The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children

Accessing quality treatment and care remains an uphill battle for families of children living with HIV/AIDS in resource-poor settings. For many years, the lack of easy-to-use pediatric formulations for some antiretroviral (ARV) medicines and the high costs of others hindered efforts to deliver medical care to this vulnerable population [1].

From an industry perspective, the disincentives to develop and produce pediatric ARVs are numerous and powerful. Pediatric ARV markets are always smaller and less attractive than adult markets. In the United States and Europe, HIV infections in infants and young children have been nearly eliminated [2], leaving little demand for pediatric ARV formulations in these markets.

In order to develop new pediatric dosage forms for use in developing countries with larger pediatric ARV demand, additional research must first be conducted in children, including costly clinical trials, bioequivalence, bioavailability, dose-ranging, and pharmacokinetic studies [3, 4]. The implementation of comprehensive services to prevent mother-to-child transmission (PMTCT) of HIV remains low in many countries [5]; however, if recent initiatives to reduce vertical HIV transmission are successful [6], pediatric antiretroviral demand will further diminish, reducing any returns on investment for developing pediatric ARVs. After development, the per-unit production costs of pediatric ARVs are likely high because small quantities impede the realization of economies of scale in production and distribution [3].

Further compounding these disincentives are the innate complexities of pediatric formulation markets. Numerous products are needed in varying strengths to accommodate changing doses as children grow, which fragments the pediatric market for a given ARV into even smaller niches. Moreover, as children move through infancy, toddler, and childhood stages, the optimal dosage form changes as well. Liquids (syrups, suspensions, and solutions) are needed to treat infants but pose logistical challenges: many need refrigeration and, because of large bottle sizes and heavy weight, are difficult for families to carry home. In low resource settings, measuring and delivering the correct liquid doses can also be challenging. Powders and dispersible tablets that can be mixed with water are an option, but they require access to clean water and often have unpleasant tastes that are unacceptable to infants. As children get older and the necessary volumes of liquid ARVs become too large, they require other products, such as chewable tablets and sprinkles, until they reach an age when they can swallow solid tablets [7].

Despite these market disincentives for pharmaceutical manufacturers, fortunately, important advances have recently been made in the development and production of pediatric ARV formulations quality-certified by the World Health Organization (WHO) Prequalification Progamme [8], the United States (US) Food and Drug Administration (FDA) [9, 10], or other stringent regulatory authorities. This progress can be credited to persistent lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations.

Médecins Sans Frontières, for example, has consistently drawn attention to the particularly glaring neglect of children in HIV/AIDS treatment programs and suggested that the lack of child-friendly versions of ARVs contributes to high rates of HIV/AIDS deaths in children under two years of age [11, 12]. In November 2004, the United Nations Children's Fund (UNICEF) and WHO held a technical consultation on improving access to appropriate pediatric ARV formulations during which experts identified missing pediatric formulations considered to be high priority and discussed ways to galvanize pharmaceutical companies to produce them [7]. Shortly thereafter, two global initiatives were launched. Unite for Children, Unite Against AIDS, was begun by UNAIDS, UNICEF, and others in 2005 as a platform for all partners engaged in pediatric HIV/AIDS programs [13]. The first WHO Model List of Essential Medicines for Children was released in 2007 [14] and Make medicines child size, led by WHO, was launched in late 2007 to raise awareness and improve access to medicines that are safe for children under age 12 [15].

On the implementation side, both the United States' President's Emergency Plan for AIDS Relief (PEPFAR) [16] and UNITAID [17] made commitments to prioritize the needs of children. The Clinton Health Access Initiative (CHAI) [18] and the Supply Chain Management System (SCMS) [19] conduct large-scale purchasing on behalf of UNITAID and PEPFAR, respectively. Given the substantial overlap of funding in some countries by UNITAID, the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM) [20], and PEPFAR, agreements were made with countries and major donors that UNITAID would initially be the primary source of funding for pediatric ARVs (D Jamieson, SCMS, personal communication) in those countries. Such coordination allows for optimization of resources and avoidance of service duplication. In countries where UNITAID and PEPFAR are not active, GFATM-supported HIV/AIDS programs procure their ARVs independently.

