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“Paxlovid Rebound” Is Just COVID Rebound

1 December 2022 by Gertrud U. Rey

by Gertrud U. Rey

Image Credit: Dreamstime

The antiviral drug Paxlovid is highly effective at inhibiting SARS-CoV-2 replication and reducing symptoms associated with COVID-19. Nevertheless, there have recently been numerous reports of recurrence of positive tests and symptoms after completing treatment with Paxlovid, leading some to infer that the drug triggers the recurrence. Is this inference actually correct, or would the recurrences happen regardless of treatment? In other words, is “Paxlovid rebound” really just COVID rebound?

Most studies aiming to address this question have been retrospective analyses, which use existing data collected from events that have already happened. A major disadvantage of examining data retrospectively is that it is impossible to randomly assign participants to experimental or control groups, or to even apply the proper controls as is typically done in a prospective study. These drawbacks often lead to a biased selection of participants such that they do not always represent the population that is intended to be analyzed, which leads to inaccurate results and false conclusions.

In an attempt to remedy this shortcoming, a group of investigators led by Michael Mina carried out a prospective study in which they compared the outcomes between two groups of COVID-19 patients: a group of 127 subjects who chose to be treated with Paxlovid and a control group of 43 subjects who chose not to be treated. The aim of the study was to determine whether Paxlovid recipients experience a higher incidence of rebounds than non-treated individuals.

To qualify for the study, all participants had to test positive for SARS-CoV-2 using a rapid antigen test. The day of the first test was then documented as day 0 and the participants continued testing themselves and recording their symptoms on days 2, 5, 7, 9, 11, 13, 15, and 17 of the study period. Any positive antigen test after a negative test within the 17-day period was defined as a viral rebound, and any recurrence of symptoms after initial symptom clearance within the same period was defined as a symptom rebound. At the 17-day time point, among the Paxlovid group, 14% of subjects had experienced a viral rebound and 19% had experienced a symptom rebound. In contrast, only 9% of subjects in the (untreated) control group had a viral rebound and only 7% had a symptom rebound. There were no noteworthy differences in the number of rebounds between the two groups at the one-month time point. Although the incidence of rebound was slightly higher in the Paxlovid group, this difference between the two groups was not statistically significant; it was likely due to random chance and the small sample sizes of the groups. In other words, the slightly higher incidence of viral and symptom rebounds in the Paxlovid group has no clinical meaning, and one can interpret the rate of rebounds between the Paxlovid and control groups to be similar, meaning that Paxlovid probably does not cause viral and/or symptom rebounds.

The authors thoughtfully note that the study has several limitations. First, the overall sample size of 170 participants is small and there was a large difference between the sizes of the two groups (i.e., 127 subjects in the Paxlovid group and 43 subjects in the control group). Large and balanced sample sizes are critical for reducing the margin of error and for obtaining results that are both accurate and clinically useful. Second, the participants tested themselves, which could have introduced unknown errors such as whether the tests were carried out properly or at the correct time. Third, participants were asked to only test every other day to ensure compliance; however, daily testing would have provided additional data points and more comprehensive findings. Larger surveys done under more controlled and standardized conditions are needed to validate the results obtained in this study.

In contrast to popular opinion, rebounds can happen after most viral infections, so there is nothing unique about SARS-CoV-2 in this regard. Even if Paxlovid does cause viral and/or symptom recurrence in a small subset of people, a preponderance of the evidence indicates that early treatment with Paxlovid results in an overwhelming reduction in hospitalization and death for COVID-19 patients. Understanding the underlying mechanisms leading to rebounds can help guide practitioners to modify timing and length of treatment with Paxlovid or other antiviral drugs to reduce the incidence of rebound.

Filed Under: Basic virology, Gertrud Rey Tagged With: antiviral, antiviral drug, COVID rebound, COVID-19, Michael Mina, Paxlovid, Paxlovid rebound, prospective study, rapid antigen test, rebound, retrospective study, SARS-CoV-2, symptom rebound, viral rebound

Should we be worried about monkeypox?

7 July 2022 by Gertrud U. Rey

by Gertrud U. Rey

The prevalence of monkeypox cases is continuing to increase around the world, with 7,243 total confirmed global cases as of today. Although this sounds awfully familiar, monkeypox virus is highly unlikely to cause a pandemic like the one we are presently experiencing, for at least two reasons: 1) monkeypox virus is not transmitted as easily as SARS-CoV-2, and 2) we have all the tools needed for quelling local outbreaks, thus hopefully preventing further community spread.

