Page 131 - MI-2-4

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

to oxidative stress and metabolic dysregulation. These Mechanistic work further supports this biological
safety signals have sparked renewed scrutiny, especially interaction. Cabrera et al. demonstrated that DTG acts
4
in resource-limited settings where DTG is being rapidly as a non-competitive antagonist of folate receptor 1,
scaled up as part of universal treatment strategies. inhibiting folate uptake despite adequate serum levels.
Real-world evidence has increasingly highlighted the Animal and cell-based studies confirmed that DTG-
neuropsychiatric burden associated with DTG. A cross- induced neurodevelopmental toxicity—including
sectional study in Uganda reported that 41.7% of adult dopaminergic neuronal loss, reduced viability of stem
patients on DTG experienced at least one NPAE, with cell-derived brain organoids, altered neurogenic gene
9.1% experiencing severe or life-threatening outcomes expression such as ngn1, and impaired locomotor activity
requiring clinical intervention. Comparable findings were in zebrafish embryos—was largely attenuated by folic acid
1
6,11-13
reported in a multicenter study in Ethiopia, underscoring supplementation.
the importance of clinical vigilance in settings with limited Although the initial NTD safety signal has been
access to psychiatric support. Further evidence from attenuated by subsequent large-scale monitoring—with
2
the randomized DOBINeuro trial showed that patients risk estimates declining as surveillance expanded and
9
switched from DTG/abacavir/lamivudine to bictegravir- pharmacovigilance studies have not confirmed a definitive
based regimens experienced improvements in sleep link between DTG and NTDs, clinical attention has shifted
14
disturbances, although other neuropsychiatric symptoms toward other emerging safety concerns, including weight
persisted, suggesting that DTG-associated tolerability gain, metabolic complications, and oxidative imbalance. 15
challenges are nuanced and may not be completely A growing body of work suggests that DTG may induce
reversible. 3
oxidative stress and mitochondrial dysfunction, leading
In parallel, a growing body of experimental and clinical to systemic metabolic dysregulation. Elevated reactive
research has examined the relationship between DTG and oxygen species (ROS) production and perturbations in
folate metabolism. Preclinical evidence demonstrates that mitochondrial pathways have been observed, contributing
DTG disrupts the expression and function of critical folate to lipid accumulation, insulin resistance, and metabolic
transporters—including reduced folate carrier, proton- dysfunction in adipocytes. These effects appear to be
coupled folate transporter, and folate receptor-α—in mediated through impairment of fatty acid oxidation,
human placental models and pregnant mice, thereby dysregulation of lipoprotein lipase, and increased
impairing cellular folate uptake under folate-deficient expression of pro-inflammatory cytokines such as tumor
conditions. In mice maintained on low-folate diets, necrosis factor α and interleukin-6, mechanisms that
4,5
DTG exposure induced neural tube defects (NTDs), mirror established pathways of oxidative stress-related
such as exencephaly and cleft palates, whereas folic acid metabolic disorders. 16,17 Such findings raise important
supplementation mitigated these abnormalities. 6 concerns regarding long-term cardiometabolic outcomes
Human evidence aligns with these findings: the in individuals on lifelong DTG therapy.
ADVANCE trial in South Africa reported divergent folate The central nervous system effects of DTG further
responses depending on the ART regimen, with women compound its safety profile. Its penetrance across the
on tenofovir alafenamide/emtricitabine (FTC) + DTG blood-brain barrier has been associated with symptoms
showing increased serum folate over 12 weeks, whereas such as insomnia, depression, and anxiety, which in some
those on tenofovir disoproxil fumarate (TDF)/FTC + cases necessitate treatment discontinuation. Systematic
DTG or TDF/FTC/Efavirenz experienced declines. This reviews estimate that up to 11.8% of patients discontinue
7
variability suggests that DTG’s impact on folate may depend DTG due to NPAEs, with older age, female sex, and ART-
on background regimen composition, baseline nutritional naïve status conferring increased risk. Pharmacogenetic
14
status, or host-related factors. The importance of adequate data suggest that individual susceptibility may be modified
folate intake in mitigating DTG-associated teratogenic by genetic variation, with polymorphisms such as NR1I2
risks has been emphasized by several investigators. A 2024 c.–22-7659C>T shown to reduce NPAE risk. Preclinical
18
review highlighted that supplementation or dietary evidence adds further mechanistic plausibility, indicating
fortification protects NTDs in pregnancies exposed to that DTG may exert neurotoxic effects through N-methyl-
DTG, particularly in populations with poor baseline D-aspartate receptor activation, glutamate-mediated ROS
folate status. Initial surveillance in Botswana suggested production, and eryptosis, with recent work implicating
8
an elevated risk of NTDs in infants conceived on DTG, endoplasmic reticulum stress at the blood-brain barrier
9
and subsequent analyses reinforced this association in the as an additional pathway of DTG-induced central nervous
context of low dietary folate intake. 10 system toxicity. 19

Volume 2 Issue 4 (2025) 123 doi: 10.36922/MI025310074