Liver transplantation for hepatocellular carcinoma in India: Are we ready for 2040?

BACKGROUND: Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been widely researched and is well established worldwide. The cornerstone of this treatment lies in the various criteria formulated by expert consensus and experience. The variations among the criteria are staggering, and the short- and long-term out comes are controversial. AIM: To study the differences in the current practices of LT for HCC at different centers in India and discuss their clinical implications in the future. METHODS: We conducted a survey of major centers in India that performed LT in December 2022. A total of 23 responses were received. The centers were classified as high- and low-volume, and the current trend of care for patients und ergoing LT for HCC was noted. RESULTS: Of the 23 centers, 35% were high volume center (> 500 Liver transplants) while 52% were high-volume centers that performed more than 50 transplants/year. Approximately 39% of centers had performed > 50 LT for HCC while the percent distribution for HCC in LT patients was 5%-15% in approximately 73% of the patients. Barring a few, most centers were divided equally between University of California, San Francisco (UCSF) and center-specific criteria when choosing patients with HCC for LT, and most (65%) did not have separate transplant criteria for deceased donor LT and living donor LT (LDLT). Most centers (56%) preferred surgical resection over LT for a Child A cirrhosis patient with a resectable 4 cm HCC lesion. Positron-emission tomography-computed tomography (CT) was the modality of choice for metastatic workup in the majority of centers (74%). Downstaging was the preferred option for over 90% of the centers and included transarterial chemoembolization, transarterial radioembolization, stereotactic body radiotherapy and atezolizumab/bevacizumab with varied indications. The alpha-fetoprotein (AFP) cut-off was used by 74% of centers to decide on transplantation as well as to downstage tumors, even if they met the criteria. The criteria for successful downstaging varied, but most centers conformed to the UCSF or their center-specific criteria for LT, along with the AFP cutoff values. The wait time for LT from down staging was at least 4-6 wk in all centers. Contrast-enhanced CT was the preferred imaging modality for post-LT surveillance in 52% of the centers. Approximately 65% of the centers preferred to start everolimus between 1 and 3 months post-LT. CONCLUSION: The current predicted 5-year survival rate of HCC patients in India is less than 15%. The aim of transplantation is to achieve at least a 60% 5-year disease free survival rate, which will provide relief to the prediction of an HCC surge over the next 20 years. The current worldwide criteria (Milan/UCSF) may have a higher 5-year survival (> 70%); however, the majority of patients still do not fit these criteria and are dependent on other suboptimal modes of treatment, with much lower survival rates. To make predictions for 2040, we must prepare to arm ourselves with less stringent selection criteria to widen the pool of patients who may undergo transplantation and have a chance of a better outcome. With more advanced technology and better donor outcomes, LDLT will provide a cutting edge in the fight against liver cancer over the next two decades.

Longitudinal efficacy and safety modeling and simulation framework to aid dose selection of belantamab mafodotin for patients with multiple myeloma.

Belantamab mafodotin, a monomethyl auristatin F (MMAF)-containing monoclonal antibody-drug conjugate (ADC), demonstrated deep and durable responses in the DRiving Excellence in Approaches to Multiple Myeloma (DREAMM)-1 and pivotal DREAMM-2 studies in patients with relapsed/refractory multiple myeloma. As with other MMAF-containing ADCs, ocular adverse events were observed. To predict the effects of belantamab mafodotin dosing regimens and dose-modification strategies on efficacy and ocular safety end points, DREAMM-1 and DREAMM-2 data across a range of doses were used to develop an integrated simulation framework incorporating two separate longitudinal models and the published population pharmacokinetic model. A concentration-driven tumor growth inhibition model described the time course of serum M-protein concentration, a measure of treatment response, whereas a discrete time Markov model described the time course of ocular events graded with the GSK Keratopathy and Visual Acuity scale. Significant covariates included baseline ß2 -microglobulin on growth rate, baseline M-protein on kill rate, extramedullary disease on the effect compartment rate constant, and baseline soluble B cell maturation antigen on maximal effect. Efficacy and safety end points were simulated for various doses with dosing intervals of 1, 3, 6, and 9 weeks and various event-driven dose-modification strategies. Simulations predicted that lower doses and longer dosing intervals were associated with lower probability and lower overall time with Grade 3+ and Grade 2+ ocular events compared with the reference regimen (2.5 mg/kg every 3 weeks), with a less-than-proportional reduction in efficacy. The predicted improved benefit-risk profiles of certain dosing schedules and dose modifications from this integrated framework has informed trial designs for belantamab mafodotin, supporting dose-optimization strategies.

Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors.

BACKGROUND: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors. METHODS: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated. RESULTS: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg. CONCLUSION: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination. TRIAL REGISTRATION NUMBER: NCT03666988.

