Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B. A randomized, double-blinded, placebo-controlled trial.

STUDY OBJECTIVE: To determine the efficacy of adenine arabinoside monophosphate (Ara-AMP vidarabine phosphate) with or without human leukocyte interferon in chronic hepatitis B. STUDY DESIGN: Randomized, double-blinded, placebo-controlled trial with 6-month treatment and an 18-month follow-up. SETTING: Referral-based liver-disease clinics at three university medical centers. PATIENTS: Twenty-five patients with chronic active hepatitis or cirrhosis and 39 with chronic persistent hepatitis. INTERVENTIONS: Thirteen patients received intramuscular Ara-AMP, 2.5 mg/kg body weight, twice daily, alternated monthly for 6 months with subcutaneous human leukocyte interferon, 5 million units, twice daily. Painful paresthesia of the legs necessitated dosage reduction and early discontinuation of enrollment. Twenty-four patients received intramuscular Ara-AMP, 2.5 mg/kg, twice daily, alternated monthly for 6 months with a matching placebo given subcutaneously twice daily. Twenty-seven patients received placebo by intramuscular and subcutaneous injections twice daily for 6 months. MEASUREMENTS AND MAIN RESULTS: Of the 64 patients, 95% had symptomatic and virologic data available and 64% had biopsies at 12 months; at 24 months, 77% had data available and 56% had repeat biopsies. The highest dropout rate was seen in the group receiving Ara-AMP. The group receiving the placebo was less symptomatic (Karnofsky score of 96% compared with 91% in the group receiving Ara-AMP/placebo and 92% in the group receiving Ara-AMP/human leukocyte interferon, p = 0.02) at 12 but not at 24 months. Loss of DNA polymerase, the hepatitis B e antigen, and the serum hepatitis B virus DNA was similar in all three groups. Histologically, erosion of the limiting plate and lobular activity favored Ara-AMP at 12 but not at 24 months and these differences did not result in differences in the histologic diagnosis. CONCLUSION: These results do not support the use of Ara-AMP and human leukocyte interferon in chronic persistent or chronic active hepatitis B.

Preliminary trial of recombinant fibroblast interferon in chronic hepatitis B virus infection.

Five patients with chronic hepatitis B were treated with 8-day courses of leukocyte (alpha) interferon (5 X 10(6) U/day) and with 8-day courses of recombinant fibroblast (betaser) interferon at dosages of 5 X 10(6), 35 X 10(6), and 105 X 10(6) U/day. Inhibition of hepatitis B virus replication as evidenced by a decrease in DNA polymerase (DNAP) activity was seen during all treatment courses. Equivalent reduction in DNAP was seen from the low-dose alpha and beta ser regimens, but beta ser interferon at 35 X 10(6) U/day achieved a significantly greater decrease in DNAP activity than did the low-dose regimens. In no patient, however, was permanent loss of DNAP noted. Because of dose-limiting toxicity, only two patients were escalated to the 105 X 10(6)-U/day dosage level. Transient proteinuria was noted in two patients while they were receiving interferon. This has not been noted in other patients receiving this preparation and could not be explained by the development of anti-interferon antibodies. This study has defined an appropriate dosage for future longer-term trials of this agent alone and in combination with other antivirals for the treatment of chronic hepatitis B.

Phase I evaluation of a synthetic mutant of beta-interferon.

A synthetic mutant of beta-interferon, produced by recombinant DNA technology, was prepared with serine substituted for the naturally occurring cysteine at amino acid 17. This molecule, after purification to homogeneity, was evaluated in 23 patients with cancer for tolerated doses, safety, and pharmacokinetics. Each patient was begun on twice weekly administration, one dose i.m., then an identical dose i.v. Doses, escalated weekly, were tolerated by 9 of 12 patients at 100 X 10(6) units i.m., 11 of 14 patients at 100 X 10(6) units i.v., and 8 of 10 patients receiving i.v. doses of 200 X 10(6) units. Fever (greater than or equal to 38.9 degrees C), the commonest cause for ceasing dose escalation, occurred in 11 of 13 patients who developed limiting i.v. toxicity and 6 of 11 who developed limiting i.m. toxicity. Patients who did not have progressive cancer after completion of dose escalation received five consecutive daily doses at their maximum tolerated single dose by each route, i.m. and i.v. These two 5-day treatments were given without difficulty. All patients treated with 300 X 10(6) units or less, i.m. (n = 13) or i.v. (n = 10), were able to receive five daily doses without limiting toxicity. Peak serum titers occurred immediately after i.v. administration and declined in an exponential manner thereafter. Despite absence of measurable titers in serum after i.m. injection, fever and significant (P less than 0.05) depression of WBC and platelet counts, serum calcium, and serum cholesterol occurred (prestudy to maximum tolerated dose). An immunoglobulin antibody to beta-interferon, detected by enzyme-linked immunoabsorbent assay, developed in 17 of 23 patients. Neutralizing activity (titer 10(2] was found in only 1 of 23 patients. No immune-mediated sequelae (symptomatic or renal) were identified. Further Phase I and II trials with this molecule will determine whether it will prove to have a better therapeutic index or different spectrum of therapeutic activity from alpha-interferon or gamma-interferon.

Infections due to herpesviruses in cardiac transplant recipients: role of the donor heart and immunosuppressive therapy.

The role of the donor heart and immunosuppressive therapy on infection due to herpesviruses in 74 cardiac transplant recipients (CTRs) was determined. When cellular blood products from donors seronegative for antibody to cytomegalovirus (anti-CMV) were used, all primary CMV infections were attributable to transmission from donor heart. None of eight CTRs negative for anti-CMV before transplant and who received an anti-CMV donor heart and anti-CMV blood products developed CMV infection compared to one (20%) of five who received unscreened blood. A change from high-dosage anti-thymocyte globulin, azothioprine, and prednisone (ATG regimen) to low-dosage anti-thymocyte globulin, cyclosporin A, and prednisone (CsA regimen) significantly decreased the severity and prevalence of lesions due to herpes simplex virus and the duration of CMV shedding in patients with recurrent CMV infection. CTRs with recurrent CMV infection treated with the ATG regimen had significantly more fever, required more parenteral antibiotics, and were more likely to be infected with opportunistic pathogens than were CsA-treated patients.