Clinical and pharmacogenetic determinants of severe nevirapine induced liver toxicity in a monocentric cohort of HIV positive patients

To determine clinical and pharmacogenetic factors involved in the development of severe nevirapine (NVP) induced liver toxicity.
We retrospectively analyzed all HIV positive patients who were followed at the Infectious Disease Unit, DIBIC L.Sacco, University of Milan from January 2000 to December 2015. All patients treated with NVP who underwent a genotypization for the functional variants mapping in ABCB1, CYP2B6, CYP3A4 were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3-4 AST/ALT increase during the first six months of NVP treatment. Hardy Weinberg equilibrium was tested in the control group. A multivariable logistic regression model was constructed including variables with p value <0.20 in the univariate analysis.
470 patients were included in the analysis, of which 12 (2.5%) experienced a severe liver toxicity. A higher prevalence of HCV coinfection (66.7% vs 33.0%, p<.0001) and higher baseline AST (47 IU/L vs 26 IU/L, p=0.014) and ALT (79 IU/L vs 28 IU/L, p=0.008) median levels were observed in patients with, as compared to those without, liver toxicity. In univariate analysis the genotypes CT/TT of ABCB1 rs1045642 showed a protective effect for liver toxicity when compared with genotype CC (OR=0.18, 95%CI 0.04-0.76; p=0.02). In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR=8.00, 95%CI 1.27-50.29; p=0.027), whereas ABCB1 CT/TT genotypes (aOR=0.10, 95%CI 0.02-0.47; p=0.004) and higher BMI (aOR=0.72, 95%CI 0.519-1.000; p=0.050) were associated with lower risk.
According to our findings ABCB1 rs1045642 represents an independent determinant of severe NVP induced liver toxicity.

Andrea Giacomelli
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