Increasing antiretroviral access for children
Polly Clayden, HIV i-Base
A paper from the American Academy of Pediatrics, published in the April 2007 edition of Pediatrics, describes the barriers to scaling up antiretroviral treatment for HIV-positive children and potential ways to overcome them; multiple paediatric organisations from across the world have endorsed this statement.
The first barrier they list is diagnostic testing, which can lead to delay in diagnosis and in turn many infants and young children dying before HIV is diagnosed or therapy can be given.
The authors remind us that because of passive transplacental transfer of maternal antibodies to the infant, babies younger than eighteen months can test positive with antibody testing although uninfected. Therefore, definitive diagnosis of HIV among younger infants and children often requires the use of HIV-specific RNA or DNA nucleic acid tests to detect the virus. These assays are more expensive, more complex to perform and not available in many parts of the world where the risk of infant infection is highest. Seroreversion occurs by 12 months of age in 95% of HIV-exposed but uninfected infants, so they suggest that HIV adult antibody testing may be used to exclude HIV in infants children older children 9 to 12 months (and not breastfeeding) in settings where these are not available.
In order to identify children at risk, it is necessary to determine maternal HIV status. Communication from maternal to child healthcare professionals often does not occur and will require system changes to optimise infant testing. In their recommendations, they write that to increase availability of ARV medicines for children will require, early identification by making appropriate virologic testing technologies available throughout the world.
In their discussion around the second barrier ie shortage of paediatric specific healthcare workers, they list examples of programmes that send healthcare workers from resource rich countries to train local healthcare workers including the CHIVA/Kwazulu Natal collaboration and Medicins sans Frontiers. They stress the need to integrate paediatric HIV care into existing comprehensive child health programmes, expanding local networks of experienced healthcare professionals and linking local, regional and international experts.
Paediatric drug formulations are discussed in more detail including their more limited availability generally: as of September 2005, 21 ARV agents were approved by the FDA for use in the USA but only 11 have paediatric formulations available.
Even when liquid formulations are available there are many impracticalities with widespread use, such as that they often require refrigeration. Large volume makes transportation and storage difficult both for the healthcare facility and the caregiver. For example a 10 kg child receiving d4T, 3TC and NVP, for whom a 3 month supply of drugs is dispensed at a clinic visit, would require 18 bottles of liquid that weigh almost half as much as the child (4.3kg). They also raise the issues of unpleasant taste and sugar content of these formulations.
In addition to these obstacles, liquid formulations carry a high cost. Some programmes have used divided adult tablets, which can be effective for older children but may lead to inexact dosing.
The authors suggest that in addition to investing time and resources developing liquid formulations, pharmaceutical companies should develop smaller tablets; tablets in which active drug is uniformly distributed and in shapes that can be easily divided; capsule sprinkle formulations that can be opened and mixed with food or tablets that can be crushed, dissolved in water or chewed.
They also recommend that the availability of new drugs for children be expediated by requiring that paediatric formulations (liquids or solid forms) be available at the time of country approval of use of the drug in adults, unless there is a biological imperative not to develop the drug for use in children.
Dosing is another barrier on the list, and they make the case for simplified dosing tables, which has now been undertaken by the WHO (www.who.int/hiv/paediatric/generictool/en/index.html). For newer drugs, they recommend that PK studies across age groups are performed where possible at the same time as phase 2 and 3 adult trials so that appropriate doses will be available for paediatrics at the time of adult approval.
Finally, they encourage manufacturers to develop more affordable fixed dose combinations (FDCs) for children and to provide drug administration devices eg syringes, bottle tops for use with syringes, medicine spoons, tablet cutters and tablet cutters.
These issues have been much discussed elsewhere but this strong statement from the American Academy of Pediatrics is very welcome.
With respect to drug dosing formulations for children, since this document was conceived, the idea of dosing tables has already been taken on by WHO – not an easy task. In addition, it is good news that some fixed dose combination minipills are now being made by generic companies (eg Pedimune by CIPLA), and data are already forthcoming about their use in African children (see CROI reports above).
New drugs, such as paediatric darunavir are also being made as mini-pills for children upfront alongside the adult pills. Abbott are making new Kaletra mini-pills and GSK are scoring their drugs, and these are now being evaluated in Africa. There is still a long way to go. In particular, fast track licensing of new formulations of new and older drugs for children, and ensuring that dosing data are kept updated, are both of critical importance.
It would be useful to have more discussion on early infant diagnosis and requirements for low cost, easy to use diagnostic assays that are needed for resource limited settings.
The difficulties of coordinating family-based care for HIV-positive children, together with their families, in settings where there is a scarcity of healthcare workers needs special attention and will require innovative thinking and bold policy making to ensure that it is embedded properly into national treatment programmes.
American Academy of Paediatrics. Paediatrics. Volume 119, Number 4, April 2007