Because monkeypox has been endemic to Central and West Africa for several decades, scientists have had ample time to develop a thorough understanding of the virus and its associated disease. Monkeypox virus belongs to the Poxviridae, a family of viruses that also includes cowpox virus, variola virus (which causes smallpox), and vaccinia virus (the source of the modern smallpox vaccine). The name “monkeypox” resulted from the fact that the virus infects primates and was initially isolated from a laboratory monkey. However, it is actually thought to also circulate in rodents, which occasionally come into contact with humans, who can then further spread it to other humans.

Human-to-human transmission of monkeypox virus is far less efficient than that of SARS-CoV-2, which is commonly spread in the absence of symptoms, whereas monkeypox virus is only thought to be transmitted while an infected person is symptomatic. In addition, SARS-CoV-2 is readily spread when an infected person breathes, sneezes, or coughs around other people. In contrast, monkeypox virus is only transmitted by direct contact with lesion material or inhalation of respiratory droplets during prolonged face-to-face interaction with an infected person. Recent news reports have highlighted clusters of infections among men who have sex with men, leading some to infer that monkeypox is a sexually-transmitted disease. However, there is no evidence to suggest that the virus is present in sexual bodily fluids, therefore, it is not considered to be a sexually-transmitted pathogen. The high incidence of infections in the gay community could be explained by transmission through very close contact, which, by definition, includes sex.

The incubation period for monkeypox virus can range from 5 to 21 days, with an average of one week between infection and onset of symptoms. Initial symptoms usually include fever, swollen lymph nodes, headache, and muscle aches; and these symptoms are followed by a distinctive skin rash consisting of clear fluid-filled vesicles. The vesicles eventually fill with pus and ultimately crust over to give way to a new layer of healthy skin. Early symptoms are similar to those of chickenpox, which is caused by varicella-zoster virus (a herpesvirus, unrelated to poxviruses). However, unlike chickenpox lesions, which can individually exist in different stages of development throughout the course of infection, monkeypox lesions typically appear, progress, and disappear together.

Should the need arise, there are at least two licensed smallpox-specific vaccines that can also prevent monkeypox. ACAM2000 is a replication-competent live-attenuated vaccinia virus developed by Sanofi Pasteur Biologics Co. This vaccine is administered with a traditional bifurcated needle, and although very effective, it is associated with pretty severe side effects, including sore arm, fever, body aches, and occasional myocarditis. MVA-BN (marketed as “Jynneos” in the US) is a highly attenuated replication-incompetent vaccinia virus produced by Bavarian Nordic. MVA-BN/Jynneos is delivered by injection under the skin, is much better tolerated than ACAM2000, and is approved to be used as a monkeypox-specific vaccine. Fortunately, because of the long incubation period, it is possible to be vaccinated shortly after an exposure to monkeypox virus and still be protected from monkeypox disease.

It is unclear how long either of the available vaccines protect a person from disease, and whether individuals who were immunized against smallpox decades ago are protected from monkeypox today. Routine global smallpox vaccination ended in the late 1970s, so it is likely that the current outbreaks are fueled by non-immune people who were born since then, and/or by vaccinated individuals whose immunity has waned. However, even if infections continue to increase in number, it is unlikely that everybody in the general population would need to be vaccinated. Instead, proactively administering the vaccine to contacts and contacts of contacts of an infected person in a strategy termed “ring vaccination” would probably be sufficient to stop spread. That is, the vaccine would be administered in an area in a ring around the outbreak.

There are also several FDA-approved antiviral drugs that could be effective against monkeypox virus infection. Tecovirimat, which can be taken orally, prevents release of newly formed viral particles from infected cells, thus potentially blocking transmission of monkeypox virus. Cidofovir (administered by infusion into the vein) and its derivative brincidofovir (taken orally), disrupt replication of smallpox virus and could thus also be used for treating monkeypox virus infection.  

Considering all these factors, the average person is at low risk of becoming infected with monkeypox virus. Nevertheless, the World Health Organization has declared that there is no room for complacency and is urging governments to take some coordinated action to stop the spread of the virus. Because we have the tools to deal with monkeypox outbreaks and have hopefully learned from the disorganized manner in which the present pandemic was handled initially, a federal preparedness response should be implemented as soon as possible.

[The monkeypox outbreak was previously covered at least on Infectious Disease Puscast episodes 3 and 4; TWiV 902, TWiV 915; and TWiV Special Monkeypox Clinical Update with Dr. Daniel Griffin.]

