Low dose hydroxychloroquine prophylaxis for COVID-19 – a prospective study


Background Since the outbreak of the COVID-19 pandemic, the world began a frantic search for possible prophylactic options. While trials on hydroxychloroquine (HCQ) prophylaxis are ongoing, concrete evidence is lacking. The study aimed to determine the relative efficacy of various doses of oral HCQ in prophylaxis and mitigating the severity of COVID-19 in healthcare workers.


This was a prospective cohort with four arms (high, medium, low dose, and control) of HCQ prophylaxis, used by healthcare workers at a tertiary care center in India. Participants were grouped as per their opting for any one arm voluntarily as per institute policy under the Government guidance. The outcomes studied were COVID-19 positivity by RT-PCR and its severity assessed by the WHO COVID-19 severity scale.

Results Total of 486 participants were enrolled, of which 29 (6%) opted for low dose, 2 (<1%) medium dose, and none for high dose HCQ while 455 (93.6%) were in the control arm. Of the 164 participants who underwent RT-PCR, 96 (58.2%) tested positive. Out of these 96 positive cases, the majority of them (79 of 96 [82.3%]) were ambulatory and were managed conservatively at home. Only 17.7% (17 of 96) participants, all of them from the control group, required hospitalization with the mild-moderate disease. None of the participants had severe disease, COVID-related complications, ICU stay, or death. The difference in the outcome assessed amongst the various arms was statistically insignificant (p-value >0.05).


This single-center study demonstrated that HCQ prophylaxis in healthcare workers does not cause a significant reduction in COVID-19 as well as mitigating its severity in those infected. At present, most of the trials have not shown any benefit. The debate continues to rage, should HCQ prophylaxis be given to healthcare workers for chemoprophylaxis?


Since late 2019, a health crisis created by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has gripped the entire world, taking a massive toll on people and nations. It has inflicted substantial societal and economic devastation and has overwhelmed healthcare systems. Directly or indirectly, the virus has had a toll on almost the entire population of the world, at a scale not seen in over a century. It has also left a considerable strain on the healthcare system, with frontline healthcare workers at a high risk of contracting the infection.

Since the onset of the covid outbreak, the world began a frantic search for possible therapeutic options. Given that hydroxychloroquine has been in use for decades with a good safety profile, there has been a lot of focus regarding its potential use against COVID-19. Many large-scale trials have been launched evaluating the efficacy of hydroxychloroquine as a therapeutic as well as a prophylactic option. An early study from China reported the in-vitro efficacy of chloroquine against the novel coronavirus. (1) It is thought to impair the terminal glycosylation of the angiotensin-converting–enzyme 2 (ACE2) receptor, which is the binding site for the envelope spike glycoprotein and has been shown to inhibit endolysosome function. (2) The pharmacokinetics of hydroxychloroquine, such as its high lung concentration (500 times the blood concentration) and the long half-life are ideally suited for its use as an agent for prophylaxis. (3)

Material and methods

Study design

We conducted pragmatic prospective multiple arms cohort studies to determine the relative efficacy of various hydroxychloroquine (HCQ) doses in the prevention and mitigation of severity of symptomatic COVID-19 disease in high-risk healthcare workers at a tertiary care hospital in India. Participants were educated regarding the various dose schedules of HCQ. They were asked to make an informed decision regarding enrolment into one of the four study arms after a valid prescription. There was no randomization since the decision for drug prophylaxis and dosing was taken by the participants themselves as per available Government guidelines and other literature.

This study was approved by the Institutional Ethics Committee (IEC) at the All India Institute of Medical Sciences, Rishikesh (CTRI/2020/06/025593). The study enrolment began on April 12, 2020, and ended on June 7, 2020, while follow-up was completed by October 26, 2020.


We included asymptomatic healthcare workers (HCWs) with a high risk of exposure to COVID-19 infection. High risk of exposure was defined as all HCW’s including residents, nurses, paramedics, and attending staff who had direct contact with COVID-19 patients in the emergency department, COVID dedicated wards, operating rooms, intensive care units (ICUs), or those who documented having contact with COVID-19 patients during their work. HCWs who were reluctant to take any prophylaxis; or those with a history of any of the following conditions: retinopathy or retinal disease, cardiomyopathy, cardiac arrhythmia, prolonged QT syndrome, psoriasis, porphyria cutanea tarda, epilepsy, myasthenia gravis, myopathy of any cause, serious hepatic or renal disease, glucose-6-phosphate dehydrogenase deficiency, severe depression; or those taking medication with known serious hepatotoxic effects or known interaction with HCQ were included in the control arm of the study.

We excluded participants with weight outside the range (45 kg-150 kg); prior enrolment into this study; active or previous COVID-19 diagnosis within the last 6 months; or self-reported current acute respiratory infection; or inability/unwillingness to be followed up for the trial period.

Study setting

All eligible HCWs employed at the hospital were enrolled in the study. Consent was obtained electronically after the participants read the online information sheet regarding the nature and implications of the study. The participants were free to withdraw from the study at any time for any reason without prejudice to future care and without any obligation to give the reason for withdrawal. However, they were educated on the importance of daily monitoring and to continue participating in the study.

