Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children
Authors: Chiappini Elena , Lisi Catiuscia , Giacomet Vania , Erba Paola , Bernardi Stefania , Zangari Paola , Di Biagio Antonio , Taramasso Lucia , Giaquinto Carlo , Rampon Osvalda , Gabiano Clara , Garazzino Silvia , Tagliabue Claudia , Esposito Susanna , Bruzzese Eugenia , Badolato Raffaele , Zanaboni Domenico , Cellini Monica , Dedoni Maurizio , Mazza Antonio , Pession Andrea , Giannini Anna Maria , Salvini Filippo , Dodi Icilio , Carloni Ines , Cazzato Salvatore , Tovo Pier Angelo , de Martino Maurizio , Galli Luisa ,   for the Italian Register for HIV Infection in Children, Parigi Sara , Orlandi Francesca , de Martino Alessandra , Pinzani Raffaella , Abbagnato Luisa , Ruggeri Maurizio , Baldi Francesco , Faldella Giacomo , Chiriacò Piergiorgio , Dessì Carlo , Pantò Maria Grazia , Anastasio Elisa , Govoni Maria Rita , Bigi Maurizio , Bondi Elisabetta , Borea Riccardo , Cenderello Giovanni , Tommasi Donato , Nogare Ernesto Renato Dalle , Saitta Marcello , Felici Leonardo , Consolini Rita , Antonellini Angelo , Anzidei Gianfranco , Genovese Orazio , Catania Salvatore , Natale Fabio , Olmeo Paolina , Cristiano Letizia , Portelli Vincenzo , Rabusin Marco , Di Pietro Giada Maria , Fabrizio Leone 
Published: January 2022

Abstract
Background
Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2–12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children.

Methods
An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018.

Results
22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063–7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported.

Conclusion
The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.