Three-drug combination of MKC-442, lamivudine and zidovudine in vitro: potential approach towards effective chemotherapy against HIV-1.

Abstract

MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil), a potent non-nucleoside reverse transcriptase inhibitor, is a promising candidate for the treatment of HIV-1 infection and is now undergoing clinical trials. We studied the in vitro activity of MKC-442 against HIV-1 replication in a three-drug combination regimen with zidovudine (ZDV) and lamivudine (3TC). Drug-drug interactions in MT-4 cells and peripheral blood mononuclear cells (PBMC) infected with HIV-1IIIB were evaluated. The multiple drug effect analysis based on the median effect principle was applied, and the combination indices were calculated using a computer software program. The occurrence of viral breakthrough was investigated during a long-term culture of HIV-1-infected MT-4 cells. When MKC-442 was combined with 3TC and ZDV, they synergistically suppressed HIV-1 replication in MT-4 cells over a wide range of doses irrespective of the endpoints for synergy calculations. Similar results were also obtained in PBMC. An arbitrary combination ratio of 10:100:1 for MKC-442:3TC:ZDV showed stronger synergism than any other ratios examined. As a result of synergy in the three-drug combination, the dose of each drug could be reduced by four- to 24-fold. The three-drug combination markedly delayed or even completely suppressed HIV-1 replication at least for 40 days. Virus emerged in the presence of three drugs at lower doses, although it did not contain any amino-acid mutations in the sequenced reverse transcriptase region and did retain full sensitivity to all three drugs. Our results demonstrate a potential efficacy of MKC-442 in combination with 3TC and ZDV, and the three-drug combination should be considered for treatment of AIDS patients.