Background
The incidence and spread of multidrug resistant tuberculosis (MDR-TB) defined as “TB caused by strains of
Mycobacterium tuberculosis (MTB) concurrently resistant to both rifampicin (R) and isoniazid (H)” are threatening to the successful control and eradication of TB [
1]. It is estimated that out of 10 million TB cases in 2019, a total 3.3% of the new and 18% of the previously treated TB cases had MDR/R resistant (RR) TB [
2]. In 2019, there were approximately 465,000 (range 400,000–535,000) incident cases of RR-TB; out of which 78% had MDR-TB [
2]. Being resistant to the powerful and safe first line anti-TB drugs (FLD) i.e. R and H, these patients are treated with a long, less effective and toxic regimen mainly comprised of multiple second-line anti-TB drugs (SLD) [
2]. This results in comparatively poor treatment outcomes in these patients [
1]. The global treatment success rates of 2017 cohorts of MDR/RR-TB and drug susceptible TB were respectively 56% and 85% [
2].
Similar with other forms of TB, drug resistant-TB (DR-TB) affects people of all age groups including children (age ≤ 14 years) [
3]. It has been estimated that each year approximately 25,000–32,000 children develop MDR-TB, which makes 3% of all childhood TB cases [
4]. Because of children incapability to expectorate sputum, paucibacillary nature of the disease, problems in obtaining specimens for culture and drug susceptibility testing (DST), and nonspecific symptoms, the diagnosis of childhood TB and DST are challenging tasks. Consequently, childhood TB including DR-TB has suffered a historical neglect and has not been a priority of national TB programs (NTP) throughout the world [
3,
5]. Although children suffering from MDR-TB have a diverse spectrum of disease, differences in metabolism of anti-TB drugs, different range of adverse events and healthcare needs than adults [
6‐
8], still they are treated with the same treatment regimens as adult MDR-TB patients. The previously published very few individual cohorts of childhood MDR-TB patients have reported variable rates of successful treatment outcomes (range 62–92%) [
6,
9,
10]. A systematic review and meta-analysis of 1413 childhood MDR-TB patients has reported a pooled treatment success rate of 73% in developing and 87% in developed countries [
11]. An individual patients’ data meta-analysis of 975 childhood MDR-TB patients has reported a treatment success rate of 78% [
12]. Variable treatment success rate among childhood DR-TB patients could be due to different proportion of comorbidities, disease severity, drug resistance patterns [
6,
9‐
12] and different DR-TB treatment regimens used over the last decade. The conventional longer treatment regimen (LTR) was introduced by WHO in 2011. For RR/MDR-TB patients without resistance to any SLD, the LTR comprised of at least 8 months treatment with
amikacin (Am)/kanamycin (Km)/capreomycin (Cm) +
levofloxacin (Lfx) +
ethionamide (Eto) +
cycloserine (Cs) +
pyrazinamide (Z) and 12 months treatment with
Lfx +
Eto +
Cs +
Z. For patients with resistance to any SLD, it was recommended to add
para-amino salicylic acid (PAS) to the abovementioned regimen [
13]. In order to overcome the disadvantages of low treatment success rate, high incidence of clinically significant adverse events, prolonged treatment duration and high cost associated with LTR [
1], in 2016 WHO recommended a shorter treatment regimen (STR). It comprised of treating MDR/RR-TB patients for 4–6 months with
Km +
moxifloxacin (Mfx) +
prothionamide (Pto) +
clofazimine (Cfz) +
Z +
ethambutol (E) +
high dose H followed by 5 months treatment with Mfx +
Cfz +
Z +
E [
14]
. However, the limited applicability of STR due to strict eligibility criteria for patients being treated with STR [
15] resulted in the introduction of updated regimens for the treatment of MDR/RR-TB patients in 2020 [
16]. These regimens comprised of (i) shorter all oral
bedaquiline containing regimen i.e. treatment for 4–6 months with
bedaquiline and 6 months with
Lfx/Mfx +
Cfz +
Z +
E +
High dose H followed by 5 months of
Lfx/Mfx +
Cfz +
Z +
E (ii) various
bedaquiline containing LTRs and (iii)
bedaquiline,
pretomanid and linezolid (BPaL) containing regimen.
