SUSTAINED VIROLOGIC RESPONSE RATE IN CHRONIC HEPATITIS C PATIENTS THROUGH DIRECT-ACTING ANTIVIRALS THERAPY.

BACKGROUND: In recent years the management of hepatitis C virus infection and the possibility of its eradication have been researched due to the importance that they represent in the health of the world population. Obtaining data that help to cope with this pathology improves the quality of life of those affected by it. The present study evaluated the effectiveness of direct-acting antiviral therapies provided by the Brazilian Ministry of Health in accordance to the Clinical Protocol and Therapeutic Guidelines of 2015. OBJECTIVE: To evaluate the epidemiological profile of patients with chronic hepatitis C and the rate of sustained virologic response using direct-acting antivirals of all individuals that attended the referral service for the treatment of chronic hepatitis C at the Hospital of the Federal University of Rio Grande. METHODS: This was an observational, retrospective/prospective study with all patients with chronic hepatitis C who had their treatments available from December 2015 to August 2017 according to the criteria of the Clinical Protocol and Therapeutic Guidelines of 2015. In the first phase, the clinical and demographic variables of all individuals enrolled in a treatment for hepatitis C were selected and collected from the Reference Service database. In the second phase, treatment data were collected. The outcome variable, sustained virologic response, was defined as an undetectable viral load on the blood test three months after the end of treatment. The descriptive and bivariate analyzes were performed with Pearson's chi-square and Fisher's Exact test, adopting a P value ≤0.05 in the SPSS 20 software. RESULTS: Of the 252 participants in the study, 228 (90.5%) had a sustained virologic response, 55.2% were male with an average age of 58.6 years (SD±9.1). Genotype 1 was the most prevalent, observed in 54.4% of the participants, and 87.4% of the patients had moderate/advanced hepatic fibrosis. After the statistical analysis, it was observed that the individuals with genotype 3 and moderate/advanced hepatic fibrosis had lower sustained virologic response rate (P=0.05 and P=0.04, respectively). CONCLUSION: It was observed that the use of direct-acting antivirals, in comparison to previous therapeutic regimens, increases the sustained virologic response, reaching all patients with mild fibrosis. This study provides information that helps in the hepatitis C treatment by showing that prescribing early treatment for patients without hepatic fibrosis and/or genotype 3 virus could increase therapeutic effectiveness.

Elimination of hepatitis C virus in Germany: modelling the cost-effectiveness of HCV screening strategies.

BACKGROUND: Chronic hepatitis C is a major public health burden. With new interferon-free direct-acting agents (showing sustained viral response rates of more than 98%), elimination of HCV seems feasible for the first time. However, as HCV infection often remains undiagnosed, screening is crucial for improving health outcomes of HCV-patients. Our aim was to assess the long-term cost-effectiveness of a nationwide screening strategy in Germany. METHODS: We used a Markov cohort model to simulate disease progression and examine long-term population outcomes, HCV associated costs and cost-effectiveness of HCV screening. The model divides the total population into three subpopulations: general population (GEP), people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM), with total infection numbers being highest in GEP, but new infections occurring only in PWIDs and MSM. The model compares four alternative screening strategies (no/basic/advanced/total screening) differing in participation and treatment rates. RESULTS: Total number of HCV-infected patients declined from 275,000 in 2015 to between 125,000 (no screening) and 14,000 (total screening) in 2040. Similarly, lost quality adjusted life years (QALYs) were 320,000 QALYs lower, while costs were 2.4 billion EUR higher in total screening compared to no screening. While incremental cost-effectiveness ratio (ICER) increased sharply in GEP and MSM with more comprehensive strategies (30,000 EUR per QALY for total vs. advanced screening), ICER decreased in PWIDs (30 EUR per QALY for total vs. advanced screening). CONCLUSIONS: Screening is key to have an efficient decline of the HCV-infected population in Germany. Recommendation for an overall population screening is to screen the total PWID subpopulation, and to apply less comprehensive advanced screening for MSM and GEP.

