Current Papers in Liver Disease - February, 1998

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

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

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Kim, J. L., Morgenstern, K. A., Griffith, J. P., Dwyer, M. D., Thomson, J. A., Murcko, M. A., Lin, C., and Caron, P. R. 1998. Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure. 6:89-100.

The hepatitis C virus (HCV) is a single stranded RNA virus. The RNA genome encodes one large polyprotein that is processed by cellular and viral proteases into several structural and enzymatic proteins necessary for viral replication. One such viral enzyme is a helicase that unwinds duplex RNA during genomic replication. Last year, Yao et al. (Nature Structural Biology. 4:463-467.) (see July, 1997 Current Papers in Liver Disease) reported the three dimensional structure of the NS3 helicase domain based on X-ray crystallographic studies. Now, Kim et al. also report on the three dimensional structure of the HCV helicase domain of NS3 bound to a single-stranded DNA oligonucleotide. They similarly used X-ray crystallography to solve the structure at a resolution of 2.2 Angstrom units. They show that the protein consists of three structural domains with the oligonucleotide lying in a groove between the first two domains and the third. The first two domains have an adenylate kinase like fold and a phosphate-binding loop is in the first domain. Knowledge of the structure of the HCV helicase and its functionally important domains could lead to the development of specific inhibitors using rational drug design that may be ultimately used in patients to prevent HCV replication.

Reichard, O., Norkrans, G., Fryden, A., Braconier, J.-H., Sonnerborg, A., Weiland, O., for the Swedish Study Group. 1998. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Lancet. 351:83-87.

Several pilot studies have suggested that the combination of interferon alpha-2b plus ribavirin may be superior to interferon alpha-2b alone in obtaining a sustained response after treatment of patients with chronic hepatitis C. This paper reports the results of a randomized, double-blind, placebo controlled trial of 100 previously untreated patients comparing 24 weeks of interferon alpha-2b (3,000,000 units three times a week) alone or in combination with ribavirin (1000 or 1200 mg/day). In the interferon alpha-2b plus ribavirin group, 18 (36%) of 50 subjects had undetectable serum virus RNA 24 weeks after stopping treatment as compared to 9 (18%) of 50 in the interferon alpha-2b alone group (P = 0.047). Sustained responses (no detectable viral RNA) were also significantly greater in the combination group one year after stopping treatment. Seven subjects were withdrawn from the combination group because of non-compliance or side effects compared to 3 subjects receiving interferon alpha-2b alone. The difference in response rates was greater in the subjects with higher (>3,000,000 equivalents per ml) pre-treatment concentrations of hepatitis C virus RNA in serum than in those with lower concentrations. The results of this study suggest that more patients with chronic hepatitis C have a sustained response (no detectable serum viral RNA) after treatment with interferon alpha-2b plus ribavirin than interferon alpha-2b alone. This difference is most dramatic in patients with high serum viral RNA concentrations prior to treatment.

Vento, S., Garofano, T., Renzini, C., Cainelli, F., Casali, F., Ghironzi, G., Ferraro, T., and Concia, E. 1998. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. New England Journal of Medicine. 338:286-290.

Hepatitis A virus (HAV) infection is usually self-limited and non-fatal, however, it may carry a worse prognosis in individuals with chronic liver disease. This study was designed to determine the effects of HAV infection in individuals with chronic hepatitis B and chronic hepatitis C. One hundred sixty-three individuals with chronic hepatitis B and 432 with chronic hepatitis C were followed for 7 years. Twenty-seven acquired HAV, 10 of whom had chronic hepatitis B and 17 chronic hepatitis C. Fulminant hepatic failure (severe liver failure with hepatic encephalopathy) developed in 7 of the patients with chronic hepatitis C but none with chronic hepatitis B. None of these 7 individuals with chronic hepatitis C had cirrhosis. All but one of the patients with chronic hepatitis C and HAV infection with fulminant hepatic failure died. None of 191 control individuals with acute HAV infection alone had fulminant hepatic failure. These results suggest that individuals with chronic hepatitis C may be at an increased risk of developing fulminant hepatic failure and death if infected with HAV. Such patients should probably be vaccinated against HAV.

Willner, I. R., Uhl, M. D., Howard, S. C., Williams E. Q., Riely, C. A., and Waters, B. 1998. Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States. Annals of Internal Medicine. 128:111-114.

In Memphis and Shelby County, Tennessee, 1700 cases of hepatitis A were reported in 1994 and 1995. This retrospective review of charts gives some insights into the clinical features of patients hospitalized during this large urban epidemic of hepatitis A. The charts of 256 patients admitted for acute hepatitis A to 15 Shelby County hospitals were reviewed. The median age was 26 years. Nineteen percent of patients had a history of exposure to an infected person, 1% a history of occupational exposure, 1% exposure to contaminated food in a restaurant and 79% no known exposure risks. Five (2%) patients died. The median age of patients who died was 40 years, however, two patients younger than 30 years of age died. Only one patient who died had evidence of underlying chronic liver disease. Patients 40 years of age and older were more likely to have serious complications and death (P = 0.014). This retrospective review confirms that complications and probably death from hepatitis A are more frequent in patients 40 years of age and older. Nonetheless, younger, healthy persons are at risk for serious complications.

