Abstract
ObjectivesTo evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI).MethodsA total of 1,060 treatment naive patients were prospectively enrolled into four treatment groups: HIV patients receiving efavirenz based HAART alone (Arm-1); TB-HIV co-infected patients with CD4≤200 cells/μL, receiving concomitant rifampicin based anti-TB and efavirenz based HAART (Arm-2); TB-HIV co-infected patients with CD4>200 cells/μL, receiving anti-TB alone (Arm-3); TB patients taking rifampicin based anti-TB alone (Arm-4). Liver enzyme levels were monitored at baseline, 1st, 2nd, 4th, 8th, 12th and 24th weeks during treatment. CD4 and HIV viral load was measured at baseline, 24th and 48th weeks. Data were analyzed using multivariate Cox Proportional Hazards Model.ResultsA total of 159 patients (15%) developed DILI with severity grades 1, 2, 3 and 4 of 53.5%, 32.7%, 11.3% and 2.5% respectively. The incidence of cholestatic, hepatocellular or mixed pattern was 61%, 15% and 24%, respectively. Incidence of DILI was highest in Arm-2 (24.2%)>Arm-3 (10.8%)>Arm-1 (8.8%)>Arm-4 (2.9%). Concomitant anti-TB-HIV therapy increased the risk of DILI by 10-fold than anti-TB alone (p<0.0001). HIV co-infection increased the risk of anti-TB DILI by 4-fold (p = 0.004). HAART associated DILI was 3-fold higher than anti-TB alone, (p = 0.02). HAART was associated with cholestatic and grade 1 DILI whereas anti-TB therapy was associated with hepatocellular and grade ≥ 2. Treatment type, lower CD4, platelet, hemoglobin, higher serum AST and direct bilirubin levels at baseline were significant DILI predictors. There was no effect of DILI on immunologic recovery or virologic suppression rate of HAART.ConclusionHAART associated DILI is mainly cholestatic and mild whereas hepatocellular or mixed pattern with high severity grade is more common in anti-tuberculosis DILI. TB-HIV co-infection, disease severity and concomitant treatment exacerbates the risk of DILI.
Highlights
Antiretroviral and anti-tuberculosis chemotherapy associated drug induced liver injury (DILI) is a common and challenging adverse event causing adherence problem leading to hospitalization and life-threatening events [1,2,3,4]
We recently reported the association of high efavirenz plasma concentration and CYP2B6*6 allele coding for slow efavirenz metabolizer phenotype with efavirenz based highly active antiretroviral treatment (HAART) associated DILI in TB-HIV patients [10,11,12]
A total of 1060 patients were enrolled in parallel and assigned into four different types of treatment groups (Arms) based on type of treatment to receive, as decided by physicians working at the study sites according to the WHO and Ethiopian national TB and HIV treatment guidelines during the study period [28]: HIV patients without TB confection receiving efavirenz based HAART only (Arm-1, n = 273); TB-HIV co-infected patients with CD4 count #200 cells/mL receiving rifampicin based short course anti-TB drugs together with efavirenz based HAART (Arm-2, n = 495); TB-HIV co-infected patients with CD4 count . 200 cells/mL receiving anti-TB drugs alone (Arm-3, n = 83); TB patients without HIV confection receiving anti-TB drugs alone (Arm-4, n = 209)
Summary
Antiretroviral and anti-tuberculosis chemotherapy associated drug induced liver injury (DILI) is a common and challenging adverse event causing adherence problem leading to hospitalization and life-threatening events [1,2,3,4]. DILI can be fatal if therapy is not interrupted on time, and the subsequent adherence problem may cause treatment failure and relapse or drug resistance [5,6,7]. About 8% to 23% of HIV-infected patients receiving highly active antiretroviral treatment (HAART) develop DILI and the pathogenic mechanisms are not fully understood [3,9]. We recently reported the association of high efavirenz plasma concentration and CYP2B6*6 allele coding for slow efavirenz metabolizer phenotype with efavirenz based HAART associated DILI in TB-HIV patients [10,11,12]. A recent case report of efavirenz induced acute liver failure requiring liver transplantation in a slow drug metabolizer indicates fatal event in susceptible patients [13]. Identification of the risk and prognostic factors is critical to identify patients at risk of developing DILI drugs for proper management
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