Barriers to chronic Hepatitis B treatment and care in Ghana: A qualitative study with people with Hepatitis B and healthcare providers.

BACKGROUND: Hepatitis B viral (HBV) infection remains an important public health concern particularly in Africa. Between 1990 and 2013, Hepatitis B mortality increased by 63%. In recent times, effective antiviral agents against HBV such as Nucleos(t)ide analogs (NAs) are available. These drugs are capable of suppressing HBV replication, preventing progression of chronic Hepatitis B to cirrhosis, and reducing the risk of hepatocellular carcinoma and liver-related death. Notwithstanding, these treatments are underused despite their effectiveness in managing Hepatitis B. This study sought to explore barriers to treatment and care for people with Hepatitis B (PWHB) in Ghana, paying particular attention to beliefs about aetiology that can act as a barrier to care for PWHB. METHODS: We used an exploratory qualitative design with a purposive sampling technique. Face-to-face interviews were conducted for 18 persons with Hepatitis B (PWHB) and 15 healthcare providers (HCP; physicians, nurses, and midwives). In addition, four focus group discussions (FGD) with a composition of eight HCPs in each group were done. Participants were recruited from one tertiary and one regional hospital in Ghana. Data were processed using QSR Nvivo version 10.0 and analysed using the procedure of inductive thematic analysis. Participants were recruited from one tertiary and one regional hospital in Ghana. RESULTS: Three main cultural beliefs regarding the aetiology of chronic Hepatitis B that act as barriers to care and treatment were identified. These were: (1) the belief that chronic Hepatitis B is a punishment from the gods to those who touch dead bodies without permission from their landlords, (2) the belief that bewitchment contributes to chronic Hepatitis B, and (3) the belief that chronic Hepatitis B is caused by spiritual poison. Furthermore, individual level barriers were identified. These were the absence of chronic Hepatitis B signs and symptoms, perceived efficacy of traditional herbal medicine, and PWHB's perception that formal care does not meet their expectations. Health system-related barriers included high cost of hospital-based care and inadequate Hepatitis B education for patients from HCPs. CONCLUSION: Given that high cost of hospital based care was considered an important barrier to engagement in care for PWHB, we recommend including the required Hepatitis B laboratory investigations such as viral load, and the recommended treatment in the National Health Insurance Scheme (NHIS). Also, we recommend increasing health care providers and PWHB Hepatitis B knowledge and capacity in a culturally sensitive fashion, discuss with patients (1) myths about aetiology and the lack of efficacy of traditional herbal medicines, and (2) patients' expectations of care and the need to monitor even in the absence of symptoms.

Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions.

Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.

Evaluating the centralized purchasing policy for the treatment of hepatitis C: The Colombian CASE.

The high cost of drugs for hepatitis C limits access and adherence to treatment. In 2017, the Colombian health care system decided to design a strategy. It consisted of centralized purchasing, regulations, clinical practice guidelines, and direct observation of the treatment and follow-up of patients. The main objective of this study was to assess the centralized purchasing strategy in Colombia. The study design was a policy implementation assessment. We analyzed the change in prices, the clinical outcomes, and the opinions of stakeholders using data from the Ministry of Health. Additional information about effectiveness came from the Colombian Fund for High-Cost Diseases and semi-structured interviews of the stakeholders. The follow-up was from October, 2017 to October, 2018. The total number of patients reported in the cohort period was 1069. The number that finished 12 weeks of treatment, completed the follow-up for the case closure, and were considered cured through the end of October, 2018 was 563 (53%). The remainder, 506 patients (47%), are currently in treatment. A total of 543 of these treated patients (96%) were cured. After implementing this strategy, the drug prices decreased by more than 90% overall. Before implementation, the total direct cost was $100 102 171.75 dollars. Afterward, the cost was $8 378 747 dollars.

Meta-analysis of influences of Biejiajian Pill combined with entecavir on serum liver fibrosis markers of compensatory period of hepatitis b cirrhosis: Protocol of systematic review and meta-analysis.

