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Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial

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Summary

Background

Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis.

Methods

We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315.

Findings

Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65–88) in the raltegravir 400 mg group, 40 patients (78%, 67–90) in the raltegravir 800 mg group, and 32 patients (63%, 49–76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment.

Interpretation

Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis.

Funding

French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.

Introduction

In patients with HIV, tuberculosis is the most common life-threatening opportunistic infection and is a leading cause of death. Concurrent treatment of HIV and tuberculosis decreases mortality,1, 2, 3 reduces tuberculosis relapse,4 and decreases community transmission of both tuberculosis and HIV.5, 6 Antiretroviral treatment should, therefore, be started early in all patients with active tuberculosis, irrespective of their WHO clinical stage or CD4 cell count.7

However, despite the increasing number of antiretroviral drugs developed for the treatment of HIV infection, few options are available for patients co-infected with tuberculosis because of drug interactions. Rifampicin is the cornerstone of tuberculosis treatment, and is a potent inducer of hepatic cytochrome P450 3A4 enzymes, the main metabolic pathway of most non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors. Induction of these enzymes leads to increased clearance, reduced drug exposure, and potentially suboptimum clinical efficacy. Efavirenz, an NNRTI metabolised mainly through the cytochrome P450 2B6 pathway, also has pharmacokinetic interaction with rifampicin, which does not necessitate dose adjustment, and is the preferred antiretroviral to be used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of patients with both HIV and tuberculosis.7 Common side-effects of efavirenz are neuropsychiatric adverse events and rash, which can lead to treatment discontinuation.8 Additionally, primary NNRTI-resistance mutations could jeopardise the efficacy of efavirenz, and its use is controversial during the first trimester of pregnancy.9, 10, 11 Alternatives to efavirenz are therefore needed for the treatment of HIV in patients with tuberculosis.

Raltegravir, a strand-transfer HIV integrase inhibitor, has shown potent antiviral activity and good tolerability in patients with HIV.12 In the long-term follow-up of the phase 3 STARTMRK study in treatment-naive patients,13 raltegravir had better virological and immunological efficacy and had a more favourable safety profile when compared with efavirenz. Raltegravir is not metabolised by the cytochrome P450 enzymes, but by uridine 5′-diphospho (UDP)-glucuronosyltransferase 1A1, an enzyme that is also induced by rifampicin. When raltegravir is given with rifampicin, and is used at the standard dose of 400 mg twice a day, findings from pharmacokinetic studies in healthy volunteers have shown a 40% decrease in plasma raltegravir area under the concentration-time curve, and a 61% decrease in plasma raltegravir trough concentration.14 Increasing the raltegravir dose to twice the standard dose (800 mg twice a day) compensates for the effect of rifampicin on the area under the concentration-time curve, although raltegravir trough concentrations remain 53% lower than expected.14 Therefore, both the US Food and Drug Administrations (FDA) and the European Medicines Agency approved the raltegravir package insert to recommend for raltegravir dosing to be increased from a standard 400 mg twice a day to 800 mg twice a day for patients taking concomitant rifampicin. Despite this recommendation, clinical experience with the combination of raltegravir and rifampicin is restricted, and the efficacy and safety of high-dose raltegravir during tuberculosis treatment has not been assessed.15, 16, 17 We assessed the efficacy and safety of two raltegravir doses in antiretroviral-naive adults receiving rifampicin-based treatment for HIV and tuberculosis co-infection.

Section snippets

Study design and participants

The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) 12180 Reflate TB trial was a multicentre, randomised, parallel-group, phase 2, 48 week study, done at eight clinical sites, six in Brazil and two in France. We enrolled adult patients (aged 18 years or older) with previously untreated HIV-1 infection and a plasma HIV RNA concentration of greater than 1000 copies per mL, who had been receiving a rifampicin-based treatment for pulmonary or extrapulmonary tuberculosis for

Results

Between July 3, 2009, and June 6, 2011, we screened 179 patients, 171 in Brazil and eight in France, of whom 155 were randomly assigned treatment (we enrolled all eight patients from France): 52 to efavirenz, 51 to raltegravir 400 mg, and 52 to raltegravir 800 mg (figure 1). 153 patients (51 in each group) received at least one dose of the study drug and were included in the modified intention-to-treat analysis (figure 1). We completed follow-up of all patients on May 3, 2012.

At baseline, the

Discussion

We recorded no statistically significant between-group differences in patients treated with 400 mg or 800 mg of raltegravir or 600 mg of efavirenz at either week 24 or week 48. We know of no other randomised controlled trial exploring efficacy and safety of raltegravir in patients co-infected with HIV and tuberculosis (panel).

The slightly higher point estimates of efficacy at week 24 in the raltegravir groups using a threshold of 50 copies per mL were expected because the decrease in plasma HIV

References (23)

  • HIV/AIDS Programme. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection

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