Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania

Sabina Mugusi,Ferdinand Mugusi,Mohamed Janabi,Muhammad Bakari,Eric Sandstrom,Omary Minzi,Eleni Aklillu,Klaus-Dieter Riedel,Eliford Ngaimisi,Juergen Burhenne,Lars Lindquist

doi:10.1371/journal.pone.0040180

Abstract

ObjectivesTo investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection.Methods and FindingsA total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI.ConclusionsAntiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians.

Highlights

Tuberculosis (TB) is the most common opportunistic infection and leading cause of morbidity and mortality in persons with HIV/AIDS in sub-Saharan Africa and worldwide
Antiretroviral and anti-tuberculosis drug-induced liver Injury (DILI) does occur in our setting, presenting early following HAART initiation
Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Summary

Introduction

Tuberculosis (TB) is the most common opportunistic infection and leading cause of morbidity and mortality in persons with HIV/AIDS in sub-Saharan Africa and worldwide. Overlapping toxicities, in particular drug-induced liver Injury (DILI) can complicate multidrug therapy of any kind. Concomitant anti-TB therapy significantly increases the risk of DILI [1,2]. Efavirenz based HAART is the first drug of choice to be given with rifampicin based anti-TB therapy in HIV-TB co-infected patients [6]. There is growing concern about efavirenz-based HAART associated liver injury. Cases of acute liver failure associated with efavirenz-based HAART requiring liver transplantation are reported [7,8]. Higher risk of severe DILI among Hispanic HIV-infected patients after initiation of HAART which is mainly due to NNRTIs has been reported recently [9]

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