Immunocompromised Patients With Persistent COVID-19 Can Harbor Drug-Resistant Variants Following Treatment

Immunocompromised individuals persistently infected with SARS-CoV-2, the virus that causes COVID-19, could harbor drug-resistant variants after continued treatment with antivirals remdesivir (Veklury; Gilead Sciences) and nirmatrelvir-ritonavir (Paxlovid; Pfizer), which could potentially spread throughout the general population.¹

Mutations in the SARS-CoV-2 virus. | Image credit: © catalin | stock.adobe.com

Drug-resistant strains of SARS-CoV-2 were isolated from individuals who hadn’t cleared the virus following 2 to 3 months of infection and treatment. These results, discovered by investigators at Weill Cornell Medicine, Cornell University, and the National Institute of Allergy and Infectious Diseases, could signify major challenges for future control of COVID-19 and management of the disease.²

“The risk in emerging mutations is the possibility of transmitting these new resistant variants to the general population with fewer viable treatment options available,” Mirella Salvatore, MD, co-senior author of the study, said in a news release. “We have to come up with better treatments for immunocompromised patients and consider investigating combinations of therapies.”²

Those who are immunocompromised not only have more severe infection outcomes compared with the general population, but the persistent nature of their infection also leads to long-term shedding of the virus. This, coupled with long-term viral replication that contributes to the emergence of new variants, represent a public health concern^.1

The effectiveness of treatments like remdesivir and nirmatrelvir-ritonavir are decreased in immunocompromised patients, who often need repeated and sustained treatment, and can lead to drug-resistant mutations forming. In this study, the investigators examined 15 immunocompromised patients who received 1 or more courses of antiviral therapy over the course of their infection for the emergence of variant mutations.¹

Prolonged infection was determined to be a duration of 28 to 190 days. All patients in the study received 1 or more courses of remdesivir, while 3 patients also received a course of nirmatrelvir-ritonavir. Drug-resistant mutations were identified through analysis of nsp5, the target of nirmatrelvir, and nsp12, the target of remdesivir.¹

Nine patients had developed variants of the virus with nsp12 mutations while 4 had viruses with nsp5 mutations. Although most of these were collected at single time points and present at low frequencies, in 3 patients, nsp12 mutations were detected at multiple time points post-treatment and became the dominant variant in the virus population, 1 patient who was also treated with nirmatrelvir-ritonavir carried viruses with nsp5 mutations as well. They were detected at multiple collection points and presented as major variants, which the study authors determined as a possible emergence of a multi-drug-resistant SARS-CoV-2 variant.¹

“For the first time, we isolated virus from a patient’s nose 77 days after disease onset that was resistant to Paxlovid and also to remdesivir,” Salvatore said. “It is concerning that some of these patients may have viable virus in their nasal secretions so far into the disease.”²

The investigators aimed to see whether the combination of nirmatrelvir and remdesivir treatment in vitro could be effective against the multi-drug-resistant variant as it presented decreased sensitivity to each therapy administered separately. Combination treatment resulted in a stronger inhibition of virus replication, which the investigators said indicated its additive effects.¹

Diego Diel, MD, said in the news release that “these findings indicate that combination therapy may be a better option to treat COVID-19 in highly vulnerable immunocompromised patients.”²

Spread of these mutated strains should not be discounted since in vitro testing demonstrated that the strain had “no apparent loss of replication fitness” compared to wild-type virus levels. Furthermore, the decreased sensitivity these strains hold to antiviral treatment “may delay viral clearance and complicate the outcome of SARS-CoV-2 infection” in those who are immunocompromised.¹

“These results also highlight the need for enhanced infection control measures in these patient populations to prevent transmission of potentially antiviral-resistant viruses to the general population,” the study authors concluded.¹

REFERENCES

1. Nooruzzaman M, Johnson K E E, Rani R, et al. Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections. Nat Commun. 2024;15:7999. doi:10.1038/s41467-024-51924-3

2. Weill Cornell Medicine Newsroom. Antiviral-resistant variants of SARS-CoV-2 can emerge in immunocompromised people. News Release. Released September 18, 2024. Accessed September 19, 2024.