Abstract
Aim:
To determine the bacteriological conversion rate after 6 months of Delamanid (DLM) based treatment in children with drug-resistant tuberculosis (DR-TB) and determine factors associated with bacteriological conversion.
Methods:
This is a descriptive retrospective study done in children between the age of 6-17 years with DR-TB who received DLM-based therapy from October 2018 to May 2021. The drug resistance pattern of TB was detected using Xpert RIF/MTB and phenotypic drug sensitivity testing (DST) on TB-MGIT culture reports. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for 6 months. Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analyzed.
Results:
Sixty patients received DLM of which two had extrapulmonary TB (EPTB) and sputum conversion could not be assessed. The mean age at presentation was 12.69 ± 3.03 years. Five patients (8.3%) died while on DLM treatment. On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which three patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation.
Conclusion:
Sputum bacteriological conversion rate was almost 80% at the end of 6 months of DLM-based treatment.
KEY WORDS: Children, delamanid, DLM, DR-TB
INTRODUCTION
The emergence of multidrug-resistant tuberculosis (MDR-TB) is on the rise worldwide with an estimated number of 8.9-11 million cases of tuberculosis (TB) in the year 2019 as per the World Health Organization (WHO) Global Tuberculosis Report 2020 with India accounting for 26% of the total world cases.[1] There was a total of 2.64 million TB cases in 2019 in India, of which 124,000 constituted MDR-TB.[2] In 2020, 102,000 children (0–14 years) were affected in India.[3] Thus, constant research into newer drugs is essential.
The two most recently developed drugs developed for the same include Bedaquiline (BDQ) (developed by Janssen, Beerse, Belgium) and Delamanid (DLM) (developed by Otsuka, Tokyo, Japan).[4] The consolidated guidelines on Drug-resistant TB (DR-TB) as per WHO now recommends a fully oral shorter regimen lasting for 9-11 months, replacing the previously shorter regimen with an injectable agent.[5]
DLM is a nitroimidazooxazole compound whose mechanism of action is the inhibition of the synthesis of mycolic acid which is a major component of the Mycobacterium cell wall.[6]
There is minimal data on the use of DLM in India in children, hence a retrospective study was conducted to determine the bacteriological conversion rate after 6 months of DLM-based treatment in children with DR-TB and determine factors associated with bacteriological conversion.
MATERIALS AND METHODOLOGY
This retrospective descriptive study was conducted from October 2018-May 2021 in all children aged 6 years to 17 years with DR-TB who were given DLM-based therapy at a tertiary care pediatric DR-TB nodal center hospital in Western India after hospital administration permission and institutional ethical committee waiver. Patients who failed standard second-line anti-tuberculosis treatment (ATT) and were started on salvage therapy based on drug sensitivity tests along with DLM were also included. HIV status was determined by HIV Elisa and if positive was confirmed by two different kits and patients with HIV coinfection were excluded from the study. DLM dose was given based on the Guidelines for the use of DLM in the treatment of drug-resistant TB in India.[3] The patient’s treatment course was recorded in the proforma and the data were collected from outpatient hospital records notes. A patient was defined as malnourished if the patient’s weight was below the 3rd percentile according to the weight-for-age growth chart by the India Academy of Pediatrics.[7] The drug resistance pattern of TB was detected using Xpert RIF/MTB testing and the presence of rifampicin resistance (RR) and the drug susceptibility was determined using first- and second-line probe assay (LPA) and/or mycobacteria growth indicator tube (MGIT) with phenotypic drug susceptibility testing (DST). DR-TB in patients was classified into Rifampicin resistance (RR), Multidrug resistance (MDR), pre-extensively drug-resistant tuberculosis (pre-XDR), and extensively drug-resistant tuberculosis (XDR) according to WHO.