PARIS - Banned in some countries, promoted in others -- the drug hydroxychloroquine as a potential treatment for the new coronavirus is dividing opinion worldwide.
Scientists looking to find licensed medicines that could be repurposed as a treatment for COVID-19 had started tests of hydroxychloroquine, normally used to treat arthritis, and chloroquine, an anti-malarial.
Both drugs can produce potentially serious side effects, particularly heart arrhythmia, leading many experts to warn against their use outside of clinical trials.
But that has not stopped prominent figures like US President Donald Trump endorsing hydroxychloroquine despite a lack of evidence of its efficacy.
Escalating the debate, The Lancet on May 22 published a study of nearly 100,000 coronavirus patients that showed no benefit in treating them with the two drugs - and even increased the likelihood of them dying in hospital.
This led the World Health Organization to suspend clinical trials of hydroxychloroquine, but dozens of scientists have since raised concerns over the study's methodology.
The Lancet corrected part of the data, but researchers have stood by their conclusions.
Countries worldwide vary on their own policies.
BANNED
The study prompts several countries to halt the use of hydroxychloroquine.
France does so on May 27, days after controversial French doctor Didier Raoult - whose own methodology has been questioned - rejected the study and stood by his belief the drug can help patients recover from the virus.
Other countries including Italy, Egypt, Tunisia, Colombia, Chile, El Salvador, Cape Verde, Albania, and Bosnia and Herzegovina also ban the use of the drug for COVID-19 patients, though in Italy it remains possible in clinical trials.
Hungary meanwhile does not use the drug "for newly diagnosed patients" but continues to do so "for patients who already started taking it", according to a government spokesperson.
Even before the study some countries had stopped using hydroxychloroquine for COVID-19 patients.
Sweden had used the drug in the early phases of the pandemic to treat patients with severe symptoms, but halted its use in April after the European Medicines Agency recommended it only be used in clinical trials.
Germany too had judged that the current studies did not allow for the drug to be used on individual COVID-19 patients and it could only be used in clinical trials.
PROMOTED
Several countries continue to promote the use hydroxychloroquine in the fight against the virus.
These include Brazil, Algeria, Morocco, Turkey, Jordan, Romania, Portugal, Kenya, Senegal, Chad and the Republic of Congo.
Russia, Bahrain, Oman and the United Arab Emirates have not yet suspended the use of the drug either, and in Iran recent social media posts of prescriptions show virus patients are still receiving it there.
Thailand is also still using hydroxychloroquine in its treatment of COVID-19 patients, and India and Venezuela continue to use the drug as a preventative measure.
Cuba too is using the drug but will revise its protocols to introduce further precautions.
In the US hydroxychloroquine can only in principle be given to COVID-19 patients in hospital, but the Food and Drug Administration (FDA) warned in April that the drug could have potential harmful impact on the heart.
Trump had promoted the use of the drug and even said he was taking hydroxychloroquine as a precaution, before saying shortly after the publication of the study that he had stopped.
CLINICAL TRIALS SUSPENDED
The study has led to the suspension of the use of the drug in several clinical trials including the WHO's Solidarity Trial and Europe's Discovery program coordinated by France's Inserm research institute.
The international trial Copcov also suspended its use of doses on medical personnel in contact with the virus.
Two trials led by the University of Tuebingen clinic in Germany and five trials in Denmark have also been suspended and Mali says it is ready to suspend its clinical trials too.
STILL TESTING
But other clinical trials are continuing, such as the Recovery trial in Britain, the one by McGill University in Canada and ones taking place in Nigeria and Mexico.
In China the drug is only used in clinical trials but its potential as a treatment, considered promising by the University of Wuhan in February, has since been called into question by a respected hospital in Shanghai.
Agence France-Presse
WASHINGTON - The antimalarial drug hydroxychloroquine has shown mixed results against the coronavirus in early studies, but a new paper out of New York suggests combining it with the dietary supplement zinc sulfate could create a more effective treatment.
