A once-daily, 1200-mg dose of raltegravir was equally effective as the standard twice-daily, 400-mg dose for treatment of HIV-1, a study has found.
In a phase 3, non-inferiority study (ONCEMRK; ClinicalTrials.gov identifier: NCT02131233), 802 participants ≥18 years of age with HIV-1 RNA of ≥1000 copies/mL and no prior antiretroviral treatment were randomly assigned into groups treated either once daily with a 1200-mg oral dose (n=533) or twice daily with 400-mg oral doses (n=269) of raltegravir in combination with tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg. A total of 797 (531 once daily and 266 twice daily) participants ultimately received treatment.
The primary end point was reached at 48 weeks with 89% of once-daily participants and 88% of twice-daily participants achieving HIV-1 RNA <40 copies/mL (treatment difference 0.5%; 95% CI: -4.2 to 5.2). Antiretroviral efficacy was also similar in both groups irrespective of demographic or prognostic factors.
The proportion of patients with drug-related and serious drug-related adverse clinical effects was similar in both groups with only 2 patients, both from the twice-daily group, discontinued from the trial. Common drug-related adverse effects in both groups were headache, nausea, and dizziness.
“This study provides strong evidence that a new formulation of raltegravir administered as 1200 mg once daily in a combination regimen provides equivalent efficacy and similar safety to the raltegravir 400 mg tablet administered twice daily,” concluded the researchers.
The authors also note that a once-daily formation is “a more convenient treatment option” and is preferred “to facilitate adherence and improve quality of life.”
Background: Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation.
Methods: In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than −10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment.
Findings: Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI −4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported.
Interpretation: A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy.
Pedro Cahn, Richard Kaplan, Paul E Sax, Kathleen Squires, Jean-Michel Molina, Anchalee Avihingsanon, Winai Ratanasuwan, Evelyn Rojas, Mohammed Rassool, Mark Bloch, Linos Vandekerckhove, Peter Ruane, Yazdan Yazdanpanah, Christine Katlama, Xia Xu, Anthony Rodgers, Lilly East, Larissa Wenning, Sandy Rawlins, Brenda Homony, Peter Sklar, Bach-Yen Nguyen, Randi Leavitt, Hedy Teppler