Letter to the editor—Response to the article “Drug‐induced liver injury associated with pretomanid, bedaquiline, and linezolid: Insights from FAERS database analysis”

With reference to the recent article by He and colleagues,1 we congratulate the authors on such commendable work based on real-world data from a spontaneous FDA Adverse Events Reporting System, i.e., FAERS database.1 India continues to face a high burden of Tuberculosis (TB) disease and TB infection.2, 3 The findings by He et al. are similar in some aspects to those of a recent systematic review and meta-analysis conducted in India.4 In the Indian study, the pooled incidence of anti-tuberculous drug-induced liver injury (ATDILI) for the HRZE regimen was 12.6% (95% CI, 9.9–15.3%, p < 0.001, I2 = 95.1%).4 The median onset time for HRZE associated ATDILI was 3 weeks4 (in 80% of the studies), versus 20 days.1 However, in contrast to this study,1 in India,4 a majority of the ATDILI patients were women. Besides, a sub-group analysis from the Indian study revealed that multiple factors – such as the type of regimen, lean body mass index (BMI), hypoalbuminemia and genetic polymorphisms (N-acetyl transferase and glutathione S-transferases) influenced ATDILI.4 In fact, ATDILI continues to be a significant barrier to the successful elimination of TB in India, as it hinders medication adherence and/or enforces a change in the treatment regimen.5 If further details about the patient data are available to the authors of1 it would be beneficial to analyse whether patients with ATDILI had a pre-existing elevated alanine aminotransaminase or aspartate aminotransferase concentrations. This would be useful since the clinical trials supporting these regimens may have excluded patients with preexisting raised enzyme levels as part of their exclusion criteria. The following two findings from this study, namely, (a) shorter onset time of DILI compared to HRZE and (b) higher mortality rate in the Bedaquiline, Pretomanid, and Linezolid (BPaL) group; are both relevant to India, considering that the Ministry of Health and Family Welfare (MoHFW) has recently adopted the BPaLM regimen consisting of a four-drug combination for multidrug-resistant (MDR) patients, which has one additional drug namely ‘Moxifloxacin’ to the standard BPaL.6 Another interesting feature of the article1 was the active reporting of adverse events in a global database with contributions not only from healthcare professionals, but also from pharmacists and patients. Similar to this, in India, there is a dedicated program called the ‘Pharmacovigilance Programme of India (PvPI)’ which acts as the National Coordination Centre for collecting and analysing data pertaining to adverse drug reactions (ADRs) and designing appropriate interventions.7 PvPI is in turn attached to the WHO-Uppsala Monitoring Centre (UMC), Sweden. The programme supports and encourages reporting from diverse stakeholders (including consumers and industry personnel). The ‘NIKSHAY’ web-enabled patient management system under the National Tuberculosis Elimination Programme (NTEP) is specifically dedicated to managing TB, including the monitoring of ADRs at regular intervals at the individual level.8 The article also highlights the need for newer and safer regimens in handling drug-sensitive TB. Although the latest WHO Bacterial Priority Pathogens List pipeline analysis (BPPL) identifies Mycobacterium tuberculosis (rifampicin-resistant) as one of the major groups, the pipeline has more drugs/trials listed under multi-drug and extremely-drug resistant categories.9 To this end, there is an urgent need to discover and develop newer drugs using publicly-funded models that can ensure sustainable access to safe and effective anti-TB drugs, especially for the drug-sensitive ones. Considering the high mortality due to MDR-TB in the BPaL regimen, the study also highlights the need for active monitoring of patients to detect underlying liver abnormalities; capacity building among healthcare workers to identify signs and symptoms of all ADRs; strengthening active pharmacovigilance to effectively capture the entire spectrum of ADRs; patient education on identifying signs and symptoms and reporting ADRs (especially through NIKSHAY and NTEP in India). Finally, the role of personalized medicine (including pharmacogenomics and therapeutic drug monitoring) has to be studied in depth in order to reduce harm from ADRs and to improve patient outcomes.10 Jaya Ranjalkar, Premila M. Wilfred and Raja Priya contributed to the conception and design of this letter. Jaya Ranjalkar prepared the first draft. Premila M. Wilfred and Raja Priya carefully reviewed the draft and provided critical technical inputs. All the authors approved this version of the letter. The authors thank Dr. Jacob Peedicayil, Senior Professor, Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, for his inputs. The authors declare no conflicts of interest. No new data were generated or analysed for this letter because it is a comment to a published article. The comment is based on the review of existing literature and programmes for tuberculosis management.