Virus World

BACKGROUND

METHODS

Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ∼20% of the treated cases. The persistence of an intermediary form of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir.

This infectious intermediate decayed slowly with a half-life of ∼1 day, suggesting that its persistence could outlive the treatment course to re-ignited SARS-CoV-2 infection as the drug is eliminated. Additional studies are needed to define the nature of this viral intermediate, but our findings point to a particular direction for future investigation and offer a specific treatment recommendation that should be tested clinically.

Available in bioRxiV (Dec. 21, 2023):

 https://doi.org/10.1101/2023.12.20.572655 

(Bloomberg) -- In a real-world study of people with Covid-19, Pfizer Inc.’s antiviral Paxlovid was less effective at preventing the infection’s most serious cases than it was in initial trials.  The pill was just 37% effective at preventing hospitalization or death in high-risk patients when compared to no Covid treatment at all, according to an observational study published Thursday in JAMA Network Open. In earlier studies, it cut the risk of hospitalization or death by as much as 89%.  Paxlovid is still an important drug for Covid’s worst outcome: The new study showed it was 84% effective against death alone. The study published Thursday measures how the drug is performing in the real world, rather than carefully designed and monitored clinical trials. Both the earlier trial and the newer study measured people at high risk of developing Covid complications. Pfizer’s initial Paxlovid studies were conducted in unvaccinated people, which could explain some of the differences in outcomes. The coronavirus has also evolved since the studies that provided more positive results.

Despite the lower efficacy against hospitalization and death in the new study, the antiviral is still “definitely recommended for high-risk patients,” says Danyu Lin, a biostatistics professor at the University of North Carolina at Chapel Hill and lead author of the study. The study also found that another therapy — Merck & Co.’s Lagevrio — had similar efficacy to Paxlovid. Merck’s drug works through a genetic mechanism and isn’t recommended for use in pregnant women. Sill, it should be considered when patients can’t take Pfizer’s, which sometimes interacts with other medications, Lin said. High-risk patients who took Lagevrio saw a 41% reduction in hospitalizations and deaths in the observational study compared to those who took no treatment, while earlier studies showed reductions of only about 30%. The Merck drug was also 77% effective against death in the JAMA study. The study looked at electronic health records of 68,867 patients at several hospitals in Cleveland and Florida.

Cited study published in JAMA Network Open (Sept. 21, 2023):

https://doi.org/10.1001/jamanetworkopen.2023.35077 

The antiviral ensitrelvir, which is not approved in the United States, shortens symptoms in people with mild COVID and might reduce risk of long COVID — but more data are needed. COVID-19 can inflict days of misery, even on people who do not develop serious illness. Now, trial data show that an antiviral called ensitrelvir shortens symptoms of mild to moderate COVID-19 by about a day — and is the first drug to make a statistically significant cut in the number of days people test positive for SARS-CoV-2. The drug’s manufacturer, Shionogi in Osaka, Japan, says the data also show that ensitrelvir has the potential to prevent long COVID. But scientists are sceptical about that claim and critical of the design of the clinical trial. The research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, on 21 February, and has not yet been peer reviewed. Two oral antivirals are already widely used to treat COVID-19: Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. Both target people who are at high risk of severe disease. But ensitrelvir was tested on people irrespective of their risk, which could have implications for its use in individuals at low risk. No drug has been conclusively shown to reduce the risk of long COVID, although preliminary evidence hints that Paxlovid might have this effect.

A pill for COVID cough

Organizers of the ensitrelvir trial investigated roughly 1,200 people, with the main goal of determining whether the drug could accelerate recovery. The results showed that participants who took 125-milligram ensitrelvir pills recovered from five specific symptoms — stuffy or runny nose, sore throat, cough, feeling hot or feverish and low energy or tiredness — about 24 hours earlier than did those in the control group. Participants who took the 125-milligram dose also tested negative for SARS-CoV-2 about 29 hours earlier than did those who took a placebo. According to Shionogi, the study was the first to show a statistically significant reduction in the time to a negative test result. A subset of participants were asked about their COVID-19 symptoms three and six months after trial enrolment as well as during their acute infection period. Those who reported two or more of the same symptoms at least twice in a row over this period were defined as having developed long COVID. Participants who had a relatively high number of symptoms during the illness's early stages had a 14% risk of developing long COVID if they took the antiviral, compared with a 26% risk for similar participants in the placebo group. This led Shionogi to conclude that participants who received ensitrelvir had a reduced risk of developing long COVID.

Doubts about design

But scientists who were not involved with the study point out that the trial was not specifically intended to investigate the risk of long COVID. That means that the pre-trial research plan didn’t describe any methods for analysing long COVID data. This means, for example, that it’s unclear whether Shionogi’s definition of long COVID was determined before the trial began, notes physician Eric Topol, director of the Scripps Research Translational Institute in San Diego, California. Because this was an exploratory phase of the study, it’s not possible to make any strong conclusions, he adds. Simon Portsmouth, head of clinical development at Shionogi in Florham Park, New Jersey, says that the company could not specify the plan for analysing long COVID data ahead of time because long COVID was less clearly defined in the past than now. He says that these results, although not definitive, will shape an ongoing trial evaluating ensitrelvir’s effect on COVID-19 symptoms. Scientists say it’s plausible that antivirals could prevent long COVID. One recent analysis found that people who took Paxlovid had a reduced risk of developing long COVID compared with those who took no antiviral drugs1. The study, published as a preprint, has not yet been peer reviewed. Study co-author Ziyad Al-Aly, chief of research and development at the VA St Louis Health Care System, in Missouri, says the ensitrelvir data make him more optimistic that attacking the virus early during an infection “seems to hold the key to reducing the risk of long COVID.” Topol agrees that the data that Shionogi have made public support the idea that antivirals protect against long COVID, at least when residual virus is involved in causing prolonged symptoms.

