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Principal Investigator: Marc Ghany
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $502,831
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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 90-95%. 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 one-third 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.
Interferon lambda (IFNL) polymorphisms have been shown to be important predictors of spontaneous and interferon treatment-related clearance of HCV. We had previously shown that interferon lambda 4 polymorphisms were also associated with outcome of chronic infection and presence of variants that produce interferon lambda 4 resulted in greater hepatic necroinflammation and worse clinical outcomes in chronic hepatitis C. Which polymorphism/s of interferon lambda, interferon lambda 3 or 4, is/are responsible for mediating the hepatic inflammation, is an unresolved issue. In collaboration with Dr. Thomas O’Brien we demonstrated that IFNL4 genotypes that either eliminate IFN-λ4 or produce a weaker IFN-λ4 protein were associated with greater hepatic inflammation. Our findings suggest IFN-λ4 may have an anti-inflammatory role in the liver.
2) Assessment of cardiovascular risk after HCV eradication
Hepatitis C virus (HCV) exploits the host lipoprotein pathway for its lifecycle. Consequently, patients with chronic HCV have hypolipidemic profile. This observation suggests that sustained eradication of HCV might lead to dyslipidemia and increase risk for cardiovascular disease. Serial lipid panels and NMR-based lipoprotein profiles were assessed at multiple timepoints from fasting chronic HCV patients participating in a study evaluating sofosbuvir/velpatasvir for 12 weeks were evaluated. We demonstrated a marked rise in all lipoprotein parameters within the first 7 days of antiviral treatment associated with viral clearance. The increase in LDL and more importantly small LDL (the most atherogenic particle) persisted 24 weeks after treatment was stopped. As a follow-up we have shown by qPCR using paired liver biopsy samples that rapid clearance of HCV from hepatocytes appears to upregulate cholesterol, lipoprotein and fatty acid biosynthesis through induction of key regulators of lipid and lipoprotein metabolism. These results suggest that patients should be evaluated for cardiovascular risk post-SVR and assessed for lipid lowering therapy. This is being prospectively done 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.
Terms: <Active Follow-up><Address><After Care><After-Treatment><Aftercare><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Anti-viral Agents><Anti-viral Therapy><Ascites><B lymphoma><B-Cell Lymphomas><Bacteria><Biopsy Sample><Biopsy Specimen><Bleeding><Blood Serum><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cancers><Cardiovascular Diseases><Cause of Death><Cell Body><Cells><Cholesterol><Chronic><Chronic Hepatitis C><Chronic type C viral hepatitis><Chronic viral hepatitis C><Cirrhosis><Clinical><Collaborations><Detection><Development><Diabetes Mellitus><Dyslipidemias><Environmental Factor><Environmental Risk Factor><Extrahepatic><Fasting><Fibrosis><GI microbiome><GI microbiota><Gastrointestinal microbiota><General Population><General Public><Genetic Polymorphism><Genotype><HCV><HCV infection><Hemorrhage><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Encephalopathy><Hepatic Parenchymal Cell><Hepatitis C><Hepatitis C virus><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocerebral Encephalopathy><Hepatocyte><Hepatoma><Human><IFN><Incidence><Individual><Interferons><Intermediary Metabolism><Intestinal><Intestines><LDL><LDL Lipoproteins><Life Cycle><Life Cycle Stages><Lipids><Lipoproteins><Liver><Liver Cells><Liver Cells Carcinoma><Liver Fibrosis><Liver diseases><Liver lesion biopsy><Low-Density Lipoproteins><Malignant Neoplasms><Malignant Tumor><Mediating><Metabolic Processes><Metabolism><Modern Man><Monitor><Natural History><Outcome><Pathogenesis><Pathway interactions><Patient Participation><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peritonitis><Persons><Play><Portal-Systemic Encephalopathy><Portosystemic Encephalopathy><Primary carcinoma of the liver cells><Proteins><Public Health><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Serum><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Time><United States><Variant><Variation><Viral><abdominal dropsy><active followup><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><beta-Lipoproteins><blood loss><bowel><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular risk><cardiovascular risk factor><chronic HCV infection><chronic hepatitis C virus infection><chronic infection><cirrhotic><cohort><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><developmental><diabetes><digestive tract microbiome><dysbacteriosis><dysbiosis><dysbiotic><enteric microbial community><enteric microbiome><enteric microbiota><environmental risk><fasted><fasts><fatty acid biosynthesis><fibrotic liver><follow up><follow-up><followed up><followup><gastrointestinal microbial flora><gastrointestinal microbiome><genetic predictors><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><hep C><hepatic body system><hepatic coma/encephalopathy><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic organ system><hepatitis non A non B><hepatopathy><hydroperitonia><hydrops abdominis><infection by hepatitis c virus><inflamed liver><intestinal biome><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><life course><liver biopsy><liver carcinoma><liver disorder><liver inflammation><malignancy><microbial><microbial imbalance><microbiome><mortality><neoplasm/cancer><new marker><non A, non B hepatitis><non-A, non-B hepatitis><novel biomarker><novel marker><particle><pathobiont><pathway><patient oriented outcomes><peritoneal dropsy><peritoneal exudate><persistent infection><polymorphism><post treatment><prospective><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><viral RNA><viral infectious disease treatment><virus RNA>