Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy

Antinori, Andrea; Baldini, Francesco; Girardi, Enrico; Cingolani, Antonella; Zaccarelli, Mauro; Giambenedetto, Simona Di; Barracchini, Annalisa; Longis, Patrizio De; Murri, Rita; Tozzi, Valerio; Ammassari, Adriana; Rizzo, Maria Gabriella; Ippolito, Giuseppe; Luca, Andrea De

doi:10.1097/00002030-200108170-00018

Cited by 69 publications

(54 citation statements)

References 7 publications

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“…Although this study is the first with an unselected outpatient clinic population including both antiretroviral naive and pretreated patients, the observed incidence was comparable to that reported in several clinical trials [9,10,11,12,13,14] and retrospective analyses [16,22,23,24]. Only seven patients (3.2%) in this population discontinued nevirapine because of rash, which is fairly low compared to other studies and reports [9,10,11,12,13,14,16,22,23].…”

Section: Discussionsupporting

confidence: 74%

“…With this strategy the incidence of rash reduced to 9-32% [9,10,11,12,13]. Other strategies that have been evaluated to reduce the occurrence of rashes include the use of corticosteroids and antihistamines as prophylaxis and the use of a slower induction phase of treatment [14,15,16,17]. The use of prophylaxis when initiating therapy with nevirapine remains controversial as contradictory results have been reported [14,15,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Other strategies that have been evaluated to reduce the occurrence of rashes include the use of corticosteroids and antihistamines as prophylaxis and the use of a slower induction phase of treatment [14,15,16,17]. The use of prophylaxis when initiating therapy with nevirapine remains controversial as contradictory results have been reported [14,15,16,17]. However, a slowly escalating dose of nevirapine (e.g., nevirapine 100 mg for the first week, and increasing 100 mg daily per week until achieving the full nevirapine dose by the fourth week) diminished the incidence of rash by approximately 40% compared to patients using the advised escalation dose (200 mg once daily the first 2 weeks) [14].…”

Section: Introductionmentioning

confidence: 99%

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Incidence and risk factors for nevirapine-associated rash

Maat

Heine

Mulder

et al. 2003

Eur J Clin Pharmacol

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Objective: To determine the incidence of rash in HIV-1 infected individuals starting a nevirapine-containing regimen in an unselected outpatient clinic population. Possible risk factors including plasma concentrations of nevirapine were evaluated for their relationship with the occurrence of a rash. Methods: The occurrence of rash was extracted from the outpatient medical records or based on a prescription of the antihistaminic cetirizine as documented by the community pharmacy within the first 90 days of nevirapine use. During regular visits to the clinic blood samples were collected for the determination of nevirapine plasma concentrations. Possible risk factors such as demographics, immunology, virology, clinical chemistry and antiretroviral pretreatment were collected at baseline for each patient. In addition, concomitantly used drugs during the nevirapine-based regimen were recorded. The association between these factors and the occurrence of rash was studied. Primary outcome was the onset of rash within the first 90 days after initiation of a nevirapinecontaining regimen. Results: Data from 216 HIV-1-infected patients were used in this study. Thirty-eight patients (17.6%) developed a rash of some grade that led to discontinuation of nevirapine in seven patients (3.2% of the included patients). The median time to occurrence of rash was 26 days (interquartile range 17-46 days). The multivariate analysis showed that patients pretreated with antiretroviral drugs less than 12 months before the initiation of a nevirapinecontaining regimen had a more than 2.5-fold increased risk of developing rash. Furthermore, nevirapine plasma concentrations were also significantly related to the occurrence of rash. A more than twofold increased risk for developing rash was observed for patients with nevirapine plasma concentrations above 5.3 mg/l. Conclusions: This is the first study demonstrating that patients with antiretroviral pretreatment less than 12 months and with nevirapine plasma concentrations above 5.3 mg/l during the first 90 days of treatment are at a higher risk for the development of rash. It is therefore advised to monitor this group of patients carefully when initiating nevirapine-containing therapy.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Incidence and risk factors for nevirapine-associated rash

Maat

Heine

Mulder

et al. 2003

Eur J Clin Pharmacol

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“…2011) 0.31 0.07 N/A Ugandan (Mukonzo et al, 2009) 0.36 0.10 NA Ghanaian (Bains et al, 2013;Griese et al 1999) 0 that it could be due to differential drug biotransformation, fat content, and exogenous and endogenous hormonal expression differences in males and females (Bersoff-Matcha et al, 2001;Dong et al, 2012;Marinho et al, 2013). Expression of liver enzymes responsible for drug metabolism has also been shown to vary with gender and BMI (Antinori et al, 2001;Bersoff-Matcha et al, 2001). In a comparison between NVP once and twice daily dosing, Schipani et al (2011) reported significantly increased NVP metabolism when body weight increased.…”

Section: Anthropometry Data and Nvp Plasma Concentrationmentioning

confidence: 99%

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-toperson variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G ( p < 0.001) and 516G/T ( p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes ( p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count ( p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter-and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.

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“…These adverse reactions are more frequent during the first 6 weeks of treatment and women (including those who are pregnant and of Asian ethnicity) seem to be at increased risk of developing NVP-related toxicities (Ho et al, 1998;Antinori et al, 2001;Bersoff-Matcha et al, 2001). Given that immunocompetence is regarded as an additional risk factor for the development of these reactions (De Lazzari et al, 2008), it is recommended that the drug should be initiated in cART-naïve-women with a CD4 cell count below 250 cells/mm 3 and below 400 cells/mm 3 in men (Thompson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity

Caixas¹,

Antunes²,

Marinho³

et al. 2012

Toxicology

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a b s t r a c tDespite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions.All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1 month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58 ± 0.8 fmol/g of hemoglobin).This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.© 2012 Published by Elsevier Ireland Ltd.Abbreviations: cART, combined antiretroviral therapy; CID, collision-induced dissociation; GSH, glutathione; Hb, hemoglobin; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; 12-OH-NVP, 12-hydroxy-nevirapine; LC-ESI-MS/MS, liquid chromatography-electrospray ionization-tandem mass spectrometry; MHC, major histocompatibility complex; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine.* Corresponding author.

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Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy

Cited by 69 publications

References 7 publications

Incidence and risk factors for nevirapine-associated rash

Incidence and risk factors for nevirapine-associated rash

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity

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