Hydroxychloroquine, Chloroquine Prescribing Patterns by Provider Specialty

Lara Bull-Otterson, PhD^1,2; Elizabeth B. Gray, MPH²; Daniel S. Budnitz, MD^3,4; Heather M. Strosnider, PhD^1,5; Lyna Z. Schieber, MD, DPhil^1,6; Joseph Courtney, PhD^1,5; Macarena C. García, DrPH^1,7; John T. Brooks, MD⁸; William R. Mac Kenzie, MD^1,7; Adi V. Gundlapalli, MD, PhD^1,9 (View author affiliations)

Summary

What is already known about this topic?

Hydroxychloroquine and chloroquine are approved to treat autoimmune diseases and to prevent and treat malaria. Earlier this year, they were widely reported to be of potential benefit in the prevention and treatment of COVID-19; however, current data indicate that the potential benefits of these drugs do not outweigh their risks.

What is added by the report?

New prescriptions by specialists who did not typically prescribe these medications (defined as specialties accounting for ≤2% of new prescriptions before 2020) increased from 1,143 prescriptions in February 2020 to 75,569 in March 2020, an 80-fold increase from March 2019.

What are the implications for public health practice?

Attention to updated clinical guidance, especially by nonroutine prescribers, will help safeguard supplies and ensure safe use of hydroxychloroquine and chloroquine for patients with approved indications.

FIGURE 2. Estimated new retail prescriptions of hydroxychloroquine or chloroquine dispensed, by prescriber category* — United States, January–June, 2019–2020

* Nonroutine prescribers = addiction medicine, allergy/immunology, anesthesiology, cardiology, cardiothoracic surgery, cardiovascular surgery, clinical neurophysiology, clinical pharmacology, colon and rectal surgery, critical care, critical care medicine, dentistry, dermatopathology, diagnostic laboratory, diagnostic laboratory immunology, emergency medicine, endocrinology, gastroenterology, general preventive medicine, general surgery, genetics, geriatric psychiatry, geriatrics, hematology, hepatology, hospice and palliative medicine, infectious disease, medical microbiology, naturopathic doctor, neurological surgery, neurology, neurosurgery-critical care, nuclear medicine, nutrition, obstetrics/gynecology, obstetrics/gynecology-critical care, occupational medicine, oncology, ophthalmology, optometry, orthopedic surgery, orthopedic surgery of spine, other, other surgery, otolaryngology, otology, pain medicine, pathology, pediatric critical care, pediatric neurosurgery, pharmacist, physical medicine and rehab, plastic surgery, podiatry, psychiatry, psychology, pulmonary critical care, pulmonary diseases, radiology, sleep medicine, sports medicine, surgery, thoracic surgery, and urology. Primary care/unspecified prescribers = family practice, general practice, internal medicine, internal medicine/pediatrics, nurse practitioner, osteopathic medicine, pediatrics, physician assistant, and specialty unspecified. Routine prescribers = allergy, dermatology, nephrology, and rheumatology.

https://www.cdc.gov/mmwr/volumes/69/wr/mm6935a4.htm

Plasmin may be link between COVID-19 comorbidities and serious illness

Why is the COVID-19 virus more dangerous in people with comorbidities?

Sadis Matalon, Ph.D., of the University of Alabama at Birmingham and colleagues in Texas and San Francisco asked that question in a hypothesis paper published online in Physiological Reviews. This study was made available online in March 2020 ahead of final publication in issue on July 1, 2020. They reviewed, in detail, research literature for comorbidities like hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease and kidney dysfunction, as well as many viral studies, studies of COVID-19 pathology and clinical presentation, and literature on the life-threatening acute respiratory distress syndrome.

Twelve days later, UAB Professor Emeritus Timothy Ness, M.D., Ph.D., posted plans on ClinicalTrials.gov for an exploratory COVID-19 outpatient study to test Matalon’s hypothesis and prevent worse clinical outcomes.

In the Physiological Reviews paper, the researchers noted that all those comorbidities feature elevated levels of the extracellular protease plasmin. Plasmin is able to nick proteins at amino acid sequences called furin sites. For many viruses, this nicking at furin sites increases their infectivity. Both SARS and MERS—the two virulent coronaviruses that are related to the COVID-19 virus—”have evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population,” the researchers wrote.

They noted that the COVID-19 virus, SARS-CoV-2, also has a furin site on its spike protein, the vital, viral protein for viral attachment to a lung cell. The researchers proposed that plasmin may cleave that furin site in the spike protein to increase its infectivity and virulence, and they hypothesized that, “the plasmin system may prove a promising therapeutic target for combating COVID-19.”

Ness already knew there is an inexpensive, commonly used drug—tranexamic acid, or TXA—that targets plasmin by inhibiting its conversion from the inactive precursor, plasminogen, to the active protease, plasmin.

TXA is approved by the U.S. Food and Drug Administration for treatment of heavy menstrual bleeding because having lower plasmin levels allows better clotting. TXA has a long track record of safety and is commonly given off-label. At UAB Hospital, TXA is used perioperatively as a standard-of-care for orthopedic and cardiac bypass surgeries; it is commonly used for hemorrhaging trauma patients and also has been used for spinal surgery, neurosurgery and corrective jaw surgeries. It is currently being studied for perioperative use in Cesarean section surgeries.

