STRENGTHS AND LIMITATIONS OF THIS STUDY

The retrospective case–control design allows the examination of multiple exposures related to a single outcome, providing valuable insights into the determinants of treatment outcomes in drug-resistant tuberculosis patients.

The study used data from the National Tuberculosis Registry database, a reliable and validated tool for tuberculosis surveillance in Malaysia.

The methodology is easily replicable, allowing for further research across different demographics and periods to validate and enhance findings.

Despite the comprehensive database, the study encountered limitations in data completeness due to potential entry errors, unavailability of certain variables and suboptimal reporting in the earlier years.

As a case–control study, the research is limited in establishing temporal relationships between exposures and outcomes, focusing instead on the strength of associations.

Introduction

Tuberculosis (TB) is an endemic airborne infectious disease in Malaysia caused by Mycobacterium tuberculosis. The End TB strategy aims to reduce TB incidence by 90% and TB-related deaths by 95% in 2035, compared with 2015 levels.1 Despite these ambitious goals, progress remains slow, as highlighted in the Global Tuberculosis Report 2024. Between 2015 and 2023, the global net reduction in the TB incidence rate was 8.3%, significantly below the WHO End TB strategy milestone of a 50% reduction by 2025, while the net reduction in the global number of deaths caused by TB during the same period was 23%, almost one-third of the way to a 75% reduction by 2025.2 In 2023, an estimated 10.8 million worldwide contracted TB, with Southeast Asia, including Malaysia, accounting for 45% of the total cases.2

Despite being preventable and treatable, the emergence of drug-resistant tuberculosis (DR-TB) complicates disease control efforts. Mutations in M. tuberculosis led to the development of resistance, causing specific treatments or medications to lose their effectiveness against the pathogen.3 The WHO’s 2021 classification of DR-TB includes isoniazid-resistant tuberculosis (HR-TB), rifampicin-resistant tuberculosis (RR-TB), multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), along with the addition of pre-extensively drug-resistant tuberculosis (pre-XDR TB).4 5 This updated classification no longer includes mono-resistant and poly-resistant TB as distinct categories, unlike the previous classification where these categories overlapped.6 7

DR-TB poses significant challenges for treatment due to prolonged therapy, high costs and drug toxicity, often leading to unfavourable outcomes that strain healthcare systems and negatively impact patients and their families.7 Globally, an estimated 400 000 cases were reported in 2023, contributing substantially to TB-related morbidity and mortality.2 However, there has been progress in treatment outcomes, with 68% of patients started on treatment in 2021 achieving favourable outcomes, up from 64% in 2020, 60% in 2019 and a steady improvement from 50% in 2012.2 Key determinants of treatment outcomes include sociodemographic factors (age, sex, education level and employment), comorbidities such as diabetes mellitus (DM) and HIV infection, and TB disease characteristics (sputum and radiological findings, site of infection and history of prior treatment).8

The average cost of TB treatment, considering both provider and patient perspectives, is MYR 2218.14 (US$727.24) per patient.9 By contrast, the economic impact of DR-TB is substantial, with estimated treatment costs of MYR 15 000 (US$4918.03) for a MDR-TB patient, compared with MYR 250 (US$ 81.97) for treating a susceptible TB patient.7 Despite these challenges, Malaysia’s DR-TB treatment success rate stands at 55%, falling short of the WHO target of 90%.2 10 11

The study focuses on Selangor and Wilayah Persekutuan Kuala Lumpur (WPKL), two states in Malaysia with a high burden of DR-TB cases.12 Moreover, Selangor has the largest population, while WPKL has the highest population density.13 Understanding the determinants of DR-TB outcomes in these high-burden areas is essential to address gaps in treatment success and guide more effective and targeted public health interventions.

Given the significant economic burden of DR-TB treatment and Malaysia’s low treatment success rate, it is imperative to identify and understand the determinants of unfavourable treatment outcomes. By examining sociodemographic and clinical factors associated with DR-TB cases in Malaysia from 2016 to 2020, this study aims to provide valuable insights that will inform strategies to improve treatment success and strengthen DR-TB control efforts nationwide.

