Raltegravir 1200 mg Once Daily vs 400 mg Twice Daily, With Emtricitabine and Tenofovir Disoproxil Fumarate, for Previously Untreated HIV-1 Infection: Week 96 Results From ONCEMRK, a Randomized, Double-Blind, Noninferiority Trial

Pedro Cahn, Paul E Sax, Kathleen Squires, Jean-Michel Molina, Winai Ratanasuwan, Mohammed Rassool, Mark Bloch, Xia Xu, Yan Zhou, Brenda Homony, Deborah Hepler, Hedy Teppler, George J Hanna, Bach-Yen Nguyen, Wayne Greaves, ONCEMRK Study Group, Pedro Cahn, Paul E Sax, Kathleen Squires, Jean-Michel Molina, Winai Ratanasuwan, Mohammed Rassool, Mark Bloch, Xia Xu, Yan Zhou, Brenda Homony, Deborah Hepler, Hedy Teppler, George J Hanna, Bach-Yen Nguyen, Wayne Greaves, ONCEMRK Study Group

Abstract

Background: Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study.

Methods: ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1-infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA <40 copies per milliliter (Food and Drug Administration Snapshot approach); the noninferiority margin was 10 percentage points.

Results: Of the 797 participants who received study therapy (84.6% were men, 59.3% were white, and mean age was 35.9 years), 694 completed 96 weeks of treatment (87.6% QD; 84.4% BID), with few discontinuations because of lack of efficacy (1.1% for both groups) or adverse events (1.3% QD; 2.3% BID). At week 96, 81.5% (433/531) of QD recipients and 80.1% (213/266) of BID recipients achieved HIV-1 RNA <40 copies per milliliter (difference 1.4%, 95% confidence interval: -4.4 to 7.3). CD4 T-cell counts increased >260 cells/mm from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens.

Conclusions: In HIV-1-infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.

Trial registration: ClinicalTrials.gov NCT02131233.

Conflict of interest statement

P.C. is an advisory board member of Merck and ViiV and received research grant support from AbbVie, Merck, and ViiV. P.S. serves as a consultant to or scientific advisory board member of AbbVie, BMS, Gilead, GSK/ViiV, Merck, and Janssen and received research grant support from Bristol Myers Squibb, Gilead, Merck, and GSK/ViiV. K.S. is an advisory board member of Bristol Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and received research grant support from Gilead. J.-M.M. is an advisory board member of Merck, Gilead, Bristol Myers Squibb, ViiV, Janssen, and Teva. M.B. received research grants, is an advisory board member, meeting presentations for Amgen, Merck, Gilead Sciences, ViiV Healthcare, and AbbVie. K.S., X.X., Y.Z., B.H., D.H., H.T., G.H., B.-Y.N., and W.G. are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and may own stock and/or stock options. The remaining authors have no conflicts of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
Disposition of study participants.
FIGURE 2.
FIGURE 2.
Proportion of participants with HIV-1 RNA

FIGURE 3.

Efficacy of raltegravir 1200 mg…

FIGURE 3.

Efficacy of raltegravir 1200 mg QD and raltegravir 400 mg BID by baseline…

FIGURE 3.
Efficacy of raltegravir 1200 mg QD and raltegravir 400 mg BID by baseline prognostic and demographic factors (Observed Failure approach).
FIGURE 3.
FIGURE 3.
Efficacy of raltegravir 1200 mg QD and raltegravir 400 mg BID by baseline prognostic and demographic factors (Observed Failure approach).

