WHO Group 5 Drugs and Difficult Multidrug-Resistant Tuberculosis: a Systematic Review with Cohort Analysis and Meta-Analysis

It is often necessary to include WHO group 5 drugs in the treatment of extensively drug-resistant tuberculosis (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about the use of group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in treatment of 162 (84%) patients, macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10% to 124%) and 55% (10% to 121%), respectively. Defining significant associations by risk ratios ≥ 1.2 or ≤ 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other group 5 drugs with respect to outcome for patients treated with linezolid, although selection bias might have led to underestimation of their effects. Our findings substantiated the use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB and call for further studies to evaluate the roles of other group 5 drugs.     

ORIGINAL ARTICLE: Associations of the growth hormone receptor (GHR) gene polymorphisms with adiposity and IGF‐I activity in adolescents

Objective: To explore the genetic effect of the GH receptor (GHR) on obesity and related metabolic parameters in Hong Kong Chinese adolescents. Context: Obesity is a growing global epidemic. Increasing evidence suggests that the GH‐IGF‐I axis plays an important role in regulating adiposity and insulin sensitivity. Design: We examined the associations of genetic variants of GHR with serum IGF‐I and IGFBP‐3 levels as well as obesity‐related metabolic traits in Hong Kong Chinese adolescents. Patients: Nine hundred and eighty‐one randomly selected Hong Kong Chinese adolescents from 14 schools. Measurements: We genotyped 17 single nucleotide polymorphisms (SNP) at GHR and measured serum IGF‐I and IGFBP‐3 levels as well as obesity‐related metabolic traits including fasting plasma glucose, insulin and lipid levels. Results: There were significant associations between rs4410646 and the body composition (P = 0·0044) and blood pressure factor scores (P = 0·00017). Carriers of the CC genotype had lower body mass index, percentage body fat, waist and hip circumferences than AC and AA genotype carriers (P = 0·00030–0·0094). There was also association between rs7703713 and the IGF‐I activity factor score (P = 0·0033). The GA and AA carriers of rs7703713 had higher serum IGF‐I, higher serum IGFBP‐3 and higher IGF‐I/IGFBP‐3 molar ratio (P = 0·00069–0·025). Haplotype analysis did not increase the significance of associations. Conclusion: Our results support the role of GHR gene polymorphisms in modulating adiposity and IGF‐I activity in adolescents. Examination of interactions of these SNPs with lifestyle, environmental and perinatal factors may provide further insights into their long‐term effects on obesity and metabolic risks.     

A nested case-control study on treatment-related risk factors for early relapse of tuberculosis

This nested case-control study aimed at evaluating treatment-related risk factors of relapse of tuberculosis under a service program of directly observed treatment. Out of 12,183 patients with pulmonary tuberculosis who completed treatment within 1 year, 113 relapsed within 30 months after commencement of therapy. The overall 30-month relapse rate was 0.9% (95% confidence interval [CI] 0.8-1.1%). On matching 113 cases with 226 control subjects in a conditional logistic model, thrice-weekly treatment increased the risk of relapse in comparison with daily treatment (odds ratio 3.92, 95% CI 1.78-8.63), whereas prolonging both intensive phase and overall treatment by 50% or more protected against relapse (odds ratio 0.24, 95% CI 0.08-0.70). When pretreatment culture was positive and cavitation was absent, the 30-month relapse rate for standard thrice-weekly regimen was 1.1% (95% CI 0.6-2.0%). The corresponding rates in the presence of cavitation were 7.8% (95% CI 4.0-14.6%) for standard thrice-weekly regimen; 3.3% (95% CI 1.9-5.5%) for standard daily regimen; 0.5% (95% CI 0.1-2.6%) for extended thrice-weekly regimen; and 0.4% (95% CI 0.1-0.9%) for extended daily regimen. Further studies are required to reduce the risk of relapse under program settings.