Many people looked at this data and believed that the convenience of a regimen that consisted of only one pill dosed twice a day compensated for Trizivir's relative deficiency in potency. This helps explain the popularity of Trizivir despite these doubts and the equipoise of the available data before A5095.
For subjects who had 48-week data, the proportion with a viral load <200 copies/mL was lower in the triple-NRTI arm (74%) compared to the pooled NNRTI arms (89%). Significantly, the differences between the triple-NRTI arm and the remaining two arms were not influenced much by baseline viral load. In fact, the triple-NRTI combination fared worse even among patients with an HIV RNA level below 100,000 copies/mL.
Further, although at baseline 95% of the 82 subjects who failed ZDV + 3TC + abacavir had wild-type virus by genotypic resistance testing, at the time of failure, 65% of those patients with a genotype available had a 3TC-associated M184V mutation (a quarter of whom also had another NRTI mutation). Notably, there was evidence of increasing cross-resistance over time following the failure of this triple-NRTI combination. More than half of the subjects who had genotype data a year following failure had M184V plus at least one thymidine-analogue-associated mutation (TAM).
The development of the 3TC-signature mutation as well as a TAM, significantly hampers the use of NRTIs in subsequent salvage regimens. These resistance data, along with the relatively greater rate of virologic failure of the triple nucleoside, are the reasons for the newfound allergy many clinicians now have to Trizivir.
On the heels of these results, a series of presentations on other triple-NRTI regimens were publicized, each of which had horrendous rates of failure and resistance development. A once-a-day regimen of tenofovir + 3TC + abacavir, when compared to ZDV + 3TC + efavirenz, performed much worse than ZDV + 3TC + abacavir did in A5095. All subjects failing this regimen had a M184V mutation, usually along with a K65R tenofovir- and abacavir-associated mutation. A smaller, single-arm study of ddI-EC (enteric-coated formulation) + 3TC + tenofovir had an astounding 91% rate of virologic failure by week 12 of the study, again with almost universal 3TC resistance at the time of failure.4
The focus of much discussion among clinicians and investigators during the latter half of 2003 has been regarding what to make of these remarkable results. Perhaps lost to a casual observer is that these triple NRTIs did not appear to be equally bad. A 74% proportion of subjects on ZDV + 3TC + abacavir did reach an undetectable HIV RNA at 48 weeks.4-5 While this is clearly not as good as its efavirenz-powered competitors, it is not altogether unrespectable and is in a different league from the miserable performance of the other triple-NRTI results that have followed.
Why the difference? Some speculate that the presence of the thymidine analogue ZDV in this combination is the key. ZDV provides pressure preventing the emergence of the M184V mutation, which is a weak-link mutation that both destroys 3TC's antiviral activity and reduces viral susceptibility to abacavir once it develops. Another potential benefit of having ZDV in the mix is that M184V mutants are generally hypersusceptible to ZDV. Therefore, it helps to keep in mind that although not all triple NRTIs are created equally, they should all be avoided.
This 1,100-subject study is still ongoing. Look for the details of the ACTG 5095 study in an upcoming issue of the New England Journal of Medicine.
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Please note: Knowledge about HIV changes rapidly. Note the date of this article, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this article.
© 2004 Body Health Resources Corporation
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