Outcomes and Adverse Events of WHO Shorter Regimen in the Treatment of Multi‐Drug Resistant Tuberculosis in Bhutan: A Longitudinal Study

ABSTRACT

Background and Aims

Bhutan first introduced the Shorter Regimen, consisting of a combination of Amikacin, Clofazamine, Ethionamide, Ethambutol, high dose Isoniazid, Moxifloxacin and Pyrazinamide, for the treatment of rifampicin or multidrug resistant tuberculosis (RR/MDR‐TB) in 2018. This study describes the outcome, time to sputum conversion and adverse events of treatment among MDR‐TB patients treated with the Shorter Regimen in Bhutan.

Methods

This was a longitudinal study among patients with RR/MDR‐TB who were treated with the Shorten Regimen between 2018 and 2020. Throughout the treatment period, sputum smear, culture, and blood investigations were monitored.

Results

There were 52 patients who received the shorter regimen for MDR‐TB. Forty‐seven patients (90%) had pulmonary TB (PTB) and five (10%) had extra‐pulmonary TB (EPTB). Forty‐one patients (79%) had confirmed MDR‐TB and 11 (21%) had RR‐TB. MDR‐TB was detected in new cases in 35 patients (69%), while 11 (22%) were cases of TB relapse and five (10%) were cases of treatment failure. There were 40 patients (86%) who achieved sputum smear conversion by the end of 4 months while all patients became culture negative by the end of 3 months. All patients achieved culture conversion by the end of 3 months. The treatment success rate was 94% and there were no deaths. The common side effects were nausea, vomiting, arthralgia, dizziness, sleep disturbances, depressed mood and skin rash. QTc prolongations were observed in six patients, for which five patients needed dose modification of Moxifloxacin. Five patients had hepatitis, and two needed dose modification. Two patients were switched to the longer regimen due to amikacin‐induced profound hearing loss and nephrotoxicity.

Conclusions

The treatment success rate of MDR‐TB was high, with high sputum and culture conversion rates. Adequate monitoring of side effects is important in providing timely intervention.

1. Introduction

Tuberculosis remains a significant burden in many countries, with an increase in number of deaths noted during the COVID‐19 period, reversing years of decline noted between 2005 and 2019 [1]. In 2023, an estimated 10.8 million people fell ill with TB worldwide, with 45% of them reported in South East Asia [2]. In 2023, there were 1.09 million deaths among HIV‐negative people and 161 000 deaths among HIV‐positive people [2]. India, Indonesia, China, Philippines, and Pakistan account for more than half of the global incident cases of TB.

In 2023, there were an estimated 400 000 rifampicin or multi‐drug‐resistant (RR/MDR) cases of TB; of which only 44% had received treatment [2]. In the South Asia region, there has been a worsening trend in drug‐resistant TB with pooled estimates increasing from 37.7% in the decade 1995–2005 to 46.1% in the decade 2006– 2015 in India [3]. The present trend in the epidemiology of TB is a major challenge to achieving the milestones and targets of the End TB Strategy [4]. Unlike the treatment for drug‐sensitive TB, the treatment for MDR‐TB is complicated due to long duration, high pill burden, and many adverse effects due to the medicines and high costs involved [5, 6]. While there has been an increase in treatment success rate, almost 15% of MDR/RR‐TB patients die from the disease [6]. The World Health Organization (WHO) in its 2020 consolidated guideline recommended the adoption of the Shorter MDR‐TB Regimen that consists of all‐oral, bedaquiline‐containing regimen [6]. The Shorter Regimen is indicated for MDR/RR‐TB patients without extensive pulmonary disease, disseminated, meningeal or central nervous system TB; those without history of previous treatment with second‐line drugs; confirmed fluoroquinolone‐susceptible strains; and not pregnant [6].

