Over 3.2 million children worldwide are infected with HIV, but only 24% of these children receive antiretroviral therapy (ART). ART adherence among children is a crucial part of managing human-immunodeficiency virus (HIV) infection and extending the life and health of infected children. Important causes of poor adherence are formulation- and regimen-specific properties, including poor palatability, large pill burden, short dosing intervals, and the complex storage and transportation of drugs. This review aims to summarize the various regimen- and formulation-based barriers to ART adherence among children to support the need for new and innovative pediatric formulations for antiretroviral therapy (ART). Detailing the arguments both for and against investing in the development of pediatric HIV medications, as well as highlighting recent advances in pediatric ART formulation research, provides a synopsis of the current data related to pediatric ART formulations and adherence.
Over 3.2 million children worldwide are infected with HIV, but only 24% of these children are on the antiretroviral therapy (ART) they need [
Adherence to ART is crucial to HIV management. Proper adherence to ART leads to lower viral loads, decreased symptoms in patients, and decreased viral resistance [
Many barriers prevent children with HIV from maintaining good adherence. These include cost of medications, access to medications, stigma associated with HIV, and disclosure of HIV to children [
Developing child-friendly formulations of ART will make it easier for caregivers to administer medications to children and easier for children to take medications. Both strategies will increase adherence, which is critical to successful long-term HIV therapy. This paper will review the current obstacles preventing adherence to pediatric ART, the barriers to creating more acceptable pediatric formulations, and evidence supporting the need for appropriate pediatric formulations of ART.
Poor palatability is directly associated with poor adherence in children with HIV [
The World Health Organization recommends lopinavir/ritonavir (LVP/r) as the first-line ART to initiate in children three years of age and younger and recommended it as the second-line treatment for children three years of age and older [
In addition to poor palatability, large pill burden has also been found to decrease adherence to ART [
In addition to FDCs, other ways of simplifying dosing regimens, such as once-a-day formulations, have also been shown to positively affect medication compliance. A study of extended-release, nevirapine-based ART, which can be given once a day, showed good immunologic response and improved adherence in children [
Liquid formulations of ART were originally created for infants and children with HIV to ease administration by caregivers. Young children are not generally physically capable of safely swallowing pills or tablets. Nonetheless, liquid formulations have many shortcomings of their own. In addition to the poor palatability of liquid ARTs, they often require caregivers to measure out and administer precise amounts of the liquid. This can be a challenge: one study found that 80% of caregivers preferred tablets over liquids due to the inability to measure accurate doses, easy spillage during administration, and the large quantities they needed to administer [
Because of the aforementioned complexity of liquids, caregivers often switch to pills as early as possible. However, many studies have found swallowing pills to be a barrier to adherence in children [
Many studies have looked into alternatives to swallowing large pills for children with HIV. Potential innovations to decrease the struggle between caregivers and their children include the following: recommendations to open capsules, combining medications with food, and knowing which pills are dispersible in water [
In another approach to this challenge, pill-swallowing training for HIV-infected children has been shown to increase ART adherence [
A significant barrier to ART compliance is the requirement for complex storage and transportation. Many of the liquid protease inhibitors require cold-chain storage. This requires both the clinic and the patient to have a refrigerator to store the medications. In resource-limited settings, such as sub-Saharan Africa, where pediatric HIV is most prevalent, this might be an impossible requirement [
In addition, caregivers often must transport large volumes of liquid ART for their children to have a monthly supply or more. This can be significant barrier for caregivers living in rural areas who may walk many kilometers to arrive at the clinic. For example, a 10 kg toddler on first-line ART (ABC + 3TC + LVP/r) would take 28 mL of ART daily, which is equal to about two and a half liters every three months. This requires caregivers to carry seventeen 160 mL bottles home from the clinic every three months. Due to the stigma associated with HIV, caregivers aim to hide medications from their community, which is difficult when caregivers must carry so many bottles. A study in Uganda found that 63% of caregivers complained about the weight of bottles as being a major barrier [
The world aims to eradicate mother-to-child transmission of HIV, therefore eliminating child cases of HIV and subsequently the need for pediatric formulations. This may be seen to significantly reduce the impetus to develop new pediatric ART formulations. Although the elimination of pediatric HIV is a shared goal among healthcare providers, pharmaceutical companies, and NGOs around the world, it will take many years before vertical transmission is prevented. For now, millions of children are still living with this disease. Until this objective is met, children need access to child-friendly formulations of ART [
Many factors continue to drive the need for pediatric ART, including the challenges of successfully implementing PMTCT and scaling up widespread access to pediatric ART. The risk of perinatal transmission remains at 2%, even if a woman is on ART, has a low or undetectable viral load, follows the recommended treatment regimen, and does not breastfeed [
Surveys of the pediatric ART market review that outdated procurement practices and gaps in supply chains are often responsible for low uptake of innovative or new pediatric drug formulations [
In its “Developing an Optimized List of Pediatric ARV Formulations” report, the WHO presents the argument that since children only make up 7% of HIV cases worldwide, increases in the number of formulation options will decrease the demand for currently available formulations. This could lead to market instability and therefore a lack of incentive for investment in the pediatric ART market [
