Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

BACKGROUND: Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM: To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS: This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS: Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION: Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

The complex, confusing and poorly understood immune responses to AAV-mediated gene transfer in haemophilia-Is more or less immunosuppression required?

Attempts to achieve a functional cure or amelioration of the severe X linked bleeding disorders haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) using AAV-based vectors have been frustrated by immune responses that limit efficacy and durability. The immune responses include adaptive and innate pathways as well as cytokine mediated inflammation, especially of the target organ cells-hepatocytes. Immune suppression has only been partly effective in clinical trials at ameliorating the immune response and the lack of good animal models has delayed progress in identifying mechanisms and developing more effective approaches to controlling these effects of AAV gene transfer. Here we discuss the arguments for and against more potent immunosuppression to improve factor expression after AAV-mediated gene therapy.

Hepatitis after gene therapy, what are the possible causes?

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.

Adeno-associated viruses for gene therapy - clinical implications and liver-related complications, a guide for hepatologists.

Gene therapy has garnered increasing interest over recent decades. Several therapies employing gene transfer mechanisms have been developed, and, of these, adeno-associated virus (AAV) vectors have demonstrated viability for use with in vivo gene therapy. Several AAV-based therapeutics have received regulatory approval in the last few years including those for retinal disease, spinal muscular atrophy or aromatic L-amino acid decarboxylase deficiency. Lately, with the introduction of novel liver-directed AAV vector-based therapeutics for the treatment of haemophilia A and B, gene therapy has attracted significant attention in the hepatology community, with the liver increasingly recognised as a target for gene therapy. However, the introduction of foreign DNA into hepatocytes is associated with a risk of hepatic reactions, with raised ALT (alanine aminotransferase) and AST (aspartate aminotransferase) being - so far - the most commonly reported side effects. The complete mechanisms underlying the ALT flairs remain to be determined and the long-term risks associated with these new treatments is not yet known. The liver community is increasingly being asked to support liver-directed gene therapy to mitigate potential liver associated harm. In this review, we focus on AAV vector-based gene therapy, shedding light on this promising technique and its remarkable success in haemophilia, with a special focus on hepatic complications and their management in daily clinical practice.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

Liver-related aspects of gene therapy for hemophilia: need for collaborations with hepatologists.

Adeno-associated virus-based gene therapies hemophilia allow long-term transgene expression with reduced annual bleeding rates. Various liver-related aspects are involved in the different phases of gene therapy, such as assessment of liver health in the pretherapy period, patient selection and follow-up, maintenance of liver health after gene therapy, and management of potential short- and long-term adverse events. Increase in alanine aminotransferease is a common adverse event that requires rapid evaluation and an immunosuppressive approach. It is therefore important that hemophilia treaters and hepatologists collaborate at all stages of gene therapy to assess potential safety issues and ensure the long-term success of gene therapy. Special attention should be given to patients with not well-defined conditions, e.g. patients with some degree of liver fibrosis or fatty liver disease, patients with a history of hepatitis C and hepatitis B infection, patients with HIV infection, and patients taking medications that may affect liver function.

Depression, anxiety, substance misuse and self-harm in children and young people with rare chronic liver disease.

The burden of mental illness in young people with chronic liver disease is not known. In this population cohort study in England, we identified 358 individuals (aged ≤25 years) diagnosed with autoimmune hepatitis or liver disease related to cystic fibrosis and 1541 propensity-score-matched controls. By the first year of follow-up, the cumulative burden of psychiatric events in participants with liver disease was high compared with controls: anxiety disorder (6.87 per 100 individuals [95% CI 4.00-9.73] v. 2.22 [95% CI 1.37-3.07]), depression (5.10 [95% CI 2.83-7.37] v. 0.86 [95% CI 0.53-1.19]), substance misuse (10.61 [95% CI 9.50-11.73] v. 1.23 [95% CI 0.71-1.75]) and self-harm (3.09 [95% CI 1.12-5.05] v. 0.20 [95% CI 0.07-0.33]). Participants with liver disease had a 2-fold increase (OR = 1.94, 95% CI 1.45-2.58), a 2.5-fold increase (OR = 2.59, 95% CI 1.91-3.50) and 4.4-fold increase (OR = 4.44; 95% CI 3.46-5.71) in the risk of anxiety, depression and substance misuse, respectively. These findings highlight the need for effective intervention in psychiatric disorders in young people with rare liver disease.

