BACKGROUND:Chronic hepatitis B (CHB) affects an estimated 254 million people globally. Historically, WHO and professional society guidelines have recommended treatment for individuals at high risk of disease progression, including those with hepatitis B virus (HBV) DNA concentrations >20 000 IU/mL. Whether individuals at lower risk, including those with HBV DNA <20 000 IU/mL and normal alanine aminotransferase concentrations, benefit from treatment remains uncertain. To inform 2024 WHO guidelines and the potential expansion of treatment threshold recommendations, we conducted two linked systematic reviews and meta-analyses; this analysis examines the incidence of clinical outcomes in untreated adults with non-cirrhotic CHB stratified by baseline HBV DNA and ALT concentrations. METHODS:In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library for longitudinal prospective and retrospective cohort studies, randomised controlled trials, and non-randomised studies of interventions, published in any language, from Jan 1, 2000, to Feb 6, 2023. We also reviewed the reference lists of included studies and systematic reviews and consulted networks of experts to identify other data sources. Included studies followed up adults (≥18 years) with non-cirrhotic CHB who had no history of antiviral therapy at enrolment, had baseline HBV DNA quantification and ALT measurement, had a follow-up period of at least 48 weeks, and assessed one or more of six key clinical outcomes (hepatocellular carcinoma, cirrhosis, liver-related mortality, all-cause mortality, liver decompensation, and indication for liver transplantation) or six additional outcomes (advanced liver fibrosis, progression of liver fibrosis, becoming eligible for antiviral treatment, hepatitis flare, and HBsAg and HBeAg seroclearance). Outcomes were required to be stratified by HBV DNA concentrations (<200 IU/mL, <2000 IU/mL, 2000-19 999 IU/mL, 20 000-199 999 IU/mL, and ≥200 000 IU/mL) or ALT concentrations (less than the upper limit of normal [ULN], 1·0-1·9 × ULN, and ≥2·0 × ULN). We excluded studies that focused solely on individuals who were pregnant; were co-infected with HIV, hepatitis C virus, or hepatitis D virus; or had another underlying condition other than CHB. We extracted aggregate data and used random-effects meta-analysis to pool incidence rates per 100 person-years. This study was registered with PROSPERO (CRD42023431652). FINDINGS:Of 13 231 studies screened, 71 met the inclusion criteria. A concentration-response relationship was observed between single baseline HBV DNA measurements and hepatocellular carcinoma incidence rates per 100 person-years: 0·131 (95% CI 0·097 to 0·177, I2=0%) for HBV DNA concentrations <200 IU/mL, 0·176 (0·117-0·266, I2=88%) for <2000 IU/mL, 0·311 (0·245-0·393, I2=13%) for 2000-19 999 IU/mL, 0·862 (0·725-1·026, I2=0%) for 20 000-199 999 IU/mL, and 0·941 (0·668-1·324, I2=58%) for ≥200 000 IU/mL (p<0·0001 for between-group difference). Similar concentration-response patterns were observed for development of cirrhosis (0·298 [95% CI 0·214-0·415], two studies, for <200 IU/mL; 0·300 [0·146-0·616], I2=88%, for <2000 IU/mL; 0·712 [0·624-0·814], I2=46%, for 2000-19 999 IU/mL; 1·436 [0·991-2·082], I2=76%, for 20 000-199 999 IU/mL; and 2·193 [1·690-2·846], I2=82%, for ≥200 000 IU/mL) and liver-related mortality (0·086 [95% CI 0·054-0·136], one study; 0·083 [0·015-0·451], I2=0%; 0·303 [0·228-0·402], I2=0%; 0·766 [0·591-0·993], one study; and 1·118 [0·951-1·314], two studies), but no concentration-response relationship was observed between a single baseline HBV DNA assessment and all-cause mortality or liver decompensation. Compared with ALT below the ULN, incidence rates of hepatocellular carcinoma, cirrhosis, and liver-related mortality were higher in individuals with baseline ALT concentrations 1·0-1·9 × ULN or ≥2·0 × ULN. A similar pattern was not found for all-cause mortality, and other outcomes were not meta-analysed due to small numbers. Within the HBV DNA strata of <2000 IU/mL, 2000-19 999 IU/mL, and ≥200 000 IU/mL, hepatocellular carcinoma incidence rates were 2-3 times higher in individuals with ALT 1·0-1·9 × ULN than in those with ALT concentrations less than the ULN. Individuals with persistently low HBV DNA concentrations (<2000 IU/mL) or persistently normal ALT concentrations across multiple assessments had slightly lower hepatocellular carcinoma incidence rates compared with those assessed by a single measurement. Our risk of bias assessment found 15 (21%) of 71 studies to be rated as good quality, 40 (56%) as fair quality, and 16 (23%) as poor quality. INTERPRETATION:These findings, alongside the linked systematic review and meta-analysis of antiviral treatment efficacy, supported the 2024 WHO guidelines expansion of treatment criteria to include individuals with HBV DNA concentrations >2000 IU/mL and ALT concentrations above the ULN. For those with HBV DNA concentrations <2000 IU/mL and persistently normal ALT concentrations, treatment can be deferred. FUNDING:WHO.