BACKGROUND: Chronic viral hepatitis b and its related complications have caused serious harm to human health and become a worldwide public health problem. Hepatitis b cirrhosis is one of the most common complications in Asia. Traditional Chinese medicine combined with antiviral therapy has become the first choice for clinical treatment of hepatitis b Cirrhosis. Biejia Pill is an effective prescription of traditional Chinese medicine in treating Compensatory period of cirrhosis, and there are more and more clinical reports about its validity in treating Compensatory period of cirrhosis. Therefore, we designed this study protocol to evaluate the adjuvant role of Biejia Pill in the treatment of Compensatory period of cirrhosis. METHOD: Electronic Databases, PubMed, EMBASE database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Scientific Journals Database (VIP) and China Biology Medicine disc, (CBM), will be systematically searched from inception to July 2019. Randomized controlled trials (RCTs) on Biejiajian Pill combined with Entecavir and Entecavir alone against Compensatory period of hepatitis b cirrhosis will be included; inclusion and exclusion criteria will be used to screen the trials. liver fibrosis biomarkers including ECM or its metabolites (serum hyaluronic acid (HA), laminin (LN), procollagen type III (PC-III), and type IV collagen (IV-C)) will be measured as primary outcomes. Liver function, including alanine aminotransferase (ALT) and aspartarte aminotransferase (AST), and improvement of related clinical symptoms will be measured as secondary outcomes. RevMan5 software will be used for literature quality evaluation and data synthesis and analysis. RESULT: To evaluate the efficacy and safety of Biejiajian Pill in combination therapy by observing the outcomes of serum liver fibrosis markers, adverse reactions and liver function. CONCLUSION: This study protocol will be used to evaluate the efficacy and safety of Biejia Pill in combination with entecavir in the treatment of Compensatory period of hepatitis b cirrhosis, as well as the adjuvant treatment of Biejia Pill in combination.PROSPERO registration number: CRD42019135402.

Cost-Effectiveness of One-Time Birth Cohort Screening for Hepatitis C as Part of the National Health Service Health Check Program in England.

BACKGROUND AND OBJECTIVES: Birth cohort screening for the hepatitis C virus (HCV) has been implemented in the US, but there is little evidence of its cost-effectiveness in England. We aim to evaluate the cost-effectiveness of one-time HCV screening for individuals born between 1950 and 1979 as part of the National Health Service health check in England, a health check for adults aged 40 to 74 years in primary care. METHODS: A Markov model was developed to analyze add-on HCV testing to the National Health Service health check for individuals in birth cohorts between 1950 and 1979, versus current background HCV testing only, over a lifetime horizon. The model used data from a back-calculation model of the burden of HCV in England, sentinel surveillance of HCV testing, and published literature. Results are presented from a health service perspective in pounds in 2017, as incremental cost-effectiveness ratios per quality-adjusted life years gained. RESULTS: The base-case incremental cost-effectiveness ratios ranged from £7648 to £24 434, and £18 681 to £46 024, across birth cohorts when considering 2 sources of HCV transition probabilities. The intervention is most likely to be cost-effective for those born in the 1970s, and potentially cost-effective for those born from 1955 to 1969. The model results were most sensitive to the source of HCV transition probabilities, the probability of referral and receiving treatment, and the HCV prevalence among testers. The maximum value of future research across all birth cohorts was £11.3 million at £20 000 per quality-adjusted life years gained. CONCLUSION: Birth cohort screening is likely to be cost-effective for younger birth cohorts, although considerable uncertainty exists for other birth cohorts. Further studies are warranted to reduce uncertainty in cost-effectiveness and consider the acceptability of the intervention.

A meta-analysis on genetic variability of RT/HBsAg overlapping region of hepatitis B virus (HBV) isolates of Bangladesh.

