@PFIZE®baba
Pathophysiological Basis and Rationale for Early
Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection
Peter A.McCulloughMD,
MPHabc
Ronan
J.KellyMDaGaetanoRuoccoMDdEdgarLermaMDeJamesTumlinMDfKevin
R.WheelanMDabcNevinKatzMDgNorman
E.LeporMDhKrisVijayMDiHarveyCarterMDjBhupinderSinghMDkSean
P.McCulloughBSlBrijesh
K.BhambiMDmAlbertoPalazzuoliMD,
PhDnGaetano
M.De FerrariMD, PhDoGregory
P.MilliganMD, MPHaTaimurSafderMD,
MPHaKristen
M.TecsonPhDb…Harvey A.RischMD, PhDq
The American Journal of Medicine, Volume 134, Issue 1, January 2021, Pages 16-22
Antimalarials
Hydroxychloroquine
(HCQ) is an antimalarial/anti-inflammatory drug that impairs endosomal transfer
of virions within human cells. HCQ is also a zinc ionophore that conveys zinc
intracellularly to block the SARS-CoV-2 RNA-dependent RNA polymerase, which is
the core enzyme of the virus replication.21 The currently completed retrospective
studies and randomized trials have generally shown these findings : 1) when
started late in the hospital course and for short durations of time,
antimalarials appear to be ineffective, 2)
when started earlier in the hospital
course, for progressively longer durations and in outpatients, antimalarials
may reduce the progression of disease, prevent hospitalization, and are
associated with reduced mortality.22, 23,
24, 25 In a retrospective inpatient study of 2541
patients hospitalized with COVID-19, therapy associated with an adjusted
reduction in mortality was HCQ alone (hazard ratio [HR] = 0.34, 95%
confidence interval [CI] 0.25-0.46, P <0.001) and HCQ with azithromycin (HR = 0.29,
95% CI 0.22-0.40, P <0.001).23 HCQ was approved by
the US Food and Drug Administration in 1955, has been used by hundreds of
millions of people worldwide since then, is sold over the counter in many
countries, and has a well-characterized
safety profile that should not raise undue alarm.25,26 Although
asymptomatic QT prolongation is a well-recognized and infrequent (<1%)
complication of HCQ, it is possible that in the setting of acute illness
symptomatic arrhythmias could develop. Data safety and monitoring boards have
not declared safety concerns in any clinical trial published to date. Rare
patients with a personal or family history of prolonged QT syndrome and those
on additional QT prolonging, contraindicated drugs (eg, dofetilide, sotalol)
should be treated with caution and a plan to monitor the QTc in the ambulatory
setting. A typical HCQ regimen is 200 mg bid for 5 days and extended to 30 days
for continued symptoms. A minimal sufficient dose of HCQ should be used,
because in excessive doses the drug can interfere with early immune response to
the virus.