Off-label drugs in our cohort of perinatally HIV-1 infected children were prescribed to 22.2% (50/225) of children at their last check in 2018. At univariate logistic regression analysis, risk factors for receiving an off-label regimen were age < 2 years, being of first HAART regimen and a detectable VL before starting that regimen. At multivariate analysis only younger age was confirmed to be an independent risk factor for receiving an off-label therapy. However, we also noticed that several children (56.52%, 13/23), aged between 11 and 12 years of age were receiving an off-label cART at last check. In this sub-group of children physicians probably considered minimal the potential risks related to an off-label use of the ARV drug since 12 years was the age for which the drug was licensed.
The most commonly antiretroviral drugs prescribed off -label were lopinavir-ritonavir (Kaletra®) in younger children, and three fixed dose combinations in older children: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya®), abacavir/dolutegravir/lamivudine (Triumeq®) and tenofovir disoproxil/emtricitabine (Truvada®).
Comparing our results to a 2016 Spanish multicentre study, conducted by Cooke et al. on a cohort of 318 perinatally HIV-1-infected children and adolescents between 1988 and 2012, it was found that our off-label therapy rates in children are lower than the ones of the Spanish sample, which reveals an off-label use of antiretroviral therapy in 69% of included children (221/318) . This difference could reflect the increase in approval coverage for the clusters under 2 years of age, which occurred after 2012 and consequently reduced the off-label incidence. For example, in 2012 atazanavir was approved in children over 6 years of age, while in 2014 the approval was brought forward to children over 3 months of age; raltegravir in 2012 was approved only in children over 2 years of age, while by 2018 it was approved from birth; efavirenz, which until 2013 was approved only for children over 3 years of age, is now approved in children over 3 months of age . Considering that efavirenz was used by the 24.5% of our population and that among the non-nucleoside reverse transcriptase inhibitors (NNRTIs) it was the most widely used after nevirapine, this fact may have contributed to reduce the off-label percentage in our population. However, in our cohort, off-label use was still widespread. The 10% of our off-label patients have reached the fifth therapeutic regimen; this confirms that off-label therapies are chosen in some multi-experienced children, failing previous therapy and probably with no in-label therapeutic options available.
In our study, before the current cART, the 48% of the off-label children had a detectable VL, while, at the last check, the 80% of the patients had an undetectable VL and the 90% a CD4+ lymphocyteS count > 25%. Similar to our results, Cooke et al. found that the main reason for the off-label use of cART was the virological failure of the previous therapy. Moreover, the onset of adverse events and problems related to the administration of drugs, such as formulations unsuitable for age, respectively led in 12% and 5% of cases to the discontinuation of treatment. Adherence to the therapy is essential for its effectiveness and this is in agreement with our data, since the main drugs used off-label are fixed-combination drugs. Clay et al. meta-analysis, comparing adult patients’ adherence of single tablet regimens (STR) to multiple tablet regimens (MTR), revealed that patients on STR cART were significantly more adherent and had a better VL suppression when compared to patients on MTR . Indeed, in our study, we observed that four MTR (lopinavir/ritonavir; emtricitabine/tenofovir disoproxil; elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and abacavir/dolutegravir/lamivudine) were the most commonly used off-label drug formulations.
Since 2012 lopinavir/ritonavir is licensed for the use in children aged > 14 days, while since 2002 it was licensed for children aged > 2 years. In our dataset, the age group receiving off-label lopinavir/ritonavir was mostly represented by children aged < 12 months. Previous studies found that lopinavir/ritonavir is more effective than nevirapine, which may be one of the reasons why physician decided to start this therapy . However, since cases of lopinavir/ritonavir cardiotoxicity (complete heart block and cardiomyopathy) have been reported in infants, caution is recommended when using this drug . No cardiac adverse event in young children was reported in our dataset. What we can observe instead, is a good therapeutic success, demonstrated by the fact that 100% of children receiving off label lopinavir/ritonavir had a CD4+ T lymphocytes percentage at last check-up > 25% and 90% had an undetectable viremia.
For what concerns elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, the age most involved by their off-label use was 8–11 years; in our cohort, 100% of off-label patients the last VL was undetectable and the CD4+ T lymphocytes percentage > 25%. In the same age group, we also find off-label use for abacavir/dolutegravir/lamivudine. In these children an undetectable VL at the last check was reached in the 87.7% of patients and undetectable and CD4+ T lymphocytes percentage > 25% in the 87.5% of them.
Regarding emtricitabine/tenofovir disoproxil, the age most involved by off-label use was 11–14 years, (the drug has to be considered off label when used in children aged 14 years since when these children started the therapy it was approved > 18 years). At the last check the VL was undetectable in the 81.8% and CD4+ T lymphocytes percentage > 25% in the 81.8%.
In our sample, a 10 years old child received an off-label treatment with rilpivirine, emtricitabine and tenofovir disoproxil. Before the current therapy the patient had a detectable viral load, while at the last check the VL was undetectable. No adverse event was reported for this patient. A previous multicentre study that enrolled 17 children and adolescents with perinatal HIV-1 infection from 2013 to 2015 demonstrated the efficacy of off-label use of rilpivirine in combination with emtricitabine and tenofovir disoproxil, as children showed good control of the infection, improved CD4+ T lymphocytes count and CD4+/CD8+ T lymphocytes ratio .
Our data suggest similar proportion of virological and immunological success at last check among children receiving off- or on-label cART. No adverse event to off-label ARV drug was reported in our dataset.
The potential limitations of our study lie in its retrospective design. In addition, even if no adverse event related to the use of off-label ARV drug was reported we may not exclude an underreporting bias. Finally, we could not explore the risk of prescription of not-corrected dose in children receiving an off-label regimen, due to a large proportion of missing data regarding body weights.
In a previous study more than 10% of children treated with an off-label prescription received an overdose and a further 10% received an underdose, defined as the administration of a 25% dose respectively above or below the recommended dose . A previous multi-centre cohort study from Ireland and UK, including 615 children aged 2–12 years and treated with cART, showed that children receiving a dose less than 90% of the recommended dose accounted for 6–62% of the study population .