Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination

Abstract

In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/ kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.As antiviral chemotherapy is established as a clinically useful modality, the spectrum of treatable disease expands, and the manifestations of toxicity are more likely to appear. As experience with a drug grows, modification of therapy on the basis of known risk factors, pharmacokinetic predictions, and drug monitoring become feasible. Clinical trials with adenine arabinoside (9-1-D-arabinofuranosyladenine; vidarabine) have been underway since 1974, and drug toxicity has been observed infrequently (10). The toxic reactions have included nausea, vomiting or diarrhea (or both), leukopenia, and thrombocytopenia in patients with cancer receiving very high doses (1 g/m2 per day),

Inactivation of S-adenosylhomocysteine hydrolase during adenine arabinoside therapy.

“…Lymphocyte counts were diminished in 98% of all treatment courses, reaching a mean nadir of 48% of pretreatment lymphocyte counts by day 5 of therapy (6). We have also demonstrated similar findings in a subgroup of five patients studied both for enzyme activity and lymphocyte effects.…”

“…However, more recent evidence has revealed, in fact, no preferential incorporation into viral DNA (5). The pharmacologic properties of ara-A therapy in the host may also contribute to toxic manifestations that occur in as many as 44% of certain groups of patients (6).…”

Polyneuropathie bei Behandlung der chronischen Hepatitis B mit Vidarabin

“…Hierbei wurden schon frühzeitig zentralnervöse Nebenwirkungen vermutet (3, 9, 11,14,16,20), die sich später bei Patienten mit Hepatitis, die einer entsprechenden Behandlung unterzogen wurden, bestätigten (1, 15). Seit einigen Jahren werden auch periphere Nervenschäden bei Vidarabin-Therapie mitgeteilt (4-7,10, 12,13,15,18 …”

Lactosaminated human serum albumin as hepatotropic drug carrier

“…However this drug produces dose-dependent side effects [6][7][8] which might be avoided or reduced by selectively delivering ara-A to hepatocytes. In mice, liver targeting of ara-A has been obtained by conjugation with asialofetuin (AF) [9] or with lactosaminated serum albumin (L-SA) [10], two galactosyl-terminating glycoproteins which penetrate by a receptor-mediated endocytosis only in hepatocytes where they are digested in lysosomes [11][12][13][14][15][16].…”