Assessment of oxidative toxicity and folate status in HIV patients on dolutegravir-based antiretroviral therapy

Abstract

Dolutegravir (DTG), a key component of antiretroviral therapy (ART), has demonstrated potent virologic suppression and superior efficacy compared to standard regimens in HIV management. However, concerns about its long-term safety persist, with emerging evidence suggesting potential adverse effects. Notably, studies have reported an increased risk of neural tube defects in infants born to women exposed to DTG during pregnancy, as well as associations with neuropsychiatric effects and sideroblastic anemia. This cross-sectional study investigated plasma folate and malondialdehyde (MDA) levels—markers of antioxidant status and oxidative stress, respectively—in HIV-positive patients receiving DTG-based ART at the University of Nigeria Teaching Hospital, Enugu. A total of 120 participants were recruited, comprising 40 treatment-naïve patients initiating DTG-based ART, 40 patients on DTG-based ART for 6 months, and 40 HIV-negative controls. Plasma folate was measured using chemiluminescence immunoassay, while MDA levels were determined spectrophotometrically. Results showed significantly elevated MDA levels in both treatment-naïve (5.72 ± 3.61 μmol/L) and 6-month DTG-treated patients (8.94 ± 5.03 μmol/L) compared to controls (1.19 ± 0.18 μmol/L). Conversely, folate concentrations were markedly lower in the DTG groups (2.23 ± 1.52 and 1.89 ± 0.54 ng/mL, respectively) than in controls (11.11 ± 1.31 ng/mL). These findings suggest that DTG-based ART may elevate oxidative stress while reducing antioxidant levels, underscoring the need for careful monitoring of its biochemical effects in HIV-positive individuals.

Keywords

Dolutegravir / Oxidative toxicity / Folate status / Antiretroviral therapy / HIV

References

[1] Mwebaza J, Meya D, Musiime V, Birungi C. Prevalence of neuropsychiatric adverse events and associated factors among adult patients on dolutegravir attending Mulago ISS clinic. HIV Med. 2023; 24(4):491-501. doi: 10.1111/hiv.13428

[2] Tesfaye E, Demelash K. Burden of care among caregivers of patients with mental illness in Ethiopia: A systematic review and meta-analysis. BMC Public Health. 2025;25:2414. doi: 10.1186/s12889-025-23461-1

[3] Rossetti B, Ferrara M, et al. Evolution of self-reported neuropsychiatric symptoms after switching from dolutegravir/abacavir/lamivudine to bictegravir/ emtricitabine/tenofovir alafenamide: Results from the randomized DOBINeuro trial. Infect Dis Ther. 2025; 14(1):293-304. doi: 10.1007/s40121-024-01083-1

[4] Cabrera RM, Souder JP, Steele JW, et al. The antagonism of folate receptor by dolutegravir: Developmental toxicity reduction by supplemental folic acid. AIDS. 2019; 33(11):1789-1798.

[5] Gilmore JC, Hoque MT, Dai W, et al. Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta. EBioMedicine. 2022;75:103771. doi: 10.1016/j.ebiom.2021.103771

[6] Tukeman GL, Wei H, Lin YL, Wlodarczyk BJ, Finnell RH, Cabrera RM. Dolutegravir-induced neural tube defects in mice are folate responsive. AIDS. 2024; 38(4):439-446. doi: 10.1097/QAD.0000000000003639

[7] Chandiwana NC, Chersich M, Venter WDF, et al. Unexpected interactions between dolutegravir and folate: Randomized trial evidence from South Africa. AIDS. 2021; 35(2):205-211. doi: 10.1097/QAD.0000000000002741

[8] Zhou Q, Dong G, Wang Q, et al. Preconception folic acid supplementation for the prevention of birth defects: A prospective, population-based cohort study in mainland China. BMC Pregnancy Childbirth. 2024; 24(1):114. doi: 10.1186/s12884-024-04319-9

[9] Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med. 2019; 381(9):827-840. doi: 10.1056/NEJMoa1805230

[10] Assefa N, Abdullahi YY, Abraham A, et al. Consumption of dietary folate estimates and its implication for reproductive outcome among women of reproductive age in Kersa: Cross-sectional survey. BMC Nutr. 2021; 7(1):69. doi: 10.1186/s40795-021-00482-w

[11] Jakimiuk A, Piechal A, Wiercińska-Drapało A, Nowaczyk A, Mirowska-Guzel D. Dolutegravir induces FOLR1 expression during brain organoid development. Front Mol Neurosci. 2024;17:1463159. doi: 10.3389/fnmol.2024.1463159

[12] Alcorn K. Adequate Levels of Folate Protect Against Neural Tube Defects When Taking Dolutegravir. NAM aidsmap. 2024. Available from: https://www.aidsmap.com [Last accessed on 2025 Sep 25].

