Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial - 22/11/11

Doi : 10.1016/S1473-3099(11)70196-7

Joseph J Eron, ProfMD ^a, Jürgen K Rockstroh, MD ^b, Jacques Reynes, ProfMD ^c, Jaime Andrade-Villanueva, MD ^d, Jose Valdez Ramalho-Madruga, MD ^e, Linda-Gail Bekker, MD ^f, Benjamin Young, MD ^g, Christine Katlama, MD ^h, Jose Maria Gatell-Artigas, MD ⁱ, Jose R Arribas, MD ^j, Mark Nelson, MD ^k, Havilland Campbell, BS ^l, Jing Zhao, PhD ^l, Anthony J Rodgers, MS ^l, Matthew L Rizk, PhD ^l, Larissa Wenning, PhD ^l, Michael D Miller, PhD ^l, Daria Hazuda, PhD ^l, Mark J DiNubile, MD ^l, Randi Leavitt, MD ^l, Robin Isaacs, MD ^l, Michael N Robertson, MD ^l, Peter Sklar, MD ^l, Bach-Yen Nguyen, DrMD ^l,^⁎

for the QDMRK Investigators^{^‡}
Members listed at end of paper

^a University of North Carolina School of Medicine, Chapel Hill, NC, USA

^b Oberarzt an der Medizinischen Universitätsklinik, Bonn, Germany

^c Centre Hospitalier Universitaire Gui de Chauliac, Montpellier, France

^d Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Mexico

^e Centro de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil

^f University of Cape Town, Cape Town, South Africa

^g Rocky Mountain CARES/Denver Infectious Disease Consultants, Denver, CO, USA

^h Hôpital Pitié-Salpêtrière, Paris, France

ⁱ Hospital Clinic I Provincial de Barcelona, Barcelona, Spain

^j Hospital Universitario La Paz, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain

^k St Stephen’s AIDS Trust/Crusaid Research Institute, London, UK

^l Merck Research Laboratories, North Wales, PA, USA

^* Correspondence to: Dr Bach-Yen Nguyen, Merck Research Laboratories, PO Box 1000, UG3D-56, North Wales, PA 19454–1099, USA

Summary

Background

Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules.

Methods

In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of −10%. This study is registered with ClinicalTrials.gov, number NCT00745823.

Findings

From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference −5·7%, 95% CI −10·7 to −0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group.

Interpretation

Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.

Funding

Merck.

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Introduction

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Role of the funding source

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Vol 11 - N° 12

P. 907-915 - décembre 2011 Retour au numéro

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Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial - 22/11/11

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