Current Papers in Liver Disease - December, 1998

By Howard J. Worman, M. D.
Columbia University

This is a past issue of Current Papers in Liver Disease.

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McHutchison, J. G., Gordon, S. C., Schiff, E. R., Shiffman, M. L., Lee, W. M., Rustgi, V. K., Goodman, Z. D., Ling, M.-H., Cort, S., and Albrecht, J. K. for the International Hepatitis Interventional Therapy Group. 1998. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. New England Journal of Medicine. 339:1485-1492.

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Davis, G. L., Esteban-Mur, R., Rustgi, V., Hoefs, J., Gordon, S. C., Trepo, C., Shiffman, M. L., Zeuzem, S., Craxi, A., Ling, M.-H., and Albrecht, J. K. for the International Hepatitis Interventional Therapy Group. 1998. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. New England Journal of Medicine. 339:1493-1499.

Several studies have already shown that interferon alpha-2b plus ribavirin is superior to interferon alpha-2b alone in inducing sustained virological responses (no detectable hepatitis C virus RNA six months after stopping treatment). In the first of these two large studies, both performed by the same group and coordinated by the company that markets interferon alpha-2b and ribavirin, McHutchison et al. show the superiority of combination therapy for patients with chronic hepatitis C not previously treated. They randomized 912 patients with chronic hepatitis C to receive either interferon alpha-2b alone or in combination with ribavirin for 24 or 48 weeks. The sustained virological response rates were 31% and 38% for those receiving combination therapy for 24 or 48 weeks, respectively, compared to 6% and 13% for those receiving interferon alpha-2b alone for 24 or 48 weeks respectively. The differences were significant between the combination and mono therapy groups. More patients in the combination group also had improvements in liver biopsy after treatment. In the second study by Davis et al., 345 patients with chronic hepatitis C who were initially treated with interferon and responded during but relapsed after stopping treatment (had detectable viral RNA after stopping interferon) were randomized to 24 weeks of either retreatment with interferon alpha-2b alone or with interferon alpha-2b plus ribavirin. In the combination therapy group, 48% had a sustained virological response compared to only 5% in the mono therapy group. In both studies, combination therapy led to falls in blood hemoglobin concentrations that occasionally required reducing the dose of ribavirin or rarely stopping the drugs. The results of these two large, randomized trials show that interferon alpha-2b plus ribavirin is superior to interferon alpha-2b alone in the treatment of patients with chronic hepatitis C.

Pileri, P., Uematsu, Y., Campagnoli, S., Galli, G., Falugi, F., Petracca, R., Weiner, A. J., Houghton, M., Rosa, D., Grandi, G., and Abrignani, S. 1998. Binding of hepatitis C virus to CD81. Science. 282:938-941.

It is not clear how the hepatitis C virus (HCV) gets into cells. In this paper, the authors used cDNA library expression screening to identify cellular proteins that bind to one of the HCV envelope proteins on the surface of the virion. They identified CD81, a transmembrane protein that is expressed on the surface of many cells, including hepatocytes and lymphocytes. They used various assays to show that HCV envelope protein E2 and viral particles bind to CD81 in vitro. Given the limitations inherent to the study of HCV (i. e. the fact that there is no cell culture system at this time to study infection), these are the best available data that suggest a particular cell membrane protein may be a receptor or co-receptor for the virus.

Poynard, T., Marcellin, P., Lee, S. S., Niederau, C., Minuk, G. S., Ideo, G., Bain, V., Heathcote, J., Zeuzem, S., Trepo, C., Albrecht, J., for the International Hepatitis Interventional Therapy Group (IHIT). 1998. Randomized trail of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C. Lancet. 352:1426-1432.

