Existing affordable drugs could rapidly reduce Covid cases, deaths in India

 The COVID-19 humanitarian calamity unfolding in India is on a scale not seen in this pandemic. This is an extraordinary situation – and it may benefit from an extraordinary response.

There exist affordable, readily available and minimally toxic drugs approved for non-COVID-19 use which show remarkable promise in preventing or treating the new coronavirus. Deploying these drugs in India is likely to rapidly reduce the number of COVID-19 patients, reduce the number requiring hospitalization, supplemental oxygen and intensive care and improve outcomes in hospitalized patients.

Some of these drugs are being tested in large-scale randomized clinical trials in the US and abroad but in most cases, definitive efficacy data is pending. With the current COVID-19 situation in India, we do not have time to wait for results of these studies. Importantly, currently available safety and outcomes data on these drugs is strong enough that it is time to incorporate them into national practice guidelines. Indian authorities should issue such guidelines on the most promising drugs for each stage of COVID-19. By so doing, physicians will be encouraged to use these interventions. The resulting real world data from a few healthcare settings in select cities should be tracked in real time and guidelines suitably revised. If such measures were adopted, we could see effects in 3-4 weeks. This strategy might be unusual but it is not unheard of: France has the Temporary Recommendation for Use, a “regulatory instrument which aims to allow, on a temporary basis, the use of a medicinal product to allow its effectiveness to be evaluated on the basis of its use.”

The choice of drugs is critical. We have worked closely with personnel at the Food and Drug Administration and have connected with the World Health Organization and the National Institutes of Health to evaluate the merits of repurposed drugs. Based on a mechanistic rationale, data in animal models, human retrospective analyses, clinical trials (some randomized, others not) and anecdotal human data, we created a prioritized list of interventions that hold the greatest promise and that could be deployed at scale. For instance, there is strong data from a randomized trial and a real-world study that administering fluvoxamine sharply reduces the need for hospitalization in COVID-19 outpatients. Moreover, anecdotal unpublished data in over 400 acutely ill COVID-19 patients from several community practitioners suggests that administering fluvoxamine and ivermectin together may be even more efficacious.

Intervention as early as possible after symptom onset is key. Ivermectin is already listed as a “MAY DO” on the ICMR and Indian government guidelines for treatment of acute mild COVID-19 and we suggest that fluvoxamine be added in this category. Also, ivermectin in the prophylactic setting merits serious consideration. For the hospitalized, there are treatments currently used for other conditions that might reduce the need for ventilator support and lower the risk of death. These include inhaled adenosine, cyproheptadine and dipyridamole. For ideas for which there is rather limited human data, the government should offer pre-approved pilot protocols and funding for rapid implementation in select centers rather than issue a recommendation for use.

To be clear, it would be ideal to pursue large clinical trials to test the efficacy of all promising interventions. A randomized adaptive design could efficiently sift through the many possibilities. It may be possible to rapidly set up parallel protocols in India if government authorities can expedite the regulatory process and offer funding. US trial investigators can be persuaded to provide protocols and web-based data collection tools.

We hope that the Indian government will take advantage of repurposed drug research and use temporary use authorizations or guidelines to rapidly promote the most promising therapies at a national level while in parallel aggressively encourage pilot studies and large-scale clinical trials with shovel-ready protocols and funding. Given the current situation, India has little to lose in piloting these approaches: the potential gains could benefit not just the country but the world.

Vikas P. Sukhatme MD, ScD, is the Robert W. Woodruff Professor of Medicine, Dean of Emory University School of Medicine, and Chief Academic Officer of Emory Healthcare. He is the founding director of the Emory-based Morningside Center for Innovative and Affordable Medicine. You can reach him at vsukhatme@emory.edu

Vidula Sukhatme, MS, is an adjunct instructor at Emory University’s Rollins School of Public Health and is the founding CEO of GlobalCures, a non-profit that aims to promote promising therapies for cancer not being pursued for lack of profitability. Her contact is vidula@global-cures.org

https://timesofindia.indiatimes.com/blogs/voices/existing-affordable-drugs-could-rapidly-reduce-covid-19-cases-and-deaths-in-india/

Oklahoma Dumps Its HCQ Stockpile

 Oklahoma will get a refund for its unused stockpile of hydroxychloroquine, the state's attorney general announced.

