September 14, 2003
There is considerable interest in the nucleoside backbone regimen component of antiretroviral therapy. Dual nucleoside regimens that don?t include thymidine analogs may result in different metabolic and/or resistance outcomes that merit study. The recent disappointing results (reported from IAS-Paris) of one thymidine-less NRTI combination (abacavir [ABC, Ziagen] + tenofovir [TDF, Viread] highlight the importance of careful clinical trials that focus on the outcomes of such NRTI backbone regimens.
CNA30024 compared the efficacy/safety of an abacavir /3TC (lamivudine, Epivir) backbone to the standard AZT (ZDV, zidovudine, Retrovir)/3TC in an efavirenz (EFV, Sustiva)-based regimen (AZT/3TC/efavirenz is one of the DHHS-2003 recommended regimens). This trial was powered as a non-inferiority study (defined as a two-sided 95 percent confidence interval that excluded differences as large as 12 percent in the direction of inferiority of the abacavir arm) and was an international, randomized, double-blind, placebo-controlled design with the primary endpoint as the 48-week virologic efficacy (defined as TLOVR = time to loss of virologic response, which is a new FDA-oriented approach to achieve more consistency across studies).
The median baseline HIV-RNA level = 4.79 log copies/mL and CD4+ T-cell count = 264 cells/mm3. Three hundred twenty-four patients were randomized to the abacavir arm and 325 to the AZT arm. At 48 weeks -- using an intent-to-treat approach -- 70 percent of the abacavir arm had HIV-RNA levels < 50 copies versus 69 percent in the AZT arm. For the as-treated analysis, the rate of suppression < 50 copies was 95 percent for the AZT arm versus 88 percent for the abacavir arm. CD4+ T cell increase was greater in the abacavir arm than in the AZT arm (+209 versus +155 cells; p= 0.005). The rate of suspected abacavir hypersensitivity reaction (HSR) was 9 percent in the abacavir arm versus 3 percent in the AZT arm. The rate of confirmed abacavir HSR after review was 7 percent.
The only other difference with regards to treatment-limiting adverse events was a 4 percent rate of anemia for the AZT arm versus 0 percent for the abacavir arm. Also, the rate of nausea, vomiting and fatigue was higher in the AZT arm, while the rate of cough was higher in the abacavir arm.
Resistance data from this trial is not yet available. The higher CD4+ T-cell increase in the abacavir arm was a point of some discussion. Some earlier trials comparing AZT to d4T (stavudine, Zerit) had also noted a higher CD4+ T-cell count in the d4T arms, but the difference in the CD4 percentage was less. The issue of why the abacavir arm did not have a superior efficacy since abacavir monotherapy trials have demonstrated greater potency than AZT alone was raised several times during the question/answer session. It is possible that the high potency of 3TC + efavirenz was high enough that any effect of the third agent was minimized (an explanation that has also been given for the equivalence of tenofovir and d4T in the Gilead 903 study).
Another explanation proposed that the conservative approach towards the management of the abacavir HSR (in the context of a blinded-placebo controlled trial) resulted in a higher than usual rate. With the intent-to-treat approach, dropouts in the abacavir arm due to possible HSR would blunt the virologic benefit seen. The study positions the 3TC/abacavir combination as a thymidine-sparing NRTI regimen which could be further developed as a once-a-day, single-pill NRTI backbone (partly as a response to the FTC/tenofovir once-a-day single pill on the horizon from Gilead).
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