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Efavirenz Stops HIV Better Than Lopinavir When Starting With Few CD4s
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XVII International AIDS Conference
August 3-8, 2008
Mexico City
Mark Mascolini
From Jules: a comment was made at the microphone that the study was not adequately powered and the presenter agreed saying that I think I recall that this was due to dropouts before randomization.
Recently reported results from AIDS Clinical Trials Group (ACTG) study 5142 showed that efavirenz harnessed HIV better than lopinavir/ritonavir in previously untreated people, even those beginning therapy with more than 100,000 HIV RNA copies/mL [1]. A nonblinded Mexican trial comparing the same two drugs in people starting with fewer than 200 CD4 cells also found a virologic advantage with efavirenz [2]. Both trials used the old capsule formulation of lopinavir/ritonavir, which requires more pills daily than the new tablet.
The 11-site Mexican study involved 95 people randomized to start efavirenz and 94 to start lopinavir/ritonavir, all with zidovudine/lamivudine (AZT/3TC) as Combivir. Pretreatment median CD4 counts stood at 64 in the efavirenz group and 52 in the lopinavir group, but that difference stopped short of statistical significance (P = 0.18). More than 40% in both treatment arms had fewer than 50 CD4 cells when the study began. About 15% of study participants were women, a rate that reflects female HIV prevalence in Mexico.
The presentation by Juan Sierra Madero caused some confusion about the lopinavir/ritonavir dose, listed on a slide as 533/133 mg twice daily. But when an attendee questioned Sierra Madero about this higher-than-usual dose, he said patients took three capsules twice daily, which would be the standard 400/100-mg twice-daily dose.
After 48 weeks a time-to-loss-of-virologic response (TLOVR) analysis determined that 70.5% assigned to efavirenz and 53.2% assigned to lopinavir/ritonavir had a sub-50-copy response (P = 0.017). In an unplanned analysis efavirenz did better than lopinavir in controlling HIV among people with a starting CD4 count below 51. While 79% taking efavirenz had a week-48 load below 50 copies, 49% taking lopinavir/ritonavir attained that benchmark (P = 0.012). Statistically equivalent proportions of people beginning treatment with more than 50 CD4 cells had an undetectable load at 48 weeks, 64% taking efavirenz and 57% taking lopinavir/ritonavir (P = 0.15).
The investigators counted 7 virologic failures in the efavirenz group (7%) and 17 (18%) in the lopinavir group, also a significant difference (P = 0.02). While 5 people (5%) dropped out of the efavirenz group because of adverse events, 11 (12%) quit the lopinavir arm for that reason, but this difference fell short of statistical significance (P = 0.1). Loss to follow-up was equivalent in the two groups. Average CD4 gains through 48 weeks were similar with the two regimens. The investigators did not report measures of adherence.
Triglyceride levels doubled with lopinavir through week 48, while rising about 40% with efavirenz (P = 0.01). Changes in total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol did not differ significantly between the two groups.
These findings merit attention in any region or clinic where a high proportion of people get diagnosed with critically low CD4 quotients. ACTG 5142 already showed that people with high viral loads do better with first-line efavirenz than with lopinavir/ritonavir, but CD4 counts are more readily available in many low- and middle-income countries.
Overall intent-to-treat response rates were worse in this trial (70.5% versus 53.2% with fewer than 50 copies for efavirenz versus lopinavir at 48 weeks) than in the ACTG study (89% versus 77% with efavirenz versus lopinavir at 96 weeks), at least partly because starting CD4 counts were substantially higher in the ACTG trial (52% below 200 CD4s versus 100% in the Mexican trial, with starting medians of 195 and 190 for efavirenz and lopinavir in ACTG 5142 versus 64 and 52 in the Mexican study). Everyone in the Mexican trial used AZT/3TC, whereas ACTG patients took 3TC plus either AZT, extended-release stavudine, or tenofovir. Recently, ACTG 5095 investigators reported equivalent virologic failure rates in previously untreated people starting efavirenz (with AZT/3TC or AZT/3TC/abacavir) at a CD4 count under 50 and in those with higher pretreatment CD4 counts [3].
References
1. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection, N Engl J Med. 2008;358:2095-2106.
2. Sierra Madero J, Villasis A, Mendez P, et al. A prospective, randomized, open label trial of efavirenz versus lopinavir/ritonavir based HAART among antiretroviral therapy naïve, HIV infected individuals presenting for care with CD4 cell counts <200/mm3 in Mexico. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract TUAB0104.
3. Ribaudo HJ, Kuritzkes DR, Lalama CM, et al. Efavirenz-based regimens in treatment-naive patients with a range of pretreatment HIV-1 RNA levels and CD4 counts. J Infect Dis. 2008;197:1006-1010.
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