Histological and Oxidative Stress Toxicity of Dolutegravir-Based Antiretroviral Therapy on the Placenta of Adult Wistar Rats
Keywords:
HIV, TLD, Wistar rats, placenta histology, oxidative stressAbstract
Tenofovir Disoproxil Fumurate/Lamivudine/Dolutegravir (TLD) is a fixed dose combination antiretroviral therapy recommended by World Health Organization (WHO) as preferred first and second-line antiretroviral therapy for people living with HIV. However, a relationship between placenta histology and oxidative toxicity of TLD is unknown. This study was designed to investigate the histological and oxidative stress toxicity of TLD on the placenta of adult Wistar rats. Ten rats weighing between 154-194g were randomly assigned into two groups; a control and TLD-treated. After pregnancy was achieved, the treated group was still administered combination drugs of Tenofovir Disoproxil Fumurate in 5mg/kg, Lamivudine in 5mg/kg and Dolutegravir in 0.8mg/kg body weight daily for 90 days. Dams were weighed on gestational day (GD) 0, 7, 14 and 21. At GD21, the dams were sacrificed, and placenta were harvested, counted, weighed, measured, and submitted for biochemical oxidative stress assessments and a section taken for histological evaluation. The findings revealed significant decrease in the body weight, placenta weight, diameter, and thickness of the treated group. Also, there was a significant decreased in placenta tissue reduced glutathione, glutathione peroxidase, superoxide dismutase, and catalase was decreased with insignificant difference, the concentration of malondialdehyde increased with insignificant difference in the treated compared to the control group. There was no significant difference in the number of number of placenta between the control and treated groups. The placenta histology of the TLD treated revealed vacuolation, congestion, and dilatation of the fetal-maternal vascular bed. These findings suggest TLD administration during pregnancy have negative effects on the placenta and could lead to abortion or cause serious negative consequences for the developing foetus. Concerns over long-term usage; especially during pregnancy, cannot be overemphasized.
References
Awodele, O., Popoola, T. D., Idowu, O., Bashua, B. M., Awolola, N. A., & Okunowo, W. O. (2018). Investigations into the risk of reproductive toxicity following exposure to Highly Active Antiretroviral Drugs in rodents. Tokai Journal of Experimental Clinical and Medicine, 43(2), 54-63.
Agarwal, A., Aponte-Mellado, A., Premkumar, B. J., Shaman, A., & Gupta, S. (2012). The effects of oxidative stress on female reproduction: a review. Reproductive biology and endocrinology, 10, 1-31.
Al-Husaini, A. M. (2009). Role of placenta in the vertical transmission of human immunodeficiency virus. Journal of Perinatology, 29(5), 331-336.
Antonio, E. R., Fontes, T. M. P., Simões, R. S, A., de Carvalho, A. M., Espiridião, S., Nakamurau, M. U., & Kulay, Jr. L. (2012). Effects of daily intake of zidovudine-stavudine on rat pregnancy outcome: Biological essay. Clinical and Experimental bstetrics Gynecology, 39(2), 205-208.
Ayeni, O. J., Ogunlade, B., Akunna, G. G., Enye, L. A., & Alao, A. A. (2013). Highly Active Antiretroviral Therapy: Effects on Foetal Parameters, Kidney and Spleen of the Dams. Scholars Journal of Applied Medical Sciences, 1(2), 131-137.
Bourinbaiar, A. S., & Lee-Huang, S. (1995). Anti-HIV effect of beta subunit of human chorionic gonadotropin (βhCG) in vitro. Immunology letters, 44(1), 13-18.
Buege, J. A., & Aust, S. D. (1978). Microsomal lipid peroxidation. In Methods in enzymology (Vol. 52, pp. 302-310). Academic press.
Cohen, G., Dembiec, D., & Marcus, J. (1970). Measurement of catalase activity in tissue extracts. Analytical Biochemistry, 34, 30-38.
Conroy, A. L., McDonald, C. R., Gamble, J. L., Olwoch, P., Natureeba, P., Cohan, D., Kamya, M. R., Havlir, D. V., Dorsey, G., & Kain, K. C. (2017). Altered angiogenesis as a common mechanism underlying preterm birth, small for gestational age, and stillbirth in women living with HIV. American journal of obstetrics and gynecology, 217(6), 684e1–17.