BACKGROUND AND AIM: Hepatitis B caused by HBV is a serious public health hazard prevalent worldwide including Bangladesh. Few scattered molecular studies of HBV have been reported in Bangladesh. This study aimed to analyze the genetic variability of RT/HBsAg overlapping region of HBV isolates of Bangladesh and determination of correlation among the genotype/serotype and HBsAg escape and/or drug-resistant mutations. METHODS: A total of 97 complete HBsAg sequences of Bangladeshi HBV isolates from 2005 to 2017 from NCBI GenBank were extracted and analyzed using several HBV bioinformatics tools such as Geno2pheno-HBV, HBV Serotyper, HIV-Grade:HBV-Tool, and CLC sequence viewer. RESULTS: The prevalence of genotypes A, C, and D are 18, 46 and 35% which correspond to serotype adw, adr, and ayw, respectively. The prevalence of HBsAg escape mutations is 51% and most of which (62%) are found in the genotype D followed by 32% in genotype C and 6% in genotype A. Interestingly most (24/36) of the sequences of HBsAg escape mutations contained 128 V mutant which all belongs to only serotype ayw3 (Genotype D). Prevalence of drug-resistant mutations is ~ 11%, most of which are from genotype C (63.64%) and D (36.36%). Lamivudine resistant mutations were found in ~ 11% of sequences followed by Telbivudine 10% and Adefovir 3% where Tenofovir showed susceptibility to all 97 sequences. Moreover, 7 among of 97 sequences showed both HBsAg and drugs resistant mutations and none of them are found due to the same nucleotide substitutions. CONCLUSION: There is a strong correlation among the genotype/serotype and HBsAg escape and/or drug-resistant mutations. This meta-analytical review will be helpful for genotype-serotype prediction by PCR-based diagnosis and development of vaccine and/or diagnostic kits, and the treatment against HBV infection in the future.

Predictors of adverse drug reactions associated with ribavirin in direct-acting antiviral therapies for chronic hepatitis C.

PURPOSE: To identify factors associated with the development of adverse drug reactions (ADR) in ribavirin therapeutic regimens. METHODS: A multicenter, prospective study was conducted in three public health hospitals in Rio de Janeiro between November 2015 and March 2018. Inclusion criteria were defined by patient follow-up at pharmaceutical consultation at the time of drug dispensing as those who used sofosbuvir in combination with simeprevir, daclatasvir, and/or ribavirin. All patients were invited to participate in the study during the first interview. Adverse drug reactions were reported according to the treatment regimen and frequency of occurrence. Statistical analysis was used to compare adverse reactions between treatments and their associated factors. RESULTS: A total of 405 patients were included in the study (mean age 59.6 ± 9.6 years); 61.0% were female, 88.1% were infected with genotype 1, and 65.4% were cirrhotic. The most prescribed treatment was the combination of sofosbuvir, daclatasvir, and ribavirin (55.3%). The majority of patients reported at least one ADR during treatment (83.2%), of which fatigue, anemia, and headache were the most common. Being female (OR = 1.86, [1.08-3.20]) and use of ribavirin (OR: 2.39; 95% CI [1.38-4.13]) were predictors for the development of ADR, which was also associated with development of anemia (OR: 10.28; 95% CI: [5.78-18.30]). Treatment efficacy was 98.1%. CONCLUSIONS: Direct-acting antiviral has been shown to be safe and effective. Therefore, use of ribavirin is questionable due to associated adverse reactions and similar efficacy to other treatments.

Improved Health Outcomes from Hepatitis C Treatment Scale-Up in Spain's Prisons: A Cost-Effectiveness Study.

