Background:  High rates of early viral failure were observed when tenofovir (TDF) + abacavir (ABC) + lamivudine (3TC) regimens were used in treatment-naïve patients. We hypothesized that co-administration of TDF would decrease the intracellular exposure of combivir triphosphates (CBV-TP), the active metabolite of ABC, and reduce phase I viral decay.

Methods:  This is a prospective, open-label, randomized trial that compared 7 days of TDF (300 mg once daily) or ABC (600 mg once daily) mono-therapy with 7 days of TDF+ABC dual-therapy in treatment-naïve subjects. Each 7 day course was separated by a 35-day washout, followed by 46 weeks of combination therapy with efavirenz (EFV) +ABC+3TC (data not presented). Viral decay rates and steady-state intracellular concentrations of CBV-TP and TFV-diphosphates (DP) were measured during each course. With a sample size of 10 subjects per arm, this study had 80% power to detect a 30% difference in phase I viral decay rates and a 30% difference in intracellular concentrations between mono- and dual-therapy. Linear mixed effects models and Wilcoxon tests were used to assess differences in viral decay rates and intracellular concentrations, respectively, between mono- and dual-therapy.

Results:  We randomized a total of 21 subjects (71% male) to initial mono-therapy with ABC (n = 11) or TDF (n = 10). Baseline characteristics were similar (median CD4 324 cells/mm³, HIV RNA 4.99 log₁₀ copies/mL), except ABC subjects were younger (32 years vs 48 years; p = 0.014). No new HIV drug-resistance mutations were observed in resistance testing obtained at baseline and after dual therapy. Samples for deoxyribonucleoside triphosphate (dNTP) intracellular concentrations for one subject randomized to ABC were insufficient and not included in this analysis. Viral decay was faster for ABC (–0.16 log₁₀/day) vs TDF (–0.11 log₁₀/day) mono-therapy, but this difference was not statistically significant (p = 0.13). Viral decay during ABC+TDF dual-therapy was 0.04 log₁₀/day faster than TDF mono-therapy (p = 0.005), but was similar to Viral decay during ABC mono-therapy (–0.16 log₁₀/day vs –0.15 log₁₀/day). Neither intracellular concentrations of CBV-TP nor TFV-DP was correlated with viral decay during mono- or dual-therapy. Addition of second NRTI did not affect the intracellular concentration of CBV-TP or TFV-DP. Intracellular concentration CBV-TP was similar during both mono- and dual-therapy (median AUCt [fmol/10⁶ cells]:  1895 vs 1694), however, intracellular concentration of TFV-DP was 2-fold higher after re-exposure in the TDF arm (median AUCt [fmol/10⁶ cells]:  2700 vs 1209; p = 0.08).

Conclusions:  TDF+ABC did not demonstrate additive antiviral potency compared to ABC alone. This lack of additive antiviral potency was not explained by differences in intracellular concentration of dNTP between mono- and dual-therapy.