Exposure-Response Analyses for Therapeutic Dose Selection of Belantamab Mafodotin in Patients With Relapsed/Refractory Multiple Myeloma.

Belantamab mafodotin is an antibody-drug conjugate comprising a humanized anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Single-agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM-1 and phase II DREAMM-2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM-2, efficacy end points (probability of response (PoR) and progression-free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, ß2 -microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM-1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM-2). Higher cys-mcMMAF maximum plasma drug concentration (Cmax ) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM-1 and DREAMM -2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies.

Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis.

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of antituberculosis agents, and the lead spectinamide 1810 has demonstrated excellent efficacy, safety, and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of Mycobacterium tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of CFU in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by the ratio of maximum free drug concentration to MIC (fCmax/MIC) and the ratio of the area under the free concentration-time curve to the MIC (fAUC/MIC) rather than the cumulative percentage of time that the free drug concentration is above the MIC (f%TMIC). A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis.

Population pharmacokinetics of belantamab mafodotin, a BCMA-targeting agent in patients with relapsed/refractory multiple myeloma.

Belantamab mafodotin (belamaf) is an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). Nonlinear mixed-effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine-maleimidocaproyl-MMAF (cys-mcMMAF) after 0.03-4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM-1, n = 73; DREAMM-2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys-mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two-compartment PopPK model with a time-varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM-2 patient was 0.936 L/day with a half-life of 11.5 days, over time CL was reduced by 28% resulting in a half-life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys-mcMMAF concentrations were described with a linear two-compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys-mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys-mcMMAF concentration-time profiles in RRMM were well-described by PopPK models, and exposure was most strongly impacted by disease-related characteristics.

The Indian Network of Drug-Induced Liver Injury: Etiology, Clinical Features, Outcome and Prognostic Markers in 1288 Patients.

BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.

How significant is the radiation exposure during electrophysiology study and ablation procedures for supraventricular tachycardia?

Radiation exposure during electrophysiology procedures has been a point of discussion. We measured the ionising radiation dosage during ablation procedures for supraventricular tachycardia. This was compared with coronary angiographies performed via the radial route to put it in perspective. We found that the radiation dosage during the ablation procedure was far lower, less than forty percent of that during coronary angiography (Air Kerma 249.1 mGy ± 266.95 mGy v/s 671.9 mGy ± 328.6 mGy; p < 0.001).

Correlation of newer indices of dyssynchrony with clinical response in patients undergoing cardiac resynchronisation therapy.

The benefits of CRT in select subsets of systolic heart failure patients with LBBB are proven. We prospectively evaluated conventional and newer echocardiographic parameters of left ventricular dyssynchrony in 35 patients who underwent CRT and were followed up after 6 months. Of the 33 surviving patients, 21 were echocardiographic responders and 24 were clinical responders. The parameters in clinical responders and non-responders were compared. The anatomic M Mode parameters of delays improved, while the radial strain and the mitral valve velocity time integral (MVVTI) did not show any significant change after CRT.

Pneumothorax leading to pneumopericardium after transvenous lead implantation in a patient with previous epicardial lead.

A 44-year-old lady, a follow-up case of idiopathic dilated cardiomyopathy and cardiac resynchronization therapy defibrillator device implantation with epicardial left ventricular (LV) lead, underwent a transvenous LV lead revision in view of epicardial lead malfunction. A chest X-ray after this, done for worsening dyspnea, revealed pneumopericardium along with left pneumothorax. The computed tomography (CT) revealed a communication between the left pleural and pericardial cavities, around the old epicardial lead. Drainage of the left pleural cavity resolved both the pneumothorax and pneumopericardium and the patient remained well on follow up.

Esophageal carcinoma: An epidemiological analysis and study of the time trends over the last 20 years from a single center in India.

BACKGROUND AND AIMS: Esophageal carcinoma is a common gastrointestinal malignancy. There is a paucity of literature about the time trends from India. The aim of the study was to evaluate the time trends over 20 years and observe how they differ from the West. MATERIAL AND METHODS: We retrospectively evaluated the data of 552 patients from the gastroenterology database (single department, single-center) over a period of 20 years from 1996 to 2015. The study period was split into two groups, namely, Group A (1996 to 2005) and Group B (2006 to 2015). RESULTS: There were 263 patients in Group A and 289 patients in Group B. The mean age was 54.83 years (range 25-89 years). There were 345 males and 207 females, with the ratio being 1.67. The most common histological type was squamous cell carcinoma (SCC) with 443 patients (80.25%). The most common location was mid esophagus with 229 patients (41.48%) followed by 208 patients (37.68%) in the lower esophagus. There was no significant increase in the lower esophageal malignancy. However, there was a significant increase in the gastroesophageal junction (GEJ) and adenocarcinoma (AC). There were no other time trend changes in gender, location, or histology. CONCLUSION: SCC is still far more common than AC in India. The mid esophagus is the most common site. There is no evidence of an increase in the lower esophageal malignancy in our study for over 20 years. However, the rates of GEJ-AC were found to be increasing.