MethodsStudy setting and subject recruitment

A case–control study was conducted using secondary data from the National Tuberculosis Registry (NTBR), Ministry of Health, Malaysia. The study included DR-TB cases registered in Selangor and WPKL between 2016 and 2020. Data collection and analysis were performed from December 2022 to May 2023. Cases were defined as DR-TB patients who experienced unfavourable treatment outcomes, which included treatment failure, death or loss to follow-up. In contrast, controls were defined as DR-TB patients who achieved favourable treatment outcomes, which comprised cure or treatment completion.

From a total of 444 DR-TB cases recorded during the study period, 19 were excluded due to missing or incomplete data, ongoing treatment, or a change in diagnosis, resulting in 425 eligible cases for analysis. Among these, 181 DR-TB cases with unfavourable outcomes were included in the case group. To ensure a representative sample of the control group, 222 DR-TB cases with favourable outcomes were selected through simple random sampling.

Study population and sample size determination

The sample size for the case–control study was determined using the power and sample size software based on two independent proportions, with the study power set at 80% and type I error at 5%. A 1:1 ratio of cases to controls was used. To account for potential data errors, an additional 10% was added to the estimated sample size, resulting in a final requirement of 222 cases per group. Due to the relatively small number of registered DR-TB cases with unfavourable treatment outcomes (181 cases), no sampling technique was applied to the case group. The study included all these cases to ensure comprehensive representation and avoid loss of valuable data. Instead, cases with favourable outcomes for the control group were selected through simple random sampling. The flow chart for the case–control study is shown in figure 1.

Figure 1

The flowchart illustrates the methodology for this study involving drug-resistant tuberculosis (DR-TB) cases registered in the National Tuberculosis Registry (NTBR) of Selangor and Wilayah Persekutuan Kuala Lumpur.

Operational definitions

The operational definitions for types of DR-TB used in this study are based on the WHO Consolidated Guidelines on Tuberculosis, Module 4: Drug-Resistant Tuberculosis Treatment (2022 update)14 and the Meeting Report of the WHO Expert Consultation on the Definition of Extensively Drug-Resistant Tuberculosis, 2021.15 DR-TB classification is determined by drug sensitivity testing of M. tuberculosis isolates and includes several categories. HR-TB is defined as resistance solely to isoniazid while maintaining susceptibility to rifampicin. MDR-TB is characterised by resistance to at least both isoniazid and rifampicin. Pre-XDR-TB involves resistance meeting the MDR/RR-TB criteria plus resistance to any fluoroquinolone. XDR-TB includes resistance meeting the MDR/RR-TB criteria, resistance to any fluoroquinolone and resistance to at least one additional Group A drug (eg, levofloxacin or moxifloxacin, bedaquiline and linezolid). Meanwhile, RR-TB denotes resistance to rifampicin, detected either phenotypically or genotypically, with or without resistance to other anti-TB drugs.

Meanwhile, the treatment outcomes categories are based on the Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis, 2014.16 Treatment outcomes for TB cases are categorised into seven types. ‘Cured’ refers to treatment completed as recommended, with subsequent negative cultures taken at least 30 days apart after the intensive phase. ‘Treatment Completed’ indicates the treatment was completed as recommended but without recorded negative cultures afterwards. ‘Treatment Failure’ occurs when treatment is terminated or requires a permanent change in the drug regimen due to failure to convert, bacteriological reversion, acquired resistance to specific drugs or adverse drug reactions. ‘Died’ refers to a TB patient who passes away for any reason during the TB treatment. ‘Lost to Follow-Up’ characterises a TB patient whose treatment is interrupted for two consecutive months or more. ‘Not Evaluated’ includes cases without a designated treatment outcome or those transferred out with unknown outcomes. Favourable treatment outcomes, which are grouped as successful, include cases categorised as ‘Cured’ and ‘Treatment Completed’, while unfavourable outcomes encompass cases designated as ‘Treatment Failure’, ‘Death’ and ‘Lost to Follow-Up’.