Bhutan is a country situated in the eastern Himalayas with an approximate population of 0.7 million. Bhutan had notified 858 cases of all forms of TB in 2021 with an increase in the number of MDR‐TB from 11 cases in 2012 to 55 cases in 2021 [7]. In 2023, there were 864 cases of all forms of TB notified and 63 were cases of MDR‐TB [8]. The country has integrated the WHO End TB Strategy into its National Strategic Plan 2017–2023 by targeting a reduction of TB deaths by 90% [9] and reducing MDR/RR‐TB incidence by 5% every year in its updated strategy for 2024–2028 [8].

The Ministry of Health introduced the WHO‐recommended rapid diagnosis using Line Probe Assay (LPA) in 2014, which is available at the Royal Centers for Disease Control, Thimphu and GeneXpert in 2016, which is now available in 17 centres as of July 2025 [9]. Bhutan adopted the WHO recommendation on the Shorter MDR‐TB Regimen in 15 patients in 2018 with the help of the Global Fund and made it available to all MDR/RR‐TB patients through its 2020 national guidelines [10]. We conducted this study to describe the outcome, time to sputum conversion and adverse events among patients with MDR/RR‐TB in Bhutan who were treated with the Shorter Regimen in 2018–2020. The Shorter Regimen consisted of a combination of Amikacin, Clofazamine, Ethionamide, Ethambutol, high‐dose Isoniazid, Moxifloxacin, and Pyrazinamide.

2. Main Text

2.1. Study Design and Setting

This was a longitudinal study conducted at the two national centres for the treatment of RR/MDR‐TB in Bhutan.

In Bhutan, healthcare is provided free of cost at all levels through a three‐tiered system with primary healthcare centres at the community level, district and general hospitals at secondary level, and referral hospitals with specialist services at the tertiary level. The three referral centres are located in geographically strategic locations in the west, east, and the central regions.

TB control activities are implemented by the National TB Control Programme. Gidakom Hospital in Thimphu, Central and Eastern Regional Referral Hospitals in Gelephu and Mongar serve as centres for the initiation of treatment of RR/MDR‐TB. As of 2024, there are 46 microscopy centres, 14 GeneXpert centres (with 17 machines) and 32 TB reporting hospitals in the country. By July 2025, GeneXpert sites have been expanded to 17 sites. Under the national programme, patients with drug‐sensitive TB are given the Pink Card to record their treatment course. Those with drug‐resistant TB are given the MDR‐TB Treatment Booklet. The inpatient stay and nutrition are provided free of cost with no direct out‐of‐pocket costs except for travel. For all patients employed by the government and most private companies, there is support regarding medical leave, safeguarding their employment.

2.1.1. Protocol for the Treatment of MDR‐TB in Bhutan (2018–2020)

The WHO updated its guideline in May 2016 and issued a conditional recommendation that MDR/RR‐TB patients may be treated with the 9–12 months regimen [7]. The WHO defined the following criteria for eligibility for the shorter MDR‐TB regimen: pulmonary TB; no infection with strains known or strongly suspected of being resistant to one or more drugs in the shorter MDR‐TB treatment regimen except for isoniazid; no exposure for ≥ 1 months to second‐line medicines included in the shorter MDR‐TB regimen; no intolerance to medicines in the shorter MDR‐TB regimen or risk of toxicity; and no pregnancy TB [11].

Patients were excluded if aged < 12 years; with deranged liver function tests (AST and ALT > 3 times above upper limit of normal) and renal function tests (creatinine clearance < 40 mL/h); corrected QT on ECG > 500 ms; those who were non‐Bhutanese, and those who did not provide valid consent.

While on Shorter Regimen, if a patient developed a severe adverse drug reaction and was required to be treated with alternative regimens, the participant was withdrawn from the study.

This Shorter Regimen consists of seven drugs and required that the patients had not been exposed to the second line drugs for more than 1 month in the past and that there should be no known resistance to any of the drugs in the regimen [12]. The Shorter Regimen was not recommended for disseminated TB and for pregnant women.

