key: cord-0032144-9v91eygq
authors: Trøseid, Marius; Hentzien, Maxime; Ader, Florence; Cardoso, Sandra Wagner; Arribas, Jose R.; Molina, Jean-Michel; Mueller, Nicolas; Hites, Maya; Bonnet, Fabrice; Manuel, Oriol; Costagliola, Dominique; Grinsztejn, Beatriz; Olsen, Inge Christoffer; Yazdapanah, Yazdan; Calmy, Alexandra
title: Immunocompromized patients have been neglected in Covid-19 trials: A call for action
date: 2022-05-25
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2022.05.005
sha: 6479163d7b95a8f0cbc5f332d22dface32988a49
doc_id: 32144
cord_uid: 9v91eygq

nan

Although several innovative and repurposed drugs have been approved for the treatment of Covid-19 during the last year, we still do not have evidence-based knowledge on the best therapeutic strategy to treat immunocompromised patients. Most treatment guidelines are structured to whether the disease state is mild, moderate or severe, and not sufficiently according to host factors including host immunity.

Whereas the omicron variant causes less severe diseases in the general population, this is not necessarily the case for individuals with an impaired immune system, such as organ transplant recipients, patients with hematological malignancies 1 , active cancer or primary immunodeficiency, or individuals treated with immunosuppressive drugs for a variety of medical conditions. In addition, the disease is not self-limited in this population and includes an increased mortality risk: the course of the disease is unpredictable, non-linear and often involves multiple episodes or protracted SARS-COV-2 detection and treatment attempts. Persistence of SARS-CoV-2 replication in immunosuppressed patients despite the use of antiviral treatments can lead to virus evolution and accumulation of resistance mutations 2 as well as the possibility of generation of new variants of concern 3 . The lack of evidence and guidelines is a consequence of almost absent inclusion of immunocompromised patients in registration clinical trials. As shown in Table 1 , only 5% immunocompromised patients were included in the PINE-TREE trial on remdesivir 4 , less than 1% in the the EPIC-HR trial on nirmatrelvir/ritonavir 5 , and completely excluded from the COMET-ICE trial on sotrovimab 6 . Moreover, for immunomodulators such as tocilizumab and baricitinib, immunocompromized patients have been largely excluded from trials due to safety concerns. As a consequence, and as a paradox, current treatment algorithms for immunocompromised patients with the omicron variant are largely based on superimposed results from trials performed on immunocompetent patients from the pre-omicron era.

Several questions require urgent response: 1. Is the antiviral or clinical effect of antiviral monoclonal antibodies (mAbs) and direct acting antivirals (DAA) reduced in immunocompromised patients? 2. Could this lead to suboptimal treatment efficacy and increased risk of antiviral resistance and persistent shedding? 3. If so, could this partially or fully be overcome by increasing the treatment duration of DAAs, increasing the dosage of mAbs or combining two or more of these treatments? 4. Is enhanced immuno-suppression a wise strategy in already immunocompromised patients, or is the risk of invasive bacterial and fungal superinfections too high? 5. Finally, how should we individualize treatment decisions in a heterogeneous population with very different risk profiles?

Immunocompromised individuals have been under-represented in trials, but are likely to be overrepresented among patients with severe or persisting symptoms due to SARS-Cov2, as they have impaired response to vaccination 7 . Unfortunately, long-acting monoclonal antibodies for passive immunization are not available in many countries, whereas in some countries where those options are available, hospitals have been using a lottery system to allocate scarce COVID-19 drugs to these patients 8 . With the widespread increase of the omicron variants being increasingly resistant to most existing antiviral mAbs 9 , immunocompromised individuals have even less options for treatment or prevention. In addition, administration of oral nirmatrelvir/ritonavir to certain sub-groups such as organ transplant recipients is difficult because of drug-drug interactions 5 .

Consequently, there is an urgent need for more robust knowledge on how to treat this large and neglected group of patients. First, ongoing clinical trials, including platform trials, should prioritize the inclusion of these patients, with well-defined sub-groups and relevant primary or core secondary endpoints. For immunomodulators this could be safety, whereas viral clearance and resistance mutations could be relevant endpoints when testing antivirals. Innovative design should be implemented for testing various drug combinations, and given the heterogeneity of conditions in immunocompromised individuals, basket trials as in oncology to assess targeted therapies could also be an option. Finally, collaboration between trials running similar arms should be encouraged to generate evidence more rapidly. As this kind of research will be the responsibility of academic researchers, access J o u r n a l P r e -p r o o f to both funding and drugs 10 are critical to allow such studies to be implemented with great urgency. We hereby urge relevant trials, funders and drug companies to respond to this call for action, so that together, we can fill the knowledge gaps and improve the care for a large and neglected patient group.

MT has participated in Eli Lilly`s European advisory board on COVID-19 therapeutics pro bono. BG has received consulting fees from Janssen and payment or honoraria from Janssen, Merck and MSD. JMM has received grants from Gilead and consulting fees from Gilead, ViiV and Merck. NJM has received consulting fees from Takeda and MSD, and support for attending meetings from Biotest. MHe has received payment or honoraria from ViiV and Gilead, and support for attending meetings from ViiV, Gilead, Menarini and Pfizer. MHi has received honoraria and travel support from Pfizer and Gilead. DC has received Grant from Janssen (payed to Inserm), and payment for lectures from Gilead and Pfizer.

JRA has received consulting fees from MSD, Serono, Astra Zeneca, Pfizer, GSK, Lilly and Sobi, and payment or honoraria from MSD and GSK. AC has received research grant from MSD and meeting support from MSD, AbbVie, Gilead, ViiV.

MT and AC drafted the first version of the manuscript. All co-authors critically reviewed and approved the final version of the manuscript.

J o u r n a l P r e -p r o o f 

Section of Clinical Immunology and Infectious diseases

Département des Maladies Infectieuses et Tropicales

De Pesquisa Clinica DST/AIDS, Instituto Nacional de Infectologia Evandro Chagas

Infectious Diseases Department

Lausanne University Hospital (CHUV)

Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report

SARS-CoV-2 evolution during treatment of chronic infection

Early remdesivir to prevent progression to severe Covid-19 in outpatients

Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19

Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab

Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis

COVID drug for the immunocompromised, is in short supply : Shots -Health News : NPR

Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2

The EU-RESPONSE project has received funding from the EU Horizon 2020 Research and Innovation programme, under the grant number 101015736.

Gottlieb et al 2022 4 Hammond et al 2022 5 Gupta et al 2021 6 RRR: relative risk reduction