Dosing of raltegravir when given with rifampicin
WHO (1) recommends that, in resource-limited settings, a first-line antiretroviral treatment (ART) regimen should contain two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor (preferably efavirenz in patients on concomitant tuberculosis treatment). Partly because of cost considerations, raltegravir is not included as a first-line option in WHO guidelines and is not widely used in resource-limited settings. In high-income settings, raltegravir is included as an option for first-line regimens (2). Even in resource-limited settings, raltegravir is an attractive option for patients who cannot tolerate efavirenz, and if its price could be reduced it might be used more widely.
Many patients with HIV need treatment for tuberculosis while on ART. Rifampicin decreases concentrations of nevirapine and protease inhibitors via induction of cytochrome P450 isoenzymes and the drug transporter p-glycoprotein. Raltegravir is not metabolised via the cytochrome P450 system; the principal enzyme involved in the elimination of raltegravir is UDP-glucuronosyltransferase (UGT1A1) (3). However, exposure to raltegravir is reduced by rifampicin because it also induces UGT1A1. The question of whether raltegravir doses need to be adjusted because of this interaction is thus an important one for patients who need tuberculosis treatment while on raltegravir. In a pharmacokinetic study of raltegravir in healthy volunteers (4), rifampicin lowered the area under the curve of raltegravir by 40% and trough concentration by 61% when raltegravir was dosed at 400 mg. When the raltegravir dose was increased to 800 mg, the effect on area under the curve was compensated but not the effect on trough concentrations because rifampicin increases the clearance and shortens the half-life of raltegravir.
On the basis of these pharmacokinetic data, the US Food and Drug Administration and European Medicines Agency recommended that raltegravir be dosed at 800 mg twice a day when given with rifampicin (5, 6). Some investigators have reported anecdotal evidence of favourable outcomes at this dose in patients being treated for tuberculosis (7, 8). In a pharmacokinetic substudy of the QDMRK trial, in which raltegravir 800 mg once daily was shown to be inferior to 400 mg twice daily, the key raltegravir pharmacokinetic parameter for antiviral effect seemed to be the trough concentration (9). The reduction in raltegravir trough concentrations was much greater (six times) in the QDMRK trial than in the previous drug-interaction study with rifampicin done in healthy individuals (4). Therefore, questions about whether double-dose raltegravir with rifampicin is sufficient or necessary remain.
In The Lancet Infectious Diseases, Beatriz Grinsztejn and colleagues (10) report findings from their randomised controlled trial in which they assessed three ART regimens in patients on concurrent rifampicin-based tuberculosis treatment that included raltegravir 400 mg twice a day, raltegravir 800 mg twice a day, or efavirenz. Their trial was a multicentre, phase 2, open-label trial done in Brazil and France, with most participants enrolled in Brazil. The trial was not powered to provide statistically robust comparisons between the three regimens, but was powered to assess whether viral suppression (to <50 copies per mL at 24 weeks) in each of the groups exceeded 70%—the average virological suppression achieved with two efavirenz based-regimens in previous trials including patients with tuberculosis patients (11, 12). This study design was unconventional and limits the strength of the conclusions that can be drawn from this trial.
The investigators randomly assigned treatment to 155 patients, 133 (86%) of whom completed follow-up at week 48. In the modified intention-to-treat analysis, virological suppression was achieved at 24 weeks in 39 (76%) of 51 patients in the raltegravir 400 mg group, 40 (78%) of 51 patients in the raltegravir 800 mg group, and 32 (63%) of 51 patients in the efavirenz group. The sample size in this trial was too small to adequately assess safety. However, one patient in the raltegravir 800 mg group had liver failure, but this event was more likely related to tuberculosis treatment because raltegravir treatment was resumed after liver transplant without a recurrence of the event; the risk of serious adverse events and laboratory adverse events was much the same between groups.
Although raltegravir 400 mg seemed as effective as the 800 mg dose in terms of virological suppression, the investigators were appropriately cautious in their recommendations. Because this was a phase 2 trial that was not powered for comparison of regimens, a phase 3 trial is needed to compare the two doses of raltegravir in patients co-infected with HIV and tuberculosis. In the interim, despite findings from the pharmacokinetic study in healthy volunteers showing a reduction in raltegravir trough concentrations with rifampicin (4), the results of Grinsztejn and colleagues' study are the best clinical outcome data available and lend support to the use of standard doses of raltegravir when given with rifampicin, pending a larger phase 3 trial.
In this trial, the investigators assessed the use of raltegravir with tuberculosis treatment in first-line ART, and the findings might not be applicable to patients on second-line and third-line regimens, in which the importance of raltegravir concentrations in the regimen might differ.
We declare that we have no competing interests.
References
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By Graeme Meintjes a c, Gary Maartens a b
a Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
b Department of Medicine, University of Cape Town, Cape Town 7925, South Africa
c Department of Medicine, Imperial College, London W2 1PG, UK
Source: The Lancet Infectious Diseases
