New LPV/r-based fixed dose HIV combination for young children: first results with Quadrimune 4-in-1
Polly Clayden, HIV i-Base
In the first 31 children who completed the LOLIPOP study, the lopinavir/ritonavir (LPV/r), abacavir (ABC) and lamivudine (3TC) 4-in-1 was safe, well-accepted and effective in achieving or maintaining undetectable viral load – according to data presented at the 12th International Workshop on HIV Pediatrics. 
The 4-in-1 gave adequate drug exposures in children weighing 6 to <20 kg but, the investigators explained, a larger sample size is needed in the 3 to 5.9 kg weight band to fully assess exposures in this group.
LPV/r + ABC + 3TC is the preferred first-line treatment option for children living with HIV less than three years old in many countries.
In partnership with Drugs for Neglected Diseases Initiative (DNDi), Cipla has developed a strawberry-flavoured ABC/3TC/LPV/r (30/15/40/10 mg) 4-in-1 granule fixed dose combination (FDC) formulation for children called Quadrimune.
The LOLIPOP study is looking at the safety, pharmacokinetics (PK) and acceptability of the 4-in-1 FDC for the first time in children.
It is an ongoing phase 1/2, open-label, partially randomised, crossover study of the 4-in-1 versus ABC/3TC 60/30 mg dispersible tablets plus LPV/r 40/10 mg pellets (reference formulation) in 50 children, conducted in Uganda (two sites in Kampala and one in rural Mbarara).
Doses are according to WHO weight bands (WB): 3 to 5.9 kg (WB1), 6 to 9.9 kg (WB2), 10 to 13.9 kg (WB3) or 14 to 19.9 kg (WB4). Children in WB 2 to 4 were randomised (1:1) by WB to the reference formulation followed by the 4-in-1 for 21 days each or the other way round. Children in WB1 only received the 4-in-1 for 21 days.
The investigators performed intensive PK sampling after 21 days of treatment with each formulation. Safety was assessed throughout the study, efficacy at the end of the study and acceptability after 21 days on the 4-in-1.
By February 2020, 33 children had been enrolled: 29 in WB2, 3 and 4 (14 assigned to reference and 15 to 4-in-1 first); 4 children in WB1, 9 in WB2, 9 in WB3 and 11 in WB4.
At baseline, mean age overall was 32.3 months (SD 17.7), weight 11.3 kg (SD 3.8). The majority (76%) had been on LPV/r- based ART for at least 6 months and 88% were virally suppressed to <400 copies/mL and 48% to <50 copies/mL. Two children did not complete the study: one lost to follow-up and one withdrew consent.
At the end of the study, 30/31 (97%) children had viral load <400 copies/mL, including 20/31 (65%) with <50 copies/mL.
There were 101 reported AEs: 96 mild, 4 moderate and 1 severe. None led to treatment discontinuation. One was serious (pneumonia) and began while receiving the reference formulation.
With the 4-in-1, the geometric mean (GM) AUC 0–12 for ABC, 3TC and LPV were 5,479, 6,059 and 88,398 ng.h/mL, respectively, and GM for Cmax were 1,754, 1,125 and 10,103 ng/mL, respectively. These values were comparable to reference formulation.
Two (of four) children in WB1 (with severe wasting secondary to failure to thrive) had LPV C12 <1,000 ng/mL but one remained virologically suppressed and one became so. Enrollment in this WB is ongoing.
Final results from this study will be available early in 2021.
Results from the acceptability sub study of the 4-in-1 were reported in a related presentation. 
The investigators conducted 18 semi-structured, qualitative interviews and questionnaires with caregiver-child pairs.
In this small sample, all caregivers, irrespective of their children’s weight, found the 4-in-1 formulation highly acceptable – according to both questionnaire data and interviews.
Caregivers highlighted the flavour (sweet taste), ease of administration (using mainly local cow’s milk, porridge or water as available, even when breastfeeding), easy storage (not needing a fridge) and the child’s acceptance as important factors.
They found the 4-in-1 simpler than the pellets/tablets combination. They reported high short-term adherence due to effective support from health workers and noticeable improvements in children’s health.
The instructions helped caregivers to find most effective and appropriate ways to administer the 4-in-1 and to overcome problems such as vomiting.
The 4-in-1 has taken its time to finally emerge: these data look pretty good, and it is clearly an improvement on LPV syrups and pellets.
Whether this formulation is widely used will be linked to recent tentative approval, pricing agreement and plans for rapid scale up of the generic, scored, dispersible 10 mg dolutegravir formulation for young children. 
- Safety, pharmacokinetics and acceptability of the ABC/3TC/LPV/r GRANULES (4-in-1) in children living with HIV (3-20 kg) in Uganda: LOLIPOP study. 12th International Workshop on HIV Pediatrics (virtual meeting). 16–17 November 2020. Oral abstract 4.
- Acceptability of a new 4-in-1 abacavir/lamivudine/lopinavir/ritonavir paediatric fixed-dose combination: the caregiver-child dyads’ perspective. 12th International Workshop on HIV Pediatrics (virtual meeting). 16–17 November 2020. Oral abstract 6.
- Clayden P. New formulation of dolutegravir will make modern ART available for babies and young children at less than $120 a year. HTB. 9 December 2020.