Ramsey Cheung

A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C

Clinical factors such as age, gender, alcohol use, and age‐at‐infection influence the progression to cirrhosis but cannot accurately predict the risk of developing cirrhosis in patients with chronic hepatitis C (CHC). The aim of this study was to develop a predictive signature for cirrhosis in Caucasian patients. All patients had well‐characterized liver histology and clinical factors; DNA was extracted from whole blood for genotyping. We validated all significant markers from a genome scan in the training cohort, and selected 361 markers for the signature building. Using a “machine learning” approach, a signature consisting of markers most predictive for cirrhosis risk in Caucasian patients was developed in the training set (N = 420). The Cirrhosis Risk Score (CRS) was calculated to estimate the risk of developing cirrhosis for each patient. The CRS performance was then tested in an independently enrolled validation cohort of 154 Caucasian patients. A CRS signature consisting of 7 markers was developed for Caucasian patients. The area‐under‐the‐ROC curves (AUC) of the CRS was 0.75 in the training cohort. In the validation cohort, AUC was only 0.53 for clinical factors, increased to 0.73 for CRS, and 0.76 when CRS and clinical factors were combined. A low CRS cutoff of <0.50 to identify low‐risk patients would misclassify only 10.3% of high‐risk patients, while a high cutoff of >0.70 to identify high‐risk patients would misclassify 22.3% of low‐risk patients. Conclusion: CRS is a better predictor than clinical factors in differentiating high‐risk versus low‐risk for cirrhosis in Caucasian CHC patients. Prospective studies should be conducted to further validate these findings. (HEPATOLOGY 2007.)

Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.

Nonalcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the U.S. and is predicted to become the leading indication for LT in the near future. The trends in NASH‐related hepatocellular carcinoma (HCC) among LT recipients in the U.S. remain undefined. We performed a retrospective cohort study to evaluate trends in the etiology of HCC among adult LT recipients in the U.S. from 2002 to 2012, using national data from the United Network for Organ Sharing registry. From 2002‐2012, there were 61,868 adults who underwent LT in the U.S., including 10,061 patients with HCC. The total number and proportion of HCC LT recipients demonstrated a significant increase following the implementation of the Model for Endstage Liver Disease (MELD) scoring system in 2002 (3.3%, n = 143 in 2000 versus 12.2%, n = 714 in 2005 versus 23.3%, n = 1336 in 2012). The proportion of hepatitis C virus (HCV)‐related HCC increased steadily from 2002 to 2012, and HCV remained the leading etiology of HCC throughout the MELD era (43.4% in 2002 versus 46.3% in 2007 versus 49.9% in 2012). NASH‐related HCC also increased significantly, and NASH is the second leading etiology of HCC‐related LT (8.3% in 2002 versus 10.3% in 2007 versus 13.5% in 2012). From 2002 to 2012, the number of patients undergoing LT for HCC secondary to NASH increased by nearly 4‐fold, and the number of LT patients with HCC secondary to HCV increased by 2‐fold. Conclusion: NASH is the second leading etiology of HCC leading to LT in the U.S. More important, NASH is currently the most rapidly growing indication for LT in patients with HCC in the U.S. (Hepatology 2014;59:2188–2195)

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection

BACKGROUND:Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.METHODS:We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.RESULTS:Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment.CONCLUSIONS:The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

Epidemiology of hepatitis C virus infection in American veterans

OBJECTIVE:This study reports the findings of hepatitis C virus (HCV) infection in a large Department of Veterans Affairs Health Care System in suburban Northern California.METHODS:All veterans who had anti-HCV (EIA II) tested during a 6-yr period (7/92 to 6/98) were included in this study. To estimate the seroprevalence of anti-HCV among our population, 126 consecutive bloodborne pathogen exposure accidents were studied.RESULTS:Of 8558 veterans tested for anti-HCV (EIA II), 2985 (35%) veterans were positive with a mean age of 48.4 yr (range, 28–89 yr). Sixty percent were between the age of 41 and 50 yr. Risk factors for HCV infection identified in 409 consecutive veterans were intravenous drug abuse (81%), unknown (11%), blood transfusion (3%), sexual/household contact (2%), transfusion and intravenous drug use (2%), and tattoo (1%). Of 215 consecutive anti-HCV-positive veterans whose sera were tested by polymerase chain reaction, 96% were viremic. The most common HCV genotypes were 1a (50.5%), 1b (22.8%), 3a (12.1%), 2b (9.7%), 2a (1.9%), undetermined (1.9%), and mixed infection (1%). Veterans infected with genotype 1b were significantly older. Among 126 consecutive bloodborne pathogen exposure accidents, hepatitis C serology was available for 72 index veterans involved in the accidents and 18% were positive.CONCLUSIONS:We found the epidemiology of hepatitis C infection was different in the veteran population when compared to other published data on nonveterans. Hepatitis C infection was much more common among veteran, within a very narrow age distribution and intravenous drug use was the major risk factor.

Viral hepatitis and other infectious diseases in a homeless population.

Goals To determine the prevalence of four common infectious diseases—hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and tuberculosis—as well as co-infection rates and risk factors in a homeless population. Background The prevalence of infectious diseases, especially viral hepatitis, among the homeless population is largely unknown. Study This study consists of a retrospective analysis of the history and laboratory data collected from all homeless veterans admitted to a Veterans Administration (VA) domiciliary from May 1995 to March 2000. Results Of the homeless veterans admitted to a VA domiciliary program, 597 of 829 were screened for markers of all four infectious diseases. The overall prevalence of anti–hepatitis C virus (HCV) antibody, and positive result for purified protein derivative (PPD), anti-HIV antibody, and hepatitis B surface antigen (HbsAg) were 41.7%, 20.6%, 1.84% and 1.17%, respectively. At least one of the four markers was positive in 52.6% and more than one in 12%. Co-infection with HCV occurred commonly in veterans who were positive for anti-HIV (72.7%) and HBsAg (57.1%). Four self-reported major risk factors (intravenous drug use, alcohol abuse, previous imprisonment, and prior stay in a shelter) were evaluated. Multivariate analysis indicates that intravenous drug use and anti-HBs reactivity are independent risk factors for HCV infection, HCV infection for anti–hepatitis B surface antibody reactivity, and older age for PPD positivity. Conclusions Chronic hepatitis C and co-infections are common among the homeless population. Patients infected with HIV and hepatitis B virus frequently are co-infected with HCV. Infections frequently are associated with certain identifiable risk factors.

