MADRID, Spain — Monoclonal antibodies are positioned as the best option against SARS-CoV-2, indomethacin synthesis reaction mainly in pre-exposure prophylaxis in adults and in patients without supplemental oxygen at high risk of progression. Although viral variants are the greatest threat to their effectiveness, in oncohematological patients, these drugs continue to be very powerful and may be combined with other therapeutic strategies.
María Jesús Peñarrubia, MD, PhD, from the University Clinical Hospital of Valladolid, Spain, and Karmele Arribalzaga, MD, from the Alcorcón Foundation University Hospital in Madrid, Spain, coordinated the COVID-19 symposium in hematology. They introduced the topic of passive immunotherapy in the prevention and treatment of SARS-CoV-2 infection, which includes anti-protein S monoclonal antibodies of the virus and convalescent patient plasma.
“Both modalities are effective if they are used early after exposure to the virus and if the infused antibodies have activity against the circulating variant at that time,” they said. They also stressed that monoclonal antibodies have also been shown to be useful in pre-exposure prophylaxis.
Rafael de la Cámara, MD, hematologist at the Princesa de la Hospital in Madrid, gave an update about passive immunotherapy in oncohematological patients. A review of 21 clinical trials (16,812 patients) conducted last year formed the basis for a strong recommendation against the use of convalescent plasma in patients with nonsevere COVID-19. The treatment also is not recommended in those with the severe-critical form of COVID-19.
The National Institutes of Health (NIH) speaks of insufficient evidence for hospitalized and immunocompetent outpatients. They are against this treatment for hospitalized patients, as well as for plasma collected before the Omicron variant.
De la Cámara pointed out that the situation has changed with the new guide from the Association for the Advancement of Blood & Biotherapies (AABB) published in August 2022, which includes data from 33 clinical trials and more than 21,900 patients. “The procedure is safe, and no cases of viral transmission have been detected,” according to the guide. “There is limited information in vaccinated patients, and there are few studies on the greater benefit in outpatients with mild COVID-19, immunocompromised [patients], and hospitalized patients without virus antibodies.”
In addition to a good clinical practice statement, the guides contain the following recommendations:
Monoclonal antibodies should be administered with standard treatment in outpatients with a high risk of progressing.
Administration is not recommended in unselected hospitalized patients with moderate or severe COVID-19.
It is not recommended for immunosuppressed patients or for patients without SARS-CoV-2 antibodies.
It is not recommended for uninfected patients in close contact with a person with COVID-19 (weak recommendation and low level of certainty).
Variants and Antibodies
Regarding monoclonal antibodies, de la Cámara said, “Their development has been very significant, so it is difficult to follow their scientific and administrative situation. In addition, their duration is shorter than with vaccines, except for the combination tixagevimab/cilgavimab, which lasts up to 6 months. Viral variants are the greatest threat to the efficacy of these antibodies, but they do not affect everyone equally, [and] combinations are better than treatment with just one.”
Of the four monoclonal antibodies authorized by the European Medicines Agency (EMA), only two are active against the omicron variant: tixagevimab/cilgavimab and sotrovimab. “With two indications for the first, pre-exposure prophylaxis in adults and a very recent indication for adults and adolescents with COVID-19 who do not require supplemental oxygen and who are at high risk of progressing to severe disease. They should be administered within the first 7 days after the onset of symptoms. The second antibody (sotrovimab) has the same second indication but is administered within the first 5 days after symptoms,” added de la Cámara.
The PROVENT study of pre-exposure prophylaxis in unvaccinated adults with negative serology and at risk of not responding to the vaccine is still in phase 3 but points to a reduction in the relative risk of symptomatic COVID-19 of almost 83%, confirmed by polymerase chain reaction testing.
De la Cámara commented on three large real-life studies with the combined antibody, saying, “It shows a lower risk of infection, hospitalization, and death in oncohematological patients and, according to the American study, it also works in vaccinated patients.”
Regarding whether an antiviral or a monoclonal antibody is better, the specialist said, “According to a UK study in Omicron outpatients with at least one risk factor and in which 88% had received three or more doses of the vaccine, treatment with sotrovimab entailed a significantly lower risk of hospitalization and death 28 days after the start of therapy, with the same result in those vaccinated vs molnupiravir therapy.
“In general, the use of antibodies is preferred if they are available, vs convalescent plasma and if they are known to be active against the predominant variant,” he concluded.
As for pre-exposure prophylaxis, the combination of tixagevimab/cilgavimab is suggested, following the current recommendations of the Spanish Ministry of Health. And regarding the treatment of mild to moderate COVID-19, sotrovimab and the combination tixagevimab/cilgavimab are indicated.