Couturier, J., Winchester, L. C., Suliburk, J. W., Wilkerson, G. K., Podany, A. T., Agarwal, N., Xuan Chua, C.Y., Nehete, P.N., Nehete, B.P., Grattoni, A., Sastry, K. J., Fletcher, C. V., Lake, J. E., Balasubramanyam, A., & Lewis, D. E. (2018). Adipocytes impair efficacy of antiretroviral therapy. Antiviral research, 154, 140-148.
Crum-Cianflone, N., Roediger, M. P., Eberly, L., Headd, M., Marconi, V., Ganesan, A., Weintrob, A., Barthel, R. V., Fraser, S., Agan, B. K., & Infectious Disease Clinical Research Program HIV Working Group. (2010). Increasing rates of obesity among HIV-infected persons during the HIV epidemic. Plos One, 5(4), e10106.
Dickover, R. E., Garratty, E. M., Plaeger, S., & Bryson, Y. J. (2001). Perinatal transmission of major, minor, and multiple maternal human immunodeficiency virus type 1 variants in utero and intrapartum. Journal of virology, 75(5), 2194-2203.
Dos Reis, H. L. B., Boldrini, N. A. T., Rangel, A. F. R., Barros, V. F., De Vargas, P. R. M., Miranda, A. E. (2020). Placental growth disorders and perinatal adverse outcomes in Brazilian HIV-infected pregnant women. PLoS One, 15(4), 1–15.
Drury, R. A. B., & Wallington, E. A. (1980). Carleton’s histological technique 5th ed. New York: Churchill Livingstone.
Du Toit, L. D., Prinsloo, A., Steel, H. C., Feucht, U., Louw, R., & Rossouw, T. M. (2023). Immune and metabolic alterations in children with perinatal HIV exposure. Viruses, 15(2), 279.
Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of biochemistry and biophysics, 82(1), 70-77.
Furukawa, S., Hayashi, S., Usuda, K., Abe, M., Hagio, S., & Ogawa, I. (2011). Toxicological pathology in the rat placenta. Journal of toxicologic pathology, 24(2), 95-111.
Furukawa, S., Kuroda, Y., & Sugiyama, A. (2014). A comparison of the histological structure of the placenta in experimental animals. Journal of toxicologic pathology, 27(1), 11-18.
Grzeszczak, K., Łanocha-Arendarczyk, N., Malinowski, W., Ziętek, P., & Kosik-Bogacka, D. (2023). Oxidative stress in pregnancy. Biomolecules, 13(12), 1768.
Holland, O. J., Hickey, A. J., Alvsaker, A., Moran, S., Hedges, C., Chamley, L. W., & Perkins, A. V. (2017). Changes in mitochondrial respiration in the human placenta over gestation. Placenta, 57, 102-112.
Ibrahim, A., Khoo, M. I., Ismail, E. H. E., Hussain, N. H. N., Zin, A. A. M., Noordin, L., Abdullah, S., Mahdy, Z. A., & Lah, N. A. Z. N. (2024). Oxidative stress biomarkers in pregnancy: a systematic review. Reproductive Biology and Endocrinology, 22(1), 93.
Ikumi, N. M., Malaba, T. R., Pillay, K., Cohen, M. C., Madlala, H. P., Matjila, M., Dilly, A., Myer, L., Newell, M., & Gray, C. M. (2020). Differential impact of antiretroviral therapy initiated before or during pregnancy on placenta pathology in HIV-positive women. Acquired Immunodeficiency Syndrome, 35(5), 717-726.
Ikumi, N. M., Malaba, T. R., Pillay, K., Cohen, M. C., Madlala, H. P., Matjila, M., Anumba, D., Myer, L., Newell, M. L., & Gray, C. M. (2021). Differential impact of antiretroviral therapy initiated before or during pregnancy on placenta pathology in HIV-positive women. Acquired Immunodeficiency Syndrome, 35(5), 717-726.
Ivanov, A. V., Valuev-Elliston, V. T., Ivanova, O. N., Kochetkov, S. N., Starodubova, E. S., Bartosch, B., & Isaguliants, M. G. (2016). Oxidative stress during HIV infection: mechanisms and consequences. Oxidative medicine and cellular longevity, 2016(1), 8910396.
Johnson, E. L., & Chakraborty, R. (2012). Placental Hofbauer cells limit HIV-1 replication and potentially offset mother to child transmission (MTCT) by induction of immunoregulatory cytokines. Retrovirology, 9, 1-11.
