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Hydroxychloroquine's World of Confusion - What you Need to Know

May 05, 2020 1:04 pm

Hydroxychloroquine has been a dominant news item since the start of the COVID-19 crisis, with a great deal of misconceptions by those who don't know or use or take the drug. HCQ leaped to the headlines on March 19th when President Trump endorsed the drug as being “approved” by FDA. Of course at that time, it was still only approved for SLE, RA and malaria and it wasn't  until 2 weeks later (March 31st) that the FDA issued an "emergency use authorization" allowing the use of either chloroquine (CQ) or HCQ for treatment of severe, hospitalized patients with COVID-19.

To provide clarity and evidence - here are some of the facts you need to know:

HCQ Potential in COVID

This is based on a) the mechanism by which HCQ works; b) potential effects on viral infection and replication and c) experience with other infections.

  • Upside: The basic drug HCQ works by accumulating lysosomes and endosomes where it increases pH, thereby disrupting normal cell function, viral access another cellular functions. This also affects toll like receptor (TLR) signaling, especially TLR7 and TLR9). And HCQ may also inhibit glycosylation of ACE2 receptor, necessary for SAR-Cov-2 binding and access.  
  • Downside: HCQ has been effective in malaria, thus it's not surprising it would be tested in other infections. Either CQ or HCQ have been studied and shown to fail in influenza prevention, and in other infections including dengue, chikungunya, ebola. 

HCQ / CQ Clinical Trials and Clinical Experience

There many current, well-designed clinical trials of antimalarial therapy in the treatment of COVID-19 infection. Currently clinicaltrials.gov lists 81 trials of HCQ (2 completed; no results) and 33 trials of CQ (none completed) to treat coronavirus in progress. Problematic has been the need for data, results and insights on the utility of antimalarials in COVID-19 and thus, there has been a number of early release data on recent studies.  The unfortunate downside here is that these data have not been published (delivered as news reports, press releases, preprints) nor peer reviewed and many of them have major limitations in trial design and reporting.

  • Updside: Optimism was created by the initial reports from Marseille, France that the use of HCQ (+/- azithromycin) in 26 COVID patients was associated with greater clearance of virus (70 vs 12.5%) compared with non- HCQ treated patients. The problem with this trial was its confused open-label uncontrolled design with many dropouts and nonsensical use of azithromycin in 6 patients. 
    • A recent plea by the Association of American Physicians and Surgeons (AAPS) to the Governor of Arizona asking him to rescind his limitations on HCQ use. They provide a table of HCQ/CQ efficacy, stating "As of this date, the total number of reported patients treated with HCQ, with or without azithromycin and zinc, is 2,333. Of these, 2,137 or 91.6 percent improved clinically. There were 63 deaths, all but 11 in a single retrospective report from the Veterans Administration where the patients were severely ill".  However, much of the content on this table is unsubstantiated data from individual physicians and hardly any of the data comes from the medical literature.
    • The HERO-HCQ study is one of many ongoing trials with HCQ.  HERO-HCQ is a randomized clinical trial of approximately 15,000 HERO Registry participants. It will evaluate whether HCQ is effective in preventing COVID-19 infection in healthcare workers. The trial will randomize participants to either one month of hydroxychloroquine or one month of placebo and will examine whether hydroxychloroquine is effective in decreasing the rate of COVID-19 infection. In addition to the benefits and risks of using hydroxychloroquine, the study also will explore how well the drug can prevent healthcare workers from unintentionally spreading the virus to others.  
  • Downside: Several studies have failed to confirm utility in either seroconversion rates or clinical outcomes and several have suggested the potential for more deaths or cardiac toxicity. 
    • Wei et al showed that when HCQ was useed in 150 patients in an open-label Chinese study of mild-moderate COVID-19 patients, ther was no difference in viral seroconversion between those on and not on HCQ (85% vs 81% at day 28). While a some patients on HCQ showed improvement n CRP and lymphopenia, there was more adverse events with HCQ (30% vs 9%) - albeit these were mild and not serious).
    • The CloroCovid trial in Brazi (Borba et al)l was suppose to prospectively enroll 444 patients with severe COVID infection, but an interim analysis after the first 81 patients revealed 11 death. There were more deaths (39% vs 15%) and more QTc prolongation (19% vs 11%)with high dose CQ therapy. However, QT prolongation itself was not associated with death. The authors cautioned against using "higher CQ doses in critically ill patients with COVID-19 because of its potential safety hazard".  In this trial the high dose CQ patients were more likely to be older with prior cardiovascular disease; and 3/5 high dose CQ CVD patients died.
    • A preprint version of the Veterans Administration retrospective cohort analysis finds that among 368 patients COVID patients treated with HCQ (+/- azithromycin), there was a higher risk of death (HR 2.61; p=0.03) and more HCQ associated deaths (22-28% vs 11% not on HCQ).  They express caution if using HCQ.
    • March 31, 2020 FDA's Dr. Janet Woodcock issued a warning about the potential for cardiotoxicty, QT prolongation with CQ and HCQ use. While such issues are very rare in rheumatology using doses
    • A recent Annals of Rheumatic Disease report (Mathian A, et al) of 17 SLE patients on chronic HCQ therapy, detailed their experience with COVID-19 infection wherein they had viral pneumonia 13/17,  11 with respiratory failure, 5 ARDS, 3 renal failure and 2 deaths. Even HCQ-treated SLE patients can get severe COVID infection.
    • A NEJM letter on the NYU experience of 86 IMID patients claimed that while "baseline biologic use was not associated with worse Covid19 outcomes", they did note that HCQ treated patients were more likely to be hospitalized (21%) than ambulatory (7%) patients. 