Data collection

Data were collected from two primary sources: the NTBR and the line listing of DR-TB cases. NTBR is Malaysia’s central electronic TB information system, which provides comprehensive data on TB cases and contacts, including sociodemographic, clinical, laboratory, treatment and follow-up details.17 The line listing of DR-TB cases, derived from the TB Information System (TBIS) 10G and Drug-resistant TB Information System (DRTBIS) 50A-1, provides additional information for comparison with the NTBR database. TBIS 10G contains information on TB cases that have failed first-line treatment and their contributing factors, while DRTBIS 50A-1 is used for the registration of all DR-TB cases, regardless of whether treatment has been initiated.

NTBR and the line listing share similarities, such as providing sociodemographic and clinical information, as well as treatment outcomes. However, the key difference lies in the scope: MyTB covers a broader range of TB cases, including both drug-sensitive and drug-resistant cases, whereas the line listing focuses specifically on DR-TB cases. These two sources were used complementarily to ensure comprehensive data collection and to avoid missing information.

A structured pro forma checklist was used to guide data extraction, ensuring the completeness and consistency of the data collected. Additionally, population density data for Selangor and WPKL were obtained from the Department of Statistics Malaysia website.13

Statistical analysis

Data entry, cleaning and analysis were conducted using IBM SPSS V. 27. Descriptive statistics were employed to summarise sociodemographic and clinical characteristics. Categorical variables were presented as frequency (n) and percentage (%). For continuous variables, the measures of central tendency and dispersion were selected based on the data distribution: mean and SD were used for normally distributed data, while median and IQR were reported for non-normally distributed data. Logistic regression analyses were performed to identify risk factors for unfavourable treatment outcomes in DR-TB patients. Each variable was analysed individually. The outcome variable was binary, with 0 representing favourable outcomes and 1 representing unfavourable outcomes. Independent variables included sociodemographic and clinical factors. A preliminary model for multiple logistic regression included variables with a p≤0.25 or those of clinical relevance identified in univariable analysis. Best-fit models were selected using forward and backward likelihood ratio methods. Multicollinearity was assessed through variance inflation factor and tolerance. Interactions between variables were also examined. Model fit was evaluated using the Hosmer-Lemeshow test, classification table accuracy (>80%) and area under the receiver operating characteristics (ROC) curve (≥0.70). The final model presented aOR with 95% CI, Wald statistics and p<0.05.

Variable definitions and measurements

The variables captured in this study were obtained from the NTBR and line listings, with information provided by notifiers or medical practitioners. Chest X-ray results were classified into four categories: no lesion, minimal, moderate and far advanced, based on radiological findings during diagnosis. Comorbidities data were extracted from medical records or history taking, with diabetes defined as a history of physician-diagnosed diabetes or ongoing diabetic treatment. Adherence to directly observed treatment (DOT) was categorised as supervised by healthcare workers, family members, no supervision or others such as non-governmental organisations. Tobacco use was documented in the NTBR or line listings based on the patient’s self-reported smoking history during history taking or existing clinical documentation by medical practitioners.

Patient and public involvement

Patients and/or the public were not involved in the design or conduct or reporting or dissemination plans of this research.

Results

Out of 444 registered DR-TB cases, 425 met the study criteria. Among these, 244 cases (58.0%) had favourable treatment outcomes, while 181 cases (42.0%) had unfavourable outcomes. All cases with unfavourable outcomes were included as the case group, while 222 cases with favourable outcomes were selected through simple random sampling to form the control group. Thus, a total of 403 cases were analysed. Unfavourable outcomes were primarily attributed to loss to follow-up (90 cases, 49.7%) and death (77 cases, 42.6%), as depicted in figure 2.

Figure 2

The pie chart depicts the categories of unfavourable treatment outcomes among drug-resistant tuberculosis cases in Selangor and Wilayah Persekutuan Kuala Lumpur from 2016 to 2020.

