Tag: Paxlovid

Categories : COVIDTags :

Time is Running out to Develop a Paxlovid Alternative

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Researchers from Rutgers University in the U.S. believe that they are ahead in a race to find an oral COVID-19 treatment to supplement or replace the antiviral Paxlovid. Their report, published in Science, shows that an alternative medication, a viral papain-like protease inhibitor, inhibits disease progression in animals while also possessing an important advantage over Paxlovid – fewer prescription drug contraindications.

“COVID-19 remains the nation’s third leading cause of death, so there’s already a massive need for additional treatment options,” said Jun Wang, senior author of the study and associate professor at Rutgers. “That need will grow more urgent when, inevitably, COVID-19 mutates in ways that prevent Paxlovid from working.”

The Rutgers team hoped to make a drug that interfered with viral papain-like protease (PLpro), a protein that performs important functions in all known strains of COVID-19.

Creating such a drug required detailed information about PLpro’s structure, which Wang’s team got from the Arnold Lab at Rutgers’ Center for Advanced Biotechnology and Medicine (CABM).

Precise knowledge of PLpro’s structure enabled Wang’s team to design and synthesise 85 drug candidates that would bond to – and interfere with – this vital protein.

“The PLpro crystal structures showed an unexpected arrangement of how the drug candidate molecules bind to its protein target, leading to innovative design ideas implemented by professor Wang’s medicinal chemistry team,” said Eddy Arnold, who is a professor at CABM.

Laboratory testing established that the most effective of those drug candidates, a compound dubbed Jun12682, inhibited several strains of the SARS-CoV-2 virus, including strains that resist treatment with Paxlovid.

Oral treatment with Jun12682 on SARS-CoV-2-infected mice was shown to reduce viral lung loads and lesions while improving survival rates.

“Our treatment was about as effective in mice as Paxlovid was in its initial animal tests,” said Wang, who added the experimental drug appears to have at least one major advantage over the older drug.

“Paxlovid interferes with many prescription medications, and most people who face the highest risk of severe COVID-19 take other prescription medicines, so it’s a real problem,” Wang said.

“We tested our candidate Jun12682 against major drug-metabolising enzymes and saw no evidence that it would interfere with other medications.”

Source: Rutgers University

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Paxlovid does not Reduce Risk of Long COVID, Study Finds

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A recent has study found that Paxlovid (Nirmatrelvir-ritonavir) did not reduce the risk of developing long COVID for vaccinated, non-hospitalised individuals during their first COVID infection. The study also revealed a higher proportion of individuals with acute symptoms rebound and test-positivity than previously reported.

The study, by a team of researchers from UC San Francisco, is published in the Journal of Medical Virology.

Paxlovid treatment for acute COVID has been shown to be effective for high-risk unvaccinated individuals. But the effect of the treatment on long COVID risk, including whether it protects vaccinated people from getting long COVID, has been less clear.

The research team selected a group of vaccinated people from the UCSF Covid-19 Citizen Science study who had reported their first positive test for COVID-19 between March and August of 2022 and who were not hospitalised.

Some of these participants reported taking oral Paxlovid treatment during the acute phase of their COVID infection, while others did not.

In December of 2022, they were invited to answer a follow-up survey with questions about long COVID, COVID rebound symptoms and how long they continued to test positive.

Researchers found the two groups were similar. About 16% of those treated with Paxlovid had long COVID symptoms compared to 14% of those who were not treated with the medication.

Commonly reported symptoms included fatigue, shortness of breath, confusion, headache, and altered taste and smell.

Those who took Paxlovid and then went on to develop long COVID reported as many long COVID symptoms as those who were not treated with Paxlovid.

A small percentage of people developed severe long COVID, and those who had received Paxlovid were just as likely to have severe Long COVID symptoms as those who did not.

Among individuals who experienced symptomatic improvement during Paxlovid treatment, 21% reported rebound symptoms.

And among those with rebound symptoms, 10.8% reported one or more Long COVID symptom compared to 8.3% without rebound symptoms.

For participants who repeated antigen testing after testing negative and completing treatment, 25.7% reported rebound test positivity.

