Application for Inclusion of Ritonavir Oral Powder on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

Table of Contents General Information ...... 2 1. Summary statement of the proposal for inclusion, change or deletion...... 2 2. Relevant WHO technical department and focal point (if applicable)...... 2 3. Name of organization(s) consulted and/or supporting the application...... 2 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine...... 2 5. Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths (if appropriate)...... 2 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class...... 2 Treatment details, public health relevance and evidence appraisal and synthesis ...... 3 7. Treatment details (requirements for diagnosis, treatment and monitoring)...... 3 8. Information supporting the public health relevance...... 3 9. Review of benefits: summary of evidence of comparative effectiveness...... 4 10. Review of harms and toxicity: summary of evidence of safety...... 5 11. Summary of available data on comparative cost and cost-effectiveness of the medicine...... 6 Regulatory information ...... 6 12. Summary of regulatory status and market availability of the medicine...... 6 13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)...... 6 14. References: Comprehensive reference list and in-text citations...... 6

General Information 1. Summary statement of the proposal for inclusion, change or deletion. This document proposes that ritonavir (RTV) oral powder 100mg/packet indicated for use in combination with other antiretrovirals in the treatment of HIV infection be added as a new formulation to the Essential Medicines List (EML) and the Essential Medicines List for Children (EMLc). We further propose RTV oral powder be added to the core list of the EML and EMLc. The principal reasons for requesting this inclusion are as follows:  Ritonavir (RTV) is available in multiple formulations for adult and pediatric patients able to swallow tablets for the purpose of pharmacological boosting of other protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV) used in second- and third-line treatment but, to date, no other formulation is available for patients unable to swallow tablets.  RTV is the only protease inhibitor indicated for pharmacological boosting of other protease inhibitors.  In pediatric patients requiring concomitant treatment of HIV and tuberculosis, RTV is recommended to “super-boost” lopinavir/ritonavir (LPV/r). 2. Relevant WHO technical department and focal point (if applicable). Martina Penazzato, WHO/HTM/HIV/ATC 3. Name of organization(s) consulted and/or supporting the application. Clinton Health Access Initiative, Inc. 4. International Nonproprietary Name (INN) and Anatomical Therapeutic Chemical (ATC) code of the medicine. INN: Ritonavir ATC: J05AE03

5. Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate paediatric dose forms/strengths (if appropriate). Each foil/laminate packet contains RTV oral powder 100mg, to be opened and mixed with soft food or liquid. RTV oral powder is available internationally from the following manufacturer: AbbVie Incorporated 1400 Sheridan Rd, North Chicago, IL 60064 USA 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class. We request inclusion of RTV oral powder 100mg as a new formulation of the HIV-1 protease inhibitor RTV (as an individual medicine). RTV is currently included in EML and EMLc section 6.4.2.3 Protease Inhibitors as oral liquid 400mg/5mL and heat stable tablets 25mg and 100mg. There are other PIs in the EML but none that are used as pharmacological boosters, therefore, there are no therapeutic equivalents.

Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring). RTV is no longer used as an active antiviral but is now used only for pharmacologic boosting of other PIs. 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 100mg of RTV combined with the adult dose of the PI. Pediatric patients may use differing amounts of RTV in boosted PI regimens based on their weight. In addition, 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.1 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. The approved RTV oral powder package insert recommends only using the product in increments of 100mg (i.e., whole packets).