BACKGROUND:In the 2015 WHO guidelines for chronic hepatitis B (CHB), antiviral therapy was recommended for individuals with cirrhosis and individuals without cirrhosis with persistently elevated alanine aminotransferase (ALT) concentrations and hepatitis B virus (HBV) DNA >20 000 IU/mL, whereas treatment was deferred for individuals with persistently normal ALT concentrations and HBV DNA <2000 IU/mL. To inform 2024 WHO guidelines on CHB and the potential expansion of treatment threshold recommendations, we conducted two linked systematic reviews and meta-analyses; this analysis examines the efficacy of antiviral therapy in adults with non-cirrhotic CHB according to baseline HBV DNA and ALT concentrations. METHODS:In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library for randomised controlled trials (RCTs) and non-randomised (prospective or retrospective) confounder-controlled cohort studies of antiviral therapy versus placebo or no treatment in people with CHB, published in any language between Jan 1, 2000, and Feb 6, 2023. We also reviewed the reference lists of included studies and systematic reviews to identify RCTs published before 2000. Eligible studies reported baseline HBV DNA and ALT concentrations of adults with CHB, had less than 30% of participants with cirrhosis at baseline, and reported on at least one of our predefined outcomes. We excluded studies focused exclusively on pregnant women, individuals co-infected with HIV, hepatitis C virus, or hepatitis D virus, or individuals with primary conditions other than CHB, and studies that included participants who had received anti-HBV therapy in the 6 months before study enrolment. We extracted aggregate data to examine clinical outcomes (ie, hepatocellular carcinoma, cirrhosis, all-cause mortality, and liver-related mortality) and intermediate outcomes (ie, liver fibrosis, liver necroinflammation, ALT normalisation, HBsAg and HBeAg seroclearance and seroconversion, and HBV DNA suppression) stratified by baseline HBV DNA concentration (<2000 IU/mL, 2000-19 999 IU/mL, 20 000-199 999 IU/mL, 200 000-1 999 999 IU/mL, 2 000 000-19 999 999 IU/mL, and ≥20 000 000 IU/mL) and ALT (less than the upper limit of normal [ULN], 1·0-1·9 × ULN, and ≥2·0 × ULN). We used random-effects meta-analysis to pool unadjusted risk ratios (RRs) from RCTs and adjusted or unadjusted hazard ratios (aHRs or HRs) or unadjusted RRs for non-randomised studies. We estimated the number needed to treat (NNT) to prevent one case of hepatocellular carcinoma with nucleoside or nucleotide (nucleos[t]ide) analogue treatment. The study was registered with PROSPERO (CRD42023437560). FINDINGS:Of 13 224 articles screened, 24 met the inclusion criteria, including 16 studies on nucleos(t)ide analogues (12 RCTs and four non-randomised studies) and eight studies on interferon alfa-2-based therapy (four RCTs and four non-randomised studies). In adults with HBV DNA concentrations ≥20 000 IU/mL or elevated ALT (ie, ≥1·0 × ULN) at baseline, nucleos(t)ide analogue therapy was associated with a reduced risk of hepatocellular carcinoma (in non-randomised studies) and improvements in multiple intermediate outcomes (ie, liver fibrosis, necroinflammation, ALT normalisation, HBV DNA suppression, and HBeAg seroclearance and seroconversion), with certainty of evidence ranging from very low to high. In adults with baseline HBV DNA concentrations <20 000 IU/mL, nucleos(t)ide analogue therapy had no statistically significant effect on the risk of hepatocellular carcinoma, and no other outcomes were evaluated. From non-randomised studies, the aHRs for the risk of hepatocellular carcinoma with nucleos(t)ide analogue therapy were 0·72 (95% CI 0·43-1·20) for HBV DNA <2000 IU/mL, 0·45 (0·14-1·47) for 2000-19 999 IU/mL, and 0·39 (0·29-0·54; I2=0·0%) for ≥20 000 IU/mL. For adults with normal baseline ALT, nucleos(t)ide analogue therapy showed some efficacy for HBV DNA suppression (RR 31·50, 95% CI 2·02-492·36), but no efficacy for the remaining outcomes. Overall, higher certainty of evidence was seen with higher baseline HBV DNA or ALT concentrations. The between-study heterogeneity for pooled estimates varied across outcomes (I2 range 0·0-82·7%) but was low for most analyses (median I2=0·0%, IQR 0·0-25·5). Of the 16 