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CHILDREN AND THE ‘BIG THREE’ EPIDEMICS Despite significant advances in HIV, many children remain at risk JUNE This article is one of a series of three. It dives into the current situa- tion for HIV, highlighting the speci c burden on children, setting out what needs to happen next in terms of product development and the remaining product gaps. It underscores the need for a diverse range of new treatments that are suitable for children, especially with the growing threat of drug resistance. 12 Despite signi cant advances in HIV, many children remain at risk 14 Market insight 16 Research & development insight 18 Ensuring access 19 Case studies: How companies and organisations are working to improve access to paediatric ARVs HIV - CONTEXT Despite significant advances in HIV, many children remain at risk ©Medicines Patent Pool ©Medicines Patent AT A GLANCE Forty years after its outbreak, HIV is one of the ARVs, healthcare providers and caregivers often greatest pandemics of modern times. Great pro- resort to manipulating adult formulations such Resistance to chloroquine in the 1990s was responsiblegress has for almost been made in the prevention and treat- as breaking or crushing pills to approximate the doubling malaria-associated deaths in sub-Saharanment Africa. of the disease, including paediatric HIV and required dose, causing issues related to absorption AIDS. This is thanks in large part to coordinated and increasing the risk of inaccurate dosing. Progress has been and sustained commitment from governments, made NGOs, civil society and industry. Ensuring uninterrupted supply In East and Southern In East and Southern Africa, mother-to-child Weaknesses or distributions in ARV supply chains Africa, mother-to- transmission of HIV has decreased by almost half are also considered driving factors behind the child transmission of since 2010. 1 At the same time, the global percent- development of HIV drug resistance, especially HIV has decreased by almost half. age of children living with HIV on antiretroviral in LMICs. When shortages or stockouts occur, (ARV) treatment has increased by 33%.2 healthcare professionals either dispense a smaller Despite these advances, almost 160,000 chil- amount than what was prescribed or temporar- dren under the age of 14 are infected each year, ily substitute components of ARV regimens, ham- with 91% living in low- and middle-income coun- pering the ability of patients to routinely adhere 3 Yet challenges tries (LMICs). Without intervention, half of these to ARV therapy. In order to maximise adherence remain children would die before the age of two.1 Most and prevent shortages and stockouts, the unin- Of 160,000 infected often, their medicine comes in hard pills or bitter terrupted supply of ARVs must be ensured. For children, 50% die syrups that are very diffi cult to swallow.4 These infants and children too young to swallow, bit- before the age of 5 suboptimal treatment options have long contrib- ter tasting syrups with a high-alcohol content that due to lack of access to treatments. uted to low treatment coverage, poor adherence require refrigeration are generally prescribed, cre- and HIV drug resistance. ating a range of adherence and supply chain chal- One in two newly diagnosed children show lenges. New formulations, such as lopinavir/ritona- resistance to the most commonly used ARVs (efa- vir pellets and granules have helped to overcome virenz and nevirapine) due to pre-exposure before this issue but product gaps in the market still exist. 5 Emerging resistance and after birth. There is a visible link between the 1 in 2 children with HIV treatment previously used for prevention of moth- A small, fragmented market with few incentives show resistance to er-to-child transmission, a single dose of nevirap- While there are still signifi cant unmet needs in ARVs. ine, and subsequent resistance in children. terms of ARV coverage, the size of the overall need is decreasing. With eff ective prevention of How can suboptimal treatments drive mother-to-child transmission, the number of new ʹ resistance? child infections has been steadily declining over Market challenges put Suboptimal treatments often result in poor adher- the past decades.1 While this is a positive trend, children at risk ence and poor absorption, ultimately promot- it has meant that the market size for infants and 1) While there is still a ing resistance, yet the relationship is multifaceted. young children is shrinking, making it commer- large unmet need for ARVs, the market size Firstly, a signifi cant proportion of children living cially less attractive for pharmaceutical companies. for infants and young with HIV have unreliable access to optimal ARVs, Further, once an ARV medicine is approved for children is shrinking; as the development of new ARVs that are child- adult use, it can take years for it to be approved for 2) Clinical trials that friendly lags considerably behind drug develop- use in children, in part due to the risks and limita- include children pose ment in adults. Several treatments that do