Tuberculosis (TB) is a major public health problem worldwide. As per Global TB report 2019, globally 10 million people developed TB disease and about a quarter of those cases were reported from India in 2018.1 The proportion of cases who are infected with strains resistant to isoniazid and rifampicin, called multidrug-resistant tuberculosis (MDR-TB) among new and previously treated cases in India, were 2.8% and 14% respectively.1

Adherence to the long course of TB treatment is a complex, dynamic phenomenon with a wide range of factors impacting on treatment taking behavior.2 However, an estimated 50% of patients on long term therapy for chronic diseases, including TB, are non-adherent.3 Non-compliance leading to treatment interruption due to any reason may affect the outcome adversely.4 Multiple number of drugs leading to adverse events (AEs) in drug resistance TB (DR-TB), patients’ personal factors, TB programme related factors and environmental factors may be responsible for the interruptions and loss to follow up (LTFU) during the treatment period.5

Bedaquiline, is a novel drug recently approved for the treatment of tuberculosis. The addition of bedaquiline to an optimized background regimen (OBR) results in faster and significantly more culture conversions leading to higher successful outcome.6 The information about interruptions and AEs, especially with newer drugs and drug combinations, in bedaquiline containing regimen is sparse.7–9

The study aimed to analyze the frequency and severity of AEs and other reasons for interruptions of treatment and loss to follow up (LTFU) during the first six months of treatment among TB patients on bedaquiline containing regimens under programmatic conditions in India.

A total of 275 patients were enrolled. The demographic, radiological, microbiological characteristics, drugs used and number of drugs in the treatment regimen are summarized in Table 1. Among the 275 study subjects, 56.4% were males, median age was 25 (IQR, 21−36) years and median BMI was 18.73 kg/m2 [IQR, 15.5−20.16]. At treatment initiation, 63.6% had cavity in chest x-ray and 73.8% were Pre-XDR (MDR + Fluoroquinolone resistant – 70.2%; MDR + Injectable resistant – 3.6%). Patients having XDR TB {MDR-TB plus resistance to any fluoroquinolone and at least one of three second-line injectable drugs (i.e., amikacin, kanamycin, or capreomycin)} were 22.6%.

This is the first observational study on treatment interruption patterns and various reasons for interruptions during the first six months of treatment among DR-TB patients from a TB endemic country who received a bedaquiline containing regimen under the national TB programme. This study also analyzed the frequency and severity of AEs due to anti-TB drugs in this cohort of patients.

The study observed that among the 275 patients, around one third of patients had treatment interruption episodes, in more than half of these patients the interruptions were temporary, and three-quarters of the interruptions were due to drug related AEs. The commonest drugs associated with temporary and permanent interruption episodes were bedaquiline (8.7%) and linezolid (5%), respectively. A retrospective study done by E. Sanchez-Padilla et al.16 found drug related AEs (11.6%) and need for return to work (24.4%) as the main cause for interruptions.

Personal factors like busy schedule, lack of family support and no improvement with treatment were the major causes (94.1%) for interruption in LTFU group. More than half of the patients (59%) interrupted treatment due to no or slow response, as many of these patients had advanced disease at baseline. Every effort should be made to retrieve these patients at the earliest and restart the treatment in timely manner. It is important that patients be actively counselled by treatment supporter on each visit to continue with the treatment.

In our study, no interruptions were observed due to service delivery and environmental related factors, thus highlighting the relatively good performance of PMDT services in study area. However, in a study by I. Zão et al.17 healthcare system related factors were one of the reasons for delay in diagnosis and management of TB patients although less common than patient related factors.

In our study, QTc prolongation was more frequent than reported in bedaquiline-treated patients in previous studies,14,18–21 possibly because most patients (96.4%) received one or more additional QTc-prolonging drugs such as moxifloxacin (high dose) (43.2%), clofazimine (88%) or delamanid (17.1%). However, majority of the events were associated with dyselectrolytemia and once corrected, bedaquiline could be reintroduced in the majority of patients. Although bedaquiline was associated with temporary treatment interruptions in around 8.7% of patients, it required permanent discontinuation in only 2.9% of patients, indicating bedaquiline may have good safety profile. However, a retrospective study by Lorenzo Guglielmetti et al.22 found that bedaquiline was permanently discontinued in 6.7% patients due to QTc prolongation.

