Adverse Drug Reactions Associated With Longer All-Oral MDR/XDR-TB Regimens: Prospective Pharmacovigilance Evidence From a High-Burden Tertiary Care Setting in North India

Abstract

Background:

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) impose a disproportionate burden on high-endemic countries, with India contributing the largest global share of rifampicin-resistant cases. The National TB Elimination Program (NTEP) introduced longer all-oral regimens to replace injectable-based therapy; however, prospective pharmacovigilance data characterizing the real-world adverse drug reaction (ADR) profile of these regimens from India remain scarce.

Objective:

To prospectively evaluate the incidence, nature, system organ class distribution, and severity of ADRs in patients receiving longer all-oral MDR/XDR-TB regimens under NTEP at a tertiary care centre in North India.

Methods:

A prospective cohort study enrolled microbiologically confirmed MDR/XDR-TB patients initiating longer all-oral regimens between March 2023 and September 2023, with follow-up through March 2025. Adverse drug reactions were actively monitored via structured interviews and clinical assessments. Severity was graded using the modified Hartwig and Siegel scale. Treatment outcomes were classified per WHO definitions. This study adheres to the STROBE reporting guidelines.

Results:

Of 143 registered patients, 102 (71.3%) were enrolled (52 males [51.0%]; mean age 34.7 ± 14.3 years). Favourable outcomes were achieved in 79 patients (77.5%). A total of 158 ADRs were reported, most of which were mild (Hartwig levels 1-2: 81.0%). Gastrointestinal disorders were most common (n = 57; 55.9%), followed by nervous system disorders, mainly linezolid-associated peripheral neuropathy, requiring dose modification or discontinuation in some cases. Other ADRs included clofazimine-related skin pigmentation, linezolid-associated haematological toxicity, and one case of bedaquiline-associated QT prolongation. Linezolid-related haematological toxicity was the most clinically significant ADR (Hartwig level 4). No severe ADRs (Hartwig levels 5-7) or deaths were reported.

Conclusion and Relevance:

Longer all-oral MDR/XDR-TB regimens demonstrated a favourable safety profile under programmatic conditions, with predominantly mild, manageable ADRs and a treatment success rate exceeding the global MDR-TB benchmark. Proactive monitoring for linezolid-induced neurotoxicity and haematological toxicity, and electrocardiographic surveillance during bedaquiline therapy, are essential.