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Microbes & Immunity Oxidative toxicity and folate in HIV on DTG-ART

depletion predisposes patients to megaloblastic anemia
and impaired immune recovery. More importantly,
27
maternal folate deficiency has been consistently linked to
NTDs, raising major public health concerns for women
of reproductive age receiving DTG-based ART. Our
findings align with prior reports showing reduced folate
levels among ART-experienced populations, 28,29 though
they contrast with recent clinical trial data from Barlow-
Mosha et al., which demonstrated more pronounced
30
folate changes. Such discrepancies may reflect differences
in baseline nutritional status, treatment duration, or
population characteristics.
Figure 1. Effects of dolutegravir treatment on malondialdehyde and folate
The oxidative and nutritional disturbances observed in
4. Discussion this study are consistent with previous reports. Elevated
MDA has been documented in both ART-naïve and
This study demonstrates that DTG-based ART is associated ART-treated HIV populations, reflecting heightened
with significant biochemical alterations, most notably lipid peroxidation and cytokine-driven inflammatory
elevated oxidative stress and reduced folate availability. pathways. 31-33 Mechanistically, cytokine-mediated
Taken together, these findings reveal two distinct but activation of lipoxygenase pathways may further potentiate
interconnected biochemical patterns. ROS generation. Similarly, folate depletion in HIV has
34
First, DTG therapy was associated with a statistically been attributed to anorexia, increased metabolic turnover,
significant and clinically meaningful increase in MDA, and viral replication-driven nucleotide demand. 35,36 Given
with effect size analysis confirming a moderate-to-large the estimated daily production of up to 10 billion virions
impact (d = 0.74). Both pre- and post-therapy MDA in untreated HIV, such demands are likely to accelerate
levels were substantially higher than in HIV-negative micronutrient depletion, compounding nutritional
controls, indicating that oxidative imbalance is both a deficiencies.
consequence of HIV infection and further exacerbated Folate deficiency has dual consequences. It impairs
by ART. The moderate-to-large increase in MDA DNA synthesis and causes defective S-phase progression,
concentrations post-treatment is consistent with elevated both of which are reversible upon repletion. In addition,
lipid peroxidation and oxidative imbalance. Oxidative it compromises immune function through reduced T-cell
stress, reflected by biomarkers such as MDA, is a well- proliferation and blunted mitogen responses. In the
37
established driver of mitochondrial dysfunction, cellular context of oxidative stress, these disturbances may act
senescence, and inflammatory activation in PLWH. 24,25 synergistically. ROS-mediated injury depletes antioxidant
These mechanisms have been implicated in neurocognitive reserves, further lowering folate bioavailability, while
decline, cardiovascular disease, and accelerated aging, folate deficiency compromises DNA repair capacity,
even among virally suppressed patients. The persistence thereby amplifying oxidative damage. This bidirectional
26
38
of high oxidative stress despite ART initiation suggests interplay could underlie the neuropsychiatric symptoms,
that integrase inhibitor therapy may not fully attenuate, hematologic toxicity, and heightened teratogenic risk
and may even exacerbate, oxidative injury through ROS reported in DTG-treated populations. An additional layer
4
generation and impaired antioxidant defenses. of complexity may arise from genetic polymorphisms in
Second, folate levels remained markedly and folate metabolism (e.g., MTHFR variants), which could
consistently lower in HIV-positive participants compared modulate individual susceptibility to drug-nutrient
with controls. The within-group change after DTG interactions and oxidative injury, further reinforcing the
therapy was small and not statistically significant (Cohen’s need for personalized monitoring strategies.
d = −0.33), but the between-group effect sizes were Clinically, these findings highlight that patients on
extremely large, with values such as d = −1.49 for pre versus DTG-based ART face a dual burden. They experience
control and d = −2.61 for post versus control. This suggests worsening oxidative stress after treatment initiation,
that while DTG initiation does not cause an acute decline, coupled with profound pre-existing folate deficiency that
HIV infection itself is strongly associated with severe remains uncorrected by therapy. This underscores the
folate depletion. Folate is indispensable for one-carbon need for integrated management approaches that extend
metabolism, DNA synthesis, and hematopoiesis, and its beyond viral suppression. Routine monitoring of oxidative

Volume 2 Issue 4 (2025) 127 doi: 10.36922/MI025310074