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

BackgroundNevirapine 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.MethodsWe 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.ResultsThree 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.ConclusionsAccording 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.

Incidence and Risk Factors of Combined-Antiretroviral Therapy-Induced Hepatotoxicity among HIV Patients at the Bali District Hospital, Cameroon

“…In our study, many more femalesdevelopedhepatotoxicitywhen compared with males (Table 1).Our findings are similar to those of studiesreported in Fako-Cameroon [29,30], elsewhere in Ethiopia [15,31,33] and in Milan-Italy [21].However, studies in Zürich-Switzerland [37], Tanzania [36] and Ethiopia [23], reported higher rates of hepatotoxicity amongmale than female patients on cART.…”

“…Highly Active Anti-Retroviral Therapy (HAART)-associated hepatoxicity/ cART-induced hepatotoxicity (CIH), arbitrarily defined as AST or ALT > 3 X upper limit of normal (ULN) in the presence of symptoms, or serum AST or ALT > 5 X ULN in the absence of symptoms, usually resolves without modification of therapy [13][14][15][16][17][18]. Hepatotoxicity, which is the most cited reason for the withdrawal of approved drugs, is damage caused by exposure to a drug or non-pharmacological agents [19],and is consequently associated with HAART/ cART [15,20] especially nevirapine-based HAART [21] or efavirenz-based drug-induced liver injury [22]. In isolated instances, serious and life-threatening conditions may arise.…”

“…While all antiretroviral drugs have some risks of hepatotoxicity, some are more implicated than others. The non-nucleoside reverse transcriptase inhibitors (NNRTI) typically cause either hypersensitivity reactions or direct drug toxicity and therefore have two peaks of onset: within days to weeks or several months after initiation [25].Nevirapine (NVP) is the NNRTI most associated with hepatotoxicity [21], though hypersensitivity reactions resulting in liver failure have been reported with the newer NNRTI etravirine.Efavirenz and stavudine can also cause hepatotoxicity but does so less frequently than NVP or etravirine [22].…”

Incidence and Risk Factors of Combined-Antiretroviral Therapy-Induced Hepatotoxicity among HIV Patients at the Bali District Hospital, Cameroon

“…Active Anti-Retroviral Therapy (HAART)-associated hepatoxicity/ cART-induced hepatotoxicity (CIH), arbitrarily defined as AST or ALT > 3 X upper limit of normal (ULN) in the presence of symptoms, or serum AST or ALT > 5 X ULN in the absence of symptoms, usually resolves without modification of therapy [13][14][15][16][17][18]. Hepatotoxicity, which is the most cited reason for the withdrawal of approved drugs, is damage caused by exposure to a drug or nonpharmacological agents [19],and is consequently associated with HAART/ cART [15,20] especially nevirapine-based HAART [21] or efavirenz-based drug-induced liver injury [22]. In isolated instances, serious and life-threatening conditions may arise.…”

“…The non-nucleoside reverse transcriptases inhibitors (NNRTI) typically cause either hypersensitivity reactions or direct drug toxicity and therefore have two peaks of onset: within days to weeks or several months after initiation [25]. Nevirapine (NVP) is the NNRTI most associated with hepatotoxicity [21], though hypersensitivity reactions resulting in liver failure have been reported with the newer NNRTI etravirine. Efavirenz and stavudine can also cause hepatotoxicity but does so less frequently than NVP or etravirine [22].…”