Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy
Abstract Background Nevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors...
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doaj-68a75015529d4ad4958b9587fdb033332020-11-25T03:37:15ZengBMCBMC Infectious Diseases1471-23342018-11-011811810.1186/s12879-018-3462-5Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapyAndrea Giacomelli0Agostino Riva1Felicia Stefania Falvella2Maria Letizia Oreni3Dario Cattaneo4Stefania Cheli5Giulia Renisi6Valentina Di Cristo7Angelica Lupo8Emilio Clementi9Stefano Rusconi10Massimo Galli11Anna Lisa Ridolfo12Infectious Diseases Unit, DIBIC Luigi Sacco - University of MilanInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanASST Fatebenefratelli-Sacco, Clinical Pharmacology UnitInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanASST Fatebenefratelli-Sacco, Clinical Pharmacology UnitASST Fatebenefratelli-Sacco, Clinical Pharmacology UnitInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanASST Fatebenefratelli-Sacco, Clinical Pharmacology UnitInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanInfectious Diseases Unit, DIBIC Luigi Sacco - University of MilanAbstract Background Nevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. Methods We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3–4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ2 test. A multivariable logistic regression model was constructed using a backward elimination method. Results Three hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04–0.76; p = 0.020) in univariate analysis. 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 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004) was associated with a lower risk. Conclusions According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.http://link.springer.com/article/10.1186/s12879-018-3462-5NevirapinePharmacogeneticHepatotoxicityABCB1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrea Giacomelli Agostino Riva Felicia Stefania Falvella Maria Letizia Oreni Dario Cattaneo Stefania Cheli Giulia Renisi Valentina Di Cristo Angelica Lupo Emilio Clementi Stefano Rusconi Massimo Galli Anna Lisa Ridolfo |
spellingShingle |
Andrea Giacomelli Agostino Riva Felicia Stefania Falvella Maria Letizia Oreni Dario Cattaneo Stefania Cheli Giulia Renisi Valentina Di Cristo Angelica Lupo Emilio Clementi Stefano Rusconi Massimo Galli Anna Lisa Ridolfo Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy BMC Infectious Diseases Nevirapine Pharmacogenetic Hepatotoxicity ABCB1 |
author_facet |
Andrea Giacomelli Agostino Riva Felicia Stefania Falvella Maria Letizia Oreni Dario Cattaneo Stefania Cheli Giulia Renisi Valentina Di Cristo Angelica Lupo Emilio Clementi Stefano Rusconi Massimo Galli Anna Lisa Ridolfo |
author_sort |
Andrea Giacomelli |
title |
Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy |
title_short |
Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy |
title_full |
Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy |
title_fullStr |
Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy |
title_full_unstemmed |
Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy |
title_sort |
clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of hiv positive patients receiving nevirapine-based antiretroviral therapy |
publisher |
BMC |
series |
BMC Infectious Diseases |
issn |
1471-2334 |
publishDate |
2018-11-01 |
description |
Abstract Background Nevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. Methods We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3–4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ2 test. A multivariable logistic regression model was constructed using a backward elimination method. Results Three hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04–0.76; p = 0.020) in univariate analysis. 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 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004) was associated with a lower risk. Conclusions According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine. |
topic |
Nevirapine Pharmacogenetic Hepatotoxicity ABCB1 |
url |
http://link.springer.com/article/10.1186/s12879-018-3462-5 |
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