The research by the NYU Grossman School of Medicine was posted on a medical preprint site on Monday, meaning it hasn't yet been peer reviewed.
Records of about 900 COVID-19 patients were reviewed in the analysis, with roughly half given zinc sulfate along with hydroxychloroquine and the antibiotic azithromycin.
The other half only received hydroxychloroquine and azithromycin.
Those receiving the triple-drug combination had a 1.5 times greater likelihood of recovering enough to be discharged, and were 44 percent less likely to die, compared to the double-drug combination.
It did not, however, change the average time patients spent in hospital (6 days), the time they spent on the ventilator (5 days), or the total amount of oxygen required.
Senior investigator and infectious disease specialist Joseph Rahimian told AFP it was the first study to compare the two combinations.
But he cautioned that a controlled experiment would be needed to prove the benefits beyond doubt.
"The next logical step would be to do a prospective study to see if this holds up in people that you give zinc to, and then you watch and compare," he said.
Hydroxychloroquine has been proposed as a treatment against the SARS-CoV-2 virus because it has antiviral properties that have been proven in lab settings, but not in people.
It interferes with the virus' ability to enter the cells -- and also seems to block them from replicating once they are already inside.
Zinc itself has antiviral properties and past research has suggested it may reduce the time people suffer from common colds.
Rahimian said that it may be that when used to treat coronavirus patients, it is the zinc that does the heavy lifting and is the primary substance attacking the pathogen.
Hydroxychloroquine, on the other hand, acts as an agent that transports the zinc into cells, increasing its efficacy, he suggested.
Agence France-Presse
The primary lupus drug to prevent disease flare and currently prescribed for long term maintenance by rheumatologists is in critical short supply in our country and worldwide.
Hydroxychloroquine is taken by lupus patients who are usually young, pregnancy-bearing-age women on their most productive years. They rely on this essential drug to keep their disease inactive. The prospect of using hydroxychloroquine to treat Covid-19 amid the novel coronavirus pandemic has sparked heated debate among politicians and scientists. Prominently endorsed by US president Trump, there have been indications that the drug is effective in treating or preventing Covid-19, but the studies have not endured the due diligence of extensive clinical trials.
Hydroxychloroquine, an old drug, is a derivative of chloroquine that originates from a compound named quinine isolated from the bark of the cinchona tree by French chemists way back in 1820. In 1934, German scientists created the synthetic chloroquine as part of a class of anti-malarial. Touted for its relatively safety profile for long term use, hydroxychloroquine is the less-toxic version of chloroquine.
In the labs, hydroxychloroquine has demonstrated some efficacy against SARS Cov-2 responsible for the present pandemic. In-vitro data demonstrated its role in preventing viral loading and replication of the coronavirus. Studies on humans to date have presented conflicting conclusions and robust studies are highly warranted. Since 2006, it has not been recommended for use in severe malaria by the World Health Organization (WHO) because of problems with resistance, and it has been primarily used since then as a disease-modifying, anti-rheumatic drug classified by the American College of Rheumatology.
Aside from the drug’s widespread and approved use for lupus, it is used to treat other autoimmune diseases like rheumatoid arthritis, juvenile arthritis and some forms of connective tissue disease mainly acting as an immune modulator. The drug has demonstrated established efficacy and safety on the innate and adaptive immune system of the body in published studies, the system that runs on overdrive among critically ill covid-19 patients.
Since the pandemic erupted, hydroxychloroquine together with chloroquine has been explored for off-label use among moderate and severe Covid-19 patients and has been included among treatment guidelines in the Philippines and abroad based on the small and limited clinical data currently available.
When the US Food and Drug Administration issued an emergency use authorization to treat Covid-19 patients with the drug, the supply dramatically ran short versus the global demand. Stockpiling of the drug to the point of hoarding became an issue among countries and even individuals, compromising the continued care of patients with these rheumatic conditions. Current inventories of here and abroad are based on the proportional demand of these rheumatic disease patients thus, overwhelming the drug supply chain brought about by this pandemic.