Arrhythmia in Children and Adolescents and Outcome of Radiofrequency Ablation for Tachyarrhythmias - A Single Center Experience Over 16 Years.

OBJECTIVE: Radiofrequency (RF) ablation for tachycardia in children poses challenges in view of slender veins and delicate cardiac structures in close proximity. METHODS: We reviewed hospital records for patients below 18 years,who underwent RF ablation from August, 2001 to February, 2017 at a single hospital. RESULTS: Among 214 patients (134 males, age12.5 (4.6) years), there were 221 tachycardia substrates: accessory pathways in 85 patients (39%), AV nodal re-entrant tachycardia in 79 patients (36%), ventricular tachycardia in 28 patients (13%) and atrial tachycardia in 21 patients (9.6%).The overall success rate of RF ablation was 95% (204/214). Success rate in those younger than 6 years was similar to those in older age groups. There were no major complication. CONCLUSIONS: RF ablation below 18 years of age has a high success rates and low complications.

What is the mechanism of paroxysmal atrioventricular block in a patient with recurrent syncope?

Paroxysmal atrioventricular (AV) block is characterized by sudden appearance of complete heart block with no escape rhythm. Three types have been described having different mechanisms namely, vagally mediated, intrinsic, and idiopathic. A rare case scenario is being described with the occurrence of paroxysmal AV block of all three types in the same patient.

Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and intrapulmonary aerosol administration in mice.

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. Intrapulmonary aerosol (IPA) administration of lead spectinamide 1599 has previously been shown to be more efficacious than subcutaneous (SC) administration at comparable doses. The objective of the current study was to characterize the disposition of 1599 in plasma and lungs in mice in order to provide a potential rationale for the observed efficacy differences. 200 mg/kg of 1599 was administered to healthy BALB/c mice by SC injection or by IPA delivery. Plasma and major organs were collected at specified time points until 8 h after dosing. Drug concentrations were measured by LC-MS/MS and analyzed by noncompartmental pharmacokinetic analysis. 1599 demonstrated rapid absorption into plasma after IPA and SC administration, resulting in very similar plasma exposure for both routes. In contrast, drug exposure in the lungs was 48 times higher following IPA as compared to SC administration, which is highly desirable as the lungs are the main site of infection in pulmonary TB. The higher local exposure in the lungs is likely the basis for the increased efficacy after IPA compared to SC administration. Overall, this study supports the pulmonary route as a potential pathway for the treatment of tuberculosis with 1599.

Dynamic time-kill curve characterization of spectinamide antibiotics 1445 and 1599 for the treatment of tuberculosis.

Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration-dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is T > MIC for 1445, but fCmax/AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post-antibiotic effect: 15.7 h for 1445 compared the 133 h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds.

Intermediate term outcome after electrogram guided segmental ostial pulmonary vein isolation using an 8 mm tip catheter for paroxysmal atrial fibrillation.

INTRODUCTION: Pulmonary vein isolation (PVI) is the most widely used procedure for ablation in patients with paroxysmal atrial fibrillation (AF). Not withstanding recent advancements in this field, including sophisticated three-dimensional (3D) based imaging and advanced ablation catheters with contact force technology, many patients and healthcare systems in developing countries will not afford such an expensive therapeutic procedure. There are no data from India analyzing the efficacy of PVI for PAF using conventional mapping and ablation. In this article, we have summarized the intermediate term outcome following PVI in patients with PAF using electrogram-based mapping and a 8 mm tip ablation catheter. METHOD: A total of 42 consecutive patients who underwent PVI for symptomatic PAF not controlled with at least one antiarrhythmic drug were studied in a tertiary care institute from March 2011 to June 2018. Patients with rheumatic AF were excluded. The pulmonary vein (PV) anatomy was assessed by pulmonary angiography during the ablation procedure. Using conventional electrophysiologic mapping, a variable curve Lasso catheter placed in the PVs was used to guide the earliest site of breakthrough. The segmental ostial PVI was performed using a 8 mm tip radiofrequency (RF) ablation catheter. Elimination of all PV ostial potentials and complete entrance block into the PV were considered indicative of complete electrical isolation. Follow-up visits were scheduled at one, three, and six months after the procedure, and every six months thereafter. History, symptom review, clinical examination, and 12-lead ECG were performed at each follow-up. RESULTS: At pre-discharge, 34 patients (81%) were in sinus rhythm, while eight patients (19%) continued to have atrial fibrillation. The age of the study population was 51.5 ± 11.7 yrs. The mean follow-up duration was 44 ± 21 months (range 6-84 months). The number of PVs isolated included one (five patients, 11.9%), two (20 patients, 47.6%), three (12 patients, 28.6%), and four (five patients, 11.9%). In 42 patients, a total of 101 PVs were isolated. The right superior PV (RSPV) was isolated in 37 patients, the left superior PV (LSPV) was isolated in 39 patients, the left inferior PV (LIPV) was isolated in 14 patients, and the right inferior PV (RIPV) was isolated in six patients. The procedure duration was 125 ± 29 min and the fluoroscopy time was 47 ± 13 min. The number of patients who remained in sinus rhythm at 1, 6, 12, and 24 months were 34 (81%), 32 (76%), 30 (71%), and 26 (62%), respectively. Two patients of these underwent repeat PVI, which was successful, and they had freedom from AF episodes. Complications were rare. One patient had a minor pericardial effusion, and one patient had transient sinus pauses, which were conservatively managed. CONCLUSION: Conventional RF ablation using PV potential-based mapping and ablation with 8 mm tip catheters is safe for patients with PAF. The intermediate term outcome is satisfactory and cost-effective in our setting with limited resources.