Hepatitis C virus (HCV) is 15 times more prevalent among persons in Spain's prisons than in the community. Recently, Spain initiated a pilot program, JAILFREE-C, to treat HCV in prisons using direct-acting antivirals (DAAs). Our aim was to identify a cost-effective strategy to scale-up HCV treatment in all prisons. Using a validated agent-based model, we simulated the HCV landscape in Spain's prisons considering disease transmission, screening, treatment, and prison-community dynamics. Costs and disease outcomes under status quo were compared with strategies to scale-up treatment in prisons considering prioritization (HCV fibrosis stage vs. HCV prevalence of prisons), treatment capacity (2,000/year vs. unlimited) and treatment initiation based on sentence lengths (>6 months vs. any). Scaling-up treatment by treating all incarcerated persons irrespective of their sentence length provided maximum health benefits-preventing 10,200 new cases of HCV, and 8,300 HCV-related deaths between 2019-2050; 90% deaths prevented would have occurred in the community. Compared with status quo, this strategy increased quality-adjusted life year (QALYs) by 69,700 and costs by €670 million, yielding an incremental cost-effectiveness ratio of €9,600/QALY. Scaling-up HCV treatment with DAAs for the entire Spanish prison population, irrespective of sentence length, is cost-effective and would reduce HCV burden.

NEW IMMUNIZATION SCHEDULE EFFECTIVENESS AGAINST HEPATITIS B IN LIVER TRANSPLANTATION PATIENTS.

BACKGROUND: Although liver transplantation is considered to be a high-risk procedure, it is well-established as a treatment option for the cure and quality of life enhancement for individuals who suffer from diseases. Preventing an infection by hepatitis B virus through immunization schedules has been the most effective way to reduce complications, since it decreases the number of people who suffer from chronic hepatitis caused by the hepatitis B virus and eradicates its transmission. OBJECTIVE: 1. Analyzing evidence in the literature on various schedules employed for immunization against hepatitis B in patients who have received a liver transplantation. 2. Suggesting potential immunization schedules against hepatitis B in patients who suffer from liver cirrhosis, without previous verifying documentation, using the Child-Turcotte Pugh score, according to evidences found in the literature. METHODS: Systematic review of the literature, conducted on the data bases MedLine, PubMed, and Lilacs, between September, 2017 and January, 2018, by using the following keywords: "Liver Transplantation, "Immunization Schedule", "Hepatitis B Vaccines". In order to analyze the articles, a summary figure was especially designed and both the results and discussion were presented in a descriptive way. RESULTS: We included 24 studies; among them, eight had accelerated immunization schedules, 13 followed the conventional schedules, and three had super accelerated schedules. Regarding immunization, 21 studies were conducted with patients in the pre-transplant period, one with a transplanted patient, one with a pre-transplant group, and one with a post-transplant group. Found articles suggest that, disregarding the chosen immunization schedule, seroconversion rates tended to be lower as the liver disease advanced, compared to the healthy population. CONCLUSION: The studies did not find seroconversion superiority between the different immunization schedules (conventional and unconventional). However, since candidates to liver transplantation are usually very vulnerable, results show that super accelerated immunization schedules are possibly recommended for such group of patients; serologic test results will be higher when the immunization schedule is completed in the pre-transplant period.

Significant Improvement in Diagnosis of Hepatitis C Virus Infection by a One-Step Strategy in a Central Laboratory: an Optimal Tool for Hepatitis C Elimination?

The remarkable effectivity of current antiviral therapies has led to consider the elimination of hepatitis C virus (HCV) infection. However, HCV infection is highly underdiagnosed; therefore, a global strategy for eliminating it requires improving the effectiveness of HCV diagnosis to identify hidden cases. In this study, we assessed the effectiveness of a protocol for HCV diagnosis based on viral load reflex testing of anti-HCV antibody-positive patients (known as one-step diagnosis) by analyzing all diagnostic tests performed by a central laboratory covering an area of 1.5 million inhabitants in Barcelona, Spain, before (83,786 cases) and after (45,935 cases) the implementation of the reflex testing protocol. After its implementation, the percentage of anti-HCV-positive patients with omitted HCV RNA determination remarkably decreased in most settings, particularly in drug treatment centers and primary care settings, where omitted HCV RNA analyses had absolute reductions of 76.4 and 20.2%, respectively. In these two settings, the percentage of HCV RNA-positive patients identified as a result of reflex testing accounted for 55 and 61% of all anti-HCV-positive patients. HCV RNA results were provided in a mean of 2 days. The presence of HCV RNA and age of ≥65 years were significantly associated with advanced fibrosis, assessed using the serological FIB-4 index (odds ratio [OR], 5.92; 95% confidence interval [CI], 3.4 to 10.4). The implementation of viral load reflex testing in a central laboratory is feasible and significantly increases the diagnostic effectiveness of HCV infections, while allowing the identification of underdiagnosed cases.

