Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial

Cahn, Pedro; Sax, Paul E.; Squires, Kathleen; Molina, Jean‐Michel; Rojas, Evelin; Rassool, Mohammed; Bloch, Mark; Vandekerckhove, Linos; Ruane, Peter; Xu, Xia; Rodgers, Anthony; East, Lilly; Wenning, Larissa; Rawlins, Sandy; Homony, Brenda; Sklar, Peter; Nguyen, Bach‐Yen; Leavitt, Randi Y.; Teppler, Hedy; Cahn, PE; Cassetti, Isabel; Losso, Marcelo; Bloch, M.P.H. Karen C.; Roth, Norman; McMahon, James; Moore, Rob; Smith, Don; Clumeck, Nathan; Vanderkerckhove, L; Vandercam, Bernard; Moutschen, Michel; Baril, Jean-Guy; Conway, Brian; Smaill, Fiona; Smith, Ghr; Rachlis, Anita; Walmsley, Sharon; Perez, Claudia de Mello; Wolff, Marcelo; Lasso, MF; Chahin, CE; Velez, JD; Sussmann, Otto; Reynes, Jacques; Katlama, Christine; Yazdanpanah, Yazdan; Ferret, Samuel; Durant, J.; Duvivier, Claudine; Poizot‐Martin, Isabelle; Ajana, F.; Rockstroh, JK; Faetkanheuer, G; Eßer, Stefan; Jaeger, Hans; Degen, Olaf; Bickel, Markus; Bogner, J. R.; Arastéh, Keikawus; Hartl, Hannah M; Stoehr, Albrecht; Rojas, EM; Arathoon, Eduardo; Gonzalez, LD; Mejia, CR; Shahar, Eduardo; Turner, Dan; Levy, Idan; Sthoeger, Zev; Elinav, Hila; Gori, Andrea; Monforte, A d’Arminio; Perri, Giovanni Di; Lazzarin, Adriano; Rizzardini, Giuliano; Antinori, Andrea; Celesia, Benedetto Maurizio; Maggiolo, Franco; Chow, TS; Lee, CKC; Azwa, R Iskandar Shah Raja; Mustafa, Mulham; Oyanguren, M; Ra, Chisei; Hercilla, L; Echiverri, C; Maltêz, Fernando; Cunha, JG Saraiva da; Neves, I; Teófilo, Eugénio; Serrão, Rosário; Нагимова, Ф. И.; Хаертынова, И. М.; Orlova-Morozova, E; Voronin, Evgeny; Sotnikov, V.; Aa, Yakovlev; Zakharova, NG; Tsybakova, O; Botes, Mariëtte E.; Mohapi, Lerato; Kaplan, Richard; Rassool, MS; Arribas, JR; Gatell, JM; Negredo, Eugènia; Ortega, Enrique; Troya, Jesús; Berenguer, Juan; Aguirrebengoa, Koldo; Antela, Antonio; Calmy, Alexandra; Cavassini, Matthias; Rauch, Angelika; Stoeckle, Marcel; Wh, Sheng; Lin, Hui; Hc, Tsai; Changpradub, Dhitiwat; Avihingsanon, Anchalee; Kiertiburanakul, Sasisopin; Ratanasuwan, Winai; Nelson, M; Clarke, Amanda; Ustianowski, Andrew; Winston, Alan; Ma, Jun; Asmuth, DM; Cade, Jerry; Je, Gallant; Ruane, P.; Kumar, PN Suresh; A, Luque; Panther, Lori; Tashima, K.; Ward, Douglas J.; Ds, Berger; Dietz, CA; Fichtenbaum, Carl J.; Gupta, Shaili; Km, Mullane; Novak, RM; Sweet, D; Crofoot, GE; Hagins, DP; Lewis, ST; McDonald, C; DeJesus, Edwin; Sloan, Louis; Prelutsky, D; Rondon, JC; Henn, S; Scarsella, AJ; Morales, JO; Ramírez,; Santiago, Lizette; Cd, Zorrilla; Ms, Saag; Hsiao, CB

doi:10.1016/s2352-3018(17)30128-5

Cited by 33 publications

(21 citation statements)

References 37 publications

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“…A new formulation of RAL, 1200 mg QD, is now available for naïve patients and will make dosing easier [ 33 ] and improve adherence. Nevertheless, this strategy should be evaluated carefully, taking into account the virological failures reported with RAL 800 mg QD, and lack of efficacy due to historical genotypic mutations that can be archived from previous treatments.…”

Section: Discussionmentioning

confidence: 99%

Raltegravir plus abacavir/lamivudine in virologically suppressed HIV-1-infected patients: 48-week results of the KIRAL study

