Source: Science Direct

Dr. Deba PrasadDhibarMD(Assistant Professor)aDr. NavneetAroraMD(Senior Resident)aDr. ArpitKakkarDNB(Senior Resident)aDr. NeerajSinglaMD(Assistant Professor)bDr. RitinMohindraMD(Assistant Professor)bDr. VikasSuriMD(Additional Professor)bDr. AshishBhallaMD(Professor)bDr. NavneetSharmaMD(Professor)bDr. Mini PSinghMD(Professor)cDr. AjayPrakashPhd(Assistant Professor)dDr. LakshmiPVMMD(Professor)eDr. BikashMedhiMD(Professor)d

Highlights

This study, which to our knowledge is the only clinical trial that was dedicated to evaluating the efficacy of HCQ as post-exposure prophylaxis (PEP) to prevent COVID-19 in asymptomatic, high risk, household contacts of the laboratory-confirmed COVID-19 cases.

The study found that there was a significant risk reduction for the incidence of COVID-19 in participants who received PEP with HCQ plus standard therapy, as compared to standard therapy alone.

The present study will encourage the researchers around the globe for further study to prove virucidal effect of HCQ in-vivo as well as to reconsider further randomized clinical trials with larger sample size for better evaluation of HCQ as PEP for the prevention of COVID-19.

Abstract

Back ground

Since the arrival of the COVID-19 pandemic many available drugs have been tried for the treatment or prevention of COVID-19 with limited success or failure. The household direct contacts of the COVID-19 patients are at highest risk for SARS-CoV-2 infection. Hydroxychloroquine (HCQ) has been tried against COVID-19 in the view of its in-vitro virucidal action against SARS-CoV-2, but the role of HCQ as post exposure prophylaxis (PEP) is still inconclusive and evolving.

Method

In this open label control clinical trial asymptomatic individual who had direct contact with laboratory confirmed COVID-19 cases or had undertaken international travel in last 2 weeks were given the option for taking HCQ prophylaxis and assigned into PEP (N=132) and control groups (N=185). The PEP group received tablet HCQ 800 mg on day one followed by 400 mg once weekly for 3 weeks. Both the groups received standard care of therapy in the form of home quarantine for 2 weeks along with social distancing and personal hygiene and followed up for 4 weeks for new onset COVID-19.

Results

Total 50 out of 317 participants (15.8%) had new onset COVID-19. The incidence of COVID-19 was significantly (p=0.033) lower in PEP group [N=14 out of 132, (10.6%)] as compared to the control group [N=36 out of 185, (19.4%)]. Total absolute risk reduction for the incidence of COVID-19 was -8.8% points. The number needed to treat (NNT) to prevent occurrence of one case of COVID-19 was 12. The overall relative risk was 0.59 (95% confidence interval, 0.33 to 1.05). The compliance was good and most common ADR was epigastric discomfort with burning sensation, reported by 3 participants and no serious ADR was noted.

Conclusion

PEP with HCQ has the potential for the prevention of COVID-19 in at-risk individuals. Till definitive therapy is available, continuing PEP with HCQ may be considered in suitable at-risk individuals for the prevention of COVID-19, as endorsed by many national/international health authorities. The present study will encourage the researchers around the globe to reconsider further randomized clinical trials with larger sample size for better evaluation of HCQ as PEP for the prevention of COVID-19.

Trial registration

clinicaltrials.gov PRS ID: CT04408456

Keywords

Hydroxychloroquine (HCQ)Post exposure prophylaxis (PEP)COVID-19SARS-CoV-2Pandemic, Prevention

1. Introduction

Novel corona virus (SARS-CoV-2) epidemic which stared from Wuhan in China is now a well established pandemic worldwide affecting more than 35 million people with nearly 1.1 million mortality [1].