The combination of interferon alpha-2b plus ribavirin was recently approved by the United States Food and Drug Administration for the treatment of patients with chronic hepatitis C who were previously treated with interferon but had detectable serum hepatitis C virus (HCV) RNA after stopping therapy. This large, multicenter, randomized trial compared interferon alpha-2b alone for 48 weeks to interferon alpha-2b plus ribavirin for either 24 weeks or 48 weeks in patients with chronic hepatitis C who had not been previously treated. Eight hundred and thirty-two patients were enrolled and randomly assigned to receive either interferon alpha-2b plus placebo for 48 weeks, interferon alpha-2b plus ribavirin for 48 weeks or interferon alpha-2b plus ribavirin for 24 weeks. The primary end point of the study was loss of detectable serum HCV RNA by reverse transcription-polymerase chain reaction 24 weeks after discontinuing treatment. No detectable serum HCV RNA was found in 43% of patients who received combination therapy for 48 weeks, 35% of patients who received combination therapy for 24 weeks and 19% of the patients who received interferon alpha-2b alone. Both combination groups had statistically significant better responses than the group who received interferon alpha-2b alone; the P value for the comparison of 48 weeks of combination therapy versus 24 weeks was 0.55 (statistical significance is usually considered for P values less than 0.5). Post treatment liver biopsy results in 68% of patients showed that all groups had improvement in inflammation with better improvements in the combination therapy groups. No group showed significant progression of fibrosis on liver biopsy and there was no differences between the three groups in progression of fibrosis. Discontinuation of therapy for adverse events was more common in both combination groups than in the group that received interferon alpha-2b alone. Five independent factors associated with a better chance of responding to therapy were: infection with HCV genotype 2 or 3, viral load less than 2,000,000 copies per milliliter, age 40 years or less, minimal fibrosis on pretreatment liver biopsy and female sex. These results show that treatment with interferon alpha-2b plus ribavirin for 48 or 24 weeks provides a better chance of having a sustained virological response than treatment for 48 weeks with interferon alpha-2b alone in patients with chronic hepatitis C who have never previously received interferon.

Ferre-D'Amare, A. R., Zhou, K., and Doudna, J. A. 1998. Crystal structure of a hepatitis delta virus ribozyme. Nature. 395:567-574.

The hepatitis delta virus or hepatitis D virus (HDV) concurrently infects individuals who are infected with the hepatitis B virus (HBV). Infection with both HDV and HBV is associated with more severe liver disease than infection with HBV alone. HDV has a circular, single-stranded RNA genome. When HDV RNA is replicated, it forms multimers (complexes of several RNA molecules) that must be processed to their actual size. Parts of the HBV genomic RNA itself and the complementary replication intermediate have catalytic activities for self-splicing that process the RNAs to their proper lengths. RNA molecules that have catalytic activities are known as a ribozymes. In this study, the authors use X-ray crystallography to determine the three-dimensional structure of the self-cleaving RNA ribozyme from HDV. They show that the HDV ribozyme has an active site that is buried deep within a crevice surrounded by a backbone and functional groups. This organization is reminiscent of protein enzymes. These important results provide fundamental information on the structure and function of the only known catalytic RNA that is essential for the viability of a human pathogen.

Neumann, A. U., Lam, N. P., Dahari, H., Gretch, D. R., Wiley, T. E., Layden, T. J., and Perelson, A. S. 1998. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 282:103-107.

Little is know about the viral dynamics (production and clearance) of hepatitis C virus (HCV) infection and its response to antiviral therapy with interferon alpha. In this paper by Neumann et al., complex mathematical modeling was used to investigate the dynamics of HCV infection and the response to treatment with interferon alpha. The data were obtained from based 23 patients who received different doses of interferon alpha. From the model, it appears that the major initial affect of interferon alpha is to block virus production and release. The estimated half-life of a viral particle was 2.7 hours with production and clearance of about one trillion viral particles a day. This rate of HCV production is significantly greater than that estimated for human immunodeficiency virus (HIV) in infected individuals. The estimated infected cell death rate varied considerably from patient to patient ranging from 1.7 days to 70 days. Fast death rates were predictive of HCV being undetectable by reverse transcription-polymerase chain reaction in serum after three months of treatment. The results of this study provide important information about the replication of HCV in infected individuals and its clearance from the body in response to treatment with interferon alpha. The high viral production rate explains why HCV mutates frequently in infected individuals and possibly why infection is often difficult to treat.