RCTs, six were rated to have a low risk of bias, four were rated intermediate, and six as high. Of the eight non-randomised studies, four each were rated as fair and poor quality, respectively. The estimated NNT for nucleos(t)ide analogue therapy to prevent one case of hepatocellular carcinoma was 149 for baseline HBV DNA <2000 IU/mL over a median treatment duration of 12·0 years (IQR 4·1-26·2), 45 for HBV DNA 2000-19 999 IU/mL over 10·6 years (3·7-24·0), and 15 for HBV DNA ≥20 000 IU/mL over 13·6 years (6·7-22·1). INTERPRETATION:Evidence supports the efficacy of nucleos(t)ide analogue therapy in adults with HBV DNA ≥20 000 IU/mL or elevated ALT. However, the efficacy of nucleos(t)ide analogues remains uncertain in adults with HBV DNA <20 000 IU/mL or normal ALT. Future research should prioritise establishing treatment benefits in these groups, especially in high-burden settings in sub-Saharan Africa. FUNDING:WHO.

Background:Chronic hepatitis D (CHD) coinfection leads to accelerated progression to liver cirrhosis, hepatocellular carcinoma, and increased mortality. Currently, only a small proportion of individuals who are HBsAg positive are tested for anti-HDV antibodies, and among those who test positive, few receive confirmatory HDV RNA testing. Reflex testing, whereby laboratory-based anti-HDV testing is automatically triggered with a positive HBsAg test result in the lab, and also HDV RNA testing in those with a positive anti-HDV result, is one approach to promote the uptake and earlier diagnosis of HDV coinfection. We undertook a systematic review and meta-analysis to evaluate the effectiveness of a laboratory-based reflex testing strategy for both anti-HDV and HDV RNA on uptake of testing and linkage to care and turnaround times across the care cascade. Methods:We searched five databases (PubMed, Scopus, Embase, Cochrane, and Global Health (EBSCOhost)) and conference abstracts for relevant studies from database inception through June 2025, with or without a non-reflex comparator arm, and that had data on at least one step in the care cascade (uptake of HDV antibody and HDV RNA testing, linkage to care, and treatment initiation). Summary estimates were calculated using random-effects meta-analyses with 95% confidence intervals (CIs). The strength of evidence was assessed using the GRADE framework. The protocol was registered with PROSPERO (CRD42023397577). Findings:Of 3160 studies identified in the search, 28 were eligible for inclusion, of which 9 also had a non-reflex comparison arm. The majority (82.1%) were conducted in high-income countries. Among the 28 studies that used a reflex testing, 97.1% (95% CI: 93.9-98.7) of HBsAg-positive individuals had anti-HDV testing, and 7.2% (95% CI: 5.8-8.9) were anti-HDV positive. Of these, 95.3% (95% CI: 90.1-97.8) had HDV RNA testing, and 43.2% (95% CI: 33.2-53.8) were RNA positive. In the nine studies with a non-reflex comparison arm, reflex testing significantly increased anti-HDV testing uptake (98.0% versus 39.7%; RR 2.55, 95% CI: 1.62-4.05). And in the six studies with a comparator arm that also examined HDV RNA testing, uptake was higher with reflex testing but this was not statistically significant (94.7% versus 79.9%; RR 1.02, 95% CI: 0.86-1.20). Nine studies reported turnaround times for reflex testing from HBsAg testing to anti-HDV reflex testing, and all were completed within the same day. Four studies also reported a same-day turnaround for HDV RNA testing. Linkage to care was reported in only three of the reflex testing studies, and all 6 HDV RNA-positive individuals were referred for care. Interpretation:Laboratory-based reflex testing significantly increased the uptake of anti-HDV antibody and HDV RNA testing across diverse populations and settings, with same day turnaround times. The 2024 World Health Organization guidelines for hepatitis B care and treatment now recommend reflex HDV testing as a scalable approach to improve HDV testing uptake, and linkage to care for surveillance for liver cancer, and access to new treatments for Delta coinfection. Funding:The Guangzhou Science and Technology Project; The National Key R& D Program; National Institutes of Health; The University of North Carolina Center for AIDS Research; World Health Organization.

