'25 at 25': Improving treatment options for children living with HIV
30 Apr 2024
Treatment options for children often lag behind those for adults. Data from trials conducted in adults cannot be simply extrapolated to children. Children are not mini-adults, and the way drugs are absorbed in the body, and the side-effects they can cause may be different. This means trials that test new drugs for children are vital to ensure children can access effective and safe treatment.
The MRC Clinical Trials Unit at UCL has been at the forefront of conducting HIV treatment trials in children, expanding the options available to them, and making treatments easier to take and tolerate.
CHAP
HIV affects the immune system, making a person less able to deal with infections. The CHAP trial was carried out in Zambia in 2001-2003, before antiretroviral therapy was available for children in sub-Saharan Africa. 541 children aged 1-14 years took part. It tested whether an inexpensive antimicrobial drug called cotrimoxazole could help prevent some of these deadly infections.
The CHAP trial showed that children of all ages with symptoms of HIV should take cotrimoxazole, even in areas where there is known resistance to this drug, as it reduced the death rate by 43% compared to the placebo.
Cotrimoxazole was licensed and supplied to all children who were HIV positive in Zambia. Researchers recommended it should be made available to all HIV-infected children in developing countries, and this became part of World Health Organisation (WHO) .
CHAPAS-1
Antiretroviral therapy for people living with HIV involves taking several different drugs, often involving several tablets each day. This can be particularly hard for children. CHAPAS-1 looked at the use of fixed dose combination tablets – several drugs in one tablet - for children. It found that Triomune Baby/Junior had an appropriate ratio of drugs for children, and that these tablets were easier for many children to take than separate liquids, as well as being easier to transport and store. CHAPAS-1 found the drugs could be dosed according to simple weight bands, enabling healthcare workers to easily prescribe the right amounts.
Data from CHAPAS-1 contributed to the US Food and Drug Administration licensing decision, making it the first fixed dose combination antiretroviral treatment (ART) to be licensed specifically for children under 12 years old. Following CHAPAS-1, these pills were included in the WHO guidelines, and widely distributed in sub-Saharan Africa. This helped enable the roll-out of ART to children in Africa, where most of the children living with HIV in the world live.
ARROW
The ARROW trial was carried out in Uganda and Zimbabwe between 2007-2012, with 1,206 children taking part. ARROW aimed to find out whether:
- Antiretroviral therapy can be given safely and effectively without doing so many blood tests
- Starting children on four anti-HIV drugs for a short period of time before continuing with 3 drugs is better over the long term, compared with being on 3 drugs from the start
- Children who are stable on HIV treatment need to continue taking the drug cotrimoxazole to reduce illness
- A once-daily dose of the drugs abacavir and lamivudine is as good as taking it twice a day
Data from the ARROW trial led to the US Food and Drug Administration approving once daily dosing of abacavir and lamivudine for children living with HIV, making treatment easier for children and carers. ARROW showed that continuing cotrimoxazole prophylaxis reduced hospital admissions and malaria even in children who had been on ART for more than 2 years. This led to WHO recommending continued use of cotrimoxazole prophylaxis until adulthood for children living with HIV in areas with high prevalence of malaria or severe bacterial infections.
CHAPAS-2
CHAPAS-2 addressed the urgent need for better formulations of lopinavir/ritonavir after it was recommended in place of nevirapine for under 3-year olds in WHO 2010 guidelines. The then current unpalatable lopinavir/ritonavir liquid formulation requiring refrigeration was far from ideal for Africa. CHAPAS-2 looked at the drug levels in blood samples (pharmacokinetics) and acceptability of and liquid for infants, standard adult size tablets for older children, and novel pellets/granules formulations for younger children. These data resulted in FDA licensing of the new pellet/granule formulation which was then rolled out in many African countries.
ODYSSEY
The ODYSSEY trial tested the use of a new antiretroviral drug, dolutegravir, in children. ODYSSEY included 792 children aged 4 weeks to 18 years at the time of enrolment; with 683 children taking part in the extended follow-up. The ODYSSEY trial was carried out in hospitals across Europe, Africa, Asia and North and South America. ODYSSEY showed that dolutegravir-based ART was better than the older drug combinations tested for children living with HIV. Dolutegravir is now recommended by WHO as part of both first- and second-line regimens for children.
ODYSSEY also found that children weighing over 20kg could safely take adult dolutegravir tablets. This data led to the US Food and Drug Administration approving use of the adult tablets for children weighing at least 20kg in June 2020. This means that children can take this simplified dosing and will not miss out on this new drug. The US Food and Drug Administration and European Medicines Agency also approved the use of smaller dispersible tablets (5mg) for children aged four weeks or older, dosed according to simple weight bands. These decisions were also based, in part, upon data from ODYSSEY. These data have also led to changes in the dosing recommendations of dolutegravir for children in the WHO guidelines.
CHAPAS-4
The CHAPAS-4 trial focused on identifying better treatments for children who are starting second-line treatment. 919 children aged 3-15 years from Uganda, Zambia and Zimbabwe took part in the trial. It found that newer antiretroviral combinations including tenofovir alafenamide and dolutegravir are superior to older second-line options for children living with HIV. These results reinforce the current WHO recommendation of DTG-based regimens being preferred second-line regimen for children. They also provide new evidence for use of TAF in second-line combinations for children.
Results from sub-studies looking at drug levels in blood samples from CHAPAS-4 will contribute to the evidence for simplified weight-band dosing of these drugs for children.
Observational studies
Randomised controlled trials provide gold-standard evidence for new treatments. However, because they only include a few hundred or thousand participants and only follow-up participants for a limited amount of time, they do not always tell us the long-term outcomes of a treatment. Our observational work, where we collect data from large numbers of children living with HIV attending routine HIV care, is complementary to our clinical trials. This work helps us understand more about treatments and side-effects, and the long-term outcomes of HIV acquired in early life. We lead research on children living with HIV in the UK and Ireland (CHIPS study) and also coordinate a cohort collaboration across Europe and Thailand. These studies help us answer questions that would be challenging or unrealistic to undertake as trials.
The CHIPS study was part of national UK surveillance of HIV and includes data on all children in paediatric HIV care in the UK and Ireland. In this study we describe the characteristics of children, adolescents and young adults with perinatal HIV, focussing on key issues such as transition from paediatric to adult care, and drug effectiveness. Our findings have highlighted particular groups who are not on treatment or not virally suppressed, and who may need additional support.
The European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC), coordinated by us together with Penta, brings together observational cohort data from across Europe and Thailand to answer questions which one cohort cannot answer alone. This collaboration allows us to explore trends outcomes such as changes in the long term risk of AIDS and death over the past 20 years, risk of rare conditions such as cancer, long term immune status and growth among children and adolescents with HIV around different regions. EPPICC also has ongoing studies assessing the long-term effectiveness and safety of new treatments including dolutegravir and tenofovir alafenamide in children and adolescents living with HIV, using real-world data. Findings from both CHIPS and EPPICC have informed European, US and international HIV guidelines.
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