Troya¹,

Montejano²,

Ryan³

et al. 2018

PLoS ONE

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BackgroundLong-term combination antiretroviral therapy often results in toxicity/tolerability problems, which are one of the main reasons for switching treatment. Despite the favorable profile of raltegravir (RAL), data on its combination with abacavir/lamivudine (ABC/3TC) are scarce. Based on clinical data, we evaluated this regimen as a switching strategy.DesignMulticenter, non-controlled, retrospective study including all virologically suppressed HIV-1-infected patients who had switched to RAL+ABC/3TC.MethodsWe evaluated effectiveness (defined as maintenance of HIV-1-RNA <50 copies/mL at 48 weeks) safety, tolerability, laboratory data, and CD4+ count at week 48 of this switching strategy.ResultsThe study population comprised 467 patients. Median age was 49 years (IQR: 45–53). Males accounted for 75.4%. Median CD4+ count at baseline was 580 cells/μL (IQR, 409). The main reasons for switching were toxicity/tolerability problems (197; 42.2%) and physician’s criteria (133; 28.5%). At week 48, HIV-1 RNA remained at <50 copies/mL in 371/380 (97.6%; 95%CI: 96.4–99.0) when non-virological failure was censured. Virological failure was recorded in 1.9% patients and treatment failure in 20.5% of patients (96/467 [95%CI, 16.9–24.2]). The main reasons for treatment failure included switch to fixed-dose combination regimens (31; 6.6%), toxicity/poor tolerability (27; 5.8%), and physician’s decision (17; 3.6%). A total of 73 adverse events were detected in 64 patients (13.7%). These resolved in 43 patients (67.2%). Of the 33 cases related or likely related to treatment, 30 were Grade-1 (90.9%). CD4+ count and renal, hepatic, and lipid profiles remained clinically stable over the 48 weeks.ConclusionsOur findings suggest that RAL+ABC/3TC could be an effective, safe/tolerable, and low-toxicity option for virologically suppressed HIV-1-infected patients.

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Section: Discussionmentioning

confidence: 99%

Raltegravir plus abacavir/lamivudine in virologically suppressed HIV-1-infected patients: 48-week results of the KIRAL study

Troya¹,

Montejano²,

Ryan³

et al. 2018

PLoS ONE

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“…9 In the ONCEMRK phase 3 trial, raltegravir 1200 mg once daily (QD) showed noninferior efficacy to raltegravir 400 mg BID, with 88.9% and 88.3% of participants, respectively, achieving HIV-1 RNA <40 copies per milliliter at week 48. 10 In addition, the immunologic efficacy and overall safety profile of raltegravir QD were similar to those of raltegravir BID at week 48. Here, we report the long-term efficacy and safety of raltegravir 1200 mg QD compared with raltegravir 400 mg BID through week 96 of the ONCEMRK trial.…”

Section: Introductionmentioning

confidence: 74%

“…The noninferior efficacy and favorable safety profile of raltegravir 1200 mg QD were first demonstrated at week 48 and have been previously reported. 10 At week 96, the efficacy of raltegravir 1200 mg QD was again shown to be noninferior to that of raltegravir 400 mg BID, as assessed by the proportion of participants with HIV-1 RNA <40 copies per milliliter. Similar results were observed for the supportive virologic endpoint of HIV-1 RNA <50 copies per milliliter, and both treatment groups continued to show substantial increases in CD4 + T-cell counts (over 260 cells/mm 3 ) through week 96.…”

Section: Discussionmentioning

confidence: 97%

“…The primary efficacy end point for this trial was assessed at week 48 and has been previously reported. 10 This report presents additional data to evaluate the secondary hypothesis that raltegravir 1200 mg QD is noninferior to raltegravir 400 mg BID, each in combination with TDF/FTC, as assessed by the proportion of participants achieving HIV-1 RNA <40 copies per milliliter at week 96. A margin of 10 percentage points was used to assess noninferiority.…”

Section: Methodsmentioning

confidence: 99%

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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

Cahn

Sax

Squires

et al. 2018

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…A subsequent pharmacokinetic‐pharmacodynamic response analysis indicated that lower trough concentrations in the once/day arm were associated with a lower virologic response . Following the results of the QDMRK study, ONCEMRK examined RAL in a new once/day formulation consisting of two 600‐mg tablets (total dose 1200 mg) given in combination with TDF/FTC in comparison with the standard 400‐mg twice/day regimen . Virologic response at 48 weeks was nearly identical between the two treatment groups (treatment difference 0.5% [95% CI −4.2 to 5.2]) despite markedly lower median trough concentration in the once/day regimen group.…”

Section: Methodsmentioning

confidence: 99%

Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come?

et al. 2019

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The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment-naive and treatment-experienced patients. At present, antiretroviral guidelines fully endorse the INSTI class as part of all first-line treatment regimens. After 10 years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK-2048 for potential use as either HIV pre-exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs. AUC = area under the curve; CYP = cytochrome P450; DHHS = U.S. Department of Health and Human Services; MATE1 = multidrug and toxin extrusion protein; OCT2 = organic cationic transporter 2; P-gp = P-glycoprotein; S cr = serum creatinine concentration; UGT = uridine diphosphate-glucuronosyltransferase. a Class drug-drug interactions: Integrase strand transfer inhibitor exposures are reduced when administered with polyvalent cation-containing supplements including acid-suppressive therapies and with potent CYP3A4/UGT1A1 inducers (e.g., carbamazepine, phenytoin, and rifamycins). b Stribild contains elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; available only as a single-table formulation. c Genvoya contains elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. d Biktarvy contains bictegravir, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. EXPERIENCE WITH INTEGRASE INHIBITORS Brooks et al

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Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial

Abstract: Merck & Co, Inc.

Cited by 33 publications

References 37 publications

Raltegravir plus abacavir/lamivudine in virologically suppressed HIV-1-infected patients: 48-week results of the KIRAL study

Raltegravir plus abacavir/lamivudine in virologically suppressed HIV-1-infected patients: 48-week results of the KIRAL study

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

Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come?

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