Silvia Boccato

Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection

Context Many persons infected with hepatitis C virus (HCV) are asymptomatic. The extent of liver disease in these persons is unclear. Contribution The researchers tested 4820 apparently healthy persons in Italy for hepatitis C virus. Among the 116 (2.4%) who tested positive, 85 were viremic; only about half of these 85 patients had elevated alanine aminotransferase (ALT) levels. Liver biopsy showed substantial inflammation or fibrosis in 19% of persons with normal ALT levels and 61% of persons with abnormal ALT levels. Implications The substantial prevalence of abnormal liver histology among asymptomatic persons is a provocative but incomplete rationale for screening for HCV. The prevalence of infection and the effectiveness of treatment are also important considerations. The Editors Although new hepatitis C virus (HCV) infections have declined during the past decade in most developed countries (1), hepatitis C remains a major health problem because of the many persons infected before serologic testing became available (2, 3). Many persons with HCV infection are asymptomatic and unaware that they are infected. While it is clear that HCV contributes greatly to end-stage liver disease, the natural history of hepatitis C in asymptomatic individuals is poorly defined. Published studies indicate that the natural history of hepatitis C is heterogeneous. Several factors, including age at infection, alcohol use, and co-infection with hepatitis B virus or HIV, increase the risk for cirrhosis (4-8). Independent of these cofactors, prognosis is related to hepatic histopathology, particularly the type and amount of liver necroinflammation and fibrosis (9-11). Our understanding of the histology of hepatitis C in asymptomatic persons comes mainly from studies of blood donors (a selected population) (12-14). We report an investigation of the prevalence, histologic activity, and stage of HCV infection in 4820 otherwise apparently healthy adults living in northeastern Italy. Methods Patients We tested for serum anti-HCV in 4820 adults (2132 men and 2688 women; age range, 16 to 60 years) who were undergoing a screening program for cardiovascular risk factors. To be eligible for this program, persons had to be free of acute or chronic illness (based on history and clinical symptoms) at the time of evaluation. Telecom Italy proposed and promoted the screening program to employees and their relatives. Participation was voluntary. Participants lived in one of three regions (Veneto, Trentino-Alto-Adige, and Friuli-Venezia-Giulia) in northeastern Italy and included a wide range of socioeconomic strata (from employees in lower positions to senior managers and their relatives). All 4820 persons (1210 employees and 3610 relatives) gave written informed consent and underwent clinical evaluation and testing for anti-HCV by enzyme-linked immunosorbent assay (ELISA) (Ortho Diagnostic Systems, Raritan, New Jersey) at the initial visit. Within 1 month, we retested persons who were positive for anti-HCV by ELISA. Serum that was confirmed to be HCV positive was tested for HCV RNA by polymerase chain reaction (PCR) (Amplicor HCV Monitor test, Roche Diagnostics, Indianapolis, Indiana). We retested serum for HCV RNA after 1 and 3 months in confirmed anti-HCVpositive persons whose initial test results for HCV RNA had been negative. We monitored serum alanine aminotransferase (ALT) levels 1, 3, 6, and 12 months after anti-HCV detection. We proposed liver biopsy for all viremic persons. These biopsies were done 6 to 14 months after detection of anti-HCV; patients provided informed consent. Liver biopsy specimens were evaluated according to the METAVIR scoring system (15). We classified patients with METAVIR scores of F2 and higher or A2 and higher as having significant liver disease according to international guidelines (16). Statistical Analysis Prevalences of HCV infection and of liver disease were compared by using the Fisher exact test for 2 2 tables. The chi-square test for linear trend was used to compare prevalences in age subgroups. Role of the Funding Source The study protocol was developed by a Scientific Committee of the Italian National Research Council (CNR), approved by a National Ethical Committee, and directly funded by the Italian National Research Council. The Italian National Research Council had no role in the collection, analysis, and reporting of the study or in the decision to publish the manuscript. Results Prevalence of HCV Infection in the Screened Population Of the 4820 persons tested, 116 (2.4% [CI, 1.97% to 2.84%]) were repeatedly positive for anti-HCV by ELISA and 12 additional persons were initially positive but were negative on repeated testing. Samples confirmed to be anti-HCV positive were tested for HCV RNA; 75 of these were positive. The 41 persons who were initially positive for anti-HCV but negative for HCV RNA were tested for serum HCV RNA 1 and 3 months after anti-HCV detection; 10 were positive in both (n = 8) or one (n = 2) follow-up test. Thus, 85 of 116 anti-HCVpositive persons (73.3%), or 85 of 4820 screened individuals (1.76 % [CI, 1.39% to 2.14%]) were positive for HCV RNA. Among the 85 HCV RNApositive individuals, ALT levels were normal (<50 U/L) at all times (at 0, 1, 3, 6, and 12 months) in 39 persons (46%), elevated at all times in 37 persons (43.5%), and abnormal at least once in 9 patients (10.5%). The 10 persons with intermittent HCV RNA positivity had persistently normal ALT levels during follow-up. Liver Histology in HCV-Infected Persons Seventy-eight of the 85 persons who were positive for HCV RNA had liver biopsies; these 78 patients included 32 of 39 persons with persistently normal ALT levels and all 46 persons with elevated ALT levels. The Figure summarizes the histopathologic characteristics of the 78 HCV-positive persons according to the ALT profile during the observation period. Overall, 52% of patients with elevated ALT levels and 19% of patients with normal ALT levels had significant fibrosis (F2 to F4), whereas 24% of patients with elevated ALT levels and none with normal ALT levels had significant necroinflammatory activity (A2 to A3). Thus, on the basis of a fibrosis score of 2 or higher or an activity score of 2 or higher, moderate to severe chronic hepatitis was seen in 28 of 46 (61% [CI, 45.4% to 74.9%]) patients with elevated ALT levels and in 6 of 32 (19% [CI, 7.21% to 36.4%]) patients with normal ALT levels (P < 0.001). Both mean and peak ALT values during the 12-month follow-up period correlated with activity and fibrosis stage (Table). The percentage of patients with significant activity or fibrosis increased with increasing ALT levels (data not shown). Figure. Histologic activity and fibrosis stage of the 78 persons with normal or elevated alanine aminotransferase levels who were positive for hepatitis C virus. Table. Liver Histology during the 12-Month Follow-up Period in 78 Hepatitis C VirusPositive Persons Prevalence of HCV Infection and Liver Disease by Age Prevalence of HCV RNA positivity increased with age: 0.67% (CI, 0.23% to 1.57%) in persons age 16 to 30 years, 1.4% (CI, 0.93% to 2.08%) in persons age 31 to 45 years, and 2.4% (CI, 1.8% to 3.2%) in persons age 46 to 60 years (P = 0.003). The percentage of persons with persistently normal ALT levels was similar in the three age groups, but severity of liver disease increased with age. The prevalence of significant fibrosis (F2) was 20% in the persons age 16 to 30 years and 48% in the persons age 46 to 60 years. When only patients with abnormal ALT levels were considered, the corresponding figures were 33% in persons age 16 to 30 years, 50% in the persons age 31 to 45 years, and 79% in the persons age 46 to 60 years. HCV Genotypes Among the 85 persons positive for HCV RNA, 52 (61.2%) were infected with HCV genotype 1b, 5 (5.8%) with genotype 1a, 20 (23.5%) with genotype 2a/2c, and 8 (9.4%) with genotype 3. Four of 5 patients age 16 to 30 years were infected with genotype 3, and the fifth was infected with genotype 1a. Genotype in persons age 31 to 45 years and 46 to 60 years did not differ significantly. The HCV genotypes were not significantly associated with ALT levels or histologic features after adjustment for age (data not shown). Discussion It has been difficult to estimate precisely how many asymptomatic HCV-infected persons are at significant risk for progressive liver disease. This is a result of the limited available information on the actual burden of HCV in the general population and uncertainty about the natural course of HCV infection in asymptomatic individuals (16). Previous studies mainly considered blood donors screened for anti-HCV and rarely reported systematic data on liver histology. Our survey was conducted in a less highly selected population and might therefore better represent the burden of HCV in the general population. Limitations of our study include the uncertain generalizability to other geographic areas, the inclusion of only working adults and their relatives, and the lack of detailed information on risk factors in the screened population and of cofactors known to influence hepatitis C progression (use of alcohol or drugs; co-infection with hepatitis B virus or HIV) in the HCV-positive persons. Our data may underestimate the prevalence of HCV because of a healthy worker effect. Despite these limitations, our data indicate that progressive liver disease can be detected in a substantial proportion of apparently healthy, asymptomatic persons with HCV infection. Of note, almost 40% of individuals positive for HCV RNA, representing 0.70% of the general population cohort screened, had active inflammatory lesions or advanced fibrosis (as shown by liver biopsy results). These histologic features are considered the hallmark of progressive HCV infection and indications for antiviral therapies (16). Our findings would suggest that broader screening for HCV in the general population might be indi