Chronic hepatitis C virus (HCV) infection remains a major cause of liver disease worldwide and requires effective strategies to achieve elimination targets. Taiwan has a substantial HCV burden, with prevalence varying by region; in Changhua County, prevalence was 4.3% before large-scale intervention. In 2019, Changhua launched a county-wide micro-elimination program-the Changhua Integrated Program to Stop Hepatitis C Infection (CHIPS-C)-which combined existing population screening with targeted outreach to higher-risk groups and decentralized delivery of curative direct-acting antiviral (DAA) treatment. Using individual-level data from a population-based cohort, we compared care cascade performance before and after CHIPS-C implementation. The program was associated with increased screening coverage (53.7% to 90.2%) and fewer individuals screened to achieve similar numbers of diagnosed infections. Improvements were driven by streamlined confirmatory testing and coordinated care delivery. Here we show that CHIPS-C substantially increased the adjusted treatment completion rate (83.9% vs 38.7% before implementation). Model-based projections indicate that these gains could reduce HCV-related liver cancer and mortality to levels meeting World Health Organization elimination targets by 2030. These findings demonstrate that integrating risk-based targeting with existing health systems can markedly improve efficiency and outcomes, providing a scalable model for accelerating HCV elimination in diverse settings.

Chronic hepatitis D coinfection affects an estimated 12 million people globally, with higher prevalence in low-income and middle-income countries, especially the African and Western Pacific regions. It leads to accelerated progression to liver cirrhosis, hepatocellular carcinoma, and increased mortality. The treatment landscape is evolving with the introduction of bulevirtide, but hepatitis D virus (HDV) testing uptake and case-finding remain low. The 2024 WHO guidelines on the management of chronic hepatitis B provide recommendations for the first time on who to test and how to test for HDV infection. WHO recommends universal anti-HDV testing among all HBsAg-positive individuals, and where this is not feasible, a complementary focused (risk-based) testing approach among higher-risk populations. We present two complementary Reviews-one on who to test and one on how to test for HDV infection. This Review on who to test summarises the evidence base and rationale for the two recommendations regarding the universal and risk-based testing approaches, as well as the recommendation for the laboratory-based reflex HDV testing both for anti-HDV and HDR RNA. Key implementation considerations include the need for countries to incorporate HDV testing into their national policies and guidelines, education and training of health-care providers in counselling and linkage to care, community awareness raising and demand creation, and the establishment of clinical care pathways for HDV infection. Research priorities include the development of HDV rapid diagnostic tests to facilitate decentralisation of HDV testing, the generation of improved epidemiological data across different populations and settings to inform testing approaches, and evaluating the cost-effectiveness and feasibility of both universal and risk-based HDV testing approaches, alongside reflex HDV serology and HDV RNA testing.