8. Information supporting the public health relevance. Despite an impressive reduction in mother to child transmission of HIV in recent years, 180,000 new pediatric infections occurred in 2017. 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 and death by the age of 2 years2, but the introduction of pediatric 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, pediatric treatment coverage still only reaches 52% of children eligible for treatment3 and in 2017 an estimated 110,000 HIV/AIDS related deaths occurred in children <15 years of age4. However, with increasing evidence about the beneficial effects of earlier ART initiation and the release of the 2016 WHO Consolidated Guidelines, new recommendations stress the need for early testing and treatment for all infants and children living with HIV. Scaling up early infant testing (including testing at birth) to identify perinatal transmission will allow many more infants to receive life-saving ARVs within the first few weeks of life. Since 2014 and as led by UNAIDS, the global community has set a target to end the AIDS epidemic by 2030, but the particular vulnerabilities of pediatric patients necessitate an even more ambitious goal - ending pediatric AIDS by 2020.5 This super fast-track target aim to reach 1.6 million children with ART by 2018. In order to successfully scale-up treatment of pediatric HIV infection, it is critical that ARV dosage forms for the most effective drugs are appropriate for use in infants and young children and are accessible, particularly in resource limiting settings. Dispersible solid dosage forms including chewable tablets have proven to confer an advantage over liquid dosage forms for older children unable to swallow tablets, and both pellets/mini tablets and granules/powders have been developed for younger children and infants. Recent years has seen the development of a variety of dosage forms for pediatric ARVs, but compared to the demand for adult ARVs, children account for just 5% of patients on ART, thereby rendering the global pediatric market smaller and more vulnerable to supply disruption. The IATT Optimal Pediatric ARV Formulary and Limited-use List was first developed in 2011 to address this challenge and now provides guidance to streamline the selection of pediatric ARV dosage forms to those that conform to a list of criteria, including dosing flexibility, user-friendliness, optimization of supply chain management, and availability of quality assured products in resource limited settings. The IATT Optimal Formulary is also revised on a regular basis to reflect current WHO recommended regimens, most recently in 2018. Current WHO pediatric treatment guidelines and the Optimal Formulary prioritize the use of dolutegravir- based treatment for all HIV-infected pediatric patients for whom there are appropriate dosing recommendations. Dosing recommendations for dolutegravir are only endorsed for children >25kg and LPV/r remains an alternate first line treatment option for infants and children for whom dolutegravir is not available.6,7 Because dolutegravir dosing has not been determined for children weighing <25kg, many children will continue to receive LPV/r-based treatment for the foreseeable future. The overlap in at-risk populations and the interactions between HIV infection and tuberculosis infection globally have been well-described and are beyond the scope of this document. It has also been well- documented that children, especially young children, are at particular risk of acquiring tuberculosis, 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 LMIC confirmed a high incidence rate (12.3% in ART naïve and 8.8% in ART exposed) of TB in this population.8 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 back- ground rates of HIV infection.9

9. Review of benefits: summary of evidence of comparative effectiveness.  Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) Supporting evidence for the use of RTV to super-boost LPV/r in pediatric patients receiving rifampicin as part of treatment for tuberculosis was gathered through a search of the scientific literature and by reviewing current and past WHO treatment guidelines. Because many of the references are relatively old, only a few representative publications are included in the dossier reference listing. This dossier will not review the evidence supporting the use of RTV as a pharmacologic booster for second- and third-line protease inhibitors as that indication 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.”10  Summary of available data (appraisal of quality, outcome measures, summary of results) Several strategies have been proposed to allow children diagnosed with tuberculosis to receive LPV/r-based ART, as the interaction between LPV/r and rifampicin was recognized from the time of the original LPV/r approval. 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.11 The adequacy of the super-boosted regimen was confirmed in a PK study being 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.12 At this time, the WHO guidelines for pediatric 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 co-treatment in children on an LPV/r-based regimen.1  Summary of available estimates of comparative effectiveness There are no other products that can be used to super-boost LPV/r in infants and children.

10. Review of harms and toxicity: summary of evidence of safety.  Estimate of total patient exposure to date There are no estimates of the number of pediatric patients exposed to RTV oral powder in a super- boosted LPV/r regimen. The product is new to the market, but other formulations have been used. The regimen had become established practice in South Africa at the time the PK study (n=80) described above was conducted in 2014/2015. However, RTV in other formulations has been widely used as a pharmacologic booster in combination with other protease inhibitors (atazanavir and darunavir) and was originally used at higher doses as an active protease inhibitor.  Description of the adverse effects/reactions and estimates of their frequency According to the Norvir package insert, the adverse event profile observed during pediatric clinical trials was similar to that for adult patients. Vomiting, diarrhea, 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 pediatric patients enrolled in NORVIR clinical trials. The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).13 RTV oral solution contains large amounts of the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v) and is extremely unpalatable. The RTV oral powder does not contain these excipients and is expected to be much better tolerated than the oral solution.  Summary of available data (appraisal of quality, summary of results) There are no randomized, controlled trials of the use of RTV as a super-booster of LPV/r but the accumulated retrospective studies and open-label, observational studies support its use in pediatric patients who require TB treatment containing rifampicin.  Summary of comparative safety against comparators The South African retrospective study evaluating PI-based ART in children younger than 2 years 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 ALT elevations in the TB co-treatment groups while receiving TB treatment compared to children on LPV/r alone.11  Identification of variation in safety that may relate to health systems and patient factors No specific safety issues associated with RTV oral powder are expected to pose a differential risk in the international health setting.

