Immediate Treatment for Early Stage SARS-CoV-2 Infections Recommended To Be Supported Nationally Starting Now

A strategic principle and practical approach to rapid response to novel pandemics

Authored by Ben Kaplan Singer, M.D.; Daniel Stickler, M.D.; Avery J. Knapp Jr., M.D.; with many contributing doctors.

BOTTOM LINE: Our primary strategic objective must be to prevent ICU overwhelm, which on our current course is imminent in most states. It is an axiom of infectious diseases that treatment in earlier stages is more effective than treating advanced stages. Early COVID-19 treatment is more likely to prevent disease progression to critical status, radically lowering hospitalizations and CFR than inaction. Current clinical drug trials are mostly focused on treating late stages of disease, when immunologic damage is a dominant threat. We believe that trials should focus on earlier stage infection to prevent progression to advanced disease. Given the suggestion of efficacy of hydroxychloroquine (HCQ), and the imperative to treat disease before it progresses to cytokine storm, we believe that the current data are sufficient to recommend FDA provisional approval for early outpatient treatment of COVID-19 with HCQ plus zinc and azithromycin. This triple combination treatment can be modified where needed in patients with prolonged QTc or other contraindications at the physicians’ discretion Following this same rationale, we recommend that other clinical trials involving drugs that have already been approved for non-COVID-19 diseases, and for which the safety profile is well understood and reasonably acceptable, should begin clinical trials on patients in early stages of COVID-19 disease, alongside patients with more advanced disease.

OVERVIEW: ICU overload in the U.S. is impending in the very near term unless immediate actions are taken that effectively reduce hospitalization needs. In addition to the critical efforts underway to decrease R0 and increase ICU capacity, advancing early outpatient treatment with known medications may be the fastest and simplest way to decrease hospitalizations and mortality rate. Given that case fatality rate and harm to frontline healthcare workers increases dramatically when hospitals and ICUs reach capacity overload, it is imperative that all reasonable approaches to prevent that risk are employed quickly and at scale. The FDA recently gave emergency authorization for hydroxychloroquine for inpatient treatment of COVID-19.[1] Around the same time France’s government authorized broader approval of HCQ for inpatient and outpatient use in infected patients after initial worldwide clinical data suggested potential benefit, especially in earlier stages of infection.[2] We propose the US emergency authorization be extended immediately to include early stage and outpatient treatment at the discretion of the prescribing physician, and that this extension also include the registration of those treated individuals into the “loose research protocol” previously proposed.

It’s important to note that HCQ, zinc, and azithromycin are very well understood drugs with clear safety profiles; they are widely available, generic, inexpensive, and can be scaled rapidly, including to the developing world, which would be expedited by US leadership in recommendations. Some health authorities have given the typical caution against early treatment until large, peer-reviewed, randomized controlled trials (RCTs) provide conclusive data.[3] We fully support the continued effort to investigate existing and novel pharmaceuticals to determine the best intervention through blinded and controlled trials. Weighing the urgency of this unprecedented situation combined with the effects of inaction, plus the relative safety of the drugs, and the preponderance of data showing effective early treatment significantly decreases the percentage of cases that progress to needing hospitalization, we believe that the proposed recommendation is not only adequately founded but ethically obligate. This suggestion conforms with the widespread precedent to treat infections early to prevent progression and hospitalization even where empirical evidence for treatment would be considered insufficient in formal terms.

According to ClinicalTrials.gov, there are 47 CQ/HCQ & COVID-19 trials with only 1 complete and results not yet published. There are two small RCTs from China available in pre-publication. The assessment in this document considers the preponderance of relevant data, factoring information we gathered from doctors currently conducting informal open label studies, emerging clinical trials, and in vitro mechanistic studies. While additional data from the trials in progress will of course be valuable, and will hopefully give additional actionable insights, the data currently available is sufficient for emergency provisional approval.

TREATMENT:

* HCQ: 6.5-15mg/kg PO in divided loading dose followed by 400-1000mg/day in divided doses for 4-9 days[4]

* Obtain baseline EKG for QTc, check on day 3 (or remote monitoring of QTc)[5]

* Check Metabolic Panel for hypokalemia, Magnesium, Liver Function Tests

* For patients with history of long QT syndrome or renal failure, consult with cardiologist

* Zinc: use zinc acetate or gluconate lozenges with minimal excipients and flavorings to provide 18-25mg of ionized zinc taken every 4 hours during days on HCQ[6]

* Azithromycin: 500mg PO on day 1 followed by 250mg for 4 more days

WHEN & WHO TO TREAT: Clinical and in vitro data suggests greatest value is in treating early, similar to other antivirals used for influenza and herpes simplex, and corresponding to nearly universal findings in treating nearly every type of infection. Early clinical reports suggest it’s best to treat within 5 days of symptom onset. Waiting until a patient is hospitalized or critically ill is unwarranted and unwise.

* Recommend immediate