BACKGROUND:More new infections with hepatitis B virus (HBV) occur annually in the WHO African region than in the rest of the world combined. We did a systematic review and meta-analysis to estimate the prevalence of hepatitis B surface antigen (HBsAg) in pregnant women and vertical transmission events in the region. METHODS:In this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, Africa Index Medicus, and Africa Journals Online for publications between Jan 1, 1992, and Jan 7, 2024, with no language restrictions. HBsAg prevalence and vertical transmission (HBsAg positivity in children aged 6-12 months) were estimated with the use of binomial mixed models with logit links, stratified by infant vaccination status. We estimated HBsAg prevalence for subregions of Africa and for the WHO African region by weighting by estimated livebirths for each subregion. We estimated transmission events using WHO and UNICEF vaccine coverage data and UN population estimates. FINDINGS:We included 113 studies reporting on HBsAg prevalence from 190 983 pregnant women and 11 studies reporting on vertical transmission. HBsAg prevalence in women receiving antenatal care in the WHO African region (based on 2014-23 data) was 6·2% (95% CI 5·3-7·2). No relationship between risk of bias and HBsAg prevalence was observed. In 2022, an estimated 172 000 vertical transmission events (95% CI 82 000-383 000) occurred (0·4% of livebirths), a fall from a peak of 339 000 (149 000-634 000; 1·2% of all livebirths) in 2001. Increasing birth dose vaccination coverage to the WHO target of 90% could reduce vertical transmission by 43·7% (95% CI 11·6-78·0) to 97 000 events per year (95% CI 58 000-160 000). Adding maternal antiviral prophylaxis with 90% coverage could reduce transmission by 86·3% (95% CI 78·4-94·6) to 24 000 events per year (95% CI 14 000-39 000; 0·06% of livebirths) and achieve WHO elimination targets. INTERPRETATION:Vertical transmission is an important contributor to HBV transmission in the WHO African region. Scaling up of hepatitis B birth dose vaccination and antiviral prophylaxis is urgently needed, which could achieve elimination of vertical transmission. FUNDING:Wellcome Trust.

Background Non-invasive tests (aspartate aminotransferase-to-platelet ratio index [APRI] and transient elastography [FibroScan]) were recommended in the 2015 WHO guidelines to guide treatment decisions in people with chronic hepatitis B. We updated the systematic review and meta-analysis that informed the 2015 guidelines to inform new cutoffs for non-invasive tests for the diagnosis of significant fibrosis and cirrhosis for the 2024 WHO guidelines for chronic hepatitis B. Methods We searched PubMed (MEDLINE), Embase, and Science Citation Index Expanded (Web of Science) for studies published in any language between Jan 1, 2014, and Feb 15, 2023. We included all studies that reported cross-sectional data on the staging of fibrosis or cirrhosis with APRI, Fibrosis-4 (FIB-4), and FibroScan compared with liver biopsy as the reference standard in people with chronic hepatitis B. We excluded studies in which the maximum interval between liver biopsy and non-invasive fibrosis test was more than 6 months; that reported on fewer than ten patients with advanced fibrosis or cirrhosis; that were done exclusively in children; and did not report diagnostic accuracy across our prespecified ranges of test cutoffs. The results of this updated search were collated with the meta-analysis that informed the 2015 guidelines. Outcomes of interest were the sensitivity and specificity of non-invasive tests using defined index test cutoffs for detecting significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) based on the METAVIR staging system. We performed meta-analyses using a bivariate random-effects model. Findings Of 19 933 records identified by our search strategy, 195 were eligible for our systematic review and combined with the 69 studies from the previous meta-analysis to total 264. Two studies were at low risk of bias, 31 studies had unclear risk of bias, and 231 studies had a high risk of bias. Of these 264, 211 studies with 61 665 patients were used in the meta-analysis. For the diagnosis of significant fibrosis (≥F2), sensitivity and specificity were 72·9% (95% CI 70·2–75·5) and 64·7% (95% CI 61·0–68·2) for the APRI low cutoff (>0·3 to 0·7), 30·5% (23·7–38·3) and 92·3% (89·3–94·6) for the APRI high cutoff (>1·3 to 1·7), and 75·1% (72·2–77·7) and 79·3% (76·2–82·2) for FibroScan (>6·0 to 8·0 kPa), respectively. For the diagnosis of cirrhosis (F4), sensitivity and specificity were 59·4% (53·2–65·2) and 73·9% (70·1–77·4) for the APRI low cutoff (>0·8 to 1·2), 30·2% (24·2–36·9) and 88·2% (85·4–90·6) for the APRI high cutoff (>1·8 to 2·2), and 82·6% (77·8–86·5) and 89·0% (86·3–91·2) for FibroScan (>11·0 to 14·0 kPa), respectively. Using a hypothetical population of 1000 unselected patients with chronic hepatitis B with a 25% prevalence of significant fibrosis (≥F2), the APRI low cutoff for significant fibrosis (≥F2) would result in 262 (26·2%) false positives but only 68 (6·8%) false negatives. The FibroScan cutoff would result in 158 (15·8%) false positives and 63 (6·3%) false negatives. In a population with a 5% prevalence of cirrhosis (F4), the APRI low cutoff for cirrhosis (F4) would result in 247 (24·7%) false positives and 21 (2·1%) false negatives and the FibroScan cutoff would result in 105 (10·5%) false positives and nine (0·9%) false negatives. Interpretation These findings have informed new thresholds of APRI and FibroScan for diagnosis of significant fibrosis and cirrhosis in the 2024 WHO guidelines on chronic hepatitis B, with an APRI score greater than 0·5 or a FibroScan value greater than 7·0 kPa considered to identify most adults with significant fibrosis (≥F2) and an APRI score greater than 1·0 or a FibroScan value greater than 12·5 kPa to identify most adults with cirrhosis (F4). These patients are a priority for antiviral treatment. Funding WHO.

