COVID-19: Beware Remdesivir Resistance

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Hogan and colleagues reported two immunosuppressed renal transplant recipients with persistent SARS-CoV-2 infection in association with the new emergence of mutations in ribonucleic acid (RNA)-dependent RNA polymerase after remdesivir treatment.

SOURCE: Hogan JI, Duerr R, Dimartino D, et al. Remdesivir resistance in transplant recipients with persistent COVID-19. Clin Infect Dis 2022;ciac769. doi: 10.1093/cid/ciac769. [Online ahead of print].

A patient in the seventh decade of life received five days of therapy with remdesivir for COVID-19 (Omicron B.1.529 subvariant BA.1.1) with clinical improvement but required readmission with symptom recurrence 24 days later. Infection with BA.1.1 was again identified, and sequencing comparison to his originally recovered virus identified a new mutation, V7921 (G15814A), in the viral ribonucleic acid (RNA) dependent RNA polymerase (RdRp). He had a protracted course with development of Epstein-Barr virus-positive diffuse large B-cell lymphoproliferative disorder. One hundred ten days after the initial COVID-19 diagnosis, the patient had new-onset cough and rhinorrhea and again was found to be infected with BA.1, but with a new mutation in RdRp at K890 (as well as two other mutations). His symptoms gradually resolved, but, at day 153, polymerase chain reaction (PCR) still was positive, although with a high cycle threshold of 34.1.

A patient in his/her 50s received a three-day course of remdesivir (and five-day course of baricitinib) for COVID-19 occurring 14 months after renal transplantation, with improvement but with recurrence of symptoms leading to readmission 18 days later. Remdesivir and methylprednisolone were administered (as well as voriconazole for possible pulmonary aspergillosis), with eventual clinical improvement and hospital discharge. Sequencing of the patient’s virus at day 32 identified a de novo V7921 mutation in RdRp, as well as two other mutations.

COMMENTARY

Remdesivir is a prodrug of a nucleoside analog that, after conversion to the active triphosphate, inhibits viral RdRp activity. The V7921 RdRp mutation that emerged in these patients increases the remdesivir half maximal effective concentration (EC50) by only 2.6-fold, but this may be increased further by additional mutations.¹ While this mutation is extraordinarily rare in the general population, V7921 has been reported with greater frequency in immunocompromised patients.¹

In addition to these cases, Ghandi and colleagues previously reported an immunocompromised patient with recrudescence of infection after remdesivir treatment in association with emergence of a new mutation in E802D, in the nsp12 RNA-dependent RNA polymerase.² This mutation was associated with a six-fold increase in remdesivir half maximal inhibitory concentration (IC₅₀).²

Rebound of symptoms with persistence of detectable SARS-CoV-2 may occur in immunocompetent patients. While this is reported most often with Paxlovid treatment, it may occur after administration of other drugs, including remdesivir, and may occur in the absence of any antiviral therapy. A small number of reports of examination of rebounding virus after Paxlovid therapy indicate that resistance to this antiviral had not emerged.

Persistent SARS-CoV-2 infection in severely immunocompromised patients despite antiviral treatment is not a rare event. The report here suggests that, in some remdesivir-treated cases, this may be associated with viral mutations that impair the activity of this antiviral, although the degree of reduction in susceptibility associated with the described mutations is limited and, in fact, may prove to not be clinically relevant. Nonetheless, these observations make ongoing surveillance for antiviral resistance a necessity. Fortunately, alternative antiviral therapies are available.

REFERENCES

Wilkinson SA, Richter A, Casey A, et al; The COVID-19 Genomics UK (COG-UK) consortium. Recurrent SARS-CoV-2 mutations in immunodeficient patients. Virus Evol 2022;8:veac050.
Gandhi S, Klein J, Robertson AJ, et al. De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report. Nat Commun 2022;13:1547.