ASSOCIATION OF SPECIFIC GENETIC MARKERS OF THE HOST WITH THE RESPONSE TO ANTIRETROVIVAL THERAPY IN HIV POSITIVE PATIENTS
Keywords:
HIV infection, High Active Antiretroviral TherapyAbstract
The aim of our study was to investigate the influence of various host genetic markers on the efficacy and safety of antiretroviral drugs in the Macedonian population. The analyzed cohort consisted of 361 HIV patients, 333(92.2%) male and 28(7.8%) female, with mean age at diagnosis of 33.6 years (range 4-65 years). The median follow-up after diagnosis was 4.3 years (0-29.5 years), within which 12 patients died. As expected, the antiretroviral treatment had a dramatic effect on reducing the viral load, from 4.702x104 (range 0-109) to 0 between their first and last PCR test (p=2.2x10-16).
We determined the allele frequencies of CYP2D6 and stratified them between HIV patients who never achieved undetectable viral load (UVL) and those who demonstrated UVL at least at one PCR test. Based on the CYP2D6 status, patients were categorized as Extensive Metabolizers (EM) and 16 as Poor Metabolizers (PM). We found that neither CYP2D6 allele or allele combination, nor the EM/PM status were significantly associated with achieving UVL (p=0.2). When adjusted for age at diagnosis and sex in a logistic regression model, neither CYP2D6 alleles nor EM/PM phenotype reached a statistically significant level of association with achieving UVL, except for the trend for CYP2D6 allele *6 to lower the odds of reaching UVL, OR=0.16 (95CI 0.02-0.974).
The results from our preliminary analysis indicate much higher frequency of CYP2D6 EM vs. PM phenotype in the Macedonian population and no significant influence on the treatment efficacy in terms of achieving UVL.
References
UNAIDS. Preliminary epidemiological estimates https://www.unaids.org/en/resources/ fact-sheet. 2021; https://www.unaids.org/en/resources/fact-sheet https://www.unaid s.org/ en/resources/documents/2021/2021-global-aids-update.
Global AIDS Update. Seizing the moment. Trackling entrenched inequalities to end epidemics. 2020. https://healtheducationresources.unesco.org/library/documents/global-aids-update-2020-seizing-moment-tackling-entrenched-inequalities.
UNAIDS.UNAIDS_2021_FactSheet_en_em. https://embargo.unaids.org/static/files/ uploaded_files/UNAIDS_2021_FactSheet_en_em.pdf.
Bulstra CA, Hontelez JAC, Otto M, Stepanova A, Lamontagne E, Yakusik A, et al. Integrating HIV services and other health services: A systematic review and meta-analysis. PLoS Med 2021; 18(11): e1003836. doi: 10.1371/journal.pmed.1003836.
Mikic V, KG, KD, BG. Report from the bio-behavioral study among men having sex with men in Skopje, Macedonia and estimation of population size, 2017-2018, Skopje instityte of public Health 2018, COBISS. MK-ID 109184266. 2019;?????
Public health institute: Reprt of activities and achieved results according to the programme for population protection from HIV in Republic of North Macedonia for 2020.2021.
World Bank. 2015. Optimizing Investments in Former Yugoslav Republic of Macedonia’s HIV Response. © World Bank, Washington, DC. http://hdl.handle.net/10986/25378 License: CC BY 3.0 IGO.”
Dominkovic Z. SM, SA, PE, TJ, MV,. Evaluation of the Continium of HIV care in North Macedonia: Assesment Report on men Who have Sex with Man. 2021; 1-15.
Tozzi V. Pharmacogenetics of antiretrovirals. Antiviral Res. 2010; 85(1): 190-200. doi: 10.1016/j.antiviral.2009.09.001.
Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA 2014; 312(4): 410-425. doi: 10.1001/jama.2014.8722. PMID: 25038359.
World Health Organizations. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendation for a public a public health approach 2 Ed. 2016; World Health Organization. https://www.who.int/publications/i/item/9789241549684.
Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 2012; 92(4): 414-417. doi: 10.1038/clpt.2012.96.
Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372(9635): 293-299. doi: 10.1016/S0140-6736(08)61113-7.
Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, et al. Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLOS ONE 2013; 8(12): e81355. doi: 10.1371/journal.pone.0081355. eCollection 2013.
Sim SC, Ingelman-Sundberg M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics 2010; 4(4): 278-81. doi: 10.1186/1479-7364-4-4-278
Petrović J, Pešić V, Lauschke VM. Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe. Eur J Hum Genet 2020; 28(1): 88-94. doi: 10.1038/s41431-019-0480-8.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41(2): 89-295. doi: 10.1080/ 03602530902843483.
Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002; 359(9300): 30-36. doi: 10.1016/S0140-6736(02)07276-8.
Van Vaerenbergh K. Study of the impact of HIV genotypic drug resistance testing on therapy efficacy. Verh K Acad Geneeskd Belg 2001; 63(5): 447-473. PMID: 11813503.
Yang Z, Wu D, Bui T, Ho RJ. A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport. J Pharmacol Exp Ther 2008; 327(2): 474-481. doi: 10.1124/jpet.108.138313.
Marasca GS, Machado AL, Kretzmann NA Filho, Souza AC, Mattos AA, Kliemann D, et al. Frequency of the mdr1 gene polymorphism rs1045642 (c3435t) in hcv-hiv co-infected patients. Arq Gastroenterol 2016; 53(4): 246-249. doi: 10.1590/S0004-28032016000400007.
Crovella S, Biller L, Santos S, Salustiano A, Brandao L, Guimaraes R, et al. Frequency of HLA B*5701 allele carriers in abacavir treated-HIV infected patients and controls from northeastern Brazil. Clinics (Sao Paulo) 2011; 66(8): 1485-1488. doi: 10.1590/s1807-59322011000800030.
Aksak-Wąs BJ, Urbańska A, Scheibe K, Serwin K, Leszczyszyn-Pynka M, Rafalska-Kosior M, et al. Factors Influencing Immune Restoration in People Living with HIV/AIDS. J Clin Med 2022; 11(7): 1887. doi: 10.3390/jcm11071887.
Vaidya SA, Streeck H, Beckwith N, Ghebremichael M, Pereyra F, Kwon DS, Addo MM, et al. Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection. Retrovirology 2013; 10: 139. doi: 10.1186/1742-4690-10-139.
Aksak-Wąs BJ, Parczewski M, Urbańska A, Hackiewicz M, Kowalska JD. Correction: Influence of HLA-B*5701 on 20 year survival rate among patients living with HIV. PLOS ONE 2022; 17(8): e0272759. ttps://doi.org/10.1371/journal.pone.0272759.
Kuzmanovska M, Dimishkovska M, Maleva Kostovska I, Noveski P, Sukarova Stefanovska E, et al. CYP2D6 allele distribution in Macedonians, Albanians and Romanies in the Republic of Macedonia. Balkan J Med Genet 2016; 18(2): 49-58. doi: 10.1515/bjmg-2015-0086.
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