Reconstruction of the historic time course of blood-borne virus contamination of clotting factor concentrates, 1974-1992.

Factor VIII and IX clotting factor concentrates manufactured from pooled plasma have been identified as potent sources of virus infection in persons with hemophilia (PWHs) in the 1970s and 1980s. To investigate the range and diversity of viruses over this period, we analysed 24 clotting factor concentrates for several blood-borne viruses. Nucleic acid was extracted from 14 commercially produced clotting factors and 10 from nonremunerated donors, preserved in lyophilized form (expiry dates: 1974-1992). Clotting factors were tested by commercial and in-house quantitative PCRs for blood-borne viruses hepatitis A, B, C and E viruses (HAV, HBV, HCV, HEV), HIV- types 1/2, parvoviruses B19V and PARV4, and human pegiviruses types 1 and 2 (HPgV-1,-2). HCV and HPgV-1 were the most frequently detected viruses (both 14/24 tested) primarily in commercial clotting factors, with frequently extremely high viral loads in the late 1970s-1985 and a diverse range of HCV genotypes. Detection frequencies sharply declined following introduction of virus inactivation. HIV-1, HBV, and HAV were less frequently detected (3/24, 1/24, and 1/24 respectively); none were positive for HEV. Contrastingly, B19V and PARV4 were detected throughout the study period, even after introduction of dry heat treatment, consistent with ongoing documented transmission to PWHs into the early 1990s. While hemophilia treatment is now largely based on recombinant factor VIII/IX in the UK and elsewhere, the comprehensive screen of historical plasma-derived clotting factors reveals extensive exposure of PWHs to blood-borne viruses throughout 1970s-early 1990s, and the epidemiological and manufacturing parameters that influenced clotting factor contamination.

International review of blood donation screening for anti-HBc and occult hepatitis B virus infection.

BACKGROUND: Hepatitis B core antibody (anti-HBc) screening has been implemented in many blood establishments to help prevent transmission of hepatitis B virus (HBV), including from donors with occult HBV infection (OBI). We review HBV screening algorithms across blood establishments globally and their potential effectiveness in reducing transmission risk. MATERIALS AND METHODS: A questionnaire on HBV screening and follow-up strategies was distributed to members of the International Society of Blood Transfusion working party on transfusion-transmitted infectious diseases. Screening data from 2022 were assimilated and analyzed. RESULTS: A total of 30 unique responses were received from 25 countries. Sixteen respondents screened all donations for anti-HBc, with 14 also screening all donations for HBV DNA. Anti-HBc prevalence was 0.42% in all blood donors and 1.19% in new donors in low-endemic countries; however, only 44% of respondents performed additional anti-HBc testing to exclude false reactivity. 0.68% of anti-HBc positive, HBsAg-negative donors had detectable HBV DNA. Ten respondents did universal HBV DNA screening without anti-HBc, whereas four respondents did not screen for either. Deferral strategies for anti-HBc positive donors were highly variable. One transfusion-transmission from an anti-HBc negative donor was reported. DISCUSSION: Anti-HBc screening identifies donors with OBI but also results in the unnecessary deferral of a significant number of donors with resolved HBV infection and donors with false-reactive anti-HBc results. Whilst confirmation of anti-HBc results could be improved to reduce donor deferral, transmission risks associated with anti-HBc negative OBI donors must be considered. In high-endemic areas, highly sensitive HBV DNA testing is required to identify infectious donors.

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups.

BACKGROUND AND OBJECTIVES: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti-HBc) prevents transfusion-transmitted HBV infection but can lead to significant donor loss. As isolated anti-HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti-HBc testing and the representation of rare blood groups in anti-HBc-positive donors. MATERIALS AND METHODS: Three hundred ninety-seven HBV surface antigen-negative and anti-HBc initially reactive blood donor samples were tested by five different anti-HBc assays. RESULTS: Eighty percentage of samples reactive in Architect anti-HBc assay were positive by the Murex assay and anti-HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty-eight percentage of anti-HBc-positive donors identified as minority ethnic groups compared with 11% representation in anti-HBc-negative donors (p < 0.0001); the frequency of the Ro blood group in anti-HBc-positive donors was 18 times higher in non-white ethnic groups. CONCLUSION: Using two anti-HBc assays effectively enabled the identification of HBV-exposed and potentially infectious donors, their deferral and potential clinical follow-up. However, the exclusion of confirmed anti-HBc-positive donors will still impact the supply of rare blood such as Ro.

