Covid-19: chloroquine and hydroxychloroquine

I was sent 2 interesting articles from Anna Wald about the role of chloroquine and hydroxychloroquine in Covid-19.

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A systematic review of the efficacy and safety of chloroquine (see covid Chloroquine reviewjcitcare2020 in dropbox, or doi.org/10.1016/j.jcrc.2020.03.005)

Details:

-- 6 articles were reviewed (one letter, one in-vitro study, one editorial, one expert consensus paper, and 2 national guideline documents)

    -- there are 23 ongoing clinical trials in China using chloroquine or hydroxychloroquine in different groups and looking at different outcomes: patients with mild to severe to critically ill Covid-19, with outcomes including conversion to a negative PCR assay, normalizing clinical symptoms, clinical recovery time, length of hospital stay, mortality rate, etc. A few studies are comparing it to lopinavir/ritonavir

Results:

-- one Chinese lab study found that of 7 antivirals tested, remdesivir and chloroquine were remarkably effective in suppressing SARS-CoV-2, even at quite low doses. chloroquine, unlike remdesivir, functioned at blocking both SARS-CoV-2 cell entry as well as at the post-entry stages of infection, remdesivir only the latter (see covid Chloroquine reviewjcitcare2020 in dropbox, or Wang M. Cell Research 2020; 30: 269), and chloroquine has good penetration into lung tissue

-- another article found that in more than 100 patients chloroquine inhibited the exacerbation of pneumonia, improved lung imaging findings, promoted a virus conversion to negative, and shortened the disease course. I should add that the above systematic review of chloroquine did not find evidence of such data in their trial registries

-- a Chinese multi-collaborative expert consensus concluded that chloroquine 500 mg twice a day for 10 days was recommended for people with mild, moderate, and severe cases of SARS-CoV-2 pneumonia. They also suggested blood testing to rule out the development of anemia, thrombocytopenia, or leukopenia as well as electrolyte disturbances or hepatic/renal dysfunction, and an EKG to rule out development of QTc prolongation. Of note, this consensus document was relying on information that has not yet been published

-- the Dutch Center of Disease Control suggested administering chloroquine to treat severe infections requiring admission to the hospital and oxygen therapy or admitted to the ICU, though treating with optimal supportive care was also considered a reasonable option

-- the Italian Society of Infectious and Tropical Disease recommended the use of chloroquine or hydroxychloroquine for 5 to 20 days according to the clinical disease severity, but including those with mild respiratory symptoms who had comorbidities

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The other article was on hydroxychloroquine and azithromycin as treatment for Covid-19 in a French study, submitted for print but not yet published (see covid Hydroxychloroquine  inprint2020 in dropbox)

Details:

-- 36 patients with confirmed SARS-CoV-2/Covid-19 were included in a single-arm protocol in March 2020

    -- 6 people were asymptomatic, 22 had upper respiratory tract infection symptoms (rhinitis, pharyngitis, or isolated low-grade fever and myalgia), and 8 had lower respiratory tract infection symptoms (symptoms of pneumonia or bronchitis; all had confirmed pneumonia on CT scan)

    -- 42% male, mean age 45

-- 20 of these patients were treated with hydroxychloroquine, and their viral loads in nasopharyngeal swabs were tested daily in a hospital setting and followed for 14 days; the other 16 patients served as controls

    -- controls were those who either refused treatment or had an exclusion criteria (allergy to meds, retinopathy/G6PD deficiency/QTc prolongation, breast-feeding and pregnant patients). ie not a real control population as in an RCT

-- all were put on hydroxychloroquine 200 mg 3 times a day for 10 days

-- 6 patients also received azithromycin (500 mg on day one, then 250 mg a day for the next 4 days) to prevent bacterial superinfection [I assume these were the sickest patients, but criteria were not included]

-- primary endpoint was virologic clearance at day 6 after enrollment

-- secondary outcome was virologic clearance over time, clinical parameters (temperature, respiratory rate, length of hospital stay and mortality), and adverse effects

Results:

-- hydroxychloroquine showed a significant reduction in the viral carriage at day 6: 70% were virologically cured, vs 12.5% in the control group (p=0.001)

    -- day 3: 10 of 20 patients had negative PCRs, vs one of 16 controls

    -- day 4: 12 of 20 patients, vs 4 of 16 controls

    -- day 5: 13 of 20, vs 3 of 16 controls

    -- Day 6: 14 of 20, vs 2 of 16 controls

-- azithromycin added to the hydroxychloroquine was significantly more efficient for virus elimination: at day 6, 100% treated with a combination were virologically cured compared to 57% treated with hydroxychloroquine alone and 12.5% in the control group (p<0.001)

