BACKGROUND: Rapid reduction of HIV viral load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, cord, breastmilk and infant plasma of DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation). METHODS:Pregnant women from Uganda and South Africa were randomised (1:1) to daily dolutegravir (50 mg) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks of delivery, with matched maternal and cord samples at delivery. Mothers switched to efavirenz and maternal and infant plasma and breastmilk samples taken 24, 48 or 72 hours post-switch. Nonlinear mixed effects (NONMEM v. 7.4) was used to describe dolutegravir in all matrices and to evaluate covariates. RESULTS:Twenty-eight women and 22 infants were included. Maternal dolutegravir was described by a two-compartment model linked to a fetal and breastmilk compartment. Cord and breastmilk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breastmilk-to-infant and infant elimination rate constants. No covariate effects were observed. Predicted infant dolutegravir half-life and time to protein adjusted-IC90 (0.064 mg/L) for those above this threshold were 37.9 hours (22.1-63.5) and 108.9 hours [(18.6-129.6); 4.5 days (0.8-5.4); n=13]. CONCLUSIONS: Breastfeeding contributed relatively little to infant plasma exposures but a median of 4.5 days additional prophylaxis to some of the breastfed infants was observed following maternal dolutegravir cessation (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.
RCT Entities:
BACKGROUND: Rapid reduction of HIV viral load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, cord, breastmilk and infant plasma of DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation). METHODS: Pregnant women from Uganda and South Africa were randomised (1:1) to daily dolutegravir (50 mg) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks of delivery, with matched maternal and cord samples at delivery. Mothers switched to efavirenz and maternal and infant plasma and breastmilk samples taken 24, 48 or 72 hours post-switch. Nonlinear mixed effects (NONMEM v. 7.4) was used to describe dolutegravir in all matrices and to evaluate covariates. RESULTS: Twenty-eight women and 22 infants were included. Maternal dolutegravir was described by a two-compartment model linked to a fetal and breastmilk compartment. Cord and breastmilk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breastmilk-to-infant and infant elimination rate constants. No covariate effects were observed. Predicted infant dolutegravir half-life and time to protein adjusted-IC90 (0.064 mg/L) for those above this threshold were 37.9 hours (22.1-63.5) and 108.9 hours [(18.6-129.6); 4.5 days (0.8-5.4); n=13]. CONCLUSIONS: Breastfeeding contributed relatively little to infant plasma exposures but a median of 4.5 days additional prophylaxis to some of the breastfed infants was observed following maternal dolutegravir cessation (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.
Authors: Aida N Kawuma; Roeland E Wasmann; Kelly E Dooley; Marta Boffito; Gary Maartens; Paolo Denti Journal: Antimicrob Agents Chemother Date: 2022-05-23 Impact factor: 5.938
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Authors: George Bello; Matthew Kagoli; Sikhona Chipeta; Andrew Auld; Joy C-W Chang; Joshua R DeVos; Evelyn Kim; Jonathan Mkungudza; Danielle Payne; Michael Eliya; Rose Nyirenda; Andreas Jahn; Taziona Mzumara; Bernard Mvula; Sufia Dadabhai; Ireen Namakhoma; Yusuf Babaye; Amalia Giron; Michael R Jordan; Silvia Bertagnolio; Gabrielle O'Malley; Nellie Wadonda-Kabondo Journal: Antivir Ther Date: 2022-08 Impact factor: 1.679