Tag: covid treatment

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

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

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 misgivingsgranting 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.

Montelukast Can Block Harmful SARS-CoV-2 Protein and Protect Immune Cells

Targeting Nsp1 with montelukast helps prevent shutdown of host protein synthesis Credit: Mohammad Afsar

Montelukast can bind to and block a crucial protein produced by SARS-CoV-2, reducing viral replication in human immune cells, according to a new study by researchers at the Indian Institute of Science (IISc).

Montelukast has been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions like asthma, hay fever and hives.

In the study, published in eLife, the researchers showed that the drug binds strongly to the C-terminal, which is one end of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins unleashed inside human cells. NSp1 can bind to ribosomes inside immune cells, shutting down production of vital proteins that the immune system needs, thereby weakening it. Nsp1 could therefore be a target to reduce the virus’s damage.

“The mutation rate in this protein, especially the C-terminal region, is very low compared to the rest of the viral proteins,” explained IISc’s Assistant Professor Tanweer Hussain, senior author of the study. Since Nsp1 is unlikely to change in future variants, targeting it with drugs is a viable strategy, he added.

The researchers screened more than 1600 FDA-approved drugs with computational modelling to find the ones that bound strongly to Nsp1, coming up with a shortlist of drugs including montelukast and saquinavir, an anti-HIV drug. “The molecular dynamic simulations generate a lot of data, in the range of terabytes, and help to figure out the stability of the drug-bound protein molecule. To analyse these and identify which drugs may work inside the cell was a challenge,” said Mohammad Afsar, first author of the study.

The researchers then cultured human cells which produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1.

“There are two aspects [to consider]: one is affinity and the other is stability,” explained Afsar. This means that the drug needs to not only bind to the viral protein strongly, but also stay bound for a sufficiently long time to prevent the protein from affecting the host cell, he adds. “The anti-HIV drug (saquinavir) showed good affinity, but not good stability.” Montelukast, on the other hand, was found to bind strongly and stably to Nsp1, allowing the host cells to resume normal protein synthesis.

The researchers then tested the effect of the drug on live viruses and found that the drug was able to reduce viral numbers in infected cells in the culture.

“Clinicians have tried using the drug … and there are reports that said that montelukast reduced hospitalisation in COVID patients,” said A/Prof Hussain, adding that the exact mechanisms behind it still need to be fully understood. His team plans to work with chemists to see if they can modify the structure of the drug to increase its potency, and also plan to continue the hunt for more drugs.

Source: Indian Institute of Science

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!

Losartan is Not Effective in Reducing Lung Injury from COVID

SARS-CoV-2 virus
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash

In a study published in JAMA Network Open, researchers reported that the blood pressure medication losartan is not effective in reducing lung injury in patients with COVID.

This drug was investigated based on early reports suggesting benefit in preclinical models of the 2003 SARS virus, a close family member to the current SARS-CoV-2 virus.

The research team sought to determine if a common blood pressure medication might decrease lung injury in patients hospitalised with COVID. Their results found that losartan treatment did not reduce lung injury in patients admitted with COVID, and had no effect on mortality.

In addition, critically-ill patients treated with losartan needed additional, temporary blood pressure support. However, this did not result in worse outcomes overall.

“Even though this particular drug was not effective for the treatment of COVID-19, repurposing inexpensive and relatively safe medications remains an important approach to contain healthcare costs,” said study co-author Michael Puskarich, MD, an associate professor in emergency medicine.

“Finding effective treatments for COVID that can be widely used across both the developed and developing world remains an important ongoing area of investigation,” Dr Puskarich added.

The researchers noted that more studies of protein and cellular signalling from ALPS-COVID trial participants are ongoing.

“We hope that future study findings of these proteins may show insights into why the body responds the way it does to COVID,” said co-author Christopher Tignanelli, MD, MS, FACS, FAMIA, an assistant professor in surgery. “Critically, this will help us understand why some people develop severe disease following COVID infection and others are asymptomatic.”

Source: University of Minnesota Medical School

Cohorting an Effective Response for an Emerging Pandemic

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During the extenuating circumstances of an emerging pandemic, grouping patients together in one area or facility, a practice known as cohorting, was successful in providing high-quality care and containing infectious patients, according to a new study published in JAMA Open.

The University of Minnesota Medical School researchers reported that cohorting was implemented by M Health Fairview early in the pandemic when there was little known about how to effectively treat patients with COVID.