The state reached an agreement with supplier FFF Enterprises of California to get back the "full purchase price paid" for the drug in April 2020.

"When it was determined the drug wasn't effective in combatting the virus, they did the right thing by refunding our money," said State Attorney General Mike Hunter (R), in a statement.

According to the official agreement, FFF Enterprises procured a supply of 100-count bottles of 200-mg hydroxychloroquine tablets from importer Rising Pharma on April 7, 2020, at the request of the Oklahoma Department of Health.

The cost was $202.32 per bottle, which then rose to $218.50 per bottle as it was sold to the health department through Beggs Pharmacy, according to the agreement.

The department ordered 12,000 bottles for a total price of $2.62 million -- and state officials have alleged that price was excessive. In addition, the health department said at the time it was acting on the fact that the FDA had issued an emergency use authorization (EUA) for hydroxychloroquine in late March 2020.

After studies found hydroxychloroquine wasn't helpful in treating COVID-19, the agency revoked the EUA in June 2020. At that point, the health department asked Hunter's office to step in and help get their money back.

To avoid protracted litigation, the company agreed to refund the state. Hunter's statement said it would be paid back in full, but the agreement does note that FFF Enterprises will give back $218.50 per bottle for all unused products that were stored properly and remain within their use-by date.

The state will be paid in installments, will the full amount returned by May 2022, according to the agreement.

FFF Enterprises is described as a private pharmaceutical wholesaler based in Temecula, California. A banner on its home page advertises returns for flu vaccines that went unused in the 2020-2021 season.

Hunter commended the company for allowing the return on Twitter: "They recognized we were in competition with every other state to get whatever we could to protect Oklahomans."

https://www.medpagetoday.com/special-reports/exclusives/92533

Nasal Vaccines for COVID-19?

Despite an arsenal of highly effective injectable vaccines, drugmakers are looking into products that will be easier to store, transport, and administer in the global crisis -- particularly, intranasal vaccines.

Could these vaccines also hold an advantage when it comes to blocking transmission? While more data has suggested the vaccines authorized in the U.S. cut transmission, some experts have argued that intranasal vaccines may do an even better job of this.

MedPage Today surveyed the global landscape of intranasal vaccines in development, the majority of which are in early stages.

Rationale for COVID-19 Mucosal Vaccines

The mucosal immune system represents the body's first line of defense against outside pathogens at surfaces like the nose, lungs, mouth, eyes, and GI tract. Because the nasopharynx is the primary entry point for SARS-CoV-2, targeting the nasal cavity could be one of the best lines of defense for vaccines, according to Michael Russell, PhD, an emeritus professor of microbiology and immunology at the University at Buffalo in New York.

"By generating effective mucosal immune responses, it should be possible to forestall coronavirus infection from the outset, and also more effectively reduce transmission of the virus," Russell told MedPage Today. "Nasal immunization aims to replicate this natural immunization process in a more effective manner."

Current injectable vaccines induce a systemic immune response by generating circulating IgG antibodies that neutralize pathogens before they can cause severe tissue damage. But IgG is not very good at controlling viral entry into the body. To do that, the mucosal immune system is needed. It produces secretory IgA at the site of viral entry, and in larger quantities than any other type of immunoglobulin in the body.

"The major advantage of mucosal vaccines would be to create a strong immune response at the initial site of virus entry. If you can stop the virus here, it won't be able to get into the lungs to cause damage," said Richard Kennedy, PhD, who studies the development of immune responses after vaccination at the Mayo Clinic.

IgA also seems to be important in early infection. In one study, researchers measured immune responses in 159 patients with COVID-19. They found that IgA dominated the early stage of infection, peaked 3 weeks after symptom onset, and neutralized virus better than IgG. The results suggest that IgA-mediated mucosal immunity may decrease infectivity of the virus in human secretions and decrease viral transmission, according to the authors.

Mucosal Vaccines in the Pipeline

While mucosal vaccines may hold promise, clinical trials have only recently begun. Among 96 vaccine candidates in clinical trials, just eight are intranasal vaccines. Clinical trials are being conducted in the U.S., U.K., China, India, Cuba, and Iran, according to World Health Organization data released on May 5.

