Natural History, Therapy and Pathogenesis of Chronic Viral Hepatitis C

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Summary: Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis, decompensated liver disease and hepatocellular carcinoma (HCC) worldwide. Globally there are an estimated 58 million persons with HCV. In the United States (U.S.), 1% of the general population or 2.7 million persons have chronic infection based on the detection of HCV RNA in serum. Prior to the COVID-19 pandemic, chronic HCV infection was the leading infectious cause of death in the U.S. These figures underscore the magnitude and impact that chronic HCV infection has on global and US public health. The treatment of chronic HCV infection has been revolutionized with the development of direct acting antiviral (DAA) agents. For most genotypes response rates to treatment now approach 93-97%. What remains unclear is the long-term outcome of patients who are treated with DAAs. In particular, what proportion of patients continue to progress, what is the incidence of hepatocellular carcinoma and how quickly does liver fibrosis/cirrhosis regress are important questions that remain to be answered. Chronic HCV is also associated with a number of extrahepatic complications including diabetes, cardiovascular disease and malignancies such as B-cell lymphomas. Whether the risk of these complications decline after successful eradication of HCV is unknown. Hypotheses/problems addressed: 1) Define the host, viral and environmental factors that determine the natural history and outcome of HCV infection. To address this problem, we have an ongoing study to prospectively follow a cohort of ~100 subjects treated successfully with direct acting antiviral agents to define the long-term outcome of patients after eradication of hepatitis C virus. The two primary aims of the study are to determine prospectively the rate of clinical outcomes (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage), hepatocellular carcinoma, liver-related mortality and all-cause mortality in treatment recovered hepatitis C and to determine the proportion and rates of fibrosis regression in subjects after successful therapy of chronic hepatitis C. A major focus of the study will be to develop novel biomarkers and genetic predictors of liver-related complications including hepatocellular carcinoma. Approximately half of the patients have returned for the 5-year follow-up liver biopsy to date. Patients will be prospectively monitored for 10 years for outcomes. An interim analysis of patients who have available paired liver biopsies showed that most patients experienced histological improvement with substantial (mean 6-point) reduction in inflammation and 39% with complete resolution of fibrosis 8.5 years after achieving cure. The interferon lambda 4 (IFNL4)-ΔG allele, which results in production of IFNL4, is strongly linked to a lower chance of spontaneous HCV clearance and poorer response to interferon-based therapies. We hypothesize that production of autoantibodies against IFNL4 may be a host response to limit damage caused by HCV or an aberrant host response to non-physiological presence of IFNL4. Moreover, IFNL4 autoantibodies may cross-react with alpha interferon and thereby dampen the host response to endogenous and exogenous alpha interferon, leading to viral persistence and poor response to treatment, respectively. We will conduct a retrospective cohort study to assess the prevalence of autoantibodies to IFNL4 and IFN alpha and their role in response to interferon alpha treatment. 2) Assessment of cardiovascular risk after HCV eradication Chronic hepatitis C virus (HCV) infection is associated with hypolipidemia as HCV hijacks the host metabolism for its viral lifecycle. HCV eradication may, therefore, result in hyperlipidemia and an increased risk for cardiovascular disease (CVD). As part of a clinical trial to assess the safety and efficacy of sofosbuvir/velpatasvir in patients with chronic HCV infection genotypes 1-4 (Protocol 15-DK-0143), we integrated an ancillary study to investigate the very early impact of HCV eradication on serum lipid and lipoprotein profiles and to assess cardiovascular risk following therapy. We collected research specimens at very early timepoints during therapy (6, 24, 48 and 72 hours) and later, during and after the end-of-treatment to measure serum lipids, apolipoproteins, and a systemic inflammatory marker, GlycA. An NMR LipoProfile (a test that uses nuclear magnetic resonance to provide a detailed lipoprotein analysis) was performed on plasma samples. Expression of genes regulating lipid metabolism was assessed from paired liver biopsies obtained before and 4 weeks on-treatment. We demonstrated a rapid increase in lipid and lipoprotein particles and perturbation in insulin levels after starting treatment that was closely correlated with the rapid decline in viremia. Paradoxically, the decrease in viremia was associated with an increased expression of hepatic genes associated with de novo lipogenesis, particularly Sterol Regulatory Element-binding Protein 1 (SREBP1) and Transmembrane 6 superfamily member 2 (TM6SF2), the latter mediating an improvement in hepatic steatosis. The subsequent increase in lipid levels led to a transient increase in systemic inflammation, and together this may drive an increased cardiovascular risk as evidenced by an increase in short‐term cardiovascular risk using two well‐validated cardiovascular risk scoring systems, Framingham and Atherosclerotic Cardiovascular Disease (ASCVD). Our findings suggest that patients cured of chronic HCV infection should be monitored for long-term cardiovascular outcomes. Those with persistent dyslipidemia should be considered for risk lowering strategies. We are prospectively monitoring cardiovascular outcomes in the long-term natural history study described in aim 1. 3) Elucidate the role of microbiome in development of outcomes in patients with chronic HCV infection after anti-viral therapy There is a symbiotic relationship between gut microbiota and the host. Humans harbor 110 intestinal bacteria for each human cell. Although each person’s microbial profile is distinct, the relative abundance and composition of bacterial species are similar among healthy individuals. The intestinal microbiome plays a major role in the pathogenesis of liver disease. Dysbiosis, or an imbalance of pathobionts and beneficial bacteria can result in deleterious effects on the host. Dysbiosis has been associated with worsening fibrosis/cirrhosis in a number of chronic liver conditions. As part of the natural history study after virological cure we will be investigating the association between changes in the gut microbiome over time and correlating that with changes in hepatic fibrosis based upon two liver biopsies performed before and 5 years after antiviral therapy.