Increased burden of cardiovascular disease in people with liver disease: unequal geographical variations, risk factors and excess years of life lost.

BACKGROUND: People with liver disease are at increased risk of developing cardiovascular disease (CVD), however, there has yet been an investigation of incidence burden, risk, and premature mortality across a wide range of liver conditions and cardiovascular outcomes. METHODS: We employed population-wide electronic health records (EHRs; from 1998 to 2020) consisting of almost 4 million adults to assess regional variations in disease burden of five liver conditions, alcoholic liver disease (ALD), autoimmune liver disease, chronic hepatitis B infection (HBV), chronic hepatitis C infection (HCV) and NAFLD, in England. We analysed regional differences in incidence rates for 17 manifestations of CVD in people with or without liver disease. The associations between biomarkers and comorbidities and risk of CVD in patients with liver disease were estimated using Cox models. For each liver condition, we estimated excess years of life lost (YLL) attributable to CVD (i.e., difference in YLL between people with or without CVD). RESULTS: The age-standardised incidence rate for any liver disease was 114.5 per 100,000 person years. The highest incidence was observed in NAFLD (85.5), followed by ALD (24.7), HCV (6.0), HBV (4.1) and autoimmune liver disease (3.7). Regionally, the North West and North East regions consistently exhibited high incidence burden. Age-specific incidence rate analyses revealed that the peak incidence for liver disease of non-viral aetiology is reached in individuals aged 50-59 years. Patients with liver disease had a two-fold higher incidence burden of CVD (2634.6 per 100,000 persons) compared to individuals without liver disease (1339.7 per 100,000 persons). When comparing across liver diseases, atrial fibrillation was the most common initial CVD presentation while hypertrophic cardiomyopathy was the least common. We noted strong positive associations between body mass index and current smoking and risk of CVD. Patients who also had diabetes, hypertension, proteinuric kidney disease, chronic kidney disease, diverticular disease and gastro-oesophageal reflex disorders had a higher risk of CVD, as do patients with low albumin, raised C-reactive protein and raised International Normalized Ratio levels. All types of CVD were associated with shorter life expectancies. When evaluating excess YLLs by age of CVD onset and by liver disease type, differences in YLLs, when comparing across CVD types, were more pronounced at younger ages. CONCLUSIONS: We developed a public online app ( https://lailab.shinyapps.io/cvd_in_liver_disease/ ) to showcase results interactively. We provide a blueprint that revealed previously underappreciated clinical factors related to the risk of CVD, which differed in the magnitude of effects across liver diseases. We found significant geographical variations in the burden of liver disease and CVD, highlighting the need to devise local solutions. Targeted policies and regional initiatives addressing underserved communities might help improve equity of access to CVD screening and treatment.

The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation.

BACKGROUND & AIMS: Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino the acid polymorphism, A150V, in the polymerase (NS5B) of G3 HCV reduces response to sofosbuvir. We now demonstrate that this polymorphism alters the response to interferon alpha. METHODS: Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons. RESULTS: We show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild-type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis. CONCLUSIONS: These results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.

Estimated impact of the COVID-19 pandemic on cancer services and excess 1-year mortality in people with cancer and multimorbidity: near real-time data on cancer care, cancer deaths and a population-based cohort study.

OBJECTIVES: To estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer. METHODS: We employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England. RESULTS: Declines in urgent referrals (median=-70.4%) and chemotherapy attendances (median=-41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=-44.5%) and chemotherapy attendances (median=-31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity. CONCLUSIONS: Dramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

Hepatosplenic schistosomiasis in Zambian adults is characterized by increased liver stiffness: A nested case-control study.

