Current Papers in Liver Disease - September, 1997

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

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

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Tong, M. J., Reddy, R., Lee, W. M., Pockros, P. J., Hoefs, J. C., Keeffe, E. B., Hollinger, F. B., Heathcote, E. J., White, H., Foust, R. T., Jensen, D. M., Krawitt, E. L., Fromm, H., Black, M., Blatt, L. M., Klein, M., Lubina, J., and the Consensus Interferon Study Group. 1997. Treatment of chronic hepatitis C with consensus interferon: a multicenter, randomized, controlled trial. Hepatology. 26:747-754.

As of September, 1997, only interferon alpha-2a and interferon alpha-2b were approved in the United States for the treatment of chronic hepatitis C. The usual treatment course is 3,000,000 units three times a week for 6 to 12 months. Only about 60% of patients respond to these drugs during therapy and about 80% who respond relapse after treatment is stopped. This study was a multicenter, randomized, controlled trial comparing two doses of consensus interferon (3 micrograms and 9 micrograms) with 3,000,000 units of interferon alpha-2b three times a week for 24 weeks in 704 patients with chronic hepatitis C. The beneficial effects of consensus interferon were better at 9 than to 3 micrograms. Sustained biochemical responses (normal serum alanine aminotransferase activity) 24 weeks after stopping therapy were similar in the 9 microgram consensus interferon group and the interferon alpha-2b group (20.3% versus 19.6%). The percentages of subjects without detectable hepatitis C virus serum RNA 24 weeks after stopping treatment were also similar in these two groups (12.1% versus 11.3%). Improvements in liver histology were similar in all three groups. The adverse-event profile was similar for consensus interferon and interferon alpha-2b. The results of this study show that consensus interferon is similar in efficacy to interferon alpha-2b for the treatment of chronic hepatitis C. Chemically, consensus interferon and interferons alpha-2a and 2b are similar compounds. Alpha-2a and alpha-2b have one different amino acid in their sequences. Consensus interferon is a non-natural compound derived by aligning the sequences of several interferon alpha nonallelic subtypes and assigning the most commonly observed amino acid in each position. It is likely that consensus interferon will be approved for the treatment of chronic hepatitis C in the United States, adding to the number of available interferon preparations. The results of this study further demonstrate that additional drugs, some of which may be used in combination with interferon, are needed for effective treatment of chronic hepatitis C.

Poupon, R. E., Lindor, K. D., Cauch-Dudek, K., Dickson, E. R., Poubon, R, and Heathcote, E. J. 1997. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 113:884-890.

Ursodiol (ursodeoxycholic acid) has been shown in several studies to slow the progression of primary biliary cirrhosis (PBC). In this study, data from three large clinical trials (one American, one Canadian and one French) were combined in which individuals with PBC were randomized to treatment with ursodiol or placebo. Subjects received treatment for up to two years in two studies and up to four years in one. Survival free of orthotopic liver transplantation was significantly improved in the patients treated with ursodiol compared to placebo. Further analysis showed that survival free of liver transplantation was significantly improved in moderate and higher risk groups and individuals with histological stage IV (i. e. biliary cirrhosis). The combined results of these three studies show that long-term treatment with ursodiol improves survival free of liver transplantation in patients with moderate or severe disease.

Martin, T. G., Somberg, K. A., Meng, Y. G., Cohen, R. L., Heid, C. A., de Sauvage, F, J., and Shuman, M. A. 1997. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation. Annals of Internal Medicine. 127:285-288.

Thrombocytopenia (low platelet count) is common in patients with cirrhosis and has historically been attributed to enlargement of the spleen that occurs secondary to portal hypertension. However, after shunt procedures to relieve portal hypertension or removal of the spleen, platelet counts do not always improve. This suggests that decreased platelet production may also contribute to thrombocytopenia in some patients with cirrhosis. In the present study, the authors measured the plasma levels of thrombopoietin, a potent stimulator of platelet production that is probably made in the liver. Measurements were made in 44 patients with cirrhosis, including 17 who had orthotopic liver transplantation. Thrombopoietin levels were undetectable in 39 of 44 patients with cirrhosis. In 16 of 17 patients, the levels became detectable after orthotopic liver transplantation. Thrombopoietin mRNA levels were also slightly decreased in liver samples from patients with cirrhosis compared to controls. These findings suggest that low thrombopoietin levels, leading to decreased platelet production, may contribute to the low platelet counts seen in individuals with cirrhosis.