“This study highlights the academic and clinical expertise of the M Health Fairview system to deliver outstanding medical care to the people of Minnesota,” said Dr Greg Beilman, a critical care surgeon at the U of M Medical School and was a co-lead of the M Health Fairview COVID response team. “In this study we demonstrated our ability to rapidly bring new developments in science to the patient’s bedside and improve outcomes for patients affected by this frequently dire disease.”

Because every person being treated in the cohorts had COVID, frontline healthcare workers quickly gained experience in COVID care. These experienced specialists worked side by side with academic physicians who were translating the latest medical research into new solutions they could apply in real time to patient care. COVID patients had access to leading-edge clinical trials, internal COVID testing capabilities, and innovative technology.

The study found that dedicated COVID units in Minnesota were associated with a 2% overall improvement in in-hospital survival rates when patients were properly matched for severity of illness. Complications associated with COVID were significantly better in this group as was the swift implementation of new care processes by health care providers.

“The opportunity to care for patients at our COVID cohort hospitals was a shining light in a dark time for many of us,” said Dr Andrew Olson, medical intensivist at the U of M Medical School and medical director of COVID hospital medicine at M Health Fairview. “We watched our colleagues develop expertise, conduct research and care for one another while staying healthy in a challenging time.”

The research team hopes the cohorting method could be implemented during other infectious disease outbreaks, like viral pneumonia. The framework helps provide infectious patients the best care during times of rapid learning in scientific research.

“As the pandemic progressed, we had broad availability of personal protective equipment, vaccinations, and more health care workers developed familiarity with treatment of COVID,” said Dr Beilman. “These developments combined with the fact that the incidence of COVID decreased last year – this care model was no longer necessary.”

Researchers plan to further investigate which patients benefit most from care at such facilities, as well as evaluate the experience for those healthcare professionals who work in them.

Source: University of Minnesota Medical School

Nitazoxanide Flops in South African COVID Trial

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Interim analysis of a South African clinical trial has revealed that nitazoxanide, an oral antiparasitic agent with antiviral properties, was ineffective in improving outcomes in ambulatory patients with mild-to-moderate COVID.

Funded by the South African Medical Research Council (SAMRC), the study was performed at four sites in South Africa. The primary goal of the trial was to evaluate the effectiveness of nitazoxanide (1g twice daily for 7 days) in reducing the progression from mild to severe COVID in ambulatory patients. Progression to severe disease was defined as hospitalisation or death. The trial underwent an interim analysis at 67% of the recruitment target (290 participants), and the data was reviewed by an independent data and safety monitoring board (DSMB). Following the interim analysis, the DSMB recommended halting recruitment of the trial on the grounds of futility.

No significant difference was seen in serious adverse events, which included all causes of hospitalisation and death, between the nitazoxanide and the placebo groups [12/144 (8.3%) vs 10/146 (6.8%)]. Hospitalisation and death specifically due to COVID showed the same pattern [7/144 (4.9%) vs 8/146 (5.5%)].

Principal investigator Prof Keertan Dheda from the University of Cape Town (UCT) and the London School of Hygiene and Tropical Medicine, said that the results of the trial, although disappointing, contributes to the growing body of evidence, clarifying what works and what doesn’t for the treatment of COVID. Thus, clarifying what does not work is as important as finding effective therapies so that clinically useful management algorithms can be developed.

Nitazoxanide is a low-cost broad-spectrum antiviral drug with an extensive safety record. Originally developed as antiparasitic, it seemed promising against SARS-CoV-2 in the lab but the real world test did not show any benefit. It is still possible that nitazoxanide may be of benefit at higher doses (greater than the dose used in the trial, which was already twice the normal dose), however this will most likely cause an increase in intolerable gastrointestinal side effects. “The next step will be to focus on formally publishing the data in a peer reviewed journal and to evaluate secondary objectives of the study, including assessing the efficacy of nitazoxanide in reducing the duration of illness, reducing SARS-CoV-2 viral load, and its efficacy, if any, in preventing COVID in close contacts,” said Prof Dheda.

Prof Dheda concluded that nitazoxanide could have a less than 30% benefit which may be detectable in a larger study. However, it is questionable whether such an effect size is clinically relevant given the number needed to treat to prevent disease progression, adverse events, cost and that other therapies have emerged (eg paxlovid) with an efficacy benefit of greater than 80%.

SAMRC President and CEO, Prof Glenda Gray said although the study did not meet its primary endpoint, the results are an important addition into the scientific repository. “COVID and HIV in their very nature are unique and complex viruses which have posed unprecedented challenges for vaccine development, globally – however, the knowledge gained from this trial will help us advance our pursuit of effective therapies and vaccines for both COVID and HIV alike,” said Prof Gray.

