Animal models of hepatocellular carcinoma: hepadnavirus-induced liver cancer in woodchucks.

Woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to hepatitis-B virus (HBV) in its virus structure, genetic organization, and mechanism of replication. As with HBV in man, persistent WHV infection is common in natural woodchuck populations and is associated with chronic hepatitis and hepatocellular carcinoma (HCC). Experimental studies have established that WHV causes HCC in woodchucks. Chronic WHV carriage as an outcome of experimental infection is a function of animal age at time of exposure, virus dose, and, possibly, virus strain. Almost all (97%) chronic carriers developed histologically confirmed HCC within 3 years while no HCC developed in uninfected animals held concurrently in the same laboratory setting. The model has application in the study of underlying mechanisms of hepadnavirus-induced hepatocarcinogenesis and to the development of prophylactic and therapeutic strategies of disease control.

Role of hepatitis delta virus infection in hepatocellular carcinoma.

Hepatitis B virus (HBV) DNA integrates into the host DNA and shows a series of potentially oncogenetic properties, but HBV is not an acutely transforming virus, because HCC develops decades after infection. Other factors, namely cirrhosis, inflammation, alcohol intake, and viral superinfections, could promote the oncogenetic process induced by HBV-DNA integration. We studied the impact of HDV infection in the pathogenesis of HCC in 62 consecutive patients. Their mean age was 59 years (range 25-75 years), 54 were male and eight female; 58 had cirrhosis. The findings suggest that HBsAg-positive patients with HDV superinfection developed cirrhosis and HCC at an earlier age than HBsAg carriers without HDV infection. HDV appears to represent a "promotion" factor for HCC in subjects with an oncogenic risk induced by HBV. A long-lasting necroinflammatory lesion of the liver substained by productive HBV and HDV infections may be a major pathogenetic mechanism.

Adenine arabinoside monophosphate and acyclovir monophosphate coupled to lactosaminated albumin reduce woodchuck hepatitis virus viremia at doses lower than do the unconjugated drugs.

The woodchuck was selected to study the efficacy of liver-targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver-targeting molecule lactosaminated human serum albumin. Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively. These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin.

Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks.

The molecular forms of genomic and antigenomic hepatitis delta virus (HDV) RNA and of woodchuck hepatitis virus (WHV) DNA and WHV RNA were studied in nonneoplastic liver (NL) tissues, hepatocellular carcinoma (HCC) tissues, and several extrahepatic tissues of chronic WHV carrier woodchucks acutely (two animals) and chronically (six animals) superinfected with HDV. HDV was shown to replicate in all NL and HCC tissues but not in any of the extrahepatic tissues analyzed, which included spleen, peripheral blood lymphocytes, kidney, ovary, testis, thymus, lung, and stomach. HDV RNA was present as species with molecular weights consistent with those of monomers, dimers, and trimers of both strand polarities, supporting the rolling circle model proposed for HDV RNA replication. WHV DNA levels in NL, HCC, spleens, and serum were 10- to 100-fold lower than the levels typically observed in chronic WHV carrier woodchucks not infected with HDV. WHV DNA replicative intermediates were rarely observed and only at very low levels, representing less than 10% of the total WHV DNA. By contrast, WHV RNA transcription was not significantly depressed and both primary WHV RNA transcripts, 2.3 and 3.6 kilobases, were observed in NL, HCC, spleens, and in one of the kidney tissues. In addition, a 2.6-kilobase WHV RNA transcript was found in the majority of the NL tissues.

Prevalence of delta antibodies among urban HBsAg-positive chronic liver disease patients in Egypt.

The prevalence of delta infection among urban Egyptians is reported for the first time. Sera of 44 HBsAg-positive chronic liver disease (CLD) patients and 48 asymptomatic HBsAg carriers were screened for antibodies to hepatitis delta antigen (anti-HD). Anti-HD was found in 21 (47.7%) of the patients compared with 4 (8.3%) of the asymptomatic carriers. The difference was statistically significant at the 0.001 level. Anti-HD was present in 14 out of 24 (58.3%) subjects with histological diagnosis of chronic active hepatitis, 4 of 9 (44.9%) with cirrhosis, and 3 out of 11 (27.2%) with chronic persistent hepatitis. This study points to a high prevalence of hepatitis delta virus in Egypt.

Prevalence of the hepatitis delta virus in Rumania.

Epidemiological data obtained to date show that the delta agent is spread all over the world. In Rumania hepatitis B virus infection is widespread and is associated with a high incidence of chronic liver disease. To determine the prevalence of delta infection, sera from 373 patients with chronic liver disease were tested for HBV markers; 228 were HBsAg positive. Anti-HD was present in 190 sera (83.33%), which reveals a very high incidence and shows a higher frequency of the active forms of the disease. However, in contrast to other studies, we found a high incidence of HDV infection in chronic persistent hepatitis and hepatocellular carcinoma.

Epidemiology of hepatitis delta virus (HDV) infection.

Markers of hepatitis delta virus (HDV) infection have been detected all over the five continents. Geographical prevalence varied heavily: HDV infection is very rare in Far East Asia, but extremely frequent in Arabian countries, in Romania and in certain Indian populations of South America. In Europe and in the USA the infection is widely spread among high risk groups such as intravenous drug abusers and haemophiliacs.

Infections with the hepatitis B virus associated delta agent in an isolated West-African community.

The occurrence of delta agent (delta) infection in the native population of the isolated Gbawein and Wroughbarh Clan region of Grand Bassa County, Liberia was studied. Sera of 97 patients with epilepsy, 73 non-epileptic relatives, and 31 non-epileptic control subjects were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs) and antibody to delta antigen (anti-delta). Of the 201 individuals tested 76 (37.8%) were HBsAg positive; the overall infection rate (HBsAg and anti-HBs positives) was 68.7%. No correlation with clinical disease could be established. Markers of delta infection were detected in seven index cases. All subjects with anti-delta were HBsAg positive except one, who was anti-HBs positive with a low titre of anti-delta (less than 1:10(2)), which is indicative of a recent delta infection. Mothers of six delta infected index cases were available for testing, one was found HBsAg and anti-delta positive, while the other five were anti-HBs positive and anti-delta negative. No delta infections occurred in children of HBV negative mothers. Presence of delta markers varied significantly (P less than 0.02) among HBsAg carriers of the Kpelle (18%) and the Bassa (2%) language group. A comparable difference in delta markers was observed among HBsAg carriers of the Gbawein (17%) and the Wroughbarh (4%) clans.