Patient Biochemistry and Treatment Need in Chronic Hepatitis B Virus Infection Across Three Continents: Retrospective Cross-Sectional Cohort Studies.

INTRODUCTION: Chronic hepatitis B virus (HBV) infection is associated with significant global morbidity and mortality. Low treatment rates are observed in patients living with HBV; the reasons for this are unclear. This study sought to describe patients' demographic, clinical and biochemical characteristics across three continents and their associated treatment need. METHODS: This retrospective cross-sectional post hoc analysis of real-world data used four large electronic databases from the United States, United Kingdom and China (specifically Hong Kong and Fuzhou). Patients were identified by first evidence of chronic HBV infection in a given year (their index date) and characterized. An algorithm was designed and applied, wherein patients were categorized as treated, untreated but indicated for treatment and untreated and not indicated for treatment based on treatment status and demographic, clinical, biochemical and virological characteristics (age; evidence of fibrosis/cirrhosis; alanine aminotransferase [ALT] levels, HCV/HIV coinfection and HBV virology markers). RESULTS: In total, 12,614 US patients, 503 UK patients, 34,135 patients from Hong Kong and 21,614 from Fuzhou were included. Adults (99.4%) and males (59.0%) predominated. Overall, 34.5% of patients were treated at index (range 15.9-49.6%), with nucleos(t)ide analogue monotherapy most commonly prescribed. The proportion of untreated-but-indicated patients ranged from 12.9% in Hong Kong to 18.2% in the UK; almost two-thirds of these patients (range 61.3-66.7%) had evidence of fibrosis/cirrhosis. A quarter (25.3%) of untreated-but-indicated patients were aged ≥ 65 years. CONCLUSION: This large real-world dataset demonstrates that chronic hepatitis B infection remains a global health concern; despite the availability of effective suppressive therapy, a considerable proportion of predominantly adult patients apparently indicated for treatment are currently untreated, including many patients with fibrosis/cirrhosis. Causes of disparity in treatment status warrant further investigation.

The case for a universal hepatitis C vaccine to achieve hepatitis C elimination.

BACKGROUND: The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS: The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS: The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS: These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.

Non-invasive assessment of portal hypertension by multi-parametric magnetic resonance imaging of the spleen: A proof of concept study.

BACKGROUND AND AIMS: Non-invasive assessment of portal hypertension is an area of unmet need. This proof of concept study aimed to evaluate the diagnostic accuracy of a multi-parametric magnetic resonance technique in the assessment of portal hypertension. Comparison to other non-invasive technologies was a secondary aim. METHODS: T1 and T2* maps through the liver and spleen were acquired prior to trans-jugular liver biopsy and hepatic vein pressure gradient (HVPG) measurement. T1 measurements reflect changes in tissue water content, but this relationship is confounded by the presence of iron, which in turn can be quantified accurately from T2* maps. Data were analysed using LiverMultiScan (Perspectum Diagnostics, Oxford, UK) which applies an algorithm to remove the confounding effect of iron, yielding the "iron corrected T1" (cT1). Sensitivity, specificity, diagnostic values and area under the curve were derived for spleen cT1, liver cT1, transient elastography, and serum fibrosis scores. HVPG was the reference standard. RESULTS: Nineteen patients (15 men) with median age 57 years were included. Liver disease aetiologies included non-alcoholic fatty liver disease (n = 9; 47%) and viral hepatitis (n = 4; 21%). There was strong correlation between spleen cT1 and HVPG (r = 0.69; p = 0.001). Other non-invasive biomarkers did not correlate with HVPG. Spleen cT1 had excellent diagnostic accuracy for portal hypertension (HVPG >5 mmHg) and clinically significant portal hypertension (HVPG ≥10 mmHg) with an area under the receiver operating characteristic curve of 0.92 for both. CONCLUSION: Spleen cT1 is a promising biomarker of portal pressure that outperforms other non-invasive scores and should be explored further.

Modelling cost-effectiveness of tenofovir for prevention of mother to child transmission of hepatitis B virus (HBV) infection in South Africa.

