Field Note

Ensuring Access to ARVs for Kids
A Challenge of Logistics

Claudia Allers, JSI/DELIVER
Steve Hawkins, Elizabeth Glaser Pediatric AIDS Foundation
Lisa Hirschhorn, MD, MPH, John Snow, Inc.
Chris Wright, JSI/DELIVER

The number of children infected by HIV continues to grow. Although accurate diagnosis and reporting are elusive, UNAIDS estimates that at least 2.1 million children worldwide are HIV positive, and more than 1,900 children are being infected daily. WHO estimates that only 15,000 to 20,000 children under age 15 in developing countries are currently receiving antiretroviral therapy (ART), out of an estimated 660,000 in need.

Until 1990, no antiretroviral (ARV) drug was specifically tested or approved for pediatric use. Over the past 15 years, various options have become available, including zidovudine (AZT), didanosine (ddl) and nevirapine. By 2002, as generic ARV drugs were introduced, MTCT prevention and ART services began to gather steam in Africa.

John Snow, Inc. (JSI) and the Elizabeth Glaser Pediatric AIDS Foundations (EGPAF) have both been at the forefront of HIV/AIDS research, care and treatment programs. Through its DELIVER project, JSI has developed logistics systems for HIV/AIDS commodities, including test kits, lab supplies and ARV drugs.

The best programs will be severely limited in their effectiveness without an uninterrupted supply of ARV drugs and other needed commodities. The Logistics Cycle (Figure 1) illustrates all the steps, activities and resources involved in ensuring that the right drugs, in the right quantities get to the right people at the right time, and hopefully, at the right cost. Logistical challenges exist for all clients, especially in resource constrained countries. The challenges are even greater for kids.

Serving Customers: Treating Children
Serving customers is the ultimate goal of any logistics system. Effective ART for any patient requires some combination of three different ARVs for their treat-ment regimen. Drug toxicity, unplanned interruption or stockouts of any part of the regimen, as well as drug resistance, can all threaten the efficacy of the treatment regimen. For young children, especially infants, these challenges may be even greater than in adults.

Infants and very young children are unable to swallow pills, and so drugs must be available in liquid forms. In addition, doses are based on children's changing weights, and must be recalculated based on current weight or body surface area and converted to the appropriate volume based on the formulation strength. This requires recalculation of dosages at every visit to a clinic, and necessitates additional training and human resources. Dosing charts have been developed by groups such as Médecins Sans Frontières (MSF), the Clinton Foundation, and Columbia University's MTCT-Plus Initiative to simplify these calculations, but monitoring children for weight changes is still required, and this can only be done effectively in a clinic.

Forecasting needs even for a small group of children is complicated by the need to change dosages as the child grows and gains weight. Because little is known about average weight gain and growth of children on ART in resource-limited settings, making a standardized approach is very challenging. Another complication for forecasting is that as the child grows, s/he needs to change from liquids to tablets or capsules, which requires changing the prescription. In addition, this formulation change may not occur simultaneously for all drugs in
the regimen.

Treatment is further complicated in that liquid formulations of many ARVs are still not available. Therefore, providers or caregivers may need to break unscored tablets for lower doses or crush pills to mix with food or fluid. Some children, therefore, will be on a mix of liquids and broken tablets. All this requires training and oversight of providers to prevent mistakes in prescribing, as well as education for caregivers to ensure that they are administering the drugs in adherence with the regimen.

The widespread shortage of trained providers in pediatric HIV care also remains an enormous hurdle. Experienced ART providers are already so overwhelmed with the flood of adult patients, that accommodating the more complex demands and challenges of treating children is often difficult.

Product Selection: A Limited Choice for Children
Despite substantial increase in the variety of adult ARV drugs over the past 15 years, for pediatric use, the choices are severely limited.

First, many available ARV drugs have not been tested or labeled with dosing instructions for children. Only three - d4T, 3TC and AZT (ZDV) - are labeled for children under two, come in liquid form, and have WHO-approved generics available. But these three drugs are all the same category of drug - nucleoside reverse transcriptase inhibitors - and, therefore, do not make up an effective triple combination therapy.

Second, some ARVs are only approved for use in older or heavier children, such as children over three years or weighing more than 10 kgs. Those labeled for wider pediatric use are often unavailable, including liquid versions (for infants); fixed dose combinations (FDCs) for children under age 12, and child-strength tablets. As a result, adult tablets - usually not scored - must be broken to the correct size and dose.

