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Despite significant efforts to increase the number of children on HIV treatment and reduce mother-to-child transmission of the disease, only 52% out of around two million children living with HIV worldwide received antiretroviral therapy in 2017, compared with 59% of adults. Without treatment, over half of children born with HIV will not live to see their second birthday.

One of the reasons that more children are not being put on antiretrovirals (ARVs) is the suboptimal variety of paediatric antiretrovirals available today. Pharmaceutical companies have invested little in developing child-appropriate drug formulations. One of the main treatment regimens currently recommended by the World Health Organization (WHO) for the youngest children was not designed with children’s needs in mind – the medicines come in the form of syrups that are horrid-tasting and hard to administer, especially to children that have both HIV and TB, and moreover they require refrigeration.

There is also limited access to diagnostic tests for infants in resource-limited settings. Because of these unmet medical needs, children with HIV are a neglected population.

The Drugs for Neglected Diseases initiative (DNDi) is a not-for-profit research and development organisation that develops new drugs for neglected diseases such as paediatric HIV, human African trypanosomiasis, leishmaniasis, Chagas disease, filarial infections, mycetoma and hepatitis C. Together with partners, DNDi is working to deliver optimal child-adapted ARVs, with a special focus on infants and young children who are at the highest risk of dying if they do not have access to treatment.

The first steps towards optimum treatment

In 2010, DNDi was asked by various organisations, including Médecins Sans Frontières/Doctors Without Borders (MSF), WHO, and the global health initiative Unitaid, to apply its expertise in neglected disease research and development (R&D) to the development of paediatric HIV treatments. DNDi established a paediatric HIV programme, and experts were consulted to build target product profiles of formulations for infants and children.

In 2012, Unitaid awarded USD 17.3 million to DNDi to support the development of a protease inhibitor (PI)-based first-line ARV regimen. WHO-guidelines published in 2013 recommended a regimen containing the PI lopinavir/ritonavir (LPV/r) as a first-line treatment for all children under three years old. Until recently, the only formulation available was a syrup that contains 40% alcohol.

Improving options for children with hiv and tb

DNDi is partnering with Cipla Ltd., an Indian company that produces generic medicines, to develop a solid first-line ‘4-in-1’ fixed-dose combination of Abacavir/Lamivudine/Lopinavir/Ritonavir (ABC/3TC/LPV/r) for infants and young children under three years of age that meets WHO recommendations. DNDi’s goal is to ensure that these easy-to-use formulations are affordable and can be rapidly introduced in countries with large numbers of eligible children.

To PrEPare countries for the 4-in-1 fixed-dose combination, DNDi and partners are introducing alternative optimised paediatric formulations and improving treatment options for children with HIV and TB. With its partners in South Africa, DNDi has addressed the negative drug-drug interactions between PI-based HIV treatments recommended by WHO and the TB drug rifampicin by providing essential evidence and data in support of a process known as ‘super-boosting’. This negative ‘drug-drug interaction’ is a major barrier in treating children that have both TB and HIV – a problem that is especially acute in southern African countries at the heart of the HIV epidemic.

To address this issue, DNDi conducted a pharmacokinetic study in five hospitals in South Africa to demonstrate the safety and effectiveness of ‘super-boosting’, which involves adding extra ritonavir to the LPV/r regimen. Results recently published show that super-boosting is safe and effective for TB/HIV co-infected children. [1]

In 2015, Cipla licensed a solid ‘2-in-1’ fixed-dose combination of lopinavir/ ritonavir pellets (i.e. mini tablets to be mixed with food or liquids). This is a clear improvement over the lopinavir/ ritonavir syrup, since it does not require refrigeration, and is an important step towards introducing the 4-in-1 once it is approved. To improve access to this interim 2-in-1 combination, DNDi has been running the LIVING implementation study in Kenya, Uganda, and Tanzania. Interim results of this study have been presented in various conferences, including CROI 2018 and the International AIDS Conference in Amsterdam in July 2018. [2,3] 82% of the children in the study were virologically suppressed at 48 weeks (viral load ≤ 1000 copies/ml), compared to a baseline of 59%. LPV/r pellets were well accepted with minimal safety concerns. Treatment naïve patients, those failing nevirapine as well as those switching from LPV/r liquid, were well suppressed at week 48 and had recuperated immunologically and clinically.

