COVID: hydroxychloroquine helped in small study

A recent small RCT in China found benefit from hydroxychloroquine in patients with Covid-19, in a pre-print study (see covid Hydroxychloroquine china preprint2020 in dropbox). Thanks to Jon Pincus for passing this on.

Details:

-- 62 patients suffering from Covid-19 in Wuhan, China were randomized, with 31 to receive an additional 5 days of hydroxychloroquine 200 mg twice a day vs 31 to receive the same baseline care, during a 24 day period in February 2020

    -- baseline care included oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin with or without steroids. [Unclear what agents were used. By their wording, it seems that they had likely been on hydroxychloroquine or chloroquine prior to randomization

-- they assessed the time to clinical recovery, clinical characteristics, and radiologic results at baseline and 5 days after treatment

-- 47% were male, mean age 45.

-- All patients were >18 yo, had PCR positive test for SARS-CoV-2, had pneumonia on chest CT, and had an SaO₂/SPO₂ ratio >93% or PaO₂/FIO₂ ratio >300 mmHg (i.e. mild illness).

-- Exclusions included severe critical illness, retinopathy, cardiac conduction block, severe liver disease, severe renal failure (eGFR<30)

Results:

-- differences in clinical outcomes, comparing those on hydroxychloroquine to those not:

    -- fever: 2.2 vs 3.2 days, p=0.008

    -- cough: 2.0 vs 3.1 days, p=0.0016

    -- progression to severe illness: 0 vs 4 patients

    -- adverse effects: 2 vs 0 (both mild: a rash, and a headache)

    -- chest CT scans, comparing day 0 vs day 6:

        -- 2 (7%) vs 9 (29%) got worse

        -- 4 (13%) vs 5 (16%) were unchanged

        -- 25 (81%) vs 17 (55%) improved; 6 (19%) vs 12 (39%) had a moderate improvement, and 19 (61%) vs 5 (16%) significantly improved

Commentary:

-- as a perhaps relevant side note not related to this study, none of their 80 patients with lupus on long-term hydroxychloroquine have been confirmed to have SARS-CoV-2 infection or related symptoms; and, contrarily, none of the 178 patients diagnosed with Covid-19 pneumonia were on hydroxychloroquine

-- this study adds to the meager high-quality information on hydroxychloroquine (and chloroquine) in ameliorating the potential ravages of SARS-CoV-2 infection. A recent French study with 20 patients on hydroxychloroquine found a significant reduction in viral carriage, with some potential benefit by adding azithromycin (though the methodology and cutpoints of the cycle threshold were a bit suspect). See http://gmodestmedblogs.blogspot.com/2020/03/covid-19-chloroquine-and.html

-- and the FDA did authorize hydroxychloroquine and chloroquine for the treatment of Covid-19 at this point, though lacking specific evidence of clear benefit (see https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html#r6, as well as  http://gmodestmedblogs.blogspot.com/2020/04/covid-presistence-of-virus-in.html ). it should be noted that European regulators are limiting their use to clinical trials only

-- as mentioned in prior studies, including in http://gmodestmedblogs.blogspot.com/2020/03/covid-19-chloroquine-and.html, there are in vitro studies showing that chloroquine effectively inhibits the replication/spread of SARS-CoV-2, and hydroxychloroquine does moderate the regulation of pro-inflammatory cytokines (TNF alpha, IL-1, IL-6) and has  antioxidant activity. It is postulated that this anti-inflammatory effect may decrease the dramatic adverse effects of cytokine storm

-- this was not a true randomized controlled trial in that there was no placebo group. In addition we do not have much information about the baseline therapy which may well have included hydroxychloroquine for an unclear amount of time. Also no data on the antibacterials used, which might have included azithromycin, and that might have had some affect on SARS-CoV-2, as above

so, what is one to make of the study?

-- Clearly, there are deficiencies of the study:

    -- much of the important background information is not evident, including the baseline therapy that was  given to all patients. Perhaps when this article is peer-reviewed, the final version will have more data

    -- this was not a formal RCT

    -- this was a pretty small study. i am not sure why we do not have better data/larger studies since the current Covid-19 count has >1 million cases so far. And, at least some of the endpoints, as above, should be evident within days. Larger and better studies are on the way, with results hopefully sooner than later

-- so, we are still in the position of having to make major clinical decisions in the absence of anything close to solid evidence. This study, though small and with the deficiencies noted, was reasonably impressive in both decreasing adverse clinical signs and symptoms, and improving the CT findings pretty impressively and, likely tied in with that, decreasing clinical deterioration.

-- My sense, which is pretty frequently wrong, is that this is the best available medication at this point for people with evidence of pulmonary involvement. And it probably makes sense to give it earlier as opposed to later (there is argument in the literature that it is more effective if given early, though, as with everything COVID-19, good studies are lacking). However, there are definitely potential serious adverse effects (e.g. prolongation of the QTc, more so if azithromycin is added, and documented cases of cardiotoxicity/heart failure, though these are quite uncommon). There is of course the added potential adverse effect of depleting medication availability to those requiring this medication for their lupus or rheumatoid arthritis, and that supplies may be diverted to those with Covid-19.  but, at this point, does seem like a reasonable med for Covid-19 (not much downside, and really impressive potential upside).....

geoff​

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