Аdverse events underlying antiretroviral therapy in children with HIV infection

Introduction. Human immunodeficiency virus infection can alter properties of blood vessels in children and increase the risk of development of cardiovascular diseases in the future. Today the actual contribution of the effects of both HIV infection and antiretroviral therapy into such changes remains unknown.
Objective. We seek to assess adverse events, including metabolic disorders (dyslipidemias), underlying antiretroviral therapy, and to determine the relation between metabolic disorders and intima injury in children receiving antiretroviral therapy (ART).
Materials and methods. The adverse events were investigated within the framework of a prospective and retrospective study. The study included evaluation of biochemical parameters in relation to the therapeutic regimen; calculation of atherogenic index of plasma; and determination of incidence of dyslipidemia in children. In addition to standard tests, children on ART were evaluated for insulin resistance (using HOMA-IR) and submitted to diagnostic imaging including Doppler ultrasonography of brachiocephalic arteries and veins.
Results. Children on protease inhibitor-based ART have higher total cholesterol, LDL and triglyceride levels in comparison to both children on NNRTI-based ART and children who do not receive ART. LDL levels in children on long-term ART remained within the tolerance range and were clearly higher than those in children who did not receive ART. Carotid IMT was higher in children on NNRTI-based ART in comparison to those who received protease inhibitor-based therapy; and the correlation analysis conducted revealed positive correlation between the age and carotid IMT: The later ART was prescribed, the greater IMT was, which most likely was attributable to HIV effects.
Conclusion. Prescription of antiretroviral therapy at an older age results in changes in the intima-media complex, which may give evidence to vasoprotective effects of the therapy. Since HIV is directly involved in causing injury to the intima, it is advisable to start managing HIV infection in children as soon as they are diagnosed with the infection; and children to whom ART is prescribed at an older age and who develop dyslipidemia should be additionally evaluated by medical imaging with Doppler ultrasonography with carotid IMT measurement.

1. Воронин Е.Е., Латышева И.Б. Об итогах службы по профилактике и борьбе со СПИДом в Российской Федерации // Уральский медицинский журнал. 2020. № 4 (187). С. 5–6. [Voronin E.E., Latysheva I.B. About the results of the Service for the prevention and control of AIDS in the Russian Federation. Ural Medical Journal, 2020, No. 4 (187), pp. 5–6 (In Russ.)]. doi: 10.25694/URMJ.2020.04.35.

2. Вирус иммунодефицита человека — медицина / под ред. Н. А. Белякова и А. Г. Рахмановой. СПб.: Балтийский медицинский образовательный центр, 2010. 752 с. [Human Immunodeficiency Virus: medicine. Edited by: prof. N. A. Belyakov, prof. A. G. Rakhmanova. St. Petersburg: Baltic Medical Educational Center, 2010, 752 р. (In Russ)].

3. Бартлет Дж., Галлант Дж., Фам П. Клинические аспекты ВИЧ-инфекции. М.: Р. Валент, 2012. 527 с. [Bartlett J., Gallant J., Pham P. Clinical aspects of HIV infection. Moscow: Рublishing house R. Valent, 2012, 527 p. (In Russ)].

4. The Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group. Factors associated with specific causes of death amongst HIVpositive individuals in the D:A:D study // AIDS. 2010. Vol. 24, No. 10. Р. 1537–1548. doi: 10.1097/QAD.0b013e32833a0918.

5. Geffner M.E., Patel К., Miller T.L., Hazra R., Silio M., Van Dyke R.B., Borkowsky W., Worrell C., DiMeglio L.A., Jacobson, D.L., Pediatric HIV/AIDS Cohort Study. Factors associated with insulin resistance among children and adolescents perinatally infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study (PHACS) // Hormone Research in Paediatrics. 2011. Vol. 76, No. 6. Р. 386–391. doi: 10.1159/000332957.

6. Jacobson D.L., Patel К., Siberry G.K., Van Dyke R.B., DiMeglio L.A., Geffner M.E., Chen J.S., McFarland E.J., Borkowsky W., Silio М., Fielding R.A., Siminski S., and Miller T.L. for the Pediatric HIV/AIDS Cohort Study. Body fat distribution in perinatally HIV-infected and HIVexposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study (PHACS) // The American Journal of Clinical Nutrition. 2011. Vol. 94, No. 6. Р. 1485–1495. doi: 10.3945/ajcn.111.020271.

