Virus World

After publication of our Lancet Article, several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication. We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.

NOTE: THIS PUBLICATION HAS BEEN RETRACTED BY THE AUTHORS

Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.

We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation)....

We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

Published in  The Lancet (May 22, 2020):

https://doi.org/10.1016/S0140-6736(20)31180-6

Objective: To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard-of-care (SOC) compared with SOC alone in adult patients with COVID-19.

Design: Multicenter, open-label, randomized controlled trial. Setting 16 government-designated COVID-19 treatment centers in China through 11 to 29 in February 2020. Participants 150 patients hospitalized with COVID-19. 75 patients were assigned to HCQ plus SOC and 75 were assigned to SOC alone (control group). Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively).

Main Outcome measures: The primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. The assessed secondary endpoints were negative conversion rate at day 4, 7, 10, 14 or 21, the improvement rate of clinical symptoms within 28-day, normalization of C-reactive protein and blood lymphocyte count within 28-day. Primary and secondary analysis was by intention to treat. Adverse events were assessed in the safety population.

Results: The overall 28-day negative conversion rate was not different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups. A significant efficacy of HCQ on alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in the post-hoc analysis (Hazard ratio, 8.83, 95%CI, 1.09 to 71.3). This was further supported by a significantly greater reduction of CRP (6.986 in SOC plus HCQ versus 2.723 in SOC, milligram/liter, P=0.045) conferred by the addition of HCQ, which also led to more rapid recovery of lymphopenia, albeit no statistical significance. Adverse events were found in 8.8% of SOC and 30% of HCQ recipients with two serious adverse events. The most common adverse event in the HCQ recipients was diarrhea (10%).

Conclusions: The administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC alone in patients hospitalized with COVID-19 without receiving antiviral treatment, possibly through anti-inflammatory effects. Adverse events were significantly increased in HCQ recipients but no apparently increase of serious adverse events.

Preprint Available in medRxiv (April 14, 2020):

https://www.medrxiv.org/content/10.1101/2020.04.10.20060558v1

The Food and Drug Administration on Sunday issued an emergency use authorization for hydroxychloroquine and chloroquine, decades-old malaria drugs championed by President Donald Trump for coronavirus treatment despite scant evidence. The agency allowed for the drugs to be "donated to the Strategic National Stockpile to be distributed and prescribed by doctors to hospitalized teen and adult patients with COVID-19, as appropriate, when a clinical trial is not available or feasible," HHS said in a statement, announcing that Sandoz donated 30 million doses of hydroxychloroquine to the stockpile and Bayer donated 1 million doses of chloroquine.

The move was supported by the White House, part of a larger Trump-backed effort to speed the use of anti-malaria drugs as a potential therapy for a virus that has no proven treatment or cure. FDA already has allowed New York state to test administering the medication to seriously ill patients, and some hospitals have added it to their treatment protocols. "Let's see how it works," Trump said at a press briefing on Sunday, referencing New York state's efforts. "It may. It may not." "Scientists in America and around the world have identified multiple potential therapeutics for COVID19, including chloroquine and hydroxychloroquine," HHS Secretary Alex Azar tweeted on Sunday night, praising Trump and the EUA.

Below are excerpts from an interview with Dr. Didier Raoult, who published the first report of a small clinical trial with results showing clinical benefit of a combination therapy of hydroxychloroquine together with azithromycin.

...Despite the echo given to the political and medical distrust regarding his clinical trial, the head of the IHU is convinced of the relevance of hydroxychloroquine to treat patients with Covid-19. Despite the media psychosis and his daily death toll, he repeats: we are more likely to die from something other than "Chinese coronavirus". 

24 patients are followed in the clinical trial, how many people have been treated since ...
Pr Didier Raoult:  We have treated others, but I won't tell you how many. I will first notify the department.

After six days of treatment, the viral load of 75% of the patients is negative, are they cured?

Pr Didier Raoult:  They are cured of the virus. But if you have lung damage, it won't go away in three days. We also don't know at the moment whether  if once cured, you can fall ill again, this has not been described by the Chinese who are two months ahead of us.

What about the 25% who are still positive? Does their situation worsen as we say around the 7th and 8th days?

Pr Didier Raoult:  We have not had any aggravation in the cases treated but we do not see people in serious condition. For the moment, serious cases are those that are neither detected nor treated and arrive with very serious respiratory failure. They go straight to resuscitation and they will die there. If we screen and treat people early, there is  a better chance of saving them than if we treat them 48 hours before the terminal phase.

Your strategy since the beginning of the epidemic is to mobilize all the IHU to make massive screening, why, it was not a national strategy from the beginning?

Pr Didier Raoult:  It's not my strategy, it's common sense. I do not know why it is not a national strategy, it is a political choice. Me, I do my duty, period. I do what I have to do, I play my score in a room. But I I who invented the theater, nor the text. I am the only one with a classic thought on infectious diseases when everyone is losing their nerves ...

What about the side effects of treatment with hydroxychloroquine?

Pr Didier Raoult:  What people say about side effects is simply delusional. These are people who haven't opened a medical book in years. Over a billion people have taken it, people who suffer from lupus take it for decades ... I know these drugs very well, I have treated 4,000 people with Plaqenil for 20 years. It's not me who's weird, it's people who are ignorant. I'm not going to be told the toxicity of this drug.