Lupus patients routinely use the drug as a steroid sparer, the steroids being another main lupus medication with more toxic side effects, making hydroxychloroquine the preferred lupus drug for chronic therapy by rheumatologists. It is also the only known therapy for primary Sjogren’s syndrome, another autoimmune disorder.
The role of hydroxychloroquine for compassionate intake among sick Covid-19 patients is currently being widely utilized but using it to prevent or protect you from being infected is highly discouraged. This alarming practice contributes to the acceleration of worldwide run of the drug and promotes shortages of supply specially to developing countries like ours. While we await large scale clinical trials including the WHO initiated global solidarity study that includes hydroxychloroquine as part of the treatment arm, data to support the use of hydroxychloroquine and chloroquine for Covid-19 at the moment are inconclusive.
Unfortunately, reports of adverse events using inappropriate dosages and preparations have increased with the anti-malarial use. These drugs in acute use can cause heart rhythm abnormalities which may pose particular risk to critically ill persons especially on high doses.
It is our ethical obligation as physicians and researchers to organize and refer patients to expedited, well-performed randomized trials that can clarify the safety and efficacy for its potential for Covid-19 fight. Whereas, the evidence supporting the use of antimalarial medications for Covid-19 is equivocal, the evidence for the use of these drugs to treat immune-mediated diseases is not.
Hydroxychloroquine is a cornerstone of therapy for systemic lupus erythematosus. Major clinical trials have demonstrated that the withdrawal of hydroxychloroquine can lead to flares of the disease, including life-threatening manifestations, such as lupus nephritis (a severe form of kidney involvement) and higher incidence of thrombotic risk namely stroke or heart attack. The Philippine Rheumatology Association (PRA) has noted a sharp rise on queries from concerned patients who are having difficulty obtaining their medication.
Given the likelihood that shortages will continue in the near term, we propose that manufacturers, clinicians, pharmacies, health systems, and governmental health agencies continue to coordinate an aggressive response to ensure that antimalarial drug use is appropriately managed during the Covid-19 pandemic.
Among the two drugs used in Covid-19 fight, PRA advocates the use of chloroquine over hydroxychloroquine among hospitalized patients using our local treatment guidelines and following safety criteria parameters for its use. This enables rationing of supply for hydroxychloroquine among patients with rheumatic conditions. The pharmacokinetics of hydroxychloroquine are an important consideration in guiding the clinicians on its optimal dosage and use given the shortages experienced by these patients. The long half-life of the drug means that brief gaps in therapy, on the order of 1 to 2 weeks, are less concerning.
However, longer treatment lapses put patients at risk for disease exacerbations, given studies showing that lower blood levels of hydroxychloroquine correlates with more lupus disease activity. A higher incidence of lupus flares was seen as soon as 2 weeks after the drug was stopped were reported. Some patients may do better than others with this approach and it is important to communicate closely with your doctor by utilizing all possible means including non-contact, electronic consults for patients on long term maintenance use of this drug during this pandemic.
The looming public health crisis for people with rheumatic diseases who will be unable to obtain hydroxychloroquine is the result of a perfect storm of fear and dissemination of overpromised data. However, there is still time to mitigate the damage. Physicians should educate themselves about the strength of available data regarding antimalarials in treating Covid-19, and public figures should refrain from promoting unproven therapies to the public.
More than 20 trials are being carried out globally and Philippines will be able to participate. In the meantime, physicians should remember our sacred oath that first, we must do no harm and always practice sound clinical judgement with the use of these potentially life-saving drugs. We must also keep in mind our Filipino patients with rheumatic disease for whom high-quality evidence shows that hydroxychloroquine improves health.
