Low rifampicin concentrations in tuberculosis patients with HIV infection.

Tanuja Narayansamy Gengiah,Kogieleum Naidoo,Julia Hillary Botha,Salim S Abdool Karim,Deepak Soowamber

doi:10.3855/jidc.4696

Abstract

The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5 hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated. In 57 patients, median (IQR) C2.5 hr was 3.6 (2.8-5.0) µg/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low median rifampicin C2.5 hr, 3.7 (2.8-5.0) µg/mL in the heterozygous and 3.4 (2.7-4.7) µg/mL in the homozygous variant carriers. Concentrations were also low in males (p < 0.0001) and those with low haemoglobin (p = 0.02). Although reinfection could not be distinguished from reactivation for the 43 patients followed post trial, the incidence of TB recurrence was 7.1 per 100 person-years. Of the eight patients in whom TB recurred, seven had the polymorphism. Approximated peak rifampicin concentrations were well below the recommended target range of 8 to 24 µg/mL in this patient population with its high frequency of the SLCO1B1 (rs4149032) polymorphism. Increased rifampicin dosage may be warranted in African, HIV- TB co-infected patients.

Highlights

The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition
Anti-TB activity and development of resistance are linked to rifampicin concentrations [13,14] and rifampicin peak concentrations of 8 to 24 μg /mL are generally considered to be associated with optimal bactericidal killing and post antibiotic effect [15]
One hundred and fifty six rifampicin concentrations were available for analysis from the 57 patients

Summary

Introduction

The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low median rifampicin C2.5hr, 3.7 (2.8-5.0) μg/mL in the heterozygous and 3.4 (2.7-4.7) μg/mL in the homozygous variant carriers. Conclusion: Approximated peak rifampicin concentrations were well below the recommended target range of 8 to 24 μg/mL in this patient population with its high frequency of the SLCO1B1 (rs4149032) polymorphism. Rifampicin induces several cytochrome P450 enzymes [10] and hepatocellular uptake is mediated by an organic aniontransporter polypeptide 1B1 (OAT1B1) coded for by the gene SLCO1B1 [11] Polymorphisms in this gene influence rifampicin pharmacokinetics significantly and are implicated in low rifampicin exposure [6,12]. Anti-TB activity and development of resistance are linked to rifampicin concentrations [13,14] and rifampicin peak concentrations of 8 to 24 μg /mL are generally considered to be associated with optimal bactericidal killing and post antibiotic effect [15]

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Results