For the clinical trial, Ness and colleagues have started a double-blind study, giving either TXA or a placebo pill to COVID-19 outpatients who were recently diagnosed with COVID-19. Patients also receive an anticoagulant. The overall goal of the exploratory study is to assess both safety and efficacy of five days of TXA versus placebo in the COVID-19 population. Enrollment is ongoing.

Ness and colleagues hypothesize that the TXA treatment will reduce the infectivity and virulence of the virus, as measured by reduced need for hospitalization within a week if a patient’s condition deteriorates. Adults 19 years old and older are eligible, and all patients—whether in the control group or the TXA group—receive standard care as directed by their primary caretakers.

Matalon says the paper has been widely noticed. “Since its publication online, it has been downloaded 26,565 times and cited 55 times,” he said.

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More information: Hong-Long Ji et al, Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility, Physiological Reviews (2020). DOI: 10.1152/physrev.00013.2020

https://medicalxpress.com/news/2020-09-plasmin-link-covid-comorbidities-illness.html

Kids can have COVID-19 antibodies and virus in their system simultaneously

With many questions remaining around how children spread COVID-19, Children’s National Hospital researchers set out to improve the understanding of how long it takes pediatric patients with the virus to clear it from their systems, and at what point they start to make antibodies that work against the coronavirus. The study, published Sept. 3 in the Journal of Pediatrics, finds that the virus and antibodies can coexist in young patients.

“With most viruses, when you start to detect antibodies, you won’t detect the virus anymore. But with COVID-19, we’re seeing both,” says Burak Bahar, M.D., lead author of the study and director of Laboratory Informatics at Children’s National. “This means children still have the potential to transmit the virus even if antibodies are detected.”

She adds that the next phase of research will be to test if the virus that is present alongside the antibodies can be transmitted to other people. It also remains unknown if antibodies correlate with immunity, and how long antibodies and potential protection from reinfection last.

The study also assessed the timing of viral clearance and immunologic response. It found the median time from viral positivity to negativity, when the virus can no longer be detected, was 25 days. The median time to seropositivity, or the presence of antibodies in the blood, was 18 days, while the median time to reach adequate levels of neutralizing antibodies was 36 days. Neutralizing antibodies are important in potentially protecting a person from re-infection of the same virus.

This study used a retrospective analysis of 6,369 children tested for SARS-CoV-2, the virus that causes COVID-19, and 215 patients who underwent antibody testing at Children’s National between March 13, 2020, and June 21, 2020. Out of the 215 patients, 33 had co-testing for both the virus and antibodies during their disease course. Nine of the 33 showed presence of antibodies in their blood while also later testing positive for the virus.

Also of note, researchers found patients 6 through 15 years old took a longer time to clear the virus (median of 32 days) compared to patients 16 through 22 years old (median of 18 days). Females in the 6-15 age group also took longer to clear the virus than males (median of 44 days for females compared to median of 25.5 days for males).

Although there is emerging data regarding this timing in adults with COVID-19, there is far less data when it comes to the pediatric population. The findings being gathered by Children’s National researchers and scientists around the world are critical to helping understand the unique impact on children and their role in viral transmission.

“The takeaway here is that we can’t let our guard down just because a child has antibodies or is no longer showing symptoms,” says Dr. Bahar. “The continued role of good hygiene and social distancing remains critical.”

Journal information:Journal of Pediatrics

https://medicalxpress.com/news/2020-09-children-covid-antibodies-virus-simultaneously.html

EU’s NICE rejects Janssen’s depression spray Spravato for second time

NICE has rejected regular NHS funding for Janssen’s depression spray Spravato (esketamine) for a second time, although the company says it could salvage the situation by providing further data and “additional discussions”.

This will likely see the company drop its price further after already offering a commercially confidential discount to the NHS following European approval late last year.

In second draft guidance NICE said Spravato, with a selective serotonin reuptake inhibitor (SSRI), or serotonin-norepinephrine reuptake inhibitor (SNRI) is not recommended for treatment resistant depression.

Janssen, the pharmaceuticals unit of Johnson & Johnson, said it was “disappointed” with the decision, which applies to England and Wales, after NICE raised multiple issues with the drug and questioned the company’s cost-effectiveness calculations.

According to Janssen the drug will cost £10,790 per Quality Adjusted Life Year (QALY) gained, while NICE estimates that the figure was likely to be between £64,000 and £73,000.

These costs were lower when a confidential discount was applied, but NICE said that they were still “substantially higher” than NICE’s cost-effectiveness threshold of £30,000 per QALY.

The drug is taken weekly or fortnightly after an induction period where it is taken more frequently. A single dose of 28 mg costs £163, although more than one dose may be used depending on a patient’s age and other factors.

Spravato is approved as an adjunctive therapy administered by a nasal spray and is based on esketamine, a form of the drug ketamine, an anaesthetic commonly used illegally for recreational purposes.

This is the second time that Spravato has been rejected following a draft decision earlier this year, although Janssen said it thinks a “route can be found” to make the drug available to patients.

