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First-Line Lopinavir Versus Efavirenz in Two European Studies
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8th International Congress on Drug Therapy in HIV Infection
November 12-16, 2006
Glasgow, Scotland
Mark Mascolini
Lopinavir/ritonavir controlled HIV as well as efavirenz in one small randomized trial [1] presented at the Glasgow meeting, and almost as well--depending on the endpoint considered--in a larger cohort study [2]. The results clash with findings of AIDS Clinical Trials Group (ACTG) study 5142 [3], but the studies differed in important ways.
The new trial enrolled 100 treatment-naive people and randomized 55 to start efavirenz and 45 to start lopinavir/ritonavir, both with fixed-dose 3TC/abacavir [1]. Pretreatment values were equivalent in the efavirenz and lopinavir groups, with CD4 counts averaging 193 and 191, total cholesterol 156 and 148 mg/dL, "bad" low-density lipoprotein cholesterol 93 and 96 mg/dL, and "good" high-density lipoprotein (HDL) cholesterol 49 and 44 mg/dL. Patricia Echeverria from German Trias i Pujol Hospital in Barcelona reported results from the 19 participating centers in Spain and Italy.
After 24 weeks of treatment, everyone in the lopinavir group and all but 1 in the efavirenz group had a viral load below 400 copies, the trial's primary endpoint. CD4 gains and hepatic enzymes did not differ between the two treatment arms at week 24. The efavirenz group had a significant jump in HDL cholesterol (P = 0.021). Seven people taking efavirenz and 2 taking lopinavir had hypersensitivity reactions. Echeverria speculated that the combination of efavirenz and abacavir may explain this higher rate.
A retrospective cohort study found similar failure rates with efavirenz and lopinavir after almost 200 weeks of follow-up in people who began therapy with fewer than 100 CD4 cells [2]. In one sensitivity analysis, time to treatment failure proved significantly longer in the efavirenz group. That finding may partly reflect use of the less tolerable lopinavir capsule rather than the new tablet in this cohort because inclusion stopped on December 31, 2004. Although this study involved 1160 patients--many more than the randomized Spanish trial (n = 100) [1] or ACTG 5142 (n = 753) [3]--bias can never be eliminated from nonrandomized comparisons.
Federico Pulido and colleagues from 93 Spanish hospitals analyzed records of 665 treatment-naive people who started efavirenz with two nucleosides and 495 who started lopinavir with two nucleosides. The groups were remarkably similar in pretreatment CD4 count (medians of 37 with efavirenz and 35 with lopinavir) and viral load (medians of 5.26 and 5.30 log). About 12% in each group were current injecting drug users, and 40% in each group had coinfection with hepatitis B or C. The groups did differ in nucleoside choices, with more in the lopinavir group using AZT/3TC (49% versus 32%) and more in the efavirenz group using ddI plus 3TC or FTC (23% versus 11%). The efavirenz group also used (1) tenofovir plus 3TC or FTC and (2) ddI/d4T more than the lopinavir group.
Defining treatment failure as virologic failure, death, opportunistic infection, or treatment discontinuation, Pulido measured median failure times of 175 weeks with efavirenz and 136 weeks with lopinavir/ritonavir, a difference that fell short of statistical significance (P = 0.11). Dropouts because of side effects proved significantly more common with lopinavir than efavirenz (11.1% versus 6.9%, P = 0.012) and so contributed to the faster failure rate in the lopinavir arm.
A secondary analysis widened the failure definition to embrace discontinuation for any cause, including regimen simplification and stopping efavirenz because of pregnancy. With time to failure reckoned by this formula, the difference between efavirenz (still 175 weeks) and lopinavir (now 110 weeks) reached statistical significance (P = 0.002). Multivariate analysis indicated that people taking lopinavir had a 34% higher risk of failure through almost 200 weeks of follow-up than did people taking efavirenz (adjusted hazard ratio 1.34, 95% confidence interval 1.11 to 1.63).
Median time to CD4 recovery above 200 cells measured 55 weeks with efavirenz and 49 weeks with lopinavir, a difference that fell short of statistical significance (P = 0.19). The groups did not differ in rates of grade 3 or 4 liver enzyme elevations, either among people coinfected with a hepatitis virus or not coinfected.
More people taking lopinavir had unhealthy lipid trends during the study, and out-of-line lipids accounted for 13% of side effect-induced dropouts in the lopinavir group. Whereas 8.9% taking lopinavir had a triglyceride reading above 500 mg/mL during the study, 4.1% taking efavirenz reached that mark (P = 0.001). And while 16% taking lopinavir had a total-to-HDL cholesterol ratio above 6.5, 12% taking efavirenz had a ratio that high, a difference short of statistical significance (P = 0.09).
ACTG 5142, presented at the International AIDS Conference earlier this year [3], found a significantly faster time to virologic failure with lopinavir than with efavirenz (P = 0.006) through 96 weeks of follow-up. In this analysis the ACTG defined early failure as lack of virologic suppression by at least 1 log (10-fold) or rebound before week 32; late failure meant never getting under 200 copies or rebound after week 32. In a second primary analysis defining failure as virologic failure or toxicity-related discontinuation of any drug in the regimen, response did not differ significantly between the two arms. Although fewer people taking efavirenz had a virologic failure, more efavirenz failures than lopinavir failures resulted in double-class resistance. Unlike the Spanish/Italian randomized trial [1] or the cohort study [2], ACTG 5142 found a significantly better CD4 response with lopinavir/ritonavir than with efavirenz (median gains of 285 versus 241 cells, P = 0.01).
The ACTG study was 4 times longer and 7.5 times bigger than the Spanish/Italian randomized trial [1], but it included three arms instead of two. The ACTG randomized treatment-naive people with relatively advanced HIV infection (median CD4 count 182, median viral load 100,000 copies) to efavirenz or lopinavir/ritonavir plus two nucleosides, or to efavirenz plus the PIs without nucleosides. Like both studies discussed above, ACTG 5142 relied on the old capsule formulation of lopinavir/ritonavir. Investigators used 3TC with either AZT, extended-release d4T, or tenofovir.
References
1. Echeverria P, Carosi G, Galves J, et al. Similar antiviral efficacy and tolerability between efavirenz and lopinavir/ritonavir, administered with abacavir/lamivudine (Kivexa), in naive patients: a multicentre, randomized study. 8th International Congress on Drug Therapy in HIV Infection, November 12-16, 2006, Glasgow. Abstract P7.
2. Pulido F, Arribas J, Moreno S, et al. Similar virologic and immunologic response to efavirenz or lopinavir/ritonavir-based HAART in a large cohort of antiretroviral-naive patients with advanced HIV infection. 8th International Congress on Drug Therapy in HIV Infection, November 12-16, 2006, Glasgow. Abstract P9.
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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