Bizollon, T., Palazzo, U., Ducerf, C., Chevallier, M., Elliott, M., Baulieux, J., Pouyet, M., and Trepo, C. 1997. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation. Hepatology. 26:500-504.

Cirrhosis caused by chronic hepatitis C is the leading indication for orthotopic liver transplantation in the United States. Recurrent hepatitis C after transplantation is a major cause of liver failure and need for retransplantation. In several studies, treatment with interferon alpha has been disappointing and has led to an increased incidence of rejection. In this nonrandomized, uncontrolled pilot study, 21 patients with recurrent hepatitis C after liver transplantation were treated for six months with a combination of interferon alpha and ribavirin followed by six months of treatment with ribavirin alone. After the combination therapy phase, all patients had normalization of serum alanine aminotransferase activities and 10 cleared viral RNA from their serum as assessed by reverse transcription-polymerase chain reaction. Improvement in liver histology was also seen in all patients. During the ribavirin alone phase, alanine aminotransferase activities remained normal in all but one patient but viral RNA reappeared in 5 patients. No patient experienced liver allograft rejection during the study period. These results warrant the initiation of larger, randomized, controlled trials of interferon alpha plus ribavirin in the treatment of patients with recurrent hepatitis C after orthotopic liver transplantation. Treatment decisions should not be based on the results of this preliminary study alone because of the lack of randomization, lack of controls and no report of long-term follow-up after the study medications were discontinued.

Kolykhalov, A. A., Agapov, E. V., Blight, K. J., Mihalik, K., Feinstone, S. M., and Rice, C. M. 1997. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science. 277:570-574.

The hepatitis C virus (HCV) is a positive-stranded RNA virus that causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. The viral genome is about 9.6 kilobases and encodes a polyprotein that is processed into at least 10 different polypeptides in cells. Laboratory research on HCV has been hampered by the lack of an infectious molecular clone or good animal model for the analysis of infections. Beside humans, HCV is known only to infect chimpanzees. In this study, the authors produced full-length functional clones of HCV by reverse transcription-polymerase chain reaction and other molecular cloning techniques. RNA transcripts encoded by the clones were injected into the livers of chimpanzees and found to cause hepatitis as documented by serum biochemical findings, liver biopsy results, the production of antibodies against HCV proteins and the ability to amplify tagged viral nucleic acids from blood. Using these methods, HCV infection can now be studied using molecularly defined, clonal infectious agents.

Bronowicki, P.-P., Venard, V., Botte, C., Monhoven, N., Gastin, I., Chone, L., Hudziak, H., Rhin, B., Delanoe, C., LeFaou, A., Bigard, M.-A., and Gaucher, P. 1997. Patient-to-patient transmission of hepatitis C virus during colonoscopy. New England Journal of Medicine. 337:237-240.

Although rare, hepatitis C virus (HCV) has been transmitted to patients during invasive medical and surgical procedures. In this brief report, the authors show that patient-to-patient transmission of HCV can likely occur during colonoscopy. Two patients with no known risk factors for hepatitis C underwent colonoscopy on the same day in the same clinic. Both had normal serum aminotransferase activities and negative HCV serological tests two months prior to undergoing colonoscopy. About three months after their procedures, both had serum antibodies against HCV and elevated serum aminotransferase activities. Liver biopsies several months later were consistent with chronic hepatitis C. All staff members involved in performing the colonoscopies did not have serum antibodies against HCV. One other patient who was known to have hepatitis C underwent colonoscopy in the same clinic and on the same day as the subjects. HCV cDNA was amplified from the serum of all three patients who had colonoscopies on that day and sequencing showed that 150 nucleotides in the NS3 gene were identical in all three. It was subsequently discovered that the biopsy-suction channel of the endoscope used in all three cases was never thoroughly cleaned with an appropriate brush. This study strongly suggests that HCV can be transmitted from patient-to-patient during colonoscopy. The transmission likely resulted from inadequate cleaning and sterilization of the endoscope between procedures.