As Italy, Spain, Germany, United Kingdom, Brazil and USA have taken over from China in term of highest burden of mortality, India has become the next epicenter of this Pandemic, next to the USA. Presently there are more than 6.6 million cases of corona virus disease-2019 (COVID-19) in India with unfortunate mortality of more than 100 thousand patients [2].

The clinical presentation of the COVID-19 varies from asymptomatic cases and mild symptoms of fever, cough, sore throat, headache, myalgia, nasal congestion, diarrhea to severe pneumonia, acute respiratory distress syndrome (ARDS) requiring mechanical ventilation and even multi-organ dysfunction syndrome (MODS), sepsis leading to death [3].

If adequate preventive and therapeutic measures are not taken, India has a very high risk of affecting more millions of people with high mortality because of the large population size along with very high population density. At present there are no definitive therapeutic drugs or vaccines are available for the treatment and prevention of SARS-CoV-2 infection.

Symptomatic and supportive care is being given to COVID-19 cases along with isolation and quarantine measures are being taken for the suspected individual at risk for COVID-19 to limit the spread of the SARS-CoV-2 infection [4]. The household direct contacts of the COVID-19 patients are at the highest risk for SARS-CoV-2 infection.

Presently many scientist and doctors are recommending many existing available drugs (Ribavirin, lopinavir, Remdesivir, chloroquine, hydroxychloroquine) for SARS-CoV-2 infection for therapeutic and as well as for prophylactic purpose [5,6].

Among which hydroxychloroquine sulfate (HCQ), a chloroquine analogue has given some rays of hope to battle against this deadly pandemic [7]. In an in-vitro study, researchers found that HCQ has some antiviral effect against SARS-CoV-2 through a mechanism targeted at the host cell [89].

HCQ is quite a safe drug as it is being used in rheumatology patients for lifelong therapy without much side effects, so it allows for a higher dose without any significant side effects and drug-drug interaction [10].

The recently published clinical trial suggested HCQ can be used for the therapeutic purpose of the SARS-CoV-2 infection [7] and many governments including the USA and India have already endorsed that due to lack of adequate better alternative drugs. Indian council of medical research (ICMR) has advised for HCQ prophylaxis for the people who are at risk for developing SARS-CoV-2 infection, all asymptomatic health care workers (HCW) involved in taking care of suspected or confirmed COVID-19 cases, and all asymptomatic household contacts of laboratory-confirmed COVID-19 cases [11].

But there is still a lack of significant scientific data to prove or disprove the efficacy of HCQ for the treatment and post-exposure chemoprophylaxis for SARS-CoV-2 infection management. Being a tertiary care centre we are catering to many states which include Punjab, Haryana, Himachal Pradesh, Uttara Khand, Uttar Pradesh, and Rajasthan. Among this Punjab has the highest population of non-residential Indian (NRI) and most of them have returned home. Initially this put our institute to handle the highest burden of suspected cases of COVID-19 in northern India.

A recently published study proposed that HCQ was not useful as post-exposure prophylaxis (PEP) for the prevention of COVID-19 in at-risk individuals [12]. But in this study majority of the participants were HCW. There is still lack of clinical trial regarding PEP with HCQ for the prevention of COVID-19 in non-HCW individuals who are at risk of SARS-CoV-2 infection.

In this open level control clinical trial we tried to evaluate the efficacy of PEP with HCQ for the prevention of COVID-19 in the asymptomatic non-HCWs population who were at risk for SARS-CoV-2 infection.

2. Method

2.1. Aims

The aim of the study was to evaluate the efficacy of post-exposure prophylaxis (PEP) with HCQ for the prevention of COVID-19 in asymptomatic non-HCW individuals who were at risk for SARS-CoV-2 infection.

2.2. Site of Study

The at-risk individuals were recruited through the special COVID-19 screening-OPD at Emergency (EMOPD) and Communicable disease ward of the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, a tertiary care center of northern India. The study was done with the collaboration of the Department of Internal Medicine, Virology, Pharmacology, and Community Medicine of the institute, PGIMER, Chandigarh.

