Lack of a metabolic and antiviral drug interaction between tenofovir, abacavir and lamivudine.
OBJECTIVE
An anti-HIV regimen composed of the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) disoproxil fumarate (TDF), abacavir (ABC) and lamivudine (3TC) has performed poorly in patients. This study evaluated the combination of TFV, ABC and 3TC for metabolic or antiviral antagonism in vitro.


METHODS
Procedures were developed to evaluate the in vitro metabolism and antiviral activity of drug combinations of TFV, ABC and 3TC in cell types relevant for HIV infection.


METHODS
Anabolism of combinations of TFV and ABC were studied over a 24 h period in the human T leukaemic CEM lymphoblast cell line and human primary peripheral blood mononuclear cells (PBMCs) stimulated with human interleukin-2 and phytohaemagglutinin. The anti-HIV activity of combinations of TFV and ABC in the presence or absence of 3TC was studied in stimulated PBMCs infected with the HXB2 strain of HIV-1.


RESULTS
Levels of the active metabolites produced from TFV and ABC after incubation with CEM or PBMCs showed no significant change upon introduction of the other NRTI. Moreover, the pool sizes for the natural substrates of 2'-deoxyadenosine triphosphate and 2'-deoxyguanosine triphosphate were also unchanged. In anti-HIV assays in PBMCs, the combination of TFV and ABC was found to be additive with respect to inhibition of HIV replication. Addition of 3TC to the combination did not result in synergistic or antagonistic effects.


CONCLUSIONS
The poor efficacy of the triple NRTI regimen of TDF, ABC and 3TC is probably not due to a metabolic drug interaction resulting in antagonism of antiviral activity.
Ray
Adrian S
AS
Gilead Sciences, Inc, Foster City, CA, USA. aray@gilead.com
Myrick
Florence
F
Vela
Jennifer E
JE
Olson
Loren Y
LY
Eisenberg
Eugene J
EJ
Borroto-Esodo
Katyna
K
Miller
Michael D
MD
Fridland
Arnold
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015224:Dideoxynucleosides / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology*; D000068698:Tenofovir; D000099227:Abacavir
D000225:Adenine; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D019259:Lamivudine; D063065:Organophosphonates; D000068698:Tenofovir; D000099227:Abacavir