Low rifampicin concentrations in tuberculosis patients with HIV infection

Abstract

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. 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. Methodology: Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C 2.5hr ) 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. Results: In 57 patients, median (IQR) C 2.5hr 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 C 2.5hr , 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. 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. 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. Increased rifampicin dosage may be warranted in African, HIV-TB co-infected patients.

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

“…African populations have shown high levels of host genetic diversity resulting in differences in tuberculosis disease susceptibility . Furthermore, genetic diversity in drug‐metabolizing and drug transport enzymes in the host leads to lower tuberculosis drug concentrations and variation in drug response …”

“…79 Furthermore, genetic diversity in drug-metabolizing and drug transport enzymes in the host leads to lower tuberculosis drug concentrations and variation in drug response. [80][81][82] Pharmacogenetics Genetic variation associated with single nucleotide polymorphisms, copy number variants, or insertions or deletions in genes coding for drug-metabolizing and transporter enzymes are increasingly recognized as factors that may affect tuberculosis drug exposure and result in variable pharmacokinetic parameters. 83 Moxifloxacin is metabolized via glucuronide and sulfate conjugation by cytosolic enzymes glucuronosyltransferase and sulfotransferase.…”

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

“…Pharmacogenetic polymorphisms are proposed to be an important factor in the high variability in rifampin exposure. More specifically, polymorphisms of the SLCO1B1 gene have been associated with lower rifampin exposure (16,34,42,43). To our knowledge, the potential impact of such polymorphisms in Indonesian TB patients has not been investigated.…”

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

“…In addition, multiple studies have documented the high interindividual variability in C max plasma concentrations of these four agents (condition 4), with levels often (in some studies more than 50 % of the patients) below the normal range for C max values, especially for rifampicin and isoniazid. However, treatment outcome in these studies was in most cases favorable in at least 80 % of the patients [56,61,126,127,[135][136][137]. A systematic review and meta-analysis of 41 studies reporting 2-h post-dose drug concentrations (C 2h ) of the first-line anti-TB drugs showed that in 67, 43, 12, and 27 % of patients, the C 2h levels were below the accepted minimum C max range for rifampicin (<8 μg/ml), isoniazid (<3 μg/ml), pyrazinamide (<35 μg/ml), and ethambutol (<2 μg/ml), respectively [138].…”