.7%) were re-tested in 2018. Over a median of 2.4 years (IQR 2.1-2.7), there were 19 new HCV infections all of which were HCV RNA positive (incidence rate 0.37/1,000 py) (95% CI 0.24-0.59). Compared to a previous estimate of incidence in the Nile Delta region (2.4/1,000 py) from 2006, there was a substantial reduction in overall incidence of new HCV infections. Exposures through surgery (odds ratio 51; 95% CI 3.5-740.1) and dental procedures (odds ratio 23.8; 95% CI 2.9-194.9) were significant independent predictors of incident infections. CONCLUSIONS: This is the first study to show a substantial reduction in incidence of new HCV infections in a sample of the general population in Egypt following attainment of high testing and treatment coverage. New infections were significantly associated with healthcare-associated exposures. LAY SUMMARY: Egypt has a major national HCV testing and treatment programme with the goal of eliminating HCV infection. We assessed the impact of a comprehensive HCV prevention, test and treat programme in 73 villages that achieved high coverage of testing and treatment on the subsequent incidence of new HCV infections in nine of the villages. We re-tested people who were previously HCV antibody negative and found that the rate of new HCV infections was greatly reduced compared to previous estimates. We also found that exposure through surgery and dental procedures were associated with these new infections. This highlights the importance of continued strengthening of infection control and prevention measures, alongside treatment scale-up.

Eliminating mother-to-child transmission of human immunodeficiency virus, syphilis and hepatitis B in sub-Saharan Africa.

Triple elimination is an initiative supporting the elimination of mother-to-child transmission of three diseases - human immunodeficiency virus (HIV) infection, syphilis and hepatitis B. Significant progress towards triple elimination has been made in some regions, but progress has been slow in sub-Saharan Africa, the region with the highest burden of these diseases. The shared features of the three diseases, including their epidemiology, disease interactions and core interventions for tackling them, enable an integrated health-systems approach for elimination of mother-to-child transmission. Current barriers to triple elimination in sub-Saharan Africa include a lack of policies, strategies and resources to support the uptake of well established preventive and treatment interventions. While much can be achieved with existing tools, the development of new products and models of care, as well as a prioritized research agenda, are needed to accelerate progress on triple elimination in sub-Saharan Africa. In this paper we aim to show that health systems working together with communities in sub-Saharan Africa could deliver rapid and sustainable results towards the elimination of mother-to-child transmission of all three diseases. However, stronger political support, expansion of evidence-based interventions and better use of funding streams are needed to improve efficiency and build on the successes in prevention of mother-to-child transmission of HIV. Triple elimination is a strategic opportunity to reduce the morbidity and mortality from HIV infection, syphilis and hepatitis B for mothers and their infants within the context of universal health coverage.

La triple élimination est une initiative visant à soutenir l'éradication de la transmission mère-enfant de trois maladies ­ l'infection au virus de l'immunodéficience humaine (VIH), la syphilis et l'hépatite B. Bien que des avancées considérables aient été observées en ce sens dans certaines régions, les progrès demeurent lents en Afrique subsaharienne, pourtant durement touchée par ces maladies. Les caractéristiques communes aux trois affections, notamment leur épidémiologie, les interactions entre elles et les principales interventions nécessaires à leur prise en charge permettent aux systèmes de santé d'adopter une approche intégrée pour éviter la transmission mère-enfant. Plusieurs obstacles entravent actuellement la triple élimination en Afrique subsaharienne, parmi lesquels l'absence de politiques, de stratégies et de ressources pour garantir la disponibilité de traitements préventifs et curatifs bien établis. Les outils existants offrent déjà de nombreuses solutions; mais pour accélérer la progression de cette triple élimination en Afrique subsaharienne, il est indispensable de développer de nouveaux produits et modèles de soins, ainsi qu'un programme de recherche prioritaire. Dans le présent document, nous voulons montrer que si les systèmes de santé collaborent avec les communautés en Afrique subsaharienne, ils pourront obtenir des résultats rapides et durables en vue d'éradiquer la transmission mère-enfant des trois maladies susmentionnées. Néanmoins, une telle démarche implique un soutien politique massif, l'expansion des interventions fondées sur des données scientifiques, et une meilleure utilisation des sources de financement afin d'améliorer l'efficacité et de s'appuyer sur les réussites en matière de prévention de la transmission du VIH de la mère à l'enfant. La triple élimination représente une occasion stratégique de réduire la morbidité et la mortalité liées à l'infection au VIH, à la syphilis et à l'hépatite B, tant chez les mères que chez les nourrissons, dans un contexte de couverture maladie universelle.

