Evaluation of patterns of liver toxicity in patients on antiretroviral and anti-tuberculosis drugs: a prospective four arm observational study in ethiopian patients.
OBJECTIVE
To evaluate the incidence, type, severity and predictors of antiretroviral and/or anti-tuberculosis drugs induced liver injury (DILI).


METHODS
A 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.


RESULTS
A 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.


CONCLUSIONS
HAART 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.
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Getnet
G
Yimer
Former AstraZeneca R&D, Global Safety Assessment, Molecular Toxicology, Södertälje, Sweden.
Marcus
M
Gry
Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; Department of Medicine, Division of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge I:73, Stockholm, Sweden.
Wondwossen
W
Amogne
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Eyasu
E
Makonnen
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden; Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Abiy
A
Habtewold
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Zelalem
Z
Petros
Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Getachew
G
Aderaye
AstraZeneca Innovative Medicines Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden.
Ina
I
Schuppe-Koistinen
Department of Medicine, Division of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge I:73, Stockholm, Sweden.
Lars
L
Lindquist
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, Stockholm, Sweden.
Eleni
E
Aklillu
D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active; D000995:Antitubercular Agents / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000453:epidemiology*; D005002:Ethiopia; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents