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ATC codes: J05AX12
EMLc
Indication
Human immunodeficiency virus disease without mention of associated disease or condition, clinical stage unspecified ICD11 code: 1C62.Z
INN
Dolutegravir
Medicine type
Chemical agent
List type
Core
Formulations
Oral > Solid: 50 mg tablet
EML status history
First added in 2017 (TRS 1006)
Changed in 2019 (TRS 1021)
Sex
All
Age
Also recommended for children
Weight restriction
≥ 25 kg
Therapeutic equivalence
The recommendation is for this specific medicine
Patent information
Main patent is active in several jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPal.org
Expert Committee recommendation
The Expert Committee recommended the addition of dolutegravir 50 mg tablets to the core list of the EMLc for treatment of HIV infection in paediatric patients weighing 25 kg or more, in combination with an optimized NRTI backbone regimen, in line with recommendations in current WHO guidelines. The Committee acknowledged the important need to expand HIV treatment options for children. The Committee noted the available evidence for use of dolutegravir in children was largely limited to pharmacokinetic and safety data from two ongoing paediatric trials, but considered that extrapolation of efficacy from adult trials was acceptable.
Background
The application requested the addition of dolutegravir to the core list of the EMLc for treatment of HIV infection in paediatric patients weighing 25kg or more. Dolutegravir was added to the core list of the EML in 2017 for treatment of adult patients.
Public health relevance
There are now 1.8 million children living with HIV, the vast majority in sub- Saharan Africa. Evidence shows that in the absence of ART, over 50% of HIV-infected infants progress to AIDS or death by the age of 2 years (1), but the introduction of paediatric ART has changed HIV infection in children from a life-threatening illness to a chronic but manageable infection. Despite recognition of the advantages of early treatment, paediatric treatment coverage still only reaches 52% of children eligible for treatment (estimated 940 000) and in 2017 an estimated 110 000 HIV/AIDS-related deaths occurred in children <15 years of age (2). Although there is limited clinical experience globally with use of dolutegravir (DTG) in children, it is recommended in this population based on extrapolation of efficacy from the larger, and more diverse adult studies (3). Regulatory and normative bodies including the WHO (and its paediatric working groups) and the US FDA have accepted the concept of extrapolation of efficacy of ARVs in paediatric patients based on bridging pharmacokinetic (PK) data and supporting safety information. Thus, the most recent WHO treatment guidelines for paediatric use of DTG are based primarily on aligning PK data collected in children receiving DTG in clinical trials to adult PK targets.
Benefits
Dolutegravir has been shown to be effective in diverse adult patient populations enrolled in multiple clinical trials conducted internationally. The results of these adult clinical trials were reviewed in the dossier submitted to support inclusion of dolutegravir 50 mg as first-line ART in the EML in 2017 and are not reproduced here. The paediatric data published to date comprises two ongoing clinical trials and several observational cohort reports. The trials on which WHO treatment and dosing recommendations are based include the IMPAACT P1093 study, sponsored by the U.S. National Institutes of Health, and the ODYSSEY study, sponsored by the Paediatric European Network for Treatment of AIDS-ID. PK and safety data from these trials have been reported and reviewed as new weight band cohorts have been completed. Both trials are evaluating paediatric patients as young as 4 weeks of age using a dispersible tablet, but data for the younger/smaller patients are not available at this time. IMPAACT P1093 is an ongoing single-arm, open-label trial of DTG in children with HIV. FDA approval of DTG for use in children weighing as low as 40 kg was based on data from 23 treatment-experienced, integrase strand transfer inhibitor (INSTI)-naive adolescents (4). Intensive PK evaluations were performed on the first 10 participants, nine of whom weighed ≥40 kg and received dolutegravir 50 mg and one of whom weighed 37 kg and received DTG 35 mg. These doses resulted in exposures comparable to those seen in adults receiving 50 mg once daily. At 48 weeks, 61% of participants had achieved HIV RNA concentration <50 copies/mL. By week 144, 39% and 30% of participants had achieved HIV RNA concentrations <400 copies/mL and <50 copies/mL, respectively. All who experienced virologic failure were reported to be nonadherent. A younger cohort of children aged ≥6 to <12 years were also enrolled in IMPAACT P1093, with those weighing ≥30 kg to <40 kg receiving the 35 mg dose and those weighing ≥40 kg receiving the 50 mg