Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

Summary

Background

Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients.

Methods

Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941.

Findings

566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per μL or less. The main analysis (with non-completion counted as failure) showed that 86·1% (n=241 patients) of the raltegravir group and 81·9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4·2%, 95% CI −1·9 to 10·3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0·0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44·1%]) than those on efavirenz (n=217 [77·0%]; difference −32·8%, 95% CI −40·2 to −25·0, p<0·0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group.

Interpretation

Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients.

Funding

Merck.

Introduction

Highly active antiretroviral therapy is the standard of care for patients with HIV infection.1, 2 Combination regimens that include inhibitors of viral reverse transcriptase and protease enzymes have proven to be cost-effective interventions resulting in improved survival and decreased morbidity for patients with low CD4 cell counts.³ Although several recommended regimens are available for the initial treatment of HIV-1 infection, the success of antiretroviral therapy continues to be limited by preferences of patients and care-providers, underlying comorbidities, drug interactions, adverse drug effects, and long-term complications. Transmission of resistant HIV-1—particularly strains resistant to non-nucleoside reverse transcriptase inhibitors—places treatment-naive patients at risk of suboptimum responses to standard first-line regimens.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Antiretrovirals from new drug classes are needed to expand options for initial treatment of HIV-1 infection and enhance the probability of achieving and maintaining optimum virological suppression.

Guidelines issued by the US Department of Health and Human Services recommend tenofovir and emtricitabine in combination with either efavirenz or a ritonavir-boosted protease inhibitor as the initial regimen for previously untreated patients.¹ The co-formulation tenofovir, emtricitabine, and efavirenz has become the preferred protease-inhibitor-sparing regimen in developed countries because of ease of dosing and potent and durable antiretroviral activity.1, 2, 14, 15, 16, 17

Raltegravir is a novel HIV-1 integrase inhibitor that prevents proviral DNA-strand transfer. The drug has potent in vitro activity against strains of HIV-1 that are susceptible or resistant to other classes of antiretroviral drugs.18, 19, 20, 21, 22, 23, 24 In the BENCHMRK studies,20, 21 use of raltegravir with an optimum background regimen was generally well tolerated and provided superior HIV-1 suppression compared with optimum background treatment alone, despite infection with virus resistant to reverse transcriptase and protease inhibitors. Results of a dose-ranging phase II trial in treatment-naive patients showed similar efficacy with raltegravir and efavirenz when each drug was used as part of a combination antiretroviral regimen with two nucleoside reverse transcriptase inhibitors.²² At 96 weeks, 83% of 160 patients on raltegravir and 84% of 38 patients on efavirenz had viral RNA (vRNA) concentration of less than 50 copies per mL.²³

We present 48-week results from the phase III STARTMRK study comparing raltegravir-based and efavirenz-based combination regimens as initial treatment for adults infected with HIV-1.