Mark A. Wainberg, PhD


November 21, 2003


What is the current understanding of the pharmacologic interaction between tenofovir (TDF) and abacavir (ABC) that has led to unacceptably high rates of virologic failure in regimens containing this pair?

Mike Burns, MD

Response from Mark A. Wainberg, PhD

It has become increasingly clear that the K65R mutation is quickly appearing in a very high proportion of patients who are receiving ABC with TDF.

The ESS30009 study showed that these 2 drugs did not affect each other's plasma levels[1]; therefore, a likely explanation for virologic failure in patients who received ABC/TDF + efavirenz might be intracellular interactions between ABC and TDF. Conceivably, ABC might be interfering with the phosphorylation of TDF, and the presence of inadequate intracellular levels of phosphorylated TDF might efficiently select for viruses containing the K65R substitution. Future studies should shed light on whether this is a plausible explanation.

Unfortunately, there is no information currently available on intracellular drug interactions between TDF and ABC. As stated, some have argued that ABC might somehow interfere with the phosphorylation of TDF. However, the reverse might also be true. Measurements of relative levels of each of the intracellular phosphorylated intermediates of each of TDF and ABC, in cells that are dosed simultaneously with both drugs, will be the best way to answer this question.

The idea of a TDF-ABC intracellular interaction is supported by the fact that patients on the ABC/3TC/EFV arm in the ESS30009 study did extremely well. A question that remains, however, is how to explain the positive responses of patients who received Trizivir + TDF in other studies if, indeed, the coadministration of ABC and TDF is contraindicated. Here, a likely explanation is that the additional presence of ZDV in the Trizivir + TDF regimen contributed to the overall suppression of viral replication. This might have suppressed further replication of mutated K65R variants, which would not have been the case with patients receiving only ABC + 3TC + TDF. In addition, ZDV and even the occurrence of thymidine-associated mutations (TAMs) are known to play a protective role with regard to the occurrence of K65R.[2]

Finally, recent studies suggesting the failure of regimens that included ddI and TDF argue that adverse drug interactions are probably also important in regard to these two compounds.[3,4] Obviously, studies of intracellular levels of the various phosphorylated forms of each of these drugs, when used concurrently, will be necessary to resolve these issues.


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