7. Dirajlal-Fargo S., Sattar A., Kulkarni M., Bowman E., Funderburg N., McComsey G.A. HIV-positive youth who are perinatally infected have impaired endothelial function // AIDS. 2017. Vol. 31, No. 14. Р. 1917–1924. doi: 10.1097/QAD.0000000000001556.

8. El-Sadr W.M., Mullin С.М., Carr А. Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviralnaive cohort // HIV Medicine. 2005. Vol. 6, No. 2. Р. 114–121. doi: 10.1111/j.1468–1293.2005.00273.x.

9. Feingold K., Krauss R., Pang М. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B // The Journal of Clinical Endocrinology & Metabolism. 1993. Vol. 76, No. 6. Р. 1423–1427. doi: 10.1210/jcem.76.6.8501146.

10. Carter R.J., Wiener J., Abrams E. J. Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999–2004: a longitudinal analysis // JAIDS: Journal of Acquired Immune Deficiency Syndromes. 2006. Vol. 41, No. 4. Р. 453–460. doi: 10.1097/01.qai.0000218344.88304.db.

11. Dapena M., Jiménez B., Noguera-Julian A., Soler-Palacín P., Fortuny C., Lahoz R., Aracil F.J., Figueras C., de José M.I. Metabolic disorders in vertically HIV-infected children: future adults at risk for cardiovascular disease // Journal of Pediatric Endocrinology and Metabolism. 2012. Vol. 25, No. 5–6. Р. 529–535. doi: 10.1515/jpem-2012-0005.

12. Dzwonek A.B., Lawson M.S., Cole T.J., Novelli V. Body Fat Changes and Lipodystrophy in HIV-infected Children: Impact of Highly Active Antiretroviral Therapy // JAIDS: Journal of Acquired Immune Deficiency Syndromes. 2006. Vol. 43, No. 1. Р. 121–123. doi: 10.1097/01.qai.0000230523.94588.85.

13. Aldrovandi G.M., Lindsey J.C., Jacobson D.L., Zadzilka A., Sheeran E., Moye J., Borum P., Meyer WA 3rd., Hardin D.S., Mulligan K., Pediatric AIDS Clinical Trials Group P1045 team. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth // AIDS. 2009. Vol. 23, No. 6. Р. 661–672. doi: 10.1097/QAD.0b013e3283269dfb.

14. Musiime V. Anthropometric measurements and lipid profiles to detect early lipodystrophy in antiretroviral therapy experienced HIV-infected children in the CHAPAS-3 trial // Antiviral therapy. 2014. Vol. 19, No. 3. Р. 269–276. doi: 10.3851/IMP2695.

15. Arpadi S., Shiau S., Strehlau R., Martens L., Patel F., Coovadia A., Abrams E.J., Kuhn L. Metabolic abnormalities and body composition of HIVinfected children on Lopinavir or Nevirapine-based antiretroviral therapy // Archives of Disease in Childhood. 2013. Vol. 98, No. 4. Р. 258–264. doi: 10.1136/archdischild-2012-302633.

16. Fabiano V., Giacomet V., Viganò A., Bedogni G., Stucchi S., Cococcioni L., Mora S., Zuccotti G.V. Long-term body composition and metabolic changes in HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to efavirenz // European Journal of Pediatrics. 2013. Vol. 172, No. 8. Р. 1089–1096. doi: 10.1007/s00431-013-2018-3.

17. Самарина А.В., Дылдина Н.С., Фертих Е.К., Ястребова Е.Б., Абрамова И.А., Гусев Д.А. Коррекция нарушений липидного обмена у детей на фоне АРТ с применением ингибитора интегразы // Журнал инфектологии. 2019. Т. 11, № 3. С. 63–70. [Samarina A.V., Dyldina N.S., Fertikh E.K., Yastrebova E.B., Abramova I.A., Gusev D.A. Lipid abnormality correction by integrase inhibitor among children taking Art. Journal Infectology, 2019, Vol. 11, No. 3, pp. 63–70 (In Russ.)]. doi: 10.22625/2072-6732-2019-11-3-63-68.

18. Bots M.L., Evans G.W., Tegeler C.H., Meijer R. Carotid Intima-media Thickness Measurements: Relations with Atherosclerosis, Risk of Cardiovascular Disease and Applicationin Randomized Controlled Trials // Chinese Medical Journal. 2016. Vol. 129, No. 2. Р. 215–226. doi: 10.4103/0366-6999.173500.

19. Steinl D.C., Kaufmann B.A. Ultrasound Imaging for Risk Assessment in Atherosclerosis // International Journal of Molecular Sciences. 2015. Vol. 16, No. 5. Р. 9749–9769. doi: 10.3390/ijms16059749.