In our study, linezolid required permanent discontinuation in 5% patients out of total 260 patients who received linezolid in their regimen. These observations are similar to studies by N. Ahmad et al.,23 Z. Lan et al.24 and R. Singla et al.25 which found that linezolid was associated with SAEs more often compared to other drugs used in the treatment regimen. Anemia was the significant SAE responsible for permanent interruption of linezolid in our study, similar to findings in systematic review and meta-analysis done by G. Sotgiu et al.26 Therapeutic drug monitoring can be utilized to measure drug levels in patients receiving long term linezolid therapy.

There are concerns regarding the use of bedaquiline and delamanid together in patients having extensive level of drug resistance beyond XDR-TB because of increased propensity for cardiotoxicity. Delamanid was used as one of companion drugs in 17% of such patients in our study, but it required permanent discontinuation in only two patients. This indicates that the addition of delamanid to bedaquiline containing regimen may not lead to significant increase in SAEs. Efficacy of this combination could not be evaluated in this study.

In India as per PMDT guidelines, patients on bedaquiline containing regimen need to be more closely monitored during first two weeks of treatment.10 However, it was observed that almost 80% of interruptions were reported after second week of treatment initiation and these interruptions were mainly due to drug related AEs. Hence, all patients on bedaquiline containing regimen need intense monitoring by the treatment supporters during follow up even after two weeks of treatment. Directly observed treatment (DOT) improves adherence to TB treatment by identifying AEs earlier and manages them appropriately. In a systematic review and meta-analysis by Toczek et al.27 lower default rates for drug-resistant TB were seen with DOT.

Twelve percent of the patients expired within six months of treatment initiation which was very similar to the studies done by Sergey E. Borisov et al.28 (13.4%) and Kathryn Schnippel et al.29 (12.6%). The India TB report 2019, at national level, also shows a death rate of 14%.30 Mortality is higher in patients with advanced or disseminated forms of TB and as found by L. Meira et al31 in their study that 36% of patients who died in first six months of TB treatment had disseminated disease. Similarly, poor general condition and severe form of disease were the main cause for mortality rather than treatment failure in patients who died, thus indicating the good efficacy of these drugs.

The interim successful outcome was 80% at the end of six months of treatment. These results are far better than the previously reported successful outcomes among the severe forms of DRTB patients treated with conventional regimens in India.32 This may indicate that bedaquiline added to a background regimen can improve the rate of successful outcome among severe DRTB patients. The successful outcome was higher in patients among non-interrupters group, although it was not statistically significant.

The strengths of this study are that this is the first study analyzing various reasons of treatment interruptions in the first six months of treatment of bedaquiline containing regimens especially in high TB burden countries, like India, under programmatic conditions. Secondly the safely profile and QTc prolongation effect of bedaquiline given along with other QTc prolonging drugs in a large number of patients was also analyzed. This study also had significant number of patients on bedaquiline with delamanid combination, with or without other QTc prolonging drugs, and showed a reassuring safety profile when used together as part of a multi-drug regimen.

There were some limitations of this study. The patients in this study cohort represented most patients with severe disease with extensive drug resistance pattern. Extrapolation of results to other MDR-TB patients without extensive disease, and extensive resistance patterns may not be appropriate.

To conclude, the study observed that drug related AEs and personal factors are the most important risk factors associated with treatment interruptions. Hence, it is important to identify AEs earlier and manage them appropriately. Although, the treatment outcome among non-interrupters was better, it was not statistically significant. Hence, larger studies may be required to evaluate this.

None.

Rupak Singla and Sekar Natarajan conceived this study and supervised all aspects of its implementation. Neeta Singla and Jose A. Caminero collaborated in the inception of the study. Amartya Chakraborty carried out the analysis of the data. Amitesh Gupta and Vikas Kumar collected the data and collaborated in the analysis. All the authors contributed to the interpretation of the results and the proof reading of the manuscript.

None.