Develop and register a solid, taste-masked, first line lopinavir/ritonavir-based fixed-dose formulation with two nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine and abacavir
current phase of drug development
updated 13 Mar 2023
Child-friendly treatment specifically designed for infants and young children with HIV
Easy-to-administer, strawberry-flavoured combination of four antiretroviral treatments
As part of DNDi’s goal to ensure children living with HIV benefit from optimum ARV formulations, the objective of the 4-in-1 project was to combine the four drugs recommended for the treatment of paediatric HIV into a single, easy-to-use granule-filled capsule, also called a fixed-dose combination, which is heat-stable, taste-masked, solid, and does not contain alcohol or inappropriate solvents.
The ‘4-in-1’ fixed-dose combination combines the protease inhibitors lopinavir and ritonavir with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir.
This new formulation represents a significant improvement over protease inhibitor-containing paediatric ARV formulations. It does not require refrigeration, has a sweet taste and is easy to administer to infants and children of different weights and ages, a major improvement over previously available formulations for both children and their caregivers.
The 4-in-1 is one among multiple new child-friendly formulations of WHO-recommended regimens being introduced – including paediatric formulations of dolutegravir-containing regimens – representing a long-awaited and long overdue ‘treatment revolution’ for children with HIV.
- Indication: Children living with HIV
- Approved by the South African Health Products Regulatory Authority (SAHPRA) in June 2022.
‘This will make a big, big, big difference to our paediatric treatment. It is a powder form, the taste is good. And also there is no after-taste. So it will be good for our children that are infected with HIV.’
Tembisa Makeleni, Clinical nurse, Ubuntu clinic in Khayelitsha township, Cape Town, South Africa
The South African Health Products Regulatory Authority (SAHPRA) approved the 4-in-1 in June 2022. US FDA approval is pending following re-inspection of the Cipla site in August 2022. Also pending are registrations in Uganda, Kenya, and Tanzania. The clinical study report for LOLIPOP, providing clinical data on the 4-in-1 in infants and young children living with HIV, was shared with the Uganda National Drug Authority, and the manuscript is expected to be submitted for peer review in early 2023.
The 4-in-1 project in Ubangi in the Democratic Republic of the Congo (DRC) began in December 2022 following temporary use approval issued by the health authorities. This project aims to expand access to testing and optimum paediatric ARV formulations in a remote part of the country where access to treatment has been particularly challenging.
The LOLIPOP study conducted in Uganda was completed, with data showing a favourable safety profile in all weight bands (3-19.9 kg). Exposure to the antiretrovirals was as expected in children ≥6 kg, while lopinavir exposure was low in some children <6 kg, as observed for the lopinavir/ritonavir combination oral solution. All 34 children included in the study showed a virological response, and 97% of caregivers described the 4-in-1 as very easy or easy to administer. US-FDA approval was further delayed due to the COVID-19 pandemic.
Following Cipla’s initial submission of its dossier for the 4-in-1 to the US FDA for tentative approval in October 2019, Cipla re-submitted its dossier to the US FDA for full approval in June 2020. The re-submission addresses scientific and labelling issues. Unfortunately, the US FDA has delayed inspections of manufacturing plants due to the ongoing COVID-19 pandemic. Because of these unforeseen issues, full US FDA approval of the 4-in-1 is now expected in the second half of 2021.
In the meantime, DNDi and partners continue to gather clinical data on the 4-in-1 in children, including neonates, children living with HIV, and children infected with tuberculosis. DNDi completed the clinical phase of the LOLIPOP study in Uganda, which will provide clinical data on the 4-in-1 in infants and young children living with HIV. At the same time, researchers at Stellenbosch University in Cape Town, South Africa, are evaluating the pharmacokinetics and safety of the 4-in-1 in neonates exposed to HIV, as part of the PETITE study, in close coordination with DNDi.
DNDi is also actively preparing to facilitate access and transition to the 4-in-1 as one of several new child-friendly treatment options, including paediatric dolutegravir-based regimens.
