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Once-Daily (1200-mg) Raltegravir Noninferior to 400 mg Twice Daily
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21st International AIDS Conference (AIDS 2016), July 18-22, 2016, Durban, South Africa
Mark Mascolini
Taking two 600-mg tablets of raltegravir once daily proved virologically noninferior to the standard 400-mg twice-daily dose at 48 weeks in antiretroviral-naive people in the international ONCEMRK trial [1]. The findings differ from the earlier QDMRK trial, in which two 400-mg tablets once daily did not meet noninferiority criteria when compared with 400 mg twice daily [2]. The QDMRK outcome placed raltegravir at a convenience disadvantage with two once-daily integrase inhibitors, elvitegravir and dolutegravir.
A new raltegravir formulation delivers 1200 mg of the drug once daily in two 600-mg tablets only slightly larger than the 400-mg tablets. ONCEMRK investigators recruited antiretroviral-naive adults with a viral load at or above 1000 copies and randomized them in a 2-to-1 ratio to 1200 mg of reformulated raltegravir once daily or 400 mg twice daily, each with tenofovir/emtricitabine (TDF/FTC). While 531 participants started once-daily treatment, 266 started twice-daily therapy. In the once-daily arm 41 people (7.7%) stopped treatment, 6 (1.1%) because of adverse events and 4 (0.8%) because of lack of efficacy. In the twice-daily arm 24 participants (8.9%) stopped treatment, 6 (2.2%) because of adverse events and 1 (0.4%) because of lack of efficacy.
The once-daily group did not differ substantially from the twice-daily group in pretreatment CD4 count (median 380 and 416) or in proportions of men (83% and 88%), whites (57% and 65%), or participants with a pretreatment viral load above 100,000 copies (28% and 29%). Both groups had a median pretreatment viral load of 4.6 log10 (about 40,000 copies).
In a noncompleter-equals-failure analysis, 88.9% in the once-daily arm and 88.3% in the twice-daily arm had a viral load below 40 copies at week 48. Those findings mean once-daily raltegravir is noninferior to twice-daily raltegravir in previously untreated people. Virologic nonresponse and rebound rates were both 3.4% with once-daily dosing and both 3.4% with twice-daily dosing. Among 14 people tested for resistance after once-daily raltegravir failed, 4 had raltegravir-related mutations emerge. Those 4 and another person had FTC-related mutations develop. Among 3 people tested for resistance after failure of twice-daily raltegravir, 2 had no mutations and 1 failed testing.
Among people with a pretreatment viral load above 100,000 copies, proportions below 40 copies at week 48 were 86.7% with once-daily dosing and 83.8% with twice-daily dosing. Through 48 weeks median CD4 count rose by 232 cells in the once-daily group and 234 cells in the twice-daily group.
Proportions of drug-related adverse events were similar with once- and twice-daily dosing (24.5% and 25.6%). Other adverse event rates were lower with once-daily dosing than with twice-daily dosing, including serious adverse events (5.8% versus 9.4%), drug-related serious adverse events (0.2% versus 0.8%), and discontinuations due to adverse events (0.8% versus 2.3%).
The ONCEMRK researchers concluded that antiretroviral-naive people taking once- and twice-daily raltegravir with TDF/FTC had "high and similar rates of virologic suppression, irrespective of baseline HIV RNA."
References
1. Cahn P, Kaplan R, Sax P, et al. Raltegravir (RAL) 1200 mg once daily (QD) is non-inferior to RAL 400 mg twice daily (BID), in combination with tenofovir/emtricitabine, in treatment-naive HIV-1-infected subjects: week 48 results. 21st International AIDS Conference (AIDS 2016). July 18-22, 2016. Durban, South Africa. Abstract FRAB0103LB.
2. Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011;11:907-915.
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