The Expert Committee recommended the addition of the new formulation of ritonavir oral powder 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, noting the importance of the availability of quality, age-appropriate paediatric dosage forms of antiretroviral medicines.
Single-agent ritonavir (RTV) has been included on the EMLc since 2007. Currently listed formulations are oral liquid 400 mg/5mL and heat-stable tablets 25 mg and 100 mg.
In a separate application to the 2019 Expert Committee, ritonavir oral liquid was proposed for deletion from the EML and EMLc (See 'Other considerations').
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 antiretroviral therapy (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).
Children are at particular risk of acquiring TB, although good epidemiologic data has been difficult to collect. A 2016 systematic review and meta-analysis of opportunistic and other infections among HIV-infected children in LMICs confirmed a high incidence rate (12.3% in ART-naive and 8.8% in ART-exposed) of TB co-infection in this population (4). Among children with TB, the WHO estimates that HIV prevalence, in countries with moderate to high prevalence, ranges from 10 to 60% with the variation in rates depending on the background rates of HIV infection (5).
RTV is used only for pharmacologic boosting of other protease inhibitors (PI). The amount of RTV used depends on the PI used as the active ARV, but most PIs currently recommended as second- or third-line antiretroviral therapy (ART) require 100 mg of RTV combined with the adult dose of the PI. Paediatric patients may use differing amounts of RTV in boosted PI regimens based on their weight.
Evidence supporting the use of RTV as a pharmacologic booster for second- and third-line PIs has previously been accepted by the EML which notes: “Ritonavir is recommended for use in combination as a pharmacological booster, and not as an antiretroviral in its own right.”
Since 2010, WHO has recommended the approach of ‘super-boosting’ LPV/r with additional ritonavir (RTV) (1:1 instead of 4:1 LPV/r ratio, i.e. equal doses of LPV and RTV) to manage rifampicin-based TB co-treatment in children on an LPV/r-based regimen (6). Although HIV therapy is life-long, the use of the RTV super-boosted LPV/r regimen is only used for the duration of TB treatment with rifampicin.
A retrospective review of ART regimens and outcomes in HIV/TB coinfected children younger than 2 years in South Africa suggested that super-boosted LPV/r led to better outcomes and less toxicity than earlier PI regimens (7). The adequacy of the super-boosted regimen was confirmed in a pharmacokinetic study conducted in South Africa, which demonstrated that LPV trough concentrations in children receiving super-boosted LPV/r and rifampicin were non-inferior to LPV concentrations in children off TB therapy (8).
RTV oral powder is currently listed as a limited use formulation on the optimal paediatric ARV formulary for superboosting of LPV/r during TB co-treatment and boosting non-coformulated PIs (9).
Evidence for the safety of ritonavir has been considered previously.
The adverse event profile of ritonavir observed during paediatric clinical trials has been reported as similar to that for adult patients. Vomiting, diarrhoea and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of paediatric patients enrolled in clinical trials. Grade 3–4 laboratory abnormalities occurring in greater than 3% of paediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors were neutropenia (9%), hyperamylasaemia (7%), thrombocytopenia (5%), anaemia (4%), and elevated aspartate aminotransferase (AST) (3%) (10).
The South African retrospective study evaluating PI-based ART in children younger than 2 years of age, also receiving TB treatment, concluded there were only few treatment interruptions due to toxicity. This suggests that the use of boosted LPV/r and TB treatment in this group was generally well tolerated. The authors also noted there were no significant differences in the proportions of children with Grade 3/4 alanine aminotransferase (ALT) elevations in the TB cotreatment groups while receiving TB treatment compared to children on LPV/r alone (7).
Cost / cost effectiveness
No cost or cost-effectiveness information is currently publicly available for ritonavir oral powder.
The manufacturer has made a general commitment to employ market-specific pricing strategies as part of their commitment to access to medicines (11).
WHO guidelines for paediatric HIV treatment recommend the approach of ‘super-boosting’ LPV/r with additional RTV (1:1 instead of 4:1 LPV/r ratio, i.e. equal doses of LPV and RTV) to manage rifampicin-based TB cotreatment in children on an LPV/r-based regimen (6).
Ritonavir oral powder is available internationally from Abbvie Inc. Generic brands are not currently available.
In consideration of a separate application requesting the deletion of ritonavir oral liquid from the Model Lists, the Committee recommended that ritonavir oral liquid be retained on the Model Lists at this time. The Committee considered that until the availability is well established of the alternative formulation recommendedat this meeting, (i.e. ritonavir 100 mg oral powder), deletion of the existing formulation could be premature.
The existing formulation could be flagged for deletion without further discussion in 2021 unless an application is received in support of its retention.
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 26 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 26 September 2019.
4. B. Lajoie MR, Drouin O, Bartlett G, Nguyen Q, Low A, Gavriilidis G, et al. Incidence and Prevalence of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis. Clin Infect Dis. 2016;62(12):1586–94.
5. Venturini E, Turkova A, Chiappini E, Galli L, de Martino M, Thorne C. Tuberculosis and HIV co-infection in children. BMC Infect Dis. 2014;14 Suppl 1:S5.
6. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach - Second edition. Geneva: World Health Organization; 2016. Available from http://www.who.int/hiv/pub/arv/arv-2016/en/, accessed 26 September 2019.
7. Frohoff C, Moodley M, Fairlie L, Coovadia A, Moultrie H, Kuhn L, et al. Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment. PLoS One. 2011;6(2):e17273.
8. Rabie H, Denti P, Lee J, Masango M, Coovadia A, Pillay S, et al. Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. Lancet HIV. 2019;6(1):e32-e42
9. The 2018 optimal formulary and limited-use list for paediatric ARVs. Geneva, Switzerland: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. Available from http://apps.who.int/iris/bitstream/handle/10665/273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1, accessed 26 September 2019.
10. U.S. Food and Drug Administration. Norvir package insert, November 15, 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209512s004lbl.pdf, accessed 26 September 2019.
11. Our commitment to access to medicines [website]. North Chicago: AbbVie. (https://www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/our-commitment-to-access-to-medicines-2.pdf, accessed 26 September 2019).