La triple eliminación es una iniciativa que apoya la eliminación de la transmisión maternoinfantil de tres enfermedades: la infección por el virus de la inmunodeficiencia humana (VIH), la sífilis y la hepatitis B. En algunas regiones se han logrado avances significativos hacia la triple eliminación, pero los progresos se han desarrollado con mayor lentitud en el África subsahariana, la región con la mayor carga de estas enfermedades. Las características comunes de las tres enfermedades, como su epidemiología, las interacciones entre ellas y las intervenciones básicas para combatirlas, permiten un enfoque integrado de los sistemas de salud para la eliminación de la transmisión maternoinfantil. Los obstáculos actuales para la triple eliminación en el África subsahariana incluyen la falta de políticas, estrategias y recursos para apoyar la adopción de intervenciones preventivas y de tratamiento bien establecidas. Aunque se puede lograr mucho con las herramientas existentes, se necesita el desarrollo de nuevos productos y modelos de atención, así como una agenda de investigación prioritaria, para acelerar el progreso de la triple eliminación en el África subsahariana. En este documento pretendemos demostrar que los sistemas de salud que trabajan conjuntamente con las comunidades del África subsahariana podrían obtener resultados rápidos y sostenibles hacia la eliminación de la transmisión maternoinfantil de las tres enfermedades. Sin embargo, se necesita un mayor apoyo político, la ampliación de las intervenciones basadas en la evidencia y un mejor uso de los flujos de financiación para mejorar la eficiencia y aprovechar los éxitos en la prevención de la transmisión maternoinfantil del VIH. La triple eliminación es una oportunidad estratégica para reducir la morbilidad y la mortalidad de la infección por el VIH, la sífilis y la hepatitis B para las madres y sus hijos en el contexto de la cobertura sanitaria universal.

Outcomes of the CT2 study: A 'one-stop-shop' for community-based hepatitis C testing and treatment in Yangon, Myanmar.

BACKGROUND: With the advent of low-cost generic direct-acting antivirals (DAA), hepatitis C (HCV) elimination is now achievable even in low-/middle-income settings. We assessed the feasibility and effectiveness of a simplified clinical pathway using point-of-care diagnostic testing and non-specialist-led care in a decentralized, community-based setting. METHODS: This feasibility study was conducted at two sites in Yangon, Myanmar: one for people who inject drugs (PWID), and the other for people with liver disease. Participants underwent on-site rapid anti-HCV testing and HCV RNA testing using GeneXpert(R) . General practitioners determined whether participants started DAA therapy immediately or required specialist evaluation. Primary outcome measures were progression through the HCV care cascade, including uptake of RNA testing and treatment, and treatment outcomes. FINDINGS: All 633 participants underwent anti-HCV testing; 606 (96%) were anti-HCV positive and had HCV RNA testing. Of 606 tested, 535 (88%) were RNA positive and had pre-treatment assessments; 30 (6%) completed specialist evaluation. Of 535 RNA positive participants, 489 (91%) were eligible to initiate DAAs, 477 (98%) completed DAA therapy and 421 achieved SVR12 (92%; 421/456). Outcomes were similar by site: PWID site: 91% [146/161], and liver disease site: 93% [275/295]). Compensated cirrhotic patients were treated in the community; they achieved an SVR12 of 83% (19/23). Median time from RNA test to DAA initiation was 3 days (IQR 2-5). CONCLUSIONS: Delivering a simplified, non-specialist-led HCV treatment pathway in a decentralized community setting was feasible in Yangon, Myanmar; retention in care and treatment success rates were very high. This care model could be integral in scaling up HCV services in Myanmar and other low- and middle-income settings.

Usability and acceptability of self-testing for hepatitis C virus infection among the general population in the Nile Delta region of Egypt.