Cost-Effectiveness of Hepatocellular Carcinoma Surveillance Strategies in Patients With Compensated Liver Cirrhosis in the United Kingdom.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness (CE) of 4 hepatocellular carcinoma (HCC) surveillance strategies in the United Kingdom, the GAAD algorithm, which combines Gender (biological sex) and Age with Elecsys® biomarker assays, alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (previously Des-γ-carboxy prothrombin); ultrasound (US); US + AFP and GAAD + US. METHODS: A de novo microsimulation state-transition Markov model was developed in Microsoft Excel® from the perspective of the United Kingdom National Health Service to calculate life-years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results. RESULTS: In a simulated cohort of 100 000 patients, discounted costs and QALYs per patient were £8663 and 6·066 for US, £9095 and 6·076 for US + AFP, £8719 and 6·078 for GAAD alone, and £9114 and 6·086 for GAAD + US. At a CE threshold of £20 000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD + US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence along with costs associated with diagnostic performance influence CE. CONCLUSION: Considering the cost of US and low incidence of HCC in the United Kingdom, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US + AFP. Although GAAD + US showed the highest QALY increase, GAAD alone is considered preferable regarding CE; however, better performance estimates for GAAD + US are needed to confirm.

Hepatitis C subtyping assay failure in UK patients born in sub-Saharan Africa: Implications for global treatment and elimination.

BACKGROUND AND AIMS: The newly developed direct-acting antivirals have revolutionized the treatment of chronic hepatitis C virus (HCV), with cure rates as high as 98% in some cohorts. Although genome sequencing has demonstrated that some subtypes of HCV naturally harbor drug resistance associated substitutions (RAS), these are often overlooked as "rarities." Furthermore, commercial subtyping assays and associated epidemiological findings are skewed towards Western cohorts and whole-genome sequencing can be problematic to deploy without significant infrastructure and training support. We thus aimed to develop a simple, robust and accurate HCV subtyping pipeline, to optimize and streamline molecular detection and sequence-based typing of diverse RAS-containing subtypes. METHODS: HCV serum derived from 146 individuals, whose likely source of infection was from sub-Saharan Africa (SSA) was investigated with a novel panel of single round polymerase chain reaction (PCR) assays targeting NS5B and NS5A genomic regions. Virus subtype assignments were determined by pairwise-distance analysis and compared to both diagnostic laboratory assignments and free-to-use online typing tools. RESULTS: Partial NS5A and NS5B sequences were respectively obtained from 131 to 135 HCV-positive patients born in 19 different countries from SSA but attending clinics in the UK. We determined that routine clinical diagnostic methods incorrectly subtyped 59.0% of samples, with a further 6.8% incorrectly genotyped. Of five commonly used online tools, Geno2Pheno performed most effectively in determining a subtype in agreement with pairwise distance analysis. CONCLUSION: This study provides a simple low-cost pathway to accurately subtype in SSA, guide regional therapeutic choice and assist global surveillance and elimination initiatives.

Scavenger receptor class B type I genetic variants associated with disease severity in chronic hepatitis C virus infection.

Analysis of host genetic polymorphisms is an increasingly important tool for understanding and predicting pathogenesis and treatment response of viral diseases. The gene locus of scavenger receptor class B type I (SR-BI), encoding a cell entry factor and receptor for hepatitis C virus (HCV), contains several genetic polymorphisms. We applied a probe extension assay to determine the frequency of six single nucleotide polymorphisms (SNPs) within the SR-BI gene locus in 374 individuals with history of HCV infection. In addition, SR-BI messenger RNA (mRNA) levels were analyzed in liver biopsy specimens of chronically infected HCV subjects. The rs5888 variant allele T was present at a higher frequency in subjects with advanced fibrosis (χ2 , p = 0.016) and after adjusting for age, duration of infection and alcohol intake as confounding factors. Haplotype analysis of SNP frequencies showed that a haplotype consisting of rs61932577 variant allele C and rs5888 variant allele T was associated with an increased risk of advanced liver fibrosis (defined by an Ishak score 4-6) (adjusted odds ratio 2.81; 95% confidence interval 1.06-7.46. p = 0.038). Carriers of the rs5888 variant allele T displayed reduced SR-BI mRNA expression in liver biopsy specimens. In conclusion the rs5888 polymorphism variant is associated with decreased SR-BI expression and an increased risk of development of advanced fibrosis in chronic HCV infection. These findings provide further evidence for a role of SR-BI in HCV pathogenesis and provides a genetic marker for prediction of those infected individuals at greater risk of developing severe disease.

