Login

Effect of Treatment with First and Second Line Fix-Dose Antiretroviral Drugs on Hematological Indices and Markers of Oxidative Stress in Wistar Rats

Vol. 3 No. 6 (2025): International Journal of Integrative and Modern Medicine:

Ezekiel U. Umoh (1), Imaikpo U. Umoh (2), Eyong U. Eyong (3)

(1) Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Science, University of Uyo, Akwa, Ibom State, Nigeria, Nigeria
(2) Department of Biochemistry, Faculty of Biological Sciences, University of Uyo, Nigeria, Nigeria
(3) Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, University of Calabar, Cross River State, Nigeria, Nigeria
Fulltext View | Download

Abstract:

There may be negative consequence on the clinical outcome of HIV-infected individuals when using combined antiretroviral drugs, a resulting in metabolic complications. This study investigated the effect of first and second line fixed-dose combination (FDC) antiretroviral drugs on hematological indices and oxidative stress markers in Wistar rats. Thirty-five (35) male Wistar rats (Raths Novegicus) were divided into seven (7) experimental groups (A, B1, B2, C1, C2, D1 and D2). Group A received normal rat pellet and clean water. Group B1 received 17.14 mg/kgbwt/24h of fixed-dose EFV/3TC/TDF as first line regimen for 15 days, while Group B2 received same regimen for 30 days. Group C1 received 6.43 mg/kgbwt/12h of fixed-dose 3TC/ZDVt3.57 mg/kgbwt/12h of LPV/r as second line regimen for fifteen (15) days, while Group C2 received same regimen for 30 days. Group D1 received first line regime for 30 days then switched to second line regimen for 15 days (a total of 45 days), while Group D2 received first line regime for 30 days, then switched to second line regimen for another 30 days (a total of 60 days). First and second line regimens showed significant change (P<0.05) in markers of oxidative stress except for glutathione (GSH) which showed significant increase (P<0.05) in groups B2, C1, C2 and D1 compared to control. Hematological indices were not significant (P>0.05) in animals treated with both regimens in all the groups when compared with the control. Toxic effect of First and second line FDC antiretroviral drugs was significant on oxidative stress markers but no effect on hematological indices in rats; however repeated dose at long term use may be tolerated.

References

1. Adikwu, E., Deo, O., Zidafamor J. & Obele. R. (2014). Effect of co-administered lopinavir/ritonavir and sulfamethoxazole/ trimethoprim on cardiac function and architecture of albino rats. International Journal of Basic and Clinical Pharmacology, 3(5): 817-823.

2. Adjene, J. O., Avbunudiogba, J. A & Igbigbi, P. S. (2011). Oxidative stress induced by chronic administration of efavirenz on the intracranial visual relay centers of adult wistar rats. Biology and Medicine, 3: 16-24.

3. Akinbami, A., Oshinaike O. & Adeyemo, T. (2010). Hematological abnormalities in treatment- naïve HIV patients, Lagos, Nigeria. Infectious Disease: Research and Treatment, 3: 45-49

4. Apostolova, N. Blas-Garcia, A. & Edplugues, J. V. (2010). Mitochondrial interference by anti-HIV drugs: Mechanisms beyond pol-y inhibition. Trends in Pharmaceutical Sciences, 32: 715-718.

5. Atiba, A. S., Oparinde, D. P., Jimoh. A. K., Babatunde, O. A. & Adelekan, A. (2012). Oxidative stress and serum selenium in HIV poatients on different antiretroviral regimen. Greener Journal of Medical Sciences, 2: 163-167.

6. Ayala, A., Munoz, M. F. & Arguelles, S. (2014). Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2- nonenal. Oxidative Medicine and Cellular Longevity, 2014:360428-360431.

7. Baunthiyal, M., Vijayata, S. & Sushmita, D. (2017). Isights of antioxidants as molecules for drug discovery. International Journal of Pharmacology, 13: 874-889.

8. Bjorlund, G. & Chirumbolo, S. (2017). Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition, 33: 311-321.

9. Chandra, S., Mondal, D. & Agrawal, K. C. (2009). HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: Protection with thymoquinone. Experimental Biology and Medicine, 234(4): 442-453

10. Dikshit, B., Wanchu, A., Sachdeva, K. R., Sharma, A. & Das, R. (2009). Profile of haematological abnormalities of Indian HIV infected individuals. Blood Disorders, 9: 5-14

11. Elias, A., Ogbuehi, I., Edikpo, N. J., Oputiri, D. & Oru-Bo, P. S. (2014). Tenofovir renal toxicity: Evaluation of chohorts and clinical studies – part 2. Journal of Pharmacology and Pharmaceutics, 5: 97-111.

12. Ellman, G. L. (1959). Tissue sulfihydryl groups. Archives of Biochemistry and Biophysics, 82(1): 70-77.

13. Enawgaw, B., Alem, M., Addis, Z. & Melku, M. (2014). Determination of haematological and immunological parameters among HIV positive patients taking highly active antiretroviral treatment and treatment naïve in the antiretroviral therapy clinic of Gondar University Hospital, Gondar, Northwest Ethiopia: a comparative cross-sectional study. Hematology, 14: 8-16.