Kandel, C. E., & Walmsley, S. L. (2015). Dolutegravir–a review of the pharmacology, efficacy, and safety in the treatment of HIV. Drug design, development and therapy, 9, 3547-3555.
Kanters, S., Renaud, F., Rangaraj, A., Zhang, K., Limbrick-Oldfield, E., Hughes, M., Ford, N., & Vitoria, M. (2022). Evidence synthesis evaluating body weight gain among people treating HIV with antiretroviral therapy-a systematic literature review and network meta-analysis. EClinical Medicine, 48. 101412.
Kanters, S., Vitoria, M., Doherty, M., Socias, M. E., Ford, N., Forrest, J. I., Popoff, E., Bansback, N., Nsanzimana, S., Thorlund, K., & Mills, E. J. (2016). Comparative efficacy and safety of first- line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta-analysis. Lancet HIV, 3(11), e510-e520.
Koethe, J. R., Jenkins, C. A., Lau, B., Shepherd, B. E., Justice, A. C, Tate, J. P, Buchacz, K., Napravnik, S., Mayor, A. M., Horberg, M. A., Blashill, A. J., Willig, A., Wester, C. W., Silverberg, M. J., Gill, J., Thorne, J. E., Klein, M., Eron, J. J., Kitahata, M. M., Sterling, T. R., & Moore R. D. (2016). Rising Obesity Prevalence and Weight Gain among Adults Starting Antiretroviral Therapy in the United States and Canada. Acquired Immune Deficiency Syndromes research and Human Immunodeficiency Virus, 32(1), 50-58.
Kojovic, D., Ghoneim, R. H., Serghides, L., & Piquette-Miller, M. (2020). Role of HIV and Antiretroviral Therapy on the Expression of Placental Transporters in Women with HIV. The AAPS Journal, 22, (6), 1-12.
Kulay, L., Hagemann, C. C., Nakamura, M. U., Simões, R. S., Carvalho, A. M., Oliveira-Filho, R. M., Espiridião, S. (2013). Administration of lopinavir/ritonavir association during rat pregnancy: maternal and fetal effects. Clinical and Experimental Obstetrics Gynecology, 40(1), 151-4.
Lewis, S. H., Fox, H. E., Reynolds-Kohler, C., & Nelson, J. A. (1990). HIV-1 in trophoblastic and villous Hofbauer cells, and haematological precursors in eight-week fetuses. The Lancet, 335(8689), 565-568.
Magdy, M., El Ghareeb, A. E. W., Eldebss, T. M., & Abd El Rahman, H. A. (2023). Investigation of the embryo-toxicity of the antiviral drug “Ribavirin” in Wistar rats during different gestation periods. Egyptian Journal of Basic and Applied Sciences, 10(1), 396-409.
Martinez Manfio, V., Tasca, K. I., Garcia, J. L., de Oliveira Góis, J., Correa, C. R., & de Souza, L. D. R. (2021). Redox imbalance is related to HIV and pregnancy. PLoS One, 16(5), e0251619.
Masiá, M., Padilla, S., Fernández, M., Rodríguez, C., Moreno, A., Oteo, J. A., Antela. A., Moreno, S., Del Amo, J., Gutiérrez, F., & CoRIS, Biobanco. (2016). Oxidative stress predicts all-cause mortality in HIV-infected patients. PloS One, 11(4), e0153456.
Mataramvura, H., Bunders, M. J., & Duri, K. (2023). Human immunodeficiency virus and antiretroviral therapy-mediated immune cell metabolic dysregulation in children born to HIV-infected women: potential clinical implications. Frontiers in immunology, 14, 1182217.
Minkoff, H. (2003). Human immunodeficiency virus infection in pregnancy. Obstetrics & Gynecology, 101(4), 797-810
Misra, H. P., & Fridovich, I. (1972). The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. Journal of Biological chemistry, 247(10), 3170-3175.
National Research Council of the National Academies. (2011). Guide for the Care and Use of Laboratory Animals, 8th Edition. Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies. The National Academies Press, Washington, DC, 220.
Nyman, M. (1959). Serum haptoglobin; methodological and clinical studies. Scandinavian Journal Clinical and Laoratory Investigation, 11, 1-169.
Obimbo, M. M., Zhou, Y., McMaster, M. T., Cohen, C. R., Qureshi, Z., Ong’ech, J., Ogeng'o, J. A, & Fisher, S. J. (2019). Placental structure in preterm birth among HIV-positive versus HIV-negative women in Kenya. Journal of Acquired Immune Deficiency Syndromes, 80(1), 94-102.
