In Vitro Evaluation of the Anti-HIV Activity and Metabolic Interactions of Tenofovir and Emtricitabine

Abstract

Background

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors (NRTIs) with once-daily dosing approved for use in HIV-1 infection. We evaluated this combination for anti-HIV activity and intracellular metabolic interactions in vitro.

Methods

Intracellular anabolism of combinations of FTC and tenofovir (TFV) were studied in the human T leukaemic cell line CEM and human peripheral blood mononuclear cells (PBMCs). The anti-HIV activity of the combination was studied in the human T leukaemic MT-2 cell line against wild-type or mutant virus (K65R and M184V) and in PBMCs against wild-type virus. Antiviral synergy was quantitated by isobologram and MacSynergy methods.

Results

Both TFV and FTC were efficiently converted to their active metabolites in PBMCs and CEM cells. In CEM cells, there was a statistically significant increase in the levels of TFV diphosphate (P=0.047) and FTC triphosphate (P=0.0069) following a 24 h incubation with the combination compared with the levels seen with the individual drugs. In PBMCs, similar levels of active metabolites were observed for each drug when they were incubated individually or in combination. The combination of TFV and FTC displayed additive to synergistic activity against HIV replication in PBMCs and resulted in strongly synergistic anti-HIV activity in MT-2 cells against both wild-type and mutant virus.

Conclusions

The combination of TFV and FTC showed additive to synergistic anti-HIV activity in vitro, which correlated with the levels of intracellular phosphorylation observed. These results support the use of these drugs as a dual NRTI backbone in combination therapy for the treatment of HIV-1.