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Clinical perspectives on human genetic screening to prevent nevirapine toxicity.

ABSTRACT: Nevirapine is one of the most extensively prescribed antiretroviral drugs worldwide. However, a concern is increased risk for severe toxicity when antiretroviral-naive individuals with higher CD4 T-cell counts initiate nevirapine-containing regimens. Several genetic variants are associated with nevirapine toxicities. The authors used data from a previous study to anticipate potential consequences of genetic screening to prevent nevirapine adverse events. That study enrolled cohorts of African, Asian and European descent in 11 countries, including 276 patients who had experienced severe cutaneous and/or hepatic adverse events with nevirapine-containing regimens and 587 matched nevirapine-tolerant controls. Associations were identified with HLA-Cw*04, HLA-B*35, HLA-DRB*01 and CYP2B6 516G>T (rs3745274); however, positive predictive values for these genetic markers were low, and most nevirapine-associated adverse events occurred in patients without these markers. Unless better genetic predictors are identified, nevirapine toxicity is best avoided by continuing to follow current prescribing guidelines that are based largely on CD4 T-cell criteria.

SUBMITTER: Haas DW

PROVIDER: S-EPMC3579661 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Clinical perspectives on human genetic screening to prevent nevirapine toxicity.

Haas David W DW Mootsikapun Piroon P Ruxrungtham Kiat K Podzamczer Daniel D

Personalized medicine 20120901 7

Nevirapine is one of the most extensively prescribed antiretroviral drugs worldwide. However, a concern is increased risk for severe toxicity when antiretroviral-naive individuals with higher CD4 T-cell counts initiate nevirapine-containing regimens. Several genetic variants are associated with nevirapine toxicities. The authors used data from a previous study to anticipate potential consequences of genetic screening to prevent nevirapine adverse events. That study enrolled cohorts of African, A ...[more]

PMID: 23439719

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Project description:Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV-1 transmission in developing countries. Despite its clinical efficacy, NVP administration is associated with a variety of toxic responses that include hepatotoxicity and skin rash. Although the reasons for the adverse effects of NVP administration are still unclear, increasing evidence supports the involvement of metabolic activation to reactive electrophiles. In particular, Phase II activation of the NVP metabolite 12-hydroxy-NVP is thought to mediate NVP binding to bionucleophiles, which may be at the onset of toxicity. In the present study, we investigated the nature and specific locations of the covalent adducts produced in human serum albumin and human hemoglobin by reaction in vitro with the synthetic model electrophile 12-mesyloxy-NVP, used as a surrogate for the Phase II metabolite 12-sulfoxy-NVP. Multiple sites of modification were identified by two different mass spectrometry-based methodologies, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-TOF-TOF-MS). These two distinct methodologies, which in some instances afforded complementary information, allowed the identification of multiple adducts involving cysteine, lysine, tryptophan, histidine, serine, and the N-terminal valine of hemoglobin. Tryptophan, which is not a common site of covalent protein modification, was the NVP-modified amino acid residue detected in the two proteins and consistently identified by both LC-ESI-MS/MS and MALDI-TOF-TOF-MS. The propensity of tryptophan to react with the NVP-derived electrophile is further emphasized by the fact that human serum albumin possesses a single tryptophan residue, which suggests a remarkable selectivity that may be useful for biomonitoring purposes. Likewise, the NVP adduct with the terminal valine of hemoglobin, detected by LC-ESI-MS/MS after N-alkyl Edman degradation, appears as an easily assessed marker of NVP binding to proteins. Our results demonstrate the merits and complementarity of the two MS-based methodologies for the characterization of protein binding by NVP and suggest a series of plausible biomarkers of NVP toxicity that should be useful in the monitoring of toxicity effects in patients administered NVP.

Project description: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 ?2 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.

Project description:ObjectivesSocial determinants of health are major drivers of health outcomes and quality of life. While several social needs screening tools have been created for use in primary care settings, the best procedures to incorporate these tools into hospital workflow remain unclear. This study aimed to elicit clinical stakeholder perspectives on proposed screening for social needs during pediatric hospitalizations, with particular focus on informing implementation strategies.MethodsWe conducted 23 semistructured interviews with pediatric clinical stakeholders (physicians, nurses, social workers, and case managers) at 1 tertiary and 2 community hospitals between July 2020 and January 2021, on topics including social needs screening practices, benefits and challenges to inpatient screening, and optimal screening and referral processes within hospital workflow. Interviews were recorded, professionally transcribed, and analyzed thematically.ResultsParticipants ranged in age from 25 to 62 years, with nearly half working in community hospitals. Regarding inpatient social needs screening, themes emerged about benefits, including enabling clinicians to identify vulnerable patients/moments, and providing clinicians with comprehensive understanding of social context; barriers, including prioritization of medical needs, lack of clinician education surrounding screening, and lack of pre-established relationships; facilitators, including duration of time spent with families, and multidisciplinary clinicians; screening process preferences, including verbal screening, and integration into pre-existing systems; and referral process preferences, including resource provision with family empowerment, and care transition to outpatient clinicians.ConclusionsClinical stakeholders identified multiple barriers, facilitators, and process preferences for pediatric inpatient social needs screening, which may inform the future development of feasible and sustainable implementation strategies.

Project description:BackgroundAtrial fibrillation (AF) is common, often without symptoms, and is an independent risk factor for mortality, stroke and heart failure. It is unknown if screening asymptomatic individuals for AF can improve clinical outcomes.MethodsmSToPS was a pragmatic, direct-to-participant trial that randomized individuals from a single US-wide health plan to either immediate or delayed screening using a continuous-recording ECG patch to be worn for two weeks and 2 occasions, ~3 months apart, to potentially detect undiagnosed AF. The 3-year outcomes component of the trial was designed to compare clinical outcomes in the combined cohort of 1718 individuals who underwent monitoring and 3371 matched observational controls. The prespecified primary outcome was the time to first event of the combined endpoint of death, stroke, systemic embolism, or myocardial infarction among individuals with a new AF diagnosis, which was hypothesized to be the same in the two cohorts but was not realized.ResultsOver the 3 years following the initiation of screening (mean follow-up 29 months), AF was newly diagnosed in 11.4% (n = 196) of screened participants versus 7.7% (n = 261) of observational controls (p<0.01). Among the screened cohort with incident AF, one-third were diagnosed through screening. For all individuals whose AF was first diagnosed clinically, a clinical event was common in the 4 weeks surrounding that diagnosis: 6.6% experienced a stroke,10.2% were newly diagnosed with heart failure, 9.2% had a myocardial infarction, and 1.5% systemic emboli. Cumulatively, 42.9% were hospitalized. For those diagnosed via screening, none experienced a stroke, myocardial infarction or systemic emboli in the period surrounding their AF diagnosis, and only 1 person (2.3%) had a new diagnosis of heart failure. Incidence rate of the prespecified combined primary endpoint was 3.6 per 100 person-years among the actively monitored cohort and 4.5 per 100 person-years in the observational controls.ConclusionsAt 3 years, screening for AF was associated with a lower rate of clinical events and improved outcomes relative to a matched cohort, although the influence of earlier diagnosis of AF via screening on this finding is unclear. These observational data, including the high event rate surrounding a new clinical diagnosis of AF, support the need for randomized trials to determine whether screening for AF will yield a meaningful protection from strokes and other clinical events.Trail registrationThe mHealth Screening To Prevent Strokes (mSToPS) Trial is registered on ClinicalTrials.gov with the identifier NCT02506244.

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Clinical perspectives on human genetic screening to prevent nevirapine toxicity.

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Clinical perspectives on human genetic screening to prevent nevirapine toxicity.

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