title: Low rifampicin concentrations in tuberculosis patients with HIV infection.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CAPRISA - Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa. gengiaht1@ukzn.ac.za.
authors.forename: Tanuja Narayansamy
authors.initials: TN
authors.lastname: Gengiah
authors.forename: Julia Hillary
authors.initials: JH
authors.lastname: Botha
authors.forename: Deepak
authors.initials: D
authors.lastname: Soowamber
authors.forename: Kogieleum
authors.initials: K
authors.lastname: Naidoo
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D010949:Plasma / Q000737:chemistry; D011110:Polymorphism, Genetic; D012008:Recurrence; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013019:South Africa; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D012293:Rifampin