An Apolitical Review of HCQ

Why I Wrote This

I’ve recently received several questions on Hydroxychloroquine (HCQ), largely because of the article published in Newsweek by Yale Epidemiologist Harvey A. Risch entitled "The Key to Defeating COVID-19 Already Exists. We Need to Start Using It" This article circulated widely on social media, and really kicked up the dust on this conversation.

In the Beginning

In March, I was optimistic that hydroxychloroquine would prevent or treat CoViD-19 based on in vitro studies. I also read several scientific papers that proposed a plausible mechanism of action – the blocking of endosomal acidification, a process required for viral entry into the cell. In the following months, there were some seemingly promising publications like this one out of France, and this one from Henry Ford in Detroit.

Both of these studies claimed exciting positive results. The French study claimed early virologic clearance and the Henry Ford study a huge mortality benefit.

However, neither of these articles represented a randomized placebo controlled trial, which is the type of study required to prove a drug beneficial within a population. To understand why this is the case, consider reading this article from leapsmag by infectious disease doctor Amesh Adalja, MD.

In addition, both of these studies had methodological flaws. Read this critique of the French article, and this critique of the Henry Ford paper.

What’s the new evidence?

Now, there are several randomized placebo controlled trials, none of which have showed positive results for the drug. I’ve reviewed all of them (as of August 6th, 2020), but the two that interest me most were published in NEJM. One randomized trial looked at HCQ for prophylaxis after SARS-CoV-2 exposures, and another at early use in mild and moderately ill patients. Neither study is perfect, but they are both randomized and placebo-controlled, and neither revealed promising results. I’ve done a more in depth review of these two articles below.

So, it doesn’t appear that HCQ is effective, but is it safe?

"Safety" is relative. It’s a judgment to be made by individuals. In my opinion, HCQ is fairly safe, but there is a significant incidence of diarrhea (at least 15% of people) and several other side effects. The most dreaded adverse effect is cardiac arrhythmia, which can be deadly. Arrhythmia is unlikely (perhaps less than 1 or 2%) in otherwise healthy people without underlying heart problems, electrolyte disturbances, drug interactions, or other complications. In at-risk patients, the rate of arrhythmia may be significantly higher; perhaps between 1 and 10%.

My Bottom Line

My conclusion is that this drug is not worth taking. It doesn’t appear to be effective at preventing, reducing, or curing SARS-CoV-2 infections, and although reasonably safe, there is a chance of suffering serious adverse-effects or even death, however unlikely. As a result, I will not be taking or recommending this drug unless new evidence comes to light.

What follows is a deeper-dive into the two randomized trials from NEJM, and my look at the Henry Ford study.

A Randomized Trial of Hydroxychloroquine as Post-exposure Prophylaxis for Covid-19

This study examined HCQ as prophylaxis in high-risk exposures to SARS-CoV-2. 11.8% (49/414) of the group receiving HCQ contracted CoViD-19 compared to 14.3% (58/407) of the placebo group. This is a small gap in favor of HCQ but doesn’t remotely approach statistical significance (p=0.35). My conclusion of this study is that it’s very unlikely HCQ will prevent you from contracting CoViD-19 even if you know you were exposed and start taking the drug right away. I think the big takeaway here, though, is that only 10-15% of people with high or moderate-risk exposures contracted the disease.

Definition: High or moderate Risk Exposure was defined as "adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure)"

What about Zinc?

Some people think that HCQ will only work as prophylaxis (or treatment) if given with zinc. They believe that HCQ works as a "zinc ionophore" (an ionophore is a substance which is able to transport ions across a lipid membrane into a cell). Essentially, some people think that HCQ helps zinc get into the cell, and then, either zinc alone, or HCQ and zinc together can disable the virus in some way. To my knowledge, there hasn’t been a great study using zinc and HCQ together as prophylaxis, but, Chris Masterjohn, PhD, a biochemist, wrote this article explaining why he doesn’t believe that this is a plausible mechanism for zinc’s antiviral activity. I don’t have the expertise to analyze this other than to say that Chris’s analysis makes sense to me based on my knowledge of biochemistry.

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 | NEJM

This study examined HCQ as treatment for mild-moderate CoViD-19 disease. Patients were randomized either to standard care, standard care + HCQ or standard care + HCQ + Azithromycin. Standard care was determined by the treating clinician, which is an important fact that I’ll mention again below. Here are the key outcomes data:

You can see the numbers for yourself in this table. Regardless of treatment group, the numbers are really similar on every level – number of people in the hospital, requiring oxygen, on ventilators, deceased, etc.

Other Treatments Used in This Study

It’s important to know the other treatments that the patients were receiving in each group. You can see that information here in the supplementary appendix for the study. No patients in this study were treated with Remdesevir, a small but equal number were treated with steroids, (about 10 in each of the 3 groups of approximately 150 patients). Most of the other treatments used were antibiotics, likely given for suspected or confirmed concurrent bacterial infections (most commonly pneumonia).

Shortcomings

One possible shortcoming to this study is the time period of 15 days. It looks like most patients were sick for a week or so before being enrolled in the study, which gives about 3 weeks of total time to see outcomes, but at the study’s conclusion, there were still ~25 patients in each group who were still hospitalized.

The other shortcoming is that "standard care" was determined by the treating physician. We can’t tell from the manuscript how else care might have differed between physicians, areas of the hospital, etc.

