Souvik Sarkar

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C

Objective Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log10 (p=0.009 vs controls) and ALT by 33% (p<0.001). Ribavirin pretreatment, while modestly augmenting ISG induction by PEG-IFN, did not modify the virological response to subsequent PEG-IFN and ribavirin treatment. However, biochemical, but not virological, response to ribavirin monotherapy predicted response to subsequent combination treatment (rapid virological response, 71% in biochemical responders vs 22% non-responders, p=0.01; early virological response, 100% vs 68%, p=0.03; sustained virological response 83% vs 41%, p=0.053). Ribavirin monotherapy lowered serum IP-10 levels but had no effect on ISG expression in PBMC. Conclusions Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

Primary Sclerosing Cholangitis. Multiple Phenotypes, Multiple Approaches.

Primary sclerosing cholangitis (PSC) is a heterogeneous, idiopathic, inflammatory disorder frequently associated with inflammatory bowel diseases. PSC patients may be classified into several subphenotypes. Investigations of pediatric, nonwhite, and female PSC patients have revealed distinguishing features. The natural history of PSC is variable in progression with numerous possible clinical outcomes. PSC patients may suffer bacterial cholangitis, cholangiocarcinoma, or colorectal adenocarcinoma. Treatments focusing on bile acid therapy and immunosuppression have not proven beneficial. Interest in PSC and international collaboration has led to improved understanding of the heterogeneity and the genetic structure and introduced possible effective therapeutics.

Disparities in hepatitis C testing in U.S. veterans born 1945–1965

BACKGROUND & AIMS Universal one-time antibody testing for hepatitis C virus (HCV) infection has been recommended by the centers for disease control (CDC) and the United States preventative services task force (USPSTF) for Americans born 1945-1965 (birth cohort). Limited data exists addressing national HCV testing practices. We studied patterns and predictors of HCV testing across the U.S. within the birth cohort utilizing data from the national corporate data warehouse of the U.S. Veterans Administration (VA) health system. METHODS Testing was defined as any HCV test including antibody, RNA or genotype performed during 2000-2013. RESULTS Of 6,669,388 birth cohort veterans, 4,221,135 (63%) received care within the VA from 2000-2013 with two or more visits. Of this group, 2,139,935 (51%) had HCV testing with 8.1% HCV antibody and 5.4% RNA positive. Significant variation in testing was observed across centers (range: 7-83%). Older, male, African-Americans, with established risk factors and receiving care from urban centers of excellence were more likely to be tested. Among veterans free of other established risk factors (HIV negative, HBV negative, ALT ⩽40U/L, FIB-4 ⩽1.45, or APRI <0.5), HCV antibody and RNA were positive in 2.8% and 0.9%, respectively, comparable to established national average. At least 2.4-4.4% of veterans had scores suggesting advanced fibrosis (APRI ⩾1.5 or FIB-4 >3.25) with >30-43% having positive HCV RNA but >16-20% yet to undergo testing for HCV. CONCLUSIONS Significant disparities are observed in HCV testing within the United States VA health system. Examination of the predictors of testing and HCV positivity may help inform national screening policies. LAY SUMMARY Analysis of United States Veterans Administration data show significant disparities in hepatitis C virus testing of veterans born 1945-1965 (birth cohort). A fifth of those not tested had evidence of advanced liver fibrosis. Our data suggests some predictors for this disparity and will potentially help inform future policy measures in the era of universal birth cohort testing for HCV.

Patient engagement and study design of PROP UP: A multi-site patient-centered prospective observational study of patients undergoing hepatitis C treatment

BACKGROUND New highly efficacious direct-acting antiviral (DAA) therapies are available to treat chronic hepatitis C viral (HCV) infection. Real-world, patient-centered data on harms and benefits associated with these therapies are needed. METHODS PROP UP is a multi-center prospective observational study that plans to enroll 1600 patients starting treatment with recently-approved DAA regimens. Informed by extensive input from a HCV patient engagement group who prioritized outcomes most important to them, patient-reported outcomes will be characterized using surveys at five time points: Baseline (T1), treatment week 4 (T2), end of treatment (T3), 12weeks post-treatment (T4), 12months post-treatment (T5). OUTCOMES (1) Changes in side effects, functioning, pre-existing conditions, and out-of-pocket costs during therapy (T1 vs T2/T3); (2) Medication adherence in relation to a history of mental health/substance abuse, treatment regimens, pill burden, reasons for missed doses, and cure rates; (3) Short term impact of cure on functioning and amelioration of symptoms (T1 vs T4); (4) Long-term treatment harms or benefits of cure on symptoms, side effects, pre-existing conditions, and functioning (T1 vs T5). Similarities between regimens will be examined where comparisons are appropriate and meaningful. CONCLUSION PROP UP complements previous clinical trials by focusing on patient-reported outcomes in a representative sample of patients treated in clinical practice, by collaborating with a patient engagement group, by characterizing the experiences of vulnerable subgroups, and by investigating long-term harms and benefits of treatments. PROP UP is designed to provide novel and detailed information to support informed decision-making for patients and providers contemplating HCV treatment (PCORI CER-1408-20,660; NCT02601820).

