Editorial Board: Emmet B. Keeffe, MD (Chair); M. Eric Gershwin, MD;

Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD;

Paul Martin, MD; Marion G. Peters, MD

HEPATOLOGY WATCH^®

OCTOBER 2003

CHRONIC VIRAL HEPATITIS

Evaluation of grade and stage of liver disease. Information concerning hepatic necroinflammatory activity and stage of fibrosis is helpful in the management of patients with chronic viral hepatitis. Chun-Tao Wai and colleagues at the University of Michigan developed a simple model utilizing a novel index, the aspartate aminotransferase (AST) to platelet ratio index (APRI), to predict significant fibrosis (Ishak score ³3) and cirrhosis in a study of 270 consecutive previously untreated patients with chronic HCV infection who had undergone liver biopsy. Significant fibrosis and cirrhosis were predicted accurately by the APRI in 51% and 81%, respectively, of patients in a training cohort (n = 192). In a validation cohort (n = 78), the areas under ROC curves for predicting fibrosis and cirrhosis were 0.88 and 0.94, respectively. These data indicate that a simple index using AST level and platelet count can accurately identify HCV patients with significant fibrosis or cirrhosis. In a second study, Guido Colloredo and others evaluated the impact of the size of the liver biopsy specimen on grading and staging of hepatic disease from 161 patients with chronic HBV or HCV infection. They found that reducing the length or width of the biopsy led to an increased frequency of underscoring the grade and stage of liver disease. These findings mitigate against the use of fine-needle biopsy in this clinical setting. (Wai C-T, et al. Hepatology 2003;38:518-526 and Colloredo G, et al. J Hepatol 2003;39:239-244)

HBV genotype, precore and core promoter variants, and potential new treatments. Chi-Jen Chu and colleagues of the US HBV Epidemiology Study Group conducted a nationwide study that enrolled 694 consecutive patients with chronic HBV infection seen in 17 US liver centers during a 1-year period to investigate the associations of HBV genotype and HBV precore/core variants with patient demographics, serum HBV DNA levels, and severity of liver disease. All HBV genotypes were found to be present in the US, and a strong association between ethnicity and HBV genotype was observed. The most common genotypes in the US were A (34.7%) and C (30.8%), which were associated with a higher prevalence of HBeAg. Precore and core promoter variants were detected in 27% and 44% of patients, respectively, and were more often found in HBeAg-negative patients. Promoter variants were associated with higher HBV DNA levels in HBeAg-negative patients, and patients with core promoter variants were more likely to have hepatic decompensation. These results suggest that HBV genotypes and precore/core promoter variants may account for the heterogeneity of disease manifestations among US patients with HBV infection. In another article, Peter Angus and associates reported the first documented case of a patient who developed resistance to the nucleotide analogue adefovir dipivoxil following the emergence of a novel mutation in the HBV polymerase gene (the substitution of threonine for asparagine at residue rt236 in domain D). Finally, in a preclinical study using a mouse model, Bruno Bordier et al demonstrated that prenylation inhibitors have antiviral activity against hepatitis delta virus (HDV). The HDV envelope requires surface antigen proteins provided by HBV, and HDV coinfection can dramatically worsen HBV liver disease. HDV virion assembly requires prenylation of its nucleocapsid-like large delta antigen protein. These experiments provide the first preclinical data of the anti-HDV efficacy of prenylation inhibition. (Chu C-J, et al. Gastroenterology 2003;125:444-451; Chu C-J, et al. Hepatology 2003;38:619-628; Angus P, et al. Gastroenterology 2003;125:292-297; and Bordier BB, et al. J Clin Invest 2003;112:407-414)

Predictors of HCV antiviral response. Brian Bressler and coworkers performed a retrospective review of all chronic HCV patients treated at the University of Toronto with antiviral therapy from 1989 to 2000 (n = 253). Logistic regression identified body mass index (BMI), HCV genotype, and cirrhosis to be indicators of whether or not a sustained virological response (SVR) was achieved. Obese patients (BMI >30) had an odds ratio (OR) of 0.23 for response compared to normal (BMI <25) and overweight (BMI = 25-30) patients. The OR for response for genotypes 2 and 3 compared to genotype 1 was 11.7 and for cirrhotic versus noncirrhotic patients was 0.15. In a second investigation, Gary Davis et al. found that 67% to 80% of chronic HCV patients treated with peginterferon alfa-2b and ribavirin who had a reduction in HCV RNA of ³2 logs by week 12 of therapy (early virologic response [EVR]) achieved a SVR. An EVR occurred in 69% to 76% of patients, and those who did not achieve an EVR did not attain a viral response to further treatment, even after an additional 9 months of therapy. Discontinuing antiviral therapy in patients who do not achieve an EVR would reduce drug costs by >20%. (Bressler BL, et al. Hepatology 2003;38:639-644 and Davis GL, et al. Hepatology 2003;38:645-652)

CIRRHOSIS

Spironolactone vs. spironolactone plus furosemide in the treatment of ascites. Justiniano Santos and colleagues randomized 100 nonazotemic patients with cirrhosis and moderate ascites to receive spironolactone alone or spironolactone plus furosemide. The response rate (94% vs. 98%), rapidity of ascites mobilization, and incidence of adverse events were similar in both treatment groups. Furthermore, diuretic dose reductions occurred more frequently in the combination therapy group (68% vs. 34%). These results show that spironolactone monotherapy is effective and safe treatment for moderate ascites due to cirrhosis and is more easily administered than combination diuretic therapy. (Santos J, et al. J Hepatol 2003;39:187-192)

REVIEW

Drug-induced hepatoxicity. The pathogenesis of drug-induced hepatoxicity, the common drug-related adverse events that involve the liver, and the process of FDA drug approval were recently reviewed. (Lee W M, et al. N Engl J Med 2003;349:474-485)

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