Cutting through the confusion about COVID-19 and hydroxychloroquine

by Alan R. Gaby, M.D.

As the United States and the world endured the trauma of a pandemic in the spring of 2020, a major controversy developed over whether hydroxychloroquine (HCQ) is useful for the prevention and treatment of COVID-19. HCQ has been widely used for more than 60 years to prevent and treat malaria and to treat several autoimmune conditions including rheumatoid arthritis and systemic lupus erythematosus. This drug has also demonstrated an antiviral effect against COVID-19 in vitro. (1) Around 5.7 million prescriptions were written for HCQ in the U.S. in the year 2017. (2) HCQ is manufactured by many generic-drug companies and it is very inexpensive, with a retail price of $10 or less for a full course of treatment against COVID-19.

HCQ can cause a number of side effects, the most serious of which include potentially life-threatening cardiac arrhythmias and rare cases of retinal toxicity. The risk of developing serious side effects appears to be related both to the dosage and to the duration of treatment. HCQ has a half-life of more than 40 days, which means that with prolonged daily use, the drug continues to build up in the body for many weeks before reaching a steady-state concentration. The short duration of treatment that is currently being recommended for COVID-19 (typically 5-10 days) results in a relatively low peak serum concentration, and would therefore be expected to have a low incidence of side effects. Physicians who have been prescribing HCQ for COVID-19 (patients with contraindications are generally not offered the drug) have reported that serious side effects are essentially nonexistent.

The positive French study

Interest in the potential value of HCQ was sparked initially by an uncontrolled trial (3) conducted in Marseilles, France. The study included 1,061 individuals who had a positive polymerase chain reaction (PCR) test for COVID-19. These cases were identified from a massive PCR-screening program, and included both symptomatic patients (n = 1,005) and asymptomatic contacts of confirmed cases (n = 56). Forty-four percent of the patients had radiological evidence of pneumonia at the time of presentation. All patients were prescribed the combination of HCQ (200 mg three times per day for 10 days) and azithromycin (a macrolide antibiotic; 500 mg on day 1 followed by 250 mg per day for 4 days). Azithromycin was included because of empirical evidence that HCQ is much more effective against COVID-19 if it is used in combination with this antibiotic. The median time between symptom onset and the start of treatment was 6 days. Patients who had contraindications (such as electrocardiographic evidence of a prolonged QT interval, which is a risk factor for HCQ-induced serious arrhythmias) were not given the treatment and were not included in the study. During the treatment period, drugs that can prolong the QT interval, and potassium-depleting drugs used to treat hypertension, were stopped. Good clinical outcomes and virological cures were seen within 10 days in 973 patients (91.7%). Eight patients (0.75%) died, all of whom were 74 years of age or older. Two additional patients (ages not specified) died after the paper was written. No arrhythmias attributable to the treatment were seen, and no patient had a prolongation of the QT interval beyond the threshold that would contraindicate treatment. The authors concluded that the administration of HCQ and azithromycin before complications occur is safe and is associated with a very low mortality rate in patients with COVID-19.

Other clinics that are using similar protocols have reported positive results similar to those in the French study. In some clinics, zinc is being added to the protocol, because of evidence that HCQ exerts its antiviral effect in part by stimulating the uptake of zinc into cells.

Negative results in the U.S. Veterans' study

After the French study appeared, a retrospective chart review was conducted on U.S. veterans who had been hospitalized with COVID-19. In those patients, the death rate was higher among those given HCQ than among those not given the drug. This study has frequently been cited to support the view that HCQ is ineffective and unsafe. However, it was not a randomized trial, and HCQ was only given to patients who were at the highest risk of having a poor outcome. (4) Furthermore, the findings from this study may not be relevant to the use of HCQ early in the course of the disease. Because it is an antiviral agent, HCQ may be most effective when used before complications have occurred. In the more advanced stages of COVID-19, treatments that suppress the cytokine storm may be more important than treatments that inhibit viral replication.