Unluckily, Pakistan is currently MDR-TB 5th high burden country, where the programmatic management of DR-TB (PMDT) was started way back in 2010 and at present there are 33 functional PMDT units in the country. Investigating the routine management and treatment outcomes of a group of patients is a conventional and effective way of assessing the program’s efficacy. In Pakistan, the previously published multiple cohorts of MDR-TB patients have reported a variable treatment success rate (range: 40.5–83.7%) [
17‐
22]. However, there was a lack of information regarding socio-demographic characteristics, drug resistance pattern, treatment outcomes and factors associated with unsuccessful outcomes among childhood RR/MDR-TB patients from Pakistan. Therefore, the present study was carried out with the objective to fill the abovementioned gap.
Discussion
To the best of our knowledge, this is the first study which has evaluated the socio-demographic characteristics, drug resistance pattern, treatment outcomes and factors associated with unsuccessful outcomes of an individual cohort of childhood RR/MDR-TB in Pakistan, an MDR-TB 5th high burden country. In compliance with reports from Peru [
9] and India [
10], majority (74.2%) of the current study participants belonged to the age group of 11–14 years. The small proportions of children of age ≤ 5 years (8.9%) and 6–10 years (16.9%) in the current study and similar findings elsewhere [
9,
10] highlights the known difficulties in the diagnoses childhood DR-TB which include the younger children incapability to expectorate sputum for culture and DST, and paucibacillary nature of the disease in these patients [
10]. In our study, the disproportionately high number of female patients (74%) was inconsistent with the reported global epidemiology of TB in which male gender predominates [
2]. However, it was in line with few reports from Pakistan [
17,
19] and India [
10] in which the proportion of female MDR-TB patients was disproportionately high. Upon cross-tabulation, we found that 140/160 female childhood patients of the current cohort were 10–14 years old. As common in poor communities, adult women and girls of this age take care of people and patients at home, this perhaps make them more susceptible to contract the infectious diseases. Furthermore, in Pakistan due to deeply rooted gender discrimination and TB related stigma, female TB patients suffer from greater delay in seeking healthcare and seek low quality care. This in turn may result in faulty diagnosis, guidelines divergent practices of healthcare providers, patients’ poor adherence with TB treatment regimen TB [
25], and the development of DR-TB [
19,
30]. In the current study, 84 patients (39.4%) suffered from RR-TB. However, only 20/84 (23.8%) of these patients were phenotypically confirmed. In the remaining 64 (76.4%) patients, the diagnosis of RR-TB was based on the results of Gene-Xpert, which could be one of the possible reasons for high proportion of RR-TB patients in the current cohort.
The high proportion of current patients with no history of previous TB treatment (37.1%) was consistent with the recent reports from Pakistan [
22,
26] and elsewhere [
10,
31,
32]. This suggests that primary transmission is becoming a major mode of spreading DR-TB in both adults and children and needs urgent measures of infection control to halt its spread [
22,
31,
32]. In this study, only 50 (23.1%) patients were resistant to any SLD of whom 49 were MDR and one was RR-TB patient. Out of these 50 SLD resistant patients, 45 were resistant to FQ. In this study, 38% of MDR-TB patients were resistant to any SLD. This was lower than the range (41.3–55.5%) reported among MDR-TB patients (children and adults combined) in Pakistan [
15,
19,
25,
33]. Prolonged delays between onset of TB symptoms and presentation to TB treatment centers, self-medication of chest symptomatics prior to TB diagnosis, treatment by inadequately aware local paramedics and private practitioners with insufficient diagnostic facilities, liberal use of pharmacy driven broad spectrum fluoroquinolones for respiratory tract infections, doctors non-compliance with TB treatment guidelines and patients non-adherence with TB treatment regimen have been reported as some of the major reasons of development of SLD resistance in DR-TB patients [
25]. As a notable proportion of patients (37.1%) had no history of TB treatment, this could be one of the possible reasons of comparatively lower prevalence of SLD resistance in MDR-TB patients in this study.
