Abstract.
Objectives.

To 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 Findings.

A 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.

Conclusions.

Antiretroviral 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.

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]. DILI may range from transient asymptomatic elevation of liver enzymes to fulminant liver failure requiring treatment interruption, and the subsequent adherence problem may cause treatment failure, relapse or drug resistance [3]–[5]. 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]. Though effective, 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].

Efavirenz, the recommended NNRTI for co-treatment with rifampicin in resource-limited settings is metabolized in the liver mainly by CYP2B6 enzyme and to a lesser extent by CYP3A4/5 [10]. Rifampicin, a potent inducer of these enzymes, reduces plasma efavirenz concentrations. P-glycoprotein and OATP1B1 coded by ABCB1and SLCO1B1 gene respectively play a key role in the transportation of anti-TB drugs including rifampicin. The genes coding for these drug metabolizing enzymes and transporters are inducible by rifampicin and are polymorphic displaying wide inter individual and inter-ethnic variation in enzyme or transporter activity. CYP2B6 516G>T (CYP2B6*6), a defective variant allele associated with high efavirenz plasma concentration, CNS side effects and altered enzyme inducibility occurs at a higher frequency (up to 40%) in sub-Saharan African populations; most being either heterozygous or homozygous genotype [11]–[15]. CYP3A5 is polymorphically expressed in black populations (60%) with common and specific defective variant alleles [16]. Significant influence of CYP3A5 variants alleles (CYP3A5*3, *6 and *7) on quinine metabolism in Tanzanians is reported [17]. Association of genetic polymorphism in ABCB1, CYP3A5 and SLCO1B1 with variation in susceptibility to adverse drug reaction and toxicity are reported previously [18]–[20]. Recently we reported significant differences in SLCO1B1 variant alleles (SLCO1B1*1B, *5 and *15) between Tanzanians and Europeans [21].

Recent studies provide evidence for implication of pharmacogenetic variation in determining susceptibility to DILI [22], [23]. Incidence and predictors of DILI varies between populations partly due to genetic or geographical variations [22]–[24]. African populations are genetically too heterogeneous [25] making it impossible to extrapolate genetic information from one population to the other and hence there is a need for more studies to identify the aetiologies and risk factors for better management of antiretroviral and anti-tuberculosis DILI and to design prevention strategies. In this study we describe the incidence of liver enzyme abnormalities and the associated risk factors including socio-demographic and baseline biochemical characteristics, pharmacokinetic and pharmacogenetic predictors in Tanzanian HIV patients receiving efavirenz based HAART with or without concomitant rifampicin based anti-TB therapy.