Published in Nature March 3, 2023:

https://doi.org/10.1038/d41586-023-00548-6 

Long Covid -- the disease encompassing the post-acute sequelae of SARS-CoV-2 (PASC) -- affects millions of people around the world. Prevention of PASC is an urgent public health priority. In this work, we aimed to examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of post-acute sequelae. We used the healthcare databases of the US Department of Veterans Affairs to identify users of the health system who had a SARS-CoV-2 positive test between March 01, 2022 and June 30, 2022, were not hospitalized on the day of the positive test, had at least 1 risk factor for progression to severe COVID-19 illness and survived the first 30 days after SARS-CoV-2 diagnosis. We identify those who were treated with oral nirmatrelvir within 5 days after the positive test (n=9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n= 47,123). Inverse probability weighted survival models were used to estimate the effect of nirmatrelvir (versus control) on a prespecified panel of 12 post-acute COVID-19 outcomes and reported as hazard ratio (HR) and absolute risk reduction (ARR) in percentage at 90 days.

Compared to the control group, treatment with nirmatrelvir was associated with reduced risk of PASC (HR 0.74 95% CI (0.69, 0.81), ARR 2.32 (1.73, 2.91)) including reduced risk of 10 of 12 post-acute sequelae in the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (deep vein thrombosis, and pulmonary embolism), fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath. Nirmatrelvir was also associated with reduced risk of post-acute death (HR 0.52 (0.35, 0.77), ARR 0.28 (0.14, 0.41)), and post-acute hospitalization (HR 0.70 (0.61, 0.80), ARR 1.09 (0.72, 1.46)). Nirmatrelvir was associated with reduced risk of PASC in people who were unvaccinated, vaccinated, and boosted, and in people with primary SARS-CoV-2 infection and reinfection. In sum, our results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.

Preprint in medRxiv (Nov. 5, 2022):

https://doi.org/10.1101/2022.11.03.22281783 

TUESDAY, Nov. 14, 2023 (HealthDay News) — For patients receiving nirmatrelvir-ritonavir (N-R) for acute COVID-19, virologic rebound (VR) occurs in about one in five, according to a study published online Nov. 14 in the Annals of Internal Medicine. Gregory E. Edelstein, from Brigham and Women’s Hospital in Boston, and colleagues conducted an observational study to compare the frequency of VR in 72 patients receiving and 55 not receiving N-R treatment for acute COVID-19. The intervention was five days of N-R treatment versus no COVID-19 treatment. The researchers found that VR occurred in 20.8 and 1.8 percent of those taking N-R versus untreated persons. All participants with VR had a positive viral culture result after a previous negative result. Only N-R use was associated with VR in multivariable models (adjusted odds ratio, 10.02).

Compared with those who started therapy two or more days after symptom onset, those who started therapy within two days of symptom onset more often had VR (26.3 versus 0 percent). Among participants receiving N-R, shedding of replication-competent virus was prolonged in those who had versus did not have VR (median, 14 versus three days). Symptom rebound occurred in eight of the 16 patients with VR; two patients were completely asymptomatic. There were no post-VR resistance mutations noted. “These data support the possibility of an N-R-specific VR phenomenon, which substantially increases the duration of shedding of replication-competent virus and has implications for post-N-R monitoring and isolation recommendations,” the authors write.

Study published in Annals of Int. Medicine:

https://doi.org/10.7326/M23-1756 

Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile.

Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Published in Science Advances (March 29, 2023)

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is the first protease inhibitor specifically developed against the SARS-CoV-2 protease 3CLpro that has been licensed for clinical use. To identify mutations that confer resistance to this protease inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) that expressed a polyprotein composed of the VSV glycoprotein (G), the SARS-CoV-2 3CLpro, and the VSV polymerase (L). Viral replication was thus dependent on the autocatalytic processing of this precursor protein by 3CLpro and release of the functional viral proteins G and L, and replication of this chimeric VSV was effectively inhibited by nirmatrelvir.

Using this system, we applied nirmatrelvir to select for resistance mutations. Resistance was confirmed by retesting nirmatrelvir against the selected mutations in additional VSV-based systems, in an independently developed cellular system, in a biochemical assay, and in a recombinant SARS-CoV-2 system. We demonstrate that some mutants are cross-resistant to ensitrelvir and GC376, whereas others are less resistant to these compounds. Furthermore, we found that most of these resistance mutations already existed in SARS-CoV-2 sequences that have been deposited in the NCBI and GISAID databases, indicating that these mutations were present in circulating SARS-CoV-2 strains.

Published in Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.abq7360