    -- comparing those with hydroxychloroquine only vs hydroxychloroquine with azithromycin

        -- day 3: 5 of 14 were virologically cured on hydroxychloroquine only, vs 5 of 6 on the combination

        -- day 4: 7 of 14 on hydroxychloroquine only, 5 of 6 on both

        -- day 5: 7 of 14 on hydroxy chloroquine only, 6 of 6 on both

        -- day 6: 8 of 14 on hydroxychloroquine, 6 of 6 on both

-- these drug effects (both hydroxychloroqiine alone or in combo with azithromycin) were significantly more impressive in patients who were symptomatic

-- one patient who was PCR positive at day 6 with hydroxychloroquine, then received azithromycin and the infection was cured at day 9

-- 6 patients were lost to follow-up because of early cessation of hydroxychloroquine treatment: 3 because they were transferred to the ICU, one patient died, and one patient left the hospital. One patient stopped treatment on day 3 because of nausea

-- clinical follow-up and adverse effects will be published subsequently, at the end of the trial

Commentary:

-- chloroquine, an immunomodulant used to treat malaria, has been shown to be effective in reducing viral replication in SARS and MERS-CoV.

-- one advantage of hydroxychloroquine is that it has a better clinical safety profile than chloroquine and has fewer drug-drug interactions

-- also there is a concern that using massive amounts of chloroquine for Covid-19 might deplete its availability to those with chloroquine-sensitive malaria

-- these data are were impressive given that in China the mean duration of PCR positivity was 20 days (37 days for the longest).  Here the viral load decreased dramatically by day 3-6

-- a Chinese study found that hydroxychloroquine was more potent than chloroquine in inhibiting SAR-CoV-2 in-vitro

-- azithromycin has been shown to be active in-vitro against other viruses, including Zika and Ebola, and to prevent severe respiratory tract infection in at-risk kids (see JAMA. 2015 Nov 17;314(19):2034-2044. doi: 10.1001/jama.2015.13896) [note: this was a general finding a few yrs ago and has nothing to do with coronavirus effect; also it is not clear if the effect of azithro is from its antibacterial effect, anti-inflammatory effect, ??other direct effects]. In the case of coronavirus above, maybe it's related to some supplemental effect to hydroxychloroqine, or has to do with even molecular alterations/other synergies in either or both of them by their combination???

-- there is concern that the combination of azithromycin and hydroxychloroquine could result in further QTc prolongation, and should be monitored

-- it is speculated that failures of hydroxychloroquine could be related to genetic variation or host factors affecting hydroxychloroquine metabolism (hydroxychloroquine failure happened in 2 patients, a mother and son; the researchers feel it is more suggestive of the latter mechanism)

-- and, as with HIV, treatment as prevention: decreasing the viral loads earlier should decrease the potential for contact infection

-- the obvious limitation of this study is that it’s very small, has a quite suspect methodology, has limited long-term follow-up, and a large percentage (6 patients) dropped out of the study. And we await the final analysis, which will include clinical and virologic followup, including adverse effects

--of note, the FDA has just come out with a pretty strong statement to investigate the use of chloroquine for mild-to-moderate Covid-19 patients to reduce the duration of symptoms as well as viral shedding. this release (see https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-development-treatments ) also comments on an ongoing remdesirvir RCT, and mentions other therapies in the works: IL-6 inhibitors, hyperimmune globulin,and vaccine

So, clearly we are very early in the development of antivirals for Covid-19, and  we sorely need RCTs, comparing the efficacy of the leading contenders at this point (eg remdesivir, chloroquine, hydroxychloroquine with or without azithromycin, lopinavir/ritonavir) in the various stages of disease, ranging from asymptomatic to critically ill persons. some studies such as this one, along with the one on lopinavir/ritonavir (see http://gmodestmedblogs.blogspot.com/2020/03/covid-19-lopinavir-does-not-work-but-is.html), have been published early and with really suboptimal methodology simply because this virus is basically out-of-control in most of the world, and we need to try some things to help people and control it... And, we have a lot to learn from China, since they are now reporting zero new cases.

and, of course, we are way, way behind on virus testing, both in those with various stages of potential clinical infection and in the asymptomatic community...... And, this needs to be a huge priority in order to contain the virus

geoff​

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