BACKGROUND: International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the need to optimize strategies for prevention, diagnosis and treatment of hepatitis B virus (HBV) infection. An important priority for Africa is to have affordable, accessible and sustainable prevention of mother to child transmission (PMTCT) programmes, delivering screening and treatment for antenatal women and implementing timely administration of HBV vaccine for their babies. METHODS: We developed a decision-analytic model simulating 10,000 singleton pregnancies to assess the cost-effectiveness of three possible strategies for deployment of tenofovir in pregnancy, in combination with routine infant vaccination: S1: no screening nor antiviral therapy; S2: screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. Our outcome was cost per infant HBV infection avoided and the analysis followed a healthcare perspective. RESULTS: Based on 10,000 pregnancies, S1 predicts 45 infants would be HBV-infected at six months of age, compared to 21 and 28 infants in S2 and S3, respectively. Relative to S1, S2 had an incremental cost of $3940 per infection avoided. S3 led to more infections and higher costs. CONCLUSION: Given the long-term health burden for individuals and economic burden for society associated with chronic HBV infection, screening pregnant women and providing tenofovir for all who test HBsAg+ may be a cost-effective strategy for South Africa and other low/middle income settings.

Case finding and therapy for chronic viral hepatitis in primary care (HepFREE): a cluster-randomised controlled trial.

BACKGROUND: The prevalence of viral hepatitis (hepatitis B virus and hepatitis C virus) in migrants is higher than among the general population in many high-income countries. We aimed to determine whether incentivising and supporting primary-care physicians in areas with a high density of migrants increases the numbers of adult migrants screened for viral hepatitis. METHODS: HepFREE was a multicentre, open, cluster-randomised controlled trial in general practices in areas of the UK with a high density of migrants (Bradford, Yorkshire, and northeast and southeast London). Participants were adult patients (aged 18 years or older) in primary care, who had been identified as a first or second generation migrant from a high-risk country. General practices were randomly assigned (1:2:2:2:2) to an opportunistic screening (control) group or to one of four targeted screening (interventional) groups: standard (ie, hospital-based) care and a standard invitation letter; standard care and an enhanced invitation letter; community care and a standard invitation letter; or community care and an enhanced invitation letter. In control screening, general practitioners (GPs) were given a teaching session on viral hepatitis and were asked to test all registered migrants. In the intervention, GPs were paid a nominal sum for setting up searches of records, reimbursed for signed consent forms, and supported by a dedicated clinician. Patients who were eligible for testing and tested positive for viral hepatitis in the intervention groups were eligible to enrol in a second embedded trial of community versus hospital based care. The primary outcomes were the proportion of patients eligible for screening, the proportion of those eligible who were sent an invitation letter in the intervention groups, the uptake of viral hepatitis screening (in the intention-to-treat population), the proportion of patients who tested positive for viral hepatitis, the proportion who complied with treatment, and the cost-effectiveness of the intervention. This trial is registered with ISRCTN, number ISRCTN54828633. FINDINGS: Recruitment and testing ran from Oct 31, 2013, to Feb 4, 2017, and each practice recruited for 18 consecutive calendar months. We approached 70 general practices in three areas with a high density of migrants, of which 63 general practices agreed to participate. Five practices withdrew and 58 practices were randomly assigned: eight to control and 50 to an intervention. In control practices, 26 046 (38·4%) of 67 820 patients who were initially registered were eligible for testing, as were 152 321 (43·3%) of 351 710 patients in the interventional groups in London and Bradford. Of 51 773 randomly selected eligible patients in the intervention groups in London and Bradford, letters were sent to 43 585 (84·2%) patients. In the eight control general practices, screening was taken up by 543 (1·7%) of 31 738 eligible participants, which included 5692 newly registered patients. However, in the 50 general practices that used the intervention, screening was taken up by 11 386 (19·5%) of 58 512 eligible participants (including 6739 newly registered patients; incidence rate ratio 3·70, 95% CI 1·30-10·51; p=0·014) and this intervention was cost-effective. 720 (4·5%) of 15 844 patients who received a standard letter versus 1032 (3·7%) of 28 095 patients who received the enhanced letter were tested (0·70, 0·38-1·31; p=0·26). In the control group, 17 patients tested positive for viral hepatitis, as did 220 patients (one with a co-infection) in the intervention groups. In the embedded study, 220 patients were randomly assigned to either hospital-based care or community care; 80 (87·9%) of 91 patients in the hospital setting complied with treatment versus 105 (81·4%) of 129 patients in the community setting. The intervention was cost-effective at willingness to pay thresholds in excess of £8540. One serious adverse event (thyroiditis) was noted. INTERPRETATION: Screening migrants for viral hepatitis in primary care is effective if doctors are incentivised and supported. Community care is expensive and there is no evidence that this offers benefits in this setting or that bespoke invitation letters add value. We suggest that bespoke invitation letters should not be used, and we suggest that outreach, community-based services for migrants should not be developed. FUNDING: National Institute for Health Research.

Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity.

BACKGROUND & AIMS: The diagnosis of non-alcoholic steatohepatitis and fibrosis staging are central to non-alcoholic fatty liver disease assessment. We evaluated multiparametric magnetic resonance in the assessment of non-alcoholic steatohepatitis and fibrosis using histology as standard in non-alcoholic fatty liver disease. METHODS: Seventy-one patients with suspected non-alcoholic fatty liver disease were recruited within 1 month of liver biopsy. Magnetic resonance data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as non-alcoholic steatohepatitis or simple steatosis, and mild or significant (Activity ≥2 and/or Fibrosis ≥2 as defined by the Fatty Liver Inhibition of Progression consortium) non-alcoholic fatty liver disease. Transient elastography was also performed. RESULTS: Magnetic resonance success rate was 95% vs 59% for transient elastography (P<.0001). Fibrosis stage on biopsy correlated with liver inflammation and fibrosis (rs =.51, P<.0001). The area under the receiver operating curve using liver inflammation and fibrosis for the diagnosis of cirrhosis was 0.85. Liver inflammation and fibrosis score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (P<.05) with an area under the receiver operating characteristic curve of 0.83 for the diagnosis of ballooning. Patients with steatosis had lower liver inflammation and fibrosis (1.3) compared to patients with non-alcoholic steatohepatitis (3.0) (P<.0001); area under the receiver operating characteristic curve for the diagnosis of non-alcoholic steatohepatitis was 0.80. Liver inflammation and fibrosis scores for patients with mild and significant non-alcoholic fatty liver disease were 1.2 and 2.9 respectively (P<.0001). The area under the receiver operating characteristic curve of liver inflammation and fibrosis for the diagnosis of significant non-alcoholic fatty liver disease was 0.89. CONCLUSIONS: Multiparametric magnetic resonance is a promising technique with good diagnostic accuracy for non-alcoholic fatty liver disease histological parameters, and can potentially identify patients with non-alcoholic steatohepatitis and cirrhosis.

Comparison of Next-Generation Sequencing Technologies for Comprehensive Assessment of Full-Length Hepatitis C Viral Genomes.

Affordable next-generation sequencing (NGS) technologies for hepatitis C virus (HCV) may potentially identify both viral genotype and resistance genetic motifs in the era of directly acting antiviral (DAA) therapies. This study compared the ability of high-throughput NGS methods to generate full-length, deep, HCV sequence data sets and evaluated their utility for diagnostics and clinical assessment. NGS methods using (i) unselected HCV RNA (metagenomics), (ii) preenrichment of HCV RNA by probe capture, and (iii) HCV preamplification by PCR implemented in four United Kingdom centers were compared. Metrics of sequence coverage and depth, quasispecies diversity, and detection of DAA resistance-associated variants (RAVs), mixed HCV genotypes, and other coinfections were compared using a panel of samples with different viral loads, genotypes, and mixed HCV genotypes/subtypes [geno(sub)types]. Each NGS method generated near-complete genome sequences from more than 90% of samples. Enrichment methods and PCR preamplification generated greater sequence depth and were more effective for samples with low viral loads. All NGS methodologies accurately identified mixed HCV genotype infections. Consensus sequences generated by different NGS methods were generally concordant, and majority RAVs were consistently detected. However, methods differed in their ability to detect minor populations of RAVs. Metagenomic methods identified human pegivirus coinfections. NGS provided a rapid, inexpensive method for generating whole HCV genomes to define infecting genotypes, RAVs, comprehensive viral strain analysis, and quasispecies diversity. Enrichment methods are particularly suited for high-throughput analysis while providing the genotype and information on potential DAA resistance.

The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.

OBJECTIVE: Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity. DESIGN: T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed. RESULTS: In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1. CONCLUSIONS: HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.