Two recent studies have found that the virus that causes Covid-19 is becoming resistant to two drugs that are used to treat patients with infections, while another has suggested that a third antiviral drug used to treat patients with Covid-19 may be driving SARS-CoV-2 to mutate.
In the first, reports MedicalXpress, a combined team from Cornell University and the US National Institutes of Health studied the treatment outcomes for patients with compromised immune systems who were given remdesivir. They have published their results in Nature Communications.
In the second study, a team of researchers from the University of Pittsburgh, Brigham and Women’s Hospital, Stanford University and Harvard University studied the outcomes for Covid-19 patients given antiviral drugs over the years 2021 to 2023.
They published their results in JAMA Network Open.
Zhuo Zhou and Peng Hong, with the Chinese Academy of Medical Sciences and Peking Union Medical College and VA New York Harbour Healthcare System, respectively, published a commentary piece in the same JAMA Network Open issue outlining the work by the second team.
Treatments
In the years since the height of the pandemic, researchers have continued to study SARS-CoV-2, along with new vaccine options. They have also been working on developing new therapies for people who are infected by the virus but have not been immunised or who have compromised immune systems.
Two such therapies, named remdesivir and nirmatrelvir, have become the go-to drugs for patients with immune systems that are not capable of fighting off the virus. But because they are antivirals, they run the risk of obsolescence as the virus mutates.
In the first study, the researchers sequenced the DNA of the virus infecting 15 Covid patients and found that the virus had developed a reduced sensitivity to both remdesivir and nirmatrelvir.
They also found that the mutated viruses could infect others in the vicinity. One positive note: the researchers found that giving both antivirals to patients cleared the virus.
In the second study, the research team studied the treatment of 156 Covid-19 patients over two years. As part of that effort, the researchers divided the patients into two groups: those who had received the antiviral drugs and those who had not.
Viruses with antiviral-resistant mutations were more likely to be found in patients who had received antiviral drugs. The effect was more evident in the immunocompromised and those who had received nirmatrelvir.
Mutation
Meanwhile, other research suggests that molnupiravir may be driving SARS-CoV-2 to mutate and evolve, with some of these new viruses being transmitted onwards. It is not clear, however, whether these pose an increased risk to patients or are able to evade the vaccine, said the scientists involved in the study.
The drug works by disrupting the virus’s genome, causing it to develop random mutations as it replicates, weakening the virus to prevent replication, and thereby enabling clearance of infection.
But in their research published in Nature, the scientists show that in some cases, mutated forms of the virus have been able to be transmitted from patients treated with molnupiravir and spread within the community.
Molnupiravir, marketed under the brand name Lagevrio, is licenced for the treatment of Covid-19 in several countries, including the UK, USA and Japan. It has been used to treat the disease since late 2021.
In the body, molnupiravir is converted into a molecule that disrupts the genome of the SARS-CoV-2 virus, introducing some nucleotide mutations in its RNA – randomly changing some Cs to Ts and some Gs to As. These changes mean that as the virus replicates, its progeny get weaker, reducing how quickly the virus is able to replicate and ridding the body of the virus.
However, concern has been expressed that in some cases, a number of mutated viruses may not be killed off quickly enough and so are able to infect other individuals, potentially allowing new mutated viruses to spread.
During the pandemic, various countries, spearheaded by the University of Cambridge-led Covid-19 Genomics UK Consortium, sequenced virus samples, depositing the information in databases such as the Global Initiative on Sharing All Influenza Data (GISAID) and the International Nucleotide Sequence Database Collaboration (INSDC).
This allowed scientists and public health agencies to track the evolution and spread of the virus, and in particular to look out for so-called “variants of concern” – versions of the virus with mutations that might make them more transmissible, more lethal, or able to evade the immune system of vaccinated individuals, such as the Delta and Omicron variants.
A team of researchers from the UK and South Africa noticed a number of viral genomes that contained a large number of mutations, particularly where Cs had changed to Ts and Gs to As. While C-to-T mutations are relatively common overall in SARS-CoV-2 evolution, G-to-A mutations occur much less frequently, and a higher proportion of G-to-A mutations is associated with molnupiravir treatment.
The team then analysed a family tree of more than 15m SARS-CoV-2 sequences in the GISAID and INSDC databases looking for which mutations had occurred at each point in the virus’s evolutionary history.
They found that viruses with this signature of mutations had begun to emerge almost exclusively from 2022 onwards and in countries and age groups where molnupiravir was being widely used to treat Covid-19.
To confirm the link, the researchers examined treatment records in England and found that at least one in three of viruses showing the mutational signature involved the use of molnupiravir.
The researchers also saw small clusters of patients infected with mutated viruses, which suggests that these new viruses were being passed from one person to another. However, none of the known variants of concern has so far been linked to the use of molnupiravir.
Dr Theo Sanderson from the Francis Crick Institute, said: “Covid-19 is still having a major effect on human health, and some people have difficulty clearing the virus, so it’s important we develop drugs which aim to cut short the length of infection. But our evidence shows that molnupiravir also results in new mutations, increasing the genetic diversity in the surviving viral population.
“Our findings are useful for ongoing assessment of the risks and benefits of molnupiravir treatment. The possibility of persistent antiviral-induced mutations needs to be taken into account for the development of new drugs that work in a similar way.”
Study 1 details
Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections
Mohammed Nooruzzaman, Katherine Johnson, Ruchi Rani, Eli Finkelsztein et al.
Published in Nature Communications on 18 September 2024
Abstract
We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n = 15). All patients received remdesivir and some also received nirmatrelvir-ritonavir (n = 3) or therapeutic monoclonal antibodies (n = 4). Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient sequentially treated with nirmatrelvir-ritonavir and remdesivir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.
Study 2 details
Emerging SARS-CoV-2 Resistance After Antiviral Treatment
Trevor Tamura, Manish Choudhary, Rinki Deo et al.
Published in JAMA Network Open on 25 September 2024
Abstract
Importance
Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood.
Objective
To examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound.
Design, Setting, and Participants
This cohort study enrolled outpatient adults with acute Covid-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicentre healthcare system in Boston, Massachusetts.
Exposure
Treatment regimen, including none, nirmatrelvir, and remdesivir.
Main Outcomes and Measures
The primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant’s treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population.
Results
Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants’ anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (<20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorisation of nirmatrelvir.
Conclusions and Relevance
In this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.
Study 3 details
A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes
Theo Sanderson, Ryan Hisner, I’ah Donovan-Banfield, Hassan Hartman, Alessandra Løchen, Thomas Peacock & Christopher Ruis
Published in Nature on 24 September 2024
Abstract
Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.
JAMA Network Open article – Emerging SARS-CoV-2 Resistance After Antiviral Treatment (Open access)
See more from MedicalBrief archives:
Remdesivir did not affect Covid-19 outcomes or mortality — DisCoVeRy trial
Paxlovid no better than placebo for long Covid – US study
Baricitinib plus remdesivir promising in severe COVID-19 — NIH clinical trial