A comparable level of virological suppression at 48 weeks across weight bands was observed in children from 5-11 months, 12-24 months, 25-40 months and 49+ months. Finally, time previously spent on ART and the type of ART did not influence the virological suppression (IAS 2018). A qualitative sub-study (RE-LIVING study) assessing the acceptability of the LPV/r pellet formulation amongst caregivers, children and healthcare workers found that the formulation was highly acceptable to caregivers due to its ease of storage, discrete packaging, and lack of bitterness compared to syrups. It was also found to be highly acceptable to children if the mix of pellets and food or liquid could be given quickly before the development of a bitter taste. [4]

Importantly, the LIVING study has built clinical capacity in Kenya and Uganda – training health workers and caregivers in the administration of new, improved formulations. It has already recruited over 1000 children in routine clinical settings – a significant achievement in the field of paediatric HIV.

4-medicines-in-1 formulation: infants aged 2 months – 3 years

DNDi’s long-term goal is to develop and deliver a taste-masked, heat-stable 4-in-1 LPV/r-based fixed-dose combination for infants and young children. This 4-in-1 fixed-dose combination (ABC/3TC/LPV/r 30/15/40/10 mg) will be simple to use with water, milk, breast milk, and food. In addition to improved taste-masking, the 4-in-1 has been formulated into granules, with individual particle sizes that are nine times smaller than the 2-in-1 pellets. This reduction in particle size is a key step in developing the 4-in-1 formulation and will facilitate swallowing by young infants, some of whom experience difficulties swallowing the 2-in-1 pellets.

To provide clinical data in young HIV-infected infants and children, DNDi is PrEParing a study named LOLIPOP (lopinavir/ ritonavir/lamivudine/ abacavir as an easy-to-use paediatric formulation in a Phase I/II study). The LOLIPOP study will begin in Uganda in 2019 and will generate pharmacokinetic, safety, and acceptability data on the 4-in-1 to provide evidence for worldwide scale-up.

With regulatory approval foreseen for 2019, the 4-in-1 should provide a decisive improvement for paediatric HIV treatment: a PI-based, all-in-one ARV regimen that is safe and efficacious; suitable and palatable for infants and very young children; easy-to-use as it will be a fixed-dose combination; and that does not require refrigeration.

Ending the neglect: multiple treatment options for children

Another new and promising child-adapted HIV treatment based on dolutegravir (DTG), from the integrase inhibitors class of ARVs, is expected to be approved in the near future. Along with the 4-in-1, this means that two new treatments will be available for children, representing the most significant ‘treatment revolution’ for children with HIV since the advent of antiretroviral therapy, a situation that was almost unimaginable just a few years ago.

Efforts are now underway to establish the safety, efficacy, and appropriate dosing of DTG for children. While adults are being switched to DTG regimens as the result of a shift in WHO guidelines, it will take more time for younger children to benefit, as the dosage for children under six years of age and formulations adapted to very young infants have yet to be approved. At the same time, regimens containing NNRTIs, such as efavirenz and nevirapine (with which the majority of HIV-positive children are currently being treated), will no longer be recommended because of poor viral suppression in children. The 4-in-1 will therefore play a critical role in closing the treatment gap for children with HIV.

Along with improvements in early infant diagnostic technology, these new formulations should contribute to ending the long-standing neglect of children living with HIV. Paediatric HIV still claims too many lives – now is the time to make improved formulations available for children.

References

  1. Rabie H, Denti P, Lee J, et al. Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy com-pared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study. [Internet]. Lancet [cited 2018 Dec 6]. Available from: https://doi.org/10.1016/S2352-3018(18)30293-5
  2. Andrieux-Meyer I, Salami O, Omollo O, et al. Effectiveness and safety of LPV/r pellets -based ART in children: 48-weeks analysis. CROI 2018, poster 842. Available from: http://www.croiconfer-ence.org/sessions/effectiveness-and-safety-lpvr-pellets-based-art-children-48-week-analysis
  3. Andrieux-Meyer I, Salami O, Omollo R, et al. Pel-let’s formulation of Lopinavir/ritonavir in children: 48 weeks evolution of viral suppression across age categories in the Living study. International AIDS Conference Amsterdam; 2018 July. Oral presentation.
  4. Onyango-Ouma, Nöstlinger C, Marchal B, et al. Assessing acceptance and acceptability of an innovative pediatric antiretroviral lopinavir/ ritonavir (LPV/r) pellet formulation. ICASA; 2017. Ivory Coast. Poster presentation.