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

Abstract

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)

Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment

“…Prior works focused on determining relationships between folate levels or transport pathways and DTG-associated birth defects failed to conclusively generate any cause and effect relationships [11,[56][57][58][59]. Exploring alternative mechanisms was required [11,[56][57][58][59]. Herein, for the first time, we show that DTG inhibits MMPs activities in fetal brain during gestation and as such impairs neurodevelopment.…”

“…This includes the mechanism(s) of action on the developing CNS [2,[9][10][11][12][13]. Prior works focused on determining relationships between folate levels or transport pathways and DTG-associated birth defects failed to conclusively generate any cause and effect relationships [11,[56][57][58][59]. Exploring alternative mechanisms was required [11,[56][57][58][59].…”

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

“…A recent study of 406 women living with HIV initiating either a DTG or an efavirenz based regimen found no significant declines in serum folate concentrations associated with DTG treatment. 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.…”

Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta

“…Beginning with the 2018 Tsepamo report of NTDs amongst pregnant women taking DTG from the time of conception, recent clinical and preclinical reports have identified mixed findings regarding folate delivery and toxicity amongst women taking DTG, with several studies identifying little or no risk. 19 , 20 , 21 , 22 , 24 , 26 , 27 , 35 In contrast, Cabrera et. al.…”

“… 19 This early signal prompted concern regarding the safety of DTG use during pregnancy, and led the World Health Organization to temporarily suspend recommendation of DTG in this population. Reassuring follow-up findings from the Tsepamo study and others demonstrated lower rates of NTDs, though in some cases still higher than rates in populations exposed to non-DTG based ART; 20 , 21 , 22 , 23 however as DTG use continues to rise among pregnant women, and women of childbearing age living with HIV, it remains critical to better understand the implications of in utero DTG exposure on fetal development. Recent reports have identified potential interactions between DTG and folate uptake pathways, though the implications of these findings remain unclear, and findings in in vivo models are limited.…”