Background and aimsThere are gaps in knowledge about the values and preferences of healthcare workers (HCW) with respect to treatment of children and adolescents living with chronic hepatitis C (HCV) infection. This study was carried out to identify these values and preferences as part of the evidence required to update World Health Organization (WHO) hepatitis C guidelines.MethodsAn online survey was designed and conducted during August/September 2021. Survey questions were developed to address two key questions about treatment of children and adolescents: who to treat, and which direct acting antiviral (DAA) regimens to use. The survey was circulated by the WHO to nine networks providing care to children and adolescents living with HCV infection, with respondents requested to cascade further within their networks.ResultsA total of 137 individuals from 38 countries responded to the survey. There was a trend toward higher preference for treating children of older age groups; 60% of respondents reported a strong preference for treating (i.e., stating they were very likely or likely to treat) children aged 3 to <6 years, 81 and 95% indicated strong preferences for treating those aged 6 to <12 years and 12 to <18 years, respectively. The most preferred DAA regimens for treatment across all age groups were: sofosbuvir/velpatasvir (SOF/VEL), sofosbuvir/ledipasvir (SOF/LDV), and glecaprevir/pibrentasvir (GLE/PIB). These were also reported to be the most commonly available drug regimens at respondents’ facilities.ConclusionThis survey provides insights from a heterogenous sample of HCWs from across the world with respect to their expressed priorities and preferences for the treatment of children and adolescents with chronic HCV.

BACKGROUND:Chronic hepatitis B is a leading cause of cirrhosis and hepatocellular carcinoma globally. In 2022, only 13% of the 254 million people with chronic hepatitis B were diagnosed and 3% were treated, highlighting a major gap in care provision. We aimed to comprehensively review service delivery models and their outcomes across the hepatitis B care cascade. METHODS:For this systematic review and meta-analysis, we searched PubMed, Embase, and Scopus for observational and interventional studies of chronic hepatitis B service delivery models that reported care outcomes, published between May 1, 2013, and July 15, 2024, with no language restrictions. Care cascade outcomes were the proportion of people diagnosed with hepatitis B who were assessed for treatment eligibility; the proportion of eligible people who started antiviral therapy; the proportion retained in care; and the proportion on therapy who had HBV DNA viral suppression. We evaluated pooled outcomes across hospital-based specialist care; co-managed care between primary and specialist care; community screening with linkage to specialist care; community screening with passive linkage to care; community test and treat clinics; primary care; and integrated care with antenatal, non-communicable disease, HIV, prison health, and substance misuse services and clinics, using a generalised linear mixed model with logit link and study random effects. For within-study comparisons of different models, we used inverse variance weighting to estimate the pooled risk ratio (RR). Heterogeneity was assessed with I2. This study is registered with PROSPERO (CRD42023410009). FINDINGS:Of 4883 studies identified in the search, we included 106 studies comprising 110 cohorts from 50 countries in our meta-analysis. 45 (41%) of 110 cohorts were from low-income and middle-income countries and 65 (59%) were from high-income countries. 76 (72%) of 106 studies were observational, 23 (22%) were non-randomised interventional studies, and seven (7%) were randomised trials. Treatment eligibility assessment occurred in 73·9% (95% CI 65·8-80·6; I2=98·5%) of patients for hospital-based specialist care (20 cohorts), 63·1% (53·0-72·2; I2=99·9%) for co-managed care (23 cohorts), 50·4% (25·9-74·8; I2=99·7%) for primary care (four cohorts), 82·3% (58·7-93·8; I2=96·1%) for community screening with linkage to specialist care (ten cohorts), 33·2% (23·1-45·1; I2=98·6%) for community screening with passive linkage to care (three cohorts), 56·9% (40·2-72·1; I2=98·8%) for diagnosis in antenatal clinics and post-delivery linkage to specialist care (five cohorts), 75·0% (37·7-93·7; I2=0·0%) for integrated care with harm reduction services (two cohorts), and 85·4% (78·0-90·6; I2=0·0%) for integrated care with prison health services (two