Integrated treatment of hepatitis C virus infection among people who inject drugs: study protocol for a randomised controlled trial (INTRO-HCV).

BACKGROUND: A large proportion of people who inject drugs (PWID) living with hepatitis C virus (HCV) infection have not been treated. It is unknown whether inclusion of HCV diagnostics and treatment into integrated substance use disorder treatment and care clinics will improve uptake and outcome of HCV treatment in PWID. The aim is to assess the efficacy of integrating HCV treatment to PWID and this paper will present the protocol for an ongoing trial. METHODS: INTRO-HCV is a multicentre, randomised controlled clinical trial that will compare the efficacy of integrated treatment of HCV in PWID with the current standard treatment. Integrated treatment includes testing for HCV, assessing liver fibrosis with transient elastography, counselling, treatment delivery, follow-up and evaluation provided by integrated substance use disorder treatment and care clinics. Most of these clinics for PWID provide opioid agonist therapy while some clinics provide low-threshold care without opioid agonist therapy. Standard care involves referral to further diagnostics, treatment and treatment follow-up given in a hospital outpatient clinic with equivalent medications. The differences between the delivery platforms in the two trial arms involve use of a drop-in approach rather than specific appointment times, no need for additional travelling, less blood samples taken during treatment, and treatment given from already known clinicians. The trial will recruit approximately 200 HCV infected individuals in Bergen and Stavanger, Norway. The primary outcomes are time to treatment initiation and sustained virologic response, defined as undetectable HCV RNA 12 weeks after end of treatment. Secondary outcomes are cost-effectiveness, treatment adherence, changes in quality of life, fatigue and psychological well-being, changes in drug use, infection related risk behaviour, and risk of reinfection. The target group is PWID with HCV diagnosed receiving treatment and care within clinics for PWID. DISCUSSION: This study will inform on the effects of an integrated treatment program for HCV in clinics for PWID compared to standard care aiming to increase access to treatment and improving treatment adherence. If the integrated treatment model is found to be safe and efficacious, it can be considered for further scale-up. TRIAL REGISTRATION: ClinicalTrials.gov.no. NCT03155906.

Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B.

BACKGROUND: Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry for ongoing or unpublished trials to 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups. DATA COLLECTION AND ANALYSIS: Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence. MAIN RESULTS: We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'. FUNDING: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.

Rationale and design of a randomized pragmatic trial of patient-centered models of hepatitis C treatment for people who inject drugs: The HERO study.

BACKGROUND: Although people who inject drugs (PWID) having the highest incidence and prevalence of hepatitis C virus (HCV) in the US, HCV treatment is rarely provided to PWID due to assumptions about poor adherence and reinfection risk. As direct-acting antiviral agents (DAAs) have achieved sustained virologic response (SVR) rates of 95% or more, evidence-based strategies are urgently needed to demonstrate real-world effectiveness in marginalized patient populations such as PWID. The objectives of this study are: 1) to determine whether either of two patient-centered treatment models - patient navigation (PN) or modified directly observed therapy (mDOT) - results in more forward movement along the HCV care cascade including treatment initiation, adherence, and SVR; 2) using quantitative and qualitative methods, to understand factors associated with lack of treatment uptake, poor adherence (<80%), failure to achieve SVR, DAA resistance, and HCV reinfection. METHODS: The HERO study is a multi-site, pragmatic randomized clinical trial conducted in eight states where 754 HCV-infected PWID were randomly assigned to either PN or mDOT. CONCLUSIONS: This study addresses an urgent need for timely and accurate information on optimal models of care to promote HCV treatment initiation, adherence, treatment completion and SVR among PWID, as well as rates and factors associated with reinfection and resistance after treatment. This clinical trial has the potential to provide valuable information on how to reduce the burden of the HCV epidemic in PWID.