(Translated from French)

The malaria drug hydroxychloroquine did not help prevent people who had been exposed to others with Covid-19 from developing the disease, according to the results of an eagerly awaited study that was published Wednesday in the New England Journal of Medicine. Despite a lack of evidence, many people began taking the medicine to try to prevent infection early in the Covid-19 pandemic, following anecdotal reports it could be effective and claims by President Trump and conservative commentators. Trump, too, said he took hydroxychloroquine to prevent infection. But the new study, the first double-blind randomized, placebo-controlled trial of hydroxychloroquine, found otherwise.

“I think in the setting of post-exposure prophylaxis, it doesn’t seem to work,” said Sarah Lofgren, an assistant professor at the University of Minnesota who is a co-author of the study. Other studies of hydroxychloroquine are ongoing. Also Wednesday, the World Health Organization said it is resuming a clinical trial testing hydroxychloroquine as a treatment after pausing it over safety concerns. “This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.” “This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.”

The latest trial enrolled 821 patients who were either living in the same household as someone with Covid-19 or who were health care workers who had been exposed to someone with Covid-19 without adequate protective gear. While the initial infections had to be confirmed with a diagnostic test, the researchers also counted patients who had symptoms consistent with disease, in part because testing wasn’t available. Approximately 12% of those given hydroxychloroquine developed Covid-19, compared to 14% who were given the vitamin folate as a placebo. There was no further benefit among patients who chose to take zinc or vitamin C. Nearly 40% of patients on hydroxychloroquine experienced side effects such as nausea, upset stomach, or diarrhea. However, the study did not see a significant increase in disturbances of heart rhythms, or an imbalance of deaths.

Published in New England J. Medicine (June 3, 2020):

https://doi.org/10.1056/NEJMoa2016638

A malaria drug widely touted by President Donald Trump for treating the new coronavirus showed no benefit in a large analysis of its use in U.S. veterans hospitals. There were more deaths among those given hydroxychloroquine versus standard care, researchers reported.

The nationwide study was not a rigorous experiment. But with 368 patients, it's the largest look so far of hydroxychloroquine with or without the antibiotic azithromycin for COVID-19, which has killed more than 171,000 people as of Tuesday. The study was posted on an online site for researchers and has been submitted to the New England Journal of Medicine, but has not been reviewed by other scientists. Grants from the National Institutes of Health and the University of Virginia paid for the work. Researchers analyzed medical records of 368 male veterans hospitalized with confirmed coronavirus infection at Veterans Health Administration medical centers who died or were discharged by April 11.

About 28% who were given hydroxychloroquine plus usual care died, versus 11% of those getting routine care alone. About 22% of those getting the drug plus azithromycin died too, but the difference between that group and usual care was not considered large enough to rule out other factors that could have affected survival. Hydroxychloroquine made no difference in the need for a breathing machine, either. 

Preprint Available at medRxiv (April 21, 2020)

https://doi.org/10.1101/2020.04.16.20065920

Aims: Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19.

Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. 

Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. 

Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.

Preprint available at medRxiv since March 31, 2020:

 https://doi.org/10.1101/2020.03.22.20040758

The study’s small size and other weaknesses mean it does not offer a lot of helpful information in determining the possible utility of hydroxychloroquine, according to experts who reviewed the study. Results from the first controlled study of hydroxychloroquine for treating COVID-19 showed no significant difference in outcomes between those who received the drug and those who received usual care. Hydroxychloroquine is one of several existing drugs that scientists are hoping will show improved symptoms and recovery in clinical trials for in patients with COVID-19. However, the study’s small size and other weaknesses mean it does not offer a lot of helpful information in determining the possible utility of hydroxychloroquine, according to experts who reviewed the study. The study also tested only hydroxychloroquine alone, not with the antibiotic azithromycin. 

“The combination therapy of azithromycin and hydroxychloroquine was thought to be better over the monotherapy of hydroxychloroquine to control the mixed infection of virus and bacteria,” explained Sunit K. Singh, PhD, a professor of molecular immunology & virology and head of the molecular biology unit at Banaras Hindu University’s Institute of Medical Sciences in Varanasi, India. 

Hydroxychloroquine, known by the brand name Plaquenil, is currently used to treat lupus and rheumatoid arthritis. It is slightly different from chloroquine phosphate, another drug, currently used to treat malaria, which is under investigation for treating COVID-19. Both drugs have been in use for decades but carry risks as well. “During any outbreaks of epidemic and pandemic levels, there is hardly any time left for new drug development and clinical trials,” Dr. Singh said. Therefore clinicians will turn to trying existing drugs, known as “repurposing.”

Preprint (Chinese) of the study available at:

http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf 

Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th , to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.

Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral
carriage at D6-post inclusion compared to controls, and much lower average carrying duration
than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load  reduction / disappearance in COVID-19 patients and its effect is reinforced by azithromycin.

Pre-Print available at medRxiv:

https://doi.org/10.1101/2020.03.16.20037135

To  Be Published in J. Antimicrob. Agents:

DOI : 10.1016/j.ijantimicag.2020.105949