TREATMENT OF COVID-19-HYDROXUCLOROQUINE SEEMS TO BE OF NO BENEFIT

Hydroxychloroquine (HCQ) with or without azithromycin (AZ) is not associated with a lower risk of requiring mechanical ventilation, according to a retrospective study of Veterans Affairs (VA) patients hospitalized with COVID-19. The study, which was posted on a preprint server April 21 and has not been peer reviewed, also showed an increased risk of death associated with COVID-19 patients treated with HCQ alone. "These findings highlight the importance of awaiting the results of ongoing prospective, randomized controlled studies before widespread adoption of these drugs," write Joseph Magagnoli, MS, with Dorn Research Institute at the Columbia VA Health Care System, Columbia, South Carolina, and the Department of Clinical Pharmacy & Outcomes Sciences, University of South Carolina, and colleagues. A spokesperson with University of Virginia School of Medicine, where several of coauthors practice, told Medscape Medical News the authors declined to comment for this article before peer review is completed. The new data are not the first to suggest no benefit with HCQ among patients with COVID-19. A randomized trial showed no benefit and more side effects among 75 patients in China treated with HCQ compared with 75 who received standard of care alone, according to a preprint posted online April 14. No Benefit in Ventilation, Death Rates The current analysis included data from all 368 male patients hospitalized with confirmed COVID-19 and treated at Veterans Health Administration (VA) medical centers in the United States through April 11. Patients were categorized into three groups: those treated with HCQ in addition to standard of care (n = 97); those treated with HCQ and the antibiotic azithromycin plus standard of care (n = 113); and those who received standard supportive care only (n = 158). Table. Outcomes for Three Study Groups GroupRates of Ventilation (%)Rates of Death (%)HCQ13.3  27.8HCQ+AZ  6.9  22.1No HCQ14.1  11.4 Compared with the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio [aHR], 2.61; 95% confidence interval (CI), 1.10 - 6.17; P = .03) but not in the HCQ+AZ group (aHR, 1.14; 95% CI, 0.56 - 2.32; P = .72).

Σελίδα 2 από 2 The risk of ventilation was similar in the HCQ group (aHR, 1.43; 95% CI, 0.53 - 3.79; P = .48) and in the HCQ+AZ group (aHR, 0.43; 95% CI, 0.16 - 1.12; P= .09), compared with the no HCQ group. This study provides another counterbalance to claims of HCQ efficacy, David R. Wessner, PhD, professor of biology and chair of the Department of Health and Human Values at Davidson College in Davidson, North Carolina, told Medscape Medical News. Interest in HCQ spiked after an open-label, nonrandomized, single-center studyof COVID-19 patients in France suggested that hydroxychloroquine helped clear the virus and had a potential enhanced effect when combined with azithromycin. But as Medscape and Retraction Watch previously reported, the 36-patient trial has since been called into question. Wait for Convincing Data Wessner, whose research focuses on viral pathogenesis, says that although the current data don't definitively answer the question of whether HCQ is effective in treating COVID-19, taking a "let's try it and see" approach is not reasonable. "Until we have good, prospective randomized trials, it's hard to know what to make of this. But this is more evidence that there's not a good reason to use [HCQ]," Wessner said. He points out that the small randomized trial from China shows that HCQ comes with potential harms. Anecdotal evidence is often cited by those who promote HCQ as a potential treatment, but "those are one-off examples," Wessner continued. "That doesn't really tell us anything." Some HCQ proponents have said that trials finding no benefit are flawed in that the drug is given too late. However, Wessner says, there's no way to prove or disprove that claim without randomized controlled trials. Conflicting Messages Despite lack of clear evidence of benefit for patients with COVID-19, HCQ is recommended off-label by the Chinese National guideline, and the US Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19. Conversely, the Infectious Diseases Society of America and a guideline panelconvened by the National Institutes of Health each concluded recently that because of insufficient data, they could not recommend any specific treatments for patients with COVID-19. The VA data for the current study came from the Veterans Affairs Informatics and Computing Infrastructure (VINCI), which includes inpatient, outpatient and laboratory data and pharmacy claims. The authors acknowledge some limitations, "including those inherent to all retrospective analyses such as non-randomization of treatments." However, they note that they did adjust for potential confounders, including comorbidities, medications, and clinical and laboratory factors. A coauthor, Jayakrishna Ambati, MD, is a cofounder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. Ambati is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work. Another coauthor has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all unrelated to this work. The other authors and Wessner have disclosed no relevant financial relationships. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

