The objective of the 4-in-1 is to combine the four drugs needed 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.

Developed for infants and young children weighing from 3 to 25kg, 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 significant improvement over the current option, a bitter-tasting syrup of lopinavir and ritonavir with high alcohol content that must be refrigerated. Full US Federal Drug Administration (FDA) approval of the 4-in-1 capsule is expected in 2021.

Project updates

2020

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.

2019

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.

2018

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.

2017

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.

2016

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.

2015

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.