PMID- 37882611
OWN - NLM
STAT- MEDLINE
DCOM- 20240322
LR  - 20240402
IS  - 1537-6591 (Electronic)
IS  - 1058-4838 (Print)
IS  - 1058-4838 (Linking)
VI  - 78
IP  - 3
DP  - 2024 Mar 20
TI  - Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A 
      Pharmacokinetic Substudy of the EMPIRICAL Trial.
PG  - 702-710
LID - 10.1093/cid/ciad656 [doi]
AB  - BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human 
      immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with 
      rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) 
      without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing >/=3 kg, 
      and receiving dolutegravir BID with rifampicin or OD without rifampicin were 
      eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). 
      Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse 
      events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had 
      evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 
      months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 
      11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with 
      rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 
      (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 
      (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin 
      had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The 
      dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 
      2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 
      82 reported AEs were possibly related to rifampicin or dolutegravir and resolved 
      without treatment discontinuation. Upon TB treatment completion, HIV viral load 
      was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of 
      infants with and without rifampicin, respectively. CONCLUSIONS: Dolutegravir BID 
      in infants receiving rifampicin resulted in adequate dolutegravir exposure, 
      supporting this treatment approach for infants with HIV-TB coinfection.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of 
      Infectious Diseases Society of America.
FAU - Jacobs, Tom G
AU  - Jacobs TG
AUID- ORCID: 0000-0001-5738-5528
AD  - Department of Pharmacy, Radboudumc Institute for Medical Innovation, Radboud 
      University Medical Center, Nijmegen, The Netherlands.
FAU - Mumbiro, Vivian
AU  - Mumbiro V
AD  - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
FAU - Cassia, Uneisse
AU  - Cassia U
AD  - Universidade Eduardo Mondlane Faculdade de Medicina, Maputo, Mozambique.
FAU - Zimba, Kevin
AU  - Zimba K
AD  - University Teaching Hospitals-Children's Hospital, Lusaka, Zambia.
FAU - Nalwanga, Damalie
AU  - Nalwanga D
AD  - Department of Paediatrics and Child Health, School of Medicine, College of Health 
      Sciences, Makerere University, Kampala, Uganda.
FAU - Ballesteros, Alvaro
AU  - Ballesteros A
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
FAU - Dominguez-Rodriguez, Sara
AU  - Dominguez-Rodriguez S
AUID- ORCID: 0000-0003-3747-9265
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
FAU - Tagarro, Alfredo
AU  - Tagarro A
AUID- ORCID: 0000-0003-2860-3455
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
AD  - Pediatric Service, Infanta Sofia University Hospital, Servicio Madrileno de 
      Salud, Madrid, Spain.
AD  - Universidad Europea de Madrid, Madrid, Spain.
FAU - Madrid, Lola
AU  - Madrid L
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
AD  - London School of Hygiene and Tropical Medicine, London, United Kingdom.
FAU - Mutata, Constantine
AU  - Mutata C
AD  - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
FAU - Chitsamatanga, Moses
AU  - Chitsamatanga M
AD  - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
FAU - Bwakura-Dangarembizi, Mutsa
AU  - Bwakura-Dangarembizi M
AD  - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
FAU - Passanduca, Alfeu
AU  - Passanduca A
AD  - Universidade Eduardo Mondlane Faculdade de Medicina, Maputo, Mozambique.
FAU - Buck, W Chris
AU  - Buck WC
AD  - Universidade Eduardo Mondlane Faculdade de Medicina, Maputo, Mozambique.
AD  - David Geffen School of Medicine, University of California-Los Angeles, Los 
      Angeles, California, USA.
FAU - Nduna, Bwendo
AU  - Nduna B
AD  - Arthur Davidson Children's Hospital, Ndola, Zambia.
FAU - Chabala, Chishala
AU  - Chabala C
AD  - University Teaching Hospitals-Children's Hospital, Lusaka, Zambia.
AD  - School of Medicine, University of Zambia, Lusaka, Zambia.
AD  - HerpeZ, Lusaka, Zambia.
