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First-Line Raltegravir Controls HIV as Well as Efavirenz for 48 Weeks
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48th ICAAC
October 25-28, 2008
Washington, DC
Mark Mascolini
Raltegravir plus tenofovir/emtricitabine made viral loads undetectable as often as efavirenz plus that backbone in a 48-week double-blind randomized trial, STARTMRK [1]. Viral loads fells significantly faster with raltegravir than with efavirenz, and raltegravir, an integrase inhibitor, caused fewer side effects.
STARTMRK enrolled antiretroviral-naive people with a viral load above 5000 copies and with no resistance to efavirenz, tenofovir, or emtricitabine. Researchers randomized 281 people to raltegravir (400 mg twice daily) and 282 to standard-dose efavirenz, both with tenofovir plus emtricitabine. Age averaged 38 years in the raltegravir group and 37 in the efavirenz group. About 40% in each group were white. CD4 count averaged 219 in the raltegravir arm and 217 in the efavirenz arm. Starting viral loads were 103,205 copies with raltegravir and 106,215 with efavirenz. While 53% of enrollees had a pretreatment viral load above 100,000 copies, 47% had a CD4 count under 200. Only 7% of enrollees had hepatitis C virus infection.
Twenty-four people (8.5%) taking raltegravir and 35 (12.4%) taking efavirenz stopped treatment before week 48. Side effects sidelined 8 raltegravir takers and 17 efavirenz takers. Lack of efficacy accounted for 4 raltegravir dropouts and 2 efavirenz dropouts.
After 48 weeks a noncompleter-equals-failure analysis figured that 86% taking raltegravir and 82% taking efavirenz had a viral load under 50 copies, the trial's primary endpoint. Those results mean raltegravir is not inferior to efavirenz for initial antiretroviral therapy. STARTMRK investigators counted 39 virologic failures with efavirenz versus 27 with raltegravir. Of 12 raltegravir failures with a viral load above 400 copies, the STARTMRK team detected no raltegravir mutations in 5 and could not amplify the integrase gene in 3. Four people had detectable integrase mutations, 2 with G120S plus Q148H/R; 1 with Y143H, L47M, E92Q, and T97A; and 1 with Y143R. Among 8 efavirenz failures at a viral load above 400 copies, efavirenz mutations could be detected in only 3 cases. Time to virologic response proved significantly shorter in the raltegravir group (P < 0.001), though the clinical significance of this difference--if any--is uncertain.
The overall clinical adverse event rate through 48 weeks proved significantly lower with raltegravir than with efavirenz (90% versus 96.5%, P = 0.002), although that small percentage difference probably has no clinical import. Adverse events judged to be drug related affected 44% of raltegravir takers versus 77% of efavirenz takers (P < 0.001). Moderate to severe drug-related problems troubled 32% taking efavirenz and 16% taking raltegravir (P < 0.001). By treatment week 8, significantly more people taking efavirenz than raltegravir endured a central nervous system side effect (18% versus 10%, P < 0.015), but such problems typically fade after the first weeks of efavirenz therapy, as they did in this trial.
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Compared with the raltegravir group, people starting efavirenz had significantly greater gains in total cholesterol, dangerous low-density lipoprotein cholesterol, and triglycerides (P < 0.001 for each comparison). Average triglycerides actually declined by a whisker in the raltegravir group. Part of the higher total cholesterol gain in the efavirenz arm could be traced to a significantly greater surge in "good" high-density lipoprotein (HDL) cholesterol with efavirenz than with raltegravir (P < 0.001). The total-to-HDL cholesterol ratio dropped slightly in both treatment arms, with no statistically significant difference between arms.
Cancer developed in 1 person taking raltegravir and in 9 taking efavirenz. Two cancer diagnoses in the efavirenz group were judged to be treatment related. Seven of the 10 cancers were Kaposi sarcoma.
Reference
1. Lennox J, DeJesus E, Lazzarin A, et al. STARTMRK, a phase III study of the safety and efficacy of raltegravir-based vs efavirenz-based combination therapy in treatment-naive HIV-infected patients. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-896a.
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