2.3. Study Design

In this open-label control, clinical trial at-risk individuals who presented at the special COVID-19 screening-OPD and through telephonic consultation were screened for enrollment in the study. After the screening of the asymptomatic individuals who had undertaken international travel in the last 2 weeks or had direct contact with laboratory-confirmed COVID-19 cases, were given the option for taking HCQ as PEP for the prevention of SARS-CoV2 infection and assigned into PEP and control groups. Participants who did not give consent for HCQ prophylaxis and the participants with contraindication for HCQ therapy were directly included in the control groups. The asymptomatic individuals with high-risk direct contact were family members, relatives, friends, or colleagues who were living with or spent hours/days with COVID-19 patients without taking any personal protective precautions. The PEP group received tablet HCQ prophylaxis and the control group did not receive HCQ prophylaxis. Both the groups received standard care of therapy in the form of home quarantine for 2 weeks along with social distancing and personal hygiene. The participants were followed up for 4 weeks telephonically or physically as and when required. The study was registered with clinicalTrial.gov (clinicaltrials.gov PRS ID: CT04408456).

2.4. Study duration

The study was carried out from March 2020 to July 2020 at the PGIMER, Chandigarh, India.

2.5. Inclusion and exclusion criteria

Irrespective of gender and age of ≥18 years, all asymptomatic individuals who had undertaken international travel in the last 2 weeks and all asymptomatic individual with direct contact with laboratory-confirmed CoVID-19 cases were included in the study. Individuals who did not give consent for HCQ prophylaxis and patients with contraindication for HCQ therapy like, known hypersensitivity to HCQ or 4-aminoquinolone derivatives, patients with known retionopathy, cardiac arrhythmia, G6PD deficiency, psoriasis, and pregnancy were directly included in the control groups. All symptomatic individuals, non-COVID suspect,s and all HCW related to suspected or confirmed COVI-19 cases were excluded from the study.

2.6. Method & Interventions

In this open level control clinical trial after screening and enrolment, all the at-risk asymptomatic participants were advised for home quarantine for 2 weeks along with social distancing and personal hygiene.

They were assigned into one PEP group and one control group as per inclusion and exclusion criteria. The PEP group received tablet HCQ 400 mg (200 mg X 2 tablets) q 12 hourly on day one followed by 400 mg once weekly for 3 weeks (total cumulative dose of 2000 mg). The control group did not receive HCQ or any drug intervention. Both the groups received standard care of therapy in the form of home quarantine for 2 weeks along with social distancing and personal hygiene.

The prophylactic dose of HCQ was decided as per ICMR recommendation for PEP with HCQ [11]. The potential antiviral and anti-inflammatory properties of HCQ, along with the low cost, very good oral bioavailability, higher concentrations in the lungs relative to the plasma levels, and acceptable safety profile supported the formulation of this national advisory.

After getting informed consent the drugs were dispensed directly to the participants during the screening-OPD visit or through doorstep delivery by the concerned HCW with help of the police officials. They were followed up for 4 weeks telephonically or physically when required and enquired regarding the development of any COVID-19 symptoms like fever, cough, sore throat, shortness of breath, diarrhea, myalgia, or any adverse drug event. During follow up nasopharyngeal and or throat swab of the participants were taken for processing reverse transcription polymerase chain reaction (RTPCR) for the detection of SARS-Cov-2 RNA to confirm CoVID-19.

Samples for RTPCR were taken when any asymptomatic participants became symptomatic and by the 5-14 days of contact in asymptomatic participants through an in-hospital visit at the institute’s communicable disease ward isolation. Only the participant with RTPCR positive for SARS-CoV-2 and with or without symptoms was defined as a definite COVID-19 case.

