Adult dolutegravir doses in children
Authors: Helena Rabie, Lisa Jane Frigati
Journal: The Lancet HIV (2020)

Most low-income and middle-income countries now use dolutegravir in first-line and second-line adult antiretroviral regimens because of its excellent antiviral activity, high barrier to resistance, and daily dosing in a fixed-dose combination.1Cahn P Pozniak AL Mingrone H et al.Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.Lancet. 2013; 382: 700-708Summary Full Text Full Text PDF PubMed Scopus (366) Google Scholar, 2WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV interim guidance.https://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: December, 2018Date accessed: May 15, 2020Google Scholar Importantly, dose adjustment for adults with tuberculosis is possible.3Dooley KE Kaplan R Mwelase N et al.Dolutegravir-based antiretroviral therapy for patients coinfected with tuberculosis and human immunodeficiency virus: a multicenter, noncomparative, open-label, randomized trial.Clin Infect Dis. 2020; 70: 549-556PubMed Google Scholar By contrast, integrase inhibitors are recommended by WHO for children as part of the first-line regimen in these settings, children are still on intolerable regimens that are less potent than those used by adults.4Penazzato M Townsend CL Rakhmanina N et al.Prioritising the most needed paediatric antiretroviral formulations: the PADO4 list.Lancet HIV. 2019; 6: e623-e631Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar The only formulations of dolutegravir that are licensed for children between 20 kg and 40 kg by stringent regulatory authorities are 25 mg and 10 mg film-coated tablets, and they are not available in less resourced settings.5Bollen PDJ, Moore CL, Mujuru HA, et al. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV; 7: e533–44.Google Scholar In The Lancet HIV, Bollen and colleagues5Bollen PDJ, Moore CL, Mujuru HA, et al. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV; 7: e533–44.Google Scholar studied simplified dosing of dolutegravir in 62 African children weighing more than 20 kg. Their most important finding is that the pharmacokinetics of 50 mg of dolutegravir once a day in children weighing more than 20 kg was similar to the current licensed dolutegravir dosing for children, the trough concentration (Ctrough) was similar to adult data and the total exposure was between reference values in adults dosed once or twice daily. Although maximum concentrations with dolutegravir 50 mg were higher in children weighing 20 kg to less than 25 kg than in adults given the drug twice daily, the treatment was safe, with three adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) that were not attributed to dolutegravir.5Bollen PDJ, Moore CL, Mujuru HA, et al. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV; 7: e533–44.Google Scholar This is an important finding because the paediatric antiretroviral market is fragmented, and there are frequent stock-outs of essential medications in countries where most children with HIV live.6Fitzgerald F Penazzato M Gibb D Development of antiretroviral resistance in children with HIV in low-and middle-income countries.J Infect Dis. 2013; 207: S85-S92Crossref PubMed Scopus (28) Google Scholar Additionally, multiple formulations of the same drug lead to incorrect dosing by caregivers and there is a need for tools to be developed to support dosing, administration, and adherence. The ability to use adult formulations and dosing allows for closer alignment with adult regimens, reduces logistic challenges and the likelihood of stock-outs of medications at a national level and also at smaller clinics where fewer children are treated, and simplifies prescribing and administration by caregivers. In paediatric and adolescent clinics doctors and nurses are frequently asked "Why can you not give me one pill a day?". With this finding it is now possible for many children to use one or two pills once a day. Children weighing more than 35 kg can use adult doses of tenofovir disoproxil fumarate2WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV interim guidance.https://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: December, 2018Date accessed: May 15, 2020Google Scholar and children weighing more than 25 kg can use abacavir, tenofovir alafenamide, and lamivudine2WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV interim guidance.https://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: December, 2018Date accessed: May 15, 2020Google Scholar, 7Natukunda E Gaur AH Kosalaraksa P et al.Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.Lancet Child Adolesc Health. 2017; 1: 27-34Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar at adult doses allowing providers to further align with adult regimens and to simplify dosing for many children and adolescents by using adult fixed dose combinations. The study team should be commended for the innovative use of nested pharmacokinetic studies to rapidly inform international guidelines rather than waiting for full efficacy trial results.8Ford D Turner R Turkova A et al.Optimizing clinical trial design to maximize evidence generation in pediatric HIV.J Acquir Immune Defic Syndr. 2018; 78: S40-S48Crossref PubMed Scopus (3) Google Scholar Efficacy has already been proved in adult studies1Cahn P Pozniak AL Mingrone H et al.Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.Lancet. 2013; 382: 700-708Summary Full Text Full Text PDF PubMed Scopus (366) Google Scholar and it is reasonable to assume that achieving pharmacokinetic targets would lead to similar results in children. These data have already informed WHO and by extension many country guidelines.2WHOUpdated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV interim guidance.https://www.who.int/hiv/pub/guidelines/ARV2018update/en/Date: December, 2018Date accessed: May 15, 2020Google Scholar By July, 2019, 19 of 21 WHO priority countries had adopted dolutegravir as first-line therapy in children weighing more than 20 kg.9Penazzato M. What's new from WHO on pediatric antiretroviral therapy. 11th International Workshop on HIV Paediatrics; Mexico City, Mexico; July 19–20, 2019.Google Scholar This rapid translation of study results to practice allows approximately 500 000 children to begin to benefit from these findings. There are still many unanswered questions. The authors5Bollen PDJ, Moore CL, Mujuru HA, et al. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial. Lancet HIV; 7: e533–44.Google Scholar comment on the scaricty of information on the use of twice-daily dolutegravir in children weighing 20–25 kg who are not ART-naive, despite the high maximum concentrations in this group. In one study done in adults, using dolutegravir 50 mg twice a day with rifampicin-containing tuberculosis treatment was well-tolerated, with no deaths or discontinuations for toxicity.3Dooley KE Kaplan R Mwelase N et al.Dolutegravir-based antiretroviral therapy for patients coinfected with tuberculosis and human immunodeficiency virus: a multicenter, noncomparative, open-label, randomized trial.Clin Infect Dis. 2020; 70: 549-556PubMed Google Scholar Recent pharmacokinetic data using 50 mg dolutegravir twice a day for children weighing more than 20 kg and aged 6 years or older also support this dose adjustment in children taking rifampicin.10Waalewijn H Mujuru H Amuge P et al.Adequate dolutegravir exposure dosed BID with rifampicin in children 6 to <18 years.Top Antivir Med. 2020; 28: 317Google Scholar Clinicians and policy makers will need to consider how to incorporate reproductive health advice into the care of younger girls accessing dolutegravir and improve the monitoring of programme outcomes. Although this is a huge leap forward, there is still a lot of work to do to ensure children with HIV can access improved regimens to the same extent that adults do. Young children in particular remain disproportionally disadvantaged with the most limited access to appropriate formulations. HR and LF work at one of the study sites included in the study, but were not on the study team. Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trialAdult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. Full-Text PDF Open Access