Application for Inclusion of Lopinavir /Ritonavir Oral Granules (LPV/r) Formulation on WHO Model List of Essential Medicines for Children Table of Contents 1. Summary statement of proposal for inclusion ......................................................................... 2 2. Antiretroviral therapy is recommended for all HIV-infected children, adolescents, and adults. ............................................................................................................................................... 2 3. Name of the focal point in WHO submitting the application: ............................................... 2 4. Name of the organization(s) consulted and/or supporting the application: .......................... 2 5. International Non-proprietary Name: ..................................................................................... 2 6. Formulation and strength proposed for inclusion:.................................................................. 2 7. International availability .......................................................................................................... 2 8. Whether listing is requested as an individual medicine or as an example of a therapeutic group: ............................................................................................................................................... 2 9. Information supporting public health relevance ..................................................................... 3 9.1 Epidemiological information on disease burden 3 9.2 Assessment of current use 3 9.3 Target population 4 10. Treatment details ................................................................................................................ 4 10.1 Reference to existing WHO guidelines 4 10.2 Dosage regimen, duration 4 Table 1: Recommended dosing of LPV/r oral granules by weight band to be taken twice daily ........ 5 11. Summary of comparative effectiveness in a variety of clinical settings .................................. 6 12. Comparative evidence on safety: ......................................................................................... 7 12.1 Estimate of total patient exposure to date 7 12.2 Description of adverse effects/reactions 7 12.3 Identification of variation in safety due to health systems and patient factors 7 12.4 Drug interactions requiring dose adjustment 7 13. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group: ................................................................................... 7 Table 2: Price per Unit and Price per Patient per Year for TDF/3TC/DTG and other First-Line Products ............................................................................................................................................................... 8 14. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): ................................................................................................................... 8 15. Availability of pharmacopoieal standards: .......................................................................... 8 16. Proposed (new/adapted) text for the WHO Model Formulary .......................................... 9 Table 3: Recommended dosing of LPV/r granules by weight band to be taken twice daily ................ 9 17. References: Comprehensive reference list and in-text citations. ........................................ 9 1 1. Summary statement of proposal for inclusion This document proposes the inclusion of lopinavir/ritonavir oral granules formulation (LPV/r, 40mg/10mg) as part of a combination treatment of HIV infection among children living with HIV/AIDS in the WHO Essential Medicines List for Children (EMLc). Low dose ritonavir is included in this product, not for its intrinsic anti-retroviral activity, but because it inhibits the metabolic clearance of lopinavir. LPV/r in the dosage forms of tablets (400mg/100mg and 100mg/25mg), oral solution (80mg/20mg/mL), and oral pellets (40mg/10mg) are currently included in the EML and EMLc. 2. Antiretroviral therapy is recommended for all HIV-infected children, adolescents, and adults. 3. Name of the focal point in WHO submitting the application: Martina Penazzato, WHO/HTM/HIV/ATC 4. Name of the organization(s) consulted and/or supporting the application: Clinton Health Access Initiative, Inc (CHAI) 5. International Non-proprietary Name: Co-formulated lopinavir + ritonavir, ATC code: J05AR10 6. Formulation and strength proposed for inclusion: Each sachet contains 40mg of lopinavir and 10mg of ritonavir as oral granules. 7. International availability LPV/r oral granules are manufactured by Mylan Laboratories, Limited: Mylan Laboratories, Limited Robert J. Coury Global Center 1000 Mylan Blvd. Canonsburg, PA 15317 8. Whether listing is requested as an individual medicine or as an example of a therapeutic group: Listing is requested on the Model List of Essential Medicines for Children as a new formulation for LPV/r intended for pediatric use; it is an example of the therapeutic class of HIV protease inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. 2 9. Information supporting public health relevance 9.1 Epidemiological information on disease burden 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 years1, 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 treatment2 and in 2017 an estimated 110,000 HIV/AIDS related deaths occurred in children <15 years of age3. 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.4 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 appropriate for use in infant and young children are accessible, particularly in resource limiting settings. The availability of solid dosage forms has proven to be an advantage over liquid dosage forms in that they are more easily stored, ease administration, and support adherence in infants and young children. The WHO now recommends that for pediatric treatment, liquid dosage forms should be avoided when possible in favor of solid dosage forms, ideally dispersible, fixed-dose combination tablets if available. 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 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. This Optimal Formulary/LUL is revised on a regular basis to reflect current WHO recommended regimens. LPV/r oral pellets and oral granules are currently listed as optimal formulations and are listed collectively as a “solid oral dosage form 40mg/10mg..”6 These two formulations are listed to be used with 2 NRTIs for alternative first-line or second-line treatment for infants and children below 10 kg or unable to swallow 100mg/25mg tablets whole. 9.2 Assessment of current use Estimates of current usage of LPV/r oral granules are not available as the formulation was only recently approved and added to the Optimal Formulary list. According to CHAI ARV market analysis, use of LPV/r in pediatric patients will remain at about 25% of the treated population for the next several years. The report notes that since late 2016, global demand for the LPV/r pellets has 3 outpaced supply, which has limited uptake in LMICs. However, increased production of LPV/r pellets and introduction of LPV/r oral granules should ease global supply constraints in the future.7 9.3 Target population Like the oral pellets, LPV/r oral granules are intended as alternate first-line treatment of HIV infection in pediatric patients younger than 3 years of age. LPV/r oral granules should not be administered to premature neonates (born one month or more before expected date