The Lancet study and the retraction

On May 22, Lancet, one of the most respected medical journals in the world, published an observational study of 96,032 patients who had been hospitalized with COVID-19 in 671 hospitals on 6 continents. Compared with the control group, patients treated with HCQ (with or without a macrolide) had a higher in-hospital mortality rate and a higher incidence of new-onset cardiac arrhythmias. (5) By the time this paper was published, HCQ was being widely used around the world for early treatment of COVID-19 and for prophylaxis in healthcare workers and others with high risk of exposure to the virus. The Lancet paper created great confusion, because it stood in stark contrast to the positive results many clinicians were seeing.

It soon became apparent that the Lancet paper was plagued with serious problems. In an open letter to the authors of the study and to the editor of Lancet, 146 international researchers raised 10 different concerns about the study. For example, the data from Australia showed an implausibly large number of cases from just 5 hospitals, and the number of COVID-19 deaths reported from those hospitals was greater than the total number of COVID-19 deaths in all of Australia during the study period. (6) Another major concern was that the authors refused to identify any of the hospitals that contributed to the data set.

Further examination of the company that compiled the database of over 96,000 patients (Surgisphere; Chicago, IL) raised concerns that the research may be fraudulent. It seemed impossible that a company that no one had ever heard of, and which had only a handful of employees (most of whom had no experience in data analysis), could have accomplished the task of coordinating complex data from hundreds of hospitals around the world in a very short time. An investigation of Surgisphere by the British newspaper, The Guardian, revealed a number of disturbing issues. (7) For example, The Guardian contacted 7 hospitals in Australia whose cooperation would have been necessary for the database to have included the reported number of Australian COVID-19 patients. All of the hospitals stated that they had no involvement with such a database, and none of them had heard of Surgisphere. In addition, Surgisphere had almost no online presence. Until June 1, the "get in touch" link on Surgisphere’s website redirected the reader to a WordPress template for a cryptocurrency website. This raised questions about how hospitals could have contacted the company to join its database.

Four authors were listed in the Lancet paper. One was Sapan Desai, the founder of Surgisphere, who was solely responsible for generating the data used in the study. After concerns were raised about the legitimacy of the data, the other 3 authors initiated an independent third-party peer review to examine the integrity of the research. The independent peer reviewers informed the 3 authors that Surgisphere would not provide the data that was needed to conduct the review, so the peer reviewers withdrew from the process. On June 4, just 2 weeks after the paper was published, the 3 authors asked Lancet to retract the paper, because they "can no longer vouch for the veracity of the primary data sources." (8)

Are hydroxychloroquine and azithromycin effective?

At present, it is not possible to provide a definitive answer to that question. Several randomized controlled trials are in progress, and we should have a better idea by September of 2020 whether this treatment is effective for treating uncomplicated COVID-19 cases or preventing infection in people at high risk of exposure to the virus. Based on my review of the available data regarding safety and efficacy, I would strongly consider taking HCQ and azithromycin if the situation warranted.

Questions raised by the hydroxychloroquine saga

There are a number of questions raised by the events surrounding the research on HCQ for COVID-19.

1. Why did Lancet to do such a poor vetting job on a paper that had such important implications for public health? Of note, the New England Journal of Medicine was also apparently scammed by Sapan Desai and Surgisphere. On June 4, that journal was forced to retract another paper on COVID-19, for which Surgisphere had supplied the data.

2. What has caused some portions of the media to become so biased that they allow political considerations to guide their views on a scientific issue? Early in the course of the pandemic, president Trump mentioned HCQ as a potential "game changer" in the fight against COVID-19. Trump later announced that he was taking HCQ prophylactically, after a few White House staff members had tested positive for the virus. What followed was a barrage of dueling narratives in the media, in which opinions about HCQ appeared to become a surrogate for opinions about the president. Media outlets that habitually opposed Trump tended to emphasize evidence that HCQ is ineffective and dangerous, whereas media outlets that typically supported the president tended to emphasize evidence that HCQ is effective and (if used properly) quite safe. A June 4 editorial in the Wall Street Journal rightly stated that HCQ "should rise or fall as a treatment on its medical merits, not whether people think it vindicates or repudiates Donald J. Trump."

