Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up.

BACKGROUND: This open, multicenter study was conducted to evaluate the efficacy and safety of lamivudine prophylaxis given to chronic hepatitis B virus-(HBV) infected patients before and after orthotopic liver transplantation (OLT). We now present long-term data that follow our previous short-term report. METHODS: Twenty-three patients were treated with lamivudine (100 mg orally, daily); 13 (57%), were serum HBV DNA positive (Abbott Genostics, Abbott Laboratories, Chicago, IL) at study entry. Patients received lamivudine for at least 4 weeks before OLT, and for up to 50 months (median 25 months) after OLT. RESULTS: Of the 23 treated patients, 17 survived to undergo OLT. Eleven patients (65%) survived up to 4 years (median 36 months) after OLT. One of the survivors stopped lamivudine because of a possible adverse reaction 9 months post-OLT, and prophylaxis with HBV immune globulin was then established. Ten survivors continue lamivudine. Eight long-term survivors have normal liver function without evidence of HBV reinfection. Of the 17 transplanted patients, 6 died. Four patients died (3 days to 5 months post-OLT) without evidence of graft reinfection. Two further patients died at 19 and 23 months post-OLT from graft failure. Both patients had YMDD variant detected at 12 months post-OLT. Two other patients with YMDD-variant HBV remain alive on lamivudine, 9 and 15 months after development of the variant. CONCLUSIONS: Lamivudine, given before and after OLT, prevents significant graft reinfection for the majority of treated patients. The study has also shown that lamivudine is extremely well tolerated by liver failure patients and for a prolonged period after transplantation.

Etiology, screening, and treatment of hepatocellular carcinoma.

The prognosis with large hepatocellular carcinomas is poor, and only palliative treatment is available. Small tumors are amenable to several modes of treatment, including liver transplantation, resection, or alcohol injection, with acceptable 5-year survival rates. Although the value of screening for hepatocellular carcinoma has yet to be shown, these data, coupled with the recognition of at-risk groups and useful diagnostic techniques, might encourage the clinician to screen at-risk patients in the clinic. New imaging techniques such as ultrasonographic angiography enhanced with CO2 microbubbles, or color Doppler ultrasound, may clarify the intratumoral blood flow of small tumors.

The role of hepatitis C virus in alcoholic liver disease.

Alcoholism is a major public health problem across the world. However, only a minority of individuals who abuse alcohol develop significant liver injury. Interactions between alcohol and hepatotrophic viruses, particularly hepatitis C virus, have been recognized for some time. The aim of this review is to examine the seroprevalence of hepatitis C virus in individuals who abuse alcohol, and to discuss the association between hepatitis C virus infection and the histopathological and clinical findings in this group of patients. The possible pathogenesis of interaction between alcohol and hepatitis C virus is discussed briefly, and treatment options are examined.

Hepatitis B virus and liver transplantation: concepts in antiviral prophylaxis.

Liver transplantation remains problematic in patients with end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection. Recurrent hepatitis is almost universal in those patients who are HBV DNA-positive prior to transplantation. Prophylactic hepatitis B immune globulin can be given to reduce the rate of hepatitis B recurrence in patients who are HBV DNA-negative prior to transplantation. More recently novel antiviral drugs such as lamivudine or famciclovir have been used specifically to inhibit hepatitis B viral replication. However, the development of drug-resistant viral mutants have been observed. Further studies are needed to investigate these drugs more extensively, particularly to assess whether combination therapy may be a more effective means of controlling viral recurrence in patients transplanted for chronic HBV infection.

Absence of anti-envelope antibodies and clearance of hepatitis C virus in a cohort of Irish women infected in 1977.

The presence or absence of antibodies to the second envelope protein (anti-E2) of hepatitis C virus (HCV) was determined in stored sera taken from a cohort of 87 Irish women with antibodies to HCV (anti-HCV) who were all infected by HCV genotype 1b from contaminated anti-D immunoglobulin given in 1977. Anti-E2 was found in 16 patients (100%) who were HCV RNA positive but only in 31 of 50 patients (62%) who were HCV antibody positive by recombinant immunoblot assay (RIBA) but HCV RNA negative. In the remaining 21 sera taken from women who had indeterminate recombinant immunoblot assays and who were repeatedly negative on testing for HCV RNA, anti-E2 was found in only three cases (14%). This suggests that loss or absence of anti-E2 may be useful in confirming clearance of HCV.

Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions.

AIMS: The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone. METHODS: In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. RESULTS: The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. CONCLUSIONS: There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.

Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.

BACKGROUND: Orthotopic liver transplantation in patients positive for hepatitis B virus (HBV) DNA is associated with a high reinfection rate, even with hepatitis B immunoglobulin (HBIG) prophylaxis. Nucleoside analogues that inhibit hepatitis B replication in patients with chronic hepatitis B could prevent reinfection after transplantation. The aim of this study was to analyse the efficacy and safety of prophylaxis both before and after transplantation with the nucleoside analogue lamivudine, without HBIG, in patients undergoing liver transplantation. METHODS: 17 HBsAg-positive patients with decompensated cirrhosis and previous evidence of viral replication were enrolled. 12 were HBV-DNA-positive by a signal amplification assay. Patients were treated with oral lamivudine (100 mg daily) for at least 4 weeks before transplantation and followed up for 18-90 weeks after transplantation. FINDINGS: HBV DNA became undetectable in serum before transplantation in all HBV-DNA-positive patients. Four died before transplantation from complications of cirrhosis; one patient was withdrawn from the study because of a cerebrovascular accident. The remaining 12 patients underwent transplantation. Two patients died after transplantation (one at 3 days and one [suicide] at 20 weeks). HBV DNA reappeared in one patient with histological evidence of recurrent hepatitis (72 weeks). By week 24 the nine remaining patients had lost HBsAg and remained negative for HBV DNA. INTERPRETATION: Lamivudine treatment may prove useful in preventing recurrence of hepatitis B after liver transplantation. The effect on survival of patients after transplantation remains to be assessed.