Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)

• Published in: PLoS medicine 2019-09, Vol.16 (9), p.e1002895
• Main Authors: Waitt, Catriona, Orrell, Catherine, Walimbwa, Stephen, Singh, Yashna, Kintu, Kenneth, Simmons, Bryony, Kaboggoza, Julian, Sihlangu, Mary, Coombs, Julie-Anne, Malaba, Thoko, Byamugisha, Josaphat, Amara, Alieu, Gini, Joshua, Else, Laura, Heiburg, Christie, Hodel, Eva Maria, Reynolds, Helen, Mehta, Ushma, Byakika-Kibwika, Pauline, Hill, Andrew, Myer, Landon, Lamorde, Mohammed, Khoo, Saye
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; AIDS treatment; Alkynes; Analysis; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Aquatic mammals; Benzoxazines - administration & dosage; Benzoxazines - adverse effects; Benzoxazines - pharmacokinetics; Biology and Life Sciences; Breast feeding; Breastfeeding & lactation; Care and treatment; CD4 antigen; Clinical trials; Cord blood; Cyclopropanes; Dolphins; Dolphins (Mammals); Dolutegravir; Efavirenz; Epidemiology; Exposure; Female; Funding; Genetic disorders; Gestation; Health aspects; Health sciences; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - adverse effects; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV; HIV - drug effects; HIV - genetics; HIV - growth & development; HIV infections; HIV Infections - diagnosis; HIV Infections - drug therapy; HIV Infections - transmission; HIV Infections - virology; HIV Integrase Inhibitors - administration & dosage; HIV Integrase Inhibitors - adverse effects; HIV Integrase Inhibitors - pharmacokinetics; Human immunodeficiency virus; Humans; Infant, Newborn; Infants; Infectious Disease Transmission, Vertical - prevention & control; Infectious diseases; Marine mammals; Maternal-Fetal Exchange; Medicine; Medicine and Health Sciences; Milk, Human - metabolism; Neonates; Newborn infants; Obstetrics; Oxazines; People and Places; Pharmacokinetics; Pharmacology; Piperazines; Placenta; Plasma; Plasma physics; Postpartum; Postpartum depression; Pregnancy; Pregnant women; Public health; Pyridones; Randomization; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacokinetics; Ribonucleic acid; Risk Assessment; Risk factors; Risk reduction; RNA; Safety and security measures; Sampling; South Africa; Supervision; Treatment Outcome; Tutu, Desmond; Uganda; University colleges; Viral Load; Womens health; Young Adult
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1002895

The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to