The will of these international organizations to invest in pediatric antiretroviral therapy (ART) created incentives for producers to enter the market, as manufacturers could be relatively certain of a minimum volume of purchases from reliable clients [21, 22]. The ensuing scale-up of ARV delivery to children in developing countries then progressed dramatically. Whereas only 10% of children in need were being treated in 2005, 38% were receiving ART by the end of 2008 [5]. However, despite these advances in product development and treatment coverage, the literature suggests that retaining children in HIV/AIDS programs remains problematic [23, 24]. In 2009 the Clinton Foundation reported infant losses to follow-up of 32% (in Cameroon) and 53% (in an eight-country meta-analysis) [25].

Clearly, critical challenges remain. Three out of five children needing ART are not receiving it [5]. A preliminary examination of ARV purchase data suggests that many countries are not yet using new, improved pediatric formulations [26, 27]. Finally, there are a number of ARVs for which appropriate pediatric formulations are still not available. According to Médecins Sans Frontières, appropriate pediatric formulations are still lacking for a range of important ARVs, including efavirenz, darunavir and other ritonavir-boosted protease inhibitors (in addition to lopinavir/ritonavir) [28].

Most pediatric fixed-dose combinations (FDCs) developed to date have included stavudine and zidovudine. Aside from low demand, few barriers existed for the development of these products. A substantial amount of research had already been conducted on these ARVs in children, patents were generally absent or unenforced [29], and manufacturers had lots of experience producing adult versions. In contrast, for newer ARVs, little research has been conducted in children, patent barriers are more widespread, and manufacturers have less experience producing adult FDCs containing these ARVs. To ensure that companies develop pediatric versions of these medicines, a better understanding is needed of both the supply and the demand side of the pediatric ARV market. However, to date, no research has been published on the characteristics or the evolution of this market.

In order to fill this knowledge gap, this paper examines trends in the availability of WHO-recommended ARVs in quality-certified pediatric formulations, and describes the rate and extent of product uptake across developing countries and among international donors to guide next steps towards improving child health.

We utilized an ARV market intelligence database comprised of data from multiple sources, including product approvals by the US FDA [9, 10] and certifications by the WHO Prequalification Progamme [8]. This database is described in more detail elsewhere [30–32]. Into it we merged 2009 transactional data of donor-funded ARV purchases provided directly to researchers by the Clinton Health Access Initiative (CHAI) [18] on behalf of UNITAID [17] and the Supply Chain Management System (SCMS) [19] on behalf of PEPFAR [16] as well as publicly posted transactions in the WHO Global Price Reporting Mechanism [27] and the GFATM Price Quality Report [26] from 2002-2009. Information and algorithms in the market intelligence database were used to clean and validate ARV transactional data, which was then limited to purchases made for ARV formulations predominantly used in children (Figure 1).

We examined trends in quality-certification of pediatric ARVs by WHO [8] and the FDA [9, 10] in relation to treatment regimens recommended by WHO for infants and children [33, 34]. We also described purchase trends for pediatric ARV formulations (liquid, solid, dispersible), including numbers of purchasing countries, from 2004 to 2009. A solid product is defined as a medicine intended to be swallowed, while a dispersible ARV tablet dissolves when placed in a small amount of water. Liquids are syrups, solutions, and suspensions. We differentiate single-component ARVs from FDC dosage forms with the labels "single" and "FDC". We describe FDC products using a "/" between ARVs included in a given FDC and use the terms brand and innovator interchangeably to denote the initial developer of a medicine.

We calculated trends in purchaser (GFATM, SCMS, UNITAID) market share by value for brand and generic pediatric dosage forms from 2002 to 2009. For FDC versions of pediatric ARVs, we provided percent purchaser market share by volume for 2008 and 2009.

Price comparisons of ARV dosage forms (pediatric FDC, liquid, and adult FDC) were calculated using prices paid by CHAI/UNITAID based upon WHO-recommended doses [33, 34] and presented as price per person per year in United States dollars (USD). All ARV prices provided by GFATM, WHO, CHAI, and SCMS in USD were adjusted to the January-December 2009 time period using the annual US Consumer Price Index [35].