BACKGROUND: Self-testing for hepatitis C virus antibodies (HCVST) may be an additional strategy to expand access to hepatitis C virus (HCV) testing and support elimination efforts. We conducted a study to assess the usability and acceptability of HCVST among the general population in a semi-rural, high-HCV prevalence region in Egypt. METHODS: An observational study was conducted in two hospitals in the Nile Delta region. A trained provider gave an in-person demonstration on how to use the oral fluid HCVST followed by observation of the participant performing the test. Usability was assessed by observing errors made and difficulties faced by participants. Acceptability of HCV self-testing was assessed using an interviewer-administered semi-structured questionnaire. RESULTS: Of 116 participants enrolled, 17 (14.6%) had received no formal education. The majority (72%) of participants completed all testing steps without any assistance and interpreted the test results correctly. Agreement between participant-reported HCVST results and interpretation by a trained user was 86%, with a Cohen's kappa of 0.6. Agreement between participant-reported HCVST results and provider-administered oral fluid HCV rapid test results was 97.2%, with a Cohen's kappa of 0.75. The majority of participants rated the HCVST process as easy (53%) or very easy (44%), and 96% indicated they would be willing to use HCVST again and recommend it to their family and friends. CONCLUSION: Our study demonstrates the high usability and acceptability of oral fluid HCVST in a general population. Further studies are needed to establish the optimal positioning of self-testing alongside facility-based testing to expand access to HCV diagnosis in both general and high-risk populations.

An educate, test and treat model towards elimination of hepatitis C infection in Egypt: Feasibility and effectiveness in 73 villages.

BACKGROUND & AIMS: Egypt has one of the highest burdens of HCV infection worldwide. It has a large treatment programme, but reaching rural communities represents a major challenge. We report on the feasibility and effectiveness of a comprehensive community-based HCV prevention, testing and treatment model whose goal was to eliminate infection from all adult villagers. METHODS: An HCV "educate, test and treat" programme was implemented in 73 villages across 7 governorates in Egypt between 06/2015 and 06/2018. The programme model comprised community mobilisation facilitated by a network of village promoters to support the education, testing and treatment of patients, as well as fundraising in the local community. Comprehensive testing, linkage to care and treatment were provided for all eligible villagers aged 12 to 80 years. RESULTS: Of 221,855 eligible villagers, 204,749 (92.3%, 95% CI 91.6-93.5) were screened for HCV antibody and HBsAg, of whom 33,839 (16.5%, 95% CI 12.2-16.1) and 763 (0.4%, 95% CI 0.3-0.5) were positive, respectively. Nearly all 33,839 HCV antibody positive individuals had a sample immediately collected for HCV RNA testing, and 15,892 were HCV RNA positive. The overall prevalence of HCV viraemia was 7.8%. A total of 14,495 (91.2%, 95% CI 89.9-96.4) patients received treatment within a median of 2.1 weeks from serological diagnosis (IQR 0.6-3.3 weeks) and a sustained virological response was achieved among 14,238 of the treated cases (98.3%, 95% CI 96.7-98.6). Cirrhosis was present in 3,192 patients (20.1%), of whom 166 (5.2%) were diagnosed with hepatocellular carcinoma. There was treatment coverage and cure of 84.6% of the estimated 17,137 infected persons aged 12-80 years across the 73 villages. CONCLUSION: In this study of more than 200,000 villagers, we demonstrated the feasibility and effectiveness of a community-based "educate, test and treat" programme as a model for the elimination of HCV infection in rural communities. LAY SUMMARY: A large community-based educate, test and treat hepatitis C programme was conducted in more than 200,000 villagers across 73 villages in Egypt. This study demonstrates that a simplified care model can achieve high uptake of testing, linkage to care and treatment, with high cure rates. We consider this a model for the elimination of hepatitis C virus infection in rural communities, which can be applied to other countries highly affected by hepatitis C.

A same day 'test and treat' model for chronic HCV and HBV infection: Results from two community-based pilot studies in Egypt.

Prompt access to confirmatory viral load testing and staging of liver disease are key barriers in uptake of treatment for chronic hepatitis B and C infection. Our objective was to establish the feasibility of a same day 'test and treat' model in two distinct community-based settings in Egypt through use of key point-of-care (POC) portable tools for HCV and HBV viral load assessment and staging of liver disease followed by treatment initiation. Community sites were a village in northern Egypt (site 1) and a government office in Cairo (site 2). The following model was adopted: community awareness raising in the week before project initiation; site assessment to ensure optimal placement and calibration of equipment and clinical care set-up; transfer of key portable laboratory instruments to the sites (four cartridge GeneXpert, FibroScan and abdominal ultrasound); screening using rapid diagnostic tests for HCV-Ab and HBsAg, with immediate venous or finger-stick blood sampling for HCV-RNA and HBV-DNA assay, FibroScan staging of liver disease and ultrasound screening for liver cancer. At site 1, 475 individuals were screened over a single day, 125 were positive for HCV-Ab and 4 for HBsAg, 43 of 56 new HCV diagnoses were HCV RNA positive, and 3 of 4 HBsAg positive were HBV DNA positive, 40 initiated HCV treatment, and one HBV treatment . At site 2, 3188 individuals were screened over 3 days, 157 were positive for HCV-Ab, and 27 for HBsAg; 38 of 76 new HCV diagnoses were HCV RNA positive, and 15 of 18 HBsAg positive were HBV-DNA positive. Across both sites, 78 patients were counselled and initiated on treatment for HCV and 12 for HBV within 3 and 4 hours, respectively, of initial positive rapid diagnostic test result. We have shown the feasibility of a same day 'test and treat' model for chronic HCV and HBV infection in two community-based settings in Egypt that achieved high levels of linkage to care and initial treatment.

