SMILE once-daily regimen non-inferior to triple ART regimen

28 Jun, 2023

Findings from the Strategy for Maintenance of HIV suppression with integrase inhibitor + darunavir/ritonavir in children (PENTA-17) trial, simply known as SMILE, were published in eClinicalMedicine on 2 June 2023. SMILE is the first randomised trial to determine whether children living with HIV on ART with suppressed viral load could maintain the suppression on a once-daily regimen compared to the standard of care (SOC) which involves three ART drugs. 

The current SOC includes NRTIs which are a potent source of adverse effects in children and adolescents and require them to take pills twice a day. Having to take medication twice a day could affect adherence, especially when adolescents take over the responsibility for administering their treatment. Poor adherence is associated with viral load rebound and an increased risk of the development of drug resistance. It is therefore important to develop and evaluate simpler ART regimens as children may be more vulnerable to adverse effects of drugs due to metabolic changes related to growth. Alternative regimens may also help improve adherence and both short and long-term outcomes for children and adolescents. Treatment simplification is also critical as this may increase access to drugs, support retention in care and reduce treatment costs. 

SMILE is an open-label, multicentre, randomized, non-inferiority phase 2/3 trial which enrolled 318 children living with HIV aged at least 12 years old, who were virologically suppressed for at least 12 months and had been on a 3-drug bPI or NNRTI containing regimen for at least 24 weeks. The participants were from Uganda, South Africa, Ukraine, Thailand, Argentina, Mexico and Europe. A computer programme was used to randomise the participating children to either switch to INSTI + DRV/r (NRTI-sparing regimen), taken once-daily, or to continue on the current SOC triple ART regimen. The trial provides promising results for the use of a once-daily ART regimen in the treatment of HIV in children. The SMILE arm of the trial demonstrated that this regimen was non-inferior to the standard triple ART regimen, while also making things easier for families and participants as medication is only taken once a day. This is an important finding, as adherence to medication is a crucial factor in the success of HIV treatment. Furthermore, the low rates of adverse events suggest that this once-daily regimen may be well-tolerated by patients. 

Alexandra Compagnucci, SMILE Chief Investigator, had this to say.

“We now have an additional treatment strategy for children and adolescents living with HIV thanks to SMILE. This treatment option has already shown to be an effective option for adults, and with these findings, clinicians now have data and proof of the effectiveness of this once-daily alternative for children who are virologically suppressed. The SMILE once-daily regimen is also important in cases when some NRTIs are not tolerated or cannot be taken due to the harm that it would cause the children. Moving forward, we must also carry out this research in other situations such as in children who are on treatment that is failing. This research has already been done in adults and it is important that we also have this data in children” 

Overall, these results suggest that a once-daily ART regimen may be a viable option for treating HIV in children and adolescents and could potentially improve patient outcomes and quality of life. The SMILE trial would not have been possible without the collaborative efforts of all our partners and generous funders and the dedication and support of the trial teams who worked to ensure the success of the SMILE trial.