3. What motivated Sapan Desai to perpetrate what appears to be a major fraud upon the world?

4. Why were official agencies so quick to interfere with clinical trials of HCQ and with the use of this medication by practicing physicians? After the Lancet paper was published, the World Health Organization halted their randomized controlled trial of HCQ, although they did resume the trial after the paper was retracted. France's public health agency warned against the use of HCQ outside of clinical trials, while around the same time French authorities suspended those clinical trials. Even before the Lancet paper was published, the U.S. Food and Drug Administration (FDA) recommended that HCQ should only be taken in the hospital or as part of a formal study. That same recommendation appeared in the COVID-19 Treatment Guidelines of the National Institutes of Health (NIH). The advice against out-of-hospital use of HCQ is difficult to understand, considering that HCQ appears to be most effective when used before the disease has become severe enough to require hospitalization.

Because of the negative press, the warnings against HCQ by government agencies, and the apparently fraudulent Lancet paper, many people are afraid to take HCQ. This has made it more difficult to enroll subjects in randomized controlled trials.

6. Is there a money trail to follow?

The COVID-19 pandemic has presented an opportunity for the pharmaceutical industry to make enormous amounts of money on vaccines and patented drugs. Widespread acceptance of a regimen such as HCQ plus azithromycin (which costs a total of less than $20 for a course of treatment) could threaten the financial success of these other treatments. One drug currently being investigated is remdesivir. This intravenously administered drug, which is manufactured by Gilead Sciences, is likely to be very expensive if it gains FDA approval. According to one report, at least 7 experts on the NIH panel that developed the COVID-19 Treatment Guidelines (which recommended against the use of HCQ) had financial ties to Gilead Sciences. The drug industry has a long history of using its financial clout to try to influence politicians, the FDA, the press, and medical researchers. While there is currently no evidence of a clandestine industry-sponsored campaign to discredit HCQ, one might be forgiven for wondering whether such a campaign exists.

Conclusion

The results of randomized controlled trials are eagerly awaited. If the results turn out to be as good or nearly as good as those observed by practitioners in Marseilles and elsewhere, an important advance will have been made and the need for lockdowns will be greatly diminished.

References

(1) Liu J, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.

(2) Hydroxychloroquine Sulfate. Drug Usage Statistics, United States, 2007 - 2017. https://clincalc.com/DrugStats/Drugs/HydroxychloroquineSulfate. Accessed June 8, 2020.

(3) Million M, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. 2020 May 5;101738.

(4) Wise J. VA secretary defends use of hydroxychloroquine for veterans, claims analysis led to 'misinformation.' The Hill, April 30, 2020. https://thehill.com/homenews/administration/495409-va-secretary-defends-use-of-hydroxychloroquine-for-veterans-claims.

(5) Mehra MR, et al. Hydroxychloroquine or Chloroquine With or Without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis. Lancet. 2020 May 22;S0140-6736(20)31180-6. Published Online.

(6) Mahase E. Covid-19: 146 researchers raise concerns over chloroquine study that halted WHO trial. BMJ. 2020; 369:m2197.

(7) Davey M, et al. Surgisphere: governments and WHO changed Covid-19 policy based on suspect data from tiny US company. June 3, 2020. https://www.theguardian.com/world/2020/jun/03/covid-19-surgisphere-who-world-health-organization-hydroxychloroquine.

(8) Mehra MR, et al. Retraction - Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 Jun 4 (published online).

Note: This article will appear as an editorial in the Townsend Letter, Aug/Sept 2020.