Merli, M., Salerno, F., Riggio, O., De Franchis, R., Fiaccadori, F., Meddi, P., Primignani, M., Pedretti, G., Maggi, A., Capocaccia, L., Lovaria, A., Ugolotti, U., Salvatori, F., Bezzi, M., Rossi, P., and the Gruppo Italliano Studio TIPS (G.I.S.T.). 1998. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Hepatology. 27:40-45.

Bleeding from esophageal varices is a life-threatening complication of cirrhosis. Treatments used to prevent rebleeding after a first variceal bleed include endoscopic sclerosis of the varices (sclerotherapy), endoscopic rubber band ligation of the varices, surgical shunt procedures, beta-blockers and transjugular intrahepatic portosystemic stent shunting (TIPS). Uncontrolled studies have demonstrated that TIPS is effective in preventing recurrent variceal bleeding, however, there have been only a few controlled studies and their conclusions have not been consistent. This multicenter, randomized trial compared TIPS to endoscopic sclerotherapy for the prevention of variceal bleeding. Eighty-one patients with cirrhosis and variceal bleeding were randomized to receive either TIPS (38 patients) or sclerotherapy (43 patients). During a mean follow-up period of 17.7 months, rebleeding was higher in the patients treated with sclerotherapy (51%) than in those who received TIPS (25%) (p = 0.011). However, mortality was not significantly different in the two groups (19% sclerotherapy versus 24% TIPS). Hepatic encephalopathy was more common in the TIPS group (55%) than the sclerotherapy group (24%) (p = 0.006). TIPS was most effective in preventing rebleeding compared to sclerotherapy in patients who had bleeds less than one week before the procedures. Considering the higher incidence of hepatic encephalopathy and lack of improvement in survival, TIPS does not appear to be superior to sclerotherapy as a first-choice treatment to prevent rebleeding from esophageal varices in patients with cirrhosis. The recently published results from another randomized trial support a similar conclusion (see Sauer et al. Gastroenterology. 13:1623-1631; reviewed in November, 1997 Current Papers in Liver Disease).

Ghany, M. C., Ayola, B., Villamil, F. G., Gish, R. G., Rojter, S., Vierling, J. M., and Lok, A. S. F. 1998. Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology. 27:213-222.

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Protzer-Knolle, U., Naumann, U., Bartenschlager, R., Berg, T., Hofp, U., Meyer zum Buschenfelde, K.-H., Neuhaus, P., and Gerken, G. 1998. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology. 27:254-263.

Orthotopic liver transplantation is effective for patients with end-stage liver disease cased by hepatitis B, however, infection of the grafted liver with persisting virus is a major problem. After transplantation, such patients are usually treated with long-term hepatitis B immune globulin (HBIG) which contains antibodies against hepatitis B surface antigen (HBsAg) and prevents graft infection. Nucleoside analogues such as lamivudine that inhibit the viral DNA-polymerase are also effective for prophylaxis against graft infection. In previous studies, resistance to lamivudine has been reported to develop in some patients after orthotopic liver transplantation as a result of mutations in the polymerase gene (see Ling et al. Hepatology. 1996;24:711-713 and Tipples et al. Hepatology. 1996;24:714-717; reviewed in September, 1996 Current Papers in Liver Disease). These two papers report on mutations in the hepatitis B virus envelope (HBsAg) gene in patients who developed graft infection while receiving HBIG. Ghany et al. report on 20 patients who developed graft infection after transplantation. Ten had 18 amino acid substitutions in the 'a' determinant region of HBsAg. Most of these mutations were predicted to alter the antigenicity of HBsAg. Seven had mutations elsewhere in HBsAg and three had the same sequences before and after transplantation. After withdrawal of HBIG, many of the substitutions reverted back to the pre-transplantation sequences. Protzer-Knolle et al. studied 34 patients who underwent orthotopic liver transplantation with hepatitis B. They found that variants with changes in amino acid residues 144 or 145 of HBsAg emerged during HBIG therapy and that these mutants showed impaired recognition by HBIG. The patients with substitutions at amino acids 144 or 145 showed a worse clinical outcome compared with other patients receiving HBIG (44% versus 23% graft failure caused by hepatitis B virus infection). These two studies show that resistance to HBIG can develop after orthotopic liver transplantation by selecting for hepatitis B virus variants with mutations in the envelope (HBsAg) gene. These mutant variants can cause post-transplantation graft infection.