In past years, great strides have been made in bringing to market quality-certified, pediatric ARV FDCs in dosage forms appropriate for use in low resource settings. Activists, international organizations and national governments have successfully lobbied for the development and production of pediatric ARV products. Five new 2-in-1 and four new 3-in-1 pediatric FDCs have been quality-certified by the WHO or FDA since 2005 in dosage forms appropriate for use in low resource settings. These new products include the first heat-stable, ritonavir-boosted protease inhibitor and five ARVs available as dispersible tablets, a formulation typically more acceptable to children than liquids and substantially less expensive, easier to store, less costly to distribute to health care facilities, and easier for care takers to carry home than liquid alternatives. The new solid and dispersible pediatric FDCs offer ease of administration and more reliable dosing than crushing or multiple-splitting of adult FDCs.

Despite these advantages, however, country purchases for ARVs in less desirable dosage formulations (liquid and solid, single-component ARVs) continue to show annual increases while uptake of the new solid and dispersible FDCs has been remarkably low outside of UNITAID-funded programs. UNITAID accounted for 97-100% of total market volume for all solid and dispersible pediatric FDCs purchased with donor-funds in both 2008 and 2009.

The GFATM provided funds to 116 countries for HIV/AIDS in 2008 [41] while UNITAID reported financing pediatric HIV/AIDS treatment in 44 countries by the end of 2009 [42]. The GFATM, SCMS, and UNITAID agreed that UNITAID would lead pediatric ARV procurement in countries they support, with UNITAID reporting pediatric ARV FDC purchases for 29 and 31 countries in 2008 and 2009, respectively. Only three and two countries from GFATM and SCMS, respectively, reported pediatric FDC ARV purchases in 2008. While donor coordination explains lack of FDC purchases in GFATM countries also receiving UNITAID funds, uptake of new pediatric FDCs in GFATM countries without UNITAID funding is remarkably low.

This study cannot explain the reasons for low uptake of improved pediatric formulations outside of UNITAID. Our results reveal the importance of additional operational research to identify barriers to product use. Still, we present some potential challenges at country level that may prevent or delay adoption of new products. To start, country-based staff may be unaware of recent developments and availability of new pediatric formulations. There may be reluctance to use new formulations, such as dispersible tablets, in regions where these types of medicines are not historically or currently used. Regulatory barriers, registration costs and difficulties, the need to revise treatment guidelines and the need to retrain all prescribers and caregivers may also contribute to under-utilization. Countries may be locked into long-term contracts that preclude them from switching to improved products or their demand may be too low to meet some suppliers' minimum purchase requirements.

To change from currently used ARVs to the new pediatric formulations may also produce challenges in supply chain management. Demand forecasting (i.e. determining the amount of medicine needed for country programs) is a challenging and complicated task [43] and insufficient focus has been placed on improving outdated procurement practices. It is possible that in the transition phase from one set of ARVs to another, the number of pediatric products in warehouses and on facility shelves increases substantially, making demand forecasting more complicated for some period of time. Thus, such transitions need to be carefully planned and monitored in order to avoid wastage and stock shortages.

It is also possible that the types of pediatric products created to date are not the products most desired at country level, or that practitioners and caregivers prefer to use half of an adult FDC instead of pediatric FDCs, when possible. Using adult FDCs for children in lieu of pediatric FDCs may simplify supply chain management of ARVs (procurement, storage, distribution, inventory management) as well as prescribing, dispensing, and administration by the caregiver. Lastly, countries may currently be in the process of transition and we are now observing a time lag between decisions to switch to newer products and actual implementation of those decisions.

While it is thus understandable for a number of reasons that the adoption of new, improved pediatric ARVs is a time-consuming process, such inertia may have undesirable side effects. For instance, it may falsely signal to pharmaceutical companies that the markets for improved pediatric ARVs are smaller than anticipated because of logistical and acceptability problems, deterring entry of new manufacturers and scale-up of production among existing ones [28].

