‘Inevitable’ or not? Experts debate antiviral resistance to COVID-19 drugs as data emerge
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Although the emergency use authorizations for antiviral medications to treat COVID-19 have proven to be crucial in helping patients at high risk for severe disease, a potential wrinkle threatens to undo that progress.
That wrinkle, which has increasingly been the subject of debate and research over the past year, is the potential development of antiviral resistance to currently approved COVID-19 drugs. However, there is still much uncertainty as to how imminent that threat is. For some experts, antiviral resistance to COVID-19 treatments is only a matter of time. For others, more data are needed before any definitive statements can be made either way.
“There are plenty of precedents from HIV, hepatitis and bacterial infections to lead me to believe that resistance is inevitable,” Reuben Harris, PhD, professor and chair of the biochemistry & structural biology department at the University of Texas Health San Antonio, told Healio in an interview.
Among these precedents, according to Harris, is that natural variants of SARS-CoV-2 have emerged, meaning that there are more opportunities for the virus to elude therapeutic intervention.
“More antiviral use also creates more opportunities for resistance,” he added.
However, not all experts are convinced of this eventuality.
“I would recommend not assuming that ‘resistance’ is a thing,” Aditya Shah, MBBS, assistant professor in medicine and senior associate consultant in the division of public health, infectious diseases and occupational medicine, at the Mayo Clinic in Rochester, Minnesota, told Healio. “This has not been completely proven.”
As experts await more data, studies of both rebound infections — defined as a return of COVID-19 symptoms after a patient has finished a 5-day course of nirmatrelvir/ritonavir (Paxlovid, Pfizer) treatment — and the potential parameters of Paxlovid and molnupiravir (Lagevrio, Merck) resistance are under way.
One paper, published in Clinical Infectious Diseases by Shah and colleagues in June, included 483 high-risk patients treated with Paxlovid for COVID-19, resulting in viral symptoms of rebound infection surfacing in four participants (0.8%) at a median of 9 days after treatment. Two patients (0.4%) required hospitalization at 30 days of follow-up. No further treatment was needed for those patients with rebound symptoms.
“These findings can make no conclusion about antiviral resistance to COVID,” Shah said.
However, there remains some speculation that rebound cases may signify, or be associated with, the presence of antiviral resistance.
“A common belief is that rebound is due to the drug effectively suppressing the replication of the virus, but once the treatment course ends, any virus that was not removed is now able to rapidly replicate,” Alejandro Chavez, MD, PhD, assistant professor of pathology and cell biology at Columbia University, told Healio.
That said, Chavez also remains skeptical.
“The basis of COVID rebound in the setting of antiviral medications remains unclear,” he added.
The data bear this out, at least in Shah’s study.
“If there were resistance issues, then we would have expected the patients who rebounded to get rebound severe enough to need additional medical care,” he said. “This did not happen.”
As more research on rebound and resistance emerges, more definitive answers may be forthcoming. For many, a starting point will be the two drugs being used most frequently to treat COVID-19.
The ‘dream’ of multiple lines of attack
In a retrospective cohort study published as a preprint in MedRxiv, Wang and colleagues assessed rebound rates and characteristics in 11,270 patients treated with Paxlovid and 2,374 patients who received molnupiravir.
For Paxlovid, results at 7 days demonstrated that 3.53% had COVID-19 infection, 2.31% had symptoms of the virus and 0.44% were hospitalized. By 30 days, the infection rate was 5.4%, symptoms occurred in 5.87% and 0.77% were hospitalized.
Among patients treated with molnupiravir, the 7-day rates were 5.86% for COVID-19 infection, 3.75% for symptoms and 0.84% for hospitalization. At 30 days, the rates were 8.59% for infection, 8.21% for symptoms and 1.39% for hospitalization.
The researchers concluded that there were no statistically significant differences between the two drugs in terms of any of these outcomes.
“Paxlovid is the most commonly used therapy for COVID-19, so it will definitely be important to monitor closely for resistance and to develop alternative therapies,” Jeffrey Sparks, MD, MMSc, director of immuno-oncology and autoimmunity at Harvard Medical School, said in an interview. “Also, the rebound phenomenon, where viral replication can occur again after a completed course of Paxlovid, needs to be better researched to understand who may be susceptible and whether longer courses may be helpful, particularly for immunosuppressed individuals.”
Chavez agreed that the data on rebound rates between the two drugs remain uncertain, and should be an area of active investigation.
According to Shah, the other relevant question is whether antiviral resistance is leading to rebound.
“Rebound could be owing to natural biphasic pattern of illness, or resumption of viral replication after completing a course of treatment,” he said. “These two are our hypotheses and we think that is more likely than resistance. However, more research is needed on this question.”
Perhaps the most important consideration is that there are, in fact, rebound infections that require intervention.
“Right now, there is limited clinical data for the best course of action in these cases,” Chavez said.
Current guidance from the CDC states that a second course of Paxlovid is not necessary for rebound cases with that drug. In the case of rebound, the CDC advises that the patient should isolate for at least 5 days.
Meanwhile, to address the current uncertainty, the FDA has asked Pfizer to conduct a clinical trial to determine if a second course of Paxlovid is appropriate for treating patients with COVID-19 rebound after having taken an initial course of its drug.
For Harris, there is a silver lining in the resistance profiles of Paxlovid and molnupiravir.
“The resistance profiles for these compounds are different, which is good news,” he said. “If you have resistance to one, you want to come at it with another drug that has a different profile.”
According to Harris, the “dream” is to have multiple drugs with different mechanisms of action.