Email: evanvistamd@yahoo.com
Sources: The Rheumatologist, American College of Rheumatology, Annals of Internal Medicine, WHO, and DOH
ABOUT THE AUTHOR:
Evan Silverio Vista, MD heads the rheumatology section of Ospital ng Makati. He is an active consultant, associate professor and research professorial chair in rheumatology at St. Luke’s Medical Center (Bonifacio Global and Quezon city) and College of Medicine Manila, Philippines. Dr. Vista currently serves in the Board of Trustees of The Philippine Rheumatology Association and the advocacy and research chair of the organization. He is a member of the fellowship training committee of University of Santo Tomas Hospital Section of Rheumatology, Clinical Immunology and Osteoporosis. He was an Associate Research Scientist at Oklahoma Medical Research Foundation-Department of Arthritis and Clinical Immunology. He authored several peer reviewed journals in rheumatology and book chapters in Lupus and a member of the American College of Rheumatology and of the Clinical Immunology Society.
• Email at : esvista@stlukes.com.ph
news.abs-cbn.com
ZURICH - Novartis has reached an agreement with U.S. regulators to hold a randomized trial of generic malaria drug hydroxychloroquine against COVID-19 disease in 440 hospitalized patients, the Swiss drugmaker said on Monday.
The decades-old medicine has received U.S. Food and Drug Administration (FDA) emergency use authorization for coronavirus disease, but so far there is no scientific proof it helps those afflicted.
"We recognize the importance of answering the scientific question of whether hydroxychloroquine will be beneficial for patients with COVID-19 disease,” said John Tsai, Novartis's top drug developer.
The drug, also used to treat lupus and rheumatoid arthritis, has been promoted by President Donald Trump, with some worried the administration's advocacy for an unproven medicine for COVID-19 has short-circuited the oversight process. (Reporting by John Miller, editing by John Revill)
-reuters-
Could a pair of decades-old, relatively inexpensive drugs be the solution to the novel coronavirus pandemic?
Around the world, countries are expanding access to hydroxychloroquine (HCQ) and chloroquine (CQ), related compounds that are synthetic forms of quinine, which comes from cinchona trees and has been used for centuries to treat malaria.
HQ which is the less toxic of the two, is also used as an anti-inflammatory to treat conditions like rheumatoid arthritis and lupus, purposes it is primarily known for outside the tropics.
The medicines have shown early promise against the COVID-19 illness in early studies in France and China, which led US President Donald Trump this week to call them a "gift from God" -- even as experts urge caution until bigger trials validate their effectiveness.
Here is what you need to know.
- Why they might work -
China used CQ on a trial of 134 patients in February, finding it was effective in reducing the severity of the illness, according to officials.
But these results haven't yet been published. Chinese respiratory expert Zhong Nanshan, who leads a government task force in response to the epidemic, said in a press conference last week that the data would be widely shared soon.
In France, a team led by Didier Raoult of the IHU-Mediterranee Infection, Marseille reported last week they had carried out a study on 36 COVID-19 patients, finding that HCQ drastically reduced the viral load in a group which received the drug.
The effects were especially pronounced when it was used with azithromycin, a common antibiotic used to sweep out secondary bacterial infections.
What's more, HCQ and CQ drugs have been proven to act against the SARS-CoV-2 virus in lab settings, and a paper published by a Chinese team last week in Cell Discovery offered a potential mode of action.
Karine Le Roch, a professor of cell biology at the University of California, Riverside, explained that both HCQ and CQ are weak bases that elevate the pH of parts of human cells called organelles -- which are analogous to organs in animals -- and which are normally acidic.
This in turn interferes with the virus' ability to enter the cells -- and also seems to block them from replicating once they are already inside.
But, she added: "While it worked in vitro, I am still waiting to see published results of large blind clinical trials demonstrating the efficacy of HCQ in vivo," she told AFP.
- The case for caution -
Promise doesn't mean proof, and the small studies carried out so far amount to "anecdotal" evidence, according to Anthony Fauci, head of infectious diseases at the US National Institutes of Health.