cohorts). Initiation of antiviral therapy when eligible was 78·1% (95% CI 68·1-85·7; I2=99·2%) in hospital-based specialist care (25 cohorts), 67·2% (55·5-77·1; I2=95·8%) in co-managed care (11 cohorts), 49·3% (32·4-66·4; I2=87·9%) in primary care (four cohorts), 97·7% (80·6-99·8; I2=39·2%) in community screening with linkage to specialist care (seven cohorts), and 49·4% (22·1-77·0; I2=84·0%) for integrated care with non-communicable disease clinics (two cohorts). Higher rates of treatment eligibility assessment (RR 2·07 [95% CI 1·65-2·59], p<0·0001; I2=97·1%; three cohorts) and initiation of antiviral therapy (1·45 [1·13-1·85], p=0·0031; I2=0·0%; three cohorts) were observed in hospital-based specialist versus primary care models. Retention in care, assessed between 12 and 48 months, was 87·7% (95% CI 79·9-92·8, I2 =96·7%) in patients on antiviral therapy in hospital-based specialist care (13 cohorts) and 47·2% (95% CI 22·2-73·6, I2=99·5%) in patients not receiving antiviral therapy (two cohorts). Overall, retention was higher in patients with versus without antiviral therapy (RR 1·72 [95% CI 1·16-2·54]; p=0·019). HBV DNA viral suppression for patients on antiviral therapy in specialist care (nine cohorts) was 73·1% (95% CI 64·3-80·4; I2=92·0%) after a median of 12 months on antiviral therapy (IQR 12-33). INTERPRETATION:Considerable attrition was seen across the chronic hepatitis B care cascade, with low rates of retention especially in patients not on antiviral therapy. Assessment for treatment eligibility and initiation of antiviral therapy were lower in primary versus hospital-based specialist care models. Chronic hepatitis B services need to adopt strategies to optimise linkage to care after diagnosis, initiation of antiviral therapy if eligible, adherence to antiviral therapy and retention in care, as promoted in 2024 WHO hepatitis B guidelines. Further research is also needed to explore simplified care models integrated with existing services to promote access. FUNDING:World Health Organization.

In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.

Chronic hepatitis B virus (HBV) infection is a major public health problem and cause of chronic liver disease and led to an estimated 1·1 million deaths in 2022, mainly due to cirrhosis and hepatocellular carcinoma. 1 WHOGlobal hepatitis report 2024: action for access in low- and middle-income countries. World Health Organization, Geneva2024https://www.who.int/publications/i/item/9789240091672Date accessed: April 9, 2024 Google Scholar In 2022, WHO estimated that 254 million people were living with chronic hepatitis B, of whom 65% were in the African and Western Pacific regions. 1 WHOGlobal hepatitis report 2024: action for access in low- and middle-income countries. World Health Organization, Geneva2024https://www.who.int/publications/i/item/9789240091672Date accessed: April 9, 2024 Google Scholar Most of this global burden can be attributed to mother-to-child transmission at the time of or shortly after birth and horizontal household transmission. Considerable progress has been made towards eliminating perinatal transmission of HBV through universal infant HBV immunisation, including timely hepatitis B birth-dose vaccination administered within 24 h of birth. This regimen is 90–95% effective in preventing infection and in reducing new infections among children. However, hepatitis B birth-dose coverage is only 45% globally, with particularly low coverage (18%) in the WHO African region. 2 WHOImmunization coverage. https://www.who.int/news-room/fact-sheets/detail/immunization-coverageDate accessed: March 14, 2024 Google Scholar For people with chronic hepatitis B, nucleoside analogue treatment with tenofovir or entecavir is highly effective, reducing progression of liver disease and incidence of hepatocellular carcinoma and improving long-term survival. However, a major testing and treatment gap remains. In 2022, only 13% of those living with chronic hepatitis B had been diagnosed and 3% treated. 1 WHOGlobal hepatitis report 2024: action for access in low- and middle-income countries. World Health Organization, Geneva2024https://www.who.int/publications/i/item/9789240091672Date accessed: April 9, 2024 Google Scholar Scaling up testing and treatment to reach the 90% testing and 80% treatment coverage targets and achieve the elimination goals will require radical simplification of treatment criteria, diagnostic approaches, and care pathways to overcome barriers in access to hepatitis B testing and treatment.