The Shorter Regimen that was first introduced consisted of an injectable Amikacin in place of kanamycin and capreomycin [11]. The rest of the drugs in the intensive phase consisted of Clofazamine, Ethionamide, Ethambutol, high‐dose Isoniazid, Moxifloxacin and Pyrazinamide. The duration of the intensive phase was 4 months and extended to 6 months depending on the sputum smear for Acid Fast Bacilli by 4th month. In the continuation phase, Amikacin, high dose Isoniazid, and Ethionamide were stopped, and the rest continued to complete a total duration of 9–12 months. The dosages were weight‐based and were given according to the WHO guideline [11]. Pyridoxine was given to all patients to help prevent neurological adverse effects. Patients were followed up with clinical assessment, blood tests, audiometry and ECG according to the TB treatment guideline.

2.2. Study Site

The study was conducted in the TB Ward and Respiratory and Chest Diseases Clinic at the Jigme Dorji Wangchuck National Referral Hospital and the Gidakom Hospital. In 2019, the Shorter Regimen for the treatment of RR/MDR‐TB was available only at these two centres in Bhutan. All pulmonary TB cases were initially admitted at Gidakom Hospital till the first sputum culture became negative.

2.3. Study Population

All patients diagnosed as RR/MDR‐TB through GeneXpert, LPA or by conventional culture; and drug sensitivity testing and on shorter regimen were selected for this study.

2.4. Study Period

The follow up for the first patient inducted into the Shorter Regimen in June 2018 ended in May 2019. The follow‐up for the last patient inducted in December 2019 ended in December 2020.

2.5. Data Variables, Sources and Data Collection

The variables were extracted into a pro forma from the MDR‐TB White Booklet. Sociodemographic and clinical details, time to sputum conversion and outcomes were extracted from the MDR‐TB Booklet. Frequency of adverse events, laboratory and ECG details on follow‐up were collected through review of patient documents.

2.6. Data Analysis and Statistics

Data were entered into Microsoft Excel between June 2018 and January 2021 and analysed using STATA (version 18.0, StataCorp LP, USA). The socio‐demographic and basic clinical characteristics, outcome, frequency of adverse events and sputum/culture conversion rate are summarized using frequency and proportions. Treatment success was the sum of cured and treatment‐completed. Time to sputum/culture conversion was calculated by subtracting the month of diagnosis from the month of sputum conversion. For evaluation of adverse events, electrocardiogram performed to record QTc prolongation (> 500 ms) and tone audiometry were performed to record hearing level (Normal hearing = 0–25 dB, Mild hearing loss = 26–40 dB, Moderate hearing loss = 41–60 dB, Severe hearing loss = 61–80 dB, and Profound hearing loss ≥ 81 dB).

2.7. Ethics Considerations

This study was approved by the Research Ethics Board of Health, Ministry of Health, Bhutan (REBH/Approval/2018/106 dated February 25, 2019). Administrative approval was obtained from the Ministry of Health and hospital administrators. Written informed consent was taken from the patient to allow us to extract information from their MDR‐TB Treatment Booklet.

3. Results

There were 52 patients who received the Shorter Regimen for RR/MDR‐TB. There were 32 females (62%), the mean age was 28 (SD ± 10) years. At the start of the treatment, 16 (31%) were underweight. There were no patients coinfected with HIV or hepatitis B and C. Five patients had comorbid hypertension, diabetes, stroke and peripheral neuropathy.

Forty‐seven patients (90%) had PTB and five (10%) had EPTB of which, four had cervical lymphadenopathy and one had axillary lymphadenopathy. Forty‐one patients (79%) had confirmed MDR‐TB, and 11 (21%) had RR‐TB. The diagnosis of resistance was made using GeneXpert in 9 patients (17%) and using both LPA and GeneXpert in 43 patients (83%). Among those with PTB, the culture was positive in 44 patients and negative in three. MDR‐TB was detected in new cases in 35 patients (69%), while 11 (22%) were cases of TB relapse and five (10%) were cases of treatment failure. The details of sociodemographic and disease profile are shown in Table 1.

Table 1.

Basic characteristics of patients with multi‐drug resistant tuberculosis (RR/MDR‐TB) treated with World Health Organization Shorter Regimen in Bhutan, 2018–2020.