In the face of the rapidly evolving COVID-19 pandemic and the absence of FDA-approved treatments, the National Institutes of Health (NIH) has issued "living" treatment guidelines. The recommendations will be updated online as new data from peer-reviewed publications and other authoritative information become available.

A multidisciplinary panel of 30 scientific, clinical, and government experts started working on the guidelines in late March. They released the first iteration online yesterday. Other groups, including the Infectious Diseases Society of America, have previously provided treatment summaries or recommendations.

The current NIH guidelines were by compiled by working groups with expertise in different areas. As per the standard process for establishing clinical guidelines, these groups systematically reviewed all relevant, credible information and scientific publications and made three levels of recommendation of varying strength on the basis of strength of evidence from randomized and nonrandomized clinical trials, well-designed observational studies, and expert opinion.

"There are not a lot of data out there to guide us, so we had to rely a lot on expert opinion," said panel co-chair Roy M. Gulick, MD, MPH, a professor of medicine and chief of infectious diseases at Weill Cornell Medicine in New York City. "We have to face the reality that we don't yet have the controlled clinical data we need in order to say whether something works. But we asked ourselves whether guidelines were needed now, and we decided that we do need to provide guidance for clinicians facing critical patients and wanting to do something to help them."

"At this moment the main sentiment we want to convey is that there are no licensed treatments for COVID-19, but there are a lot of good ideas. And the sooner we can test them, the sooner we can update the guidelines," panel co-chair H. Clifford Lane, MD, clinical director of the National Institute of Allergy and Infectious Diseases, told Medscape Medical News.

The panel hopes to have results from clinical drug trials within a matter of weeks.

"We're expecting data soon from randomized clinical trials [RCTs] of remdesivir and also data from RCTs of hydroxychloroquine, and these are the first things on the horizon that will help us refine these recommendations," Lane added.

In the meantime, "I hope treating practitioners will see these as guidelines, not prescriptions ― information they can use to talk with patients about what makes sense for each individual patient. Each decision about treatment is between the healthcare provider and the patient, and we hope this will help them make that decision without telling them what that decision should be."

COVID-19-Specific Treatment

"[W]henever possible, the Panel recommends that promising, unapproved or unlicensed treatments for COVID-19 be studied in well-designed controlled trials," the panelists write. They acknowledge, however, that many providers will be unable to access such trials and need guidance on whether to use these agents.

The guidelines address two much-discussed categories of drug treatment, antivirals and immunomodulators. Overall, the panel concluded that the data are insufficient to recommend for or against any antiviral or immunomodulatory therapy for patients with severe COVID-19, nor are there sufficient data to recommend for or against any broad-spectrum antimicrobial agent in the absence of an existing indication.

Among other specific recommendations:

The guideline panel includes representatives from federal agencies, healthcare and academic organizations, and professional medical societies across the spectrum of relevant specialities from critical care and thoracic medicine to pediatric infectious diseases and infectious-disease pharmacy.