“You want a first line, a second line, a third line,” he said. “From there, you can begin to develop combination therapies with different mechanisms and different resistance profiles.”
Researchers are working on turning this dream into a reality. In the meantime, other investigators are exploring other therapeutic targets in SARS-CoV-2.
Problems of scale
In another preprint published in BioRxiv, Moghadasi and colleagues examined the susceptibility of natural variants of the main protease of SARS-CoV-2 — Mpro/3CLpro — to protease inhibitors. The researchers noted that there are multiple single amino acid changes in Mpro that may confer resistance to the nirmatrelvir component of Paxlovid. With that in mind, they looked at ensitrelvir (Shionogi), a protease inhibitor with a resistance mutation profile that is different from that of nirmatrelvir.
“Importantly, phylogenetic analyses indicate that nirmatrelvir-resisting variants have pre-existed the introduction of this drug into the human population and are capable of spreading,” Moghadasi and colleagues wrote. “A similarly strong argument can be made for ensitrelvir.”
Their findings indicate that monotherapy with a protease inhibitor may not be an ideal approach to COVID-19 treatment. Rather, other drugs with different resistance profiles should be explored.
According to Harris, the challenge lies in scaling up the synthesis of these compounds.
“These are not easy compounds to formulate and distribute,” he said.
As such, researchers are also exploring the possibility of optimizing currently approved therapies as a way to prevent resistance.
In another paper published in BioRxiv, Iketani and colleagues investigated the possibility of SARS-CoV-2 becoming resistant to nirmatrelvir. They examined this possibility by in vitro passaging of SARS-CoV-2 in increasing concentrations of nirmatrelvir, using two different approaches, including on a large scale in 480 wells. In the approach performed at scale, 53 independent viral lineages were selected with mutations at 23 different residues of the enzyme.
According to the findings, one mutation — E166V — conferred the strongest resistance, at approximately 300-fold. However, this mutation resulted in a loss the ability of the virus to replicate, the researchers wrote.
“Structural explanations are discussed for some of the mutations that are proximal to the drug-binding site, as well as cross-resistance or lack thereof to ensitrelvir, another clinically important 3CL protease inhibitor,” Iketani and colleagues wrote. “Our findings indicate that SARS-CoV-2 resistance to nirmatrelvir does readily arise via multiple pathways in vitro, and the specific mutations observed herein form a strong foundation from which to study the mechanism of resistance in detail and to shed light on the design of next generation protease inhibitors.”
For Harris, the amount of drug in any given dose may only be one component of the battle against resistance.
“You need to take the full course of the drug,” he said. “If you do not take the complete course, you create a selective environment where resistance can occur.”
Meanwhile, another consideration pertains to treatment duration, according to Chavez.
“Increasing treatment duration may give the immune system sufficient time to remove a sufficient number of infected cells to the point that rebound, if it occurs, may be mostly asymptomatic,” he said. “Given that Paxlovid and molnupiravir target different parts of the viral replication machinery, it is possible that rebound is a general property of all treatments that target viral replication if given for insufficient time frames.”
Researchers will take all of these factors into account to determine the optimal dosing and treatment duration for any COVID-19 antivirals. As research has shown, the drugs are generally effective in most populations, even if rebound infections occur. However, many more questions remain for immunocompromised patients.
‘Elevated chance of COVID rebound’
“We already know that some immunosuppressed patients can have a lengthy duration of viral shedding and could be a reservoir for viral evolution where new variants could become resistant to current therapies,” Sparks said. “Therefore, it will be very important to monitor how these patients do with antiviral therapy.”
Although immunosuppressed individuals are not generally included in early clinical trials, the rheumatology community is aware of this need, according to Chavez.
“Initial studies suggest that patients that are immunocompromised due to medication or underlying disease may experience an elevated chance of COVID rebound,” he said. “Although these data should not preclude a patient from taking these medications, as rebound cases are usually short-lived and self-limited, with few being associated with severe illness.”
According to Shah, it is theoretically possible that immunocompromised patients can face difficulties clearing the virus.
“These patients can continue to test positive for a long time, depending on their specific nature of immune compromise,” he said. “If this were to happen, theoretically, it is possible that continued low level viral replication could mean genetic mutations that could lead to new variants or resistance to antivirals.”
However, it is important to note that this, too, is just a hypothesis that has not been proven or confirmed, Shah added.
“We had under-representation of the immune compromised patients, as these patients preferred monoclonal antibodies vs. Paxlovid at our organization,” he said.
Rheumatologists can hope that more data on immunocompromised patients will emerge, so they can better understand both how to treat those patients and how factors such as dosing and duration, along with vaccination, can impact rebound and resistance.
However, the question of resistance remains unanswered, at least for the moment, according to Sparks.
“I am not sure whether or not resistance to antivirals will be inevitable,” he said. “Treatment to some viruses have remained relatively stable for some time. However, others like HIV have developed resistance that require combination therapy and many novel therapies.”
Such novel therapies for COVID-19 are likely to emerge sooner than later, according to Harris.
“There are many components of the coronavirus that are very targetable,” he said. “Pharma is working on it, so we are hoping to see multiple products on the market that hopefully can be used safely and effectively for all of our patients.”
References:
Iketani S, et al. BioRxiv. 2022;doi: 10.1101/2022.08.07.499047.
Moghadasi SA, et al. BioRxiv. 2022;doi: 10.1101/2022.08.07.503099.
Ranganath N, et al. Clin Infect Dis. 2022;doi: 10.1093/cid/ciac481.
Wang L, et al. medRxiv. 2022;doi:10.1101/2022.06.21.22276724.
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