Characteristics	Total	Pulmonary tuberculosis		Extrapulmonary tuberculosis
		n	(%)	n	(%)
Patient profile
Hospital
Gidakom Hospital	45	44	(98)	1	(2)
Jigme Dorji Wangchuck National Referral Hospital	7	3	(43)	4	(57)
Age (years)
16 – 24	23	22	(96)	1	(4)
25 – 34	16	13	(81)	3	(19)
35 – 44	9	9	(100)	—	—
45 – 54	3	2	(67)	1	(33)
55 – 64	1	1	(100)	—	—
Sex
Male	20	17	(85)	3	(15)
Female	32	30	(94)	2	(6)
Body mass index (kg/m2) at the start of regimen
Underweight (< 18.5)	16	16	(100)	—	—
Normal (18.5 – 24.9)	34	30	(88)	4	(12)
Overweight (25 – 29.9)	2	1	(50)	1	(50)
Occupation
Student	19	18	(95)	1	(5)
Businessman	11	8	(73)	3	(27)
Government service	6	5	(83)	1	(17)
Housewife	6	6	(100)	—	—
Farmer	5	5	(100)	—	—
Private companies	3	3	(100)	—	—
Unemployed	2	2	(100)	—	—
Comorbidities
Diabetes	2	1	(50)	1	(50)
Hypertension	1	1	(100)	—	—
Stroke	1	1	(100)	—	—
Peripheral neuropathy	1	1	(100)	—	—
Description of tuberculosis
Contact of MDR‐TB	14	14	(100)	—	—
Type of resistance
Rifampicin resistance	11	6	(55)	5	(45)
Multi‐drug resistance	41	40	(100)	—	—
Confirmation of drug resistance
GeneXpert	9	4	(44)	5	(56)
Both	43	43	(100)	—	—
Treatment category
New case	35	34	(97)	1	(3)
Relapse case	12	10	(83)	2	(17)
Failure after past treatment	5	3	(60)	2	(40)
Clinical outcome
Cured	39	39	(100)	—	—
Completed	10	5	(50)	5	(50)
Changed to longer regime	2	2	(100)	—	—
Not known	1	1	(100)	—	—
Failed	0	—	—	—	—
Defaulted	0	—	—	—	—

3.1. Outcomes of Treatment

There were 40 patients (86%) who achieved sputum smear conversion by the end of 4 months of therapy while all patients became culture negative by the end of 3 months. In only two patients, the intensive phase needed to be extended to 6 months. The treatment success rate was 94% (49/52), and there was no death. The clinical profile and outcomes of treatment of MDR‐TB is shown in Table 1. The rates of conversion of sputum smear and culture among those with MDR pulmonary TB is shown in Figure 1.

Figure 1.

Sputum smear and sputum culture conversion rates among multi‐drug resistant pulmonary tuberculosis (n = 47) treated with the World Health Organization Shorter Regimen in Bhutan, 2018–2020.

3.2. Adverse Effects of Treatment

The common side effects reported during the period of therapy were nausea (50, 96%), arthralgia (41, 79%), sleep disturbances (39, 75%), vomiting (34, 65%), dizziness (34, 65%), tinnitus (28, 54%), depressed mood (26, 50%) and headache (25, 50%). Seizures, vertigo and psychosis were less frequent side effects. QTc prolongation were observed in six patients for which five patients needed dose modification of moxifloxacin. Five patients had hepatitis and two needed dose modification. Two patients were changed to the longer regimen due to amikacin‐induced profound hearing loss and nephrotoxicity that progressed despite the modification of its dose and frequency. The details of the adverse events reported with the drug regimen are shown in Table 2.

Table 2.

Frequency of adverse drug reactions among patients with multi‐drug resistant tuberculosis (RR/MDR‐TB) treated with the World Health Organization Shorter regimen in Bhutan, 2018–2020.