Two intranasal vaccine candidates are in phase II clinical trials. One uses a live-attenuated influenza virus adapted to express the spike protein of SARS-CoV-2, and is being developed by the University of Hong Kong, Xiamen University, and the Beijing Wantai Biological Pharmacy Enterprise, in partnership with the Coalition for Epidemic Preparedness Innovations (CEPI). The second is a protein subunit vaccine that is being developed by Razi Vaccine and Serum Research Institute in Iran.

In the U.S., two intranasal vaccine candidates are in phase I trials. The first is Altimmune's nonreplicating adenoviral vector vaccine called AdCOVID. On March 25, the company released preclinical results in mice suggesting that the vaccine was protective against illness, decreased levels of replicating virus in the nose and respiratory tract, and produced a "robust" IgG response. Past results in mice had shown that IgA antibodies were maintained for at least 6 months after a single dose of the vaccine.

The second is Meissa's live-attenuated candidate. Preclinical data in nonhuman primates have suggested that the candidate induced mucosal IgA and serum neutralizing antibodies, and was "highly protective" against infection with SARS-CoV-2 in the upper and lower respiratory tract.

Other intranasal vaccine candidates in clinical trials include: Cuba's Center for Genetic Engineering & Biotech protein subunit vaccine (phase I/II); the University of Oxford/AstraZeneca's Covishield, a nasal spray version of its ChadOx1 vaccine (phase I); Codagenix/Serum Institute of India's live-attenuated SARS CoV-2 COVI-VAC vaccine (phase I); and India's Bharat Biotech's non-replicating adenoviral vector vaccine.

Recently, China's CanSino Biologics announced plans to start a phase I/II trial of another inhaled vaccine, according to an emailed news release from the data and analytics company Global Data.

Because SARS-CoV-2 also infects the GI tract, another potential site of mucosal immunity, oral vaccines are also in clinical trials. Maryland's Vaxart recently announced that it will be advancing one oral vaccine candidate to a phase II trial, and two oral vaccine candidates to phase I/II trials. California's Immunity Bio has a nonreplicating human adenoviral vector vaccine in a phase Ib trial, and Symvivo/Merck's DNA-based vaccine is in a phase I trial in Australia.

Advantages and Drawbacks

Both oral and intranasal vaccines offer the advantage of being stable at room temperature, making them easier to ship and potentially improving access to vaccination in remote or resource-poor settings. Both offer the advantage of easier administration, in the form of a nasal spray, pill, or drop on the tongue. That, in turn, may help improve acceptance, especially among children and the needle-shy, Russell said.

Nevertheless, mucosal vaccines do have drawbacks. While they can produce both systemic and local immunity, one stumbling block is producing effective, long-lasting immunity. Mucosal surfaces contain various barriers to pathogens -- high acidity in the upper GI tract, sticky layers of mucous in the respiratory system -- which may interfere with the ability of vaccines to access and activate the mucosal immune system. That could contribute to poor immunogenicity and faster waning immunity.

For instance, the intranasal flu vaccine FluMist has had a rocky road, in part because of lower effectiveness compared to injectable flu vaccines.

"There are not many licensed mucosal vaccines," Kennedy said. "These vaccines are effective for certain pathogens, but this may or may not be true for SARS-CoV-2."

Safety is another consideration. The majority of mucosal vaccines licensed in the U.S. are delivered via the oral route. Perhaps because of closer proximity to the brain, vaccine regulators appear to have shied away from the intranasal route. For example, Berna Biotech's inactivated intranasal influenza vaccine was discontinued in Switzerland after it was found to be associated with increased risk of Bell's Palsy.

Still, because oral vaccination tends to produce an antibody response that is not so strong in the respiratory tract, Russell contends that intranasal immunization "makes the most sense" for a respiratory pathogen like SARS-CoV-2.

