Liver enzyme abnormalities and associated risk factors in HIV patients on efavirenz-based HAART with or without tuberculosis co-infection in Tanzania.
OBJECTIVE
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.


RESULTS
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%, 10.7 per 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.
Infectious Disease Unit, Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
Sabina
S
Mugusi
Eliford
E
Ngaimisi
Mohamed
M
Janabi
Omary
O
Minzi
Muhammad
M
Bakari
Klaus-Dieter
KD
Riedel
Juergen
J
Burhenne
Lars
L
Lindquist
Ferdinand
F
Mugusi
Eric
E
Sandstrom
Eleni
E
Aklillu
D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D060085:Coinfection / Q000150:complications* / Q000453:epidemiology; D003521:Cyclopropanes; D003710:Demography; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D016016:Proportional Hazards Models; D012307:Risk Factors; D013636:Tanzania / Q000453:epidemiology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications* / Q000453:epidemiology
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz