Evaluation of Patterns of Liver Toxicity in Patients on Antiretroviral and Anti-Tuberculosis Drugs: A Prospective Four Arm Observational Study in Ethiopian Patients

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.

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

“…The study participants for the present GWAS were included from a recent observational, prospective cohort study where the incidence and patterns of ARV drugs and/or ATDinduced liver toxicities were investigated (Yimer et al, 2014). In brief, newly diagnosed treatment naïve patients enrolled into the following study arms were considered for the present study:…”

“…All patients received treatment according to the national and the WHO treatment guidelines for HIV and TB as previously described (Yimer et al, 2014). In brief, all HIV patients received ARV drugs containing efavirenz and lamivudine with stavudine, zidovudine, or tenofovir.…”

“…The upper limit of normal (ULN) for liver biochemical parameters used for the study population were alanine aminotransferase (ALT 33 U/L, male; 29 U/L, female), aspartate aminotransferase (AST, 41 U/L), alkaline phosphatase (ALP, 128 U/L), and 1.0 mg/dL for total bilirubin (T Bil) (Yimer et al, 2014). All cases met at least one of the following criteria: (1) ALT ‡5 · ULN, (2) ALP ‡2 · ULN, or (3) ALT ‡3 · ULN along with T Bil ‡2 · ULN.…”

“…The risk of developing drug-induced hepatotoxicity (DIH) after treatment initiation is much higher for TB-HIV co-infected patients than for those with HIV or TB mono-infection (Araujo-Mariz et al, 2016;Mugusi et al, 2012;Yimer et al, 2011Yimer et al, , 2014. ARVand anti-tuberculosis drug (ATD)-induced hepatotoxicity have become major clinical challenges because of high morbidity, mortality, and frequent hospitalization as a leading cause of acute liver failure and complications requiring liver transplantation (Elsharkawy et al, 2013;Fink and Bloch, 2013;Nunez, 2010;Turkova et al, 2009).…”

Current characteristics of tuberculosis and human immunodeficiency virus co-infection in a cohort of hospitalized patients in Medellín, Colombia

“…Exploring risk factors for late diagnosis in 191 co-infected patients, Rossato, et al (2) found that extrapulmonary TB and smear-negative TB contributed significantly to this delay.…”