INTRODUCTION:

In 2018 approximately 10.0million people fell ill with tuberculosis (TB) and 1.2million (TB) - related deaths were reported. The risk factors for tuberculosis include a weakened immune system, traveling or living in TB prevalent areas, poverty, substance abuse and genetic factors.¹The organism can develop resistance to the antimicrobial drugs used to cure the disease.

Patients infected with isoniazid and rifampicin-resistant strains of Mycobacterium tuberculosis, known as multidrug-resistant tuberculosis (MDR-TB), are almost incurable with standard first-line treatment. Pre-Extensively drug-resistant (Pre-XDR) TB is defined as TB that has developed resistance to isoniazid and rifampicin, as well as to either a fluoroquinolone (FQ) or a second-line injectable agent, but not both. Extensively drug-resistant (XDR) are those MDR-TB strais that are resistant to any fluoroquinolone and at least one of three second-line injectable drugs.^2-6

The problem of drug-resistant TB is of immense importance and concern at global, regional, and countrywide levels. In 2018, nearly half a million new cases of rifampicin-resistant tuberculosis had been reported (78% of which had MDR-TB).⁷Rising numbers of drug-resistant TB (DR-TB) cases pose a serious threat to TB control, as the duration of treatment for drug-resistant tuberculosis (DR-TB) is longer than that for drug-sensitive TB and is often associated with poor and unfavorable outcomes.⁸ According to the WHO Global TB Report 2019, only 56% of MDR-TB and 39% of XDR-TB patients were successfully treated in 2016. Current regimens for DR-TB are complicated, lengthy, and expensive compared to those used to treat drug-susceptible TB, leaving patients with much less effective treatment options.^9-12 Delays in diagnosis complicate disease prognosis and increase community transmission at the individual level, therefore training of healthcare workers on their knowledge and practice regarding case findings is essential.¹³Providing information, education and communication to improve the knowledge about TB and its prevention and to influence change in health-care seeking behavior among both TB patients and the general public is a need of hour in India.^14-16Inappropriate and extensive use of antibiotics is a factor that contributes to the emergence of antibiotic resistance. The important mechanism of antibiotic resistance include enzymatic transformation, modification of molecular target, sequestration of the drug, active efflux from the cell interior and prevention of entry of the compound into the cell. To overcome the resistance, development of new antibiotics is required.¹⁷Research on plant extracts has also shown certain antimycobacterial activity.¹⁸

Bedaquiline (BDQ) is a novel drug that belongs to a new class of Diarylquinoline that has strong bactericidal and sterilizing activities against MTB.¹⁹ In high MDR-TB burden countries, adding bedaquiline to the standard regimen improves patient health outcomes and reduces cost of healthcare.²⁰ Having considered DR-TB as a medical emergency with high mortality and disease of significant concern in the Indian health scenario, the Apex Committee for Supervising Clinical Trials on New Chemical Entities, set up by the Ministry of Health and Family Welfare of the Government of India, recommended that local clinical trials be waived at this stage and approved BDQ with a restriction to be used only under the Revised National TB Control Programme (RNTCP) framework for conditional access through the Programmatic management of drug-resistant TB (PMDT) program for the treatment of MDR-TB patients. In March 2016, RNTCP introduced BDQ to six DR-TB centers in the country.²¹ Bedaquiline has a promising cure and culture conversion rate.^22,23 The recommended daily dose of bedaquiline is 400mg orally once a day for two weeks, followed by 200mg orally three times a week for 22 weeks. Bedaquiline should be taken with food to increase bioavailability by two-fold. ^24,25 The objective of the present study was to evaluate the utilization of Bedaquiline among drug-resistant tuberculosis patients in a tertiary care hospital.

MATERIALS AND METHODS:

A hospital-based retrospective observational study was conducted at Government General and Chest Hospital, Erragadda, Hyderabad, India to which suspected tuberculosis cases are referred to as well as providing health care services to the population of Telangana and neighboring states. Bedaquiline was successfully initiated on 18^th June 2018 at the study site. The study was conducted as a part of the project for Pharm.D students in their fifth year. The study population included Pulmonary TB patients with evidence of resistance to Rifampicin and/or Isoniazid and FQs and/or Injectables (Kanamycin/Amikacin/Capreomycin) by Drug susceptibility testing (DST). All the patients registered in the hospital having age >18 years and receiving Bedaquiline regimen from June 2018 to December 2019 were included in the study. Clinical and laboratory data were collected using a structured data collection form. The information recorded from the TB register for all patients included age, sex, type and category of resistant-TB, HIV status, and presence/ absence of co-morbid conditions, TB treatment history, time of BDQ initiation, Adverse events, and final treatment outcome. The study was reviewed and approved by the institutional ethics committee, Osmania Medical College, Koti, Hyderabad.