dose. At 48 weeks, data from 23 participants demonstrated a favourable safety profile, adequate PK and virologic efficacy, with HIV RNA concentrations of <50 copies/mL achieved in 74% of participants. These data led to FDA approval of the lower strength filmcoated tablets (10 mg plus 25 mg) for children with HIV weighing at least 30 kg. Using similar data, the European Medicines Agency (EMA) approved the lower strength film-coated tablets for children aged ≥6 years and weighing ≥15 kg based on population PK modelling and simulation analyses (5). The EMA approved doses of 20 mg for children weighing 15 kg to <20 kg and 25 mg doses for those weighing 20 kg to <30 kg. Because the available PK data in these weight bands were very limited and the observed trough concentrations (Ctrough) were lower than expected, the FDA did not approve dosing for children weighing <30 kg. The ODYSSEY trial is enrolling both treatment-naive and -experienced paediatric patients in the EU, Thailand and several African countries, and initially evaluated the EMA-approved doses for children weight > 15kg. A total of 674 children <18 years of age were enrolled; 282 starting dolutegravir as first-line therapy and 392 starting second-line therapy (6). Nested pharmacokinetic substudies within ODYSSEY are evaluating simplified paediatric dosing aligned with WHO-recommended weight bands. PK data have been reported from a cohort of children >25 kg switching to the 50 mg adult tablet (n=27). These children receiving the 50 mg film-coated tablet achieved exposures similar to those of adults. When given to children 14 to <25 kg, the DTG 25 mg film-coated tablet resulted in lower exposure than the adult target exposure, particularly Ctrough. The lower Ctrough was more marked in the 20 to <25 kg group. Higher doses are currently under study in these weight bands and doses have been adjusted for lower weight bands (7, 8). After careful review and discussion, the WHO-convened Paediatric Antiretroviral Working Group endorsed the simplified dosing using the dolutegravir 50 mg tablet in children weighing >25kg. In the adult clinical studies to date, dolutegravir-based regimens were either non-inferior or superior in efficacy to comparator regimens containing other integrase inhibitors, boosted protease inhibitors and NNRTIs, regardless of patient population. In patients initiating first-line treatment, successful virologic suppression occurred in more patients receiving DTG than the comparators. There are no comparative paediatric trials available but both the WHO working groups and multiple regulatory agencies (including the U.S. FDA and the EMA) endorse the concept of extrapolating efficacy from well-designed, adequatelypowered adult trials on the basis of similar pharmacokinetic profile and supplemental safety data.
Harms
A French, retrospective, multicentre cohort study evaluated 50 adolescents who initiated dolutegravir-based ART. In this cohort, only one patient discontinued DTG-based treatment because of a significant adverse effects (dizziness and sleep disturbance) (9). Another cohort of adolescents reported from Barcelona received the fixed-dose combination product Triumeq (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg). No serious safety concerns were reported, however, patients complained about the size of the tablet and six reported having to crush or split the tablet in order to swallow it, potentially contributing to adherence issues (10). In the original clinical trials, patients on dolutegravir experienced significantly fewer incidences of nervous system disorders and psychiatric disorders than those receiving efavirenz, however, there have been postmarketing reports of neuropsychiatric events (such as insomnia or depression) among adults receiving DTG-based treatment since its approval. Causality for these events has been difficult to determine as many patients are reported to have a previous history of psychiatric symptoms. In a surveillance study of birth outcomes among pregnant women on ART in Botswana, an increased rate of neural tube defects was observed among infants born to women who were receiving dolutegravir at the time of conception (11). As children and young adolescents mature, and before they become sexually active, paediatric and adolescent providers should discuss this potential risk with patients who are receiving or initiating dolutegravir and their caregivers. The WHO 2018 interim guidelines (3) note the following in their guidance on this topic: – Dolutegravir appears to be safe when started later in pregnancy: after the period of risk of neural tube defects and after the first trimester. – Adolescent girls and women of childbearing potential who do not currently want to become pregnant can receive DTG together with consistent and reliable contraception; hormonal contraception and DTG have no reported or expected drug–drug interactions although data are limited.