14. Faria, N. R., Rambant, A., Suchard, M. A., Baele, G., Bedford, T., Ward, M. J., Tatem, A. J., Sousa, J. D., Arinaminpathy, N., Pepin, J., Posada, D., Peters, M., Pybus, O. & Lemey P. (2014). HIV epidemiology: The early spread and epidemic ignition of HIV in human populations. Science, 346: 56-61.

15. Forman, H. J., Davies, K. J. A. & Ursini, F. (2014). How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radical Biology and Medicine, 66: 24-35.

16. Gil, I., Tarinas, A. & Hernandez, D. (2011). Altered oxidative stress indexes related to disease progression marker in human immunodeficiency virus infected patients with antiretroviral therapy. Biomedicine and Aging Pathology, 1(1): 8-15.

17. Gutowski, M. & Kowalczyk, S. (2013). A study of free radical chemistry: Their role and pathophysiological significance. Acta Biochimica Polonica, 60(1): 1-16.

18. Ifeanyichukwu O. M. & Bright, E. O. (2016). Effect of HIV infection on some hematological parameters and immunoglobulin levels in HIV patient in Benin City, Southern Nigeria. Journal of HIV and Retrovirus, 2: 2-8.

19. Jiang, B., Hebert, V. Y., Khandelwal, A. R., Stokes, K. Y. & Dugas, T. R. (2009). HIV-1 antiretroviral induce oxidant injury and increase intima-media thickness in an atherogenic mouse model. Toxicology Letters, 187: 164-171.

20. Kashou, A. H. & Agarwal, A. (2011). Oxidants and antioxidants in the pathogenesis of HIV/AIDS. Open Reproductive Science Journal, 3: 154-161.

21. Kerkhoff, A. D., Wood, R., Cobelens, F. G., Gupta-Wright, A., Bekker, L. G. & Lawn, S. D. (2014). Resolution of anaemia in a cohort of HIV-infected patients with a high Prevalence and incidence of tuberculosis receiving antiretroviral therapy in South Africa. Clinical Infectious Disease, 14: 3860.

22. Kibaru, E. G., Nduati, R., Wamalwa, D. and Kariuki, N. (2015) Impact of highly active antiretroviral therapy on hematological indices among HIV-1 infected children at Kenyatta National Hospital-Kenya: Retrospective study. AIDS Research and Therapy, 12: 26-34.

23. Kohler, J. J., Hosseini, S. H., Hoying-Brandt, A., Green, E. & Johnson D. M. (2009). Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Laboratory Investigation, 89:513-519.

24. Kort, J. J., Aslanyan, S. & Scherer, J. (2011). Effects of tipranavir, darunavir, and ritonavir on platelet function, coagulation, and fibrinolysis in healthy volunteers. HIV Research, 9: 237-246.

25. Krambovitis, E., Porichis, F. & Spandidos, D. A. (2005). HIV entry inhibitors: A new generation of antiretroviral drugs. Acta Pharmacologica Sinica, 26: 1165-1173.

26. Kusfa, I. U., Abubakar, A. A., Muktar, H. M., Ibrahim, I. N., Awwalu, S., Balogun, M. S., Shebu, L. & Ahmadu, I. (2017). Comparative analysis of some haematological and immunological parameters of HIV-positive patients at a tertiary HIV treatment center in Zaria, Nigeria. Sub-Saharn African Journal of Medicine, 4: 15-19.

27. Liebman, H. A. (2008). Viral-associated immune thrombocytopenic purpura. Education Program of the American Society of Haematology. American Society of Hematology, 212-218.

28. Loelius, S. G., Lannan, K. L. & Casey, A. E. (2007). Antiretroviral drugs and tobacco smoke dysregulate human platelets: A novel investigation into the etiological of HIV co- morbid cardiovascular disease. Journal of Immunology, 198(125):10-23.

29. Mocroft, A., Kirk, O. & Barton, S. E. (1999). Anemia is and independent predictive marker for clinical prognosis in HIV infected patients across Europe. AIDS, 13: 943-950.

30. Mondal, D., Pradham, L., Ali, M. & Agrawal, K. C. (2004). HAART drugs induced oxidative stress in human endothelial cells ad increase endothelial recruitment of mononuclear cells. Cardiovascular Toxicology, 4: 287-302.

31. Moore, R. D. (2009). Human immunodeficiency virus infection, anemia, and survival. Clinical Infectious Disease, 29: 44-49.

32. Muluneh, A. & Fessahaye, A. (2009). Hematologic abnormalities among children on HAART in Jimma University Specialized Hospital. Southwestern Ethiopia. Ethiopian Journal of Health Sciences, 19(2): 83-89.

33. Ngondi,, J. L. Oben, J. Forkah, D. M. Etame, L. H. & Mbanya, D. (2006). The effect of different combination therapies on oxidative stress markers in HIV infected patients in Cameroon. AIDS Research and Therapy, 3(1): 19-26.

