Universal versus targeted screening for HCV infection in pregnancy in a diverse, multi-ethnic population: Universal screening is more comprehensive.

Universal hepatitis C screening in pregnancy is not recommended by NICE due to a lack of effective interventions to prevent mother to child transmission (MTCT) and is only offered to pregnant women at increased risk of infection (intra-venous drug use [IVDU] or with a HCV positive family member). No testing is offered to patients from high endemic areas. However, data regarding true seroprevalence in multi-ethnic inner-city populations in the UK are required. This study aimed to determine test positivity rates of HCV infection in an unselected South East London ethnically diverse population of pregnant women by universal screening during routine antenatal care compared with a "targeted" screening approach. "Targeted" risk-based screening was performed in two eras (2016, n = 1002) and subsequently in 2018, after modifying the HCV risk questionnaire (n = 1122). Universal opt out screening was similarly performed in two eras in 2017 (n = 1012) and again in 2019 (n = 1057). During screening for HBV, HIV and syphilis, anti-HCV was tested, followed by an iterative HCV RNA test in those positive for anti-HCV. All anti-HCV-positive women were referred to the specialist hepatology service, and testing was offered to all family members. All HCV RNA-positive patients were followed during pregnancy and post-delivery period and were offered treatment. All infants of HCV RNA-positive mothers were linked to care with paediatric team. In the 2016 "targeted" screening cohort 212/1002 had a risk of BBV (blood borne viral) infection and (0.6%) were anti-HCV positive and HCV RNA positive. 0.3% patients were newly diagnosed. In the 2017 universal screening cohort, 1012/1038 pregnant women consented to testing. 0.96% were anti-HCV positive and 0.86% women were HCV RNA positive with 0.67% newly diagnosed. After modification of the risk-based questionnaire, a second risk-based targeted cohort were tested in 2018: 342/1122 (31%) were assessed as at risk and were offered an anti-HCV test. 0.71% were anti-HCV positive and 0.27% were HCV RNA positive. In the 2019 cohort tested by universal screening, 1049/1057 women were tested and 0.85% tested positive for anti-HCV, 0.28% women were HCV RNA positive. All newly diagnosed patients were born abroad. All patients had mild liver disease and had normal pregnancies. All patients were treated post-delivery and achieved SVR. All patients were negative for other BBV infections. In conclusion, the anti-HCV test positive rate in this ethnically diverse pregnant cohort ranged between 0.96% and 0.6% (whole cohort) but the rate depended upon the era and screening methodology used. Universal screening detected a higher numbers of anti-HCV positive women during pregnancy, including those not previously aware of their hepatitis C. While there was not significant drop in seroprevalence in pregnant women between 2016 and 2019, we observed that the ratio of HCV RNA positive to anti-HCV positive women has declined over time, from 0.86% in 2016 (100% HCV RNA+) to 0.28% in 2019 (33% HCV RNA+) for whole cohort probably due to increased HCV treatment rates from 2016. These data have important implications for hepatitis C testing in pregnancy and the appropriate methodology to use for maximal accuracy.

Hepatitis delta genotype 5 is associated with favourable disease outcome and better response to treatment compared to genotype 1.