Cost / cost effectiveness
The indicative average price per patient per year (PPPY) for dolutegravir 50 mg tablets is approximately US$ 50 for children weighing between 25 and 35 kg. This price is lower than PPPY for other ARVs suitable for children. In November 2015, the Clinton Health Access Initiative (CHAI), UNAIDS, and Unitaid announced a pricing agreement for DTG 50 mg single tablets that had been brokered with Aurobindo Pharma (12). Under the agreement, Aurobindo agreed to make generic DTG 50 mg tablets available at a price of US$ 44.00 PPPY (or US$ 3.67 per pack).
WHO guidelines
The WHO-recommended dose of DTG in integrase inhibitor treatment naive adults and paediatric patients weighing more than 25 kg is one tablet (50 mg) once daily (3). Dolutegravir should be given together with two NRTIs appropriate for paediatric patients (i.e. abacavir plus lamivudine or zidovudine plus lamivudine). In addition, the WHO 2018 interim guidelines also recommend that DTG in combination with an optimized NRTI backbone is the preferred second-line regimen for children with approved DTG dosing for whom non- DTG-based regimens are failing.
Availability
Dolutegravir 50 mg tablets are manufactured by multiple pharmaceutical companies, including generic and WHO prequalified manufacturers.
1. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236–43. 2. UNAIDS Core Epidemiology Slides. Geneva: Joint United Nations Programme on HIV/AIDS; 2018. Available from http://www.unaids.org/en/resources/documents/2018/core-epidemiology-slides, accessed 29 September 2019. 3. Updated recommendations on first-line and second-line antiretroviral regimens and postexposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines, supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1 with accompanying Annex 3: Dosages of ARV drugs. World Health Organization, Geneva. December, 2018. Available from https://www.who.int/hiv/pub/guidelines/ARV_Guidelines-2018- Annex3.pdf?ua=1. Both accessed 29 September 2019. 4. Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E et al. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J. 2015;34(11):1207–13. 5. Summary of Product Characteristics: Tivicay [website]. London: European Medicines Agency; 2014. (https://www.ema.europa.eu/documents/product-information/tivicay-epar-product-infor mation_en.pdf, accessed 29 September 2019). 6. Moore C, Kekitinwa A, Kaudha E, Lugemwa A, Mujuru H, Cotton M et al. ODYSSEY: A randomised trial evaluating the efficacy and toxicity of dolutegravir-based antiretroviral therapy compared to standard of care in HIV-infected children starting first-line or second-line therapy: design, current status and baseline characteristics. Abstract 34. 10th International Working on HIV Pediatrics. 21–22 July 2018, Amsterdam, The Netherlands. Reviews in Antiviral Therapy & Infectious Diseases. 2018;8:37. 7. Bollen P, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A et al. Steady-state pharmacokinetics and early safety data in HIV-infected African children weighing 14 to <25kg on film-coated dolutegravir 25mg tablets in the ODYSSEY trial. Abstract 22. 10th International Working on HIV Pediatrics. 21–22 July 2018, Amsterdam, The Netherlands. Reviews in Antiviral Therapy & Infectious Diseases 2018;8:27. 8. Turkova A, Bollen P, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A et al. Steady-state pharmacokinetics and early safety data in HIV-infected African children weighing ≥25kg after switching to 50mg film-coated dolutegravir tablets in the ODYSSEY trial. Abstract 3. 10th International Working on HIV Pediatrics. 21–22 July 2018, Amsterdam, The Netherlands. Reviews in Antiviral Therapy & Infectious Diseases. 2018;8:5. 9. Briand C, Dollfus C, Caseris M et al. Abstract: Dolutegravir-based cART in vertically HIV-1-infected adolescents, real-world setting.” 24th Conference on Retroviruses and Opportunistic Infections. Seattle, WA. 2017. 10. Bossacoma Busquets F, Noguera-Julian A, Sanchez E, Fortuny C. Dolutegravir plus abacavir/ lamivudine works in adolescents, but size matters. J Antimicrob Chemother. 2017;72(10):2958–60. 11. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018;379(10):979–81. 12. Three new agreements announced with the potential to expand access to innovative HIV treatment in low- and middle-income countries [Press Release]. Harare/Geneva: UNAIDS; 2015. Available from http://www.unaids.org/en/resources/presscentre/pressreleaseandstatement archive/2015/november/20151130_PR_CHAI_UNITAID, accessed 29 September 2019.