Sociodemographic and clinical characteristics of DR-TB cases

The median age of the patients was 39 years (IQR=24 years). Male patients constituted the majority (71.2%, p<0.001), and most were Malaysian citizens (79.7%). The Malay ethnic group made up the largest portion (49.6%), with no significant association observed between ethnicity and treatment outcomes (p=0.551). A significant proportion of patients had education up to the secondary school level (51.6%), with a significant association between education level and treatment outcomes (p=0.047). Marital status (56.6% married, p=0.002) and employment status (52.6% employed, p=0.024) were also significantly associated with treatment outcomes. Specifically, unmarried (51.4%) and unemployed (53.6%) patients had higher proportions of unfavourable outcomes.

Clinically, diabetes was slightly prevalent in the unfavourable outcome group (24.9%) compared with the favourable outcome group (22.5%), but the association between diabetes and treatment outcomes was not significant (p=0.582). DR-TB cases among people living with HIV were more likely to experience unfavourable outcomes, with 18.2% of the unfavourable group compared with 5.9% of the favourable group (p<0.001). Smokers were also more prevalent among those with unfavourable outcomes (42.5%) than those with favourable outcomes (30.2%) (p=0.010). The favourable outcome group had a higher proportion of new cases compared with retreatment cases, whereas the unfavourable outcome group had more retreatment cases (56.4%) (p=0.024). Smear positivity was common in both groups, with a slight tendency towards more negative smear results in the favourable outcome group, though this difference was not significant (p=0.731). Regardless of the outcome, most patients had minimal lesions on chest X-rays; however, those with unfavourable outcomes exhibited more moderate to advanced lesions compared with the favourable outcome group (p=0.017). HR-TB cases were predominant in the favourable outcome group, while MDR/pre-XDR/XDR-TB cases were more common in the unfavourable outcome group (p<0.001). DOT supervision was mainly provided by healthcare workers. Both the sociodemographic and clinical characteristics are detailed in table 1.

Table 1

Characteristics of DR-TB cases in Selangor and WPKL from 2016 to 2020 (n=403)

Factors associated with unfavourable treatment outcomes of DR-TB cases

Simple and multiple logistic regression analyses were conducted to determine factors associated with unfavourable treatment outcomes among DR-TB cases (table 2). The univariable analysis identified 13 variables for inclusion in the multivariable analysis: age, gender, ethnicity, level of education, marital status, employment status, HIV status, smoking status, treatment category, chest X-ray status, DM, DOT supervision and DR-TB category.

Table 2

Multiple logistic regression for factors associated with unfavourable treatment outcomes among DR-TB cases in Selangor and WPKL from 2016 to 2020 (n=403)

In multivariable analysis, all selected variables were entered using a stepwise likelihood ratio approach. This was followed by refinement using the enter method, where variables with p values greater than 0.05 were manually excluded. Confounding variables, including age, sex, HIV status and DR-TB category, were controlled to ensure robust findings. The analysis revealed that being male, being single or divorced, having no formal education, people living with HIV and having DR-TB categories such as RR-TB and MDR/pre-XDR/XDR-TB were significantly associated with unfavourable treatment outcomes when adjusting for other variables. The final model demonstrated an adequate fit (Hosmer-Lemeshow test, p=0.859) and acceptable discriminative power, with an area under the ROC curve of 0.728 (95% CI 0.679 to 0.777), as shown in online supplemental figure S1.

Discussion

The most vulnerable and underprivileged people in society are frequently affected by DR-TB, with sociodemographic factors playing a significant role in treatment outcomes.18 These factors, alongside clinical considerations, should be thoroughly addressed to improve patient care and achieve better treatment outcomes.