RESULTS:

The study included a total of 23 patients. 15 Patients (65.21%) were male, and 8 (34.79%) were female. Most of the patients belonged to the age group of 21-40 years. The mean age of the patients was 41±14.24 years. All 23 patients were suffering from pulmonary tuberculosis and no extrapulmonary case was identified during the study period. Six (26.09%) patients showed the presence of co-morbidities (Table 1). Overall 5 patients were found to have diabetes mellitus, 3 had hypertension, 1 was HIV positive, and 1 had asthma. The patients prescribed with bedaquiline regimen failed either on shorter MDR-TB regimens or conventional MDR-TB regimens as shown in table 1. Eight patients were diagnosed with Pre-XDR TB, all of them were males whereas 15 were diagnosed as XDR-TB of which 7 patients were males and 8 were females. All the patients received bedaquiline and the selection of other second-line anti-TB drugs was based on the resistance pattern exhibited by individual patients. The common BDQ regimen consisted of 6-12 months treatment with Capreomycin (Cm), Eto, Cs, Z, Lzd, Cfz,E and 6 months of BDQ during the initial phase and at least 18months of Mfx, Eto, Cs, Lzd, Cfz therapy during the continuation phase. The time of initiation of BDQ regimen is shown in Table 1.

During the study period, 12(52.17%) patients reported at least one adverse event. Table 2 shows the adverse events documented in the case files of each patient. The most common (58.33%) adverse events were related to the gastrointestinal tract. ECG data was available for 8 patients, but only one patient showed slight QTc prolongation (485ms). At the end of the study duration, only 2 patients (8.70%) successfully completed the treatment, 3(13.04%) died and 18(78.26%) were still receiving the anti-tubercular treatment either in the initial or the continuation phase.

Table 1 Demographic features of the subjects

Number of prescriptions containing BDQ

Gender distribution

Male

Female

Age distribution

19-20 years

21-40 years

41-60 years

61-70 years

Age(mean±SD)

41 ± 14.24

Weight(mean±SD)

48.87 ± 13.25

Social/Surgical History

Smoking

Alcoholic

Hysterectomy

Co-morbidities

Diabetes Mellitus

HIV

Diabetes mellitus + Hypertension

DiabetesMellitus+Hypertension+Asthma

Treatment failures before starting BDQ regimen

Shorter MDR-TB Regimen:

Mfx/Lvx, Km, Eto, Cfz, Z, H, E (4-6months) and Mfx/Lvx, Cfz, Z, E (5 months)

Conventional MDR-TB Regimen:

(6-9) Km, Lvx, Eto, Cs, Z, E (6-9months) and Lvx, Eto, Cs, E (18 months)

Diagnosis:

Pre-XDR-TB

XDR-TB

Time of Initiation of BDQ regimen

October 2018

November 2018

Jan 2019

Feb 2019

Mar 2019

April 2019

June 2019

July 2019

Aug 2019

Sept 2019

Nov 2019

Dec 2019

SD: Standard deviation; HIV: Human Immunodeficiency virus; BDQ: Bedaquiline; MDR-TB: Multidrug resistant tuberculosis; Mfx: Moxifloxacin; Lvx: Levofloxacin, Km: Kanamycin; Eto: Ethionamide; Cfz: Clofazimine; Z: Pyrazinamide; H: Isoniazid; E: Ethambutol; Cs: Cycloserine;

DISCUSSION:

There are few studies highlighting the utilization of bedaquiline in India. Although the drug was made available at six TB centers in India in the year 2016, it was initiated in June 2018 at the study site. Therefore, a retrospective study was carried out from June 2018 to understand the prescribing pattern and safety concerns of BDQ containing multi-drug regimens.

Of the 23 cases with pre-XDR/XDR-TB receiving BDQ regimen in the present study, 15(65.21%) were male and 12(52.17%) belonged to the age group of 18-40 years. This indicates that the candidates eligible for the BDQ regimen are mostly young. The study of Udwadia, et al²⁶ reported 14(70%) out of 20 patients on the BDQ regimen were female and that all patients belong to the age group of 18-40 years with a mean age of 27.5years. The mean age in the present study was found to be higher, 41± 14.24 years.

