The Expert Committee recommended the the addition of a new formulation of raltegravir granules for oral suspension 100 mg to the core list of the EML and EMLc for the treatment of HIV infection, in line with recommendations in current WHO guidelines. The Committee considered that this formulation of raltegravir could facilitate treatment of neonates and paediatric patients, and would be a suitable alternative for adult and paediatric patients for whom dolutegravir is not available or is not tolerated.
The Committee recommended that raltegravir 100 mg chewable tablets be retained on the Model Lists at this time. The Committee considered that until the availability is well established of the alternative formulations recommended, deletion of the existing formulation could be premature. The 100 mg chewable tablet formulation could be flagged for deletion without further discussion in 2021 unless an application is received in support of its retention.
Raltegravir was added to the Model Lists in 2017 for use in pregnant women and as a second-line treatment option for children in accordance with WHO guidelines. Currently listed formulations include 400 mg tablets and 25 mg and 100 mg chewable tablets.
In a separate application to the 2019 Expert Committee, raltegravir 100 mg chewable tablet formulation was proposed for deletion from the EML and EMLc.
Public health relevance
Despite an impressive reduction in mother-to-child transmission of HIV in recent years, 180 000 new paediatric infections occurred in 2017. There are now 1.8 million children living with HIV, the vast majority in sub-Saharan Africa (1). Evidence shows that in the absence of ART, over 50% of HIV-infected infants progress to AIDS and death by the age of 2 years (2), 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 (1) and in 2017 an estimated 110 000 HIV/AIDS-related deaths occurred in children <15 years of age (3).
Data supporting general effectiveness of raltegravir in adults has been considered previously. The application only presented evidence relevant to the use of raltegravir granules for oral suspension.
Data from IMPAACT P1066, a Phase I/II open-label multicentre trial to evaluate the pharmacokinetic profile, safety, tolerability and efficacy of RAL in HIV-infected children (4) have been considered previously, and are not reproduced here.
The safety and pharmacokinetics of raltegravir granules for oral suspension were evaluated in 42 full-term HIV-1-exposed neonates at high risk of acquiring HIV-1 infection in a Phase I, open-label, multicentre clinical study (IMPAACT P1110) (5). Cohort 1 neonates received 2 single doses of RAL powder for oral suspension: the first within 48 hours of birth and the second at 7 to 10 days of age. Cohort 2 neonates received daily dosing of RAL powder for oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through Day 7 (week 1); 3 mg/kg twice daily on Days 8 to 28 of age (weeks 2 to 4); and 6 mg/kg twice daily on Days 29 to 42 of age (weeks 5 and 6). Sixteen neonates were enrolled in Cohort 1 and 26 in Cohort 2; all infants received a standard of care ARV drug regimen for prevention of mother-to-child HIV transmission. All enrolled neonates were followed for safety for a duration of 24 weeks. HIV-1 status was assessed by nucleic acid test at birth, week 6 and week 24 and all remained HIV-1 negative.
IMPAACT P1066 also enrolled HIV-infected infants and toddlers from 4 weeks to less than 2 years of age who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir granules for oral suspension was administered in combination with an optimized background regimen, and without regard to food. None of the enrolled subjects were completely treatment naive (all had prenatal/in utero ARV exposure or postnatal prophylaxis or treatment). Of the 26 treated subjects, 24 subjects were included in the week 48 efficacy analyses. All 26 treated subjects were included for safety analyses. At week 48, 45% achieved HIV RNA <50 copies/mL and 67% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to week 48 was 527 cells/mm3 (7.3%) (6). A recent follow-up publication reports the outcomes of those patients receiving raltegravir at the final selected doses through 240 weeks of treatment. In this analysis, 13 of 15 infants receiving raltegravir oral granules for 240 weeks achieved virologic success (>1 log decrease in HIV RNA from baseline or HIV RNA <400 copies/mL) (7).
Raltegravir granules for oral suspension is currently listed as a limited use formulation on the optimal formulary and limited-use list for neonatal treatment only.
Evidence of the safety and tolerability of raltegravir has been previously considered. The overall safety of raltegravir in paediatric patients, including neonates, was similar to that observed in adults.
Overall, the safety profile in paediatric patients, including neonates, is similar to that observed in adults. Raltegravir is metabolized primarily by UGT1A1 (the same metabolic pathway as bilirubin) and UGT1A1 activity is greatly reduced in neonates. Concerns regarding potential competition with bilirubin for albumin binding sites and resulting jaundice in infants have not been borne out. The dose recommended in neonates takes into consideration the rapidly increasing UGT1A1 activity and drug clearance in this age group (5).
Cost / cost effectiveness
The reported price per patient per year for raltegravir oral granules is US$ 260. No cost-effectiveness information for this formulation is currently available.
The WHO 2018 updated recommendations on first- and second-line ARV regimens make the following recommendations in relation to raltegravir-based regimens in children:
A raltegravir-based regimen may be recommended as an alternative first-line regimen for infants and children for whom approved dolutegravir dosing is not available (condition recommendation, low-certainty evidence).
A raltegravir-based regimen is recommended as the preferred first-line regimen for neonates (conditional recommendations, very-low-certainty evidence).
Raltegravir-based regimens for neonates are recommended for use for no longer than three months, when transition to LPV/r solid formulations is possible (8).
Raltegravir granules for oral suspension are manufactured by Merck Sharp & Dohme Ltd.
Raltegravir granules for oral suspension are not recommended in pre-term neonates or in paediatric patients weighing less than 2 kg.
1. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. Geneva: Joint United Nations Programme on HIV/AIDS; 2018. Available from http://www.unaids.org/sites/default/files/media_asset/miles-to-go_en.pdf, accessed 29 September 2019.
2. 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.
3. 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.
4. Nachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2014;58(3):413–22.
5. Isentress U.S. package insert. Silver Spring: U.S. Food and Drug Administration; 2018. Available from https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022145s038,205786s007,0203045s015lbl.pdf, accessed 29 September 2019.
6. Nachman S, Alvero C, Acosta EP, Teppler H, Homony B, Graham B et al. Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age. J Pediatric Infect Dis Soc 2015;4(4):e76–83.
7. Nachman S, Alvero C, Teppler H, Homony B, Rodgers AJ, Graham BL et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715–e22.
8. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure 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, accessed 29 September 2019.