Ultrasensitive PCR system for HBV DNA detection: Risk stratification for occult hepatitis B virus infection in English blood donors.

Occult hepatitis B (HBV) infection (OBI), characterized by low viral loads, accounts for much of the risk of HBV transfusion-transmitted infection. With anticore antibodies (anti-HBc) screening introduced in England, the imperative to identify OBI donors has increased. We aimed to develop an ultra-sensitive PCR system and investigate risk factors for HBV DNA presence in blood donations. Seven extraction methods and three PCR assays were compared. The optimal system was sought to determine HBV DNA presence in anti-HBc-positive donations. Predictors of DNA positivity were subsequently investigated. Extraction from 5 mL of plasma increased sample representation and resulted in HBV DNA detection in low viral load samples (~0.5 IU/mL). Screening of 487 763 donations in 2022 identified two OBI donors and 2042 anti-HBc-positive donors, 412 of the latter with anti-HBs < 100 mIU/mL. Testing of 134 anti-HBc-positive donations utilizing the 5 mL extraction method identified two further HBV DNA-positive donations. Higher anti-HBc titer and anti-HBs negativity were significant predictors of DNA detectability in anti-HBc-positive donations. An ultrasensitive PCR assay identified potentially infectious donations increasing HBV DNA detection in anti-HBc-positive donors from 0.5% to 1.9%. Anti-HBc titers may further complement the risk stratification for DNA positivity in anti-HBc screening and minimize unnecessary donor deferral.

Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK.

BACKGROUND: Previous studies show the uptake of biannual ultrasound (US) surveillance in patients with cirrhosis is suboptimal. Here, our goal was to understand in broader terms how surveillance is being delivered to cirrhosis patients with cured hepatitis C in the UK. METHODS: Hepatitis C cirrhosis patients achieving a sustained viral response (SVR) to antiviral therapies were identified from the national Hepatitis-C-Research-UK resource. Data on (i) liver/abdominal US examinations, (ii) HCC diagnoses, and (iii) HCC curative treatment were obtained through record-linkage to national health registries. The rate of US uptake was calculated by dividing the number of US episodes by follow-up time. RESULTS: A total of 1908 cirrhosis patients from 31 liver centres were followed for 3.8 (IQR: 3.4-4.9) years. Overall, 10 396 liver/abdominal USs were identified. The proportion with biannual US was 19% in the first 3 years after SVR and 9% for all follow-up years. Higher uptake of biannual US was associated with attending a liver transplant centre; older age and cirrhosis decompensation. Funnel plot analysis indicated significant inter-centre variability in biannual US uptake, with 6/29 centres outside control limits. Incident HCC occurred in 133 patients, of which 49/133 (37%) were treated with curative intent. The number of US episodes in the two years prior to HCC diagnosis was significantly associated with higher odds of curative-intent treatment (aOR: 1.53; 95% CI: 1.12-2,09; p = .007). CONCLUSIONS: This study provides novel data on the cascade of care for HCC in the UK. Our findings suggest biannual US is poorly targeted, inefficient and is not being delivered equitably to all patients.

Geographical variation in hepatitis C-related severe liver disease and patient risk factors: a multicentre cross-sectional study.