[13] Quirós Roldán M, Bresciani A, Savoldi A. Dolutegravir and folic acid interaction during neural system development: Zebrafish embryo model. Int J Mol Sci. 2024; 25(9):4640. doi: 10.3390/ijms25094640

[14] Saint-Lary O, Martin C, Leclerc T. Post-marketing safety concerns with dolutegravir: A comprehensive pharmacovigilance review. Front Pharmacol. 2025;16:1399821. doi: 10.3389/fphar.2025.1399821

[15] Masenga SK, Kabwe LS, Chakulya M, Kirabo A. Mechanisms of oxidative stress in metabolic syndrome. Int J Mol Sci. 2023; 24(9):7898. doi: 10.3390/ijms24097898

[16] Jain RG, Furfine ES, Pedneault L, White AJ, Lenhard JM. Metabolic complications associated with antiretroviral therapy. Antiviral Res. 2001;51:151-177. doi: 10.1016/S0166-3542(01)00147-7

[17] Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol. 2012;2012:936486. doi: 10.1155/2012/936486

[18] De Greef J, Yombi JC, Vincent A, et al. Dolutegravir and risk of neuropsychiatric adverse events: A pharmacogenetic study. J Infect Dis. 2025; 231(6):1425-1429. doi: 10.1093/infdis/jiaf098

[19] Jakimiuk A, Piechal A, Wiercińska-Drapało A, Nowaczyk A, Mirowska-Guzel D. Central nervous system disorders after use of dolutegravir: Evidence from preclinical and clinical studies. Pharmacol Rep. 2023; 75(6):1138-1151. doi: 10.1007/s43440-023-00515-y

[20] National Agency for the Control of AIDS (NACA). National HIV/AIDS Indicator and Impact Survey (NAIIS) 2021: Technical Report. Abuja, Nigeria: NACA; 2021.

[21] Azim M, Hasan M, Ansari IH, Nasreen F. Chemiluminescence immunoassay: Basic mechanism and application. Bangladesh J Nuclear Med. 2018; 18(2):171. doi: 10.3329/bjnm.v18i2.35240

[22] Gutteridge JM, Wilkins SC. Copper dependent hydroxyl radical damage to ascorbic acid; formation of thiobarbituric acid reactive products. FEBS Lett. 1982;137:327-330. doi: 10.1016/0014-5793(82)81330-8

[23] Buege JA, Aust SD. Microsomal lipid peroxidation. In: Fleischer S, Packer L, editors. Methods in Enzymology. Vol. 52. United States:Academic Press; 1978. p. 302-310.

[24] Piantadosi CA, Suliman HB. Mitochondrial dysfunction in oxidative stress. Free Radic Biol Med. 2017; 122:134-146. doi: 10.1016/j.freeradbiomed.2018.01.003

[25] Shytaj IL, Norelli S, Chirullo B, Palamara AT. Oxidative stress and HIV infection: Role in pathogenesis and therapeutic strategies. Expert Rev Anti Infect Ther. 2020; 18(5):447-460. doi: 10.1080/14787210.2020.1762438

[26] Reust CE. Common adverse effects of antiretroviral therapy for HIV disease. Am Fam Physician. 2011; 83(12):1443-1451.

[27] Bailey LB, Gregory JF 3^rd. Folate metabolism and requirements. J Nutr. 2015; 145(3):593-596. doi: 10.3945/jn.114.204009

[28] Flax VL, Adair LS, Allen LH, et al. Plasma micronutrient concentrations are altered by antiretroviral therapy and lipid-based nutrient supplements in lactating HIV-infected Malawian women. J Nutr. 2015; 145(8):1950-1957. doi: 10.3945/jn.115.220109

[29] Alani A, Vincent O, Adewumi A, et al. Plasma folate studies in HIV-positive patients at the Lagos University Teaching Hospital, Nigeria. Indian J Sex Transm Dis AIDS. 2010; 31(2):99-103. doi: 10.4103/0253-7184.74995

[30] Barlow-Mosha LN, Ahimbisibwe GM, Chappell E, et al. Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: A sub-study of the ODYSSEY randomized controlled trial. J Int AIDS Soc. 2023; 26(9):e26174. doi: 10.1002/jia2.26174

[31] Korencak M, Byrne M, Richter E, et al. Effect of HIV infection and antiretroviral therapy on immune cellular functions. JCI Insight. 2019; 4(12):e126675. doi: 10.1172/jci.insight.126675

[32] Oyeyipo IP, Skosana BT, Everson FP, Strijdom H, du Plessis SS. Highly active antiretroviral therapy alters sperm parameters and testicular antioxidant status in diet-induced obese rats. Toxicol Res. 2018; 34(1):41-48. doi: 10.1039/c7tx00205h

[33] Dhonju K, Gautam A, Dahal A, et al. Dolutegravir-induced acquired sideroblastic anemia in an HIV-positive patient: A challenging hematologic complication. Clin Case Rep. 2023; 11(12):e8301. doi: 10.1002/ccr3.8301

[34] Kovacic P, Somanathan R. Broad overview of oxidative stress and its complications in human health. Open J Prev Med. 2013; 3(1):32-41. doi: 10.4236/ojpm.2013.31005

[35] Rothenberg SP. Increasing the dietary intake of folate: Pros and cons. Semin Hematol. 1999; 36(1):65-74.

[36] Babafemi T. General HIV Medicine. Vol 1. Hyderabad: TFC Press; 2004. p. 10-11.

[37] Dhur A, Galan P, Herberg S. Folate status and the immune system. Prog Food Nutr Sci. 1991; 15(1-2):43-60.

[38] Molloy AM, Scott JM. Folates and prevention of disease. Public Health Nutr. 2001; 4(2B):601-609. doi: 10.1079/PHN2000128

[39] Lewis W, Dalakas M, Biesecker GM. Mitochondrial toxicity of antiviral drugs. Nat Med. 2003; 6(3):249-255. doi: 10.1038/nm0303-249

[40] Savinelli S, Newman E, Mallon PWG. Metabolic complications associated with use of integrase strand transfer inhibitors (INSTI) for the treatment of HIV-1 infection: Focus on weight changes, lipids, glucose and bone metabolism. Curr HIV/AIDS Rep. 2024;21:567-580. doi: 10.1007/s11904-024-00683-5