Hydroxychloroquine as prophylaxis

Clinical Question

What is the current evidence for using Hydroxychloroquine as prophylaxis against COVID-19?

Key Findings

  • There are currently no randomized control trials showing chloroquine or hydroxychloroquine to be effective in preventing COVID-19 disease.

Summary of Information

In vitro studies

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been shown to affect the glycosylation process of ACE2 receptor that COVID-19 requires to bind human cells.[1][2] In vitro studies have also shown that these drugs may inhibit the fusion of the virus by altering pH.[1] Xueting Yao et al. performed in vitro studies that showed promising results of HCQ’s use as a prophylactic agent with an EC50 of 6.25 uM and 5.85 uM at 24 and 48 hours respectively.[1]

Unfortunately, similar in vitro experiments performed by Clementi N et al. did not show viral suppression in the prophylactic group and suggested a combination of prophylactic/therapeutic use of HCQ in order to maximize it’s antiviral effects.[2] Previous in vitro studies of HCQ showed its effectiveness as prophylaxis against influenza,[3] however it did not prevent infection in a randomized, placebo-controlled, double-blind trial.[4] Possible prophylactic dosing regimens have been proposed by comparing doses used for current approved medical conditions including malaria and autoimmune diseases and the EC50 required to inhibit COVID-19 as established by Wang et al.[5] Although, clinical trials are currently underway, no data is yet published.

Two in vitro studies have been conducted looking at hydroxychloroquine and chloroquine’s in vitro antiviral and prophylactic activity. Xueting Yao et al. pretreated Vero cells (derived from a species of African green monkey; commonly used in microbiology, and molecular and cell biology research) with chloroquine and hydroxychloroquine for two hours, then virus-containing medium was added to the cells for two hours. Viral RNA was extracted and detection of SARS-CoV-2 was performed using RT-PCR kit. In this study HCQ showed superior in vitro antiviral effect in comparison to chloroquine in the pre-treatment group. EC50 values for chloroquine were >100 and 18.01 uM at 24 and 48 hours respectively. EC50 values for HCQ were 6.25 and 5.85 uM at 24 and 48 hours respectively, see Figure D.[1]

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On the other hand, Clementi N et al. performed a similar experiment using Vero6 cells comparing prophylactic and therapeutic use of hydroxychloroquine against SARS-CoV-2 in vitro. This study used 10uM of HCQ in each three treatment group: Full-time treatment, pre-adsorption (prophylaxis) treatment and post-adsorption (therapeutic). This study showed no effect on the viral replicative cycle in the prophylaxis group and limited antiviral activity in the therapeutic group. However, significant antiviral activity was observed in the full-time treatment group.[2]

Mechanism of action

The mechanism of action of hydroxychloroquine and chloroquine specifically against COVID-19 has not been fully elucidated. However, various in vitro mechanisms have been studied including inhibiting fusion of virus to cell membrane by altering pH, inhibition of glycosylation of viral proteins, and inhibiting viral replication. This has been demonstrated against several viruses including Ebola, Influenza and SARS coronavirus.17 COVID-19 has been shown to bind human cells via ACE2 receptor and in vitro studies of chloroquine have shown that the glycosylation process of ACE2 receptor is affected.12

Using HCQ as prophylaxis in humans

Chang and Sun proposed two prophylactic schedules for CQ antiviral against COVID-19 by comparing dosages that CQ is currently used for including malaria and autoimmune diseases to the EC50 Wang determined is required to inhibit COVID-19.[5] The two prophylactic schedules are listed below:

  1. CQ 8mg/kg/day for 3 days in post-exposure but asymptomatic cases, ideally to be taken within hours after known viral exposure.
  2. CQ 500mg a day as chronic prophylaxis for people in outbreak locales or endemic areas with a high risk of exposure, to reduce to 250mg a day after 30 days to continue until the threat of infection is abated.[6]

However, it is important to note that despite promising in vitro data to use HCQ as prophylaxis for influenza3 HCQ did not prevent influenza infection in a randomized, placebo-controlled, double-blind trial.[4]

Clinical trials to determine the effect of HCQ for prophylaxis and treatment of COVID-19 are currently underway; however, no data has been published yet. Although there is no strong evidence, Agrawal et al. reports that the Indian Council of Medical Research has started recommending the use of HCQ for prophylaxis for the following situations:

  1. All health care workers who are involved in the care of suspected or confirmed cases of COVID-19: 400mg BID on day 1, followed by 400mg once weekly for the next 7 weeks (with meals)
  2. Asymptomatic household contacts of lab confirmed cases may be prescribed 400mg BID on day 1 followed by 400mg one weekly for 3 weeks (with meals)

Gaps in Knowledge

Although in vitro studies have been performed on HCQ and CQ, there is still a lack of data from randomized clinical trials. This data will better elucidate the effectiveness of these drugs for pre- and post- exposure prophylaxis.

Author Information

Author: Amanda Khoury, MD
Completed on: April 14, 2020
Last updated on: Not yet revised

Reviewed by: Gary Smithson MD
Reviewed on: April 18, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu


  1. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020.  [PMID:32150618]
  2. Clementi N, Criscuolo E, Diotti RA, et al. Combined prophylactic and therapeutic use maximizes hydroxychloroquine anti-SARS-CoV-2 effects in vitro. bioRxiv. March 2020:2020.03.29.014407. doi:10.1101/2020.03.29.014407
  3. Ooi EE, Chew JS, Loh JP, et al. In vitro inhibition of human influenza A virus replication by chloroquine. Virol J. 2006;3:39.  [PMID:16729896]
  4. Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis. 2011;11(9):677-683. doi:10.1016/S1473-3099(11)70065-2
  5. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.  [PMID:32020029]
  6. Chang R, Sun W-Z. Repositioning Chloroquine as Ideal Antiviral Prophylactic against COVID-19 - Time is Now. March 2020. doi:10.20944/preprints202003.0279.v1