Amanda Cunnington, director of health economics, market access and reimbursement and advocacy at Janssen-Cilag, said: “It is a real shame that this treatment will now need to go through a third appraisal committee and is extremely frustrating for clinicians and for patients living with treatment-resistant major depressive disorder who are in desperate need of an alternative treatment option.”

NICE rejects Janssen’s depression spray Spravato for second time

Vertex Pharmaceuticals reports 7.1% stake in Kymera

Vertex Pharmaceuticals (NASDAQ:VRTX) acquires ~3.15M shares of Kymera Therapeutics (NASDAQ:KYMR), representing 7.1% of its total shares outstanding.

Shares were acquired pursuant to Vertex’s collaboration with Kymera and in a private placement that was closed concurrently with the closing of Kymera’s IPO on August 25, 2020.

Vertex had paid an initial consideration of $70M, including $50M upfront payment and $20M worth equity investment.

Press Release

https://seekingalpha.com/news/3611623-vertex-pharmaceuticals-reports-7_1-stake-in-kymera-therapeutics

J&J COVID-19 vaccine prevents severe disease in preclinical studies

Johnson & Johnson (JNJ -2.7%) announces that its COVID-19 vaccine candidate, Ad26.COV2.S, prevented severe clinical disease in a challenge study in Syrian golden hamsters. The results were just published in Nature Medicine.

Results showed robust protection, as indicated by vaccine-elicited binding and neutralizing antibody responses, against severe clinical disease after high-dose SARS-CoV-2 infection, the first such report on this stage of the disease, according to the company.

Viral loads in the lung decreased from day 2 to day 7 while inflammatory markers continue to escalate, correlated with continue weight loss.

https://seekingalpha.com/news/3611552-j-and-j-covidminus-19-vaccine-prevents-severe-disease-in-preclinical-studies

COVID-19 insurance crisis may not be as drastic as initially feared: study

ember 3, 2020

• A slew of competing research has attempted to estimate the number of Americans that lost job-based insurance due to the economic effects of the coronavirus, varying in projections from the millions to multiple tens of millions. But the losses may not be as drastic as initially thought, according to a new report from the Urban Institute.
• Researchers performed a comparative analysis on four studies on COVID-19’s effects on job-based insurance coverage published between early May and mid-July, and found they differ wildly in methodology, assumptions and completeness. Smaller household surveys conducted during the pandemic have found little immediate change in insurance status, suggesting studies estimating more modest long-term changes in the number of uninsured people as a result of COVID-19 may be more accurate than others.
• Despite the importance of waiting for definitive data next year, the models are still valuable for informing policymakers on the scope of the insurance crisis spurred by COVID-19. And researchers are continuing to pursue the question: New research released by the Economic Policy Institute on Wednesday found it’s likely 12 million people have lost employer-sponsored insurance since February.

Despite the Trump administration touting a rebounding economy, more than 1 million Americans applied for unemployment benefits last week, according to data released Thursday by the Department of Labor. The number of jobless claims has topped 1 million every week but one since late March.

Since the majority of Americans get coverage through their job, ongoing unemployment has given rise to concerns about an insurance crisis stemming from the pandemic and the threadbare U.S. safety net.

But recent household surveys suggest net changes in insurance coverage so far have been relatively minimal, Urban Institute pointed out in its brief. The surveys, conducted by groups like the Census Bureau and the Commonwealth Fund, are more timely but more limited than federal surveys with larger sample sizes. But none have found large increases in uninsurance at this point in the recession.

For example, the Coronavirus Tracking Survey conducted mid-May by Urban Institute and the Robert Wood Johnson Foundation found no change in employer-sponsored insurance, or in the number of uninsured people, for the overall sample. However, for those in families losing jobs, employer-based coverage dipped by 4.9 percentage points. That drop, though, was offset by a 3.5 percentage point increase in private non-group coverage.

More longitudinal estimates, like the four analyzed by the Urban Institute, are much more severe in their projections, but vary widely. They don’t all address the same exact questions, act on different methodology and assumptions and generally differ in completeness, Urban said.

Two earlier estimates from the Urban Institute pegged the number of people losing employer-based coverage over 2020 as 10.1 million workers and dependents, or between 17.7 million and 30 million workers and dependents over several months to a year.Both studies tried to incorporate projections of how many people would gain access to coverage through a family member, or through subsidized Medicaid or individual marketplace coverage.

One study from the Kaiser Family Foundation estimated 27 million workers and dependents were losing employer-based coverage over the remainder of 2020. However, the KFF study did not quantify the number of people who would become uninsured due to job loss.

Another from Families USA, looking at losses already occurred, estimated 5.4 million workers lost job-based insurance, but didn’t factor in family members and dependents who would also lose coverage as a result of the policyholder being let go.

The data are still shifting, and it’s important to wait for more definitive data points next year to get a fuller understanding of the pandemic’s effects on insurance coverage, Urban Institute said, though the projections are important for informing the nation’s public health response.

https://www.healthcaredive.com/news/covid-19-insurance-crisis-may-not-be-as-drastic-as-initially-feared-study/584336/