Prevalence and burden of HBV co-infection among people living with HIV: A global systematic review and meta-analysis.

Globally, in 2017 35 million people were living with HIV (PLHIV) and 257 million had chronic HBV infection (HBsAg positive). The extent of HIV-HBsAg co-infection is unknown. We undertook a systematic review to estimate the global burden of HBsAg co-infection in PLHIV. We searched MEDLINE, Embase and other databases for published studies (2002-2018) measuring prevalence of HBsAg among PLHIV. The review was registered with PROSPERO (#CRD42019123388). Populations were categorized by HIV-exposure category. The global burden of co-infection was estimated by applying regional co-infection prevalence estimates to UNAIDS estimates of PLHIV. We conducted a meta-analysis to estimate the odds of HBsAg among PLHIV compared to HIV-negative individuals. We identified 506 estimates (475 studies) of HIV-HBsAg co-infection prevalence from 80/195 (41.0%) countries. Globally, the prevalence of HIV-HBsAg co-infection is 7.6% (IQR 5.6%-12.1%) in PLHIV, or 2.7 million HIV-HBsAg co-infections (IQR 2.0-4.2). The greatest burden (69% of cases; 1.9 million) is in sub-Saharan Africa. Globally, there was little difference in prevalence of HIV-HBsAg co-infection by population group (approximately 6%-7%), but it was slightly higher among people who inject drugs (11.8% IQR 6.0%-16.9%). Odds of HBsAg infection were 1.4 times higher among PLHIV compared to HIV-negative individuals. There is therefore, a high global burden of HIV-HBsAg co-infection, especially in sub-Saharan Africa. Key prevention strategies include infant HBV vaccination, including a timely birth-dose. Findings also highlight the importance of targeting PLHIV, especially high-risk groups for testing, catch-up HBV vaccination and other preventative interventions. The global scale-up of antiretroviral therapy (ART) for PLHIV using a tenofovir-based ART regimen provides an opportunity to simultaneously treat those with HBV co-infection, and in pregnant women to also reduce mother-to-child transmission of HBV alongside HIV.

Deriving the optimal limit of detection for an HCV point-of-care test for viraemic infection: Analysis of a global dataset.

BACKGROUND & AIMS: Affordable point-of-care tests for hepatitis C (HCV) viraemia are needed to improve access to treatment in low- and middle-income countries. Our aims were to determine the target limit of detection (LOD) necessary to diagnose the majority of people with HCV eligible for treatment, and identify characteristics associated with low-level viraemia (LLV) (defined as the lowest 3% of the distribution of HCV RNA) to understand those at risk of being misdiagnosed. METHODS: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA measurements linked to demographic and clinical data. We excluded individuals on HCV treatment. We analysed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates. RESULTS: The dataset included 66,640 individuals with HCV viraemia from across the world. The LOD for the 95th and 99th percentiles were 3,311 IU/ml and 214 IU/ml. The LOD for the 97th percentile was 1,318 IU/ml (95% CI 1,298.4-1,322.3). Factors associated with LLV, defined as HCV RNA <1,318 IU/ml, were younger age 18-30 vs. 51-64 years (odds ratios [OR] 2.56; 95% CI 2.19-2.99), female vs. male sex (OR 1.32; 95% CI 1.18-1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44; 95% CI 1.21-1.69). Only the younger age group had a decreased relative sensitivity below 95%, at 93.3%. CONCLUSIONS: In this global dataset, a test with an LOD of 1,318 IU/ml would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable point-of-care diagnostics to expand HCV testing and linkage to care in low- and middle-income countries. LAY SUMMARY: We created and analysed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1,300 IU/ml or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 IU/ml of virus, our findings suggest that increasing the level of detection closer to 1,300 IU/ml would maintain good test accuracy and will likely enable development of more affordable portable tests for use in low- and middle-income countries.