Table 2: Adverse drug events documented

S.No	Adverse events documented
1	Pedal Edema, Abdominal tightness, burning skin on edema, Nose Bleed, right sided chest pain
2	Bilateral joint swelling and pain, Diarrhoea
3	Psychosis, Paranoma, irrelevant talk, tachpnea, bilateral tinnitus, pedal edema, facial puffiness, hoarseness of voice
4	Nausea, Vomiting
5	Gastritis, Drowsiness, SOB
6	Burning gastric pain
7	Diarrhoea
8	Streaky hemoptysis, Ototoxicity
9	Rashes all over the body, constipation, Vomitings
10	Tingling sensation in both the legs
11	Hemoptysis, GI Bleeding
12	Disproportionate loss of vision

It was observed that 6 patients had co-morbid conditions, where diabetes mellitus (5 out of 6) was the most common condition followed by hypertension (3), HIV, and Asthma (1 each). Udwadia, et al²⁶reported two co-morbid conditions (one HIV positive, one diabetes mellitus) whereas Mase S, et al²⁷ reported HIV co-infection in 1 and diabetes mellitus 5 of 14 patients on BDQ regimen. However, the presence of co-morbid conditions did not influence the treatment outcomes or adverse events.

The present study found 8 pre-XDR and 15(65.12%) XDR-TB cases eligible for the BDQ treatment regimen. Udwadia, et al²⁶ reported 60% (12 out of 20) patients having XDR-TB and 40% having MDR-TB with additional fluoroquinolone resistance. Extensive resistance and treatment failure were the indications for the BDQ in the present study whereas Mase S, et al²⁷ reported extensive resistance, intolerance to medications, poor clinical response to treatment, and treatment failure as indications for BDQ regimen.

The present study has witnessed the documentation of adverse events in 12 patients, the most common effect being related to the gastrointestinal tract. One case reported ototoxicity and another showed loss of vision. None of the adverse effects could be solely attributed to BDQ. One patient showed slight prolongation of QTc interval with no symptoms. QT prolongation is strongly associated with an increased risk of Torsades de Pointes that can cause sudden cardiac death, if severe. All the adverse effects were manageable, none were considered serious and there was no requirement of discontinuation of any drug due to adverse effects. Mase S, et al²⁷ did not report any serious AEs due to the use of bedaquiline but 50% of the patients had significant QTc interval prolongation, which was not attributed to BDQ alone. Similarly, no major AE was reported by Udwadia, et al¹⁷ but all patients showed mild prolongation of QTc interval with no symptoms. Salhotra VS, et al²⁸ reported ≥60-ms increase in QTc interval in 6.3% of patients receiving BDQ regimen. This indicates that BDQ is well tolerated together with other second-line drugs in the treatment regimen with continuous monitoring.

Three patients died during the study period. The deaths were not found to be related to the anti-TB drugs and none of them were having any co-morbid condition. Mase S, et al²⁷ reported culture conversion in all 14 patients who completed the treatment except one and reported one death. According to the study of Udwadia, et al²⁶ 14 out of 20 patients were culture-negative towards the end of 6 months of bedaquiline therapy while six remained positive. Gao JT, et al²⁹ reported 47.1% of patients experienced adverse effects with BDQ containing regimen and 1.2% experienced adverse effects leading to death but none of them were directly related to BDQ. Only two patients completed the treatment during the study period. The present study was conducted for a fixed duration as it was an academic project. Therefore complete follow-up for all patients could not be achieved.

CONCLUSION:

The use of bedaquiline in this tertiary care hospital follows the recommended treatment guidelines to a great extent. Bedaquiline containing regimen is well tolerated with less number of adverse effects.

ACKNOWLEDGEMENT:

The authors would like to express their gratitude to G. Pulla Reddy College of Pharmacy and Government General and Chest Hospital for their generous support. The authors would also like to thank everyone who helped with data extraction from the patient's medical record.

CONFLICTS OF INTEREST:

There are no conflicts of interest.

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Received on 13.10.2021 Modified on 05.12.2021

Asian J. Pharm. Res. 2022; 12(2):132-136.

DOI: 10.52711/2231-5691.2022.00020