References

    1. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune DeficSyndr. 2013;63:77–85.
    1. Eron JJ, Cooper DA, Steigbigel RT, et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis. 2013;13:587–596.
    1. Sharma M, Walmsley SL. Raltegravir as antiretroviral therapy in HIV/AIDS. Expert OpinPharmacother. 2014;15:395–405.
    1. Calcagno A, D'Avolio A, Bonora S. Pharmacokinetic and pharmacodynamic evaluation of raltegravir and experience from clinical trials in HIV-positive patients. Expert Opin Drug MetabToxicol. 2015;11:1167–1176.
    1. Parienti JJ, Bangsberg DR, Verdon R, et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009;48:484–488.
    1. Cooper V, Moyle GJ, Fisher M, et al. Beliefs about antiretroviral therapy, treatment adherence and quality of life in a 48-week randomised study of continuation of zidovudine/lamivudine or switch to tenofovir DF/emtricitabine, each with efavirenz. AIDS Care. 2011;23:705–713.
    1. Cooper V, Horne R, Gellaitry G, et al. The impact of once-nightly versus twice-daily dosing and baseline beliefs about HAART on adherence to efavirenz-based HAART over 48 weeks: the NOCTE study. J Acquir Immune DeficSyndr. 2010;53:369–377.
    1. Jayaweera D, Dejesus E, Nguyen KL, et al. Virologic suppression, treatment adherence, and improved quality of life on a once-daily efavirenz-based regimen in treatment-Naive HIV-1-infected patients over 96 weeks. HIV Clin Trials. 2009;10:375–384.
    1. ISENTRESS HD (raltegravir) Film-Coated Tablets. Kenilworth, NJ: Merck & Co., Inc; 2017.
    1. Cahn P, Kaplan R, Sax PE, et al. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovirdisoproxilfumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV. 2017;4:e486–e494.
    1. U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0; 2009. Available at: . Accessed October 7, 2013.
    1. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4:213–226.
    1. Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015;2:e127–36.
    1. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune DeficSyndr. 2015;70:515–519.
    1. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13:927–935.
    1. Wohl D, Oka S, Clumeck N, et al. Brief report: arandomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune DeficSyndr. 2016;72:58–64.
    1. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulate delvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune DeficSyndr. 2013;63:96–100.
    1. Rockstroh JK, DeJesus E, Henry K, et al. A randomized, double-blind comparison of coformulate delvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulate demtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune DeficSyndr. 2013;62:483–486.
    1. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461–471.
    1. Lennox JL, Dejesus E, Berger DS, et al. Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune DeficSyndr. 2010;55:39–48.
    1. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008;359:355–365.
    1. Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis. 2010;50:605–612.
    1. Elzi L, Erb S, Furrer H, et al. Adverse events of raltegravir and dolutegravir. AIDS. 2017;31:1853–1858.
    1. van Halsema C, Whitfield T, Lin N, et al. Five years' real-life experience with raltegravir in a large HIV centre. Int J STD AIDS. 2016;27:387–393.
    1. Naumann U, Moll A, Schleehauf D, et al. Similar efficacy and tolerability of raltegravir-based antiretroviral therapy in HIV-infected patients, irrespective of age group, burden of comorbidities and concomitant medication: real-life analysis of the German 'WIP' cohort. Int J STD AIDS. 2017;28:893–901.
    1. Eron JJ, 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.
    1. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir–emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomized non-inferiority trial. Lancet. 2014;384:1942–1951.
    1. Maliakkal A, Walmsley S, Tseng A. Critical review: review of the efficacy, safety, and pharmacokinetics of raltegravir in pregnancy. J Acquir Immune DeficSyndr. 2016;72:153–161.
    1. Squires KE, Bekker LG, Eron JJ, et al. Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRKstudy. AIDS ResHum Retroviruses. 2013;29:859–870.
    1. Squires K, Bekker LG, Katlama C, et al. Influence of sex/gender and race on responses to raltegravir combined with tenofovir-emtricitabine in treatment-naive human immunodeficiency Virus-1 infected patients: pooled analyses of the STARTMRK and QDMRK studies. Open Forum Infect Dis. 2017;4:ofw047.
    1. Taramasso L, Cenderello G, Riccardi N, et al. Role of Raltegravir in patients co-infected with HIV and HCV in the era of direct antiviral agents. New Microbiol. 2017;40:227–233.
    1. Wang R, Lagakos SW, Ware JH, et al. Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357:2189–2194.

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