July 13, 2004
Currently, abacavir is given twice daily and tenofovir and lamivudine are both taken once daily. However, high rates of virologic non-response were found, prompting early termination of this regimen.
The question remains as to why so many people with apparently good adherence to this regimen had such poor viral load responses and developed such high rates of resistance to one or all of the drugs in the regimen. The substudy presented here looked at the plasma concentrations of each of these drugs to assess whether there was any kind of drug interaction which would perhaps lower one or all of the drug concentrations to sub-therapeutic levels that would result in a loss of anti-HIV activity.
Plasma samples were obtained just before a dose (pre-dose) and 1.5 hours after a dose (post-dose) in a subset of patients from the larger trial. These plasma samples were tested for their concentration of each of the 3 drugs in patients who demonstrated a good viral load response and in those who were nonresponders, using a LC/MS/MS (mass spectroscopy)-based assay. The concentrations of each drug were compared to those of historical control patients for whom drug concentrations for each of these drugs had been previously obtained. Sixteen patients (15 male) provided at least one sample: 11 were virologic nonresponders and 5 were responders. Eleven and 15 patient samples were available for pre- and post-dose abacavir and lamivudine levels, respectively, but only 7 and 8 pre- and post-dose samples were available for tenofovir levels, respectively. For those patients who could be evaluated, there was no difference in trough (pre-dose) or peak (post-dose) concentrations of any of the 3 drugs between viral load responders and nonresponders in this study, and there was no difference between the two time point concentrations for all 3 drugs in this study compared to historical controls. The authors conclude that plasma concentration does not explain the high rate of failure with this regimen.
The study presented here is limited by the number of subjects analyzed as well as the fact that the investigators did not measure intracellular concentrations of each drug. Cellular concentrations, rather than plasma concentrations, would directly reflect the antiviral activity of these drugs. Cellular-based drug concentration assays are extremely difficult to do and measure the active form of a drug. However, another poster (TuPeB4627), which did present intracellular data for a small number of patients, indicated that there was no interaction between abacavir and tenofovir.
Another possible explanation for the failure of this combination may be due to a low barrier or threshold for developing resistance to these drugs. This refers to the fact that these drugs can fail with the development of only one mutation (i.e., the K65R mutation for tenofovir and the 184V mutation for lamivudine). So, in the face of a detectable viral load (ongoing replication), these drugs might have a greater chance of failure.
It is important for patients and practitioners to note that this particular once-daily, triple combination should not be prescribed given the high, but as yet unexplained, failure rate.
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