HepCare Europe: a service innovation project. HepCheck: enhancing HCV identification and linkage to care for vulnerable populations through intensified outreach screening. A prospective multisite feasibility study.

OBJECTIVES: Hepatitis C is one of the main causes of chronic liver diseases worldwide. One of the major barriers to effecting EU- and WHO-mandated HCV elimination by 2030 is underdiagnosis. Community-based screening strategies have been identified as important components of HCV models of care. HepCheck Europe is a large-scale intensified screening initiative aimed at enhancing identification of HCV infection among vulnerable populations and linkage to care. METHODS: Research teams across four European countries were engaged in the study and rolled out screening to high-risk populations in community addiction, homeless and prison services. Screening was offered to 2822 individuals and included a self-administered questionnaire, HCV antibody and RNA testing, liver fibrosis assessment and referral to specialist services. RESULTS: There was a 74% (n=2079) uptake of screening. The majority (85.8%, n=1783) were male. In total 44.6% (n=927) of the sample reported ever injecting drugs, 38.4% (n=799) reported ever being homeless and 27.9% (n=581) were prisoners. In total 397 (19%) active HCV infections were identified and 136 (7% of total sample and 34% of identified active infections) were new cases. Of those identified with active HCV infection, 80% were linked to care, which included liver fibrosis assessment and referral to specialist services. CONCLUSIONS: HepCheck's screening and linkage to care is a clear strategy for reaching high-risk populations, including those at highest risk of transmission who are not accessing any type of care in the community. Elimination of HCV in the EU will only be achieved by such innovative, patient-centred approaches.

From peer-based to peer-led: redefining the role of peers across the hepatitis C care pathway: HepCare Europe.

BACKGROUND: HCV infection disproportionately affects underserved populations such as homeless individuals, people who inject drugs and prison populations. Peer advocacy can enable active engagement with healthcare services and increase the likelihood of favourable treatment outcomes. OBJECTIVES: This observational study aims to assess the burden of disease in these underserved populations and describe the role of peer support in linking these individuals to specialist treatment services. METHODS: Services were identified if they had a high proportion of individuals with risk factors for HCV, such as injecting drug use or homelessness. Individuals were screened for HCV using point-of-care tests and a portable FibroScan. All positive cases received peer support for linkage to specialist care. Information was gathered on risk factors, demographics and follow-up information regarding linkage to care and treatment outcomes. RESULTS: A total of 461 individuals were screened, of which 197 (42.7%) were chronically infected with HCV. Referral was made to secondary care for 176 (89.3%) and all received peer support, with 104 (52.8%) individuals engaged with treatment centres. Of these, 89 (85.6%) started treatment and 76 (85.4%) had a favourable outcome. Factors associated with not being approved for treatment were recent homelessness, younger age and current crack cocaine injecting. CONCLUSIONS: Highly trained peer support workers working as part of a specialist outreach clinical team help to identify a high proportion of individuals exposed to HCV, achieve high rates of engagement with treatment services and maintain high rates of treatment success amongst a population with complex needs.

Integrating primary and secondary care to optimize hepatitis C treatment: development and evaluation of a multidisciplinary educational Masterclass series.

