The antagonism of folate receptor by dolutegravir

Cabrera, Robert M.; Souder, Jaclyn Paige; Steele, John W.; Yeo, Lythou; Tukeman, Gabriel; Gorelick, Daniel A.; Finnell, Richard H.

doi:10.1097/qad.0000000000002289

Cited by 41 publications

(61 citation statements)

References 45 publications

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“…However, a slight decrease was reported at 12 weeks of treatment compared to baseline in those treated with DTG administered with TDF/FTC which recovered to baseline levels by week 24, while an increase in folate levels was seen in those treated with DTG administered with tenofovir-alafenamide/FTC [39] . Although these findings do not indicate suppression of maternal folate status by DTG, in vitro studies have suggested that DTG is a non-competitive inhibitor of FOLR1 [31] , which could impair maternal-fetal folate transport. Partial inhibition of in vitro FOLR1-mediated folic acid endocytosis by DTG was also reported in a second study, although this was deemed to be not clinically relevant [30] .…”

Section: Discussionmentioning

confidence: 68%

“…Folate status is an established modifier of risk for fetal anomalies, and NTDs in particular [ [27] , [28] , [29] ]. In vitro studies have identified a potential interaction between DTG and folate-receptor 1 (FOLR1) [30] , with DTG acting as a partial antagonist of FOLR1 in vitro [31] . We compared maternal liver folate profiles and total fetal folate levels by mass-spectrometry methodology that allows analysis of unmetabolized folic acid and the six major folates, including their polyglutamated forms.…”

Section: Resultsmentioning

confidence: 99%

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Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

et al. 2021

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Background Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential. Methods Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5 mg/kg-peak plasma concentration ~3000 ng/ml – therapeutic level), or 5x-DTG (12.5 mg/kg-peak plasma concentration ~12,000 ng/ml – supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50 mg/kg tenofovir+33.3 mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry. Findings 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group. Interpretation Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake. Funding This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

et al. 2021

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“…Instead, valproate inhibits placental folate receptors, lowering the micronutrient's bioavailability [ 27 , 29 ]. Two studies using cell culture evaluated dolutegravir–folate interactions and found that dolutegravir was a partial blocker or inhibitor of folate receptor (FOLR1), one of which also showed that folic acid supplementation can lessen the toxic effects of dolutegravir in the early embryonic period in zebrafish [ 18 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…First, the drug may increase folate metabolism in the body and thus lower the amount of folate available for foetal metabolism [ 17 ]. Second, the drug may partially block folate uptake at the cellular level, meaning that the amount of folate available for foetal metabolism is reduced, while blood levels remain normal, or even elevated [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa

Chandiwana

Chersich

Venter

et al. 2021

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Objective: Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect (NTD) risk. As low maternal folate levels are linked with NTDs, we aimed to assess serum folate concentrations in women starting dolutegravir. Design: We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. Methods: We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/L) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1,053 treatmentnaïve participants were randomised to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC+DTG), tenofovir-disoproxil-fumarate (TDF)/FTC+DTG, or TDF/FTC/efavirenz (EFV). Results: Analysis includes 406 females, mean age 31.5 years and baseline CD4 count 356 cells/mm 3. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC+DTG arm (+4.0 ±8.1 nmol/L), while folate concentrations decreased slightly in the TDF/FTC+DTG arm (-1.8 ±8.9 nmol/L) and decreased in the TDF/FTC/EFV arm (-5.9 ±8.1 nmol/L). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (p<0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ±7.1 nmol/L in the TAF/FTC+DTG arm and 2.3 ±8.4 nmol/L in the TDF/FTC+DTG arm, but decreased by-3.3 ±8.1 with TDF/FTC/EFV arm. Conclusions: Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the efavirenz arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation. Words: 250 (max 250)

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“…Although studies conducted in a mammalian experimental model at high DTG exposures have not identified a potential risk for EFD, DTG appears to be embryo‐toxic to the early stages of the zebrafish embryo (Cabrera et al, ). This finding is not surprising as DTG is known to be hazardous to aquatic life at relatively high concentration, similar to what was used in the Cabrera et al, experiments, and as part of the environmental risk assessment was classified using the GHS classification (Globally Harmonized System of Classification and Labelling of Chemicals) as very toxic to aquatic life with long lasting effects (https://pubchem.ncbi.nlm.nih.gov/compound/Dolutegravir-sodium#datasheet=LCSS&section=GHS-Classification). It is likely that this toxicity of DTG to fish embryos confounded their interpretation of the data making extrapolation to human risk assessment difficult.…”

Section: Discussionmentioning

confidence: 99%

Absence of developmental and reproductive toxicity in animals exposed to dolutegravir

Stanislaus

Posobiec

Laffan

et al. 2019

Birth Defects Research

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The success of new antiretroviral medicines for HIV resulted in a change to guidelines of standard therapy where continuation of antiretroviral therapy is recommended to maintain the low viral load during pregnancy, thereby preventing transmission of the virus to the fetus. As a result, pregnancy related exposure to HIV medicines has increased. Understanding the safety of these medicines during pregnancy is of paramount importance to ensure health of mothers and their offspring; well-designed animal studies that evaluate the reproductive life cycle play a key role in this effort. As part of the medicine development program for dolutegravir (DTG), a series of reproductive and developmental toxicity studies were conducted using rats and rabbits. In a fertility study, where exposure to DTG occurred in female rats before mating through conception and up to implantation of the embryo, no effects on reproductive cycles, ovulation, fertility) or preimplantation embryonic growth were observed. In rat and rabbit embryo-fetal development studies, where exposure to DTG occurred during organogenesis, no malformations or other developmental abnormalities were observed. In a rat pre-and post-natal development study, where DTG exposure to the pups occurred during pregnancy and postnatally via milk, no malformations or other developmental abnormalities were observed. In these studies, no DTG-related effects occurred on fertility, embryonic (pre-and post-implantation loss, resorptions, abortions, and malformations) or fetal development where the multiples of exposure at the maximum recommended human dose were up to 27 times higher in rats or below the human exposure in rabbits.

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The antagonism of folate receptor by dolutegravir

Cited by 41 publications

References 45 publications

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa

Absence of developmental and reproductive toxicity in animals exposed to dolutegravir

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