What's more, a small Chinese study on 30 patients that was also published this month found HCQ was no better than standard care -- meaning treating the symptoms via bed rest, fluids and so on -- adding a note of caution to the discourse.
The only way to know for sure is to carry out randomized clinical trials, scientists say. Such experiments are considered the gold standard in the field but last months or years and involve thousands of patients, often from around the world.
Patients are assigned at random to either receive the drug under investigation or a placebo, and the studies are "blinded" meaning the participants and their doctors are unaware which group they are in, to further reduce bias.
Overhyping medicine can have several unintended effects, warn experts.
"One of the unintended consequences are drug shortages of chloroquine, for people that need to manage their rheumatoid arthritis, for example," Peter Pitts, a former commissioner of the Food and Drug Administration told AFP.
A few countries are taking a cautious approach. Spain, for example, announced Monday said that "until further notice" these arthritis and lupus patients would be given priority access to the drug.
French Health Minister Olivier Veran meanwhile said the compounds can be used only to treat the most severe cases of COVID-19.
Another problem is that people may try to self-medicate. A US man from Arizona died this week after ingesting a form of chloroquine intended to fight aquatic parasites.
- Side effects -
Several countries have now embarked on clinical trials, including the United States, where one began in New York this week.
Italy is carrying out a trial on 2,000 people, while scientists are also awaiting the results from bigger trials in China.
But while the drugs are being rolled out for compassionate use, it is critical to bear in mind safety precautions.
About one percent of people are at high risk of blackouts, seizure or even sudden death from cardiac arrest because of heart rhythm issues they may themselves be unaware of, Michael Ackerman, a genetic cardiologist at Mayo Clinic told AFP.
Medical teams must therefore perform electrocardiograms to inform their risk analysis before using these medicines, he said.
"All focus is placed on the hope for therapeutic efficacy of these medications, without any reasonable amount of respect, not fear, but respect for what the potential side effects of these very powerful medications are," said Ackerman.
source: news.abs-cbn.com
PARIS - France's drug safety agency warned on Monday of potentially serious side effects of treatments being tested against the new coronavirus after the deaths of three people possibly linked to self-medication.
Another two dozen patients have reported undesirable side effects after taking Plaquenil -- the brand name of hydroxychloroquine -- as well as other medicines such as the antiretroviral Kaletra, the agency's head Dominique Martin told AFP.
He said experts were trying to determine whether the drugs were linked to the side effects, with initial conclusions expected by the end of the week.
The drug safety agency (ANSM) began boosting its surveillance two weeks ago of trials of drugs against COVID-19, "in particular when they are used outside of clinical trials of chloroquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir (Kaletra), tocilizumab (and) colchicine," Martin said.
"It's perfectly normal that treatments be tried, given the circumstances, but that doesn't mean we shouldn't observe surveillance... of these substances," Martin said.
Combining hydroxychloroquine with the antibiotic azithromycin has been in the spotlight since French researcher Didier Raoult published two studies that he said showed the treatment's effectiveness against COVID-19.
The treatment needs "particular attention", Martin said, because using the two drugs together runs the risk of arrhythmia and could provoke a heart attack.
This was "even more the case with patients suffering from COVID-19" because of metabolic problems associated with the disease, he said.
Agence France-Presse
The United States has recorded more than 43,000 cases of COVID-19 including 20,000 in New York state alone, a report by the ABS-CBN North America News Bureau said Tuesday.
The report said there are now 3,000 COVID-19 cases in New Jersey, 2,000 in California and more than 2,000 in Washington state.
President Donald Trump earlier pushed for hydroxychloroquine, an anti-malarial drug, as a treatment for the coronavirus.
Dr Anthony Fauci, the head of the US National Institute of Allergy and Infectious Diseases, however, said claims that hydroxychloroquine can be used to treat COVID-19 are "anecdotal reports."
DZMM, March 24, 2020
