Hepatitis C virus (HCV) is a major causative agent of liver disease and liver cancer. In recent years, new therapies with direct-acting-antiviral agents (DAAs) against HCV has led to greatly improved cure rates of approximately 95% in clinical trials settings. Our studies include patient treatment and their outcomes in the real-world setting as well as basic research into HCV biology and the impact of HCV and HCV cure on the immune system of patients. HCV cure does not completely eliminate the risk of developing liver cancer, hepatocellular carcinoma (HCC). Our studies also include developing biomarkers of HCC risk and determining mechanisms of HCC development in post HCV-cure patients.
Studies of the Hepatitis C Virus Program
A few of our current studies are described below.
In our studies to assess risk factors for HCC development in post HCV-cure patients, we found that nearly one-third of patients that developed HCC had neither cirrhosis or steatosis (increased liver fat), which have been the traditional biomarkers for HCC risk in chronically infected HCV patients. Therefore, biomarkers of HCC risk post HCV-cure are needed and may differ from the biomarkers of HCC risk established for patients with chronic HCV infection. Our studies indicate that the level of circulating alpha fetoprotein (AFP) could be a potential HCC biomarker in post HCV-cure patients. Additionally, among post HCV-cure patients with cirrhosis, we found that a reduced liver volume (determined by CT/MRI imaging) relative to body mass may also be a non-invasive indicator of HCC risk. In additional clinical studies, we determined that an important risk factor in HCV treatment failure is due to non-adherence (missed doses) which underscores the need for providers to clearly communicate dosing information and ensure that patients have access to an uninterrupted supply of medication. Our clinical research studies also include one where we are studying the immune system of patients before, during and after DAA treatment.
In basic research to explore mechanisms which may be involved in HCC development post HCV-cure, we developed an in vitro cell culture system to analyze the molecular changes that may persist in cells after viral clearance with DAAs. We and others have shown that mutations in the HCV core gene are associated with increased HCC risk. Our cell culture system demonstrated that cells infected with a high HCC risk virus had a gene expression profile similar to those found in the liver biopsies of HCV patients who later went on to develop HCC. We are determining what persistent epigenetic changes remain in cells post HCV-cure using our in vitro system and will apply bioinformatics tools to find potential drugs that can alter a high HCC risk gene expression profile for their use in HCC chemoprevention. Candidate drugs will be tested in our cell culture system. Furthermore, studies of the HCV core gene led to our discovery of a new family of HCV proteins that we termed minicores. They are truncated forms of the HCV core protein. We determined that these minicores circulate in patient blood. If HCV core antigen assays were developed to include the detection of these minicores, they would greatly enhance the sensitivity of the current assay. The assay can be used to determine active HCV infection in patients in lieu of an HCV PCR assay. Minicores can also be potentially used in the development of an HCV vaccine.
- Del Bello D, Cha A, Sorbera M, Bichoupan K, Levine C, Doyle E, Harty A, Patel N, Ng M, Gardenier D, Odin J, Schiano TD, Fierer DS, Berkowitz L, Perumalswami PV, Dieterich DT, Branch AD. Real-world Sustained Virologic Response Rates of Sofosbuvir-containing Regimens in Patients Coinfected with Hepatitis C and HIV. Clin Infect Dis. 2016 62(12):1497-504. PMID: 26936665
- Perumalswami PV, Patel N, Bichoupan K, Ku L, Yalamanchili R, Harty A, Motamed D, Khaitova V, Chang C, Grewal P, Liu L, Schiano TD, Woodward M, Dieterich DT and Branch AD. High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in HCV-infected patients treated with sofosbuvir-containing regimens. J Viral Hepat. 2016. PMID: 26989855
- Crismale JF, Martel-Laferrière V, Bichoupan K, Schonfeld E, Pappas A, Wyatt C, Odin JA, Liu LU, Schiano TD, Perumalswami PV, Bansal M, Dieterich DT, Branch AD. Diabetes mellitus and advanced liver fibrosis are risk factors for severe anaemia during telaprevir-based triple therapy. Liver Int. 2014; 34:1018-24. PMID: 24118693
- Klepper A, Eng FJ, Doyle EH, El-Shamy A, Rahman AH, Fiel MI, Avino GC, Lee M, Ye F, Roayaie S, Bansal MB, MacDonald MR, Schiano TD, Branch AD. Hepatitis C virus double-stranded RNA is the predominant form in human liver and in interferon-treated cells. Hepatology. 2016 Sep 19. [Epub ahead of print] PMID: 27642141.
- El-Shamy A, Eng FJ, Doyle EH, Klepper AL, Sun X, Sangiovanni A, Iavarone M, Colombo M, Schwartz RE, Hoshida Y, Branch AD. A cell culture system for distinguishing hepatitis C viruses with and without liver cancer-related mutations in the viral core gene. J Hepatol. 2015; 636:1323-33. PMID: 26220749, PMCID: PMC4654634
Meena Bansal, MD
Associate Professor of Medicine, Division of Liver Diseases, Director of Translational Research, Liver Diseases
Douglas Dieterich, MD
Professor of Medicine, Division of Liver Diseases
Francis J. Eng, PhD
Assistant Professor of Medicine, Division of Liver Diseases
M. Isabel Fiel, MD
Professor of Pathology, Director of Pathology
Peter D. Gorevic, MD
Professor of Medicine, Division of Rheumatology
Peter S. Heeger, MD
Professor of Medicine, Nephrology, Director of Transplant Research
Sara Lewis, MD
Assistant Clinical Professor, Division of Radiology
Ponni Perumalswami, MD
Assistant Professor of Medicine, Division of Liver Diseases, Recanati/Miller Transplant Institute
Thomas Schiano, MD
Professor of Medicine, Medical Director of Adult Liver Transplantation