Effects of Interferon and Adenine Arabinoside Treatment of Hepatitis B Virus Infection on Cellular Immune Responses

Abstract

Fifteen patients with chronic hepatitis B were treated with adenine arabinoside (Ara-A) or human leukocyte interferon (HLI). Cellular immune response to hepatitis B virus surface antigen and antigens prepared from herpes simplex virus, varicella zoster virus, and cytomegalovirus was measured by a lymphocyte blast transfornation assay and an assay for interferon production. Measurements were made before, during, and after antiviral treatment. Unlike patients convalescing from acute hepatitis B, only 2 of 15 patients with chronic hepatitis B had significant blast transformation to hepatitis B surface antigen. One such response occurred during the pretreatment period of HLI therapy, and the other was in a patient undergoing low-dose (<105 U/kg per day) HLI therapy. Mononuclear cell cultures were tested for interferon production in the presence of hepatitis B surface antigen. Cells from only 1 of 15 patients produced detectable levels of interferon. In contrast, all of these patients had normal cellular immune responses to herpesvirus antigens. Transformation responses to herpes antigens decreased three-to fivefold after patients were treated with >iO5 U of HLI per kg per day.Antiviral therapy with <105 U of HLI per kg per day or Ara-A did not produce a detectable depression of transformation response. Ara-A produced marked lymphocytopenia and a marked lymphocyte fragility after 5 or more days of therapy. In vitro Ara-A was toxic to lymphocytes at concentrations as low as 0.5 pg/ml. These changes in lymphocyte parameters may affect the outcome of antiviral therapy.In preliminary trials of human leukocyte interferon (HLI) and adenine arabinoside (Ara-A) administration in chronic hepatitis B virus (HBV) infection (CH/HB5Ag+), variable therapeutic responses were observed. Although some patients with CH/HB6Ag+ experienced rapid and prolonged depression of HBV markers such as Dane particle-associated deoxyribonucleic acid polymerase, others with apparently similar disease states (as measured by physical examination, HBV markers, and liver function tests) had less depression of HBV markers; these changes were observed only during therapy (12,21). Ara-A and HLI might influence immune cell function adversely and thereby produce the less durable antiviral response observed in some patients. Altematively, changes in immunity may occur only in certain patients and may not be a universal response.To

Cellular and virological mechanisms of HBV drug resistance

“…Attempts in the early 1980 s to block HBV replication using inhibitors of viral DNA synthesis were generally unsuccessful because of the poor efficacy and/or toxicity of available drugs, for example, as found with adenosine arabinoside [8][9][10][11][12][13][14][15]. Moreover, with the lack at that time of tissue culture and in vitro systems for virus growth or viral polymerase expression, which were suitable for high throughput screening, antiviral compound libraries could not be tested against HBV.…”

Hepatocyte targeting of adenine‐9‐β‐D‐arabinofuranoside 5′‐monophosphate (ara‐AMP) coupled to lactosaminated albumin

“…In chronic hepatitis B, ara-A, administered alone or in combination with interferon, inhibits viral replication and in some patients brings about a disappearance of Dane particles from blood [29,30] and liver [30]. However, ara-A produces side effects, such as gastrointestinal and neurological disturbances, which can necessitate discontinuation of the therapy [33]; it also cause a marked lymphocytopenia which may affect the outcome of the treatment since succesful antiviral therapy appears to require the cooperation of the host immune response [34]. Selective concentration of ara-A or ara-AMP into hepatocytes, as achieved by coupling ara-AMP to GSA, should reduce the side effects and improve the efficacy of the treatment.…”

Effect of Prolonged Administration of Interferon-Alpha on Pharmacokinetics, Fever, Lymphocyte Proliferative Response, and NK Cell Activity

“…In the beginning, we thought that the patient's NK cells were refractory to interferon since (1) circulating NK levels were not elevated after 44 days of treatment (Table 4) and (2) there was no consistent immediate elevation of NK activity 5 h to seven days after a dose of interferon (Table 5). However, circulating NK levels rose after about three months of therapy and 100 million units of interferon (periods A-C, Tables 1 and 4).…”