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.

Background:Point-of-care (PoC) hepatitis B virus (HBV) DNA viral load (VL) assays represent an alternative to laboratory-based standard-of-care (SoC) VL assays to accelerate diagnosis and treatment. We evaluated the impact of using PoC versus SoC approaches on the uptake of VL testing, treatment, and turnaround times from testing to treatment across the HBV care cascade. Methods:We searched 5 databases, 6 conference websites, and contacted manufacturers for unpublished reports, for articles with or without a comparator (SoC VL testing), and had data on the uptake of VL testing, treatment, or turnaround times between hepatitis B surface antigen (HBsAg) testing, VL testing, and treatment in the cascade. We performed a random-effects meta-analysis on rates of VL testing and treatment initiation. Results:Six studies, composing 9 arms, were included. Three PoC arms reported less than 1 day between screening for HBsAg positivity and VL testing, and the other one (2 arms) reported it between 7 and 11 days. Five arms reported the time to available VL test results (<1 day). Three studies reported 1-8 days between VL testing results and treatment initiation. Two studies reported the turnaround times between a positive HBsAg screening and treatment initiation (the same day and 27 days). Overall, 84.1% of those with HBsAg positivity were tested for DNA VL and 88.3% of eligible people initiated treatment. Conclusions:HBV PoC DNA testing appears to be associated with a turnaround time of <1 day for receipt of VL results and appears associated with high rates of DNA testing and initiation of treatment among those eligible. Clinical Trials Registration:PROSPERO CRD42023398440.

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. Direct-acting antiviral (DAA)-associated resistance is common among individuals with chronic HCV failing initial or re-treatment pan-genotypic DAAs. There is need for surveillance of DAA-associated resistance, to assess risk factors for their selection, and clinical impact to inform re-treatment regimen selection.

Abstract Background To inform the development of updated World Health Organization (WHO) guidelines on simplified service delivery for HCV infection, a global survey was undertaken among people affected or infected by HCV. The objective of this analysis is to identify specific needs and preferences among people who inject drugs. Methods A multi-country, anonymous, self-administered online survey conducted in 2021 was developed by Coalition PLUS and the World Hepatitis Alliance in partnership with the WHO. Preferences for test and treat locations and simplifying HCV care were collected among people affected or infected by HCV. Chi-square tests were used to compare respondents who identified with current or former injection drug users through identification with key population to other respondents who did not identify with this key population. Results Among 202 respondents, 62 (30.7%) identified with current/former injection drug users. Compared to other respondents, they were: older [median (IQR): 48 (36–57) vs. 39 (31–51) years, p = 0.003]; more likely to have been tested for HCV (90.2% vs. 64.3%, p = 0.001); more likely to prefer testing in a community-based centre (CBC) (55.4% vs. 33.3%, p = 0.005); or in a support centres for people who use drugs (SCPUD)(50.0% vs. 9.8%, p < 0.001). The most important considerations regarding testing locations among people identified with current/former injection drug users (compared to the other respondents) were: non-judgemental atmosphere (p < 0.001), anonymity (p = 0.018) and community worker (CW) presence (p < 0.001). People identified with current/former injection drug users were more likely to prefer to receive HCV treatment in a CBC (63.0% vs. 44.8%, p = 0.028) or in a SCPUD (46.3% vs. 9.5%, p < 0.001), compared to the other respondents. The most important considerations regarding treatment locations among people identified with current/former injection drug users were the non-stigmatising/non-judgemental approach at the site (p < 0.001) and the presence of community-friendly medical personnel or CW (p = 0.016 and 0.002), compared to the other respondents. Conclusion The preferences of people identified with current/former injection drug users indicated specific needs concerning HCV services. Integration of HCV services in community-based risk reduction centres may be an important element in the development of adapted services to increase uptake and retention in HCV care among this population.