Panel co-chairs Lane, Gulick, and Masur have disclosed no relevant financial relationships. Several other panelists have disclosed ties to industry, including Gilead Sciences, which makes remdesivir.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Questions remain about how effective the convalescent therapy will be. While experts know that the COVID-19 antibodies "can be helpful in fighting the virus, we don't know how long the antibodies in the plasma would stay in place," Bennett-Guerrero says. Nor do doctors know who the therapy might work best for, beyond people with a severe or life-threatening illness. When it's been used for other infections, it's generally given in early stages once someone has symptoms, Joyner says. Joyner says he sees the treatment as a stopgap ''until concentrated antibodies are available." Several drug companies are working to retrieve antibodies from donors and make concentrated antibody drugs. "Typically we would think convalescent plasma might be a helpful bridge until therapies that are safe and effective and can be mass-produced are available, such as a vaccine or a drug," Bennett-Guerrero says. Even so, he says that he doesn't think he will have a problem attracting donors, and that he will have repeat donors eager to help. More Information for Potential Donors Blood banks, the American Red Cross, and others involved in convalescent plasma therapy have posted information online for potential donors. People who don't meet the qualifications for COVID-19 plasma donations are welcomed as regular blood donors if they meet those criteria. According to the FDA, a donation could potentially help save the lives of up to four COVID-19 patients. Father Pace is already planning another visit to the blood bank. To pass the time last time, he says, he prayed for the person who would eventually get his blood. Sources Father Robert Pace, Fort Worth, TX. John Burk, MD, pulmonologist, Texas Health Harris Methodist Hospital, Fort Worth. Michael Joyner, MD, professor of anesthesiology, principal investigator, Convalescent Plasma Expanded Access Program, Mayo Clinic, Rochester, MN. Elliott Bennett-Guerrero, MD, medical director of perioperative quality and patient safety; professor, Renaissance School of Medicine, Stony Brook University, NY. Julia Sabia Motley, 57, Merrick, NY. Mayo Clinic: "Mayo Clinic named national site for Convalescent Plasma Expanded Access Program." FDA: "Recommendations for Investigational COVID-19 Convalescent Plasma." The Journal of the American Medical Association: "Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma." Press Medicine: "Treatment of Argentine hemorrhagic fever with convalescent's plasma. 4433 cases." Proceedings of the National Academy of Sciences of the United States of America: "Effectiveness of convalescent plasma therapy in severe COVID-19 patients." News release, FDA: "Coronavirus (COVID-19) Update: Daily Roundup, March 24, 2020." News release, Stony Brook Medicine: "Volunteers Needed to Donate Blood Plasma to Help Hospitalized Patients with COVID-19," April 9, 2020. News release, FDA: "Coronavirus (COVID-19) Update: FDA Coordinates National Effort to develop Blood-Related Therapies for COVID-19," April 3, 2020. News release, Takeda: ''Global Plasma Leaders Collaborate to Accelerate Development of Potential COVID-19 Hyperimmune Therapy," April 6, 2020. Open Forum Infectious Diseases: "High-Dose Intravenous Immuoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019."

Σελίδα 2 από 3 Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center. As an Episcopal priest, Father Robert Pace of Fort Worth, TX, is used to putting others first and reaching out to help. So when the pulmonologist who helped him through his ordeal with COVID-19 asked if he would like to donate blood to help other patients, he did not hesitate. "I said, 'Absolutely,'" Pace, 53, recalls. He says the idea was ''very appealing." During his ordeal with COVID-19 in March, he had spent 3 days in the hospital, isolated and on IV fluids and oxygen. He was short of breath, with a heartbeat more rapid than usual. Father Robert PaceNow, fully recovered, his blood was a precious commodity, antibody-rich and potentially life-saving. As researchers scramble to test drugs to fight COVID-19, others are turning to an age-old treatment. They're collecting the blood of survivors and giving it to patients in the throes of a severe infection, a treatment known as convalescent plasma therapy. Doctors say the treatment will probably serve as a bridge until other drugs and a vaccine become available. Although the FDA considers the treatment investigational, in late March, it eased access to it. Patients can get it as part of a clinical trial or through an expanded access program overseen by hospitals or universities. A doctor can also request permission to use the treatment for a single patient. "It is considered an emergent, compassionate need," says John Burk, MD, a pulmonologist at Texas Health Harris Methodist Hospital, Fort Worth, who treated Pace. "It is a way to bring it to the bedside." And the approval can happen quickly. Burk says he got one from the FDA just 20 minutes after requesting it for a severely ill patient. How It Works The premise of how it works is ''quite straightforward," says Michael Joyner, MD, a professor of anesthesiology at the Mayo Clinic, Rochester, MN. "When someone is recovered and no longer symptomatic, you can harvest those antibodies from their blood and give them to someone else, and hopefully alter the course of their disease." Joyner is the principal investigator for the FDA's national Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19, with 1,000 sites already signed on. Convalescent therapy has been used to fight many other viruses, including including Ebola, severe acute respiratory syndrome (SARS), the "bird" flu, H1N1 flu, and during the 1918 flu pandemic. Joyner says the strongest evidence for it comes from the 1950s, when it was used to treat a rodent-borne illness called Argentine hemorrhagic fever. Using convalescent plasma therapy for this infection reduced the death rate from nearly 43% before the treatment became common in the late 1950s to about 3% after it was widely used, one report found.