Filed Under: Basic virology, Gertrud Rey, Information Tagged With: acam2000, antiviral drug, bifurcated needle, bodily fluids, brincidofovir, cidofovir, fluid-filled vesicles, Jynneos, lesion, men who have sex with men, monkeypox, MVA-BN, Poxviridae, ring vaccination, sexually transmitted disease, smallpox, symptoms, tecovirimat, transmission, vaccine, vaccinia, variola

TWiV 894: Dinner with the TMPRSS family

28 April 2022 by Vincent Racaniello

TWiV explains what is known about cases of acute, severe hepatitis of unknown origin in children, and discovery of an inhibitor of TMPRSS2 protease that blocks SARS-CoV-2 infection.

Hosts: Vincent Racaniello, Alan Dove, Kathy Spindler, and Brianne Barker

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: adenovirus, antiviral drug, coronavirus, COVID-19, hepatitis, pandemic, peptidomimetic, SARS-CoV-2, Tmprss2, viral, virology, virus, viruses

TWiV 888: Molnupiravir with Richard Plemper

14 April 2022 by Vincent Racaniello

Richard joins TWiV to discuss the SARS-CoV-2 antiviral drug Molnupiravir , including how it was discovered, its mechanism of action, whether it is a mutagen for cells, and the future of drugs for treatment of COVID-19.

Hosts: Vincent Racaniello, Alan Dove, and Brianne Barker

Guest: Richard Plemper

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Filed Under: This Week in Virology Tagged With: antiviral drug, coronavirus, COVID-19, Molnupiravir, remdesivir, ribavirin, SARS-CoV-2, viral, virology, virus, viruses

Molnupiravir, a SARS-CoV-2 antiviral drug, is mutagenic in cells

14 October 2021 by Vincent Racaniello

Molnupiravir might be the first highly effective antiviral drug given emergency use authorization for treatment of COVID-19. Should we be concerned about the results of a recent study which show that the drug is mutagenic in cells?

Molnupiravir is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase (pictured above). Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been previously shown to have broad-spectrum anti-RNA virus activity and blocks transmission of influenza virus in a guinea pig model of infection. It has been shown to block SARS-CoV-2 transmission in ferrets and results of a phase 2/3 clinical trial look promising, leading to a request for emergency use authorization.

N4-hydroxycytidine could be metabolized by the host to produce the 2’-deoxyribonucleotide form, which could be incorporated into cellular DNA and lead to mutagenesis. To test this hypothesis, a mutagenesis assay was used in Chinese hamster ovary cells (CHO-K1). These cells have one copy of the gene encoding the enzyme hypoxanthine phosphoribosyltransferase (HPRT), which makes the cells sensitive to the base analog 6-thioguanine (6-TG). If NHC were mutagenic, changes in the HPRT gene would allow cells to survive in the presence of 6-TG.

Cells were exposed to NHC for 32 days and assayed for sensitivity to 6-TG. The drug conferred 6-TG resistance in a dose-dependent manner. Two other antivirals that are base analogs, ribavirin and favipiravir, displayed either no or modest mutagenic activity in this assay. Sequence analysis of HPRT mRNA revealed the presence of base changes.

Molnupiravir is a far more active coronavirus antiviral than favipiravir and ribavirin, yet NHC has the distinct ability of causing mutations in cell DNA. The concern is that such mutations could lead to cancer or birth defects in a developing fetus. Whether or not Molnupiravir might cause cancer in humans is not known. However Merck, the developer of Molnupiravir, is required to carry out a series of gene toxicity studies before phase I testing of the compound in humans. Included is the Ames test, which uses bacteria to assess mutagenic activity of a compound. Bacteria do have the enzyme which can convert NHC to the DNA form. The results of these safety studies will not be published until after the drug receives EUA, but presumably nothing was observed that would preclude clinical trials.

Consequently until we have further information about preclinical studies on NHC, we should be cautious in our interpretation of the results of mutagenesis assays in CHO cells.

Filed Under: Basic virology Tagged With: antiviral drug, COVID-19, Molnupiravir, mutagenesis, pandemic, SARS-CoV-2, viral, virology, virus, viruses

TWiV 693: Vax to the future

16 December 2020 by Vincent Racaniello

On this episode, FDA EUA for Pfizer mRNA vaccine, efficacy of AstraZeneca ChAdOx1 COVID-19 vaccine, and an orally administered drug that blocks SARS-CoV-2 transmission in ferrets.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Brianne Barker

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Filed Under: This Week in Virology Tagged With: antiviral drug, ChAdOx1, coronavirus, COVID-19, EIDD-2801, ferret, MK-4482, mRNA vaccine, nucleoside analog, pandemic, Pfizer, SARS-CoV-2, vaccine, viral, virology, virus, virus transmission, viruses

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