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Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients

Goicoechea, Miguela; Jain, Soniaa; Bi, Lucunb; Kemper, Carolc; Daar, Eric Sd; Diamond, Catherinee; Ha, Belindaf; Flaherty, Johng; Sun, Shellya; Richman, Douglasa,h; Louie, Stani; Haubrich, Richarda; the California Collaborative Treatment Group

doi: 10.1097/QAD.0b013e32833676eb
Clinical Science

Objectives: To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF).

Design and methods: This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined.

Results: Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (−0.15 log10 per day vs. −0.16 log10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/106 cells) 3293 vs. 4638; P = 0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/106 cells) 3238 vs. 4534; P = 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (ρ = −0.529; P = 0.045).

Conclusion: In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

aUniversity California San Diego, San Diego, California, USA

bCovance, Shanghai, China

cSanta Clara Valley Medical Center, San Jose, USA

dLos Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the David Geffen School of Medicine at UCLA, Los Angeles, USA

eUniversity California Irvine, Irvine, California, USA

fGlaxoSmithKline, Research Triangle Park, North Carolina, USA

gGilead Sciences Inc., Foster City, USA

hVeterans Affairs San Diego Healthcare System, San Diego, USA

iUniversity Southern California, Los Angeles, California, USA.

Received 7 October, 2009

Revised 8 December, 2009

Accepted 9 December, 2009

Correspondence to Miguel Goicoechea, MD, University California San Diego, Antiviral Research Center, 220 Dickinson Street, Suite A San Diego, CA 92103, USA. Tel: +1 619 543 8080; fax: +1 619 298 0177; e-mail: mgoicoechea@ucsd.edu

© 2010 Lippincott Williams & Wilkins, Inc.