Description of tuberculosis	Total	Pulmonary tuberculosis		Extrapulmonary tuberculosis
		n	(%)	n	(%)
Patient‐reported outcomes
Nausea	50	45	(90)	4	(10)
Arthralgia	41	37	(90)	4	(10)
Sleep disturbances	39	34	(87)	5	(13)
Vomiting	34	30	(88)	4	(12)
Dizziness	34	29	(85)	5	(15)
Tinnitus	28	26	(93)	2	(7)
Depression	26	22	(85)	4	(15)
Headache	25	22	(88)	3	(12)
Skin rash	14	13	(93)	1	(7)
Diarrhoea	11	9	(82)	2	(18)
Peripheral neuropathy	10	8	(80)	2	(20)
Hearing disturbances	9	8	(89)	1	(11)
Abdominal pain	4	4	(100)	—	—
Vertigo	1	1	(100)	—	—
Seizures	1	1	(100)	—	—
Psychosis	1	1	(100)	—	—
Visual disturbances	0	—	—	—	—
Investigation findings
Hyperuricaemia (> 7 mg/dL)	35	32	(91)	3	(9)
Sensorineural hearing loss	12	11	(92)	1	(8)
Mild (26 – 40 dB)	6	6	(100)	—	—
Moderate (41 – 60 dB)	3	2	(67)	1	(33)
Severe (61 – 80 dB)	1	1	(100)	—	—
Profound (≥ 81 dB)	2	2	(100)	—	—
Significantly prolonged QTc (> 500 ms)	6	6	(100)	—	—
Hepatitisa	5	4	(80)	1	(20)
Acute kidney injury	1	1	(100)	—	—

^a Hepatitis defined as ALT ≥ 5× upper limit of normal (ULN), or ALT ≥ 3× ULN with clinical manifestations, or ALT ≥ 3× ULN with concomitant increase in bilirubin ≥ 1.5× ULN [10].

4. Discussion

This study describes the clinical experience of WHO Shorter Regimen in Bhutan at the time of its adoption in 2018. Based on the sample cohort of patients from 2018 to 2020, the treatment success rate in the treatment of RR/MDR‐TB with WHO Shorter Regimen was high at 94% compared to relapse‐free cure rate of 88% in Georgia [13], 75% in South Korea [14], 64.5% in Indonesia [15] and 65.3% in India [16] using the WHO recommended regimen. In Bhutan, treatment for all patients is provided through government hospitals and patients are followed up actively by healthcare workers and the National TB Control Programme with coverage of all 20 districts. While outcome data on MDR TB is not available, in a study of 1816 patients with drug‐susceptible

TB in Sarpang district from 2005 to 2021, successful outcome defined as treatment completed or cured was 93.4% [17]. Successful treatment outcome among 634 patients with drug susceptible TB in Samtse district from 2008 to 2019 was 89.5% [18].

Our study reports a favourable sputum conversion rate with 86% becoming sputum‐negative by 4 months and culture‐negative by 3 months. This is similar to the findings of STREAM study where favourable cultures were attained in around 80% at the end of 132 weeks of treatment [19] and 88% by 4 months and 94% by 6 months among patients in Georgia [13]. In Bhutan, as of 2025, culture for Mycobacterium tuberculosis is available only at the Royal Centers for Disease Control, the national TB reference laboratory located in Thimphu. For patients with RR/MDR‐TB being treated at the centres in Mongar and Gelephu, the test‐positive specimens are transported to Thimphu and the reports of the culture and drug susceptibility testing are provided through the online Tuberculosis Information System. With concerted efforts towards improving access to services, there are plans to establish culture and drug susceptibility testing at the regional referral hospitals. All the labs performing tuberculosis smear and GeneXpert undergo standard external quality assurance procedures.

This rise in the overall number of MDR‐TB cases, particularly new cases, is a major cause of concern [8, 20]. The profile of patients with RR/MDR‐TB treated in this cohort reflect younger group aged between 16 and 34 years, among students and the majority were new cases detected. Many students reside in school hostels which are often crowded. Given this close contact, it calls for active interventions in improving ventilation of the hostel rooms, decongestion of the hostels and importantly, early detection and treatment of those with TB. A survey among teacher trainees in Bhutan showed major gaps in the knowledge of TB with teachers, family, and friends being the common sources of information [21]. Among those with pulmonary TB, there were high proportions of females similar to previously observed trends in Bhutan [20, 22] and represents a priority group for health education interventions. Given the rising number of MDR‐TB cases, it is recommended to conduct a detailed evaluation of epidemiological drivers in Bhutan and implement targeted interventions.