In October 2019, Cipla submitted the ‘4-in-1’ fixed-dose combination of abacavir, lamivudine, lopinavir, and ritonavir (ABC/3TC/LPV/r) to the US Food and Drug Administration (FDA) for tentative approval. In December, Cipla announced that this strawberry-flavoured HIV treatment will be priced at under one dollar a day for children weighing up to 14 kg.
The 4-in-1 combines the protease inhibitors lopinavir and ritonavir (LPV/r) with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir in the form of granule-filled capsules. Developed for infants and young children weighing from 3 to 25 kg, parents and caregivers will be able to administer the drugs by opening the capsules and sprinkling the granules on soft food, water, or milk. The 4-in-1 does not require refrigeration and is a great improvement over the current option, a bitter-tasting syrup of LPV/r with high alcohol content that must be refrigerated.
Currently, DNDi is running the LOLIPOP study in Uganda to provide clinical data on the 4-in-1 in infants and young children living with HIV. The first patient was enrolled in June 2019 at the Regional Referral Hospital in Mbarara, Uganda. The study will be key to assist scale-up of the product if tentative FDA approval is received.
A first-line ‘4-in-1’ fixed-dose combination of abacavir/lamivudine/lopinavir/ritonavir (ABC/3TC/LPV/r) is on track to be submitted for registration in 2019. This 4-in-1 fixed-dose combination will be simple to use with water, milk, breast milk, and food. It will be taste-masked and heat-stable – a great improvement over the current option, a paediatric syrup of lopinavir/ritonavir (LPV/r) with high-alcohol content.
To provide clinical data in young HIV-infected infants and children, DNDi is preparing a study, called LOLIPOP, to assess this 4-in-1 combination as an easy-to-use paediatric formulation in a Phase I/II study. The LOLIPOP study, which has received ethical approval, will begin in March 2019 in Uganda and will generate pharmacokinetic, safety, and acceptability data on the 4-in-1 to provide evidence for worldwide scale-up.
Preliminary pharmacokinetic studies in healthy human volunteers were conducted in 2017 with a final 4-in-1 formulation. Bioequivalence studies in healthy human volunteers will be performed in 2018, enabling regulatory filing. Safety, acceptability, and efficacy data on this new formulation will also be generated in sub-Saharan Africa to provide evidence for worldwide scale-up. The objective is to submit the 4-in-1 dossier for registration in late 2018.
Following preliminary studies, the best formulation candidates in terms of bioavailability and taste-masking have been chosen – out of the 30 formulations evaluated since 2014 – for testing in healthy human volunteers in on-going Phase I studies.
Three of the most promising formulations tested in previous in vivo studies were assessed, and were found to be highly bioavailable in phase I studies in man. Additional bioavailability studies and standardized electric tongue taste testing (e-tongue) of granules with modified coatings and different polymers will be performed in 2016.
News & resources
- 29 June 2022 - HIV child medicine that cut the ‘Yuck’ cleared in South Africa, Bloomberg
- 25 June 2022 - New ‘breakthrough’ treatment for infants with HIV, The Citizen
- 15 June 2022 - Cipla introduces HIV drug for children in South Africa that won’t need refrigeration, CNBC-TV18
- 15 June 2022 - New HIV treatment designed for young children gains first approval in South Africa, HealthCare Africa
- 14 June 2022 - Cipla and DNDi launch child-friendly 4-in-1 antiretroviral treatment for young children living with HIV in South Africa
- 29 November 2019 - HIV treatment for children to be produced for under one dollar a day
- 1 November 2019 - Ending the Neglect of Paediatric HIV
- 17 June 2019 - First patient for “LOLIPOP” study for HIV treatment
- 4 June 2019 - Study for a child-friendly HIV treatment begins in Uganda
- 11 December 2012 - Grant from UNITAID awarded to bolster development and delivery of child-adapted antiretroviral (ARV) formulation
- 19 July 2012 - DNDi and Cipla to Develop 4-in-1 Paediatric Antiretroviral Drug Combination – New formulation to fill the deadly gap in appropriate HIV medicines
Get our latest news, personal stories, research articles, and job opportunities.