The participant with new-onset symptoms, but RTPCR negative for SARS-CoV-2 or could not be performed for any reason was defined as a probable COVID-19 case. Both the definite and probable COVID-19 cases together were defined as COVID-19 case. Asymptomatic participants with negative RTPCR were defined as a non-COVID case. Incidence of COVID-19, definite COVID-19, and probable COVID-19 in previously asymptomatic participants were compared between the PEP and control groups.

Baseline routine investigations (blood, CXR, ECG) at upfront could not be possible as each participant was the potential source of SARS-CoV-2 and additional contact with HCW could spread the virus to the healthy individual. The participants, who turned out to be definite COVID-19, were shifted to the Nehru Hospital Extension (NHE), a dedicated COVID-19 centre, of the institute PGIMER, Chandigarh, and managed as per institutional COVID-19 protocol. Participants with probable COVID-19 were advised to continue with home quarantine.

2.7. Outcome

Primary outcomes of the study were incidence of COVID-19, definite COVID-19, and probable COVID-19 among the participants. Secondary outcomes were new-onset COVID-19 symptoms, compliance with the advised HCQ therapy and home quarantine, the difficulty faced during quarantine, and the incidence of adverse drug events.

2.8. Sample size & statistical analysis

At the beginning of the study, there was no clinical trial available to predict the incidence of COVID-19 or decrease in the incidence of COVID-19 with HCQ prophylaxis in individuals at risk for SARS-CoV-2 infection.

This was being a pilot study we were expecting monthly around 100-150 or less asymptomatic COVID-19 suspected individuals to visit COVID-19 screening OPD set at the emergency of the institute PGIMER, depending upon the worsening or improving status of the ongoing pandemic.

The power of the study could not be extrapolated at the beginning of the study because of the lack of clarity regarding the outcome. Participants were assigned into either control or PEP group as per the inclusion and exclusion criteria.

Participants did not give consent for HCQ therapy and those with contraindication for HCQ therapy were directly included in the control group. Total of 1582 individuals were screened for enrolment in the study. Out of which 836 individuals had COVID-19 like symptoms at presentation. Out of 746 asymptomatic individuals, 82 individuals were HCW and 339 individuals were non-COVID suspects.

Finally, 325 participants were included in the study out of which 8 participants were lost from follow-up. Final data analysis was done among 317 individuals, 132 participants in the PEP group, and 185 participants in the control group (Figure 1). The data was managed in database system through Microsoft Excel and statistical analysis was performed by SPSS 21.0 version.

The parametric data were analyzed by paired or unpaired “t”-test and the binominal/categorical endpoints were analyzed with a non-parametric chi-squire test with yet’s correlation and the proportions were compared by Fisher’s exact test. The relative risk (RR) and number needed to treat (NNT) were determined for the safety and risk assessment. The p-value of less than 0.05 was considered statistically significant (95% CI).

Figure 1

3. Results

3.1. Baseline characteristics of the study population

Out of 317 participants 174 (54.9%) participant were male and 143 (45.1%) participants were female and only 10 (3.1%) participants had history of international travel within 2 weeks prior to the enrollment. Mean age of the study population was 37.2 (±13.9) years.

Most common co-morbidity was diabetes mellitus (N=14, 4.4%), followed by hypothyroidism (N=7, 2.20%), hypertension (N=4, 1.3%), bronchial asthma (N=2, 0.6%), chronic obstructive airway disease (N=1, 0.3%) and coronary artery disease (N=1, 0.3%). Among the participants, 53 (16.7%) were alcohol consumers and 29 (9.1%) were smokers. The distributions of age, gender, and co-morbidity were similar between the study groups (Table 1).