11. Summary of available data on comparative cost and cost-effectiveness of the medicine. At this time, RTV oral powder is available only through the original manufacturer, AbbVie. Although no pricing information is currently publicly available for RTV (100 mg) powder, AbbVie has committed to employ market-specific pricing strategies as part of their commitment to access to medicines.14 At the time of submission, no cost-effectiveness analyses or special pricing arrangements have been conducted for RTV (100 mg) powder.

Regulatory information 12. Summary of regulatory status and market availability of the medicine. RTV oral powder 100mg/packet (Norvir, AbbVie) was approved by the U.S. FDA on June 7, 2017. There are currently no approved or tentatively approved generic versions of this product. The product is available for procurement from AbbVie.

13. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia). Ritonavir is included in the International Pharmacopoeia, Eighth Edition.

14. References: Comprehensive reference list and in-text citations. 1. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. World Health Organization. June, 2016. http://apps.who.int/iris/bitstream/handle/10665/208825/9789241549684_eng.pdf?sequence=1 2. Newell ML, Coovadia H, Cortina-Borja M, et.al. “Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.” Lancet. 2004 Oct 2-8;364(9441):1236-43. 3. UNAIDS Core Epidemiology Slides. UNAIDS. July 2018, http://www.unaids.org/en/resources/documents/2018/core-epidemiology-slides. 4. Global AIDS Update 2018 – Miles to Go, Breaking Barriers, Righting Injustices. UNAIDS. August 2018. http://www.unaids.org/sites/default/files/media_asset/miles-to-go_en.pdf 5. Start free, stay free, AIDS free: A super-fast-track framework for ending aids in children, adolescents and young women by 2020. UNAIDS, 2016, https://free.unaids.org. 6. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidance. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.18). http://apps.who.int/iris/bitstream/handle/10665/273632/WHO-CDS-HIV-18.18-eng.pdf?ua=1 7. 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. http://apps.who.int/iris/bitstream/handle/10665/273153/WHO-CDS-HIV-18.15-eng.pdf?ua=1 8. Marie-Reneé B-Lajoie, Olivier Drouin, Gillian Bartlett, 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. 9. Elisabetta Venturini, Anna Turkova, Elena Chiappini, et al. Tuberculosis and HIV co-infection in children. BMC Infect Dis 2014, 14(Suppl 1):S5, http://www.biomedcentral.com/1471- 2334/14/S1/S5 10. WHO Model List of Essential Medicines, 20th edition. 2017. http://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1 11. Cordula Frohoff, Magendhree Moodley, Lee Fairlie, et al. Antiretroviral therapy outcomes in HIV- infected children after adjusting protease inhibitor dosing during tuberculosis treatment. PLoS ONE 2011;6(2): e17273. doi:10.1371/journal.pone.0017273 12. Rabie H, Denti P, Lee J, et al. Abstract LB-1 Lopinavir ritonavir (1:1 ratio) in the presence of rifampicin is not inferior to lopinavir ritonavir (4:1 ratio) in the absence of rifampicin in Human Immune Deficiency Virus (HIV) children. Interim analysis of an open label sequential non- randomized pharmakinetics study. Presented at the 7th International Workshop on HIV Pediatrics, Vancouver, Canada, 17-18 July 2015. 13. U.S. Food and Drug Administration. Norvir package insert, November 15, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209512s004lbl.pdf 14. AbbVie website, https://www.abbvie.com/content/dam/abbvie-dotcom/uploads/PDFs/our- commitment-to-access-to-medicines-2.pdf