[8] Previously treated patients were classified by the outcome of their most recent course of treatment into two groups: Previously treated patients with relapse and treatment failure patients. Relapse patients were defined as having previously been treated for TB, were declared cured or treatment completed at the end of their most recent course of treatment, and are now diagnosed with a recurrent episode of TB. Treatment failure patients are those who were on treatment for TB and whose treatment failed at the end of their most recent course of treatment.[9] The second line of anti-tuberculous therapy (ATT) was started based on DST.[10] Salvage therapy was given in patients who had treatment failure and consisted of a regimen combining new and previously used drugs in a final effort to attain sputum conversion in patients including patients on home-based injectable meropenem and amoxicillin-clavulanate therapy or a combination of BDQ and DLM based therapy with other sensitive drugs.[11]
Pre-DLM initiation workup, as well as follow-up tests, were carried out to determine serum magnesium, serum albumin, and QTcF values on electrocardiogram (ECG) along with complete blood count (CBC), liver function test, and renal function test. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for the first six months and then 6 monthly. Sputum bacteriological culture conversion was considered in two consecutive negative sputum cultures taken at least 30 days apart following an initial positive culture.[12] Adverse effects in the form of prolonged QTcF, sensorineural deafness, hypoalbuminemia, and hypothyroidism were monitored monthly. Sensorineural hearing loss was defined as hearing loss of at least 30 dB (dB) in three sequential frequencies in the standard pure tone audiogram.[13] Peripheral neuropathy was defined as a tingling sensation and numbness in the fingers. Hypoalbuminemia was defined as serum albumin level <3.5 g/dl. Hypothyroidism was defined as an elevated TSH value concerning their age as determined by laboratory values. Prolonged QTc was defined as prolonged if the QT interval was greater than 440 ms in male patients and greater than 460 ms in female patients.
Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analysed.
Data Analysis
Chi-square or Fisher’s exact test was used to evaluate the associations among the categorical variables and an independent T-test to evaluate associations among quantitative variables.
All calculations in this study were carried out using the SPSS program. P value <0.05 was considered statistically significant.
RESULTS
A total of 60 patients were administered DLM. Five patients (8.3%) died while on DLM treatment. The mean age of patients on presentation was 12.69 ± 3.03 years. Male:female ratio was 1: 3.6. Forty-three (71.7%) had PTB, 2 (3.3%) had extra-pulmonary TB (EPTB) of which one had humeral osteomyelitis and the second had disseminated lymph node TB, 15 (25%) had both PTB and EPTB. Of the patients with PTB, 5 (8.3%) children had miliary TB, 20 (33.3%) had fibrocavitatory TB and 33 (55%) had primary progressive TB. Among the lung parenchymal involvement, 31 (51.67%) had bilateral involvement and 27 children (45%) had unilateral involvement. Thirty-four (56.6%) children had malnutrition. Considering different DST patterns, 27 (45%) had XDR-TB, 23 (38.3%) had Pre-XDR-TB, and 10 (16.7%) had MDR-TB. Thirty-six (60%) patients had treatment failure before DLM administration of which 18 (30%) were given a salvage regimen. Four (6.7%) patients were given all oral + Second line injectables, 37 (61.67%) were on all oral regimens only, 18 (30%) were given salvage therapy and 1 (1.67%) was given a regimen that was based on DST pattern. Eighteen (30%) patients were administered DLM at 100 mg/day, 1 (1.7%) was given 75 mg/day and, 41 (68.3%) were given 200 mg/day of DLM for a period of 168 days.[14]
Adverse effects experienced by the study population included 4 (6.7%) children who had behavioural problems such as irritability, aggressive behaviour, and agitation. 4 (6.7%) children had subclinical sensorineural hearing loss (SNHL), 4 (6.7%) had peripheral neuropathy, 3 (5%) children had sub-clinical hypothyroidism, 1 (1.7%) child had hypoalbuminemia and 1 (1.7%) child had rashes. No patient had QTcF prolongation. The patient demographic characteristics mentioned are depicted in Table 1.
Table 1.
