Top Ten Research Reports of 2003
2. ACTG 5095: A Comparative Study of Three Protease Inhibitor-Sparing Antiretroviral Regimens for the Initial Treatment of HIV Infection
Gulick R. M., Ribaudo H. J., Shikuma C. M. et al. ACTG 5095: A Comparative Study of Three Protease Inhibitor-Sparing Antiretroviral Regimens for the Initial Treatment of HIV Infection. Presented at: 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 41.
BackgroundTriple-NRTI therapy as HAART was ushered into common usage with the introduction of Trizivir -- the single tablet formulation of ZDV/3TC/abacavir. Early studies comparing these three nucleoside analogues to PI-based therapies had mixed results. The open-label trials demonstrated similar efficacy, but the blinded studies indicated better virologic outcomes with PI-containing regimens.1-3
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.
What Is New Here?No single clinical trial result presented in the past year has had as dramatic an impact on how U.S. HIV specialists treat their patients as the ACTG 5095 study. As described in my summary of the U.S. DHHS treatment guidelines, the interim results have prompted considerable modification to the initial treatment of HIV infection. This study was the most significant of several events that spelled the beginning of the end of our love affair with triple-nucleoside therapy.
This blinded study was originally designed to compare three combinations: ZDV + 3TC + abacavir versus ZDV + 3TC + efavirenz versus ZDV + 3TC + abacavir + efavirenz. A scheduled interim analysis after a mean of 32 weeks on-treatment revealed a higher rate of virologic failure (HIV RNA PCR > 200 copies/mL after 16 weeks following entry) among those subjects assigned to the triple-NRTI arm compared to those on the pooled efavirenz-containing arms (21% vs. 10%, respectively, p<0.001).
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.
The Bottom LineThe ACTG 5095 data seem to validate earlier blinded studies that cast shadows across the claims of equipotence of ZDV + 3TC + abacavir and PI-based regimens. They also raise concern that although this triple-NRTI combination may perform well at the onset, late failures with crippling mutations can occur.
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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