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

stress markers and serum folate should be considered, 4.3. Folate depletion: Clinical and public health
alongside adjunctive strategies such as targeted antioxidant significance
support and folate supplementation. Such interventions The extreme folate deficiency in our cohort highlights
may mitigate metabolic toxicity, improve hematological a major nutritional challenge. Folate insufficiency
outcomes, and reduce neurodevelopmental risks in exposed predisposes PLWH to anemia, impaired immune recovery,
infants. Although concerns about potential teratogenicity and teratogenic risk. While ART has transformed HIV
with DTG have been reported mainly from observational into a chronic condition, quality of life and comorbidity
studies of exposure at conception, our study did not include prevention remain pressing concerns. Nutritional
pregnant women. Therefore, our findings do not provide supplementation represents a low-cost intervention with
direct evidence on this risk but rather suggest the need the potential to improve outcomes.
for further validation in pregnant populations. Further
longitudinal and interventional studies are warranted to Globally, the intersection between HIV and folate
establish causality and evaluate the therapeutic efficacy of deficiency is particularly concerning in sub-Saharan Africa,
where both HIV prevalence and baseline micronutrient
these strategies.
deficiencies are high. Women of reproductive age are a critical
4.1. Perspectives on oxidative stress in HIV population, as folate deficiency is directly linked to NTDs.
The Botswana findings of increased NTDs among infants
The elevated oxidative stress observed in this study must exposed to DTG at conception underscore the urgency of
be contextualized within the broader landscape of HIV integrating micronutrient monitoring into HIV programs. 9
management. Chronic HIV infection induces a pro-oxidant
state, and while ART effectively reduces viral load, residual 4.4. Systematic interplay: Folate, one-carbon
immune activation continues to sustain ROS generation. metabolism, and redox balance
Mitochondria, as key regulators of cellular metabolism and Folate deficiency compromises one-carbon metabolism,
apoptosis, are particularly vulnerable to oxidative injury. leading to impaired DNA synthesis, methylation defects,
Persistent mitochondrial dysfunction has been linked to and reduced production of nicotinamide adenine
ART-related toxicities, including neuropathy, lipoatrophy, dinucleotide phosphate, which is essential for regenerating
and lactic acidosis. Although DTG is considered safer glutathione. Thus, folate deficiency and oxidative stress
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than thymidine analogues in this regard, the rise in MDA reinforce each other in a vicious cycle. This mechanistic
suggests that integrase inhibitors may not be metabolically insight provides a strong rationale for dual-target
inert. interventions: antioxidant therapy to counteract ROS and

Importantly, oxidative stress acts as a bridge between folate supplementation to restore one-carbon metabolism.
HIV and its non-AIDS comorbidities. Cardiovascular 4.5. Clinical implications and future directions
disease, osteoporosis, frailty, and neurocognitive
impairment are all more prevalent in PLWH compared The clinical implications of our findings are multifaceted.
with the general population, even among those on Monitoring oxidative stress markers (e.g., MDA,
suppressive ART. Our findings strengthen the hypothesis F2-isoprostanes) and serum folate in routine HIV care
that oxidative stress contributes to this excess burden and may help identify high-risk patients early. Nutritional
may serve as a therapeutic target. counseling and supplementation should be prioritized,
especially for women of childbearing age. Although
4.2. Comparative insights across ART classes antioxidant interventions are not yet standardized, they
Previous studies have shown differential effects of ART warrant further study in the context of DTG-based therapy.
classes on oxidative stress. Protease inhibitors, for instance, Future research should move beyond observational
increase oxidative stress by inducing mitochondrial ROS findings to include randomized controlled trials evaluating
production and promoting dyslipidemia. Nucleoside the efficacy of folate and antioxidant supplementation in
reverse transcriptase inhibitors, particularly stavudine and improving hematological, neurocognitive, and pregnancy
zidovudine, cause direct mitochondrial DNA depletion outcomes. Moreover, integrating genetic screening for
through inhibition of polymerase-γ. By contrast, folate metabolism polymorphisms may allow for more
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integrase inhibitors were initially thought to spare personalized care.
mitochondria, yet our findings suggest that the benefits
may be relative rather than absolute. Understanding these 5. Conclusion
nuances is critical as DTG becomes entrenched as the This study provides preliminary evidence that DTG-based
global first-line regimen. ART is associated with alterations in oxidative stress and

Volume 2 Issue 4 (2025) 128 doi: 10.36922/MI025310074