Patient demographic characteristics
| Demographic Markers | n (%) n=60 |
|---|---|
| 1) Age at presentation (years) | 12.69±3.03 |
| 2) Male:Female | 1: 3.6 |
| 3) Pulmonary Tuberculosis | 43 (71.7%) |
| 4) Extrapulmonary Tuberculosis | 2 (3.3%) |
| • Humeral Osteomyelitis | 1 (1.6%) |
| • Disseminated Lymph node Tuberculosis | 1 (1.6%) |
| 5) Both Pulmonary and Extrapulmonary Tuberculosis | 15 (25%) |
| 3) Pulmonary Tuberculosis pattern | |
| • Miliary pattern | 5 (8.3%) |
| • Fibrocavitory | 20 (33.3%) |
| • Primary Progressive | 33 (55%) |
| 7) Lung Parenchyma Involvement | |
| • Unilateral Involvement | 27 (45%) |
| • Bilateral involvement | 31 (51.67%) |
| 8) Malnutrition | 34 (56.6%) |
| 9) Type of Drug-Resistant Tuberculosis | |
| • MDR | 10 (16.7%) |
| • Pre-XDR | 23 (38.3%) |
| • XDR | 27 (45%) |
| 10) Treatment Failure | 36 (60%) |
| 11) Type of Treatment | |
| • Salvage regimen | 18 (30%) |
| • All oral + Second line injectables | 4 (6.7%) |
| • All oral Regimen | 37 (61.67%) |
| • Regimen tailored based on DST | 1 (1.7%) |
| 12) Dose of DLM | |
| • 75 mg/day | 1 (1.7%) |
| • 100 mg/day | 18 (30%) |
| • 200 mg/day | 41 (68.3%) |
| 13) Adverse effects | |
| • Behavioural Problems | 4 (6.7%) |
| • Sensorineural hearing loss | 4 (6.7%) |
| • Peripheral Neuropathy | 4 (6.7%) |
| • Sub- Clinical Hypothyroidism | 3 (5%) |
| • Hypoalbuminemia | 1 (1.7%) |
| • Rash | 1 (1.7%) |
Note: DLM – Delaminid, MDR -Multidrug resistance, Pre-XDR - pre-extensively drug-resistant tuberculosis, and XDR- Extensively drug-resistant tuberculosis
On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which 3 patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation.
Out of 46 patients who had a successful sputum bacteriological culture conversion 8 (13.3%) had MDR-TB, 19 (31.67%) had Pre-XDR TB and 19 (31.67%) had XDR-TB. Thirty-five (58.3%) patients had PTB and 11 (18.3%) patients had both PTB and EPTB. Three (5%) had miliary TB, 16 (26.7%) had fibrocavitory TB and 27 (45%) had primary progressive TB. Twenty-one (35%) had unilateral lung parenchymal involvement and 25 (41.7%) had bilateral lung parenchymal involvement. Twenty-six (43.3%) patients have had previous treatment failure. Twelve (20%) were on salvage regimens, 31 (51.7%) on all oral regimens, and 3 (5%) on all oral + second-line injectable drugs.
Out of 8 patients who had a positive sputum bacteriological culture despite six months of DLM treatment, 7 (11.7%) had PTB, and 1 (1.7%) had EPTB + PTB. Four (6.7%) had miliary TB and 4 (6.7%) had primary progressive TB. Three (5%) had unilateral lung parenchymal involvement and 5 (8.3%) had bilateral lung parenchymal involvement. Six (10%) patients have had previous treatment failure. One (1.7%) had MDR-TB, 2 (3.3%) had Pre-XDR TB and 5 (8.3%) had XDR TB. Three (5%) were on a salvage regimen, 4 (6.7%) were on an oral regimen and 1 (1.7%) was on a regimen based on DST.
Factors associated with sputum conversion and DLM-based therapy are depicted in Table 2.
Table 2.
