Donald M. Jensen

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon α-2a (40 kd)/ribavirin therapy†‡§

Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon α‐2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow‐up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty‐one of 216 (24%) genotype 1 patients in the 24‐week treatment groups had a RVR. SVR rates were considerably higher in patients with than without a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2‐22.5; P < .0001) or 200,000‐600,000 IU/mL (OR 3.6, 95% CI 1.5‐9.1; P = .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9‐3.7; P = .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1‐61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. >600,000 IU/mL, 95% CI 1.1‐6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. In conclusion, patients infected with HCV genotype 1 and treated with peginterferon α‐2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment. (HEPATOLOGY 2006;43:954–960.)

Epidemiology of Hepatitis B and C Viruses: A Global Overview

This article reviews the prevalence, disease burden, genotype distribution, and transmission patterns of hepatitis B virus (HBV) and hepatitis C virus in the 6 World Health Organization regions. The global epidemiology of hepatitis B and C demonstrates a predominantly declining prevalence of the diseases. Improvement in the control of hepatitis B has been largely achieved with implementation of a more universal HBV vaccine program, although a large gap still remains in the effort toward global prevention of hepatitis B. The transmission of hepatitis C has been greatly impacted by mandatory screening of blood donors in most countries in the world, although intravenous drug use continues to be a major source of infection. Public education regarding the risks of exposure to infected paraphernalia as well as household items such as razors is necessary in the continuing effort to curb this disease.

A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus.

BACKGROUND & AIMS The incidences of decompensated cirrhosis (defined by ascites, hepatic encephalopathy, or bleeding esophageal varices), hepatocellular carcinoma (HCC), and liver-related mortality among patients infected with hepatitis C virus (HCV) who achieve a sustained viral response (SVR), compared with patients who fail treatment (treatment failure), are unclear. We performed a meta-analysis to quantify the incidences of these outcomes. METHODS This meta-analysis included observational cohort studies that followed HCV treatment failure patients; data were collected regarding the incidence of decompensated cirrhosis, HCC, or liver-related mortality and stratified by SVR status. Two investigators independently extracted data on patient populations, study methods, and results by using standardized forms. The agreement between investigators in data extraction was greater than 95%. Data analysis was performed separately for studies that enrolled only HCV patients with advanced fibrosis. RESULTS We identified 26 appropriate studies for meta-analysis. Among treatment failure patients with advanced fibrosis, rates of liver-related mortality (2.73%/year; 95% confidence interval [CI], 1.38-4.080), HCC (3.22%/year, 95% CI, 2.02-4.42), and hepatic decompensation (2.92%/year; 95% CI, 1.61-4.22) were substantial. Patients with SVR are significantly less likely than patients who experienced treatment failure to develop liver-related mortality (relative risk [RR], 0.23; 95% CI, 0.10-0.52), HCC (RR, 0.21; 95% CI, 0.16-0.27), or hepatic decompensation (RR, 0.16; 95% CI, 0.04-0.59). CONCLUSIONS HCV patients with advanced fibrosis who do not undergo an SVR have substantial liver-related morbidity and mortality. Achieving SVR is associated with substantially lower liver-related morbidity and mortality.

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial

BACKGROUND Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING Gilead Sciences.

Detection of Antibodies Directed against a Liver-Specific Membrane Lipoprotein in Patients with Acute and Chronic Active Hepatitis

A specific and sensitive radioimmunoassay was used to measure the levels of antibody to a liver-specific membrane lipoprotein in patients with acute and chronic liver disease. Antibody was detected in 29 of 30 patients with chronic active hepatitis (all of 15 HBsAg-negative and 14 of 15 HBsAg-positive cases), and in 10 of 17 patients with chronic persistent hepatitis but at significantly lower titer. The titer of antibody to the lipoprotein showed a significant correlation with activity of disease as judged histologically and biochemically. Transiently elevated levels were found in 20 of 21 patients with acute viral hepatitis, but there was no correlation with the degree of liver damage. Antibody to liver-specific membrane protein may be part of the final common pathway of liver-cell damage in both HBsAg-positive and HBsAg-negative chronic activite hepatitis, whereas other immune mechanisms determine the liver-cell injury in acute viral hepatitis.

Transjugular intrahepatic portosystemic shunt (TIPS) for Budd-Chiari syndrome or portal vein thrombosis : review of indications and problems