Quantitative analysis of hepatitis C virus in peripheral blood and liver: Replication detected only in liver

Prior studies seeking evidence of viral replication in peripheral lymphocytes of hepatitis C virus (HCV)-infected patients have yielded conflicting results. This study sought to quantitatively determine whether a permissive HCV cell interaction could be detected in leukocytes from infected patients. Peripheral leukocytes from chronically infected patients were purified and were tested for HCV RNA. The results show that virus load is highest in B cells. Other subsets of peripheral leukocytes consistently had very low levels of viral RNA or were negative. Negative-strand HCV was found only in hepatocytes. To determine whether HCV replication could be induced by activation, B cells from HCV-infected patients were stimulated in vitro. No HCV replicating in peripheral leukocytes was detected by a highly sensitive assay. If HCV replication occurs in the leukocyte subsets analyzed here, it is at extremely low levels or occurs under alternate physiological conditions.

Chronic hepatitis C in Latinos: natural history, treatment eligibility, acceptance, and outcomes.

OBJECTIVES:The natural history of chronic hepatitis C and treatment response are different between blacks and Caucasians, but little comparable data is available about Latinos.METHODS:A cross-sectional secondary analysis to investigate differences between 421 anti-HCV-positive, treatment-naïve, HCV-viremic Latinos and 2,510 Caucasians in 24 VA medical centers enrolled in a prospective study.RESULTS:Latinos were infected at a younger age and were less likely to have blood contact during combat, surgery, and needle stick injury, but were more frequently HIV coinfected (20.4% vs 3.9%, p < 0.0001) and prior HAV infection (39.9% vs 26.4%, p = 0.0001). Latinos were more likely to be treatment candidates, but less likely to actually initiate treatment. Liver histology (123 Latinos, 743 Caucasians) showed no difference in fibrosis or fibrosis rate, but steatosis (54.7% vs 43.2%, p = 0.038) was more common in Latinos. Eighty-eight Latinos and 481 Caucasians were subsequently treated with interferon-ribavirin: body mass index (BMI), duration of infection, baseline tests, liver histology and genotype distribution were similar. Compared with Caucasians, Latinos discontinued treatment prematurely more often (39.8% vs 28.9%, p = 0.043) and tended to have lower sustained virological response (SVR) rates (14.8% vs 22.5%, p = 0.10). Multivariate analysis found Latino race and history of recent alcohol use to be associated with early treatment discontinuation, whereas genotype and viral load but not ethnicity to be associated with SVR.CONCLUSIONS:Latinos were infected younger, more frequently HIV coinfected, more likely to meet criteria for antiviral therapy yet less likely to initiate treatment and had a trend toward lower SVR rates than Caucasians, but not in severity of liver disease. Latino ethnicity was associated with early discontinuation but not as an independent predictor of SVR.

Depression, anxiety, post-traumatic stress, and alcohol-related problems among veterans with chronic hepatitis C.

OBJECTIVE:The aim of this study was to determine the incidence of psychiatric comorbidities among veterans with chronic hepatitis C.METHODS:Depression, anxiety sensitivity, post-traumatic stress symptoms, and alcohol use were assessed using standardized questionnaires in 120 consecutive veterans with chronic hepatitis C referred to the Liver Clinic.RESULTS:Using well-established scoring criteria of the questionnaires, clinically significant levels of depression (44.2%), anxiety (38.1%), post-traumatic stress disorder (20.8%), and alcohol-related problems (26.7%) were observed. The majority of patients had a clinically significant score for at least one questionnaire, whereas 37.2% had significant scores in two or more questionnaires. Positive correlations were found between post-traumatic symptoms and depressive symptoms, anxiety sensitivity, and alcohol use problems. Depressive symptoms were also correlated with anxiety. Responses to the questionnaires, in general, correlated poorly with psychiatric histories documented in the medical record. Overall, 79 (65.8%) patients had one or more possible contraindications to antiviral therapy: coexisting unstable psychiatric disorders and/or recent substance use was found in 73.4% of these patients.CONCLUSIONS:Psychiatric comorbidities were very common among veterans with chronic hepatitis C and correlated poorly with diagnoses documented in the medical record. We recommend a multidisciplinary approach that includes psychological assessment using standardized questionnaires in the evaluation of these patients for antiviral therapy.

Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection

BACKGROUND/AIMS Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms. METHODS We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples. RESULTS We identified several SNPs in the toll-like receptor 4 (TLR4) and syntaxin binding protein 5-like (STXBP5L) loci that were associated with fibrosis risk independently of the original significant SNPs. Haplotypes consisting of these SNPs in TLR4 and STXBP5L were strongly associated with fibrosis risk (global P=3.04 x 10(-5) and 4.49 x 10(-6), respectively). CONCLUSIONS Multiple variants in TLR4 and STXBP5L genes modulate risk of liver fibrosis. These findings are of relevance for understanding the pathogenesis of HCV-induced liver disease in Caucasians and may be extended to other ethnicities as well.

Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort

Limited data exist on the effectiveness of boceprevir and telaprevir in routine practice.