Third, pediatric ARV drugs cost significantly more than comparable adult formulas, due to the lack of generics and limited choices combined with expensive liquid or hard-to-find children's strength dosing. Branded pediatric ARV drug formulations cost 50 to 90 percent more than the adult versions of the same regimen.

Forecasting and Procurement
For ART, forecasting needs and planning appropriate procurement is currently more of an art than a science. Quantification relies heavily on assumptions because of the limited quality and quantity of data, which rarely captures the number of patients on treatment, the regimens prescribed, or the patients' response over time. Data on consumption and stockouts is scarce and unreli-able. Data based on targets often grossly overestimates drug requirements that are usually far beyond the absorptive capacity of existing infrastructure, human capacity for service provision, logistics capacity for managing increased volumes of product, or funding capacity for drug procurement.

Lack of communication and coordination between policymakers, service providers, funding sources, and procurement agents in the selection and quantification of ARV drugs can lead to procurement of the wrong drugs, the wrong quantities, or both.

Research indicates that drug adherence rates must exceed 95 percent for effectiveness. But adherence is often not possible where there is high risk of stock-outs. Such risk exists when drug storage is often substandard and limited, inventory control systems underdeveloped, and cold chains poorly maintained. Medicines, laboratory tests and other essential commodities are often stocked out or wasted due to expiry or damage. These challenges are even more critical in ART for infants due to their need for liquid formulations, which have even greater demands for storage and distribution than adult formulations.

Most liquid formulations come only in large bottles of 100 ml, 200 ml, or 240 ml. Typically, a bottle contains enough medicine for about three weeks, depending on the child's weight. Without pediatric FDC liquids, each triple combination regimen includes at least three bottles per patient per month. The space needed to store tablets or capsules to treat 40 adults in a year can only accommodate enough liquid formulations for about six children - and the liquids will weigh twice as much. The bottles will break when dropped, may require refrigeration, and may expire in as little as six months.

One solution to preventing wastage after large bottles are opened is to repackage liquid formulations into smaller units or single-use syringes. Another option is to stipulate smaller units from the manufacturer, although this requires re-registration of the drug and adds to the cost. However, developing more convenient and easier to use pediatric formulations such as granules or powders for reconstitution into liquids, and packaged in unit dose sachets would facilitate dispensing, patient adherence, and storage and distribution while decreasing the potential for wastage.

Improving Access
Most HIV-positive infants in resource-poor settings do not survive to their third birthday. ART for children is complicated by the lack of appropriate ARV drugs and few trained providers. Although effective pediatric ART is complex and challenging, it is an achievable goal and must be a priority in ART scale-up.

With the introduction of inexpensive generic FDCs, access to ART for adults has increased dramatically during the past two years. Yet, formidable challenges limit access to quality ART for children. Some solutions are complex and long term, such as fixing the decimated health systems in many countries and devel-oping more effective and easier to use ARVs for children. But others are easier and more manageable, and all should be the focus of increased political will and commitment.

For example, increased advocacy can work to increase the number of available pediatric ARV drugs, develop the needed dosage requirements, and develop and make widely available both branded and generic equivalents approved by both FDA and WHO.

Generics are critical to improving access to pediatric ART. Although many manufacturers have lowered the price of their products to only one-tenth of standard commercial prices, these can still range from $500 to $1,000 per treatment-year for children. Effort is needed to move these prices toward $100 per year and lower.

Many organizations are hard at work to solve these problems. The Clinton Foundation's work to make generics and generic FDCs widely and cheaply available for pediatric patients is a great start. These efforts should be supported with advocacy for quick approval by WHO and FDA to allow rapid availability to the maximum number of kids.

But the challenge to ensure access to ART for all children in need will not end with achieving the goals of better and cheaper ARVs for pediatrics. Work must continue to ensure that more providers are trained to work with HIV positive children and that more programs focus on providing effective care to this vulnerable population.

DELIVER is a project funded by the U.S. Agency for International Development (USAID) to improve public health logistics systems in more than 30 countries around the world. The views expressed herein do not necessarily reflect those of USAID. For more information
on this topic, visit www.deliver.jsi.com or contact deliver_info@jsi.com

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