Lau, D. T.-Y., Kleiner, D. E., Ghany, M. G., Park, Y., Schmid, P., and Hoofnagle, J. H. 1998. 10-year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology. 28:1121-1127.

Interferon-alpha is effective in the treatment of chronic hepatitis C. At the present time, however, little data exist as to the efficacy of treatment with interferon-alpha in the long-term. Even before the discovery of the hepatitis C virus (HCV) in 1989, a trial of interferon-alpha for what was then called "non-A, non-B" hepatitis was conducted at the United States National Institutes of Health. Serum samples were stored on the patients who participated in this trial. This small study reports on the follow-up of 10 patients who were treated for chronic hepatitis C with interferon-alpha between 1984 and 1987. All patients were showed to have HCV RNA in serum samples stored from before treatment. Patients were treated with interferon-alpha for around one year. Five patients had no detectable serum HCV RNA six months after stopping treatment and five did. Of the five who had no detectable serum HCV RNA after treatment, all continued to have no detectable HCV RNA after 6 to 13 years of follow-up and had improvements in liver biopsy results performed 5 to 11 years after treatment. Of the five who did not respond to treatment, all continued to have detectable serum HCV RNA after treatment and all except one had progression in fibrosis or cirrhosis on follow-up liver biopsies; one required liver transplantation. Although very small, the results of this study suggest that patients with chronic hepatitis C who do not have detectable serum HCV RNA six months after treatment have a favorable long-term prognosis.

Moriya, K., Fujie, H., Shintani, Y., Yotsuyanagi, H., Tsutsumi, T., Ishibashi, K., Matsuura, Y., Kimura, S., Miyamura, T., and Koike, K. 1998. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nature Medicine. 9:1065-1067.

Patients with chronic hepatitis C virus (HCV) infection are at an increased risk for the development of hepatocellular carcinoma (primary liver cancer). It is not clear whether HCV itself is directly involved in the development of cancer or if cancer develops secondary to chronic inflammation and development of cirrhosis. In this study, Moriya et al. bred two lines of transgenic mice that expressed the HCV core protein (one of the structural proteins of the virus) in their livers. Transgenic mice between 3 and 12 months had steatosis (fatty liver) but no ntumors. However, approximately 25% of transgenic mice between the ages of 16 months and 19 months had hepatic nodules, some of which developed as well-differentiated hepatocellular carcinomas. The results of this study show that overexpression of HCV core protein in mouse liver causes fatty liver and, in some animals, nodule formation and hepatocellular carcinoma. Of note, other studies of transgenic mice that expressed HCV core protein reported conflicting results. Despite these results, it remains unclear if HCV core protein can directly induce hepatocellular carcinoma or if cancer formation is a response to some other unusual injury (e. g. fatty liver) in the transgenic mice.

Wiley, T. E., McCarthy, M., Breidi, L., McCarthy, M., and Layden, T. J. 1998. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 28:805-809.

Individuals who have hepatitis C and drink alcohol may be at an increased risk for progression of liver disease and the development of cirrhosis. This retrospective study examined the effect of alcohol intake on the progression of liver disease in individuals with chronic hepatitis C. The data were obtained primarily from a review of the medical records and liver biopsies of 176 patients. Patients were divided into two groups: those with significant and non-significant alcohol intake. Significant intake was defined as more than 40 grams of alcohol (about 4 drinks) for women and more than 60 grams of alcohol (about 6 drinks) a day for 5 years or more. There were more men and intravenous drug users in the significant alcohol intake group. There were no differences in the age or length of time of infection in the two groups. There was a two to three fold increased risk of developing cirrhosis in the significant alcohol group. The significant alcohol group appeared to progress more rapidly in that 58% had cirrhosis in the second decade of hepatitis C virus infection compared to 10% in the other group. This study suggests that alcohol intake is an independent risk factor for the progression of liver disease in patients with hepatitis C virus infection. As always, caution must be used in interpreting the results of a retrospective study.

Copyright, 1998, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.