The currently observed rate of sputum culture conversion (85.4%) among PTB patients was comparable with a study conducted in India (88%) [
10]. However, median time to sputum culture conversion in our study (2 months, IQR: 1–3 months) was relatively shorter than what was observed in the Indian study (3 months, IQR: 3–4 months) [
10]. Furthermore, in the current cohort, 89.8% of the patients who achieved SCC were culture negative by third month of treatment as compared to 73% in the Indian study [
10].
The treatment success rate (81.7%) in the current cohort was above the target set by WHO (> 75%) and success rates observed among children and adolescent MDR-TB patients in India (62%) [
10], children MDR-TB patients in Peru (77.3%) [
9] and pooled treatment success rate of childhood MDR-TB (73%) in developing countries [
11]. Furthermore, it was above the success rates (range: 40.5–76.9%) reported among MDR-TB patients (adults and children combined) treated with LTR in Pakistan [
17‐
21]. However, it was lower than the success rate observed among childhood MDR-TB patients in South Africa (92%) [
6] and the pooled treatment success rate observed in developed countries (87%) [
11]. A total of 35 (16.4%) participants of this study died. This was consistent with the death rate (16%) among children and adolescent MDR-TB patients reported from India [
10], but above the rates reported from Peru (4.3%) [
9], by a meta-analysis of 1343 childhood MDR-TB patients (8%) [
11] and a study from South Africa (2%) [
6]. In our study, none of the participants was LTFU. The comparatively lower mortality rate in aforementioned studies could be due the masking of deaths by high comparatively high LTFU rates in these studies (range: 5–13.7%) [
6,
9,
11]. In the current study, no significant difference in treatment success rate was observed between RR and MDR-TB patients. However, out of 15 patients who were on STR, only one (6.5%) developed unsuccessful outcome vs 38/198 (19.2%) who were on LTR. But due to its use in limited number of patients it did not achieve the level of significance in the model predicting treatment outcomes. In this study, all six patients (100%) who were on
bedaquiline containing regimen achieved successful outcomes. The use of
bedaquiline containing regimen has previously been reported to produce high treatment success rate and decrease in mortality among DR-TB patients [
1], therefore, it has recently been included in group A anti-TB core drugs, recommended by WHO [
16] and adopted by NTP as an integral component of DR-TB treatment regimens for eligible DR-TB patients of age 6 years and above. However, similar to STR,
bedaquiline containing regimen was received by a fraction of the current study participants (2.8%). The
bedaquiline containing regimens for eligible DR-TB patients in Pakistan was initially introduced at 6 PMDT sites in 2016 and then expanded to all PDMT sites. As now after the recommendations of WHO, all oral STR containing
bedaquiline has been adopted by all PMDT sites in the country [
23], therefore, it is suggested to evaluate its effectiveness in Pakistani settings. In multivariable analysis, the use of ethambutol emerged as the only predictor of treatment outcomes. Patients who were using ethambutol were significantly less likely to develop unsuccessful outcomes than their counterparts. In the treatment of DR-TB ethambutol is not used as a core drug but a companion drug to prevent the acquisition of additional drug resistance. In the published literature, the use of ethambutol has not been reported as a predictor of successful outcomes in DR-TB patients. Furthermore, our finding of ethambutol as a predictor of successful outcome should be interpreted with the poor discrimination power of the final model visualized by the ROC curve analysis (AUC = 0.651, 95% CI 0.562–0.740, p-value = 0.003) (Fig.
1). Patients’ age, use of second-line injectable anti-TB drugs, high dose isoniazid and malnutrition which have previously been reported as predictors of treatment outcomes among childhood MDR-TB patients [
6,
10,
12] were not significantly associated with treatment outcomes in the current study.
Large number of microbiologically diagnosed RR/MDR-TB patients from multiple centers is the major strength of the current study. However due to retrospective nature of data collection, the lack of information about chest radiography to document the extent and severity of pulmonary disease which has previously been reported as a predictor of unsuccessful treatment outcomes in children MDR-TB patients [
6,
9], lack of information about adverse events and their impact on treatment outcomes and the absence of post-treatment follow-up to ensure the absence of relapses among children with treatment success are the major limitations associated with this study.
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