In this study, sex, marital status, level of education, HIV status and DR-TB category were significant risk factors associated with unfavourable treatment outcomes among DR-TB patients in Selangor and WPKL. Male patients had a 2.38 times higher risk of unfavourable treatment outcomes compared with females. Males typically have a higher prevalence of specific comorbidities that can impact treatment outcomes in DR-TB. Higher rates of smoking, illicit drug abuse and alcohol consumption among males, along with being immunocompromised due to certain diseases like HIV and DM, as well as other comorbidities such as chronic obstructive pulmonary disease, contribute to prolonged treatment duration and unfavourable sequelae. Previous local studies8 19 20 and a study in Pakistan21 and South Africa22 support this conclusion. Studies have shown that alcohol consumption significantly increases the likelihood of unfavourable treatment outcomes, nearly doubling the odds of death, treatment failure and loss to follow-up in MDR-TB patients.23 Treatment adherence also poses a significant challenge for them due to work responsibilities, fear of stigmatisation and poor social support.24 25 Men and women often have different societal roles and occupations, with men commonly working as daily labourers, which not only increases their risk of contracting TB but also limits their access to medical care.26 Loss of employment or time away from work to attend clinic appointments results in a significant income reduction, placing their family under a catastrophic financial burden. This may lead to voluntary withdrawal from therapy to prioritise their work and ensure their household needs.27 Societal expectations of masculinity and financial pressure further hinder their treatment adherence, leading to treatment failure, relapse, drug resistance and mortality.7

Furthermore, being single or divorced increases the odds of unfavourable treatment outcomes by 1.61 times compared with married patients. Marriage provides crucial emotional, financial and practical support, enhancing treatment adherence. Tola et al found that being unmarried is associated with psychological distress among TB patients (aOR 4.29, 95% CI 2.45 to 7.53).28 Married patients often benefit from spousal accompaniment to clinic appointments and their spouse’s role as a DOT supervisor. Moreover, married individuals often adopt healthier lifestyles, discouraging high-risk behaviours such as smoking and substance abuse. Conversely, being single or divorced is usually associated with a lack of immediate social support, leading to stress, loneliness and depression, which negatively affect treatment adherence and outcomes.29 30 Another contributing factor is that unmarried individuals may have fewer economic resources and limited access to healthcare services compared with married counterparts. Married patients often share financial burdens, making it easier to afford transportation, medication or other treatment-related expenses. In contrast, single or divorced individuals might experience financial constraints, leading to delays in seeking treatment or incomplete treatment.31 This economic vulnerability further exacerbates the risk of unfavourable treatment outcomes.32

DR-TB patients with no formal education have 3.09 times the odds of unfavourable outcomes compared with those with a tertiary education level. Higher education correlates with better knowledge, leading to early treatment initiation and good adherence to therapy.24 It improves understanding of drug management, reduces resistance risk and enhances communication with healthcare providers for better access to quality care. Improved health literacy empowers patients to take charge of their health, ultimately leading to better outcomes.33 Despite Malaysia’s high literacy rate (95.1% in 2017), the low postsecondary education enrolment (16–17%) raises concerns about educational access, particularly as most of the patients in this study had attained education only up to the secondary level.34 Low educational attainment is also often associated with lower socioeconomic status, limiting access to stable, well-paying jobs. This economic disadvantage makes it difficult for patients to afford treatment-related expenses and time away from work, ultimately leading to treatment default and unfavourable outcomes.35 Targeted health education campaigns and socioeconomic interventions are essential for fostering awareness, motivation for treatment adherence, and ensuring that financial constraints do not hinder access to care.36 37

Our study highlights that DR-TB cases among people living with HIV are nearly three times more likely to experience unfavourable treatment outcomes compared with people living without HIV. The incidence of HIV–TB coinfection in Malaysia was 1700 (5.2 per 100 000 population), indicating a substantial burden.38 Most people living with HIV, especially those with low CD4+ counts, often require frequent hospital admissions, which increases their risk of medication resistance and treatment complications.39 HIV infection can also lead to malabsorption of anti-TB medications, further complicating the management of coinfections.40 Malnutrition, commonly observed in HIV–TB patients, has been identified as a significant risk factor for high mortality in DR-TB cases.41 Alarmingly, people living with HIV who were infected with DR-TB experience exceptionally high 1 year mortality rates, reported at 71% for MDR-TB and 83% for XDR-TB cases.42 Managing HIV–TB coinfection effectively necessitates simultaneous antiretroviral and antimycobacterial treatment, often involving multiple drugs, which poses challenges in adherence and increases the risk of drug adverse effects.40 The stigma surrounding both diseases further complicates treatment adherence issues.27 43 Therefore, integrated healthcare strategies are essential to address the dual burden of HIV and TB in Malaysia, ensuring both conditions are managed concurrently to improve treatment outcomes and reduce mortality.44

