Remdesivir resistance in kidney transplant patients with long COVID-19

Scientists have worked to protect individuals from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Invented a new pharmaceutical and non-pharmaceutical strategy.

Despite their efforts to contain the disease, the emergence of new SARS-CoV-2 mutants around the world has prolonged the pandemic.

Background

A recent meta-analysis involving approximately 12,000 solid organ transplant (SOT) recipients showed a significant reduction in the humoral response induced by COVID-19 vaccination in the study group compared to immunocompetent hosts. did. This finding indicates that vaccination reduced the incidence of severe COVID-19 disease in the majority of immunocompetent hosts, but did not significantly protect SOT recipients from potentially fatal infections. I am.

Remdesivir, a prodrug of the nucleoside analog GS-441524, effectively inhibits the function of RNA-dependent RNA polymerase (RdRps) in multiple RNA viruses. It was the first drug approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19.

Recently, researchers have reported cases of remdesivir resistance in patients with persistent SARS-CoV-2 infection. The patient was also treated with rituximab and bendamustine for lymphoma. Few studies address the issue of resistance to COVID-19 treatment during treatment.

New research

New research currently posted Research Square* The preprint server reported two cases of kidney transplantation in which individuals developed resistance to the drug after exposure to remdesivir. this is, Also V792I RNA-dependent RNA polymerase (RdRp) mutation.

The first patient to undergo a kidney transplant was 60 years old and had a history of diabetes, vascular disease, and hypertension. The patient underwent a dead donor kidney transplant (DDKT) after reaching end-stage renal disease (ESRD). Scientists reported that the patient had been vaccinated twice with the COVID-19 vaccine (BNT162b2) prior to transplantation. Prior to transplantation, patients were exposed to immunosuppressive drugs such as basiliximab and methylprednisolone.

Clinicians observed elevated levels of anti-A titers in blood group B recipients, resulting in a rapid transition of patients from basiliximab to anti-thymocyte globulin (ATG). Six months after transplantation, after making some changes to the treatment process, patients tested positive for SARS-CoV-2 with a cycle threshold (Ct) of 27.1.

Genomic sequencing showed that the patient was infected with the Omicron variant. The patient was treated with a 5-day course of remdesivir and showed improvement in symptoms.However, 24 days after the initial diagnosis of COVID-19 infection, the patient worsened and required readmission. COVID-19 Symptoms And it showed Ct of 24.4. After another course of remdesivir (5 days) and dexamethasone (10 days) Also The RdRp mutation V792I (G15814A) was observed.

The patient was also diagnosed with Epstein-Barr virus (EBV) -positive diffuse large B-cell lymphoma (DLBCL), consistent with monomorphic post-transplant lymphoproliferative disorder (PTLD), thereby initiating chemotherapy. it was done. Patients tested positive for SARS-CoV-2 110 days after the initial diagnosis of COVID-19 with Ct of 22.6. Also A synonymous mutation in RdRp was identified in K890.

The second patient to undergo a kidney transplant was 50 years old and had a history of diabetes, splenectomy, and vascular disease. Like the first patient, the second patient was vaccinated twice with the COVID-19 vaccine (mRNA-1273). The patient was also exposed to immunosuppressants (methylprednisolone and ATG) and various other drugs.

The second patient tested positive for SARS-CoV-2 14 months after transplantation and was treated with a course of remdesivir (3 days) and baricitinib (4 days).The clinician Also V792I (G15814A) mutation of RdRp. The patient responded well to treatment and was discharged immediately. However, 18 days after the diagnosis of COVID-19, he was readmitted because the symptoms of SARS-CoV-2 worsened. The Ct score this time is 17.4, Also With mutations in nsp14 exonucleases Spike protein The area was observed.

Implications

Current studies have shown that both patients suffer from long-term COVID-19 infection, despite being vaccinated. Ineffective immune clearance is responsible for persistent viral replication in immunocompromised hosts. This condition also increases the likelihood of viral mutations.

When kidney transplant patients infected with SARS-CoV-2 infection were exposed to remdesivir due to extensive immunodeficiency, unchecked viral replication occurred for a long period of time.Both patients developed independently Also V792I replacement of ORF1ab, an open reading frame encoding nsp12. Effectiveness of Remdesivir in these patients.

In this study, the authors highlighted the risk of antigenic escape in immunocompromised hosts. In addition, they reported that viral mutations in these hosts caused remdesivir resistance. Researchers have stated that timely identification, treatment, and limitation of spread of the mutant virus are important factors in containing the COVID-19 pandemic.

*Important Notices

Research Square publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information. ..