Exploring remdesivir resistance in COVID-19-infected transplant recipients

A recent study published in the Clinical Infectious Diseases journal assessed the remdesivir resistance developed in coronavirus disease 2019 (COVID-19)-infected transplant recipients.

Background

Proactive therapy is necessary for patients needing hospitalization due to the significant risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in solid organ transplant (SOT) recipients. Remdesivir, a prodrug of the nucleoside analog GS-441524, is the first Food and Drug Administration (FDA)-approved direct-acting antiviral for the treatment of COVID-19. It suppresses viral ribonucleic acid (RNA)-dependent RNA polymerase (RdRp) activity.

Recently, a patient who underwent a prolonged course of COVID-19 while being treated with rituximab and bendamustine for lymphoma was found to have developed remdesivir resistance. It is uncertain how often clinically significant mutations are in the community and the likelihood that patients would become resistant to COVID-19 therapies while undergoing treatment.

Characteristics of case 1

In the present study, researchers assessed the first instances of a V792I RNA-dependent RNA polymerase mutation emerging in renal transplant recipients following remdesivir exposure.

Case 1 was a patient with end-stage renal disease (ESRD) in their 60s who had a history of diabetes and had undergone a deceased donor kidney transplant (DDKT). The patient was treated with two doses of the BNT162b2 vaccine before the transplant. Basiliximab and methylprednisolone were used as induction immunosuppressive agents. Anti-thymocyte globulin (ATG), plasmapheresis, and maintenance immunosuppression with prednisone, mycophenolate, and belatacept was used to treat the patient. The patient started experiencing malaise, fever, and cough six months after the transplant.

SARS-CoV-2 was detected by reverse transcription–polymerase chain reaction (RT-PCR) at the time of admission. The SARS-CoV-2 B.1.529 (Omicron) subvariant BA.1.1 was discovered by genomic sequencing. The patient was prescribed a five-day course of remdesivir and was discharged after symptomatology improvement was observed. The patient was re-hospitalized with exhaustion, cough, dyspnea, stomach pain, and fever 24 days following the initial COVID-19 diagnosis. SARS-CoV-2 RT-PCR was positive, and Omicron BA.1.1 was detected through sequencing. The patient was treated with a second five-day course of remdesivir and a 10-day treatment of dexamethasone in the presence of a significant oxygen requirement.

The de novo RdRp mutation V792I was discovered 38 days after the first COVID-19 diagnosis via genomic analysis. Following admission, a computed tomography (CT) scan revealed a pleural effusion as well as mass-like soft tissue infiltration with the renal graft. Several cycles of antineoplastic therapy, comprising cyclophosphamide, rituximab, doxorubicin, prednisone, and vincristine were administered to the patient. Administration of belatacept and mycophenolate was terminated since the patient's condition worsened and approached ESRD. The patient's cough, fever, and hypoxemia vanished throughout the course of a three-month stay. The Epstein-Barr virus (EBV) viral load was also sharply reduced, and interval reimaging revealed a minor kidney graft with accompanying lymphadenopathy.

SARS-CoV-2 nucleocapsid immunoglobulin (Ig)-G was found three months after the initial COVID-19 diagnosis; the Ct increased while the patient showed no signs of active respiratory infection symptoms. A fresh dry cough and rhinorrhea appeared in the patient 110 days after COVID-19 was diagnosed, and RT-PCR revealed the presence of SARS-CoV-2. At that time, genomic sequencing discovered a de novo synonymous mutation in RdRp at K890. The patient's minor symptoms subsided over many weeks, and no additional care was required. During the prolonged course of the patient's infection, two further de novo non-synonymous mutations in non-structural protein (nsp)-6 and open reading frame (orf)-3 were also found.

Characteristics of case 2

Case 2 was a 50-year-old patient who underwent DDKT to treat ESRD and had a history of diabetes and splenectomy. The patient was immunized with two doses of messenger RNA (mRNA)-1273 vaccine before the transplant. Methylprednisolone and ATG were prescribed for the patient's initial immunosuppression, and prednisone, mycophenolate, and tacrolimus were administered after. Delayed graft function (DGF) suggested empiric methylprednisolones. After the transplant, the patient experienced coughing, dyspnea, and general malaise for 14 months. SARS-CoV-2 was detected by RT-PCR, but no samples were available for sequencing.

The patient improved after receiving a three-day treatment of remdesivir along with a four-day course of baricitinib for pulmonary infiltrates and hypoxemia. The patient was re-hospitalized 18 days after being diagnosed with COVID-19 and displayed a worsening cough, hypoxia, and SARS-CoV-2 positivity. An X-ray showed spotty infiltrates that were getting worse. As a result of the patient's need for high-flow oxygen, a CT scan revealed many cavitary lung lesions. Methylprednisolone with a five-day course of remdesivir was used to treat the patient. Voriconazole was provided to treat pulmonary aspergillosis based on raised galactomannan levels in bronchoalveolar lavage, and high dosage corticosteroids were administered to treat biopsy-confirmed organizing pneumonia.

On day 25 of the illness, genomic sequencing revealed a de novo V792I mutation in RdRp. On day 32, de novo mutations in the SARS-CoV-2 spike protein and nsp14 exonuclease were also discovered. Eventually, the patient's symptoms improved, the hypoxia cleared up, and the patient was discharged.

Overall, the study highlighted the need for surveillance efforts to identify alterations in immunocompromised individuals as the findings demonstrated the presence of mutations associated with remdesivir resistance in vivo.