Despite promising steps towards the elimination of hepatitis C virus (HCV) in the UK, several indicators provide a cause for concern for future disease burden. We aimed to improve understanding of geographical variation in HCV-related severe liver disease and historic risk factor prevalence among clinic attendees in England and Scotland. We used metadata from 3829 HCV-positive patients consecutively enrolled into HCV Research UK from 48 hospital centres in England and Scotland during 2012-2014. Employing mixed-effects statistical modelling, several independent risk factors were identified: age 46-59 y (ORadj 3.06) and ≥60 y (ORadj 5.64) relative to <46 y, male relative to female sex (ORadj 1.58), high BMI (ORadj 1.73) and obesity (ORadj 2.81) relative to normal BMI, diabetes relative to no diabetes (ORadj 2.75), infection with HCV genotype (GT)-3 relative to GT-1 (ORadj 1.75), route of infection through blood products relative to injecting drug use (ORadj 1.40), and lower odds were associated with black ethnicity (ORadj 0.31) relative to white ethnicity. A small proportion of unexplained variation was attributed to differences between hospital centres and local health authorities. Our study provides a baseline measure of historic risk factor prevalence and potential geographical variation in healthcare provision, to support ongoing monitoring of HCV-related disease burden and the design of risk prevention measures.

Increasing SARS-CoV-2 seroprevalence among UK pediatric patients on dialysis and kidney transplantation between January 2020 and August 2021.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was officially declared a pandemic by the World Health Organisation (WHO) on 11 March 2020, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the world. We investigated the seroprevalence of anti-SARS-CoV-2 antibodies in pediatric patients on dialysis or kidney transplantation in the UK. METHODS: Excess sera samples were obtained prospectively during outpatient visits or haemodialysis sessions and analysed using a custom immunoassay calibrated with population age-matched healthy controls. Two large pediatric centres contributed samples. RESULTS: In total, 520 sera from 145 patients (16 peritoneal dialysis, 16 haemodialysis, 113 transplantation) were analysed cross-sectionally from January 2020 until August 2021. No anti-SARS-CoV-2 antibody positive samples were detected in 2020 when lockdown and enhanced social distancing measures were enacted. Thereafter, the proportion of positive samples increased from 5% (January 2021) to 32% (August 2021) following the emergence of the Alpha variant. Taking all patients, 32/145 (22%) were seropositive, including 8/32 (25%) with prior laboratory-confirmed SARS-CoV-2 infection and 12/32 (38%) post-vaccination (one of whom was also infected after vaccination). The remaining 13 (41%) seropositive patients had no known stimulus, representing subclinical cases. Antibody binding signals were comparable across patient ages and dialysis versus transplantation and highest against full-length spike protein versus spike subunit-1 and nucleocapsid protein. CONCLUSIONS: Anti-SARS-CoV-2 seroprevalence was low in 2020 and increased in early 2021. Serological surveillance complements nucleic acid detection and antigen testing to build a greater picture of the epidemiology of COVID-19 and is therefore important to guide public health responses. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Impact of Real-Time Whole-Genome Sequencing in Controlling Healthcare-Associated SARS-CoV-2 Outbreaks.

Nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have severely affected bed capacity and patient flow. We utilized whole-genome sequencing (WGS) to identify outbreaks and focus infection control resources and intervention during the United Kingdom's second pandemic wave in late 2020. Phylogenetic analysis of WGS and epidemiological data pinpointed an initial transmission event to an admission ward, with immediate prior community infection linkage documented. High incidence of asymptomatic staff infection with genetically identical viral sequences was also observed, which may have contributed to the propagation of the outbreak. WGS allowed timely nosocomial transmission intervention measures, including admissions ward point-of-care testing and introduction of portable HEPA14 filters. Conversely, WGS excluded nosocomial transmission in 2 instances with temporospatial linkage, conserving time and resources. In summary, WGS significantly enhanced understanding of SARS-CoV-2 clusters in a hospital setting, both identifying high-risk areas and conversely validating existing control measures in other units, maintaining clinical service overall.

Serum Levels of Proinflammatory Lipid Mediators and Specialized Proresolving Molecules Are Increased in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 and Correlate With Markers of the Adaptive Immune Response.

