Comment
Dosing of raltegravir when given with rifampicin Published Online April 10, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70739-X See Articles page 459
442
WHO1 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 colleagues10 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
Dosing of raltegravir when given with rifampicin Published Online April 10, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70739-X See Articles page 459
442
WHO1 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 colleagues10 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
