Combination chemotherapy for human immunodeficiency virus infection

Sammanfattning: The worldwide spread of human immunodeficiency virus (HIV) has spurred the search for effective drugs to combat this deadly virus. The limited effect of monotherapy treatment, in large measure due to the development of drug resistant viral strains, has led to increased emphasis on combination chemotherapy for the treatment of HIV, the focus of this study. Using a newly designed extraction method, the metabolism of 3'-azido-3'- deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) was examined alone or in combination in Iymphocytes. It was found that the activation of ddI to its triphosphate form was increased two fold in all combinations with AZT, compared to ddI alone. The addition of ribavirin (RBV) to the two-drug combination of AZT and ddI did not change the intracellular metabolism of AZT or ddI. In the next stage, cytotoxicity tests showed reduced toxicity for two of the combinations of AZT and ddI compared to the separate drugs. This reduced toxicity together with the increased activation of ddI makes these combinations promising for the treatment of HIV, and recent clinical trials have reported the benefit of combination chemotherapy with AZT and ddI. The anti-cytomegalovirus (CMV) drug ganciclovir (GCV), used to treat CMV infections in HIV patients, reduces the anti-HIV activity of AZT. This study revealed that GCV causes a specific decrease in the phosphorylation of AZT in CMV-infected cells, which may explain the antagonistic interaction of this drug combination. In further combination chemotherapy research, the anti-HIV activity and cytotoxicity of three new combinations of foscarnet (PFA)/ddI, PFA/2',3'-dideoxycytidine (ddC) and ddI/ddC were assessed in vitro. The combinations of PFA/ddI and PFA/ddC were found to synergistically inhibit all HIV strains tested, includrng AZT-resistant HIV strains. All combinations showed reduced cytotoxicity in human peripheral blood mononuclear cells (PBMCs) compared to the separate drugs. The presence of the ribonucleotide reductase inhibitor, hydroxyurea (HU), increased the intracellular phosphorylation of both AZT and 2'-deoxy-3'-thiacytidine (3TC) when all three drugs were combined in Iymphocytes. The ratios of drug triphosphate to their respective competing cellular nucleotide were also elevated for AZT and 3TC indicating that HU may further enhance the antiviral activity of this potent anti-HlV combination. The in vitro kinetics and inhibition by azidothynudine triphosphate (AZT TP) of RT from paired AZT-sensitive and -resistant primary isolates were examined. No significant changes were found in the Vmax, Km for dTTP, or Ki for AZT TP that would account for the observed resistance to AZT of the post-therapy isolates. Further research is required to clarify the effects of RT gene mutations on RT activity and susceptibility to AZT TP. ISBN 91-628-2159-8