Carolina García-Vidal, MD, PhD, hematologist at the Infectious Diseases Department of the Hospital Clinic of Barcelona, Spain, provided an update on the management of immunosuppressed patients with SARS-CoV-2 infection.
“In oncohematological patients, the virus kills more than the inflammation. Mortality in these patients remains very high, around 9%, despite the Omicron variant and the high rate of vaccinated patients. The good news is that by paying attention to blood tests and starting treatment early, we can change this trend,” she said.
The specialist provided preliminary data from an ongoing study at her hospital that support these assertions about the phenotype of the hematological patient with COVID-19 by Omicron, compared with the non-hematological patient. “In the first, we see a clear effect of the virus (95%) according to the number of lymphocytes and the days of symptoms, compared with 61% in non-hematological patients. In contrast, in the former, inflammation (C-reactive protein, ferritin, and low-density lipoproteins) is present in 33% vs 68% in non-hematological patients.”
New Viral Variants
Likewise, viral persistence is much higher in these patients: 25% have viable viruses lasting 4 to 5 weeks, which was 6 to 8 weeks in the first waves. “These patients have established themselves as reservoirs that are generating new variants, and therefore we cannot leave them with persistent viruses,” added García.
On the other hand, in the absence of specific treatment guidelines for hematological patients, one of the best is the one stated in ECIL-9, “where a total change of scenario is shown thanks to antivirals.”
García concluded, “An early, personalized treatment, probably combining antiviral strategies, is necessary in patients with pneumonia. In addition, early therapy in high-risk hematological patients with oral antivirals has been associated with excellent prognosis and low viral persistence.”
Another aspect that continues to cause concern is the appearance of hypercoagulability phenomena in hospitalized COVID-19 patients. In these cases, the incidence of venous and arterial thrombosis is significantly higher than that of patients hospitalized for other reasons, so “in the absence of contraindication, all hospitalized patients should receive at least prophylactic low molecular weight heparin,” Peñarrubia and Arribalzaga pointed out.
José Antonio Páramo, MD, PhD, director of the Thrombosis and Hemostasis Unit of the Navarra University Clinic, Pamplona, Spain, described the current management of thrombotic events, according to the latest guidelines, in the different clinical scenarios of COVID-19.
“You have to treat early. We focus on antithrombotic therapy where we not only act on procoagulant factors, but also on the underlying inflammatory process,” he said, pointing out that in 2021, the New England Journal of Medicine reported that therapeutic doses of heparin increased survival and were associated with fewer days in respiratory failure in noncritical patients with thrombosis. He also pointed out that the critically ill patient should not be given therapeutic doses of heparin.
But the newest guidelines of the International Society on Thrombosis and Hemostasis (ISTH) state that the prophylactic dose of low molecular weight or fractionated heparin in hospitalized noncritical patients reduces the risk of death, and in patients without high bleeding risk, therapeutic doses can be considered, based on the results of the multiplatform study.
“What we should not do in hospitalized critical patients is to give intermediate doses. Therefore, therapeutic doses are not recommended vs prophylactic doses in these patients,” Páramo added.
Anticoagulation at Discharge?
When these patients are discharged, probably nothing needs to be done, but direct-acting oral anticoagulants may also be considered in selected patients, as pointed out by the MICHELLE study, which used rivaroxaban. A clear benefit was seen 15 to 35 days after discharge, but only in patients over age 75 with cardiovascular risk factors, impaired kidney function, IMPROVEDD score greater than four, and in patients who spent a long time in the intensive care unit.
“After discharge, in principle, no treatment works, even if patients have elevated D-dimer, as all the studies (ETHIC and OVID) show no benefit overall,” said Páramo. The American Society of Hematology (ASH) also opposes anticoagulant thromboprophylaxis at discharge, with the exceptions mentioned.
Regarding ongoing studies, Páramo highlighted the FREEDOM study, “where prophylactic doses of enoxaparin are being prospectively compared with therapeutic doses of apixaban in more than 3000 patients. Hopefully, the results will help us to ascertain which patients are better responders to these treatments.
“Up to 1 year after treatment, cardiovascular and cerebrovascular complications may appear, dysrhythmias, heart disease, and thrombotic problems are multiplied by two and three for all stages of patients, outpatients, nonserious hospitalized, and especially critical patients,” he concluded.
García has given talks sponsored by Pfizer, MSD, Gilead, GSK, Shionogi, Janssen, and Advisor and has received grants from Gilead, MSD, and Pfizer. De la Cámara and Páramo declared no relevant financial conflicts of interest.
Follow Javier Cotelo of Medscape Spanish Edition on Twitter: @Drjavico.
This article was translated from the Medscape Spanish edition.
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