In total, 26.1% reported rebound symptoms or test positivity.

“We found a higher proportion with clinical rebound than previously reported but did not identify an effect of post-treatment rebound on long COVID symptoms,” said study first author Matthew Durstenfeld, MD, MAS, a cardiologist and UCSF assistant professor of Medicine.

“Our finding that Paxlovid treatment during acute infection is not associated with lower odds of long COVID surprised us, but it is consistent with two other rigorously conducted studies finding no difference in post-COVID conditions between 4 and 6 months after infection.”

The authors note that the study may have been impacted by limitations arising from its observational nature with researchers relying on patient self-reporting of treatment and Long COVID symptoms.

Source: University of California San Francisco Medical Center

Categories : Cardiovascular Disease COVIDTags :

Paxlovid may Interact with Common Heart Drugs

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Nirmatrelvir-ritonavir (Paxlovid) is often given to heart disease patients with symptomatic COVID to prevent progression to severe disease – but it can interact with some previously prescribed medications. A review paper published in the Journal of the American College of Cardiology examines the potential drug-drug interactions (DDIs) between Paxlovid and commonly used cardiovascular medications, as well as potential options to mitigate severe adverse effects.

“Awareness of the presence of drug-drug interactions of Paxlovid with common cardiovascular drugs is key. System-level interventions by integrating drug-drug interactions into electronic medical records could help avoid related adverse events,” said Sarju Ganatra, MD, senior author of the review.

He continued: “The prescription of Paxlovid could be incorporated into an order set, which allows physicians, whether it be primary care physicians or cardiology providers, to consciously rule out any contraindications to the co-administration of Paxlovid. Consultation with other members of the health care team, particularly pharmacists, can prove to be extremely valuable. However, a health care provider’s fundamental understanding of the drug-drug interactions with cardiovascular medications is key.”

In December 2021, Paxlovid received emergency use authorisation from the US Food and Drug Administration as an oral antiviral agent for the treatment of symptomatic, non-hospitalised adults with mild to moderate COVID infection who are at high risk for progression to severe disease. Patients with heart disease and other risk factors, including diabetes, high blood pressure, chronic kidney disease and smoking make up a large portion of the high-risk population for whom Paxlovid is beneficial.

According to the authors, Paxlovid has been shown to be very effective in patients with existing heart disease, but it has significant DDIs with commonly used cardiovascular medications, highlighting the importance for all clinicians to be familiar with these DDIs. As there is limited clinical information regarding DDI-related adverse events, the authors used existing knowledge and data regarding how therapies like Paxlovid typically react with other medications to provide guidance regarding potential interactions and the associated likely consequences based on the degree of interaction.

The review provides an in-depth overview of a variety of cardiovascular medications used to treat many forms of heart disease. Five of the most important cardiovascular drug interactions with Paxlovid to be aware of include:

