July 14, 2003
Triple nucleoside (nucleotide) reverse transcriptase inhibitor (NRTI) regimens have been frequently used in the management of HIV-infected patients because of their convenience and tolerability, but many investigators and clinicians have been concerned about their potency. The most commonly used triple NRTI regimen, AZT (zidovudine, Retrovir)/3TC (lamivudine, Epivir)/abacavir (ABV, Ziagen) (the fixed dose combination of Trizivir), was recently shown to be inferior to efavirenz (EFV, Sustiva)-based regimens (Abstract 41, Gulick). Dr. Charles Farthing, on behalf of the AIDS Healthcare Foundation of Los Angeles, California, presented results from a single-arm, pilot study of a different triple NRTI combination, once-daily abacavir/3TC/tenofovir (TDF, Viread). The authors thought this regimen might perform better than Trizivir because tenofovir is more potent than AZT (i.e., leads to a larger drop in HIV viral load when given as monotherapy), tenofovir has fewer side effects than AZT and because once-daily dosing is more convenient. This regimen also has the advantage of using the three NRTIs having the least effect on mitochondrial DNA.
There were 19 participants included in the analysis. About half had an HIV viral load greater than 100,000 copies/ml, and the median baseline CD4 count was 277 cells/mm3. This study measured HIV viral load at two, four and eight weeks. Overall, 11 of 19 participants (58 percent) experienced virologic failure by week eight. The average drop in HIV viral load was lower at week four than week eight. Genotyping of the 11 failures found that two participants had wild-type virus (non-adherence was suspected in these cases), five had the signature 3TC resistance mutation (M184V) and the remaining four had M184V and a tenofovir-associated mutation (K65R).
The authors discussed possible explanations for the extremely poor performance of this regimen. Adherence was ruled out as the major cause since although two participants were known to have poor adherence, the other patients in the study had adherence between 92 percent and 100 percent whether assessed by MEMS-Cap or self-report. There is no in vitro evidence for a drug interaction, and no previous clinical trial results suggest that these drugs should not be used together. However, an intercellular interaction between tenofovir and abacavir cannot be excluded. Or perhaps this regimen failed because of the once-daily dosing of abacavir. Clearly this study strongly suggests that the once-daily abacavir, epivir and tenofovir combination should be avoided as an antiretroviral regimen. It also suggests that both the efficacy of once-daily abacavir and possible interactions between tenofovir and abacavir should be investigated further.
For another report on this study, click here.
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