Fibrosis progression in initially mild chronic hepatitis C

Summary.  The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 ± 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 ± 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow‐up parameters. Sixty‐four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (ΔF/year) was associated with age (P < 0.0001), baseline and follow‐up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two‐thirds of patients with initially mild chronic hepatitis C within 5–10 years and advanced fibrosis/cirrhosis develops in one‐third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.

Comparison of thrice weekly vs daily human leucocyte interferon-alpha therapy for chronic hepatitis C. TVVH Study Group.

Standard treatment for chronic hepatitis C currently consists of 3–6 million units (MU) of interferon‐α (IFN‐α) given thrice weekly (t.i.w.) for 12 months, obtaining rates of sustained response (SR) that usually do not exceed 15–25%. Some recent reports have suggested that daily administration of IFN‐α may be more efficacious. More than 7 years ago, when standard therapy for hepatitis C was usually given for 6 months, we conducted a randomized clinical trial comparing daily vs t.i.w. treatment. In this study, 149 patients with chronic hepatitis C were randomized to received 3 MU of IFN‐α either t.i.w. for 6 months or daily for 3 months followed by t.i.w. for 3 months. All patients were treated with human leucocyte IFN‐α and were followed‐up for up to 72 months after inclusion. Overall, patients treated daily or t.i.w. had similar rates of virological response after 3 months of induction [24/49 (50%) vs 40/100 (40%)], at the end of therapy [15/49 (31%) vs 36/100 (36%)] and at the end of follow‐up [6/49 (12%) vs 9/100 (9%)]. However, when patients infected with HCV types other than HCV‐1 were studied, there was a trend favouring the daily schedule that was associated with a higher [5/20 (25%) vs 5/48 (10%)] rate of long‐term SR. All patients with a virological response – hepatitis C virus (HCV) RNA negative in serum as determined using the polymerase chain reaction – at 6 months after therapy remained in biochemical and virological remission at long‐term follow‐up, while seven of eight subjects who had normal alanine aminotransferase (ALT) levels but were serum positive for HCV RNA at 6 months, relapsed later, indicating that serum HCV RNA is better than ALT at predicting long‐term cure after IFN‐α therapy in chronic hepatitis C.

Clinical trial: comparison of weekly once versus twice half-dose weekly administration of pegylated interferon alpha 2b in combination with ribavirin for the treatment of HCV-1 positive patients with chronic hepatitis C

Background  Pegylated interferon (PEG‐IFN) alpha2b is currently used as a once weekly injection in combination with ribavirin for the treatment of chronic hepatitis C.