Conclusion

Overall, I think this study is high-quality evidence suggesting that HCQ is unlikely to be helpful in mild-moderate disease.

Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19

This paper was based on data analysis of patients who were hospitalized at the Henry Ford hospital system in Detroit from March 10, 2020 to May 2, 2020. The patients were all treated based on the physician’s discretion, and then, after the fact, they were separated into four groups.

1. Neither medication
2. HCQ
3. Azithromycin
4. HCQ+Azithromycin

They found a huge mortality benefit in the groups who received HCQ. For the most stark comparison, the HCQ group had a 13.5% mortality rate (162/1202) vs. the "neither medication" group which had a mortality rate of 26.4% (108/409). The other two groups followed the same trend, but had a less impressive difference. See the table here – mortality numbers are in the first row under the header of the table:

But, don’t get too excited. This study is seriously problematic.

The major problem with this study is at the bottom of the chart (see my highlights). Look at the two HCQ groups. Three-quarters (75%) of the HCQ groups received steroids whereas only 1/3 of the other groups received steroids. Similarly, the rate of administration of tocilizumab (an IL-6 inhibitor) to the HCQ groups was much higher.

So, it’s impossible to tell which drug, or combination of drugs was helping or hurting here.

But, the huge difference in treatments between the groups is actually interesting for a hidden reason. It is an indicator that these patients were different in some fundamental way. The reason for massive differences in treatments is much more likely to be explained by patient prognosis, individual characteristics, location in the hospital, location in the hospital system (there are 6 possible hospitals), the treating physician, and many other possible factors which we’ll never know.

The bottom line is that this study epitomizes the problems with a retrospective non-randomized uncontrolled study. There is no way to tell how these patients arrived in their respective treatment groups. We just can’t tell anything from this study in terms of which drugs may or may not have been effective.

If you want a marked up PDF with my highlights and comments on this study, go here.

Reference Library

This link will take you to a dynamic reference library. If I read a new article on this topic that I think is important, I’ll add it to the library.

Hydroxychloroquine References

• Randomized Controlled Studies
  • Boulware, David R., Matthew F. Pullen, Ananta S. Bangdiwala, Katelyn A. Pastick, Sarah M. Lofgren, Elizabeth C. Okafor, Caleb P. Skipper, et al. 2020. “A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.” New England Journal of Medicine link.
  • “Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 | NEJM.” n.d. Accessed August 3, 2020. link.
  • Tang, Wei, Zhujun Cao, Mingfeng Han, Zhengyan Wang, Junwen Chen, Wenjin Sun, Yaojie Wu, et al. 2020. “Hydroxychloroquine in Patients with Mainly Mild to Moderate Coronavirus Disease 2019: Open Label, Randomised Controlled Trial.” BMJ 369 (May). link.
  • Skipper, Caleb P., Katelyn A. Pastick, Nicole W. Engen, Ananta S. Bangdiwala, Mahsa Abassi, Sarah M. Lofgren, Darlisha A. Williams, et al. 2020. “Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19.” Annals of Internal Medicine, July. link.
  • “No Clinical Benefit from Use of Hydroxychloroquine in Hospitalised Patients with COVID-19 — RECOVERY Trial.” n.d. Accessed August 8, 2020. link.
• Observational or Retrospective
  • Geleris, Joshua, Yifei Sun, Jonathan Platt, Jason Zucker, Matthew Baldwin, George Hripcsak, Angelena Labella, et al. 2020. “Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.” New England Journal of Medicine 382 (25): 2411–18. link.
  • Scholz, Martin, Roland Derwand, and Vladimir Zelenko. 2020. “COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study,” July. link.
• Mechanism
  • “Are Chloroquine and Hydroxychloroquine Zinc Ionophores? [COVID-19 Updates].” n.d. Chris Masterjohn, PhD. Accessed August 8, 2020. link.
• Heavily Sited Sources in Favor of HCQ
  • The Henry Ford Study
    • Arshad, Samia, Paul Kilgore, Zohra S. Chaudhry, Gordon Jacobsen, Dee Dee Wang, Kylie Huitsing, Indira Brar, et al. 2020. “Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19.” International Journal of Infectious Diseases 97 (August): 396–403. link.
      • Critique of the Henry Ford Study
        • Rosenberg, Eli S., David R. Holtgrave, and Tomoko Udo. 2020. “Clarifying the Record on Hydroxychloroquine for the Treatment of Patients Hospitalized with COVID-19.” International Journal of Infectious Diseases, July. link.
  • The French Viral Clearance Paper
    • Gautret, Philippe, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, et al. 2020. “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial.” International Journal of Antimicrobial Agents 56 (1): 105949. link.
      • Critique of the French Viral Clearance Paper
        • Rosendaal, Frits R. 2020. “Review of: “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial Gautret et al 2010, DOI:10.1016/j.Ijantimicag.2020.105949.” International Journal of Antimicrobial Agents 56 (1): 106063. link.
• Newsweek piece by Yale Epidemiologist, Risch
  • “The Key to Defeating COVID-19 Already Exists. We Need to Start Using It | Opinion.” 2020. Newsweek. July 23, 2020. link.
• The Guardian Article about Surgisphere and the retracted Lancet Study
  • Washington, Melissa Davey Stephanie Kirchgaessner in, and Sarah Boseley in London. 2020. “Surgisphere: Governments and WHO Changed Covid-19 Policy Based on Suspect Data from Tiny US Company.” The Guardian, June 3, 2020, sec. World news. link.