In vitro evaluation of the anti-HIV activity and metabolic interactions of tenofovir and emtricitabine.
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 iindividually 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.
Borroto-Esoda
Katyna
K
Department of Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA. kborrotoesoda@gilead.com
Vela
Jennifer E
JE
Myrick
Florence
F
Ray
Adrian S
AS
Miller
Michael D
MD
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D000068679:Emtricitabine; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000378:metabolism / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests / Q000379:methods; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D019259:Lamivudine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine