Study design and setting
A longitudinal prospective study was conducted among patients medicated with anti-tubercular drugs in DOTS center, Tribhuvan University Teaching Hospital(TUTH) from November 2018 to December 2019. This is the only hospital where patients from the whole nation come for treatment due to its best-health-care facilities and super-specialty-care at an affordable cost. 177 patients (both bacteriologically confirmed and clinically diagnosed) who receives a complete course of ATT were enrolled in this study. As per the guideline of Nepal’s NTP, the treatment category was selected, fixed-dose-regimen was calculated, and the treatment outcome was affirmed.
Nepal’s NTP therapeutic guidelines to ATT
About NTP guideline, Isoniazide(H), Rifampicin(R), Pyrazinamide(Z), Ethambutol(E), Streptomycin(S), other groups of antibiotics(aminoglycosides and fluroquinolones) are enlisted as potent anti-tubercular therapy. Combining these potent antibiotics, Fixed-Dose-Combination (FDC) was adjusted accordingly.
FDC for adult
- H(75mg)+R(150mg)+Z(400mg)+E(275mg)= HRZE combination
- H(75mg)+R(150mg)= HR combination
- H(75mg)+R(150mg)+E(275mg)= HRE combination
FDC for children(0-14 years)
- H(50mg)+R(75mg)+Z(150mg)= HRZ combination(Intensive phase)
- H(50mg)+R(75mg)= HR combination(Continuation phase)
The treatment guidelines of NTP, Nepal: the treatment category selection and dose calculation as per patient’s body weight was shown in Table-1 and Table-2(12)
Use of streptomycin
Streptomycin, previously placed in CAT II regimen, is now phase outfrom Nepal’s’ NTP guidelines. However, when other drugs have to be replaced cause of toxicity, especiallyethambutol, streptomycin still can be used(12).
Variable definition
All diagnosed cases were broadly divided into BCC and CDC. The bacilli of Mycobacterium tuberculosis when observed or detected either on smear microscopy, culture, and gene Xpert, the cases were BCC. However, the diagnosis when made on clinical suspicion and/or with supplementary tests (radiological and histo-cytological impressions), the cases were CDC. When smear-negative result and/or symptomatic resolution was observed upon the periodic examination by the physician, BCC was presumed as cured cases and CDC as completed cases.
ADRs is defined as noxious and unintended reaction induced from the implicated therapy even at an appropriate dose; it warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product(9)(13).
Inclusive and exclusive criteria
The patients with at least two adverse effects observed during a complete-course of ATT were included.However, the patient medicated with ATT for a short or incomplete course,and those who loss to follow-up or defaulter were excluded. Known patients being treated forunderlying diseases were also excluded since ADRs from other than anti-tubercular drugs might give a false interpretation. Due to the high probability of adverse effects and individualization of treatment protocols single XDR case reported in TUTH was excluded.
Data collection
All patients, those meeting inclusion criteria, were interviewed with a questionnaire that collects information on demography, medical history, co-morbidities, diagnosis of TB, current use of medication, and observed side-effects(supplementary material: S1).Further, clinical details were extracted from the repository files.
The following data were extracted for analysis from the clinical records of the repository file and with our assessments: patients’ behavior (smoker/drinker/both or none), type of diagnosis i.e. BCC(bacterial confirmed cases) or CDC(clinically diagnosed cases), BMI in kg/m2 (normal: 18.5-24.9; overweight: ≥25; underweight: <18.5), type of TB (PTB or EPTB), treatment category (CAT-I or CAT-II), treatment phase (intensive treatment phase or continuation phase), adverse side effects (Y or N).
Follow-up and responses
The clinical evaluation of mild to serious ADRs was done by the consultant physician relying upon the physical test, radiological and laboratory investigation. The decision of temporary therapeutic discontinuation and symptomatic treatment, where necessary, was made by the respective physicians.
Statistical methods
The data obtained was entered in Microsoft Office Excel 2010 and analyzed by Statistical Package for Social Sciences (SPSS) version 16.0. Frequencies and percentages were calculated, multivariate logistic analysis against independent variables was done, the odds ratio was calculated, and nominal 95% confidence intervals (CIs) were presented for elucidating the associations(if any). Those variables with P-value less than 0.05 were assessed as statistically significant.