Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children.

SETTING: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. OBJECTIVE: To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. METHODS: Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. RESULTS AND CONCLUSIONS: Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 µg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.

Efficacy of the 6-month thrice-weekly regimen in the treatment of new sputum smear-positive pulmonary tuberculosis under clinical trial conditions.

BACKGROUND: Under the Revised National Tuberculosis Control Programme of India, patients with new smear-positive pulmonary tuberculosis are treated with a thrice-weekly regimen of antitubercular drugs (2H(3)R(3)Z(3)E(3)/4H(3)R(3) [H isoniazid, R rifampicin, Z pyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacy andtolerability of this regimen under clinical trial conditions in HIV-negative patients with newly diagnosed smear-positive pulmonary tuberculosis. METHODS: We retrospectively analysed the data on patients assigned to the control regimen (2H (3)R(3)Z(3)E(3)/4H(3)R(3)) in two clinical trials during 2001-06 at the National Institute for Research in Tuberculosis, Chennai, India. RESULTS: Of the 268 patients treated with this regimen, data for efficacy analysis were available for 249. At the end of treatment, of 249 patients, 238 (96%) had a favourable status. Treatment failure occurred in the remaining 11: 7 in whom the organisms were initially drug-susceptible and 4 with initial drug resistance. Of the 238 patients who had a favourable status at the end of treatment, 14 (6%) had recurrence of tuberculosis during the following 24 months. In the intention-to-treat analysis, 245 (94%) of 262 patients had a favourable status at the end of treatment. Of the 28 patients with initial drug resistance, 24 (86%) had a favourable outcome. Only 4 of these 24 patients were found to have recurrence of tuberculosis in 2 years of follow-up. Among the 221 patients initially infected with drug-susceptible organisms, drug resistance did not develop in any of the 7 patients in whom the treatment failed or the 10 who had recurrence of tuberculosis. Further, 5 of the 7 patients in whom the treatment failed continued to excrete drug-susceptible bacilli at 6 months. Adverse drug reactions were observed in 38 (14%) of the 262 patients. Only 3 (1.1%) needed a modification in the treatment. CONCLUSION: This thrice-weekly 6-month regimen of antitubercular drugs, when administered under full supervision, is associated with a high rate of favourable treatment outcomes in HIV-negative patients with newly diagnosed sputum smearpositive pulmonary tuberculosis. There are few adverse drug reactions in these patients.

Contact screening and chemoprophylaxis in India's Revised Tuberculosis Control Programme: a situational analysis.

BACKGROUND: India's Revised National Tuberculosis Control Programme (RNTCP) recommends screening of all household contacts of smear-positive pulmonary tuberculosis (PTB) cases for tuberculosis (TB) disease, and 6-month isoniazid preventive therapy (IPT) for asymptomatic children aged <6 years. OBJECTIVE: To assess the implementation of child contact screening and IPT administration under the RNTCP. METHODS: A cross-sectional study conducted in four randomly selected TB units (TUs), two in an urban (Chennai City) and two in a rural (Vellore District) area of Tamil Nadu, South India, from July to September 2008. The study involved the perusal of TB treatment cards of source cases (new or retreatment smear-positive PTB patients started on treatment), interview of source cases and focus group discussions (FGDs) among health care workers. RESULTS: Interviews of 253 PTB patients revealed that of 220 contacts aged <14 years, only 31 (14%) had been screened for TB, and that of 84 household children aged <6 years, only 16 (19%) had been initiated on IPT. The treatment cards of source cases lacked documentation of contact details. FGDs revealed greater TB awareness among urban health care workers, but a lack of detailed knowledge about procedures. CONCLUSION: Provision for documentation using a separate IPT card and focused training may help improve the implementation of contact screening and IPT.

Assessment of long term status of sputum positive pulmonary TB patients successfully treated with short course chemotherapy.

