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

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.

Bulevirtide als erster spezifischer Wirkstoff gegen Hepatitis-D-Virusinfektionen – Mechanismus und klinische Wirkung

ZusammenfassungDie Blockade des Zelleintritts von Krankheitserregern ist ein geeigneter Ansatz, um Neuinfektionen zu verhindern. Der therapeutische Einsatz von Eintrittsinhibitoren bei chronisch infizierten Patienten war jedoch bisher nur begrenzt erfolgreich. Zur Behandlung von chronischen Hepatitis-D-Virus-(HDV-)Infektionen wurde im Juli 2020 mit Bulevirtide (BLV) ein vielversprechender Wirkstoff bedingt zugelassen, der auf diesem Wirkprinzip beruht. Zuvor hatten für HDV keine gezielte Medikation zur Verfügung gestanden und die Behandlung beruhte auf dem Off-Label-Einsatz von Interferon-Alpha/Peginterferon-Alpha (IFNα/Peg-IFNα). In diesem Beitrag wird ein Überblick über die Grundlagen des Wirkmechanismus von BLV gegeben und bisher vorliegende klinische Daten werden zusammengefasst.Eine HDV-Infektion manifestiert sich als Ko- oder Superinfektion bei Hepatitis-B-Virus-(HBV-)Infektionen und betrifft 4,5–15 % der HBV-Patienten weltweit. HDV nutzt die Hüllproteine von HBV zur Verbreitung. BLV wirkt, indem es den HBV/HDV-Rezeptor natriumtaurocholat-co-transportierendes Polypeptid (NTCP) blockiert und so den Eintritt von HBV/HDV in Hepatozyten verhindert. BLV senkt die HDV-Serum-RNA-Spiegel und führt bei HBV/HDV-infizierten Personen zur Normalisierung der Alanin-Aminotransferase-(ALT-)Werte. Es hat ein ausgezeichnetes Sicherheitsprofil, selbst wenn es über 48 Wochen in hohen Dosen (10 mg täglich) verabreicht wird. In Kombination mit Peg-IFNα zeigt BLV synergistische Effekte auf die Senkung der HDV-RNA im Serum, aber auch auf die Hepatitis-B-Oberflächenantigen-(HBsAg‑)Spiegel. Dies führte bei einer Untergruppe von Patienten zu einer funktionellen Heilung, wenn 2 mg BLV plus Peg-IFNα verabreicht wurden. Der Mechanismus dieser wahrscheinlich immunvermittelten Eliminierung wird in Folgestudien untersucht.

Use of Rituximab as an off-Label medication in Glomerular Diseases: Clinical Perspective

Objectives: We review rituximab (RTX) use and outcomes in immune-mediated glomerular diseases (GN) and compare it to established literature. Methods: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with literature supporting RTX use. Lupus nephritis (LN), 1o focal segmental glomerulosclerosis (1o FSGS), IgA nephropathy (IgAN), IgG4 related disease, and C3GN had insufficient literature support for RTX use. Clinical Remission was assessed six months after receiving RTX. Results: A total of 61 cases analyzed. RTX was an add on therapy in 87%. Remission rate was 95% in MCD and MN vs. 56 % in off-label group (P=.002). LN patients had a mean initial eGFR of 69mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. Mean initial eGFR for 1o FSGS was 33mL/min and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-related disease cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission achieved in only 2 ANCA vasculitis cases, and none in IgA vasculitis cases. Conclusion: Our data support RTX use in resistant MCD and MN. RTX showed success in LN and IgG4 related disease, but not FSGS or C3GN. The small vasculitis cases number does not allow drawing a conclusion on RTX effectiveness.

Neuromodulation in 2035

Neuromodulation devices are approved in the United States for the treatment of movement disorders, epilepsy, pain, and depression, and are used off-label for other neurologic indications. By 2035, advances in our understanding of neuroanatomical networks and in the mechanism of action of stimulation, coupled with developments in material science, miniaturization, energy storage, and delivery, will expand the use of neuromodulation devices. Neuromodulation approaches are flexible and modifiable. Stimulation can be targeted to a dysfunctional brain focus, region, or network, and can be delivered as a single treatment, continuously, according to a duty cycle, or in response to physiologic changes. Programming can be titrated and modified based on the clinical response or a physiologic biomarker. In addition to keeping pace with clinical and technological developments, neurologists in 2035 will need to navigate complex ethical and economic considerations to ensure access to neuromodulation technology for a rapidly expanding population of patients. This article provides an overview of systems in use today and those that are anticipated and highlights the opportunities and challenges for the future, some of which are technical, but most of which will be addressed by learning about brain networks, and from rapidly growing experience with neuromodulation devices.

Less invasive treatments for pure aortic insufficiency: Are we there yet?

The gold standard for the treatment of pure aortic insufficiency (PAI) is surgical valve repair or replacement.1 With the newest transcatheter heart valve technologies and the accumulating years of experience of heart teams with the current transcatheter aortic valve replacement (TAVR) prostheses, implanters have push the envelope with off-label use of those valves designed and approved for aortic stenosis, in patients with pure aortic insufficiency especially those at higher risks or for compassionate use.3 However, new prostheses are currently under investigation in clinical use and evidences are provided on the safety and efficacy of those latter. It will be discussed in this commentary, the actual clinical evidences and the use of transcatheter heart valves, in and off label, for the treatment of pure aortic insufficiency.

Future of anti-VEGF: biosimilars and biobetters

The advent of Anti- VEGFs like Lucentis (Ranibizumab), Eylea (Aflibercept) and off-label Avastin (Bevacizumab) have radically improved visual outcomes in patients of neovascular Age Related Macular Degeneration (nARMD), Diabetic Macular Edema (DME) and Retinal Vein Occlusion (RVO). It is a matter of great concern that the US patents for Ranibizumab and Aflibercept expired in 2020 with European patents to expire in 2022 and 2025, respectively. With the expiry of these biologics, Biosimilars can prove to be saviours in the posterior segment pharmacotherapy owing to their cost effectiveness and availability of various options. Numerous biosimilars are expected to gain approval for clinical use from the US-FDA and EMA soon. Biobetters are better than the original biologic in one or more parameters but require more research and development resources. With the emergence of better manufacturing and purification processes it is imperative that the biologics and biosimilars become better. The Ophthalmologists need to have in depth knowledge about these Biosimilars and Biobetters before these molecules take over the mainstream market.

Portal Steal Syndrome From a Large Linton’s Splenorenal Shunt after Liver Transplantation: Successful Endovascular Management Through Off-Label Application of a 30 mm Amplatzer Cardiac Plug

A 34-year-old patient underwent liver transplantation for progressive hepatic failure in the setting of congenital hepatic fibrosis. In past medical history, the patient had undergone splenectomy with proximal Linton’s splenorenal surgical shunt creation for symptomatic portal hypertension with hypersplenism. The patient developed an early allograft dysfunction, with radiologic evidence of a reduced portal flow associated to portal steal from the patent surgical shunt. The patient was successfully treated through endovascular placement of a 30 mm Amplatzer cardiac plug at the origin of the splenic vein.