Monotherapy study may explain previous poor clinical results when abacavir and tenofovir are used in combination

Goicoechea and colleagues from San Diego presented a detailed analysis that might explain the previous poor performance of some antiretroviral regimens that contain both abacavir and tenofovir, especially as this group and others found no evidence of reduced intracellular levels of either carbonavir triphosphate or tenofovir diphosphate, the active metabolites of abacavir and tenofovir respectively.

This study randomised 21 HIV-positive treatment-naive patients to seven days monotherapy with either abacavir or tenofovir, followed by seven days dual therapy with both drugs. Following a 35-day washout, the study was repeated with patients switched to receive the alternative nuke as initial monotherapy.

Intracellular levels of endogenous purines (dGTP for abacavir and dATP for tenofovir) were also measured and the ratio to intracellular metabolites was compared to the slopes of viral decay during the mono- and dual-therapy periods.

As the rate of viral decay remained unchanged following addition of tenofovir to abacavir alone (-0.15 log/day vs. -0.16 log/day) the researchers concluded that this confirmed a lack of additive antiviral effect.

Median dGTP and dATP (fmol/million cells) both tended to increase during dual vs. monotherapy, though not to statistical significance (2798 vs. 4301, p=0.11 and 3293 vs. 4638, p=0.08).

However, when abacavir was added to tenofovir monotherapy, the dATP increase was significant during dual therapy (3238 vs. 4534, p=0.047).

No intracellular parameters or ratio was related to abacavir viral response during monotherapy, but during tenofovir monotherapy viral decline was weakly correlated with dATP levels (rho= -0.05, p=0.07) and in all patients during dual therapy there was a weak trend for higher dATP to negatively correlate with viral decline (rho=0.407, p=0.13). However, the ratio of tenofovir TP:dATP was significantly associated with viral decline (rho=-0.529, p=0.045).

Comment

These results provide insight into a previously unexplained clinically significant interaction. As study numbers were low it would be important to confirm these initial findings in a larger trial.

The median viral load in these patients was around 5.0 log copies/mL and it is unclear whether two periods of two-week monotherapy resulted in the development of resistance that would limit future treatment.

These results may have clinical significance for patients currently using abacavir and tenofovir in the same combination.

Goicoechea M et al. Alterations in endogenous purines may explain a non-additive antiviral effect with co-administration of tenofovir disoproxil fumerate (TDF) and abacavir (ABC). 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Oral abstract O-08.