20. Лебедев А.В., Малявская С.И., Соболева Е.В. Толщина комплекса интима–медиа у детей и подростков с высоким нормальным артериальным давлением // Журнал научных статей «Здоровье и образование в XXI веке». 2014. Т. 16, № 1. С. 22–23. [Lebedev A.V., Malyavskaya S.I., Soboleva E.V. The intima-media thickness in children and adolescents with high normal blood pressure. The Journal of Scientific Articles «Health & education millennium», 2014, Vol. 16, No.1, рр. 22–23 (In Russ.)].

21. Садыкова Д.И., Галимова Л.Ф., Леонтьева И.В., Сластникова Е.С. Оценка толщины комплекса интима–медиа у детей с семейной гиперхолестеринемией // Российский вестник перинатологии и педиатрии. 2018. Т. 63, № 5. С. 152–154. [Sadykova D.I., Galimova L.F., Leontyeva I.V., Slastnikova E.S. Evaluation of the thickness of the intima-media complex in children with familial hypercholesterolemia. Russian Bulletin of Perinatology and Pediatrics, 2018, Vol. 63, No. 5, рр. 152–154 (In Russ.)]. doi: 10.21508/1027–4065–2018–63–5-152–154.

22. Giuliano Ide C., de Freitas S.F., de Souza M., Caramelli B. Subclinic atherosclerosis and cardiovascular risk factors in HIV-infected children: PERI study // Coronary Artery Disease. 2008. Vol. 19, No. 3. Р. 167–172. doi: 10.1097/MCA.0b013e3282f6dffb.

23. McComsey G.A., O’Riordan M., Hazen S.L., El-Bejjani D., Bhatt S., Brennan M.L., Storer N., Adell J., Nakamoto D.A., Dogra V. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children // AIDS. 2007. Vol. 21, No. 8. Р. 921–927. doi: 10.1097/QAD.0b013e328133f29c.

24. Sainz T. Subclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents: the CaroVIH Study // JAIDS: Journal of Acquired Immune Deficiency Syndromes. 2014. Vol. 65, No. 1. Р. 42–44. doi: 10.1097/QAI.0b013e3182a9466a.

25. Vigano A., Bedogni G., Cerini C., Meroni L., Giacomet V., Stucchi S., Fabiano V., Coletto S., Catalano M., Minola M., Zuccotti G.V. Both HIVinfection and long-term antiretroviral therapy are associated with increased common carotid intima-media thickness in HIV-infected adolescents and young adults // Current HIV Research. 2010. Vol. 8, No. 5. Р. 411–417. doi: 10.2174/157016210791330419.

26. Chanthong P., Lapphra К., Saihongthong S., Sricharoenchai S., Wittawatmongkol O., Phongsamart W., Rungmaitree S., Kongstan N., Chokephaibulkit K. Echocardiography and carotid intima-media thickness among asymptomatic HIV-infected adolescents in Thailand // AIDS. 2014. Vol. 28, No. 14. Р. 2071–2079. doi: 10.1097/QAD.0000000000000376.

27. Ross A.C., Storer N., O’Riordan M.A., Dogra V., McComsey G.A. Longitudinal changes in carotid intima-media thickness and cardiovascular risk factors in human immunodeficiency virus-infected children and young adults compared with healthy controls // The Pediatric Infectious Disease Journal. 2010. Vol. 29, No. 7. Р. 634–638. doi: 10.1097/inf.0b013e3181d770c4.

28. Doyon А. Carotid artery intima-media thickness and distensibility in children and adolescents: reference values and role of body dimensions // Hypertension. 2013. Vоl. 62, No. 3. Р. 550–556. doi: 10.1161/HYPERTENSIONAHA.113.01297.

29. National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents // Pediatrics. 1992. Vol. 89, No. 3. Р. 495–501.

30. Ковтун О.П., Устюжанина М.А. Полиморфизм генов PPARG (P12A), APOA1 (G75A) и APOE (C112Aи A158C) у детей с ожирением и артериальной гипертензией: исследование «случай–контроль» // Вопросы современной педиатрии. 2018. Т. 17, № 4. С. 307–315. [Kovtun O.P., Ustyuzhanina M.A. Polymorphism of PPARG (P12A), APOA1 (G75A), and APOE (C112A and A158C) Genes in Children with Obesity and Arterial Hypertension: A Case-Control Study. Current Pediatrics, 2018, Vol. 17, No. 4, рр. 307–315 (In Russ.)]. doi: 10.15690/vsp.v17i4.1924.