  • Anti-arrhythmic agents
    • Many anti-arrhythmic agents are metabolised in a way that increases plasma levels when co-administered with Paxlovid. While it may be possible to start Paxlovid after 2–2.5-day temporary discontinuation of the anti-arrhythmic agents, this may not be feasible from a practical standpoint. Clinicians are advised to consider alternative COVID therapies and avoid co-administration of these agents with Paxlovid. Sotalol, another anti-arrhythmic agent, is renally cleared and does not interact with Paxlovid.
  • Antiplatelet agents and anticoagulants
    • Antiplatelet agents are used for the treatment of coronary artery disease, particularly if a patient has received a stent. Aspirin and prasugrel are safe to co-administer with Paxlovid. There is an increased risk of blood clots when Paxlovid is given alongside clopidogrel and an increased risk of bleeding when given with ticagrelor. When possible, these agents should be switched to prasugrel. If patients have contraindication to taking prasugrel, then co-administration of Paxlovid should be avoided and alternative COVID therapies should be considered.
    • Anticoagulants such as warfarin may be co-administered with Paxlovid but require close monitoring of clotting factors in bloodwork. The plasma levels of all direct oral anticoagulants increase when co-administered with Paxlovid, therefore dose adjustment or temporary discontinuation and use of alternative anticoagulants may be required.
  • Certain statins
    • Co-administration of simvastatin or lovastatin with Paxlovid can lead to increased plasma levels and subsequent myopathy and rhabdomyolysis, a condition in which the breakdown of muscle tissue releases a damaging protein into the bloodstream. These agents should be stopped prior to initiation of Paxlovid. A dose reduction of atorvastatin and rosuvastatin is reasonable when co-administered with Paxlovid. The other statins are considered safe when given along with Paxlovid.
  • Ranolazine
    • Plasma concentration of ranolazine, used to treat angina and other heart-related chest pain, is exponentially increased in the presence of CPY450 inhibitors like Paxlovid, thereby increasing the risk of clinically significant QT prolongation and torsade de pointes (a type of arrhythmia). Co-administration of Paxlovid is therefore contraindicated. Temporary discontinuation of ranolazine is advised if prescribing Paxlovid.
  • Immunosuppressive agents
    • The plasma levels of immunosuppressive agents prescribed for patients who have undergone heart transplantation exponentially rise to toxic levels when co-administered with Paxlovid. Temporary reduction of dosing of immunosuppressive agents would require frequent monitoring and be logistically difficult. Therefore, alternative COVID therapies should be considered in these patients.

The authors conclude awareness and availability of other COVID therapies enable clinicians to offer alternative treatment options to patients who are unable to take Paxlovid due to DDIs.

Categories : COVIDTags :

Few Patients get ‘Rebound COVID’ after Paxlovid Treatment

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Mayo Clinic researchers studied the outcomes of 483 high-risk patients  treated for COVID with a five-day oral regimen of Paxlovid, a combination of nirmatrelvir and ritonavir. Only a handful developed COVID rebound symptoms, something which the researchers say needs further investigation. Their findings appear in the journal Clinical Infectious Diseases.

All of the patients benefited from Paxlovid and recovered, including the patients who developed rebound symptoms, which were generally mild.

“We found that rebound phenomenon was uncommon in this group of patients,” says senior author Aditya Shah, MBBS, an infectious diseases physician and researcher at Mayo Clinic. “The four individuals who experienced rebound [symptoms] represent only 0.8% of the group, and all of them recovered quickly without additional COVID-directed therapy.”

Most of the patients had been vaccinated, and many had received booster vaccinations. The median age was 63. While these patients were high-risk for COVID, none was immunocompromised. Only two patients were admitted to the hospital, and it was for reasons other than COVID.

The study focussed on four patients with rebound symptoms:

  • A 75-year-old man with coronary artery disease who had increased cough and muscle aches 19 days after treatment.
  • A 40-year-old woman with obesity, hypertension and kidney disease who developed fatigue and sore throat six days after treatment.
  • A 69-year-old man with hypertension and obesity who exhibited nasal discharge and cough 10 days following therapy.
  • A 70-year-old man with a history of prostate cancer, obesity, hypertension and high cholesterol, who developed significant sinus congestion 10 days after treatment.

Why did some rebound?

Researchers think one explanation could be that a replication of SARS-CoV-2 could have triggered a secondary immune response, which showed up as mild COVID symptoms. This question could be answered by prospective studies could answer the question. They also note that all four patients with rebound symptoms had many serious health problems known as comorbidities — a factor shown to complicate recoveries. And all four patients had been vaccinated more than 90 days before becoming infected with COVI.

Source: Mayo Clinic

Categories : COVIDTags :

End of the Road for Ivermectin as COVID Treatment in South Africa

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Stop sign

South Africa’s medicines regulator has officially terminated the special dispensation to use Ivermectin as a treatment for COVID, stating that “there is currently no credible evidence to support a therapeutic role for Ivermectin” in the treatment of the disease.

On Monday 30 May, the South African Health Products Regulatory Authority (SAHPRA) officially withdrew its authorisation [PDF], bringing to end something of a saga which saw vocal proponents pitched against the scientific and regulatory establishment.

