Spectrum of Adverse Effects and it’s Associations in Patient Medicated with Anti-Tubercular Drugs

Evidence suggests that adverse drug effects (ADRs) from long-term therapeutic intervention in tuberculosis are obvious; however, were taken insouciantly due to the only therapeutic alternative. Hence, this study was undertaken to characterize the adverse effects and its association among patients medicated with anti-tubercular drugs. A longitudinal prospective study was conducted among the patient medicated with anti-tubercular drugs. As per the guideline of Nepal’s National tuberculosis control program (NTP);the treatment category was selected, xed-dose-regimen was calculated, and the treatment outcome was armed. Patients’ demographics and other clinical details were extracted from the repository les and via a pre-tested questionnaire. Upon a consecutive follow-up, observed adverse effects were noted and multivariate logistic analysis against independent factors was done for elucidating any association.

female, abnormal body mass index (BMI) i.e. underweight and overweight cases, patients' behaviors i.e. smoking/drinking or both, clinically diagnosed cases, and intensive treatment phase were independently associated with adverse side effects. Loss of appetite (85.4%) was the commonest while dermatologic manifestations (1.2%) and severe weight-loss (1.2%) were the least observed side-effects among the patient medicated with anti-tubercular drugs.

Conclusions
Adverse effects of anti-tubercular therapy are associated with patients' demographics variables, study settings, treatment phase, and treatment categories. For the clinical management, the symptomatic treatment, regular follow-up after implicated therapy, and temporary therapeutic-discontinuation may be required.

Background
Although, a treatable and transmission chain could be curtailed; for decades, tuberculosis has been existing as a major public-health-threat round the globe.Billions of dollars are being spent on research, prevention, and control programs; however, the infection is still untamed. Every year, more than 10 million people get infected worldwide, of which more than 44% are from South-East-Asia (1).De cient molecular and diagnostic modalities due to economic constraints, low socio-economic conditions, and inaccessible health-care facilities are the major reasons behind this regional unyielding infection (2)(3)(4) (5).
Turning to Nepal, nearly half of the population is infected and each year approximately 6000-7000 patients are dying from TB (6). About Nepal's National TB Program(NTP) report 2017/18, 32474 presumed TB cases were registered; of which 91% new cases and 89% retreatment cases were treated successfully (6).Likewise, in global prospects,there is a signi cant success rate-nearly 85%(1). This evidence suggests, timely diagnosis and antitubercular therapy(ATT) could cure the infection but why a bulk of the population(> 1.5 million) succumbed to death every year(1)? The question is yet to be answered.Depending upon the drug resistance status of the pathogen and consistency of patient to prescription, long-term therapeutic intervention(up to 12months) is required while treating tuberculosis. At the same timea diverse therapy-induced-toxicity, mild to fatal, could appearunbidden(7) (8).Several cases of morbidity and mortality due to the therapy-induced-toxicity come to the surface time and again(9)(10) (11).Although, these toxicity or adverse effectsare often neglected since no alternative to ATT was sought to the date. Therefore,the characterization of adverse effects is equally paramount as compelling therapeutic interventions. As to the pro le of adverse effects upon ATT, no consensus has been reached in Nepal. Hence, the study was undertakento characterize the adverse effects and it's associations among patients medicated with anti-tubercular drugs.

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 con rmed 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, xed-dose-regimen was calculated, and the treatment outcome was a rmed.
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 uroquinolones) are enlisted as potent anti-tubercular therapy. Combining these potent antibiotics, Fixed-Dose-Combination (FDC) was adjusted accordingly. 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 de nition
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 de ned as noxious and unintended reaction induced from the implicated therapy even at an appropriate dose; it warrants prevention or speci c 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 sideeffects(supplementary material: S1).Further, clinical details were extracted from the repository les.
The following data were extracted for analysis from the clinical records of the repository le and with our assessments: patients' behavior (smoker/drinker/both or none), type of diagnosis i.e. BCC(bacterial con rmed 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 O ce 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% con dence intervals (CIs) were presented for elucidating the associations(if any). Those variables with P-value less than 0.05 were assessed as statistically signi cant.

Results
Patient's demographics Of 177 cases (including 99 male and 78 female) enrolled, 138(77.9%) reported at least two adverse effects ( g.1). The mean age of study participants was 33.48±15.80 ranging from 3 to 90 years. A higher proportion of the enrolled patients were either underweight 99(55.9%) or overweight 55(31.1%). 24(12.5%) patients were the habitual smoker/alcoholics/both while 155(87.5%) had no such behaviors. Of the total study subjects, 80(45.2%) were bacteriological con rmed TB cases, while the predominance TB type was EPTB (extrapulmonary tuberculosis) 96(54.2%). In our study, 88.1% of the patients were medicated with CAT-1 regimen and the most adverse effects were observed during intensive phase 133(75.14%) of the therapy.

