Safety Monitoring of Drug-Resistant Tuberculosis Medicines in Indonesia Using Pharmacovigilance Framework

According to the World Health Organization (WHO), tuberculosis (TB) remains a global health issue to this day. The estimated incidence of TB in Indonesia in 2023 was approximately 387 cases per 100.000 population, according to the WHO. This highlights Indonesia as one of the countries with a high TB burden globally. More than 10 million people contract TB each year. Without treatment, the mortality rate from TB is high (around 50%). Based on the 2024 Global TB Report, Indonesia ranks second in the world in (absolute?) terms of TB burden, following India, and is followed by China.(1,2)

The development of resistance due -among other things- to the misuse of anti-tuberculosis medicines has resulted in new forms of TB including multi-drug resistant tuberculosis (MDRTB). MDR-TB is a particularly dangerous form of tuberculosis, characterized by its resistance to both isoniazid and rifampicin, the two main and most effective anti-tuberculosis medicines. Indonesia is estimated to have 30,000 cases of MDR-TB. Moreover, when medicines are misused or mismanaged, which is usually a sign of inadequate clinical care, patients may develop extensively drug-resistant tuberculosis (XDR-TB). XDR-TB is a form of TB that is caused by a strain of M. tuberculosis complex that is resistant to rifampicin (and may also be resistant to isoniazid), and that is also resistant to at least one fluoroquinolone (levofloxacin or moxifloxacin) and to at least one other Group A drug (bedaquiline or linezolid).(1) An additional factor, of uncertain relative importance for both patient outcome and drug resistance, that has received scant attention and which may require more investigation, is the quality of TB medicines that patients take. (1,2,3) Based on WHO Global Tuberculosis Report 2024, Indonesia has 30,000 cases of MDR-TB in 2023.(1)

Monitoring medicines safety is crucial for ensuring their proper and effective use. Safe and appropriately-used medicines play a vital role in delivering high-quality healthcare, especially for conditions requiring complex treatments, such as MDR-TB and XDR-TB. Second-line anti- TB medicines generally have higher toxicity than first-line medicines, highlighting the importance of pharmacovigilance in managing MDR and XDR TB.(4,5,6) Although some National Tuberculosis Programs (NTPs) report adverse drug reactions in patients undergoing treatment, in many programs, the nature and frequency of these adverse effects remain poorly documented and are often inferred indirectly from treatment interruptions or failures.(7,8,9) Managing these reports is crucial to show ADR profiles or safety profiles of circulating drugs, safety signals that appear during drug use, and severe and life-threatening ADRs that need immediate follow-up. (10)

This research aims to assess pharmacovigilance system among MDR- and XDR-TB medication in Indonesia.

This research will address the following objectives:

1. To assess the current suspect ADR report profile in MDR- and XDR-TB medicines
2. To assess the safety profile of treatments used for MDR- and XDR- TB in Indonesia.
3. To estimate the adherence to WHO recommendation on MDR- and XDR-TB treatment in a sample of reference hospitals in Indonesia.
4. To identify the predictors of behavioral intention/act to report suspect ADRs of TB medications to the PV system among health care professionals in Indonesia.

Methodology

To assess the report profile, an evaluation of the quantity and quality of suspect ADR reports of MDR- and XDR-TB medicines will be conducted. The quantity of the reports will be counted and the quality of the filled information will be evaluated according to a ‘sufficiency’ criterion to apply the Karch-Lasagna causality algorithm. The discrepancy between the frequency of ADRs reported voluntarily to National Regulatory Authority will be compared with the number of ADRs identified in Sistem Informasi Tuberkulosis (SITB) – a national database of electronic medical records of TB patients.

To assess the safety profile of treatments used for MDR- and XDR TB in Indonesia, a retrospective cohort study of patients treated for MDR-TB and XDR- TB from 1 January 2022 – 31 December 2024 will be observed. Patients characteristics of the cohort including age, sex, weight classes, TB treatment history, comorbidities, and medicines regimen will be collected and described. All possible adverse drug reactions (ADR) will be described clinically and by severity grade. A quantitative safety signal detection will be conducted by calculating the Proportional Reporting Ratio(PRR),Reporting Odds Ratio(ROR), and Informational Component(IC). The signal found will be verified against registered product labels, books, and reports from other countries’ databases, to confirm if it had been listed in the literature and databases of other countries. If not, it was referred to as a new safety signal of the medicine. Given the complexity of MDR and XDR treatment regimens, more reflection may be needed to disentangle the safety profile of a single medicine from synergic effects and interactions.

To estimate the adherence to WHO recommendation on MDR- and XDR-TB treatment, we will also evaluate the compliance to WHO recommendation in term of prescription and doses and patient’s persistence. Compliance will be evaluated in two ways: firstly, persistence to program by evaluating the overall treatment completion and secondly, persistence to the medicines initially prescribed during each phase of MDR and XDR-TB treatment. This retrospective cohort study will also be carried out using data from patients treated for MDRTB and XDR- TB from 1 January 2022 – 31 December 2024.

To identify the predictors of behavioral intention/act to report ADRs to the PV among health care professionals in a sample of reference hospital in Indonesia and to assess the relative importance of the predictors, a convergent mixed-methods design based on the theory of planned behavior will be conducted.
Key words: pharmacovigilance, public health, MDR-TB, XDR-TB, medicines safety, adverse reactions.

References:
1. World Health Organization. Global tuberculosis report 2024. Geneva: WHO; 2024.
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