Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1–2 trial

Ruel, Theodore; Acosta, Edward P.; Liu, Jessica P.; Gray, Kathryn P.; George, Kathleen; Montañez, Nicole; Popson, Stephanie; Buchanan, Ann M.; Bartlett, Mattie; Dayton, Dale; Anthony, Patricia; Brothers, Cynthia H.; Vavro, Cynthia; Singh, Rajendra; Koech, Lucy; Vhembo, Tichaona; Dobbels, Els; Hazra, Rohan; Townley, Ellen; Wiznia, Andrew; Deville, Jaime G.; Carter, Michele F; Mansky, Hannah; Pinto, Jorge; Ferreira, Flavia F; Romeiro, Juliana Ribeiro; D'Angelo, Jessica; Williams, Ruth; Jundi, Fernanda; Cruz, Maria Letícia Santos; Sidi, Claude Leon; Kataike, Hajira; Owor, Maxensia; Ahimbisibwe, Grace Miriam; Rensburg, Ms Anita Janse van; Andrea, Catherine; Ponatshego, Ponego; Budu, Marian E.; Tirelo, Lesedi; Masheto, Gaerolwe; Raesi, Mpho S.; Ramogodiri, Moakanyi; Chanthong, Jiraporn; Khamrong, Chintana; Aurpibul, Linda; Fairlie, Lee; Patel, Faeezah; Soma-Kashiram, Hamisha; Archary, Moherndran; Hanley, Sherika; Govender, Vani; Sturzbecher, Fernanda Tomé; Cervi, Maria Célia; Mmbaga, Blandina T; Njau, Boniface N.; Matibe, Petronilla; Mukonowenzou, Ruvimbo; Marozva, Catherine C; Keter, Winnie C; Bii, Priscilla C; Ounchanum, Pradthana; Cressey, Tim R.; Sukrakanchana, Pra-ornsuda; Chokephaibulkit, Kulkanya; Rungmaitree, Supattra; Pilotto, José Henrique; Fernandes, Luis Eduardo; Gomes, Ivete Martins

doi:10.1016/s2352-3018(22)00044-3

Cited by 16 publications

(16 citation statements)

References 14 publications

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“…Countries around the world, including those in sub-Saharan Africa, have rapidly adopted dolutegravirbased regimens as first-line and second-line therapies for adults and older children (≥20 kg), following pharmacokinetic and efficacy results from the main ODYSSEY trial that showed children weighing at least 20 kg could safely take the once-daily adult formulation, 16,15 and subsequent recommendations by WHO. 30 Pharmacokinetic and safety data from nested substudies in ODYSSEY 19 and from IMPAACT P1093 18 were submitted by ViiV Healthcare (with collaborative support from the Penta and IMPAACT networks) for regulatory approvals of dispersible dolutegravir for young children (age ≥4 weeks). Cooperation between generic drug manufacturers, the Clinton Health Access Initiative, WHO, Unitaid, and pharmaceutical industry has resulted in rapid evaluation, approval by the FDA, and availability of the 10 mg scored dispersible dolutegravir tablet for young children from age 4 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…19 Both pharmacokinetic studies provided data for regulatory submission of 5 mg paediatric dispersible dolutegravir formulation. 18,19 Here we report on the results of the ODYSSEY efficacy and safety study in children weighing less than 14 kg.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

“…Worldwide, adults and children weighing at least 20 kg are rapidly switching to dolutegravir-based ART for first-line or second-line therapy. 17 While a paediatric single-arm dolutegravir dose-finding study (IMPAACT P1093; NCT01302847) was ongoing, 18 ODYSSEY randomly assigned a cohort of children aged 4 weeks and older and weighing between 3 kg and less than 14 kg (<14 kg cohort) in South Africa, Uganda, and…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

Mosala

Rojo

Abdulla)³

et al. 2022

The Lancet HIV

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Section: Discussionmentioning

confidence: 99%

Section: Implications Of All the Available Evidencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

Mosala

Rojo

Abdulla)³

et al. 2022

The Lancet HIV

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“…Furthermore, RAL can also be used as early as birth. Recently in the United States there have been many approvals of additional pediatric formulations such as: (1) a dispersible tablet for oral suspension for DTG for infants as young as 4-weeks old, (2) a low FDC of BIC/FTC/TAF for children weighing at least 14 kg, and (3) a low FDC of DTG/ABC/3TC for children weighing 10–25 kg [ 22 , 142 ]. It is important to note, however, that the dosing between adult and pediatric formulations cannot be interchanged on a mg-to-mg basis due to their varying pharmacokinetic profiles, specifically with DTG.…”

Section: Main Textmentioning

confidence: 99%

“…CAB can also be used with or without a lead-in with oral CAB for this indication. Refer to Table 1 for a summary of pertinent clinical characteristics of the INSTIs [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection

Zhao

Crutchley

Guduru³

et al. 2022

Retrovirology

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Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

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Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

Chandasana,

Thapar,

Hayes

et al. 2023

Clin Pharmacokinet

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Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1–2 trial

Cited by 16 publications

References 14 publications

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

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