Incentives are required to drive further investment in research and development for pediatric formulations and innovations that have been shown to increase adherence. Recognizing the potential lack of incentives for this work, recent initiatives such as Drugs for Neglected Diseases Initiative (DNDi), the NIH’s Development of Appropriate Pediatric Formulations and Pediatric Drug Delivery Systems RO1, and the Accelerating Children’s HIV/AIDS Treatment (ACT) initiative supported by the Presidents Emergency Plan for AIDS Relief (PEPFAR) and the Children’s Investment Fund Foundation (CIFF) have created incentives for the investment in pediatric ART formulation development [
Pharmacokinetics, toxicity, and delivery preferences for pediatric medications can differ greatly from adult medications, requiring specific research to evaluate the safety and efficacy of pediatric medications [
In addition to lack of pediatric formulations, there are many other factors that influence adherence to ART. Medication properties that influence adherence include poor palatability, large pill size, regimen complexity, and short dosing intervals, but these properties are only encountered if the child is given the opportunity to take the medication. Stigma, lack of medical literacy, disclosure status of the child, child-caregiver relationship, and high costs of HIV medications also prevent children from receiving treatment or being compliant [
The link between adherence and formulation properties is the most poignant argument for the development of child-friendly ART. Many studies show a significant connection between adherence and ART attributes such as palatability, pill size, pill burden, short dosing intervals, and regimen complexity. Over 21% of caregivers in a South African study reported difficulties giving medication due to poor palatability [
The significant impact that HIV medication formulations have on adherence has led to the study of alternatives and new formulations to help with medication administration in children. Studies have looked at how to decrease poor palatability by adding flavoring and creating pH-sensitive microparticles to hide the bitter taste of many ARTs. A study in Thailand examined the addition of a flavoring agent to generic ART, using FLAVORx®, whose ingredients include a flavoring agent, propylene glycol, ethyl alcohol, water, and triacetin, in ten different flavors: strawberry, orange, banana, grapes, bubble gum, watermelon, lemon, cherry, vanilla, and chocolate [
In addition to manipulating taste, other innovators have been studying the impact of different modes of administration. These modes include sachets that deliver liquid or gel ART all at once, sprinkles and nanoparticles that allow caregivers to mix medications with food or liquids, and dissolvable tablets that can be incorporated into fluids. Nanotechnologies have been used to administer insoluble LPV/r in sprinkles or sachet formulations and have shown stability and good bioavailability [
Because fixed-dose combinations and once-a-day formulations are associated with better adherence, innovators have also aimed to create innovative solutions for children to help decrease pill burden. LPV/r, which has been recommended as first-line treatment by the WHO, has been combined with abacavir/lamivudine or zidovudine/lamivudine in a study to create a more tolerable, first-line, fixed-dose combination for children [
In addition to FDC and once-a-day formulations, long-acting formulations of ART, such as once-a-month injectable antiretroviral and weekly ART infusions, are on the horizon and could help children and adults who struggle with adherence to daily therapy [
Increased adherence in children with HIV has benefits for both the child and the larger HIV-positive community. Proper adherence leads to sufficient viral suppression, which leads to longer and healthier lives for children living with HIV. In addition, proper adherence reduces viral resistance [
In addition to better adherence in children, pediatric formulations of ART have the possibility of reducing the time and energy investment required of caregivers to administer medication to their children. Many studies have reported that a significant cause of nonadherence is child refusal [
Concealing and hiding medications on the go is important for both caregivers and children as a way to reduce stigma and bullying. Sachets, such as the Pratt Pack created by Duke University, can ease transportation of medications and aid caregivers in concealing medications [
Despite many innovations, pediatric formulations are still very limited in comparison to the number of adult formulations [
The pediatric market for ART is not a small version of the adult market, but rather a unique niche which requires developers to consider different routes and methods of administration, different strengths, and a variety of flavors [
Many organizations, including UNITAID, Drugs for Neglected Diseases initiative (DNDi), Medicines Patent Pool (MPP), Clinton Health Access Initiative, President’s Emergency Plan for AIDS Relief, and Elizabeth Glaser Pediatric AIDS Foundation, have called for the prioritization of pharmaceutical companies to address the need for new innovative formulations [
To improve the lack of pediatric formulations, the World Health Organization launched the global campaign “Make Medicines Child Size.” The case is even more critical in the case of poverty-related diseases that mainly affect children in poor countries, such as HIV [
Over 3.2 million children worldwide are waiting for pediatric formulations of antiretroviral drugs. To address this need, innovations in pediatric formulations must strive towards (1) safe and effective ART for children, (2) palatable and easy-to-swallow medications, (3) fixed-dose combinations to decrease pill burden, (4) once-a-day formulations to lengthen dosing intervals, (5) medications that are easy to transport and store, (6) formulations that are simple for caregivers to administer, and (6) securing incentives to drive investments in the development of these critical formulations. Investment must be made in pediatric-friendly formulations, especially for infants, toddlers, and young children, to allow this generation to survive and thrive.
Dr. Rachel C. Vreeman has served on the HIV scientific advisory committee for Teva Pharmaceuticals.
The authors acknowledge and thank Carole McAteer and Megan McHenry for their assistance in editing and reviewing this paper. This research was supported in part by a grant (1K23MH087225) to Dr. Rachel C. Vreeman from the National Institutes for Mental Health.