BACKGROUND: Long term status of pulmonary tuberculosis (PTB) patients treated with short course chemotherapy (SCC) regimens remains unknown. OBJECTIVE: To assess the clinical, bacteriological, radiological status and health related quality of life (HRQoL) of PTB patients 14-18 years after successful treatment with SCC. METHODOLOGY: In a cross-sectional study, cured PTB patients treated during 1986-1990 at the Tuberculosis Research Centre (TRC) were investigated for their current health status including pulmonary function tests (PFT). The St Georges respiratory questionnaire (SGRQ) was used to assess the HRQoL. RESULTS: The mean period after treatment completion for the 363 eligible participants was 16.5 yrs (range 14-18 yrs., 84% coverage); 25 (7%) had been re-treated and 52 (14%) died. Among the investigated, 58 (29%) had persistent respiratory symptoms; 170 (86%) had radiological sequelae but none had active disease. Abnormal PFT was observed in 96 (65%) with predominantly restrictive type of disease in 66 (45%). The SGRQ scores for activity and impact were high implying impairment in HRQoL. CONCLUSION: Assessment of long term status of cured PTB patients showed an impairment of lung functions and HRQoL highlighting the need to address these issues in the management of TB that may provide added value to patient care.

Reduced erythrocyte CR1 levels in patients with pulmonary tuberculosis is an acquired phenomenon.

Complement receptor 1 expressed on erythrocytes is involved in the transport of circulating immune complexes from the circulation to the mononuclear phagocyte system for safe disposal. The prevalence of complement receptor 1 genotypes and the association between circulating immune complexes and expression of complement receptor 1 on erythrocytes in pulmonary tuberculosis are not fully understood. Observations from this study showed increased occurrence of HH genotype in patients with pulmonary tuberculosis. Patients with tuberculosis had decreased erythrocyte complement receptor 1 and increased immune complex levels compared to healthy controls which also correlated with increasing severity of the disease. In addition, the expression of complement receptor 1 on erythrocytes correlated inversely with the levels of circulating immune complexes. This study suggests that the presence of HH genotype is high in pulmonary tuberculosis patients and the reduced complement receptor 1 in patients may be an acquired phenomenon related to disease pathogenesis.

Sputum conversion at the end of intensive phase of Category-1 regimen in the treatment of pulmonary tuberculosis patients with diabetes mellitus or HIV infection: An analysis of risk factors.

BACKGROUND & OBJECTIVE: New smear-positive pulmonary tuberculosis (PTB) patients in the Revised National Tuberculosis Control Programme (RNTCP) are treated with a 6-month short-course chemotherapy (SCC) regimen irrespective of co-morbid conditions. We undertook this retrospective analysis to compare sputum conversion rates (smear, culture) at the end of intensive phase (IP) of Category-1 regimen among patients admitted to concurrent controlled clinical trials: pulmonary tuberculosis alone (PTB) or with type 2 diabetes mellitus (DM-TB) or HIV infection (HIV-TB), and to identify the risk factors influencing sputum conversion. METHODS: In this retrospective analysis sputum conversion rates at the end of intensive phase (IP) in three concurrent studies undertaken among PTB, DM-TB and HIV-TB patients, during 1998 - 2002 at the Tuberculosis Research Centre (TRC), Chennai, were compared. Sputum smears were examined by fluorescent microscopy. HIV infected patients did not receive anti-retroviral treatment (ART). Patients with DM were treated with oral hypoglycaemic drugs or insulin (sc). RESULTS: The study population included 98, 92 and 88 patients in the PTB, DM-TB and HIV-TB studies. At the end of IP the smear conversion (58, 61, and 62%) and culture conversion (86, 88 and 92%) rates were similar in the three groups respectively. The variables associated with lack of sputum smear or culture conversion were age >45 yr, higher pre-treatment smear and culture grading, and extent of the radiographic involvement. INTERPRETATION & CONCLUSION: Our findings confirm that the current policy of the control programme to treat all pulmonary TB patients with or with out co-morbid conditions with Category-I regimen appears to be appropriate.