BACKGROUND & AIMS: Coinfection with HDV causes rapid progression to liver cirrhosis and hepatic decompensation in patients with chronic hepatitis B. Factors that are associated with disease progression are poorly understood. In this study we aim to identify risk factors associated with disease progression and better characterise clinical differences and treatment response between HDV genotype 1 and 5. METHODS: In this retrospective study, all patients under our care between 2005 and 2016 with HBV/HDV coinfection (HBsAg+, anti-HDV antibodies positive) were analysed. Patients were excluded if follow-up was less than 6 months, if they had HCV and/or HIV coinfection or an acute HDV infection. Demographic data, stage of liver disease, development of liver complications and treatment response were recorded. RESULTS: One-hundred seven patients (mean age 36.0 years, 57% male) were followed for a median period of 4.4 years (range 0.6-28.1 years); 64% were of African origin and 17% were of European origin, with 28% of patients being cirrhotic at first visit; 43% patients had actively replicating HDV virus (anti-HDV-IgG+, anti-HDV-IgM+ or HDV RNA+) and 57% of patients were HDV exposed (anti-HDV-IgG+, HDV RNA-). Patients with actively replicating HDV more often developed liver complications than HDV-exposed patients (p = 0.002), but no differences in baseline characteristics were observed. Patients with HDV genotype 5 less often developed cirrhosis or hepatic decompensation compared to patients with HDV genotype 1. Twenty-four patients were treated with peg-IFN and post-treatment response was significantly better in patients infected with genotype 5 (10% GT1 vs. 64% GT5, p = 0.013). CONCLUSION: Patients infected with HDV genotype 5 appear to have a better prognosis with fewer episodes of hepatic decompensation and better response to peg-IFN treatment than patients infected with HDV genotype 1. LAY SUMMARY: Hepatitis delta is a virus that affects the liver. The virus is known to have different subtypes, called genotypes. With this research we discovered that hepatitis delta virus genotype 1 behaves differently than genotype 5 and causes faster development of liver disease. This is important for education of our patients and to determine how often we need to check our patients.

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C.

BACKGROUND & AIMS: HCV subtypes which are unusual in Europe are more prevalent in the African region, but little is known of their response to direct-acting antivirals (DAAs). These include non-1a/1b/ non-subtypeable genotype 1 (G1) or non-4a/4d (G4). In this report we aimed to describe the genotype distribution and treatment outcome in a south London cohort of African patients. METHODS: We identified all patients born in Africa who attended our clinic from 2010-2018. Information on HCV genotype, treatment regimen and outcome were obtained. Non-subtypeable samples were analysed using Glasgow NimbleGen next-generation sequencing (NGS). Phylogenetic analysis was carried out by generating an uncorrected nucleotide p-distance tree from the complete coding regions of our sequences. RESULTS: Of 91 African patients, 47 (52%) were infected with an unusual subtype. Fourteen novel, as yet undesignated subtypes (G1*), were identified by NGS. Three individuals were infected with the same subtype, now designated as subtype 1p. Baseline sequences were available for 22 patients; 18/22 (82%) had baseline NS5A resistance-associated substitutions (RASs). Sustained virological response (SVR) was achieved in 56/63 (89%) overall, yet only in 21/28 (75%) of those with unusual G1 subtypes, with failure in 3/16 G1*, 1/2 G1p and 3/3 in G1l. Six treatment failures occurred with sofosbuvir/ledipasvir compared to 1 failure on a PI-based regimen. The SVR rate for all other genotypes and subtypes was 35/35 (100%). CONCLUSIONS: Most individuals in an unselected cohort of African patients were infected with an unusual genotype, including novel subtype 1p. The SVR rate of those with unusual G1 subtypes was 75%, raising concern about expansion of DAAs across Africa. Depending on the regimen used, higher failure rates in African cohorts could jeopardise HCV elimination. LAY SUMMARY: Direct-acting antiviral medications are able to cure hepatitis C in the majority of patients. The most common genotype of hepatitis C in Europe and the United States is genotype 1a or 1b and most clinical trials focused on these genotypes. We report that in a group of African patients, most of them had unusual (non-1a/1b) genotype 1 subtypes, and that the cure rate in these unusual genotypes was lower than in genotypes 1a and 1b.

Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders.

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.

Cost-Effectiveness Analysis of Alternative Antiviral Strategies for the Treatment of HBeAg-Positive and HBeAg-Negative Chronic Hepatitis B in the United Kingdom.

BACKGROUND: Seven drugs are licensed for the treatment of chronic hepatitis B (CHB) in the United Kingdom. Which initial treatment, secondary therapy, and whether antivirals should be given alone or in combination are questions of considerable uncertainty. OBJECTIVE: The aim of this model was to undertake a comprehensive economic evaluation of all antiviral treatments for CHB to recommend the most cost-effective therapeutic sequence. METHODS: We developed a probabilistic Markov model to compare the cost-effectiveness of all clinically relevant antiviral treatment sequences for nucleos(t)ide-naive adults with hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative CHB. Relative rates of HBeAg seroconversion and viral suppression were obtained from a network meta-analysis. Data on mortality, antiviral drug resistance, durability of response, adverse events, and costs were obtained from published literature. Results are reported in terms of lifetime costs, quality-adjusted life-years (QALYs), and expected net benefit. RESULTS: In the base-case analysis, pegylated interferon alpha-2a (peg-IFN α-2a) followed by tenofovir disoproxil fumarate was most effective and cost-effective in HBeAg-positive patients, with a cost of £7488 per QALY gained compared with no treatment. In HBeAg-negative patients, peg-IFN α-2a followed by entecavir was most effective and cost-effective, with a cost of £6981 per QALY gained. The model was robust to a wide range of sensitivity analyses. CONCLUSIONS: Peg-IFN α-2a followed by tenofovir disoproxil fumarate or entecavir is the most effective antiviral treatment strategy for people with both variants of CHB. At a cost of less than £10,000 per QALY gained, these sequences are considered cost-effective in England and Wales. The results of this analysis were used to inform 2013 National Institute for Health and Care Excellence guideline recommendations.

Treatment of chronic hepatitis B virus infection in resource-constrained settings: expert panel consensus.

Most of the estimated 350 million people with chronic hepatitis B virus (HBV) infection live in resource-constrained settings. Up to 25% of those persons will die prematurely of hepatocellular carcinoma (HCC) or cirrhosis. Universal hepatitis B immunization programmes that target infants will have an impact on HBV-related deaths several decades after their introduction. Antiviral agents active against HBV are available; treatment of HBV infection in those who need it has been shown to reduce the risk of HCC and death. It is estimated that 20-30% of persons with HBV infection could benefit from treatment. However, drugs active against HBV are not widely available or utilized in persons infected with HBV. Currently recommended antiviral agents used for treatment of human immunodeficiency virus (HIV) infection do not adequately suppress HBV, which is of great concern for the estimated 10% of the HIV-infected persons in Africa who are co-infected with HBV. Progressive liver disease has been shown to occur in co-infected persons whose HBV infection is not suppressed. In view of these concerns, an informal World Health Organization consultation of experts concluded that: chronic HBV is a major public health problem in emerging nations; all HIV-infected persons should be screened for HBV infection; HIV/HBV co-infected persons should be treated with therapies active against both viruses and that reduce the risk of resistance; standards for the management of chronic HBV infection should be adapted to resource-constrained settings. In addition, a research agendum was developed focusing on issues related to prevention and treatment of chronic HBV in resource-constrained settings.

Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom.

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central [adjusted odds ratio (aOR) 2.40 (95% confidence interval (CI) 1.23--4.67) and West [2.10 (1.29-3.41)] African ancestry was associated with HBV and Central [6.98 (2.00-24.43)] African ancestry with HCV.

Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection.

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically "tolerant" since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.

Cost-utility analysis of tenofovir disoproxil fumarate in the treatment of chronic hepatitis B.

OBJECTIVE: The aim of this study was to assess the cost-effectiveness of tenofovir disoproxil fumarate (TDF) in the treatment of chronic hepatitis B (CHB) versus alternative nucleos(t)ides from a UK National Health Service (NHS) perspective. METHODS: A Markov model was used to calculate costs and benefits of nucleos(t)ide strategies in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with hepatitis B virus mono-infection and compensated liver disease. The model included 18 disease states representing CHB progression. Quality-of-life data and costs for severe disease states were based on published studies, while monitoring costs for other disease states were based on expert opinion. Transition probabilities for movements between states were based on a meta-analysis, clinical trials, and natural history studies. RESULTS: First-line TDF generated the highest net benefits of all 211 nucleos(t)ide strategies evaluated at a threshold of £ 20,000 per quality-adjusted life-year (QALY) gained. First-line TDF cost £ 19,084/QALY gained compared with giving lamivudine (LAM) first-line and switching to TDF when LAM resistance occurs. First-line TDF was also more effective and less costly than first-line entecavir (ETV), and showed extended dominance over first-line adefovir and strategies reserving adefovir, ETV, or combination therapy until after LAM resistance develops. For patients who have developed LAM resistance, TDF was also the most cost-effective treatment, generating greater net benefits than any other second-line strategy. CONCLUSIONS: First-line TDF is the most cost-effective treatment for patients with CHB at a £ 20,000 to £ 30,000/QALY ceiling ratio, costing £ 19,084/QALY gained compared with the next best alternative.

Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission.

Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.

Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramers.

Hepatitis C virus (HCV) has infected over 170 million people world wide, and in the majority sets up a chronic infection associated with hepatic inflammation. How it evades host immunity, particularly CD8+ T cells (CTL) is unclear, but two major factors are likely to operate, viral escape mutation and T cell exhaustion. We have investigated the role of CTL in control of infection during acute disease using Class I peptide tetramers. Although the immune response is quite diverse and numerous epitopes can be targeted, we observe that, especially during acute disease, one epitope (NS3 1073-81) is commonly recognised in HLA-A2 positive individuals. However, the levels of response to this epitope (and others) are very much lower if persistence is established. We examined in detail whether the cause of this low level of reactivity is due to mutation within the epitope. We find that, in fact this epitope is highly conserved during chronic infection, at a clonal level, between individuals, and over time. Thus, although variation within the epitope does occur, lack of reactivity in peripheral blood against this epitope in chronic disease, and loss of control of virus cannot be explained entirely by viral escape. Escape through mutation probably does play an important role in persistence of HCV, but we also discuss other mechanisms which lead to attenuation of T cell responses which may be important in determining the outcome.

Telaprevir or boceprevir based therapy for chronic hepatitis C infection: development of resistance-associated variants in treatment failure.

The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics.

A genetic analysis of hepatitis C virus transmission between injection drug users.

Hepatitis C virus (HCV) genotype 1a and 3a partial NS5B gene segment sequences obtained from 154 HCV-infected injection drug users were studied to determine the extent to which HCV transmission occurs between injection drug user communities in London, Edinburgh, Glasgow (United Kingdom), Marseilles (France), and Melbourne. Phylogenetic relationships between sequences were analyzed by conventional methods and by a recently developed method that numerically scores the extent of sequence segregation between groups through calculation of association indices. The association indices revealed that none of the cities sampled support an HCV population that is completely isolated from that circulating in the other cities. Sequences from Melbourne were most isolated, whereas those from London were most dispersed. This suggests that HCV transmission between these cities occurs, with London playing a pivotal role. The degree of city-specific segregation of HCV subtype 1a sequences was linearly related to that of subtype 3a, indicating that these subtypes have spread through similar transmission networks.

Frequency and phenotype of circulating Valpha24/Vbeta11 double-positive natural killer T cells during hepatitis C virus infection.

Natural killer T (NKT) cells are thought to be involved in innate responses against infection. We investigated one specific type of NKT cell, Valpha24/Vbeta11 double positive, in hepatitis C virus (HCV) infection. Lower frequencies of this population were detected in the blood of HCV PCR-positive patients than in controls. Unlike Valpha24/Vbeta11 NKT cells found in blood, those in the liver appeared to be recently activated.

Long-term patterns of hepatitis C virus RNA concentrations in a cohort of HIV seronegative men with bleeding disorders.

Little is known about the natural history of hepatitis C virus (HCV) RNA concentrations over the course of infection. The aim of this study was to describe the natural history of HCV RNA concentrations in 85 HIV negative men with bleeding disorders infected with HCV for up to 30 years. HCV RNA concentrations were measured in yearly serum samples using a branched DNA assay. HCV RNA concentrations increased over time in this cohort. Two years after exposure to HCV, 53% of patients had undetectable concentrations and no patients had levels >7 log(10)(genome Eq/ml); by 20 years, these proportions had changed to 23% and 32% respectively. The RNA concentration correlated strongly with alanine aminotransferase (ALT; correlations of 0.41-0.71 depending on stage of infection) and aspartate aminotransferase (AST; 0.20-0.51) levels. Patients with haemophilia A had significantly higher HCV concentrations than those with other disorders. An effect of HCV genotype on HCV RNA concentrations became nonsignificant after excluding patients who were persistently HCV PCR negative and who could not be genotyped. The correlation of HCV RNA concentrations with other markers of liver function, such as ALT, means that studies with clinical outcomes are required to assess whether HCV RNA concentrations provide additional prognostic information to that provided by these other markers.