COVID: hydroxychloroquine post-exposure prophylaxis

A randomized trial did not find benefit of hydroxychloroquine used as postexposure prophylaxis for Covid-19 (see covid hydroxychloroquine PEP nejm2020 in dropbox or DOI: 10.1056/NEJMoa2016638)

 

Details:

-- 821 asymptomatic people from the United States and Canada exposed to someone with confirmed Covid-19 were randomized to hydroxychloroquine (800 mg x1, 600 mg 6 to 8 hours later, then 600 mg daily for 4 more days, for a total course of 5 days) vs placebo

-- exposure: household or occupational exposure to someone with known Covid-19, at a distance of less than 6 feet for more than 10 minutes while wearing neither a facemask nor an eye shield (high risk exposure) or whiole wearing a facemask but no eye shield (moderate risk exposure)

-- median age 40, 52% women, 27% with chronic health conditions (hypertension 12%, asthma 8%)

-- 66% of the participants were healthcare workers, majority being physicians or physicians assistants (63%) and nurses are nursing assistants (24%)

-- healthcare workers: exposure was from patients (77%) or ill coworkers (20%)

-- household contacts (30%): contact was a spouse or partner (47%) or a parent (18%)

-- time from exposure to enrollment: one day in 17%, 2 days in 25%, 3 days in 25%, 4 days in 31%

-- exposures: high risk (no eye shield or masks) 88% (719 people), with 60% not using any personal protective equipment

-- patient recruitment was primarily with use of social media outreach, as well as traditional media platforms

-- participants reported their exposure, preferably within 3 days after exposure (before the median incubation period of 5 to 6 days). Healthcare workers could initially be enrolled on the basis of a presumptive high risk exposure to patients with pending Covid PCR tests

-- the definition of Covid in participants was: having a symptomatic illness with a positive test (confirmed cases); the presence of cough, shortness of breath, or difficulty breathing, or the presence of 2 or more of the symptoms of fever, chills, rigors, myalgias, headaches, sore throat, and new olfactory/taste disorders (probable cases); or one or more of the compatible symptoms, which could include diarrhea (possible cases)  

-- primary outcome: incidence of laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days

-- secondary outcome: incidence of hospitalization for Covid or death, incidence of PCR confirmed SARS-CoV-2 infection, incidence of Covid 19 symptoms, incidence of discontinuance of trial intervention owing to any cause, and severity of symptoms at days 5 and 14 according to visual analog scale (range of 0 to 10)

 

Results:

-- incidence of new illness compatible with Covid-19, over 14 days of follow-up:

    -- hydroxychloroquine 49 of 414 (11.8%) vs placebo 58 of 107 (14.3%), p=0.35

-- 2 hospitalizations were reported: one in each group

-- of the 113 people with symptomatic illness, 16 had PCR-confirmed disease, 74 had illness that was compatible with probable Covid, and 13 had possible Covid.

-- 4 participants had asymptomatic positive Covid PCR tests

-- most frequent symptoms were: cough 45%, fever 35%, shortness of breath 19%, fatigue 50%, sore throat 40%, myalgias 37%, anosmia 23%

-- median symptom severity score on the visual analog scale from 0-10: 2.8 if on hydroxychloroquine and 2.7 on placebo

-- adherence: 75% on hydroxychloroquine, 83% on placebo (incomplete adherence largely because of adverse effects)

-- adverse effects: hydroxychloroquine 40%, placebo 17%. Mostly nausea, loose stools, and abdominal discomfort. No serious adverse events were reported

-- no reported arrhythmias or deaths occurred

 

Commentary:

--so, no evident benefit for hydroxychloroquine, even at a quite high dose, in those starting it within 4 days of contact

--the importance of the study is that hydroxychloroquine was given early when it is likely to be more effective, since it impairs binding of the spike glycoprotein of SARS-CoV-2 on the ACE2 receptor. In vitro, hydroxychloroquine also inhibits replication of SARS-CoV-2

    --All previous studies have focused on much sicker patient: eg, an almost-RCT in Detroit finding no benefit (http://gmodestmedblogs.blogspot.com/2020/04/covid-hydroxychloroquine-trial-in.html ), another small study from China did find some benefit (http://gmodestmedblogs.blogspot.com/2020/04/covid-hydroxychloroquine-helped-in.html), and a large (96,032 patient) compilation of observational data looking at chloroquine, hydroxychloroquine, and hydroxychloroquine with a macrolide found significant harm without benefit, as compared to no treatment (see https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2931180-6 , or covid hydroxychloroquine no benefit but harm lancet2020 in dropbox). [none of these were real RCTs, so their results are a bit suspect, though the large Lancet study did mathematically control for many likely confounders]

-- that being said, it is still important to look at hydroxychloroquine as a preventative strategy, since the above patients were treated well after the exposure and likely well after SARS-CoV-2 attached to the nasal epithelial ACE-2 receptors

-- it is unclear what the correct dose of hydroxychloroquine might be: they chose this rather intensive regimen based on pharmacokinetic simulations to achieve reasonable plasma concentrations. ie, unliklely to be underdosing the med, with that leading to a negative result

-- potential biases from their definition of Covid:

    --they may have missed some people because they had asymptomatic cases, a not uncommon finding (see http://gmodestmedblogs.blogspot.com/2020/06/covid-asymptomatic-infections-and-viral.html), and it is conceivable that hydroxychloroquine decreased the rate of minimal or asymptomatic infections (which is important, since those with asymptomatic infections may be vectors for the continued spread of Covid-19)

    -- they may have excluded people who had negative PCR tests, which we know are quite inaccurate early in the course of disease (http://gmodestmedblogs.blogspot.com/2020/05/covid-false-negative-pcr-results-over.html)

    -- their definition of probable cases is based on the generally accepted one, as above. and this was the most common diagnostic group (<3% had positive Covid PCRs). but the specificity of these symptoms is unclear in participant reports

-- a result of their pragmatic approach to enrollment, using largely social media,likely explained their skewed population with predominantly younger and healthier people. Though this might explain why these patients all did so well, the risk of developing symptomatic infection is still high in this group. The lack of cardiovascular adverse events from hydroxychloroquine might also be explained by this being such a healthy group

 

Limitations of trial:

-- all data were from participant reports, leading to several potential concerns:

    -- there is unknown specificity of the diagnostic criteria above in the setting

    -- no definite proof that the index patients were Covid –positive

    -- no proof of adherence to medications

    -- as a younger, healthier group, unclear if these results would be generalizable to others (in particular older patients with more comorbidities, who might also have more significant adverse effects to the hydroxychloroquine, but also might get more benefit)

 

So, another nail in the hydroxychloroquine coffin. However, there are many trials in the offing with different designs and potentially different outcomes. Given our understanding of how hydroxychloroquine works with SARS-CoV-2, the predominant benefit may be for primary prevention (i.e., preexposure prophylaxis); there are apparently about 60 ongoing trials looking at this. We shall see…

geoff

 

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org

 

to get access to all of the blogs:

1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order

2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

3. or you can just click on the magnifying glass on top right, then  type in a name in the search box and get all the blogs with that name in them

 

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list