An Epidemiologic Investigation of a Case of Acute Hepatitis E

ABSTRACT Hepatitis E virus (HEV) is considered a zoonotic infection in developed nations. A case of acute hepatitis E in a researcher following a scalpel injury while working on a pig prompted a seroepidemiologic study to identify potential modes of transmission and determine the seroprevalence of HEV among animal handlers at the institute. Sera from personnel (n = 64) in two animal facilities and age/sex-matched blood donors (n = 63) as controls were tested for IgG anti-HEV and, if positive, for IgM anti-HEV and HEV RNA. Sera and stool from pigs aged 6 to 12 weeks from the breeding farm and older pigs from animal facilities were tested similarly. The median age of personnel was 36 years, 74% were white, 56% were male, and 74% had direct exposure to pigs. The prevalence of anti-HEV was 3.1% among personnel compared to 3.2% among blood donors; none were positive for IgM anti-HEV or HEV RNA. IgG anti-HEV was detected in sera from 10% of pigs aged 6 to 8 weeks, 80% aged 10 weeks, 100% aged 12 weeks, and 76% aged >12 weeks. HEV RNA was detected in stool but not sera from three 12-week-old pigs. Sequencing revealed HEV genotype 3 with ∼10% difference between the patient and pig sequences. Parenteral transmission is a potential mode of acute HEV infection. The low and similar seroprevalence of anti-HEV between the at-risk group and age-matched blood donors suggests low transmission risk with universal precautions among animal handlers.

Psychometric properties of the PROMIS short form measures in a U.S. cohort of 961 patients with chronic hepatitis C prescribed direct acting antiviral therapy

To better understand symptoms experienced by patients infected with chronic hepatitis C virus (HCV), valid and reliable patient‐reported outcome (PRO) measures are needed.

Non-alcoholic Fatty Liver Disease in South Asians: A Review of the Literature

Abstract Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are national and global epidemics. The disease is characterized by a spectrum of liver steatosis (fat deposition), inflammation (in NASH) and fibrosis. NAFLD and specifically NASH can lead to cirrhosis, which carry risks of progression to portal hypertension and hepatocellular carcinoma (HCC). NASH is also associated with higher mortality from cardiovascular causes. Most of the data for NAFLD has been obtained from the perspective of developed nations, although the disease is increasing and threatening to reach epidemic proportions across the world. Emerging data is notable for high prevalence of NAFLD in South Asian populations, presumably resulting from a combination of underlying genetic polymorphisms and changes in socio-economic status. It is also notable that an ‘Asian Paradox’ has been defined for NAFLD based upon the observation of lower than pre-defined body mass index (BMI), otherwise termed as “lean NAFLD”, among this population. Yet, data remains limited in regards to the characteristics of NAFLD/NASH in this population. In this article, we present a review of the literature and discuss the prevalence, associated risk factors and burden of HCC in South Asians with NAFLD.

Colitis Following Initiation of Sofosbuvir and Simeprevir for Genotype 1 Hepatitis C.

Sofosbuvir and simeprevir are used for the treatment of chronic hepatitis C (HCV) genotype 1. Both drugs have been well-tolerated, with diarrhea noted in 6% cases with sofosbuvir, 16% with sofosbuvir plus simeprevir, and 0% with simeprevir. No prior reports exist of colitis secondary to either drug or their combination. We report a patient with no prior history of inflammatory bowel disease who developed significant bloody diarrhea within 2 weeks of sofosbuvir/simeprevir initiation. Colonoscopy and biopsy confirmed pancolitis, which responded to mesalamine and completion of sofosbuvir/simeprevir.

Fatigue and serum carnitine levels in chronic liver disease

SIRS, Fatigue is the most common and potentially most limiting symptom of liver disease, but strangely, is rarely the focus of study or research. Indeed, most studies of natural history and trials of therapy in liver disease do not measure, or even mention, fatigue. This shortcoming is particularly striking in chronic hepatitis C, where large numbers of trials of antiviral therapy have been published, but few have provided information on symptoms and whether they change with treatment. Fatigue is often mentioned as an ‘adverse event’ of treatment, and its frequency before starting and after stopping is not always given. The reasons for this are many: fatigue is nonspecific, multi-factorial, often mild, capable of fluctuating from week to week and difficult to measure objectively. Most importantly, the field of hepatology is yet to develop or accept a validated and reproducible instrument for assessing fatigue, and those that have been used have shown little correlation with disease activity (serum transaminase levels, histology activity scores) and stage (fibrosis scores short of cirrhosis). Anty et al. have taken on some of these issues, attempting to shed light on the nature of fatigue in liver disease. They report an association between fasting serum carnitine levels and the severity of fatigue, as assessed by a Fatigue Impact Scale questionnaire in 70 noncirrhotic patients with chronic hepatitis C. The association was mostly statistical, the dot-plots in figure 3 showing overlap of carnitine levels at different levels of fatigue and lack of homogeneity of the results (driven by the 5 or 6 ‘outliers’). Nevertheless, Anty et al. have taken on an important area in hepatology research with interesting results. Clearly, more investigation is needed into the frequency and nature of symptoms of liver disease, their clinical significance, pathogenesis and fluctuation with both specific and non-specific therapies.

Improving Healthcare Systems to Reduce Healthcare Disparities in Viral Hepatitis.

Chronic hepatitis B (CHB) and C (CHC) represent significant public health problems worldwide. Combined, over 7 million persons in the USA are chronically infected with either the hepatitis B or the hepatitis C virus. Although the populations affected by the viruses differ, both CHB and CHC are ideal conditions for preventive screening because of a high prevalence and low rate of diagnosis; an early asymptomatic period; highly sensitive and specific test; and treatments which have been shown to result in improved clinical outcomes including liver-related mortality and hepatocellular carcinoma. Improving healthcare delivery for CHB and CHC requires interventions that will increase screening for the infections, expanded capacity for evaluation and monitoring of the infection, and ultimately improved access to treatment. Many of these interventions may leverage opportunities within electronic health records, but must also address unique social, cultural, and language barriers that may prevent effective implementation of novel interventions. Herein, we will review current knowledge related to strategies employed to improve healthcare systems to reduce disparities in viral hepatitis.