FAU - Najjingo, Elizabeth
AU  - Najjingo E
AD  - Mbarara Regional Referral Hospital, Mbarara, Uganda.
FAU - Musiime, Victor
AU  - Musiime V
AD  - Department of Paediatrics and Child Health, School of Medicine, College of Health 
      Sciences, Makerere University, Kampala, Uganda.
AD  - Joint Clinical Research Centre, Kampala, Uganda.
FAU - Moraleda, Cinta
AU  - Moraleda C
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
AD  - Pediatric Service, Hospital Universitario 12 de Octubre, Servicio Madrileno de 
      Salud, Madrid, Spain.
FAU - Colbers, Angela
AU  - Colbers A
AUID- ORCID: 0000-0002-0389-9934
AD  - Department of Pharmacy, Radboudumc Institute for Medical Innovation, Radboud 
      University Medical Center, Nijmegen, The Netherlands.
FAU - Mujuru, Hilda A
AU  - Mujuru HA
AD  - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe.
FAU - Rojo, Pablo
AU  - Rojo P
AD  - Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health 
      Research Institute, Biomedical Foundation of Hospital Universitario 12 de 
      Octubre, Madrid, Spain.
AD  - Pediatric Service, Hospital Universitario 12 de Octubre, Servicio Madrileno de 
      Salud, Madrid, Spain.
AD  - Complutense University of Madrid, Madrid, Spain.
FAU - Burger, David M
AU  - Burger DM
AD  - Department of Pharmacy, Radboudumc Institute for Medical Innovation, Radboud 
      University Medical Center, Nijmegen, The Netherlands.
CN  - EMPIRICAL Clinical Trial Group
LA  - eng
GR  - RIA2017MC-2013)/European Union/
GR  - Mozambique/
GR  - EMPIRICAL/
GR  - PediCAP/
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Infect Dis
JT  - Clinical infectious diseases : an official publication of the Infectious Diseases 
      Society of America
JID - 9203213
RN  - DKO1W9H7M1 (dolutegravir)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (Oxazines)
RN  - 0 (Piperazines)
RN  - 0 (Pyridones)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - Female
MH  - Humans
MH  - Infant
MH  - Male
MH  - *Heterocyclic Compounds, 3-Ring/pharmacokinetics
MH  - HIV
MH  - *HIV Infections
MH  - Oxazines
MH  - Piperazines
MH  - Pyridones
MH  - *Rifampin/therapeutic use
PMC - PMC10954323
OTO - NOTNLM
OT  - HIV
OT  - dolutegravir
OT  - drug-drug interaction
OT  - infants
OT  - rifampicin
COIS- Potential conflicts of interest. A. C. reports research grants from ViiV 
      Healthcare, Gilead Sciences, and Merck, all paid to institution; consulting fees 
      for serving on a Gilead advisory board and Merck advisory board, all paid to 
      institution; participation in the Pharmacokinetics and Safety of DolutegravIr in 
      Neonate (PETITE) study on a data and safety monitoring board (DSMB) and in the 
      Doravirine Dose Optimisation in Pregnancy (DORADO) study on a DSMB; and a role as 
      member of Paediatric Antiretroviral Working Group (PAWG) and as co-chair of the 
      HIV, Hepatitis and STIs Pregnancy and Breastfeeding Therapeutics Working Group. 
      P. R. reports grants from ViiV Healthcare and Merck. D. B. reports being 
      cofounder of Global DDI solutions and that his employer, RadboudUMC, has received 
      grants from ViiV Healthcare, Gilead Sciences, Merck, and Pfizer. W. C. B. reports 
      support for attending the Pediatrics & HIV 2023 Conference in Brisbane, 
      Australia, to present an EMPIRICAL abstract with study funding. V. M. reports 
      support for attending international conference from Viatris and participation on 
      a DSMB and advisory board for ViiV Healthcare. All other authors report no 
      potential conflicts. All authors have submitted the ICMJE Form for Disclosure of 
      Potential Conflicts of Interest. Conflicts that the editors consider relevant to 
      the content of the manuscript have been disclosed.