BACKGROUND: It is increasingly being recognized that the elimination of HCV requires a multidisciplinary approach and effective cooperation between primary and secondary care. OBJECTIVES: As part of a project (HepCare Europe) to integrate primary and secondary care for patients at risk of or infected with HCV, we developed a multidisciplinary educational Masterclass series for healthcare professionals (HCPs) working in primary care in Dublin and Bucharest. This article aims to describe and evaluate the series and examine how this model might be implemented into practice. METHODS: GPs and other HCPs working in primary care, addiction treatment services and NGOs were invited to eight 1 day symposia (HCV Masterclass series), examining the burden and management of HCV in key populations. Peer-support sessions were also conducted, to give people affected by HCV and community-based organizations working with those directly affected, an update on the latest developments in HCV treatment. RESULTS: One hundred percent of participants 'strongly agreed' or 'agreed' that the Masterclass helped them to appreciate the role of integrated services in 'the management of patients with HCV'. One hundred percent of participants indicated the importance of a 'designated nurse to liaise with hospital services'. An improvement of knowledge regarding HCV management of patients with high-risk behaviour was registered at the end of the course. CONCLUSIONS: Integrated approaches to healthcare and improving the knowledge of HCPs and patients of the latest developments in HCV treatment are very important strategies that can enhance the HCV care pathway and treatment outcomes.

Integrating hepatitis C care for at-risk groups (HepLink): baseline data from a multicentre feasibility study in primary and community care.

OBJECTIVES: To examine HCV prevalence and management among people who inject drugs (PWID) attending primary care and community-based health services at four European sites using baseline data from a multicentre feasibility study of a complex intervention (HepLink). METHODS: Primary care and community-based health services in Dublin, London, Bucharest and Seville were recruited from the professional networks of the HepLink consortium. Patients were eligible to participate if aged ≥18 years, on opioid substitution treatment or at risk of HCV (i.e. injecting drug use, homeless or incarcerated), and attended the service. Data on patient demographics and prior HCV management were collected on participants at baseline. RESULTS: Twenty-nine primary care and community-based health services and 530 patients were recruited. Baseline data were collected on all participants. Participants' mean age ranged from 35 (Bucharest) to 51 years (London), with 71%-89% male. Prior lifetime HCV antibody testing ranged from 65% (Bucharest) to 95% (Dublin) and HCV antibody positivity among those who had been tested ranged from 78% (Dublin) to 95% (Bucharest). Prior lifetime HCV RNA testing among HCV antibody-positive participants ranged from 17% (Bucharest) to 84% (London). Among HCV antibody- or RNA-positive participants, prior lifetime attendance at a hepatology/infectious disease service ranged from 6% (London) to 50% (Dublin) and prior lifetime HCV treatment initiation from 3% (London) to 33% (Seville). CONCLUSIONS: Baseline assessment of the HCV cascade of care among PWID attending primary care and community-based health services at four European sites identified key aspects of the care cascade at each site that need to be improved.

The cost-effectiveness of an HCV outreach intervention for at-risk populations in London, UK.

BACKGROUND: HCV disproportionately affects marginalized communities such as homeless populations and people who inject drugs (PWID), posing a challenge to traditional health services. The HepFriend initiative in London is a model of care utilizing HCV outreach screening and peer support to link vulnerable individuals to HCV treatment in secondary care. OBJECTIVES: To assess the cost-effectiveness of the HepFriend initiative from a healthcare provider perspective, compared with standard-of-care pathways (consisting of testing in primary care and other static locations, including drug treatment centres, and linkage to secondary care). METHODS: Cost-effectiveness analysis using a dynamic HCV transmission and disease progression model among PWID and those who have ceased injecting, including housing status and drug treatment service contact. The model was parameterized using London-specific surveillance and survey data, and primary intervention cost and effectiveness data (September 2015 to June 2018). Out of 461 individuals screened, 197 were identified as HCV RNA positive, 180 attended secondary care and 89 have commenced treatment to date. The incremental cost-effectiveness ratio (ICER) was determined using a 50 year time horizon. RESULTS: For a willingness-to-pay threshold of £20000 per QALY gained, the HepFriend initiative is cost-effective, with a mean ICER of £9408/QALY, and would become cost saving at 27% (£10525 per treatment) of the current drug list price. Results are robust to variations in intervention costs and model assumptions, and if treatment rates are doubled the intervention becomes more cost-effective (£8853/QALY). CONCLUSIONS: New models of care that undertake active case-finding with enhanced peer support to improve testing and treatment uptake amongst marginalized and vulnerable groups could be highly cost-effective and possibly cost saving.