title: Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status.
abstract: OBJECTIVE
  To compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between HIV-infected and HIV-uninfected children with tuberculosis (TB) and correlate it with TB treatment outcome.
  
  
  METHODS
  HIV-uninfected (n = 84) and HIV-infected (n = 77) children with TB receiving standard thrice weekly treatment were recruited from 6 hospitals in India. Semi-intensive pharmacokinetic sampling was performed during intensive phase of TB treatment after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography. INH acetylator status was determined, and nutritional assessment was done. Children were followed-up and treatment outcomes noted.
  
  
  RESULTS
  Children with HIV and TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1 μg/mL; P < 0.001) and exposure [area under the time-concentration curve (AUC0-8); 10.4 vs. 23.4 μg/mL h; P < 0.001] than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs. 29%; P < 0.001) and underweight (73% vs. 38%; P < 0.001) compared with children with TB. Combining both groups, RMP Cmax (P = 0.001; adjusted odds ratio = 1.437; 95% confidence interval: 1.157-1.784) and PZA Cmax (P = 0.027; adjusted odds ratio = 1.041; 95% confidence interval: 1.005-1.079) significantly influenced treatment outcome.
  
  
  CONCLUSIONS
  HIV infection was associated with lower Cmax of RMP and INH and AUC0-8 of RMP. Over 90% of children in both groups had subtherapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV and TB.
authors.affiliation: From the Departments of *Biochemistry & Clinical Pharmacology, †Statistics, and; ‡Clinical Research, National Institute for Research in Tuberculosis (ICMR), Chetpet, Chennai, India; §Department of Medicine, Government Hospital of Thoracic Medicine, Chennai, India; ¶Department of Pulmonary Medicine, Institute of Child Health, Chennai, India; ‖Department of Pediatrics, Government Rajaji Hospital, Madurai, India; **Department of Medicine, Indira Gandhi Institute of Child Health, Bengaluru, India; and ††Department of Pediatrics, Sarojini Naidu Medical College, Agra, India.
authors.forename: Geetha
authors.initials: G
authors.lastname: Ramachandran
authors.forename: A K Hemanth
authors.initials: AK
authors.lastname: Kumar
authors.forename: T
authors.initials: T
authors.lastname: Kannan
authors.forename: P K
authors.initials: PK
authors.lastname: Bhavani
authors.forename: S Ramesh
authors.initials: SR
authors.lastname: Kumar
authors.forename: N Poorana
authors.initials: NP
authors.lastname: Gangadevi
authors.forename: V V
authors.initials: VV
authors.lastname: Banurekha
authors.forename: V
authors.initials: V
authors.lastname: Sudha
authors.forename: S
authors.initials: S
authors.lastname: Venkatesh
authors.forename: N
authors.initials: N
authors.lastname: Ravichandran
authors.forename: S
authors.initials: S
authors.lastname: Kalpana
authors.forename: G
authors.initials: G
authors.lastname: Mathevan
authors.forename: G N
authors.initials: GN
authors.lastname: Sanjeeva
authors.forename: Dipti
authors.initials: D
authors.lastname: Agarwal
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000150:complications*; D006761:Hospitals; D006801:Humans; D007194:India; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044967:Serum / Q000737:chemistry*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin