GENETIC MARKERS OF CLINICALLY MANIFESTED ADVERSE EFFECTS IN HIV PATIENTS RECEIVING ANTIRETROVIRAL THERAPY

The presence of the alleles UGT1A1*28 and HLA B*5701 was checked up in 47 and 366 adult HIV patients, respectively. The rate and severity of the adverse effects of using Atazanavir or Abacavir in ART during 2003-2013 were compared with the genetic findings. The prevalences of grade 3 or 4 increases in unconjugated bilirubin and of overt jaundice upon ART were 36,2% and 10.6%, respectively. The highest risk of profound hyperbilirubinemia was featured by patients homozygotic for UGT1A1*28. This allele was found in 57,4% of patients, including 14,9% homozygotes. HLA B*5701 was found in 13 patients (3,7%). Taking account of testing results decreased the rate of ART discontinuation to 4,7%. The specificity of the test was 100% and its sensitivity and informativeness was 99,2%.

ВИЧ-инфекция, антиретровирусная терапия, гипербилирубинемия, желтуха, реакция гиперчувствительности, HIV infection, antiretroviral therapy, hyperbilirubinemia, jaundice, hypersensitivity reactions

1. Phillips E.J., Mallal S.A. Pharmacogenetics and the potential for the individualization of antiretroviral therapy // Curr. Opin. Infect. Dis., 2008.- Vol. 21 (1).- P 16-24.

2. Bosma P.J., Chowdhury J.R., Bakker C., Gantla S., de Boer A., Oostra B.A., Lindhout D., Tytgat G.N., Jansen P.L., Oude Elferink R.P. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome // N. Engl. J. Med., 1995.- Vol. 333 (18).- P 1171-1175.

3. Molina J.M., Andrade-Villanueva J., Echevarria J., Chetchotisakd P., Corral J., David N., Moyle G., Mancini M., Percival L., Yang R., Wirtz V., Lataillade M., Absalon J., McGrath D. Once-daily atazanavir/ritonavir versus lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the Castle study // Lancet, 2008.- Vol. 372 (9639).- P 646-655.

4. Rubio R., Serrano O., Carmena J., Asensi V., Echevarria S., Flores J., Ribera E., Zarraga M., Ocampo A., de la Fuente B., Sepulveda M.A., Marino A.I., Minguez C., Vicent R., Carton J.A., Moyano B., Esteban H., Mahillo B., Serrano L., Gonzalez-Garcia J. Effect of simplification from protease inhibitors to boosted atazanavirbased regimens in real-life conditions // HIV Med., 2010.- Vol. 11 (9).- P 545-553.

5. Rotger M., Taffe P., Bleiber G., Gunthard H.F., Furrer H., Vernazza P., Drechsler H., Bernasconi E., Rickenbach M., Telenti A. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia // J. Infect. Dis., 2005.- Vol. 192 (8).- P 1381-1386.

6. Beutler E., Gelbart T., Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? // Proc. Natl. Acad. Sci. U SA, 1998; Vol. 95 (14).- P 8170-8174

7. Ki C.S., Lee K.A., Lee S.Y., Kim H.J., Cho S.S., Park J.H., Cho S., Sohn K.M., Kim J.W. Haplotype structure of the UDP-glucuronosyl-transferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population // Clin. Chem., 2003.- Vol. 49 (12).- P 2078-2081.

8. Takeuchi K., Kobayashi Y., Tamaki S., Ishihara T., Maruo Y., Araki J., Mifuji R., Itani T., Kuroda M., Sato H., Kaito M., Adachi Y. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert’s syndrome as well as in healthy Japanese subjects // J. Gastroenterol. Hepatol., 2004.- Vol. 19 (9).- P 1023-1028.

9. Yamamoto K., Sato H., Fujiyama Y., Doida Y., Bamba T. Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert’s syndrome and Crigler-Najjar syndrome type II // Biochim Biophys Acta, 1998.- Vol. 1406 (3).- P 267-273.

10. Park W.B., Choe P.G., Song K.H. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDPglucuronosyltransferase 1A1*28 allele frequency // Clin. Infect. Dis., 2010.- Vol. 51 (1).- P 101-106.

11. Lankisch T.O., Moebius U., Wehmeier M., Behrens G., Manns M.P., Schmidt R.E. Gilbert’s disease and atazanavir: from phenotype toUDP-glucuronosyltransferase haplotype // Hepatology, 2006.- Vol. 44 (5).- P 1324-1332.

12. Torti C., Lapadula G., Antinori A., Quirino T., Maserati R., Castelnuovo F., Maggiolo F., De Luca A., Paraninfo G., Antonucci F., Migliorino G., Lazzarin A., Di Perri G.,Rizzardini G., Esposito R., Carosi G. Hyperbilirubinemia during atazanavir treatment in 2,404 patients in the Italian atazanavir expanded access program and MASTER Cohorts // Infection, 2009.- Vol. 37 (3).- P 244-249.

13. Lubomirov R., Colombo S., Di Iulio J., Ledergerber B., Martinez R., Cavassini M., Hirschel B., Bernasconi E., Elzi L., Vernazza P., Furrer H., Gunthard H.F., Telenti A. Association of Pharmacogenetic Markers with Premature Discontinuation of First-line Anti-HIV Therapy: An Observational Cohort Study // J. Inf. Dis., 2011.- Vol. 203.- P 246-257.

14. Инструкция по медицинскому применению препарата кивекса /kivexa / ЗАО ГлаксоСмитКляйн Трейдинг.- 21. с.- URL:http://arvt.ru/sites/default/files/Kivexa.pdf (дата обращения 01.02.2014 г.).

15. Туманов А.С., Лага В.Ю., Казеннова Е.В., Туманов А.С., Лага В.Ю., Казеннова Е.В., Козырев О.А., Сотников В.П., Кулагин В.В., Тонких О. С., Хафизов К.М., Ульянина Н.И., Рахманова А.Г., Потемина Л.П., Цыбакова О.А., Воронин Е.Е., Вдовина В.Н., Ольшанский А.Я., Бобкова М.Р. Оценка распространенности аллеля HLA-B*5701 среди ВИЧ-инфицированных лиц на территории европейской части Российской Федерации // Медицинская генетика, 2010.- № 8.- С. 36-39.

16. Кравченко А.В., Канестри В.Г. Нуклеозидные ингибиторы обратной транскриптазы ВИЧ - препараты абакавир и ламивудин а схемах антиретровирусной терапии первой линии // Эпидемиология и инфекционные болезни. Актуальные вопросы, 2011.- № 2.- С. 49-55.

17. Миронов К.О., Дунаева Е.А., Дрибноходова О.П., Дедков В.Г., Шипулин Г.А. Детекция генетических полиморфизмов с использованием системы генетического анализа на основе пиросеквенирования PyroMark Q24. Справочник заведующего КДЛ.- М., 2011.- № 4.- С. 39-48.

18. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events/ Versoin 1.0, December 2004; Clarification August 2009.- http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf (дата обращения 05.03.2014).

19. Squires K.E., Young B., Dejesus E., Bellos N., Murphy D., Zhao H.H., Patel L.G., Ross L.L., Wannamaker P.G., Shaefer M.S. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients // AIDS.- 2010.- Vol. 24 (13).- Р. 2019-2027.