Health authorities in the Democratic Republic of the Congo, Kenya, Mali, Mozambique, and Uganda approved and registered the 4-in-1 for use in their countries in 2023. US FDA approval remained pending.

Under temporary use protocol, 39 children were initiated on treatment with the 4-in-1 in the North and South Ubangi provinces of the Democratic Republic of the Congo. 100% viral suppression at six months was achieved for the first nine children initiated on treatment. In South Africa, Cipla began distribution of the 4-in-1 for use when needed as an alternative to paediatric dolutegravir.

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.