G. Piras et al., 3-DRUG COMBINATION OF MKC-442, LAMIVUDINE AND ZIDOVUDINE IN-VITRO - POTENTIAL APPROACH TOWARDS EFFECTIVE CHEMOTHERAPY AGAINST HIV-1, AIDS, 11(4), 1997, pp. 469-475
Objectives: MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil), a pot
ent nonnucleoside reverse transcriptase inhibitor, is a promising cand
idate for the treatment of HIV-1 infection and is now undergoing clini
cal 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). Methods: Drug-drug interactions in MT-4 cells an
d peripheral blood mononuclear cells (PBMC) infected with HIV-1(IIIB)
were evaluated. The multiple drug effect analysis based on the median
effect principle was applied, and the combination indices were calcula
ted using a computer software program. The occurrence of viral breakth
rough was investigated during a long-term culture of HIV-1-injected MT
-4 cells. Results: When MKC-442 was combined with 3TC and ZDV, they sy
nergistically suppressed HIV-1 replication in MT-4 cells over a wide r
ange of doses irrespective of the endpoints for synergy calculations.
Similar results were also obtained In PBMC. An arbitrary combination r
atio 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-d
rug 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 th
e 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. Conclusions: Our
results demonstrate a potential efficacy of MKC-442 in combination wit
h 3TC and ZDV, and the three-drug combination should be considered for
treatment of AIDS patients.