Prof Gray, who also has led numerous trials in search of effective HIV and COVID vaccines, said COVID poses substantial challenges for those living with HIV which evades the immune system. “Until an effective vaccine has been found, all people living with HIV should take all recommended preventive measures to minimise their exposure to COVID,” concluded Prof Gray.

Source: South African Medical Research Council

Heparin’s Beneficial Impact on COVID Outcomes

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Researchers at the Medical University of Vienna have now shown that the anticoagulant heparin not only has a beneficial effect on survival of COVID patients, but also influences the duration of active infection with the SARS-CoV-2 coronavirus. The results were published in the journal Cardiovascular Research.

COVID is now known to be a multifaceted infectious disease, which affects several functional systems in the human body following infection with the pathogen SARS-CoV-2. One of these functional systems is blood clotting. COVID patients are at greater risk of thromboses and embolisms, such as strokes, pulmonary or myocardial infarctions, and even deep vein thromboses. The use of drugs that inhibit blood clotting has been part of the treatment guidelines for COVID since July 2020. “These complications during hospitalisation have a direct impact on the well-being of patients and increased the risk of dying from COVID,” said first author David Pereyra from MedUni Vienna’s Department of General Surgery. The underlying coagulopathy is still not fully understood.

“The coagulopathy observed in COVID patients is novel and differs in many respects from previously known coagulation problems,” said senior author Alice Assinger, group leader at the Institute of Vascular Biology and Thrombosis Research at the Medical University of Vienna. “COVID-associated coagulopathy displays characteristics that, although partially comparable with other coagulation diseases, cannot be fully explained by them.” Alice Assinger’s group therefore started to look for an explanation for this sub-condition of COVID in the spring of 2020, in an early phase of the pandemic.

In a multi-centre analysis of COVID patients, the group saw that COVID-associated coagulopathy occurs almost exclusively in patients requiring intensive care or in patients who die as a result of COVID. While anticoagulant drugs improve the survival of COVID patients, they show no effect on immunological processes related to blood coagulation (immunothrombosis).

However, an analysis of the results showed that the length of active SARS-CoV-2 infection is shortened in patients treated with low-molecular-weight heparin, the most commonly used anticoagulant. “In patients who receive this drug, infection time is an average of four days shorter than in patients who are not treated with low-molecular-weight heparin. We were surprised to see that low-molecular-weight heparin may have a direct effect on coronavirus and its infectivity,” said David Pereyra. Experimental data show that heparin can inhibit the ability of SARS-CoV-2 to bind to cells, thereby preventing them from being infected.

These observations were made in the context of a close collaboration between the three hospitals involved – the Favoriten Hospital in Vienna, the Innsbruck Regional Hospital Innsbruck and the Johannes Kepler University Hospital in Linz – as well as through the active exchange between basic researchers and clinicians,” says Alice Assinger, underscoring the relevance of good cooperation during the COVID pandemic for a better understanding of the disease and its treatment.

Source: Medical University of Vienna

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

Enzymes Speed up Production of Molnupiravir for COVID

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Molnupiravir is being developed for the treatment of COVID, which has been submitted for review by the US Food and Drug Administration, but large-scale production to treat COVID is still a challenge. Now, researchers have engineered enzymes to help manufacture the pill, resulting in a much shorter synthesis with a higher yield than current methods. The details of their work are reported in ACS Central Science.

The oral antiviral molnupiravir was originally developed to treat influenza, and works by causing viruses to make errors when copying their own RNA, introducing mutations that inhibit replication. Recently, interim phase 3 clinical trial findings indicated that molnupiravir reduced the risk of hospitalisation and death from COVID for newly diagnosed, at-risk patients, and that it had equal effectiveness against different SARS-CoV-2 variants. Researchers set out to develop a shorter, higher-yielding and sustainable way to synthesise the molecule.

The team came up with a three-step synthesis of molnupiravir from ribose, a sugar molecule. They identified enzymes or chemical treatments to sequentially add the appropriate chemical groups to ribose to generate the molecule. For the second step of the synthesis, the team identified bacterial enzymes that weakly catalysed the desired reactions. Using in vitro evolution, they greatly enhanced these enzymes’ activities. The new synthetic route, which also included a phosphate recycling strategy, was 70% shorter and had a seven-fold higher overall yield than the original route.

Source: American Chemical Society