Cirrhosis commonly complicates portal hypertension worldwide but in Zambia hepatosplenic schistosomiasis (HSS) dominates as the cause of portal hypertension. We need easier and non-invasive ways to assess HSS. Transient elastography (TE), a measure of liver stiffness can diagnose liver cirrhosis. TE remains unexplored in HSS patients, who generally have normal liver parenchyma. We aimed to explore liver stiffness in HSS. This nested case control study was conducted at the University Teaching Hospital, Lusaka, Zambia between January 2015 and January 2016. We enrolled 48 adults with HSS and 22 healthy controls. We assessed liver stiffness using TE while plasma hyaluronan was used to assess liver fibrosis. Plasma tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) were used to assess inflammation. The median (interquartile range) liver stiffness was higher in patients, 9.5 kPa (7.8, 12.8) than in controls, 4.7 kPa (4.0, 5.4), P < 0.0001. We noted linear correlations of hyaluronan and TNFR1 with the liver stiffness, P = 0.0307 and P = 0.0003 respectively. HSS patients seem to have higher liver stiffness than healthy controls. TE may be useful in identifying fibrosis in HSS. The positive correlations of inflammatory markers with TE suggest that HSS has both periportal and parenchymal pathophysiology.

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis.

The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected i.p. with caerulein or l-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and l-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels, including TNF-α and IL-10, and reduced NF-κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-α improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNF-α expression, but not histological injury or serum amylase. WT/Stat2-/- bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow-derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Final analysis of the international observational S-Collate study of peginterferon alfa-2a in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. METHODS: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. RESULTS: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions. CONCLUSIONS: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics.

Interferon lambda 4 impacts the genetic diversity of hepatitis C virus.

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

Seroprevalence and demographic factors associated with hepatitis B, hepatitis C and HIV infection from a hospital emergency department testing programme, London, United Kingdom, 2015 to 2016.

BackgroundProgress towards HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) elimination requires local prevalence estimates and linkage to care (LTC) of undiagnosed or disengaged cases.AimWe aimed to estimate seroprevalence, factors associated with positive blood-borne virus (BBV) serology and numbers needed to screen (NNS) to detect a new BBV diagnosis and achieve full LTC from emergency department (ED) BBV testing.MethodsDuring a 9-month programme in an ED in east London, England, testing was offered to adult attendees having a full blood count (FBC). We estimated factors associated with positive BBV serology using logistic regression and NNS as the inverse of seroprevalence. Estimates were weighted to the age, sex and ethnicity of the FBC population.ResultsOf 6,211 FBC patients tested, 217 (3.5%) were positive for at least one BBV. Weighted BBV seroprevalence was 4.2% (95% confidence interval (CI): 3.6-4.9). Adjusted odds ratios (aOR) of positive BBV serology were elevated among patients that were: male (aOR: 2.7; 95% CI: 1.9-3.9), 40-59 years old (aOR: 1.9; 95% CI: 1.4-2.7), of Black British/Black other ethnicity (aOR: 1.8; 95% CI: 1.2-2.8) or had no fixed address (aOR: 2.9; 95% CI: 1.5-5.5). NNS to detect a new BBV diagnosis was 154 (95% CI: 103-233) and 135 (95% CI: 93-200) to achieve LTC.ConclusionsThe low NNS suggests routine BBV screening in EDs may be worthwhile. Those considering similar programmes should use our findings to inform their assessments of anticipated public health benefits.

The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis.

BACKGROUND: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. AIM: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. METHODS: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation. RESULTS: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. CONCLUSION: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.

Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase Protein Affect Responses to Sofosbuvir.

BACKGROUND & AIMS: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. METHODS: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. RESULTS: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. CONCLUSIONS: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.

Safety and efficacy of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C in patients aged 65 years or older.

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1-6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3-99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6-98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection.

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.