Investigating Remdesivir Resistance in Transplant Recipients Infected with COVID-19

September 29, 2022

A recent study published in clinical infection The journal evaluated remdesivir resistance that developed in transplant recipients infected with coronavirus disease 2019 (COVID-19).

Background

Due to the high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in solid organ transplant (SOT) recipients, patients requiring hospitalization require aggressive treatment. Remdesivir, a prodrug of the nucleoside analogue GS-441524, is the first direct-acting antiviral drug approved by the Food and Drug Administration (FDA) for the treatment of COVID-19. Inhibits viral ribonucleic acid (RNA)-dependent RNA polymerase (RdRp) activity.

Recently, it was found that a patient who had a long course of COVID-19 while being treated with rituximab and bendamustine for lymphoma developed remdesivir resistance. It is unknown how often clinically important mutations are present in the community and how likely the patient will become resistant to her COVID-19 treatment during treatment.

Features of Case 1

In the present study, investigators evaluated the first example of a V792I RNA-dependent RNA polymerase mutation that emerges in renal transplant recipients after exposure to remdesivir.

Case 1 was a 60s patient with end-stage renal disease (ESRD) who had a history of diabetes and had undergone cadaveric kidney transplantation (DDKT). The patient received her BNT162b2 vaccine twice before transplantation. Basiliximab and methylprednisolone were used as induction immunosuppressants. Antithymocyte globulin (ATG), plasmapheresis, and maintenance immunosuppression with prednisone, mycophenolic acid, and belatacept were used to treat the patient. The patient began experiencing malaise, fever, and cough 6 months after her transplant.

SARS-CoV-2 was detected by reverse transcription-polymerase chain reaction (RT-PCR) on admission. SARS-CoV-2 B.1.529 (Omicron) subvariant BA.1.1 was discovered by genome sequencing. The patient was discharged from the hospital after remdesivir was prescribed to him for 5 days and an improvement in symptoms was observed. The patient was readmitted with fatigue, cough, dyspnea, stomach pain, and fever 24 days after she was first diagnosed with COVID-19. SARS-CoV-2 RT-PCR was positive and sequencing detected Omicron BA.1.1. The patient was treated with her 5-day second course of remdesivir and her 10-day treatment with dexamethasone in the presence of significant oxygen demand.

of Also The RdRp mutation V792I was discovered 38 days after the initial COVID-19 diagnosis by genomic analysis. After admission, a computed tomography (CT) scan revealed pleural effusion and massive soft-tissue infiltration by the renal graft. The patient received several cycles of antineoplastic therapy including cyclophosphamide, rituximab, doxorubicin, prednisone, and vincristine. Belatacept and mycophenolic acid were discontinued as the patient’s condition deteriorated and approached ESRD. The patient’s cough, fever, and hypoxemia resolved during the 3-month stay. Epstein-Barr virus (EBV) viral load also decreased sharply, and interval reimaging revealed a small renal graft with lymphadenopathy.

SARS-CoV-2 nucleocapsid immunoglobulin (Ig)-G was discovered three months after the initial diagnosis of COVID-19. Although the Ct was elevated, the patient showed no signs of active respiratory infection. He presented the patient with a fresh dry cough and nasal discharge 110 days after being diagnosed with COVID-19, and RT-PCR revealed the presence of SARS-CoV-2. At that time, genome sequencing Also Synonymous mutation of RdRp at K890. The patient’s mild symptoms resolved over the course of weeks and required no additional care.In the course of the patient’s prolonged infection, two additional Also Non-synonymous mutations in nonstructural protein (nsp)-6 and open reading frame (orf)-3 were also found.

Features 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 received two doses of the messenger RNA (mRNA)-1273 vaccine before transplantation. Methylprednisolone and ATG were prescribed for the patient’s initial immunosuppression, followed by prednisone, mycophenolic acid, and tacrolimus. Graft function delay (DGF) suggested empirical methylprednisolone. After transplantation, the patient experienced cough, dyspnea, and general malaise for 14 months. SARS-CoV-2 was detected by her RT-PCR, but no samples were available for sequencing.

The patient improved after 3 days of treatment with remdesivir and a 4-day course of baricitinib for pulmonary infiltrates and hypoxemia. The patient was readmitted 18 days after she was diagnosed with COVID-19 and presented with worsening cough, hypoxia, and SARS-CoV-2 positivity. X-ray showed a worsening patchy infiltrate. A CT scan revealed many cavitary lung lesions as a result of the patient’s need for high-flow oxygen. The patient was treated with her 5-day course of methylprednisolone and remdesivir. Voriconazole is offered to treat pulmonary aspergillosis based on elevated galactomannan levels in the bronchoalveolar lavage fluid, and high-dose corticosteroids are offered to treat biopsy-confirmed organizing pneumonia. was administered.

On day 25 of illness, genome sequencing revealed Also V792I mutation in RdRp. On the 32nd day, Also Mutations in SARS-CoV-2 spike protein and nsp14 exonuclease were also found. Eventually, the patient’s symptoms improved, hypoxia resolved, and the patient was discharged.

Overall, the findings demonstrated the presence of mutations associated with remdesivir resistance, thus highlighting the need for surveillance efforts to identify alterations in immunocompromised patients. in vivo.