The antiparasitic Ivermectin gained considerable notoriety as the COVID pandemic went on, based on preliminary studies that seemed to demonstrate its effectiveness. Pressure born out of desperation for some kind of treatment led to SAHPRA – amidst its own apparent misgivings – granting compassionate use authorisation under strict guidelines in January 2021. Use was allowed under Section 21 guidelines without having to wait for Section 21 authorisation, which was misinterpreted as full authorisation by some media sources.

The social media furore and misinformation surrounding Ivermectin led to dangerous instances of COVID self-treatment, with hospitalisations and even deaths reported.

In its terribly botched response to COVID, Brazil adopted Ivermectin on a mass scale, and essentially became a living laboratory for its effectiveness. Despite even administering Ivermectin as prophylaxis, Brazil’s health system was overwhelmed with COVID patients during the surge caused by the Gamma variant.

Studies turned up scant evidence in favour of Ivermectin’s effectiveness, with serious flaws and even outright data fabrication were picked up in a number of studies that seemed to show a significant benefit – even flying right through the peer review process only to be picked up at a later stage. This lead to a major meta-analysis by Hill et al. showing a effectiveness instead being retracted, which SAHPRA noted in its decision.

Finally, the I-TECH and the Together randomised clinical trials of 2021 showed no effect. Like hydroxychloroquine before it, Ivermectin prescribing was found to be driven by political interests. Thus, Ivermectin quietly disappeared from the media as viable antivirals such as Paxlovid came into the market.

The termination comes after a distinct decline in demand for Ivermectin use in South Africa, with no new applications for importation of unregistered Ivermectin products place since August 2021. SAHPRA also noted a marked decline in the number of health facilities applying for permission to hold bulk stock after August 2021.

Furthermore, no individual named patient applications have been approved since December 2021. Finally, there was little in the way of reporting of outcomes achieved by the treating healthcare providers.

Categories : COVIDTags :

WHO Panel Recommends Paxlovid for at-Risk Mild COVID

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Pfizer’s oral antiviral Paxlovid (nirmatrelvir/ritonavir) is strongly recommended for patients with non-severe COVID with greater hospitalisation risk, such as unvaccinated, older, or immunosuppressed patients, according to a WHO Guideline Development Group writing in The BMJ. 

The experts explained that Pfizer’s Paxlovid, a comnbination of nirmatrelvir and ritonavir tablets, is likely a better choice for these patients because it may prevent more hospitalisations than the alternatives, is safer than molnupiravir, and is easier to administer than intravenous options such as remdesivir and antibody treatments. 

Use in low-risk patients is not recommended due to trivial benefits. It is also not recommended for patients with severe or critical COVID, as there are currently no trial data on nirmatrelvir/ritonavir for this group.

Their recommendation is based on new data from two randomised controlled trials with 3100 patients.

In these trials, moderate certainty evidence showed that nirmatrelvir/ritonavir reduced hospital admission (84 fewer admissions per 1000 patients), low certainty evidence suggested no important difference in mortality, and high certainty evidence suggested little or no risk of adverse effects leading to drug discontinuation.

Additionally, WHO also makes a conditional (weak) recommendation to use the antiviral drug remdesivir for patients with non-severe COVID at highest risk of hospitalisation.

This is based on new data from five randomised controlled trials involving 2700 patients and replaces a previous recommendation against treatment with remdesivir in all patients with covid-19 regardless of disease severity.

Antiviral drugs should be administered as early as possible, but this may be challenging in low- and middle-income countries, the panel noted, and also that access to these drugs is tied to COVID tests.

The emergence of resistance is also an uncertain risk, they add.

This guidance adds to previous conditional recommendations for the use of molnupiravir for high-risk patients with non-severe COVID and for the use of sotrovimab or casirivimab-imdevimab (monoclonal antibody treatments) in selected patients; and against the use of convalescent plasma, ivermectin and hydroxychloroquine in patients with COVID regardless of disease severity. For patients with severe COVID, WHO strongly recommends corticosteroids, with the addition of IL-6 receptor blockers or baricitinib.

Source: EurekAlert!