At the time of enrolment, we collected demographic information, comorbidities, and relevant medical history of all participants along with general and physical examination. Blood investigations including complete blood count, renal and liver function tests, and G6PD levels were measured. A baseline electrocardiogram and ophthalmological evaluation were also done.


Participants were educated regarding the different prophylaxis dose schedules of HCQ and asked to take a voluntary decision for enrolment into one of the four arms of the study: ICMR/low-dose (400mg HCQ twice daily on Day 1 followed by 400mg weekly for 7 weeks) or Medium-dose (400mg HCQ once daily for 4 days followed by twice weekly for 3 months) or High-dose (400mg HCQ once daily for 4 days followed by 200 mg daily for 3 months) or Control arm which included HCWs with any contraindication to HCQ or they did not opt for any prophylaxis.

Study Assessments

Follow-up and assessment of participants were done through a combination of telephonic interviews as well as self-reporting on web-based software (@Zifo RnD Solutions, Chennai, India). Participants used a secure clinical registry form (eCRF) login to self-record a daily census with questions regarding symptoms, exposure, and treatment adherence. They were sent a reminder through text message by the software on their mobile phones with a link to the website. Along with self-reporting, all participants were required to physically report symptoms, general wellbeing, and compliance at enrolment followed by on days 30, 60, 90, or whenever they completed prophylaxis. In the case of participants reporting COVID-19 related symptoms, they were asked to undergo RT-PCR testing, if tested positive was managed according to the institute treatment protocol.

The study participants were monitored for two months post completion of prophylaxis or development of confirmed symptomatic COVID-19 infection to determine the outcome in terms of recovery/severity/mortality. All adverse events were recorded with clinical symptoms and accompanied by a simple, brief description of the event. Each adverse event was assessed for severity, causality, seriousness, and expectedness.


The primary outcomes were measured in terms of incidence of COVID-19 in each one of the four arms and the peak severity of COVID-19 in the positive study participants over the study period. Confirmed COVID-19 was defined as a participant with reverse transcriptase-polymerase chain reaction (RT-PCR) positive for SARS-CoV-2. Severity was graded on the Ordinal WHO COVID-19 severity scale. These outcome definitions were based on WHO R&D Blueprint consensus definitions for COVID-19.(9)

Secondary outcomes included incidence of COVID-19 related complications such as respiratory failure requiring intubation, acute respiratory distress syndrome, delirium, shock requiring inotropes, sepsis, acute kidney injury and acute liver injury, duration of ICU stay, and mortality.

Statistical analysis

Summary of the baseline characteristics of all participants was estimated by frequency and percentage for categorical variables whereas mean and standard deviation (or median and inter-quartile range for non-normally distributed data) for continuous variables. The primary endpoint of incidence of COVID19 was presented as a proportion of participants reported with the RTPCR positive test. Association between RT-PCR positivity and COVID-19 severity was estimated by the Chi-Square test. Comparison between the means of COVID-19 severity scores among the two arms was done using the Mann-Whitney test.


In this cohort study, evaluating hydroxychloroquine (HCQ) for the pre-exposure prophylaxis of COVID-19 in healthcare workers (HCWs), we found no statistically significant reduction in the incidence of COVID-19 in those receiving the 400 mg weekly dose of HCQ compared to controls. We also intended to evaluate the prophylactic efficacy of medium and high-dose hydroxychloroquine, but they were excluded since only two participants were enrolled.

The reason for no benefit with HCQ may be due to it being ineffective in vivo or the drug concentration being too low. (10) Although we did not measure the serum concentrations of HCQ, in a similar study done by Rajasingham et al., they found no difference in the drug concentrations between those who developed COVID-19 and those who did not. (11) The ICMR dose (400 mg once weekly HCQ) is predicted to achieve a plasma concentration that is more than the in-vitro half-maximal effective concentration (EC50). (12) However many studies have found that there is a discrepancy in the simulated and observed drug concentrations and the reason may lie in the sequestration of drugs in the leukocytes and platelets. (11,13) considering this correction, the extrapolated plasma concentrations are unlikely to reach EC50 even with daily dosing of HCQ. (11) This underscores the need for drug concentration measurement in any future or ongoing trial evaluating the efficacy of HCQ in the context of COVID-19. The present study shows that prophylaxis with 400 mg of HCQ weekly is ineffective, but it is doubtful whether even a significantly higher dose would have been any better. In one double-blind randomized trial of 125 patients, even 600 mg of daily HCQ did not reduce the incidence of COVID-19 in HCWs.(14) Even in a pre-clinical investigation in the COVID-19 macaque model, there was no difference in the antiviral activity with varied doses of hydroxychloroquine. (10)

Credited to Mayank Agarwal

1Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), Rishikesh, India buy hydroxychloroquine | buy hydroxychloroquine online | buy hydroxychloroquine australia | buy hydroxychloroquine canada | buy hydroxychloroquine Amazone | buy hydroxychloroquine Online Singapore |

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