Oluwaseun, H. I., Olamide, A., Akinyemi, A. R., Jibril, O., Olatoye, I. B. A., & Selimot, H. A. (2013). Effects of lamivudine, nevirapine and zidovudine combination regimen on the estrus cycle and body weight in female Wister rats. Journal of Pharmaceutical Sciences, 2(10), 292-298.
Oyeyipo, I. P., Skosana, B. T., Everson, F. P., Strijdom, H., Stefan, S. (2018). Highly Active Antiretroviral Therapy Alters Sperm Parameters and Testicular Antioxidant Status in Diet-Induced Obese Rats. Toxicology Reseach, 34(1), 41-48.
Pereira, A. C., & Martel, F. (2014). Oxidative stress in pregnancy and fertility pathologies. Cell biology and toxicology, 30, 301-312.
Pontes, R. D. V., Amed, A. M., de Jesus Simões, M., Oliveira-Filho, R. M., Simões, R. S., Kulay, L. Jr. (2005). Effect of Lamivudine on the Rat Pregnancy Outcome. International Journal of Morphology, 23(3), 205-208.
Quintino, M. P., Nakamura, M. U., de Jesus Simões, M., Araujo Júnior, E., de Oliveira Filho, R. M., Torloni, M. R., Espiridião, S., & Kulay Júnior, L. (2011). Chronic use of indinavir in albino rat pregnancy (Rattus norvegicus albinus, Rodentia, Mammalia): biological assay. Journal of Obstetrics and Gynaecology Research, 37(9), 1212-1215.
Ross, A. C., Leong, T., Avery, A., Castillo‐Duran, M., Bonilla, H., Lebrecht, D., U. A. Walker U. A., Storer, N., Labbato, D., Khaitan, A., Tomanova-Soltys, I., McComsey G. A. (2012). "Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress." Human Immunodeficiency Virus Medicine, 13(2), 98-106.
Sattler, F.R., He, J., Letendre, S., Wilson, C., Sanders, C., Heaton, R., Ellis, R., Franklin, D., Aldrovandi, G., Marra, C.M, Clifford, D., Morgello, S., Grant, I., McCutchan, J. A. (2015). Abdominal obesity contributes to neurocognitive impairment in HIV-infected patients with increased inflammation and immune activation. Journal of Acquired Immune Deficiency, 68(3), 281-288.
Scarsi, K. K., Havens, J. P., Podany, A. T., Avedissian, S. N., & Fletcher, C. V. (2020). HIV-1 integrase inhibitors: a comparative review of efficacy and safety. Drugs, 80(16), 1649-1676.
Vrooman, L. A., Xin, F., & Bartolomei, M. S. (2016). Morphologic and molecular changes in the placenta: what we can learn from environmental exposures. Fertility and sterility, 106(4), 930-940.
Wagner, A., Nakamura, M. U., Simões, R. S., Oliveira-Filho, R. M., Fontes, T. M. P., Carvalho, L. P. F., Espiridiao, S., & Kulay L. (2011). Chronic action of association of zidovudine, lamivudine and ritonavir on pregnant rats. A biologic assay. Clinical and Experimental Obstetrics Gynecology, 38(1), 28-32.
Wakefield, S. L., Lane, M., & Mitchell, M. (2011). Impaired mitochondrial function in the preimplantation embryo perturbs fetal and placental development in the mouse. Biology of reproduction, 84(3), 572-580.
World Health Organization. (2018). Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Available from: http://apps. who. int/iris/bitstream/handle/10665/273632/WHO-CDS-HIV-18.18eng. pdf? ua= 1. Accessed 23rd January, 2024.
World Health Organization. (2019). WHO recommends dolutegravir as preferred HIV treatment option in all populations. World Health Organization News.-treatment-option-in-all-populations.Available: https://www.who.int/news/item/22-07-2019-who-recommendsdolutegravir-as-preferred-HIV . Accessed: 2nd July, 2024.
World Health Organization. (2021). Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Accessed: 1st July, 2024.
Yampolsky, M., Shlakhter, O., Deng, D., Kala, S., Walmsley, S. L., Murphy, K. E., Yudin, M. H., MacGillivray, J., Loutfy, M., Dunk, C., & Serghides, L. (2021). Exploring the impact of HIV infection and antiretroviral therapy on placenta morphology. Placenta, 04, 102-109.