Among the study participants, there were 12 cases of relapse and 5 cases of failure of past treatment. Patients who had received TB treatment in the past have been noted to have up to six times higher odds of getting MDR‐TB in Bhutan [22]. While the treatment of DS‐TB is decentralized across all 20 districts, it is timely to review the quality indicators including adherence to treatment protocols and adequate follow‐up. A review of DS‐TB treatment outcomes reported treatment failure of 5.4% (and default in 0.2%) in Samtse [18], 2.6% in Sarpang [17] and up to 7% in Samdrup Jongkhar district [23]. In addition given the practical difficulties in sample transportation and follow‐up of results with the national reference laboratory, there is a need to perform a diagnostic network optimization exercise to improve accessibility and follow up on drug susceptibility testing. In addition to providing training to medical officers in the treatment and follow‐up of drug‐susceptible TB, the clinical teams at the MDR‐TB treatment centres must be provided with continuing education on the updates of the treatment guidelines [8].

For successful completion of antitubercular therapy, treatment‐related adverse events remain one of the major challenges. In the comparison of 6‐month MDR Shorter Regimen, treatment‐related severe adverse events and death rates were similar to that of control [19]. In clinical experience from Georgia, the incidence rate of severe adverse events related to the Shorter Regimen was 1.3 per 100 person‐months [13]. In the cohort in Bhutan, nausea and vomiting were frequent side effects reported among the patients, and there were no deaths. Two patients were changed to the longer regimen due to amikacin‐induced profound hearing loss and nephrotoxicity.

The data from this study have given good clinical experience on the use of Shorter Regimen. The Ministry of Health incorporated it to its revision of the national TB management guideline in 2020 and led to its subsequent roll out in the regional referral hospitals located in Mongar and Sarpang districts. There was good uptake from the patients with all‐oral regimen being the major enabler compared to other regimen with injectable.

5. Conclusion

The use of WHO Shorter Regimen for the treatment of RR/MDR‐TB in Bhutan had high success rates, sum of cured and treatment completed. The majority of the patients became smear negative by the end of 4 months, and all were culture negative by the end of 3 months. Common patient‐reported adverse events were nausea, arthralgia, sleep disturbances, vomiting and dizziness. Given the shorter duration of this therapy, this regimen may be recommended for eligible patients with guideline‐based monitoring for adverse events.

Author Contributions

Gaki Nima: conceptualization, investigation, methodology, writing – original draft, visualization, writing – review and editing, software, data curation, resources, formal analysis, validation, and project administration. Thinley Dorji: conceptualization, investigation, methodology, validation, visualization, writing – review and editing, software, data curation, resources, formal analysis, writing – original draft, project administration, and supervision. Chencho Dorji: conceptualization, investigation, writing – original draft, methodology, software, data curation, resources, writing – review and editing. Tandin Zangpo: conceptualization, investigation, writing – original draft, methodology, validation, writing – review and editing, and resources.

Ethics Statement

This study was approved by the Research Ethics Board of Health, Ministry of Health, Bhutan (REBH/Approval/2018/106 dated February 25, 2019). Administrative approval was obtained from the Ministry of Health and hospital administrators.

Consent

Written informed consent was taken from the patient to allow us to extract information from their MDR‐TB Treatment Booklet.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The corresponding author, Thinley Dorji, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Nima G., Dorji T., Dorji C., and Zangpo T., “Outcomes and Adverse Events of WHO Shorter Regimen in the Treatment of Multi‐Drug Resistant Tuberculosis in Bhutan: A Longitudinal Study,” Health Science Reports 8 (2025): 1‐8, 10.1002/hsr2.71241.

Data Availability Statement

The data set from this study is available from the corresponding author after reasonable request and after approval from the Ministry of Health, Royal Government of Bhutan. Data set is available from the corresponding author upon reasonable request.