Categories : COVIDTags :

SARS-CoV-2 Shows no Signs of Resistance to Paxlovid – For Now

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SARS-CoV-2 infecting a human cell
Infected cell covered with SARS-CoV-2 viruses. Source: NIAID

Researchers monitoring SARS-CoV-2 for signs of resistance have found that Pfizer’s COVID drug Paxlovid is still effective against the coronavirus. Published in the journal Cell Research, [PDF] the study is one of the first to explore the full extent of mutations, but also provides evidence that mutations are moving in the direction of developing resistance to the drug.

Researchers concluded that Paxlovid’s mechanism of suppressing SARS-CoV-2 is still effective. The antiviral drug works by jamming the cell machinery of a key protein, known as the ‘main protease’ or Mpro, involved in replicating the virus. A number of antiviral drugs target viral proteases, such as those for HIV and hepatitis C.

With the global spread of Omicron, resulting in recent severe outbreaks in Asian countries which have previously pursued “zero COVID” strategies, the virus has been observed for signs of evolving treatment resistance. With only a few drugs that are available to treat COVID, physicians are counting on treatments like Paxlovid to stem the spread.

However, while the virus is currently not resistant, genetic analysis showed that the virus is starting to evolve in the direction of strains that could evade current treatments.

“There is hope, at least for now,” said study author Jun Wang, an associate professor at Rutgers University. “At this point, Omicron is still new enough so that treatments are still working. But as more people take Paxlovid, we will expect drug resistance to emerge.”

The scientists accessed a public database known as GISAID, studying the Mpro sequences of all strains of COVID detected so far. The protein is central to the reproduction of the virus and the target of the antiviral Paxlovid.

Comparing more recent strains with earlier strains around the world, the scientists searched for mutations in genetic sequences of Mpro that occur when a virus replicates. Mutations can lead to possible new structures of Mpro, which are generally correlated with drug resistance.

“We wanted to pick out if there is a mutation in the protease that’s a ‘red flag,’” A/Prof Wang said. “We did that because, generally speaking, as we have seen in the past, this would be the first sign of the development of resistance.”

The researchers found the top 25 most common new mutations in the main protease of many Omicron strains, a discovery A/Prof Wang characterised as “concerning,” with the most common one called P132H. When they tested Paxlovid against the Mpro with the P132H mutation, the antiviral was still effective. X-ray crystallography confirmed this by showing that the P132H did not change the Mpro structure significantly.

“Although this mutation does not cause drug resistance to Paxlovid, this implies that the virus can still evolve to create additional mutations that might cause drug resistance,” A/Prof Wang stated. “When a drug gets widespread use, it is just a matter of time before resistance appears.”

A/Prof’s Wang’s lab is working to develop new antivirals against COVID by targeting the Mpro and another key protein known as the papain-like protease. The best approach, he said, is to create a “cocktail” containing multiple antivirals to thwart resistance, as with HIV/AIDS and HCV.

Source: Rutgers University

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Paxlovid Ramped up and No ‘Red Flags’ for Omicron Yet

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In the face of a renewed global surge in COVID cases, Pfizer has ramped up production of Paxlovid, even while the efficacy of Merck’s molnupiravir appears to be less than believed.

Pfizer is now expecting to make 80 million courses of Paxlovid by the end of 2022, Pfizer CEO Albert Bourla told CNBC, a significant increase over its earlier planned capacity of 50 million courses.

This news came after Merck reported the risk reduction in hospitalisation and death from its COVID antiviral, molnupiravir, fell from 50% in the interim analysis to 30% in the final analysis. The reduction came after results were updated with participants that became evaluable after the interim analysis. This drop has led to predictions of increased demand for Paxlovid, which has shown an 89% risk reduction in outpatients.

The increase in production comes just in time to fight the Omicron variant, for which South Africa is now better prepared, according to experts.

‘No red flags’
According to Professor Salim Abdool Karim, director of the Centre for the Aids Programme of Research in South Africa, the numbers appear to be on the rise across all continents, but as yet there are “no red flags” he said.

Omicron has been identified by South African scientists as a major driver of the spike in cases in Gauteng.

