Predictors, Outcome, Profile of Anti-tubercular Drug-Induced Hepatitis: A Prospective Nested Case-Control Study in a South Indian Tertiary Hospital

Abstract

OBJECTIVES: This study was conducted to determine the incidence of anti-tubercular drug (ATT) induced hepatitis and to study the clinical risk factors, clinical, laboratory profile and outcome of patients with ATT induced hepatitis. METHODOLOGY: This case-control study was nested in a cohort of patients from Christian Medical College, Vellore. It was carried out from April 2014 to May 2015. All patients newly diagnosed to have tuberculosis, started on ATT were eligible for this study. All patients who present with suspected ATT related hepatotoxicity were also enrolled in the study. All patients were clinically assessed for symptoms of hepatitis at every visit until completion of treatment. Once the patient developed ATT induced hepatitis, all hepatotoxic drugs were stopped and a non-hepatotoxic regimen was continued. Once the liver function tests normalized, patients were re- introduced with first line regimen as per decision of the treating physician and followed up till the completion of treatment. The incidence of ATT induced hepatitis was obtained from the cohort. The identification of risk factors of ATT induced hepatitis was based on a case control design nested in the cohort study. A descriptive study of clinical profile and outcome of patients with ATT induced hepatitis was also conducted. The risk factors for ATT induced hepatitis were identified by bivariate analysis and logistic regression analysis with odds ratio and 95 % confidence interval. RESULTS: A total of 393 patients were eligible for our study which included 5 patients presenting with ATT induced hepatitis. In the cohort, 61% were male and 81% were in the age group 20-59. HIV infection was found in 72 patients (18.3%). One hundred and fourteen patients (29%) were started on DOTS regimen and the remaining 279 patients (71%) were treated with weight based daily regimen. Patients on DOTS regimen had lower rates of HIV infection and disseminated disease but had greater undernutrition when compared with patients on daily regimen. Majority of the patients (38.9 %) patients had sputum positive pulmonary tuberculosis. A total of 281 patients (72%) had localized disease and 112 patients (28%) had disseminated disease. Forty three patients out of 393 patients developed DILI. The incidence of anti-tubercular drug induced liver injury was 9.7 % (95% C.I 7-13.2%) with lower incidence among patients on DOTS regimen (DOTS 3.5% (95% C.I 2.4%-4.8%) Vs Daily 14% (95% C.I 7.9 – 22.4%)). HIV infection (OR 2.84, p value 0.002, 95% C.I 1.42 – 5.67), daily regimen (OR 4.46, p value 0.003, 95% C.I 1.55 – 12.81), disseminated disease (OR 1.769, p value 0.006, 95% C.I 1.23-2.55), hypoalbuminemia ( OR 1.92, p value 0.045, 95% C.I 1.01 – 3.68) and chronic liver disease (OR 4.72, p value 0.004, 95% C.I 1.5-14.82) were independent risk factors for development of drug induced liver injury. On multivariate logistic regression analysis, HIV infection, hypoalbuminemia, chronic liver disease and daily regimen were found to be significant risk factors for DILI. A prediction score based on the above risk factors is suggested to identify patients who will develop DILI. A score of > 5 will predict DILI with a sensitivity and specificity of 74% and 67%. Vomiting was the most common symptom seen in 58.1% of patients with drug induced hepatitis followed by jaundice in 30.2 % of patients. Four patients developed acute liver failure. The majority of patients (77%) developed drug induced liver injury within first 2 months. The mean time duration for normalization of liver function was 22 days ranging from 3 to 81 days. Fifteen patients (35%) had severe hepatitis. All cause mortality in DILI was 4.7 % (2 patients). 36 patients (84%) had complete resolution of hepatitis. At least 1 drug was successfully rechallenged in 28 out of 29 patients. Rechallenge by both ATS and BTS guidelines had similar successful rechallenge. The rates of rechallenge hepatitis were similar in patients who were rechallenged according to both ATS and BTS guidelines (13.3% Vs 13% respectively). CONCLUSION: Incidence of ATT induced hepatitis from our study was 9.7% (95% C.I 7-13.2%) with lower incidence among patients on DOTS regimen. HIV infection, daily regimen, disseminated disease, hypoalbuminemia and chronic liver disease were independent risk factors for development of DILI. Mortality rate was low (4.3%) among patients who developed DILI. Rechallenge by both ATS and BTS guidelines had similar successful rate. The predictive scoring system proposed from our study needs to be validated by a well designed prospective study. The study suggests that the combination of risk factors of extensive TB disease, HIV and undernutrition increase the vulnerability to drug induced liver disease particularly with daily TB treatment regimen, emphasizing the role of acquired risk factors in the development of DILI.