Cardiac resynchronization therapy device implantation in a patient with persistent left superior vena cava without communicating innominate vein - should we proceed from the same side? - A dilemma revisited.

Persistent left superior vena cava (PLSVC) is an uncommon congenital anomaly. We report a case of implantation of cardiac resynchronization therapy - pacemaker (CRT-P) device in a 38-year-old lady with idiopathic dilated cardiomyopathy. After left axillary vein puncture, we faced an unexpected entry of left subclavian to PLSVC draining into the coronary sinus (CS). The target posterolateral vein which had been identified before, seemed to have an acute angle at its entry into the CS. Hence, at this stage we were in a dilemma, whether to switch to the right side or to continue from the same side. We continued the procedure from the left side and completed it successfully after some manipulation and improvisation.

Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality

ABSTRACT Introduction and aims. Drug-induced liver injury (DILI) is rare; however, it is one of the important causes of acute liver failure which results in significant morbidity or mortality. Material and methods. Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months or until normalization of liver tests. Causality assessment was done by applying the Roussel Uclaf Causality Assessment Method model. Results. We collected data from 82 individuals diagnosed with DILI at our hospital from 2014 through 2015 (41 men; median age, 38 years). The most commonly implicated drugs were antitubercular therapy (ATT) (49%), antiepileptic drugs (12%), complementary and alternative medicine (CAM) in 10%, antiretroviral drugs (9%) and non-steroidal anti-inflammatory drugs (6%). 8 out of 13 deaths were liver related. Also, liver related mortality was significantly higher for ATT DILI (17.5%) vs. those without (2.4%) (P = 0.02). There was no significant difference in overall as well as liver related mortality in hepatocellular, cholestatic or mixed pattern of injury. Laboratory parameters at one week after discontinuation of drug predicted mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephalopathy, MELD (Model for end stage liver disease) score and alkaline phosphatase at one week, independently predicted mortality. Conclusion. DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence of jaundice, encephalopathy, MELD score and alkaline phosphatase at one week are independent predictors of mortality.(AU)

Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality.

INTRODUCTION AND AIMS: Drug-induced liver injury (DILI) is rare; however, it is one of the important causes of acute liver failure which results in significant morbidity or mortality. MATERIAL AND METHODS: Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months or until normalization of liver tests. Causality assessment was done by applying the Roussel Uclaf Causality Assessment Method model. RESULTS: We collected data from 82 individuals diagnosed with DILI at our hospital from 2014 through 2015 (41 men; median age, 38 years). The most commonly implicated drugs were antitubercular therapy (ATT) (49%), antiepileptic drugs (12%), complementary and alternative medicine (CAM) in 10%, antiretroviral drugs (9%) and non-steroidal anti-inflammatory drugs (6%). 8 out of 13 deaths were liver related. Also, liver related mortality was significantly higher for ATT DILI (17.5%) vs. those without (2.4%) (P = 0.02). There was no significant difference in overall as well as liver related mortality in hepatocellular, cholestatic or mixed pattern of injury. Laboratory parameters at one week after discontinuation of drug predicted mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephalopathy, MELD (Model for end stage liver disease) score and alkaline phosphatase at one week, independently predicted mortality. CONCLUSION: DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence of jaundice, encephalopathy, MELD score and alkaline phosphatase at one week are independent predictors of mortality.