인면역결핍바이러스감염에서 Ribavirin의 Lamivudine에 대한 길항효과

Abstract

Background : One of the main concerns of interferon/ribavirin(RBV) treatment in Human immunodeficiency virus(HIV)/Hepatitis C virus(HCV) coinfected patients is that of drug-drug interactions. Recent studies reveal that RBV is antagonistic with zidovudine(ZDV), stavudine(d4T) and synergistic with didanosine(ddI). The phosphorylation of lamivudine(3TC) utilizes the enzyme deoxycytidine kinase. Manipulation of 3TC phosphorylation is a possible therapeutic strategy for modulating antiretroviral efficacy and cvtotoxicity of 3TC. Methods : MT-4 cell lines were maintained in RPW 1640 growth medium as a cell suspension(1.96 x 106cells/ml), doubling approximately every 48-72 hr. Cells were incubated with ZDV(0.0001-1000mM) and 3TC(0.00001- l OOmM) in the. presence and absence of RBV(2,uM) in 96-well microtiter plates and cytotoxicity was determined using modified MTT assay. At the end of the 7 days, the cell-free supernatant was serially diluted and samples(100 /-LL) were then assayed for p24 antigen with ELISA to evaluate the inhibitory effect on HIV-1 replication. The results were expressed in terms of the 50% inhibitory concentration(IC50). Analysis was done by Wilcoxon rank sum test. Results : 3TC alone significantly reduced p24 antigen production, with an IC50 0.067mM and addition of RBV increased -the IC50 approximately 8.4 fold (0.563mM). However, at higher concentration of 3TC, the antagonistc effect of RBV was lost. The decrease in the cytotoxic and antiviral efficacy of ZDV in the presence of RBV is consistent with previous studies that have demonstrated reduced ZDV activation. Conclusion : The addition of RBV siginificantly reduced cytotoxicity and antiretroviral efficacy of 3TC in MT-4 cell lines and the antagonistic effect of RBV is concentration dependent. This study provides further insight into the complex interaction between RBV and 3TC in vitro.