exist in tions associated with clinical trials that include chil- challenges; 3) Pharma companies such form are currently facing high levels of resist- dren. Such challenges combined with a small and have few incentives to ance, including efavirenz and nevirapine. Secondly, fragmented market concentrated mainly in LMICs, take action. in the absence of new and optimal paediatric HIV has left few incentives in place for pharmaceutical 12 Access to Medicine Foundation companies to develop and market paediatric HIV medicines. be used across different age and weight bands and that are Yet, over the last number of years, progress has been made in easy to use for parents and caregivers. In doing so, they can the face of these challenges. increase ARV uptake amongst the paediatric population, prevent further fragmentation of the market and help limit the The role for pharmaceutical companies spread of resistance. While market challenges exist, increased attention and activ- ities have emerged in the field of access to paediatric HIV treatment. Pharmaceutical companies have an important role to play in this space by developing formulations that can COLLABORATIVE ACTION IN RESPONSE TO MARKET CHALLENGES In response to paediatric market challenges, multiple initiatives have arisen The Global Accelerator for Paediatric Formulations (GAP-f), a collabora- in the past number of years. Mechanisms such as the WHO-led Paediatric tive network convened by WHO, aims to accelerate the availability of opti- Antiretroviral Drug Optimization (PADO) group, WHO Optimal Formulary mal HIV treatments for children in LMICs by coordinating support across List and the ARV Procurement Working Group aim to overcome consensus sectors.6 It supports various stakeholders including pharmaceutical com- challenges and market fragmentation by setting priorities and shaping a panies, to study and develop optimal paediatric formulations, while har- healthy market, respectively. Efforts to harmonise paediatric drug develop- monising efforts with regulators, and coordinating communication with ment and availability with the adult market can promote a faster, more effi- suppliers. Building on lessons learned and best practices from the HIV cient approach to paediatric formulation development and help secure the community, such a unified and active response to development and access long-term future of the paediatric market. issues has already helped shorten the time lag of paediatric product development compared to adults and bring more paediatric formulations to market. Generic companies have FIGURE 2 Timelines for paediatric ARV approvals are shortening but unnecessary delays historically been the first to remain develop a paediatric formulation of an existing ARV This figures shows the time from initial approval of adult ARVs to the approval of paediatric formulations. 1990 2000 2010 2020 60/ 30mg 2014 abacavir abacavir/lamivudine 1988 lamivudine Cipla GSK 1995 GSK 40/10mg lopinavir/ ritonavir 2000 2015 2018 25mg AbbVie 100mg Cipla* Mylan raltegravir 2007 2011 2013 5mg Merck & Co, Inc Merck & Co, Inc 10mg dolutegravir 2013 2020 2020 ViiV Healthcare ViiV Mylan/ Healthcare** Macleods** * 4-in-1 LPV/r/ABC/3TC (bringing together ABC + 3TC above and LPV/r on this line) has been submitted for FDA approval by Cipla in November 2019 ** Expecting approval in 2020 13 Article series on the 'big three' HIV - MARKET INSIGHT While many companies are making paediatric ARVs, gaps still remain The optimisation of ARVs for infants and children has been a Gaps in the market key pillar in the HIV and AIDS global health agenda over the In 2018, WHO recommended dolutegravir (DTG)-based reg- past number of years. Since 2002, WHO recommends treat- imens as the preferred first-line regimen for adults, adoles- ment regimens for all populations that are most effective, cents and children, to promote the phase out of efavirenz well tolerated and have the highest barrier to resistance. In (EFV) and lopinavir/ritonavir (LPV/r), respectively. In general, 2011, the Optimal Formulary List for Paediatric ARVs and the DTG has a high rate of efficiency and higher barrier to resist- Limited Use List were developed to address the challenge of ance compared to other ARVs.7 However, the lack of paedi- market fragmentation with over 60 formulations and dos- atric indication and corresponding adapted paediatric formu- ages on the market — of which many were suboptimal and- lation of DTG for children weighing below 15kg explains its far less were actually necessary to implement WHO guide- absence from the Optimal Formulary despite its important lines. Further, the lists help guide country programmes, pro- position in WHO treatment guidance. In addition to DTG, ten- curement entities and funding agencies to deliver the WHO ofovir alafenamide (TAF), which is recommended as an alter- recommended treatment regimens to the paediatric HIV and native first-line treatment for children above 25kg, is currently AIDS population.6 The Optimal Formulary List currently con- not available in paediatric form.

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