"If similar resources can be made available for the accelerated development of intranasal vaccines, as have been deployed for the existing vaccines, my guess is that we might see some of them becoming available within about a year," he said.

https://www.medpagetoday.com/special-reports/exclusives/92527

COVID Risks Raised in Rheumatoid Arthritis

 Patients with rheumatoid arthritis (RA) were at increased risk for both COVID-19 and related hospitalization and death, a national VA study found.

Compared with non-RA patients and after adjustment for demographics, comorbidities, healthcare utilization, and local incidence rates, patients with RA had a 25% higher risk of COVID-19 (HR 1.25, 95% CI 1.13-1.39, P<0.05), reported Bryant R. England, MD, PhD, of the University of Nebraska Medical Center in Omaha, and colleagues.

Patients also had a 35% higher risk of COVID-19 hospitalization and death (HR 1.35, 95% CI 1.10-1.66, P<0.05), according to the study online in Arthritis & Rheumatology.

Patients with RA have an elevated risk for infections overall because of the immune dysregulation inherent in their disease, their common comorbidities, and from the immunosuppressive medications required for disease control. However, most research into infection risks among RA patients has focused on bacterial, not viral, infections.

England and co-authors noted that with the widening use of COVID-19 vaccines, priority had been given to individuals with a number of chronic conditions such as cancer, cardiovascular disease, chronic kidney disease, and diabetes, but patients with rheumatic diseases were not included in those early priority recommendations.

The team noted that although a few studies have considered rates of COVID-19 and outcomes among patients with rheumatic diseases, they were mostly limited by selection bias, heterogeneous populations, and the inclusion of a wide variety of conditions and treatments.

Therefore, to look specifically at the risks in RA, England and colleagues conducted a retrospective cohort study using Veterans Health Administration data collected from January to December 2020. Comorbidities were reported according to the Elixhauser comorbidity index, focusing on conditions that are recognized as conferring increased risks for COVID-19. Local incidence rates of COVID-19 were obtained from the data repository at Johns Hopkins University in Baltimore.

Medication use for the patient data assessed included prednisone, conventional synthetic disease-modifying anti-rheumatoid drugs (DMARDs) such as methotrexate, biologics such as tumor necrosis factor inhibitors, and targeted synthetic DMARDs such as JAK inhibitors.

The analysis included 33,886 patients with RA who were matched with the same number of non-RA patients. Those with RA were more likely to have more comorbidities, to be smokers, to have a high body mass index (BMI), and to have been hospitalized within the previous year. Recent use of DMARDs was reported for 73% of RA patients, while biologics or targeted DMARDs had been used by 34.2%.

The researchers found that during 62,894 patient-years of follow-up, there were 1,503 cases of COVID-19 among RA patients, with 388 leading to hospitalization or death (345 hospitalizations; 84 deaths). During the same follow-up period, 288 patients died of non-COVID causes.

Factors other than RA found to be significantly associated with a higher risk of COVID-19 infection (P<0.05) were:

• Black race, HR 1.22 (95% CI 1.07-1.39)
• Hispanic ethnicity, HR 1.48 (95% CI 1.23-1.78)
• Higher Elixhauser comorbidity score (per one unit), HR 1.12 (95% CI 1.09-1.15)
• Having no insurance, HR 1.40 (95% CI 1.24-1.58)
• Having a VA service-connected condition, HR 1.22 (95% CI 1.10-1.37)
• Number of hospitalizations in previous year, HR 1.11 (95% CI 1.05-1.16)
• County incidence rate per 100,000, HR 1.00 (95% CI 1.00-1.00)

In addition, having a BMI either below or above the normal range was associated with increased risk, with hazard ratios ranging from 1.36 to 1.78.

For COVID-19 hospitalization/death, increased risks (P<0.05) were observed for patients with a higher Elixhauser comorbidity score (HR 1.24, 95% CI 1.20-1.30), lack of insurance (HR 1.88, 95% CI 1.49-2.37), hospitalization in the previous year (HR 1.13, 95% CI 1.06-1.21), and county COVID-19 incidence rate (HR 1.00, 95% CI 1.00-1.00).

The investigators also undertook secondary analyses looking at the influence of medications, and found an increased risk both of COVID-19 infection (HR 1.66, 95% CI 1.36-2.03) and hospitalization/death among patients treated with DMARDs, biologics and targeted synthetic drugs, and prednisone (HR 2.12, 95% CI 1.48-3.03).