34. Opii, W. O., Sultana, R., Abdul, H. M., Ansari, M. & Nath A. (2007). Oxidative stress and toxicity induced by the Nucleoside Reverse Transcriptase Inhibitor (NRTI)-2: 3-dideoxycytidine (ddC): Relevance to HIV dementia. Experimental Neurology, 204: 29-38.

35. Owiredu, W. K., Quaye, L., Amidu, N. & Addai-Mensah, O. (2011). Prevalence of anemia and immunological markers among Ghanian HAART-naïve HIV-patients and those on HAART. African Journal of Medical and Health Science, 11:2-15.

36. Pande, P. P. (2009). Computational approach towards designing potential HIV inhibitors. Journal of Antiviral and Antiretroviral, 1: 082-085.

37. Perkins, A., Nelson, K. J., Parsonage, D., Poole, L. B. & Karplus, P. A. (2015). Peroxiredoxing: Guardians against oxidant stress and modulators of peroxide signaling. Trends in Biochemical Science, 40(8): 435-445.

38. Pinola, M., Lazzarin, A., Antinori, A., Carosi, G. & Di Perri, G. (2010). Lopinavir/ritonavir + tenofovir dual therapy versus lopinavir/ritonavir-based triple therapy in HIV-infected antiretroviral naïve subjects: The Kalead study. Journal of Antiviral and Antiretroviral, 2: 056-062.

39. Ramamoorth, H., Issac B. & Abraham, P. (2012). Evidence for the roles of oxidative stress, nitrosative stress ad Nf-Kb activation in Tenofover Disoproxil Fumarate (TDF) induced renal damage in rats. Journal of infectious Disease, 12:1-6.

40. Renner, L., A., Dicko, F., Koueta, F., Malateste, K., Gueye, R. D., Aka, E., Eboua, T., Azondekon, A., Okomo, U., Toure, P., Ekouevi, D. & Leroy, V. (2013). Anaemia and zidovudine-containing antiretroviral therapy in paediatric antiretroviral programmes in the lidea paediatric West African database to evaluate AIDS. Journal of the International AIDS Society, 16: 18024-18035.

41. Subodh, K. M., Pulin, K. G., Rajesh, S. T. & Akanksha, S. (2018). Zidovudine-induced lactic acidosis with acute pancreatitis and myopathy: Lethal and renal complications. Indian Journal Pharmacology, 50(4): 212-214.

42. Thomas, N., Ernest O. U., Nubila, N. I. & Godfrey, I. O. (2012). Examination of haematotoxicity of fixed-dose highly active antiretroviral drug in wistar rats. International Scholarly Research Network (ISRN), 6-18.

43. Ukoha U. U., Kosisochukwu, E., Umeasalugo, U. D., Godwin, N., Arthur, E., Anyabolu, I. & Emefo, L. E. (2015). Effects of zidovudine on hemostatic and hematologic parameters in adult rats. Journal of Experimental and Integrative Medicine, 5: 2-18.

44. Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M. & Telser, J. (2007). Antioxidant in physiological functions and human disease. International Journal of Biochemistry and Cell Biology, 39: 44-84.

45. Vassimon, H. S., Deminice, R. Machado, A. A. Monteito J. P. & Pordao, A. (2010). The association of lipodystrophy and oxidative stress biomarkers in HIV-infected men. HIV Research, 8: 364-369.

46. Wang, X. H., Chai, Q., Yao, R. & Chen, C. (2007). Molecular mechanisms of HIV protease inhibitor or induced endothelial dysfunction. Journal Acquired Immune Deficiency Syndrome, 44: 493-499

47. Watanbe, L. M., Barbosa, F., Jordao, A. A. & Navarro, A. M. (2016). Influence of HIV infection and the use of antiretroviral therapy on selenium and selenomethionime concentrations and antioxidant protection. Nutrition, 32(11-12): 1238-1242.

48. Weiϐ, M., Kost, B., Renner-Muller, I., Wolf, E., I. & Bruning, A. (2016). Efavirnez causes oxidative stress, endoplasmic reticulum stress, ad autophgy in endothelial cells. Cardiovascular Toxicology, 16(1): 90-99.

49. World Health Organization (2015) Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: WHO.

50. Wu, X., Sun, L., Zha, W., Studer, E. & Gurley, E. (2010). HIV protease inhibitors induce endoplasmic reticulum stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology, 138: 197-209.

51. Yamamoto, T., Kikkawa, R., Yamada, H. & Horii, I. (2005). Identification of oxidative stress-related proteins for predictive screening of hepatotoxicity using a proteomic approach. Journal of Toxicology Science, 30: 213-227.

52. Zhou, H., Gurler, E. C., Jarujaron, S., Ding, H. & Fang, Y. (2006). HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. American Journal of Physiology, 291: 1071-1080.

53. Zhu, T., Korber, B. T., Nahmias, A. J., Hooper, E., Sharp, P. M. & Ho, D. D. (1998). An African HIV-I sequence from 1959 and implications for the origin of the epidemic. Nature, 391(6667): 594-597.