OBJECTIVE The aim of this study was to evaluate the role of transjugular intrahepatic portosystemic shunt (TIPS) in patients who present with portal vein thrombosis (PVT) or Budd-Chiari Syndrome (BCS). METHODS Nine patients with recent PVT and four patients with BCS underwent TIPS. The diagnosis was confirmed by color Doppler ultrasound and by angiogram in most patients. Patients were followed clinically and had TIPS checked periodically for patency. The end point was mortality, subsequent surgical shunting or orthotopic liver transplantation (OLT). RESULTS TIPS was placed in 13 of 15 (87%) patients with BCS or PVT. The mean decrease in pressure gradient was 56%. Median and mean follow-up were 14 months and 16.9 months. Procedure related complications occurred in two of 13 (15%), both in the PVT group. Direct procedural mortality was one of 13 (8%). The majority of patients with PVT (five of eight) underwent OLT. Of the remaining three, one patient subsequently developed a cavernous transformation of portal vein but is stable, one patient is stable, without further variceal bleeding, and one patient died because of multiple organ failure. In patients with BCS, three of four (75%) did well with TIPS, but one patient required immediate surgical shunting after occlusion of the TIPS. Two patients underwent OLT and the fourth patient is stable 2 yr later but has cirrhosis on biopsy. CONCLUSIONS In patients with BCS, TIPS placement is effective and can be used as a bridge to liver transplantation. TIPS in the noncavernous PVT group should only be recommended when cirrhosis and uncontrollable variceal bleeding are present.

Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD).

Non‐alcoholic fatty liver disease (NAFLD) patients with elevated serum alanine aminotransferase (ALT) generally undergo a liver biopsy to evaluate for possible non‐alcoholic steatohepatitis (NASH) or advanced fibrosis. However, patients with normal ALT could also have advanced stages of NAFLD.

High sustained virologic response rates in rapid virologic response patients in the large real‐world PROPHESYS cohort confirm results from randomized clinical trials

The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment‐naive HCV monoinfected patients (N = 7,163) age ≥18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country‐specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow‐up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3‐50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4‐71.7%), 68.4% (95% CI: 65.7‐71.0%), and 60.3% (95% CI: 58.5‐62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8‐86.5%), 76.3% (95% CI: 73.3‐79.1%), and 74.2% (95% CI: 71.3‐76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1‐73.1%), 67.3% (95% CI: 64.2‐70.3%), and 63.8% (95% CI: 61.0‐66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6‐76.3%), 63.3% (95% CI: 54.3‐71.6%), and 54.3% (95% CI: 47.5‐60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. Conclusion: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype. (HEPATOLOGY 2012;56:2039–2050)

Influence of ethnicity on histological differences in non-alcoholic fatty liver disease

BACKGROUND/AIMS Previous studies examining ethnic differences in non-alcoholic fatty liver disease (NAFLD) are limited by small sample sizes and the lack of liver biopsy as a diagnostic modality. METHODS We retrospectively examined the influence of ethnicity on the biochemical and liver histological differences in NAFLD patients. RESULTS The proportion of African Americans (AA) in the NAFLD sample (total 238 patients; 15.1% AA) was lower than in the base population (68.2%). Median ALT (47 IU/L; p=0.05) and triglyceride (134mg/dL, p=0.002) levels were lower in AA than other ethnicities. AA showed lower degrees of steatosis [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.22-0.89; p=0.02] than Whites. In contrast, Asians showed higher grades of ballooning than Whites (OR 2.67, 95% CI 1.03-6.93; p=0.04) and other ethnicities combined (OR 2.71, 95% CI 1.06-6.92; p=0.04). Hispanics showed a higher rate of Mallory bodies than Whites (OR 2.38, 95% CI 1.05-5.39; p=0.04) and other ethnicities combined (OR 2.41, 95% CI 1.09-5.34; p=0.03). CONCLUSIONS African Americans showed a lower degree of steatosis than Whites. In contrast, Asians and Hispanics showed higher grades of ballooning and Mallory bodies, respectively, than Whites and other ethnicities combined. These findings highlight the need for prospective studies to evaluate ethnic differences in NAFLD.

Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis.

Goals The aim of this study is to evaluate the prevalence and the clinical and histologic correlates of autoantibodies in patients with nonalcoholic steatohepatitis (NASH). Background Antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) have been identified in patients with NASH. The significance of autoantibodies in NASH is uncertain. Study Clinical data from patients with a histologic diagnosis of NASH at a university hospital in Chicago, Illinois between January 1999 and April 2003 were reviewed retrospectively. Seventy-four patients who were tested for autoantibodies and had no history of alcohol abuse or a systemic autoimmune disease were included. Demographic information and laboratory data were collected. Autoantibody titers ≥1:40 were considered positive. A single pathologist reviewed all liver biopsies and scored features of NASH and identified characteristics of autoimmune hepatitis. Results Thirty-four percent of patients with NASH had positive ANA titers and 6% were ASMA positive. Demographic and laboratory parameters did not differ by ANA status, except that women were more frequently ANA positive then men (P = 0.01). The severity of steatosis, inflammation, and fibrosis on liver biopsy were similar in the ANA positive and negative groups. Only 15% of ANA positive patients with NASH had a plasma cell infiltrate on liver biopsy and there was no difference in the frequency of histologic features of autoimmune hepatitis between ANA positive and negative patients. Conclusions Antinuclear antibodies are common in patients with NASH and most frequently represent a nonspecific antibody response that is not associated with the pattern or severity of injury on liver biopsy.