Advancing pharmacogenetic testing in a tertiary hospital: a retrospective analysis after 10 years of activity.

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy.

Identification and Functional Analysis of Variants in a Cohort of Hypercholesterolemic Patients.

Mutations in are the second most frequent cause of familial hypercholesterolemia (FH). is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize variants in patients with hypercholesterolemia.

Analytical validation of a laboratory-development multigene pharmacogenetic assay.

Objective: The implementation of pharmacogenetics (PGx) in clinical practice is an essential tool for personalized medicine. However, clinical laboratories must validate their procedures before being used to perform PGx studies in patients, in order to confirm that they are adequate for the intended purposes.

Methods: We designed a validation process for our in-house pharmacogenetic PCR-based method assay.

Familial hypercholesterolemia: A single-nucleotide variant (SNV) in mosaic at the low density lipoprotein receptor (LDLR).

Background And Aims: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes.

Loss-of-function mutation of PCSK9 as a protective factor in the clinical expression of familial hypercholesterolemia: A case report.

Rationale: Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events.

Patient Concerns: We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease.

A new variant in is associated with glycogen storage disease type IXa.

Glucogenosis type IX is caused by pathogenic variants of the gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. , , , and genes were analyzed by Next Generation Sequencing (NGS).

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

Background: Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF.

Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting.

Introduction: Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression.

Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.

Background: A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients.

Methods: DNA was available for 161 patients with validated outcomes.

Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/hepatitis C virus-coinfected patients treated for chronic hepatitis C.

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction.

Background: Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD.

Methods: TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4(+) cells and monocyte-derived macrophages (MDMs).

Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV–hepatitis C virus-coinfected patients with prior nonresponse or relapse.

IL28B polymorphisms predict treatment response in chronic hepatitis C. However, no information exists in prior treatment failures. A total of 62 HIV/hepatitis C virus (HCV) patients who completed retreatment with peginterferon-α/ribavirin were examined, of whom 25 (40%) had been cured.

Plasma raltegravir exposure influences the antiviral activity and selection of resistance mutations.

Raltegravir (RAL) resistance is associated with the selection of integrase mutations at positions 92, 143, 148, and/or 155. A substantial proportion of RAL failures, however, occurs in the absence of these changes. An examination of RAL plasma concentrations may help in interpreting this observation.

Short communication: use of serum bilirubin levels as surrogate marker of early virological response to atazanavir-based antiretroviral therapy.

Given that atazanavir (ATV) increases bilirubin in an exposure-dependent manner, we tested whether bilirubin levels could be used as a surrogate of virological response to ATV-based regimens in 182 patients. Bilirubin increases of ≥0.7 mg/dl were independently associated with early virological response with an odds ratio of 5.

Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients.

Introduction: Knowledge of drug interactions is vital to maximize antiretroviral efficacy and avoid drug-related toxicities. Treatment of co-morbidities has become a difficult task in HIV-infected individuals because pharmacokinetic and/or pharmacodynamic interactions are common when other medications are prescribed along with antiretroviral agents.

Areas Covered: This article provides an update of the most relevant drug interactions that occur between antiretroviral agents and other drugs.

Noncirrhotic portal hypertension in HIV infection.

Purpose Of Review: Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH).

Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial.

Background: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half-life might allow once-daily (qd) administration.

Methods: Consecutive HIV-infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir.

Population pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism and unboosted atazanavir clearance.

Atazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXR single nucleotide polymorphism (SNP) 63396C→T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations.

Influence of a single nucleotide polymorphism at the main ribavirin transporter gene on the rapid virological response to pegylated interferon-ribavirin therapy in patients with chronic hepatitis C virus infection.

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin.

Use of the HCP5 single nucleotide polymorphism to predict hypersensitivity reactions to abacavir: correlation with HLA-B*5701.

Objectives: To study the correlation between the HLA-B*5701 allele and the single nucleotide polymorphism in HCP5 (rs2395029).

Patients And Methods: All HIV patients naive for abacavir seen at our institution between September 2007 and December 2008 were prospectively screened for HLA-B*5701. HCP5 rs2395029 genotyping was carried out by allelic discrimination using the TaqMan 5'-nuclease assay.

Renal toxicity associated with tenofovir use.

Importance Of The Field: Tenofovir (TFV) is a nucleotide analogue widely used for the treatment of HIV infection. Despite its proven efficacy and safety, cases of kidney tubular dysfunction have increasingly been reported and concern exists about the risk of nephrotoxicity associated with the long-term use of TFV.

Areas Covered In This Review: Evidences about the renal toxicity associated with TFV use as well as predictors are examined.

Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C.

Chronic hepatitis C affects one-third of HIV(+) patients worldwide. High ribavirin (RBV) exposure is crucial to maximize the response to hepatitis C therapy in this population, although it may increase the risk for hemolytic anemia. PERICO is a prospective multicenter trial in which HIV/HCV-coinfected patients are randomized to receive peginterferon (pegIFN) alfa-2a 180 microg/week plus either weight-based RBV (1000-1200 mg/day) or RBV 2000 mg/day, the latest along with erythropoietin alfa (EPO) 30,000 IU/week from the first day until week 4.