Σελίδα 3 από 3 Data about convalescent therapy specifically for COVID-19 is limited. Chinese researchers reported on five critically ill patients, all on mechanical ventilation, treated with convalescent plasma after they had received antiviral and anti-inflammatory medicines. Three could leave the hospital after 51-55 days, and two were in stable condition in the hospital 37 days after the transfusion. In another study of 10 severely ill patients, symptoms went away or improved in all 10 within 1 to 3 days after the transfusion. Two of the three on ventilators were weaned off and put on oxygen instead. None died. Chinese researchers also reported three cases of patients with COVID-19 given the convalescent therapy who had a satisfactory recovery. Researchers who reviewed the track record of convalescent therapy for other conditions recently concluded that the treatment doesn't appear to cause severe side effects and it should be studied for COVID-19. Although information on side effects specific to this treatment is evolving, Joyner says they are "very, very low." According to the FDA, allergic reactions can occur with plasma therapies. Because the treatment for COVID-19 is new, it is not known if patients might have other types of reactions. Who Can Donate? Blood bank officials and researchers running the convalescent plasma programs say the desire to help is widespread, and they've been deluged with offers to donate. But requirements are strict. Donors must have evidence of COVID-19 infection, documented in a variety of ways, such as a diagnostic test by nasal swab or a blood test showing antibodies. And they must be symptom-free for 14 days, with test results, or 28 days without. The treatment involves collecting plasma, not whole blood. Plasma, the liquid part of the blood, helps with clotting and supports immunity. During the collection, a donor's blood is put through a machine that collects the plasma only and sends the red blood cells and platelets back to the donor. Clinical Trials Requirements may be more stringent for donors joining a formal clinical trial rather than an expanded access program. For instance, potential donors in a randomized clinical trial underway at Stony Brook University must have higher antibody levels than required by the FDA, says study leader Elliott Bennett-Guerrero, MD, medical director of perioperative quality and patient safety and professor at the Renaissance School of Medicine. Julia Sabia Motley and Sean Motley both recovered from COVID-19 and hope to donate their blood to help other patients.He hopes to enroll up to 500 patients from the Long Island, NY, area. While clinical trials typically have a 50-50 split, with half of subjects getting a treatment and half a placebo, Bennett-Guerrero's study will give 80% of patients the convalescent plasma and 20% standard plasma. Julia Sabia Motley, 57, of Merrick, NY, is hoping to become a donor for the Stony Brook study. She and her husband, Sean Motley, 59, tested positive in late March. She has to pass one more test to join the trial. Her husband is also planning to try to donate. "I can finally do something," Sabia Motley says. Her son is in the MD-PhD program at Stony Brook and told her about the study. Many Questions Remain The treatment for COVID-19 is in its infancy. Burk has given the convalescent plasma to two patients. One is now recovering at home, and the other is on a ventilator but improving, he says. About 200 nationwide have received the therapy, Joyner says. He expects blood supplies to increase as more people are eligible to donate.