FIR - Sacarlal, Jahit
IR  - Sacarlal J
FIR - Sidat, Muhammad
IR  - Sidat M
FIR - Manjate, Elias
IR  - Manjate E
FIR - Martins, Sonia
IR  - Martins S
FIR - Langa, Stella
IR  - Langa S
FIR - Nipaco, Natalia
IR  - Nipaco N
FIR - Machava, Sara
IR  - Machava S
FIR - Chirindza, Anastancia
IR  - Chirindza A
FIR - Martins, Luzidina
IR  - Martins L
FIR - Nhaca, Mercia
IR  - Nhaca M
FIR - Nathoo, Kusum J
IR  - Nathoo KJ
FIR - Chitsamatanga, Moses
IR  - Chitsamatanga M
FIR - Marange, Ruth
IR  - Marange R
FIR - Mudzingwa, Shepherd
IR  - Mudzingwa S
FIR - Murungu, Dorothy
IR  - Murungu D
FIR - Namuziya, Natasha
IR  - Namuziya N
FIR - Zulu, Idah
IR  - Zulu I
FIR - Shankalala, Perfect
IR  - Shankalala P
FIR - Mukubesa, Mulima
IR  - Mukubesa M
FIR - Namwinwa, Juliet
IR  - Namwinwa J
FIR - Chibuye, Chalwe
IR  - Chibuye C
FIR - Chipoya, Terence
IR  - Chipoya T
FIR - Mulenga, Veronica
IR  - Mulenga V
FIR - Simunyola, Bwalya
IR  - Simunyola B
FIR - Tembo, John
IR  - Tembo J
FIR - Inambao, Muleya
IR  - Inambao M
FIR - Chitondo, Salome
IR  - Chitondo S
FIR - Mumba, Wyclef
IR  - Mumba W
FIR - Mankushe, Endreen
IR  - Mankushe E
FIR - Musukwa, Henry
IR  - Musukwa H
FIR - Sondashi, Davies
IR  - Sondashi D
FIR - Kamugisha, Albert
IR  - Kamugisha A
FIR - Econi, Karen
IR  - Econi K
FIR - Kiggwe, Andrew
IR  - Kiggwe A
FIR - Beinomugisha, Judith
IR  - Beinomugisha J
FIR - Nkinzi, Sharafat
IR  - Nkinzi S
FIR - Kakooza, Lawrence
IR  - Kakooza L
FIR - Namisanvu, Henriator
IR  - Namisanvu H
FIR - Mark, Nancy Lajara
IR  - Mark NL
FIR - Mwesige, Josam Thembo
IR  - Mwesige JT
FIR - Segawa, Ivan
IR  - Segawa I
FIR - Ssessanga, Joseph
IR  - Ssessanga J
FIR - Mbavu, Paul
IR  - Mbavu P
FIR - Kafufu, Bosco
IR  - Kafufu B
FIR - Nansera, Denis
IR  - Nansera D
FIR - Najjingo, Elizabeth
IR  - Najjingo E
FIR - Mbabazi, Bashira T
IR  - Mbabazi BT
FIR - Lugemwa, Abbas
IR  - Lugemwa A
FIR - Kasozi, Mariam
IR  - Kasozi M
FIR - Ankunda, Rogers
IR  - Ankunda R
FIR - Manukyan, Lilit
IR  - Manukyan L
EDAT- 2023/10/26 12:43
MHDA- 2024/03/22 06:44
PMCR- 2023/10/26
CRDT- 2023/10/26 09:23
PHST- 2023/07/21 00:00 [received]
PHST- 2024/03/22 06:44 [medline]
PHST- 2023/10/26 12:43 [pubmed]
PHST- 2023/10/26 09:23 [entrez]
PHST- 2023/10/26 00:00 [pmc-release]
AID - 7330359 [pii]
AID - ciad656 [pii]
AID - 10.1093/cid/ciad656 [doi]
PST - ppublish
SO  - Clin Infect Dis. 2024 Mar 20;78(3):702-710. doi: 10.1093/cid/ciad656.