Finally, this study demonstrates a significant association between unfavourable treatment outcomes and different DR-TB categories. Compared with monoresistant HR-TB patients, those with RR-TB and MDR/pre-XDR/XDR-TB have 3.34 and 2.57 times the odds of experiencing unfavourable treatment outcomes, respectively. The complexity of the treatment regime, longer durations and higher toxicity risk contribute to a lower success rate.27 Additionally, XDR-TB patients were reported to have a 50% greater risk of mortality than MDR-TB patients due to limited treatment options.45 In contrast to another study,46 which identified XDR-TB as the strongest predictor of unsuccessful treatment, with XDR-TB patients being almost eight times more likely to experience unfavourable outcomes compared with those with MDR-TB alone, this study found higher odds in RR-TB patients. This is likely due to the widespread use of rifampicin in TB treatment, including its role as part of the regimen for latent TB. The increased use of rifampicin has led to rising resistance, further complicating treatment and leading to unfavourable outcomes for RR-TB patients.47

Limitations and strengths

Despite these encouraging findings, this study had certain limitations, including potential data entry errors, incomplete variables and the inability to achieve the calculated sample size due to the limited number of DR-TB cases in the early years. Additionally, the case–control design used in this study poses limitations in establishing temporal relationships, as the exposure was assessed postdiagnosis. Furthermore, the study lacked data on important variables such as residency, household income, comorbidities, treatment duration and high-risk behaviours, potentially introducing selection bias and an incomplete understanding of the study’s outcomes. Future research should address these limitations to provide a more comprehensive analysis of DR-TB treatment outcomes.

The study has several key strengths. The study’s focus on Selangor and WPKL, two states in Malaysia with a high DR-TB burden, makes the findings particularly relevant and offers valuable insights applicable to other regions. The study’s design enabled the identification of critical sociodemographic and clinical determinants associated with unfavourable treatment outcomes. Using multiple logistic regression, the analysis effectively controlled for confounding variables and identified independent factors associated with DR-TB treatment outcomes through a stepwise selection and refinement process. This study significantly contributes to the expanding literature on DR-TB in Malaysia and globally, offering a model that can be replicated in other contexts.

Conclusion

This study identifies key factors associated with unfavourable treatment outcomes in DR-TB cases in Malaysia, including sex, education level, marital status, HIV status and DR-TB categories. These findings highlight the importance of addressing both sociodemographic and clinical determinants to improve treatment outcomes. The insights gained from this study can assist policymakers in understanding the challenges faced by patients with DR-TB and guide future strategies for TB control and prevention efforts.

Data availability statement

Data may be obtained from a third party and are not publicly available. The data used for this study were obtained from the National Tuberculosis Registry (NTBR) in Malaysia. Access to this data is restricted and requires approval from the Ministry of Health, Malaysia.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

This study received human ethics approval from the Medical Research and Ethics Committee of the Malaysian Ministry of Health (NMRR ID-23-00038-72L) and the Human Research Ethics Committee of Universiti Sains Malaysia (USM/JEPeM/22110712). Informed consent was waived as the study involved secondary data, and no direct interaction with subjects or vulnerability occurred.

Acknowledgments

The authors would like to thank all the respective personnel from the State Health Department of Selangor, Kuala Lumpur and Putrajaya, and the Institute of Respiratory Medicine, Kuala Lumpur, for their assistance during data collection.