In order to reduce the extrahepatic side-effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara-AMP), conjugated with lactosaminated human serum albumin (L-HSA) and administered to hepatitis B virus (HBV)-infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side-effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine (Lac-poly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac-poly(Lys) conjugates, one with ara-AMP and one with ribavirin, are reported in this review.

We studied the interaction between HBV and HDV infection in 149 consecutive subjects with HBsAg positive chronic hepatitis and in 22 chronic HBsAg healthy carriers. Liver HBcAg was detected in 52 (30.4%) of the 171 subjects. Of these 52, 35 were HBV-DNA and HBeAg positive, 11 HBV-DNA positive only; two HBeAg positive only and four were negative for both HBeAg and HBV-DNA. None of the 119 HBcAg-negative subjects had detectable HBV-DNA in serum. HD-Ag in hepatocytes was detected in 31 of the 171 subjects (18%); it was detectable in none of the 22 HBsAg healthy carriers, in four of the 56 patients with chronic persistent hepatitis (7.2%), in six of the 24 patients with chronic lobular hepatitis (25%), in 16 of the 40 patients with chronic active hepatitis (40%) and in five of the 29 with cirrhosis (17%). A presence of anti-HD in serum in the absence of liver HD-Ag was found in 54 of the 171 subjects (32%). This condition was observed not only in patients with a progressive disease (37.7% of chronic active hepatitis or cirrhosis and 33% of chronic lobular hepatitis), but also in healthy carriers (36%) and in chronic persistent hepatitis patients (21.4%). Liver HBcAg was detected in 6.4% of the 31 HD-Ag-positive patients, in 12.9% of the 54 HD-Ag-negative/anti-HD positive, but in 50% of the 86 with no marker of HDV infection. HDV appears to inhibit HBV genome and such inhibition may persist even when anti-HD is the only HDV marker detectable.

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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.

Data on the distribution of HBV-DNA and other serological markers of hepatitis B virus infection in a population of asymptomatic carriers in Ethiopia are reported. As compared to data from other countries of similar or lower levels of endemicity, it has been found that HBV-DNA prevalence and its correlation with HBeAg/anti-HBe status is similar to that of northern Europe. HBV-DNA is present in 84% of HBe Ag-positive sera but in only 4% of anti-HBe-positive sera, where the lowest concentration of DNA (less than 5 pgr/20 microliters) was found. The trend of increasing prevalence of serological markers with age seems to indicate a considerable horizontal transmission still present in this age range (18-30). In keeping with data of other authors a 3% of HBV-DNA positivity in anti HBc only positive sera was found. No regional or ethnical differences of HBV-DNA positive sera across the country were observed. There is also no evidence of any correlation between HBV-DNA prevalence and HBsAg subtypes ad and ay.

The results of Hepatitis Delta virus (HDV) antibody determinations carried on 566 HBsAg positive serum samples from a population of 5270 Ethiopian military recruits are reported. The prevalence of anti-HDV among apparently healthy HBsAg carriers was 5.8%. The prevalence increases with age within the available range (18-30 years). Differences might exist by area of origin and ethnic groups. The distributions of HBV markers was similar in anti HDV positive and anti HDV negative individuals, possibly due to the relatively young age of the population and/or the hyperendemic condition of the area.