BACKGROUND: Specialized proresolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and to identify potential relationships with innate responses and clinical outcome. METHODS: Serum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age- and sex-matched controls collected prior to the pandemic (SARS-CoV-2 negative), were processed for quantification of bioactive lipids and anti-nucleocapsid and anti-spike quantitative binding assays. RESULTS: SARS-CoV-2 serum had significantly higher concentrations of omega-6-derived proinflammatory lipids and omega-6- and omega-3-derived SPMs, compared to the age- and sex-matched SARS-CoV-2-negative group, which were not markedly altered by age or sex. There were significant positive correlations between SPMs, proinflammatory bioactive lipids, and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid were significantly lower in SARS-CoV-2 patients who died. CONCLUSIONS: SARS-CoV-2 infection was associated with increased levels of SPMs and other pro- and anti-inflammatory bioactive lipids, supporting the future investigation of the underlying enzymatic pathways, which may inform the development of novel treatments.

Real-World Outcomes of Direct-Acting Antiviral Treatment and Retreatment in United Kingdom-Based Patients Infected With Hepatitis C Virus Genotypes/Subtypes Endemic in Africa.

BACKGROUND: Chronic hepatitis C virus (HCV) infection affects 71 million individuals, mostly residing in low- and middle-income countries (LMICs). Direct-acting antivirals (DAAs) give high rates of sustained virological response (SVR) in high-income countries where a restricted range of HCV genotypes/subtypes circulate. METHODS: We studied United Kingdom-resident patients born in Africa to examine DAA effectiveness in LMICs where there is far greater breadth of HCV genotypes/subtypes. Viral genome sequences were determined from 233 patients. RESULTS: Full-length viral genomic sequences for 26 known subtypes and 5 previously unidentified isolates covering 5 HCV genotypes were determined. From 149 patients who received DAA treatment/retreatment, the overall SVR was 93%. Treatment failure was associated primarily with 2 subtypes, gt1l and gt4r, using sofosbuvir/ledipasvir. These subtypes contain natural resistance-associated variants that likely contribute to poor efficacy with this drug combination. Treatment failure was also significantly associated with hepatocellular carcinoma. CONCLUSIONS: DAA combinations give high SVR rates despite the high HCV diversity across the African continent except for subtypes gt1l and gt4r, which respond poorly to sofosbuvir/ledipasvir. These subtypes are widely distributed across Western, Central, and Eastern Africa. Thus, in circumstances where accurate genotyping is absent, ledipasvir and its generic compounds should not be considered as a recommended treatment option.

Sero-reactivity to three distinct regions within the hepatitis C virus alternative reading frame protein (ARFP/core+1) in patients with chronic HCV genotype-3 infection.

Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three -20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.

Retrospective screening of routine respiratory samples revealed undetected community transmission and missed intervention opportunities for SARS-CoV-2 in the United Kingdom.

In the early phases of the SARS coronavirus type 2 (SARS-CoV-2) pandemic, testing focused on individuals fitting a strict case definition involving a limited set of symptoms together with an identified epidemiological risk, such as contact with an infected individual or travel to a high-risk area. To assess whether this impaired our ability to detect and control early introductions of the virus into the UK, we PCR-tested archival specimens collected on admission to a large UK teaching hospital who retrospectively were identified as having a clinical presentation compatible with COVID-19. In addition, we screened available archival specimens submitted for respiratory virus diagnosis, and dating back to early January 2020, for the presence of SARS-CoV-2 RNA. Our data provides evidence for widespread community circulation of SARS-CoV-2 in early February 2020 and into March that was undetected at the time due to restrictive case definitions informing testing policy. Genome sequence data showed that many of these early cases were infected with a distinct lineage of the virus. Sequences obtained from the first officially recorded case in Nottinghamshire - a traveller returning from Daegu, South Korea - also clustered with these early UK sequences suggesting acquisition of the virus occurred in the UK and not Daegu. Analysis of a larger sample of sequences obtained in the Nottinghamshire area revealed multiple viral introductions, mainly in late February and through March. These data highlight the importance of timely and extensive community testing to prevent future widespread transmission of the virus.

Impact of direct-acting antiviral agents on liver function in patients with chronic hepatitis C virus infection.

Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3 years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.

Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy.

Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n = 55, GT3a n = 54) of the cohort. 40% (n = 58) of patients had liver cirrhosis of whom 7% (n = 4) were decompensated, 10% (n = 14) had hepatocellular carcinoma (HCC) and 8% (n = 12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR = 81%, p = .009), cirrhosis (47/58; SVR = 81%, p = .01) and prior treatment with SOF/VEL (12/17; SVR = 71%, p = .02) or SOF+DCV (14/19; SVR = 74%, p = .012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis. METHODS: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686). RESULTS: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%. CONCLUSIONS: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide. LAY SUMMARY: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.

Epidemiology and natural history of hepatitis C virus infection among children and young people.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is a global health burden. Although HCV infection rarely contributes to morbidity during childhood, most HCV-infected children develop chronic HCV with a lifetime risk of liver disease. Little is known about the development of long-term liver disease and the effect of treatment in patients infected with HCV in childhood. METHOD: This study was a retrospective review of patients infected with HCV in childhood enrolled in HCV Research UK. A total of 1,049 patients were identified and included. RESULTS: The main routes of infection were intravenous drug use (53%), blood product exposure (24%) and perinatal infection (11%). Liver disease developed in 32% of patients, a median of 33 years after infection, irrespective of the mode of infection. Therefore, patients with perinatal exposure developed cirrhosis at an earlier age than the rest of the risk groups. The incidence of hepatocellular carcinoma (HCC) was 5%, liver transplant 4% and death occurred in 3%. Overall, 663 patients were treated (55% with interferon/pegylated interferon and 40% with direct-acting antivirals). Sustained virological response (SVR) was achieved in 406 (75%). There was a higher mortality rate among patients without SVR vs. those with SVR (5% vs. 1%, p = 0.003). Treatment was more effective in patients without cirrhosis and disease progression was less frequent (13%) than in patients with cirrhosis at the time of therapy (28%) p < 0.001. Patients with cirrhosis were more likely to develop HCC, require liver transplantation, or die. CONCLUSION: HCV infection in young people causes significant liver disease, which can now be prevented with antiviral therapy. Early treatment, especially before development of cirrhosis is essential. Detection of HCV should be aimed at relevant risk groups and antiviral therapy should be made available in childhood to prevent long-term liver disease and spread of HCV. LAY SUMMARY: Chronic hepatitis C virus (HCV) infection is a global health problem, which can now be treated with potent direct-acting antiviral drugs. This study demonstrates that HCV infection in childhood causes serious liver disease in 32% of patients, a median of 33 years after infection, irrespective of age, mode and route of infection. Disease outcomes were better in patients treated before the development of advanced liver disease. Antiviral therapy should be made available in childhood to prevent long-term liver disease and the spread of HCV.

Testing for hepatitis C virus infection in UK prisons: What actually happens?

Prisons are a key demographic in the drive to eradicate hepatitis C virus (HCV) as a major public health threat. We have assessed the impact of the recently introduced national opt-out policy on the current status of HCV testing in 14 prisons in the East Midlands (UK). We analysed testing rates pre- and post-introduction of opt-out testing, together with face-to-face interviews with prison healthcare and management staff in each prison. In the year pre-opt-out, 1972 people in prison (PIP) were tested, compared to 3440 in the year following opt-out. From July 2016 to June 2017, 2706 people were tested, representing 13.5% of all prison entrants (median 16.6%, range 7.6%-40.7%). Factors correlating with testing rates were as follows: pre-admission location of the PIP (another prison or the community, OR 2.2, 95% CI 1.9-2.3, P < 0.001); whether the PIP could access health care independently of prison officers (OR 1.7, 95% CI 1.5-1.8, P < 0.001); the absence of out-reach services for HCV treatment (OR 1.3, 95% CI 1.2-1.5, P < 0.001), whether >50% of PIP reported ease of access to a nurse (OR 2.0, 95% CI 1.8-2.2, P < 0.001), and whether prison health care was supplied by private or NHS providers (OR 1.3, 95% CI 1.2-1.5, P < 0.001). Testing rates remained far below the minimum national opt-out target of 50%. Inadequacy of healthcare facilities and constraints imposed by adherence to prison regimens were cited by healthcare and management staff at all prisons. Without radical change, the prison estate may be intrinsically incapable of supporting NHSE to deliver the HCV elimination strategy.