Endorsements

  • Upside: endorsements for continued HCQ use in Rheumatic patients came from NICE/UK on April 3rd and ACR on April 11th. Both stated that in non-infected patients, HCQ (and other DMARDs) should be continued. They also stated that for COVID(+) infected patients that HCQ should be continued as other therapies are considered.  Both of these agencies made these recommendations without knowledge of recent clinical trials but with the knowledge of potential benefit and vast experience on the safety of HCQ in SLE, RA, etc patients. 
    • There have been nearly 1000 rheumatic disease patients enrolled in the worldwide and EULAR Rheum-COVID.org registry started by the Global Rheumatology Alliance, with nearly 22% of these COVID(+) patients taking HCQ.  So far, there is no clear analysis showing that HCQ-treated rheumatic patients do any better or worse than those not receiving HCQ.
  • Downside:
    • NIH Guidelines on the treatment of COVID-19 infection did not endorse the use of antimalarials for the prevention or treatment of COVID-19.  Moreover they state that to date (then 4/21), they stated there is  "insufficient data to recommend either for or against any antiviral or immunomodulatory therapy in COVID-19 patients" (based on strong expert opinion)
    • Both the FDA and Health Canada (by April 25th) had issued a public warning against the use of HCQ/CQ outside of hospitalized or clinical trials and against the use of off label HCQ or CQ in the prevention or treatment of COVID-19. 

Supply and Shortage

The frenzy over HCQ use in COVID-19 resulted in a great deal of angst for HCQ-treated patients, rheumatologists and many other healthcare providers.

While there appeared to be early reports of HCQ being in short supply - there appears to be little current evidence of a short supply as the FDA website, only has one note of "limited" availability from one manufacturer (Sun Pharmaceuticals) - but there are many suppliers of HCQ.   The AHSP site lists numerous makers/suppliers of HCQ including  Amneal, Dr. Reddy's, Major, Concordia, Mylan, Prasco, Rising Pharmaceuticals, Sandoz, Sun Pharma,Teva, and Zydus.  Of these, only Major, Rising, Sun, Teva and Zydus are listed as having a short supply and half of these are on track to replenish supply.

Stockpiling - at least 22 states and local governments have been reported to 30 million doses of HCQ.  In April, FEMA shipped 19.1 million HCQ tablets to various cities around the USA; half (10.1 million) of these going to the Departments of Defense and Veterans Affairs and Washington, DC, Baton Rouge, St. Louis, Philadelphia, Baltimore,  Miami, Milwaukee, Indianapolis, Houston and Pittsburgh. Another 9 million tablets were sent to Detroit, New Orleans, New York City and Chicago.

My Recommendations

  1. Do not start, give nor continue HCQ if your intent is to prophylax against COVID - there is no evidence to support this. 
  2. Don't stop HCQ in your patients who take it chronically. Don't lower the dose or change the interval of delivery. So far we are seeing that the vast majority of our patients are not doing poorly with the coronavirus; mostly because their disease is well controlled and their therapies are safe.
  3. There is no need to stop HCQ in patients who are COVID-19 infected. Such chronic dosing would likely exclude them from being in a future HCQ/CQ clinical trial.
  4. There is an exceedingly rare risk of cardiotoxicity or CV death with the doses commonly employed in RA and SLE.
  5. Continue to use and start HCQ as you normally would; including the need to start HCQ as a preferred agent in a new or established patient whose rheumatic disease will benefit from HCQ therapy. 
  6. I would recommend you refill HCQ as you normally would (eg, 3 month supply is OK) and let the local pharmacy be impose gatekeeping restraint - if need be.
  7.  If  you have a patient with suspected or confirmed COVID-19 infection, please enroll that patient in the https://rheum-covid.org/  Registry established by the Glogal Rheumatology Alliance.
Disclosures
The author has no conflicts of interest to disclose related to this subject

Rheumatologists’ Comments

George A Housley Jr MD

| May 08, 2020 3:26 am

Very nice summary, Jack, but these agents and one's use of them have become gang colors, no longer just therapeutic agents. George A Housley Jr MD

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