HIV and ID Observations

Winner, 1923 White House Easter Egg Roll

The Infectious Diseases Society of America (IDSA) gathered a series of experts for what were undoubtedly many late-night calls, reviews of published and pre-print literature, and revisions (of revisions), and admirably generated a set of treatment guidelines for COVID-19.

The problem — there is no proven effective treatment for COVID-19.

That is, there’s no proven treatment based on our usual highest standard metric for efficacy, the randomized clinical trial — nor the next-best thing, a carefully done observational study that meticulously accounts for potential confounders.

Which means these guidelines have a Groundhog Day-like quality. In a series of clear and comprehensive sections, they review the available evidence, then repeatedly conclude the same thing:

The IDSA guideline panel recommends the use of [insert putative COVID-19 treatment here] in the context of a clinical trial. (Knowledge gap.)

Well, not exactly the same thing — for some of these treatments they insert the word “only”, yielding “… only in the context of a clinical trial.”

Here’s the difference between the two, according to the lead author:

For interventions with certainty regarding risks and benefits, the expert panel recommended their use “in the context of a clinical trial”. The guideline panel used “only in the context of a clinical trial” for interventions with higher uncertainty and/or more potential for harm.

But the message is clear. We don’t have sufficient evidence now to recommend any specific treatment.

That’s right — for chloroquine/hydroxychloroquine (HCQ), hydroxychloroquine with azithromycin, tocilizumab, corticosteroids for acute respiratory distress syndrome (ARDS), lopinavir/ritonavir — all are readily prescribable by clinicians (each is FDA-approved for other indications), yet none is proven to work for COVID-19.

That might be hard to believe given the publicity surrounding some of the approaches, in particular hydroxychloroquine. But those are the facts as of today.

So where does that put clinicians on the front lines managing this new disease?

Highly conflicted.

Hey #IDTwitter and other clinicians who are caring for people with #COVID19. Have you prescribed (or recommended) hydroxychloroquine or chloroquine for this infection? Please vote and comment. Thank you!

— Paul Sax (@PaulSaxMD) April 11, 2020

Those favoring the use of hydroxychloroquine for COVID-19 say that there is at least some evidence that hydroxychloroquine helps — enough so that controlled studies are ongoing. We certainly don’t have anything else to offer, and people are sick!

Plus, there’s a plausible mechanism of action, with in vitro antiviral activity. Maybe even two mechanisms if we consider the anti-inflammatory effect.

In addition, there’s this comment, posted by a critical care specialist in response to my poll:

Yes. No idea if it works, but it’s plausible, and it’s part of the YNHH [Yale New Haven Hospital] treatment algorithm for now. Wonder if those on the only-clinical-trials high horse have ever prescribed Haldol for agitated delirium?

High horse, ivory tower, unconnected to “real practice” — these are common charges levied at academic medicine, with some justification. Certainly not everyone has access to clinical trials.

And even when clinicians do have access to these studies, not all patients meet inclusion criteria, and some others might choose not to participate.

Indeed, at our hospital — which, like many academic medical centers, both has clinical trials for COVID-19 and prides itself on following evidence-based medicine — approximately a third of our COVID-19 cases have received hydroxychloroquine.

(Thanks to our crack ID PharmD Jeff Pearson for the quick data review.)

But why just a third? Why not all of them?

Let’s take up the nay-sayers view. They cite the weakness of the data. One study was, on further scrutiny, so flawed the journal publishing it raised concerns about the low quality of the study.  How often do we see that?

Another trial has not yet been published in a peer-reviewed journal, was quite small, and showed improvement in some minor endpoints only — with tremendous heterogeneity in other treatment approaches.

Furthermore, people already receiving hydroxychloroquine for rheumatologic indications have already acquired COVID-19 — how effective can it be? Plus, there’s an abstract of a study (inadvertently circulated before publication) that not only shows no benefit, but also suggests harm.

If we have questions about clinical benefit, all must acknowledge that any treatment can cause harm. Of particular concern with hydroxychloroquine for elderly patients — those at greatest risk of severe COVID-19 disease — is QT prolongation, a problem worsened with concomitant azithromycin, many other medications, and underlying heart disease.

Is it any wonder the poll results are so split? This is a real tough one.

Often in such circumstances, it’s helpful to ask what one would do for a loved one — or yourself — if having to make the decision.

Personally, I would not take hydroxychloroquine for COVID-19, concerned about side effects and not so sanguine about its potential antiviral activity. The road is littered with drugs that have in vitro activity for respiratory tract infections, and yet do nothing when given to people.

In fact, our list of effective antiviral treatments for these infections is very short! For common respiratory tract infections, we have only the influenza drugs — and even with the flu, some argue the benefits are marginal.

I do understand the opposite view. I would listen carefully to a patient who strongly wanted treatment and go forward with prescribing it, provided they understood the risks and there were no contraindications.

But a well-designed clinical trial? Sign me up. We’ve got to learn more about this disease, and fast.

So take it away, Mabel and Olive. You two are giving me great pleasure at a time when we all really need it.