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Trizivir Maintenance After Efavirenz vs Lopinavir Induction
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8th International Congress on Drug Therapy in HIV Infection
November 12-16, 2006
Glasgow, Scotland
Mark Mascolini
A 72-week induction-maintenance trial recorded a trend to more virologic failures during maintenance among people whose induction regimen included efavirenz rather than lopinavir/ritonavir [1]. But a surprisingly high proportion of study participants did not make it to the trial's maintenance phase.
Josep Mallolas and Barcelona colleagues randomized 209 antiretroviral-naive people to efavirenz or lopinavir/ritonavir plus Trizivir (fixed-dose AZT/3TC/abacavir) for 24 weeks. Median pretreatment CD4 count stood at 201.5 in the efavirenz arm and 205 in the lopinavir arm, and respective median viral loads measured 144,233 copies and 160,000 copies. About one quarter of each group had AIDS when the trial began.
The study design called for people to drop their efavirenz or lopinavir if they remained in the trial and had a viral load under 50 copies at week 24, but only 54 (52%) in the efavirenz group and 45 (43%) in the lopinavir group met those criteria. Most dropouts reflected "adverse events" (side effects or clinical problems), including 33 people taking efavirenz (66% of dropouts) and 26 taking lopinavir/ritonavir (57% of dropouts). Three people in each study arm did not proceed to the maintenance phase because of virologic failure.
A high dropout rate also plagued an earlier induction-maintenance trial involving Trizivir plus efavirenz (but not lopinavir/ritonavir) [2]. In that study 37% quit the study before the maintenance phase began at week 48, but enough people stayed in the trial to support statistical calculations after the maintenance phase. Mallolas said his trial had enough power to compare study groups after maintenance, but he did not present the power calculations.
Of the adverse event-related dropouts in the efavirenz group, 15 resulted from hypersensitivity reactions attributed to abacavir, 3 from gastrointestinal (GI) side effects, 7 from neurologic problems probably caused by efavirenz, and 5 from hematologic abnormalities. Of the 25 adverse event-related dropouts in the lopinavir arm, 10 resulted from hypersensitivity reactions, 8 from GI problems, 1 from neurologic problems, and 5 from hematologic abnormalities.
A strict intent-to-treat analysis in which switching drugs or missing data meant failure determined that 31% in the efavirenz group and 43% in the lopinavir group had a viral load below 50 copies after 48 weeks of three-drug maintenance, a difference that fell just short of statistical significance (P = 0.076). In a less strict intent-to-treat analysis in which missing data equaled failure, 43% in the efavirenz group and 53% in the lopinavir group had a sub-50-copy load after 48 weeks of Trizivir maintenance, also a nonsignificant difference (P = 0.199). And in an on-treatment analysis, 63% in the efavirenz arm and 75% in the lopinavir arm had fewer than 50 copies after 48 weeks of Trizivir maintenance, still a nonsignificant difference (P = 0.172). Kaplan-Meier analysis of time to treatment failure also suggested a (nonsignificant) trend favoring induction with lopinavir/ritonavir (P = 0.076).
Because the trial did not include control arms of people who continued four drugs during maintenance, there is no way to tell if the Trizivir maintenance regimen did as well as Trizivir plus efavirenz or lopinavir would have during the 48-week maintenance phase. The intent-to-treat sub-50-copy results after 48 weeks of maintenance and 72 weeks of total therapy are not as good as those seen in some trials in which people continued a standard efavirenz or lopinavir regimen that long. In the earlier Trizivir/efavirenz induction-maintenance trial [2], researchers recorded 16 maintenance-phase failures in the Trizivir-only arm and 8 in the Trizivir/efavirenz group, a difference that did not reach statistical significance (P = 0.134).
After 12 months of study in the Mallolas trial, people who started with lopinavir/ritonavir gained significantly more CD4 cells than those who started with efavirenz (P = 0.034), a result reflecting better CD4 gains with lopinavir than efavirenz (with 3TC plus AZT, d4T, or tenofovir) in ACTG 5142 [3]. But at earlier and later points of follow-up in the induction-maintenance trial, CD4 gain differences between the lopinavir and efavirenz arms lacked statistical significance.
References
1. Mallolas J, Penaranda M, Domingo P, et al. Induction maintenance antiretroviral therapy with Trizivir plus either efavirenz or lopinavir/r: results of a multicenter randomised clinical trial at 72 weeks. 8th International Congress on Drug Therapy in HIV Infection, November 12-16, 2006, Glasgow. Abstract 2.3.
2. Markowitz M, Hill-Zabala C, Lang J, et al. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients. JAIDS. 2005;39:257-264.
3. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV infection--ACTG 5142. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0204.
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