The investigators noted that the elevated risk of COVID-19 in RA patients was similar to what has been observed for patients with other chronic conditions. "Consideration should be given to establishing RA, and potentially other conditions that require treatment with similar immunosuppressive medications, as a chronic condition that receives prioritization for COVID-19 prevention and management strategies," England and co-authors wrote.

A limitation of the study, they said, was the observational design and the possibility of unmeasured confounding.

Disclosures

The study was supported by the University of Nebraska Medical Center, the VA, the Rheumatology Research Foundation, and the National Institute of General Medical Science.

England reported a financial relationship with Boehringer-Ingelheim; co-authors reported financial relationships with Bristol Myers Squibb, Horizon, Pfizer, Sanofi, and Gilead.

Primary Source

Arthritis & Rheumatology

Source Reference: England BR, et al "Risk of COVID-19 in rheumatoid arthritis: A national Veterans Affairs matched cohort study in at-risk individuals" Arthritis Rheum 2021; DOI: 10.1002/art.41800.

https://www.medpagetoday.com/rheumatology/arthritis/92530

More states ending boosted unemployment benefits amid hiring concerns

 A growing number of GOP-led states are planning to end supplemental unemployment benefits designed to help out-of-work Americans weather the coronavirus pandemic, a move they say will help businesses struggling to hire employees.

Alabama, Iowa and Mississippi joined Arkansas, Montana and South Carolina on Tuesday in cutting off the sweetened aid, which provided an extra $300 a week on top of regular state unemployment benefits. The supplemental benefit is not slated to expire until Sept. 6, 2021.

Arizona reinstated a policy requiring people who want to collect unemployment benefits to actively search for work. Vermont also reimplemented a similar policy as of this week.

The new measures come in light of the Labor Department's April payroll report, which revealed the economy added just 266,000 jobs last month – sharply missing the 1 million forecast by Refinitiv economists. GOP lawmakers were quick to blame the extra unemployment aid for the lackluster job growth, although experts have also cited a lack of child care and fears of contracting COVID-19 for the hiring shortage. 

There remain about 8.2 million fewer jobs than there were in February 2020, before the pandemic shut down broad swaths of the nation's economy. 

"It has become clear to me that we cannot have a full economic recovery until we get the thousands of available jobs in our state filled," Mississippi Gov. Tate Reeves, a Republican, said in a tweet.  

The average state unemployment benefit is about $330 per week. With the federal supplement, Americans are receiving about $630 in weekly unemployment benefits. (For comparison's sake, that's about $32,000 annually, or roughly double the nation's minimum wage.)

President Biden and Democrats have rejected the notion that Americans are choosing to stay home and collect the extra unemployment benefits – part of the $1.9 trillion coronavirus relief law passed in March – rather than returning to work. 

"We don't see much evidence of that," Biden told reporters during a White House press conference on Monday. "Americans want to work."

But even as he maintained that his administration would not "turn our backs on our fellow Americans," Biden pledged to enforce unemployment insurance laws so that no American can "game the system" to get paid not to work

"We’re going to make it clear to anyone collecting unemployment who is offered a suitable job they must take the job or lose their unemployment benefits," Biden said.

During a news conference last week, Federal Reserve Chairman Jerome Powell said it was unclear whether the $300-a-week bump was hurting businesses' efforts to onboard new employees. Powell said if it is a factor, it won't be in a few months, when the program expires. 

"My guess is we'll come back to this economy where we have equilibrium between labor supply and labor demand," he said. "It may take some months, though." 

https://www.foxbusiness.com/economy/states-ending-boosted-unemployment-benefits-hiring-concerns

Data on Covid-19 Vaccines for Children Under 12 Expected by Late Fall

 There will likely be enough evidence by late fall this year to potentially extend the use of Covid-19 vaccines to many children under age 12, Biden administration health officials told a U.S. Senate panel Tuesday.

"We expect to have data on the safety and effectiveness of vaccines for children under 12" by that time, David Kessler, the administration's chief Covid-19 scientific officer, told the Senate Committee on Health, Education, Labor and Pensions.