“We have been amazed at how fast the numbers are going up,” he said. “But we were not caught with our pants down. We expected and prepared for a fourth wave. [The scientists] gave us the best fighting chance by giving us information early. We didn’t know exactly when it would come and what it would look like,” Prof Karim said, speaking to the Daily Maverick.

While a number of mutations enable the variant to escape immunity, a clear picture of Omicron’s nature won’t emerge for two to four weeks, he cautioned.

Speaking about travel bans imposed on South Africa by Mauritius, Rwanda, Egypt and the Seychelles, President Cyril Ramaphosa said ahead of a West African tour: “I am concerned. Out of due respect to them, they have their own reasons. We would like to have a discussion with them in a way we prefer that they do not react like our former colonisers who are very quick to close Africa down,” Ramaphosa told journalists.

EU accelerates child vaccinations
EU President von der Leyen has said that vaccines for children aged five to 11 will be available in the bloc by December 13, a week ahead of schedule and that she is pushing for the consideration of mandatory vaccination. This comes amidst news that Omicron was detected in the Netherlands before its first detection in South Africa. Meanwhile, in Asia, South Korea has reported its first five cases of Omicron.

Categories : COVIDTags :

Pfizer’s Paxlovid Could Deliver Knockout Blow to COVID

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Pharmaceutical giant Pfizer announced today that Paxlovid, its investigational novel COVID oral antiviral candidate, significantly reduced hospitalisation and death, based on an interim analysis of its phase II/III clinical trials showing an 89% reduction of risk of hospitalisation or death due to COVID. 

The phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomised, double-blind study of non-hospitalised adult patients with COVID, who are at high risk of progressing to severe illness. The scheduled interim analysis showed an 89% reduction in risk of COVID-related hospitalisation or all-cause mortality compared to placebo in patients treated within three days of symptom onset (primary endpoint). Only 0.8% of patients who received Paxlovid were hospitalised through Day 28 with zero deaths, compared to 7.0% of patients who received placebo and were hospitalised or died. Similar reductions in COVID-related hospitalisation or mortality were seen in patients treated within five days of symptom onset; 1.0% of patients in the intervention arm were hospitalised through Day 28 with zero deaths, compared to 6.7% of placebo arm patients. In the overall study population through Day 28, no deaths were reported in intervention arm patients as compared to 10 (1.6%) deaths in placebo arm patients.

The results show such an overwhelming effectiveness that Pfizer, in consultation with the US Food and Drug Administration (FDA), will cease further enrollment into the study and will apply for Emergency Use Authorization (EUA) as soon as possible.

If it gets the green light, Pfizer’s Paxlovid, would be the first oral antiviral of its kind, a specifically designed SARS-CoV-2-3CL protease inhibitor. PF-07321332 inhibits viral replication at the proteolysis stage, before viral RNA replication. Co-administration with a low dose of ritonavir helps slow the metabolism of PF-07321332 in order for it to remain active in the body for longer at higher concentrations. It has shown effectiveness against multiple variants, and could have broad general effectiveness against coronaviruses.

“All of us at Pfizer are incredibly proud of our scientists, who designed and developed this molecule, working with the utmost urgency to help lessen the impact of this devastating disease on patients and their communities,” said Mikael Dolsten, MD, PhD, Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer. “We’re thankful to all of the patients, investigators, and sites around the world who participated in this clinical trial, all with the common goal of bringing forth a breakthrough oral therapy to help combat COVID.”

The review of safety data included a larger cohort of 1881 patients in EPIC-HR, whose data were available at the time of the analysis. Adverse events were comparable between paxlovid (19%) and placebo (21%), which were mostly mild.

Pfizer kicked off the EPIC-HR study in July 2021 after positive results from Phase I clinical trials, followed in August by the Phase II/III EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients), to evaluate efficacy and safety in patients with a confirmed diagnosis of SARS-CoV-2 infection who are at standard (low) risk. This trial includes a cohort of vaccinated at-risk patients who have an acute breakthrough COVID infection. A further trial is investigating prophylaxis among household members of patients with a COVID infection. 

Source: Pfizer