Spectrum of ADRs
Loss of appetite (85.4%) was the commonest while dermatologic manifestations (1.2%) and severe weight-loss (1.2%) were the least observed side-effects among the patient medicated with anti-tubercular drugs. The spectrum of observed ADRs was shown in g.2.
Association between patient's demographics and adverse effects When the logistic model of independent factors was assessed; female, abnormal body mass index (BMI) i.e. underweight and overweight cases, patients' behaviors i.e. smoking/drinking or both, clinical diagnosed cases and intensive treatment phase were associated with adverse side effects ( P-value <0.05)( Table-3).

Assessment of anti-TB treatment effects and treatment
Upon the clinical evaluation of adverse effects by the expert clinicians, 11(6.2%) study subjects required temporary therapeutic discontinuationdue topossible fatality and complexity. Those patient reporting adverse effects were treated with H2 blockers, proton pump inhibitors, antihistamine, vitamin B6,amitriptyline, gabapentin,inhaled beta-agonists, corticosteroids, potassium, magnesium, and calcium replacement therapy(where necessary). The ancillary medications against likely occurring ADRs were prescribed in reference to the guidelines endorsed by the WHO for clinical management(9).

Discussion
Evidence suggests a wide range of adverse effects, mild to fatal, are attributed with an implicated therapy to tuberculosis; however, were taken nonchalantly due to the only therapeutic alternative(7)(8) (14). The results of this study indicate that adverse effect in ATT is a serious problem; therefore, a meticulous follow-up along with early symptomatic treatment and therapeutic discontinuation may require depending upon the case.
The study settings primarily contribute to the severity and diversities of adverse effects. Several aforementioned studies revealed population-based studies are commonly attributed to somehow lenient adverse effects compared to that of hospital-based studies (15)(16)(18)(21). The hospitalized patients likely to have a range of underlying diseases and other complications, and were monitored periodically, thus increasing the probability of discovering ADRs (7)(16)(21). Our study design wassketched as the hospital-based studypatients with underlying diseases could have included although known cases were excluded. Probably, this could be a reason behind the higher incidence of adverse effects in our study.
About previous studies conducted in different localities, the patients' demographic variables including ethnicity, age, sex, nutritional status, social behaviors, pre-existing diseases or dysfunction had shown a signi cant association to the likely occurring ADRs in ATT medicated patients (2)(8)(15)(16)(17) (19). Likewise, in our multivariate logistic analysis: female, abnormal BMI, patients' behaviors i.e. smoking/drinking or both, and clinically diagnosed cases, are the coherently associated variables with ADRs. The ndings unequivocally re ect the role of patient's demographics in ADRs.
Similar to the previous ndings, the most ADRs (75.14%)observed in our study was during the intensive treatment phase while a few cases (2.82%) during the continuation phase reported(7)(17)(19)(22)(23). Since gradual adaptation to FDC could have attained in the continuation phase.
Currently, for patients who have failed the CAT I regimen or with MDR suspicion, CAT II regimen is recommended. The treatment would be individualized following the drug susceptibility testing(DST) report (12).
Additional group of antibiotics, uoroquinolones (o oxacin, levo oxacin, moxi oxacin,), aminoglycosides (kanamycin, capreomycin, amikacin), cycloserine, prothionamideoften gets elected along with CAT II regimen(12) (20). As an outcome, the ADRs are more obvious in patients medicated to CAT I than CAT II. The above-stated statement is further supported by our ndings. In our study, 81% of the patient implicated to CAT II regimen had a minimum of 2 ADRs.
As the serious consequences from ATT, numerous toxicities (nephrotoxicity, electrolyte wasting, hypothyroidism, ototoxicity, liver toxicity, psychiatric disturbances) with potent morbidity and mortality had also been attributed (9). These types of toxicities necessitate extra monitoring-also temporary therapeutic discontinuation of particular antibiotics may be required(12)(9) (24). In this study,6.2% cases were de ned as serious ADRs which was similar to the previous reports(7) (17). For these speci c cases of ADRs,temporary therapeutic discontinuationofspeci c antibiotics (those inducing the particular toxicities) was done, later-on the particular antibiotics was re-added,upon the symptomatic resolution.
Limitations A multi-centered study with a large sample size could elucidate the real picture of ADRs, its spectrum, and the associated factors. Lacking this setting was the major drawback of our study.

Conclusions
Adverse effects of ATT are associated with patients' demographics variables, study settings, treatment phase, and treatment categories. The ADRs could be mild to fatal; hence depending upon the cases, symptomatic treatment, and regular follow-up after implicated therapy, and temporary therapeutic-discontinuation ismandatory for the successful outcomes. Kathmandu, Nepal. A written informed consent was taken from all patients orfrom their legal parents before participating in the study. To maintain anonymity and con dentiality in this study, no personal identi ers were recorded.

Consent for publication
Not applicable.

Availability of data and materials
Data generated or analyzed during this study are included in this manuscript and remaining are available from the corresponding author on reasonable request.

Competing interest
The authors declare that they have no competing interests.
Authors' contributions PK1 and BR made the diagnosis, designed the manuscript, reviewed the literature, and prepared the article for submission. PK3 helped for the literature review, gave the concept of the research paper, and critically reviewed the manuscript. Allauthors read and approved the nal manuscript.