Kenneth Kintu1, Thokozile R Malaba2, Jesca Nakibuka1, Christiana Papamichael3, Angela Colbers4, Kelly Byrne3, Kay Seden5, Eva Maria Hodel5, Tao Chen3, Adelline Twimukye1, Josaphat Byamugisha6, Helen Reynolds7, Victoria Watson3, David Burger4, Duolao Wang3, Catriona Waitt8, Miriam Taegtmeyer9, Catherine Orrell10, Mohammed Lamorde1, Landon Myer11, Saye Khoo12. 1. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda. 2. Division of Epidemiology and Biostatistics, University of Cape Town, Cape Town, South Africa. 3. Tropical Clinical Trials Unit, Liverpool School of Tropical Medicine, Liverpool, UK. 4. Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, Netherlands. 5. Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. 6. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; Department of Gynaecology and Obstetrics School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda. 7. Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. 8. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. 9. International Public Health, Liverpool School of Tropical Medicine, Liverpool, UK. 10. School of Public Health & Family Medicine, and Desmond Tutu HIV Centre, Department of Medicine, Institute of Infectious Diseases & Molecular Medicine, University of Cape Town, Cape Town, South Africa. 11. Division of Epidemiology and Biostatistics, University of Cape Town, Cape Town, South Africa; Centre for Infectious Diseases Epidemiology and Research, University of Cape Town, Cape Town, South Africa. 12. Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. Electronic address: khoo@liverpool.ac.uk.
Abstract
BACKGROUND: Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. METHODS: In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. FINDINGS:Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) orefavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31-2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. INTERPRETATION: Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. FUNDING: Unitaid.
RCT Entities:
BACKGROUND: Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. METHODS: In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31-2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. INTERPRETATION: Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. FUNDING: Unitaid.
Authors: Sean S Brummel; Jeff Stringer; Ed Mills; Camlin Tierney; Ellen C Caniglia; Angela Colbers; Benjamin H Chi; Brookie M Best; Myriam El Gaaloul; Sharon Hillier; Gonzague Jourdain; Saye H Khoo; Lynne M Mofenson; Landon Myer; Sharon Nachman; Lynda Stranix-Chibanda; Polly Clayden; Memory Sachikonye; Shahin Lockman Journal: J Int AIDS Soc Date: 2022-07 Impact factor: 6.707
Authors: Matthew L Romo; Rena C Patel; Jessie K Edwards; John M Humphrey; Beverly S Musick; Caitlin Bernard; Mercy W Maina; Ellen Brazier; Barbara Castelnuovo; Jeremy Penner; Katarzyna Wyka; Sandra Wagner Cardoso; Penh Sun Ly; Cordelia Kunzekwenyika; Claudia P Cortés; Radoslaw Panczak; Elizabeth A Kelvin; Kara K Wools-Kaloustian; Denis Nash Journal: Ann Intern Med Date: 2021-11-30 Impact factor: 51.598
Authors: Maria de Lourdes Benamor Teixeira; Trevon L Fuller; Maria Isabel Fragoso Da Silveira Gouvêa; Maria Letícia Santos Cruz; Loredana Ceci; Fellipe Pinheiro Lattanzi; Leon Claude Sidi; Wallace Mendes-Silva; Karin Nielsen-Saines; Esau Custodio Joao Journal: Antimicrob Agents Chemother Date: 2020-11-17 Impact factor: 5.191
Authors: Shahin Lockman; Sean S Brummel; Lauren Ziemba; Lynda Stranix-Chibanda; Katie McCarthy; Anne Coletti; Patrick Jean-Philippe; Ben Johnston; Chelsea Krotje; Lee Fairlie; Risa M Hoffman; Paul E Sax; Sikhulile Moyo; Nahida Chakhtoura; Jeffrey Sa Stringer; Gaerolwe Masheto; Violet Korutaro; Haseena Cassim; Blandina T Mmbaga; Esau João; Sherika Hanley; Lynette Purdue; Lewis B Holmes; Jeremiah D Momper; Roger L Shapiro; Navdeep K Thoofer; James F Rooney; Lisa M Frenkel; K Rivet Amico; Lameck Chinula; Judith Currier Journal: Lancet Date: 2021-04-03 Impact factor: 79.321
Authors: Nadia M Ikumi; Komala Pillay; Tamara Tilburgs; Thokozile R Malaba; Sonwabile Dzanibe; Elizabeth Ann L Enninga; Rana Chakraborty; Mohammed Lamorde; Landon Myer; Saye Khoo; Heather B Jaspan; Clive M Gray Journal: J Infect Dis Date: 2021-12-08 Impact factor: 7.759
Authors: Jasmini Alagaratnam; Helen Peters; Kate Francis; Natasha Kay; Yvonne Gilleece; Fionnuala P Finnerty; Rosanna E Grimes; Sarah Parry; Mags Portman; Brenton C Wait; Rimi Shah; Sherie Roedling; David A Hawkins; Sarah Chitty; Liat Sarner; Rebecca Marcus; Anna Hartley; Achyuta V Nori; Melanie Rosenvinge; Graham P Taylor Journal: AIDS Res Ther Date: 2020-07-13 Impact factor: 2.250
Authors: Kimberly K Scarsi; Joshua P Havens; Anthony T Podany; Sean N Avedissian; Courtney V Fletcher Journal: Drugs Date: 2020-11 Impact factor: 9.546