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

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch™

Timely Information for Practicing Physicians

 

June 2004

Hepatocellular Carcinoma (HCC)

Woodchuck hepatitis virus (WHV) animal model and N-myc rearrangements.  HBV infection is a known risk factor for the development of HCC.  Malignant transformation of hepatocytes in HBV-infected individuals is thought to require multiple genetic and epigenetic alterations.  A multistage process of carcinogenesis is suggested by histologic changes in the liver, which may be related to molecular events within hepatocytes that lead to aberrant gene expression and the development of malignancy.  WHV is a member of the same virus family as HBV, and experimental WHV infection of newborn woodchucks leads to the development of HCC.  In this animal model, WHV integrations affecting the myc family of protooncogenes, especially the N-myc-2 retroposon, have been frequently demonstrated.  James Jacob and colleagues utilized the WHV animal model to determine the relationship between size and histologic grade of hepatic neoplasms in woodchucks and the presence of WHV DNA integrations and N-myc-2 rearrangements.  They analyzed 55 HCC neoplasms and matched nontumor hepatic specimens obtained postmortem from 13 chronic WHV carriers.  Fifty-one of the neoplasms were classified as HCC and 4 were classified as adenomas.  There were 7 grade 1, 20 grade 2, and 24 grade 3 HCCs.  Integrated sequences of WHV DNA were found in 2 of the 4 adenomas.  In the grade 1 HCCs, 43% had WHV DNA integrations, but none had N-myc rearrangements.  In the grade 2 HCCs, 80% had WHV DNA integrations and 38% had N-myc rearrangements.  In the grade 3 HCCs, 79% had WHV DNA integrations and 74% had N-myc rearrangements.  Evidence of both WHV DNA integrations and N-myc rearrangements were found in 83% of the 12 largest HCC tumors.  These findings suggest that a progression of genetic alterations was associated with worsening tumor grade and increasing tumor size.  It remains to be determined if these mechanisms of malignant transformation will apply to humans.  (Jacob JR et al. Hepatology 2004;39:1008-1016.)

 

HBV mode of transmission.  HBsAg carriers are at high risk for developing HCC and 70% of HBsAg-positive patients with HCC acquired HBV infection perinatally.  Perinatal transmission of HBV may lead to familial clustering of HBV infection, which in turn may cause familial aggregation of HCC.  Chien-Hung Chen et al performed a retrospective cohort study on the differences in HBV carrier rates and HCC-related mortality between 2 generations of HCC families.  Patients’ relatives with HCC were prospectively screened from 1992 to 1997 with ultrasonography, serum alpha-fetoprotein, serum biochemistry, and viral markers.  The study included 13,676 relatives in 2 generations (the index-patient generation and the offspring generation); there were 117 HCC-related deaths in this population.  More HCC-related deaths occurred in the index-patient generation than in the offspring generation.  This may be related, in part, to the younger age of the offspring generation (mean, 38 y) compared with the age of the index generation (mean, 44 y).  Offspring of female index patients had higher rates of HCC-related mortality than did offspring of male index patients.  These data indicate that perinatal transmission of HBV and maternal viral load may be important risk factors for HCC. (Chen C-H et al. J Hepatol 2004;40:653-659.)

 

Superinfection

Impact of acute hepatitis C in patients with chronic HBV infection.  Superinfection in patients with chronic HBV is common.  While acute hepatitis delta virus (HDV) superinfection is known to be associated with severe progressive liver disease, the clinical course following acute HCV superinfection has not been well described.  Yun-Fan Liaw and others at the Chang Gung Memorial Hospital in Taipei followed a cohort of 64 HBV patients with acute HCV infection for ³1 year (range, 1-20 y).  The authors also identified a cohort of 64 HBV patients with HDV superinfection and a control group of 64 HBV patients without superinfection.  Both the HDV superinfection group and the control group were matched with the HCV superinfection patients for age, sex, and HBeAg status.  Acute HCV superinfection was typically heralded by acute icteric hepatitis.  After 10 years of follow-up, the cumulative incidence of cirrhosis was 48% in the HCV cohort compared with 21% in the HDV group and 9% in controls.  The cumulative probability of HCC development was 14% in the HCV group, 3% in the HDV group, and 2% in controls.  None of the HDV-infected patients died, while the annual mortality rate for the HCV-infected patients was 0.64%.  These data demonstrate that HCV superinfection in patients with chronic HBV is associated with a worse long-term prognosis than is HDV superinfection or HBV without superinfection.  (Liaw Y-F et al. Gastroenterology 2004;126:1024-1029.)

 

Lamivudine-resistant HBV INFECTION

Tenofovir disoproxil treatment.  Tenofovir disoproxil is a nucleotide analogue that has demonstrated antiviral activity against wild-type and lamivudine-resistant HBV.  Unlike adefovir dipivoxil, there is no clear association between tenofovir disoproxil and renal toxicity.  Alexander Kuo and others at the Massachusetts General Hospital report a series of 9 patients with lamivudine-resistant HBV treated with tenofovir 300 mg daily.  The addition of tenofovir to lamivudine therapy in these patients resulted in a median decline of 4.5 log10 copies/mL in HBV DNA levels after a median treatment duration of 12 months (range, 6-16 mo).  Serum ALT levels normalized in 4 of 7 patients with elevated ALT levels at baseline.  HBeAg seroconversion occurred in 2 patients.  No significant adverse events were reported.  These preliminary findings show that tenofovir is clinically active in patients with lamivudine-resistant HBV and is well tolerated without renal toxicity.  (Kuo A et al. Clin Gastroenterol Hepatol 2004;2:266-272.)

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