Patient and Treatment Characteristics based on sputum bacteriological conversion
| Patient characteristics | Sputum bacteriological conversion (n=46) | No sputum bacteriological conversion (n=8) | P | |
|---|---|---|---|---|
| Age (years) | 12.69+3.03 | 11.9+4.2 | 0.524 | |
| Gender | Male | 7 (15.2%) | 3 (37.5%) | 0.1561 |
| Female | 39 (84.8%) | 5 (62.5%) | ||
| Type of TB | PTB | 35 (76.1%) | 6 (75%) | 1 |
| EPTB + PTB | 11 (23.9%) | 2 (25%) | ||
| Parenchymal involvement | Unilateral | 21 (44.1%) | 3 (37.5%) | 0.72 |
| Bilateral (%) | 25 (55.9%) | 5 (62.5%) | ||
| Type of DR-TB | XDR (%) | 19 (41.3%) | 5 (62.5%) | 0.68 |
| Pre-XDR (%) | 19 (41.3%) | 2 (25%) | ||
| MDR(%) | 8 (17.4%) | 1 (12.5%) | ||
| Prior treatment failure | Yes (%) | 26 (56.5%) | 6 (75%) | 0.449 |
| No (%) | 20 (43.5%) | 2 (25%) | ||
| Treatment Regimen | Salvage (%) | 12 (26.1%) | 3 (37.5%) | 0.21 |
| Oral + SLI (%) | 3 (6.5%) | 0 (0%) | ||
| All oral (%) | 31 (67.4%) | 4 (50%) | ||
| DST based | 0 (0%) | 1 (12.5%) | ||
Note PTB – Pulmonary tuberculosis, EPTB – ExtraPulmonary tuberculosis, MDR -Multidrug resistance, Pre-XDR - pre-extensively drug-resistant tuberculosis, and XDR- Extensively drug-resistant tuberculosis, SLI – Second line injectables, DST – Drug sensitivity testing
The duration of DLM administration is 6 months as per WHO guidelines however we had 5 outliers who received DLM administration for (>11 months) on compassionate grounds.
DISCUSSION
DLM was used in our study in conjunction with an optimized background regimen designed based on DST performed in our laboratory. The recommended dose of DLM as per NTEP guidelines is 50 mg (100 mg) twice a day for 24 weeks in children aged 6-11 years and 100 mg twice daily (200 mg) for 24 weeks for > =12 years of age.[14] The duration of DLM administration is 6 months as per WHO guidelines however we had 5 outliers who received DLM administration for (>11 months) on compassionate grounds.
The common adverse drug reactions of DLM are gastrointestinal involving nausea and vomiting and dizziness. DLM is well known to cause QT interval prolongation (>500 ms), especially in association with other second-line drugs such as fluoroquinolones; however, it is not associated with symptoms of syncope or arrhythmias.[15,16] In our study, there was no incidence of QT prolongation. Adverse events experienced by children in our study were behavioural problems like irritability, aggression, agitation, sensorineural hearing loss, peripheral neuropathy in the form of tingling sensation in fingers, hypothyroidism, hypoalbuminemia, and rashes. However, these adverse reactions were not specific to DLM and may be caused by the other drugs administered simultaneously.
Our study showed that DLM-based therapy has a 79.3% sputum conversion rate at the end of 6 months, similar to that reported in other studies. In the study by Ghosh et al.,[17] they reported a sputum conversion rate of 80% in the pediatric subgroup (6-17 years) after 24 weeks of DLM treatment and Pecora et al.[18] reported a successful outcome of 75% at the end of 6 months, Hafkin et al.[19] reported a sputum conversion rate of 80% at the end of 24 weeks. In a study that analyzed the treatment outcome of DRTB cases amongst children and adolescents not taking DLM and BDQ as part of ATT, showed an 88% sputum conversion at 6 months after treatment initiation.[20]
There were no factors associated with the clinical outcome. Sputum bacteriological conversion was similar in males and females nor was it affected by age. The outcome remained unchanged irrespective of the type of TB, type of parenchymal involvement, or type of drug resistance patterns in our patients. In patients with prior treatment failure, the outcomes remained unchanged as compared to children with no previous treatment failure Different DR-TB treatment regimens did not result in different outcomes.
The analysis of sputum conversion of children being treated with DLM within 6-month period is of vital importance in the attempt to shorten the drug-resistant regimen with the novel all-oral bedaquiline, pretomanid, and linezolid (BPaL) regimen.[21] The BPaL regimen attempts a 6-month shortened drug-resistant treatment plan and our study provides insight into the ground reality of sputum bacteriological conversion of DLM in children.
Our study had limitations in the form that it had a small patient population and we did not have a control group and also final treatment outcomes have not been studied. However, this study is a pilot study to determine the safety of DLM in Indian children and the short-term sputum bacteriological conversion rate in children with DR-TB.
CONCLUSION
This study shows that Delamanid-based therapy has 79.3% sputum bacteriological conversion at the end of 6 months.
Disclaimer
The work represents the personal opinion of the authors and not that of the organization for whom they work.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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