aidsВИЧ-инфекция и иммуносупрессииHIV Infection and Immunosuppressive Disorders2077-9828Baltic Medical Education Center10.22328/2077-9828-2022-14-3-65-76aids-735Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESФармакогенетические эффекты однонуклеотидных полиморфизмов, влияющих на метаболизм антиретровирусных препаратовPharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolismhttps://orcid.org/0000-0002-7086-2779БаженоваА. Я.BazhenovaA.

Баженова Александра Ярославна — лаборант-исследователь лаборатории молекулярных методов изучения генетических полиморфизмов

111123, Москва, Новогиреевская ул., д. 3а

Moscow

bazhenovaaleksandra@gmail.comhttps://orcid.org/0000-0001-8207-9215МироновК. О.MironovK.

Миронов Константин Олегович — доктор медицинских наук, заведующий лаборатории молекулярных методов изучения генетических полиморфизмов 

111123, Москва, Новогиреевская ул., д. 3а

Moscow

mironov@pcr.ruhttps://orcid.org/0000-0001-7857-3763КравченкоА. В.KravchenkoA.

Кравченко Алексей Викторович — доктор медицинских наук, профессор, ведущий научный сотрудник 

111123, Москва, Новогиреевская ул., д. 3а

Moscow

alexey-kravtchenko@yandex.ruhttps://orcid.org/0000-0003-4228-9044АкимкинВ. Г.AkimkinV.

Акимкин Василий Геннадьевич — доктор медицинских наук, профессор, академик РАН, директор

111123, Москва, Новогиреевская ул., д. 3а

Moscow

akimkin@pcr.msЦентральный научно-исследовательский институт эпидемиологииРоссияCentral Research Institute of EpidemiologyRussian Federation2022101120221436576Copyright © Баженова А.Я., Миронов К.О., Кравченко А.В., Акимкин В.Г., 20222022Баженова А.Я., Миронов К.О., Кравченко А.В., Акимкин В.Г.Bazhenova A., Mironov K., Kravchenko A., Akimkin V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://hiv.bmoc-spb.ru/jour/article/view/735Введение

Введение. Определение фармакогенетических особенностей при назначении антиретровирусной терапии (АРТ) является важной составляющей персонализированного лечения ВИЧ-позитивных пациентов. АРТ может приводить к развитию различных нежелательных явлений (НЯ). Эффективность терапии и возникновение НЯ могут быть обусловлены генетической предрасположенностью, которую следует учитывать при выборе схемы АРТ. Некоторые известные аллели (HLAB*57:01 и UGT1A1*28) связаны с развитием НЯ и прекращением приема АРТ. В настоящее время важной клинической задачей является расширение спектра клинически значимых генетических тестов.

Цель

Цель. В обзоре представлены данные об эффектах генетических полиморфизмов, влияющих на переносимость АРТ. Проведен анализ данных об однонуклеотидных полиморфизмах (SNP) в генах, участвующих в метаболизме и транспорте АРТ. Результаты обзора предполагается использовать для разработки основанных на полимеразной цепной реакции методик определения аллелей риска в европейской популяции.

Материалы и методы

Материалы и методы. Проанализированы данные 46 публикаций. При анализе учитывались данные о частотах аллелей SNP в европейской популяции.

Результаты

Результаты. Выбрано несколько наиболее перспективных SNP. Полиморфизмы в генах ABCC4 (rs1751034, rs3742106) и ABCC10 (rs9349256, rs2125739) связаны с повышенным риском нарушения функции почек, обусловленного более высокой концентрацией в плазме крови препарата тенофовир. Показана эффективность одновременного исследования SNP в этих генах и CYP24A1 (rs2248359) как потенциального маркера нефротоксичности. Полиморфизм в гене CYP2B6 (rs3745274) связан с повышением концентрации эфавиренца в плазме крови, повышенным риском гепатотоксичности и развития НЯ со стороны ЦНС. SNP в CYP2B6, CYP2A6 (rs28399433) и CYP3A4 (rs4646437) следует исследовать вместе, поскольку все три SNP ассоциированы с высоким риском развития НЯ.

Заключение

Заключение. Описанные аллели SNP являются новыми диагностическими маркерами, которые могут быть использованы при назначении АРТ. Для оценки их клинической значимости и перспектив практического применения у пациентов с ВИЧ-инфекцией в России требуется проведение дополнительных исследований.

Introduction

Introduction. Identification of pharmacogenetic effects on antiretroviral therapy (ART) has become an important milestone to reach in the advancement of personalised treatment for HIV-positive patients. The therapy schemes are accompanied by multiple side effects. Therapy effectiveness and adverse reactions can be dictated by individual genetic predisposition factors, which should be taken into account for an optimal prescription. Some genetic markers (HLA-B*57:01 and UGT1A1*28), were already proven to improve discontinuation rates, and efforts are allocated to expand the range of clinically-relevant genetic tests.

Objective

Objective. In this review, an updated summary of genetic polymorphisms and their effects defining patients’ tolerability to ART is presented. The aim of this research is to assess single nucleotide polymorphisms (SNPs) present in the genes that encode proteins involved in ART metabolism and transport. This review will be used to develop a PCR-based testing methodology for the detection and confirmation of risk alleles in the Caucasian population.

Materials and methods

Materials and methods. Data from 46 original research papers and reviews was analysed. Allele frequencies of the most relevant polymorphisms were checked against the data for European population.

Results

Results. As an outcome of this review, a few most promising SNPs were selected for future research. Firstly, ABCC4 rs1751034 and rs3742106 and ABCC10 rs9349256 and rs2125739 were associated with an increased risk of renal impairment, higher plasma concentration, and toxicity when treated with tenofovir. Parallel analysis of ABCC4 and ABCC10 SNP effects on renal impairment together with CYP24A1 rs2248359 that was recently reported as a potential renal toxicity marker might be more informative. Secondly, CYP2B6 rs3745274 that was associated with an increased efavirenz plasma concentration, and increased risk of liver and CNS toxicity should be evaluated. SNPs in CYP2B6, CYP2A6 (rs28399433), and CYP3A4 (rs4646437) should be evaluated in parallel since possession of all three variants might put patients at a much higher risk.

Conclusion

Conclusion. Identified alleles could become new markers used in drug prescription protocols if significant effect in Caucasian population will be found. The most relevant SNPs should be tested in in supporting future studies to evaluate the significance for patients with HIV in Russia.

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The authors declare that there are no conflicts of interest present.