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

Summary

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. This study is registered with ClinicalTrials.gov, number NCT02131233.

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.

Funding

Merck & Co, Inc.

Introduction

Raltegravir was the first integrase strand-transfer inhibitor approved for the treatment of HIV-1 infection and is one of the recommended agents for initial therapy in multiple treatment guidelines.1, 2, 3 The poloxamer-based formulation of raltegravir 400 mg, approved in 2007 for twice daily use, has potent and durable antiviral activity, favourable tolerability and safety profiles, and few and manageable drug interactions.⁴ Because HIV-1 infection requires lifelong treatment, once daily regimens are preferred to facilitate treatment adherence and improve quality of life.5, 6, 7, 8, 9 In the QDMRK study,¹⁰ administration of raltegravir 800 mg once daily (as two 400 mg poloxamer-based tablets) in patients with previously untreated HIV-1 infection was not non-inferior to raltegravir 400 mg twice daily, both given with tenofovir disoproxil fumarate and emtricitabine. A subsequent exposure–response analysis¹¹ showed that C_trough concentrations of raltegravir correlated with the likelihood of virological response in the 800 mg once daily group. To optimise raltegravir exposure after once daily administration, a new 600 mg tablet with higher bioavailability than the 400 mg tablet has been developed. In a multiple-dose, phase 1 study, the area under the curve_0–24 for raltegravir was 21% higher after two 600 mg tablets once daily than after three 400 mg tablets once daily, and 2·3 times higher than after 400 mg twice daily.¹² Additionally, food had a smaller effect on the pharmacokinetics of raltegravir when given as a single dose of two 600 mg tablets compared with three 400 mg tablets (42% vs 73% decrease in the area under the curve_0–last).¹² In view of its favourable profile with respect to bioavailability and food effects, and the high probability of it showing non-inferiority to the twice daily tablet based on modelling and simulation,¹³ the new raltegravir once daily formulation was selected for evaluation in a large phase 3 study (ONCEMRK) in which it was compared with the marketed twice daily tablet, both in combination therapy, as initial treatment for adults infected with HIV-1.

Research in context

Evidence before this study

In the QDMRK study, administration of raltegravir 800 mg once daily was associated with inferior virological efficacy and lower trough concentrations than reported with the 400 mg twice daily regimen. To achieve once daily dosing of raltegravir, a new 600 mg tablet was developed, to be administered as 1200 mg once daily. We searched PubMed for articles published in any language up to May 12, 2017, using the search term “raltegravir 1200” and found four publications describing five phase 1 studies, which examined the single-dose and multiple-dose pharmacokinetics of the new formulation and the potential for drug interactions with atazanavir, efavirenz, and metal-cation antacids.

Added value of this study

This is the first randomised controlled trial of the efficacy and safety of a new once daily formulation of raltegravir given in combination with tenofovir disoproxil fumarate and emtricitabine in 797 antiretroviral therapy-naive patients with HIV-1 infection. We found that raltegravir 1200 mg once daily was non-inferior to raltegravir 400 mg twice daily, showing potent antiviral activity and a similar safety profile. The raltegravir trough concentrations were somewhat lower for the 1200 mg once daily regimen than for the 400 mg twice daily regimen; however, the proportions of patients with virological suppression were similar across all quartiles of the trough concentration values for both regimens. Although the proportion of patients who developed viral resistance to raltegravir once daily (0·8%) was slightly higher than for raltegravir twice daily in this study (0%), it was low and consistent with previously reported resistance to raltegravir twice daily.

Implications of all the available evidence

The results from ONCEMRK showing the non-inferior efficacy and similar safety of raltegravir 1200 mg once daily (new formulation) versus raltegravir 400 mg twice daily support the use of raltegravir 1200 mg once per day for initial treatment of HIV-1 infection. Additionally, the exposure–response analysis shows that maximum viral suppression (HIV-1 RNA <40 copies per mL) is probably achieved across the range of pharmacokinetic exposures obtained from both regimens.