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Compelling 96-Week Findings on Raltegravir as First-Line Option
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XVII International AIDS Conference
August 3-8, 2008
Mexico City
Mark Mascolini
From Jules: I emailed a full slideset report of the presentation today at IAC earlier and it will be posted on the NATAP website tomorrow.
After 96 weeks of therapy with raltegravir or efavirenz plus tenofovir and lamivudine (3TC), more than 80% in both of these previously untreated groups sustained a viral load below 50 copies [1]. But raltegravir, the first licensed integrase inhibitor, outdid efavirenz in safety through 96 weeks, and those findings beg the question whether raltegravir--licensed as a salvage drug--should replace efavirenz as the favored first-line option. Martin Markowitz (Aaron Diamond AIDS Research Center, New York) reported no serious side effects and a good lipid profile with raltegravir through 96 weeks.
This trial enrolled people with a viral load above 4999 copies and a CD4 count above 99 to take efavirenz or one of four raltegravir doses plus tenofovir and 3TC in a double-blind design. After 48 weeks 85% to 95% of patients across the four study arms had a viral load under 50 copies, with no substantial differences between arms [2]. At that point the blinded study phase ended and all raltegravir-treated patients not already taking 400 mg twice daily switched to that dose; the new analysis compared all 160 people taking raltegravir with 38 who continued efavirenz.
People starting efavirenz had a slightly higher pretreatment viral load than those starting raltegravir (67,554 versus 55,266 copies) and a slightly lower CD4 count (280 versus 305 cells), but these differences lacked statistical significance. By week 96 equivalent proportions quit efavirenz (6 or 15%) and raltegravir (22 or 14%).
A 96-week noncompleter-equals-failure analysis determined that 83% taking raltegravir and 84% taking efavirenz sustained a viral load under 50 copies. In an on-treatment analysis 92% in the raltegravir group and 91% in the efavirenz group had fewer than 50 copies. CD4 gains were similar with the two drugs--a 221-cell jump with raltegravir and a 232-cell hike with efavirenz.
At week 48, 5 people (3%) taking raltegravir and 1 taking efavirenz (#%) met the definition of virologic failure. After week 48, 1 more person in each treatment group met failure criteria. Merck reported resistance data. Two raltegravir-related mutations emerged in the 5 failure cases, Y143C and N155H, both with the 3TC mutations M184I/V. Only M184I/V arose in 1 person with raltegravir failure, and in the other 2 raltegravir failures no detectable resistance mutations emerged.
Nearly three quarters of patients taking an efavirenz regimen for 96 weeks had treatment-related side effects or complications, compared with half taking raltegravir. The most common side effects--nausea, dizziness, and headache--occurred with equal frequency in the raltegravir and efavirenz groups. Neuropsychiatric problems troubled 32% taking efavirenz versus 16% taking the integrase inhibitor.
Total cholesterol rose by an average 1.1 mg/dL with raltegravir versus 24.0 mg/dL with efavirenz through 96 weeks (P = 0.002), but the total-to-high-density lipoprotein (HDL) cholesterol ratio fell by 0.7 in both treatment arms. Average triglycerides dropped 10.8 mg/dL with raltegravir while climbing 13.4 mg/dL with efavirenz, but that difference did not reach statistical significance (P = 0.145).
Although 100 or 200 mg of raltegravir twice daily controlled HIV well through 48 weeks, Markowitz said 400 mg twice daily was chosen for continued treatment because of marked interpatient and intrapatient variability in raltegravir levels.
References
1. Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naive HIV-1 infected patients: 96-week data. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract TUAB0102.
2. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125-133.
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