International organizations and countries already face challenges obtaining existing pediatric ARV medicines. Reports that Bristol-Myers Squibb will encounter interruptions in the production of pediatric didanosine have created great concern for upwards of 7,000 children treated with this medicine [44, 45]. Bristol-Myers Squibb is currently the only quality-certified producer of pediatric didanosine tablets and the amount of didanosine currently available may be insufficient to meet the needs of children on treatment during the period of supply interruption. Médecins Sans Frontières reports difficulty purchasing the quality-certified pediatric 3TC/ZDV due to low-volume purchase requests (G Arreghini, Médecins Sans Frontières, personal communication). Médecins Sans Frontières also notes difficulty obtaining the quality-certified pediatric ABC/3TC/ZDV, a new FDC not purchased by CHAI/UNITAID and therefore in low demand.

Even when pediatric ARVs are procured by large-scale purchasers like UNITAID, an unfortunate paradox comes into play in pediatric HIV/AIDS treatment: the more that pediatric ARV formulations are tailored to the needs of specific sub-groups, the less demand there is for a given product. This becomes particularly problematic in convincing companies to produce age-appropriate strengths of fixed-dose combination ARVs in multiple formulations. The WHO list of priority ARVs needs to be complete but also succinct, to aggregate demand around the most important products and avoid the development and production of ARVs that go unused by countries.

Because of the inherent disincentives for manufacturers in the pediatric ARV market, extreme care must be taken to ensure that price negotiations between producers and large-scale purchasers are conducted in a manner that ensures sufficient profit to sustain prices and stabilize the market over the long term. Activists, civil society organizations, researchers, international organizations and others must not only lobby for pediatric investments, but also monitor the movement of manufacturers in and out of the pediatric market, the extent and rate of new product uptake and their impact on child health. If countries are in a transition to new products, it is important for donors and suppliers to know and predict the amount of time needed for such transitions.

Operational research to identify and address reasons for low product utilization is a critical next step towards meeting two major global targets for 2015: Millennium Development Goal (MDG)-4, calling for a two-thirds reduction in mortality rates for children under five, and MDG-6, which aims to halt and begin to reverse the spread of HIV [46].

Success in the case of pediatric HIV/AIDS treatment cannot be determined only by market availability of new and improved ARV products. Until the barriers to uptake can be identified and addressed, and country demand stabilizes, organizations like UNITAID which offer the equivalent of advance market commitments will be needed to encourage the entry of new manufacturers and "hold the market" until countries can adopt the newer formulations.

Treatment of children with HIV/AIDS is a high priority for the international community. However, ensuring that needed pediatric medicines are developed and delivered to those who need them remains a complex, challenging task. In order to improve performance in this area, a better understanding of the pediatric ARV market is needed - where it is performing well, and where substantial market failures persist.

This study has demonstrated that the pediatric ARV market is not simply a smaller version of the adult market (described elsewhere [30–32]). Compared to HIV/AIDS treatment options for adults, far fewer ARVs have been proven safe and effective in children. Whereas multiple donors and countries buy substantial quantities of adult first-line ARVs, one international institution, UNITAID, plays a dominant role in the pediatric market, buying an overwhelming proportion of some pediatric ARVs. Pediatric markets become fragmented into niches with little demand as manufacturers develop more acceptable, age-appropriate pediatric products, and adopting improved formulations may present logistical challenges in some countries. While most adult FDCs are produced by several quality-certified manufacturers, many pediatric FDCs have only one quality-certified manufacturer, leaving HIV/AIDS treatment programs highly dependent on a single supplier to meet global demand.

Ensuring a long-term supply of high-quality, effective, affordable and well-adapted ARVs for children in different age groups will require ongoing monitoring and improved understanding of the global pediatric ARV market. Furthermore, much research is required at country level to understand better why uptake of new, improved formulations has been so slow, and what can be done to accelerate children's access to quality AIDS care in resource-poor settings. Continued innovation in pediatric ARV development may be threatened by outdated procurement practices failing to connect clinicians making prescribing decisions, supply chain staff dealing with logistics, donors, international organizations, and pharmaceutical manufacturers. Perceptions of global demand must be better informed by accurate estimates of actual country-level demand.