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  while UNITAID reported financing pediatric HIV/AIDS treatment in 44 countries by the end of 2009 . 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  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 .
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 .
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.
While we systematically cleaned and validated purchases [30–32], it is possible that misreported purchases are still present in our analytic data set. The historical GFATM ARV transactional data posted in WHO GPRM, in particular, required considerable cleaning. We note a substantial number of ARV transactions in the "miscellaneous" category. Most of these miscellaneous transactions were reported by procurement agencies and we suspect many of these miscellaneous reports are actually purchases made by GFATM recipients. ARV transactions for GFATM recipients have been inconsistent in both the older GFATM Purchase Price Report and the WHO GPRM. We observed many instances over the past few years when transactions appeared and disappeared from both of these databases.
For this paper, we used 2002-2009 purchases downloaded from the WHO and GFATM on 1 May, 2010. We noted the absence of SCMS, UNITAID, and GFATM purchases in the WHO GPRM after April 2009 and therefore obtained this information directly from those organizations. The GFATM data was publicly available on its website. CHAI provided ARV purchase data to researchers on behalf of UNITAID without restrictions and SCMS staff provided transactional data to researchers under conditions that they review and comment on manuscripts utilizing their data prior to submission.
Recent interventions to improve the quality of transactions in the GFATM PQR have resulted in longer delays from the time countries report purchases to public posting. Our data therefore underestimate 2009 GFATM purchases. It is possible that GFATM-supported countries purchased new pediatric formulations in 2009 that do not yet appear in publicly posted data. In addition, some organizations (i.e., World Bank, PEPFAR purchases outside of SCMS, Médecins Sans Frontières) do not report ARV purchases to the WHO GPRM. Similarly, governments that purchase ARVs with their own funds do not report transactions to WHO. Delays in reporting, data restrictions imposed by some donors, and unwillingness to report ARV purchases will limit the ability to monitor and evaluate global ARV markets in a timely and unbiased manner.
We limited our analytic data set to ARV formulations used predominantly in children and infants. Our analyses did not include three ARVs (3TC150, EFV 600, and DRV) listed as pediatric ARVs by WHO (Table 1) as these are more commonly used for adults.
We calculated ARV regimen prices for new and liquid formulations using UNITAID/CHAI-reported prices because UNITAID was the only consistent purchaser of FDCs. These prices may not accurately reflect prices paid by countries outside of UNITAID programs. We acknowledge that some programs may still be splitting adult FDCs into quarters or crushing adult FDCs for use in children. We did not compare pediatric FDC prices to quarters of adult FDCs because WHO recommends against splitting adult tablets more than one time .
Liquid ARV prices are the most difficult to clean and validate given the multitude of different ways countries have misreported purchases. The Russian Federation accounted for more than 80% of GFATM brand purchases in 2008. It is possible that the Russian purchases were reported in error, but prior benchmarking price analysis of ARV purchases in the Former Soviet Union revealed that Russian prices (confirmed with procurement staff) were consistently and remarkably higher than other countries .
In addition, these Russian purchases passed through new quality improvement processes implemented when the new PQR system at the GFATM was recently established.