Administration medical adviser Anthony Fauci told the panel that such steps to vaccinate younger children will probably occur in stages, progressing younger and younger, as study evidence accumulates.

The testimony occurred a day after the Food and Drug Administration greenlighted the use of a Covid-19 vaccine from Pfizer Inc. and BioNTech SE in youngsters 12 through 15. That vaccine was authorized late last year by the FDA for broad use in adults from age 16 and older.

It also followed last week's decision by the Biden administration to support the temporary waiver of intellectual property provisions to allow developing nations to produce Covid-19 vaccines created by pharmaceutical companies, citing the need to stop the virus's spread globally.

Sen. Richard Burr (R., N.C.), the committee's ranking Republican, criticized that decision, calling on the U.S. to "let the private sector continue" its impressive performance on vaccines so far.

Dr. Kessler acknowledged that "a waiver alone won't result in the scale and speed" of vaccine production needed to end the global pandemic.

To combat Covid-19 around the world, the Biden administration has just redirected a U.S. order of AstraZeneca vaccine manufacturing supplies to India, which will allow that nation to make over 20 million doses of vaccine, Dr. Kessler said. The U.S. is also delivering supplies to help supply medical oxygen for patients in India, he said, as the pandemic there rages largely out of control.

The Senate hearing covered a swath of Covid-19 topics. Rochelle Walensky, director of the federal Centers for Disease Control and Prevention, testified that despite the widespread U.S. vaccination campaign, continued mask-wearing, social distancing and other fundamental public-health measures still are necessary to avoid Covid-19 variants that could spread much more quickly than the original virus.

While the U.S. vaccination campaign has had considerable success, she said, "available data suggest that antibodies elicited by vaccination with the currently authorized vaccines are able to neutralize the [U.K.] B.1.1.7 variant but have reduced neutralization" against those first identified in South Africa and Brazil.

Peter Marks, the director of the FDA's center that evaluates vaccines, said the agency continues to consider whether to license a troubled vaccine plant in Baltimore run by Emergent BioSolutions Inc. The facility made about 110 million total doses of Johnson & Johnson vaccine and AstraZeneca PLC vaccine.

The doses, about 60 million from AstraZeneca and the remainder from Johnson & Johnson, can't be used until the FDA signs off on safety of the plant.

Dr. Marks said those doses already manufactured "will undergo additional testing and will be thoroughly evaluated to ensure their quality before any potential distribution."

https://www.marketscreener.com/quote/stock/PFIZER-INC-23365019/news/Data-on-Covid-19-Vaccines-for-Children-Under-12-Expected-by-Late-Fall-Health-Officials-Say-33227850/

Bharat Biotech COVID Vax Recommended For Phase 2/3 Trials On 2-18 Year-Olds

 Bharat Biotech's COVID-19 vaccine Covaxin was on Tuesday recommended by an expert panel for phase II/III clinical trial on those aged between two to 18 years, official sources said.

The trial will take place in 525 subjects at various sites, including AIIMS, Delhi, AIIMS, Patna and Meditrina Institute of Medical Sciences, Nagpur.

The Subject Expert Committee (SEC) on COVID-19 of the Central Drugs Standard Control Organization (CDSCO) on Tuesday deliberated upon Hyderabad-based Bharat Biotech's application seeking permission to conduct phase II/III clinical trials to evaluate the safety, reactogenicity and immunogenicity of Covaxin jabs in children aged 2 to 18 years.

"After detailed deliberation, the committee recommended for conduct of proposed phase II/III clinical trial of whole virion inactivated coronavirus vaccine in the 2 to 18 years age group subject to the condition that the firm should submit the interim safety data of phase II clinical trial along with DSMB recommendations to the CDSCO before proceeding to phase III part of the study," a source said.

Earlier the proposal was deliberated in the SEC meeting dated February 24 and the firm was asked to submit a revised clinical trial protocol.

Covaxin, indigenously developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR), is being used in adults in India's ongoing COVID-19 vaccination drive.

https://www.newindianexpress.com/nation/2021/may/12/bharat-biotechs-covaxin-recommended-by-expert-panel-for-phase-ii--iiitrials-on-2-18-year-olds-2301376.html