Table 1. Baseline demographic and clinical parameters of the study population

ParametersPEP/HCQ group (N=132)Control group (N=185)P value
Mean age (years ±SD)36.4±11.837.7 ±15.20.428
Male78(59.1%)96(51.9%)0.204
Female54(40.9%)89(48.1%)0.204
Smoker15(11.4%)14(7.6%)0.248
Alcohol consumer23 (17.4%)30 (16.2%)0.776
Diabetes8 (6.0%)6(3.2%)0.229
Hypertension1 (0.7%)3(1.6%)0.497
Coronary artery disease0 (0.0%)1(0.5%)0.398
Hypothyroidism3 (2.3%)4(2.2%)0.947
Bronchial asthma1 (0.7%)1(0.5%)0.809
COAD*0 (0.0%)1(0.5%)0.398

COAD: Chronic obstructive air way disease

3.2. Primary outcome

A total of 50 out of 317 participants (15.8%) had COVID-19 during the follow-up. The incidence of COVID-19 was significantly (p=0.033) lower in the PEP group [N=14 out of 132, (10.6%)] which received HCQ prophylaxis as compared to the control group [N=36 out of 185, (19.4%)] which did not receive HCQ prophylaxis (Table 2).

Total absolute risk reduction for the incidence of COVID-19 in participants received PEP with HCQ was -8.8% points as compared to the participants who did not receive PEP with HCQ. The number needed to treat (NNT) was 12, suggesting to prevent the occurrence of one case of COVID-19, 12 at-risk individuals would need to be treated with HCQ prophylaxis and the overall relative risk was 0.59 (95% confidence interval, 0.33 to 1.05).

Table 2. Incidence of COVID-19 after post-exposure prophylaxis with HCQ and in control group

OutcomesPEP/HCQ group (N=132)Control group (N=185)P value
COVID-19*14(10.6%)36(19.4%)0.033
Definite COVID-19α10(7.6%)28(15.1%)0.041
Probable COVID-19β4(3.0%)8(4.3%)0.552
New onset symptoms6(4.5%)15(8.1%).209
Moderate to severe COVID-1900

The participant with either definite or probable COVID-19 was defined as COVID-19 case.α

The participant, RTPCR positive for SARS-CoV-2 and with or without symptoms was defined as a definite COVID-19 case.β

The participant with new-onset symptoms but RTPCR negative for SARS-CoV-2 or could not be performed for any reason was defined as a probable COVID-19 case.

A total of 38 out of 317 participants (12.0%) had definite COVID-19 (RTPCR positive with or without symptoms) during the follow-up. The incidence of definite COVID-19 was also significantly (p=0.041) lower in the PEP group [N=10 out of 132, (7.6%)] which received HCQ prophylaxis as compared to the control group [N=28 out of 185, (15.1%)] which did not receive HCQ prophylaxis (Table 2).

Total absolute risk reduction for the incidence of COVID-19 in participants received PEP with HCQ was -7.5% points as compared to the participants who did not receive PEP with HCQ. The number needed to treat (NNT) to prevent the occurrence of one case of COVID-19 in at-risk individuals was 14. The overall relative risk was 0.50 (95% confidence interval, 0.25 to 0.99).

Total 12 out of 317 participants (3.8%) had probable COVID-19 (symptomatic with RTPCR negative or could not be performed for any reason) during the follow up. The incidence of probable COVID-19 was also lower in the PEP group [N=4 out of 132, (3.0%)] which received HCQ prophylaxis as compared to the control group [N=8 out of 185, (4.3%)] which did not receive HCQ prophylaxis, but was insignificant (p=0.552) statistically (Table 2).

RTPCR of the nasopharyngeal/throat swab could not be possible in 17 (5.4%) out of 317 participants because of some reasons, the strict lock down, lack of adequate number of testing kits initially and few participants did not show interest for testing.

All of them followed the advice as per the study protocol and were cooperative to complete the follow-up. If we consider only the participants (N=300) in whom RTPCR could be performed, even then the incidence of definite COVID-19 was also significantly (p=0.023) lower in the PEP group [N=10 out of 130, (7.7%)] which received HCQ prophylaxis as compared to the control group [N=28 out of 170, (16.5%)] which did not receive HCQ prophylaxis.

3.3. Symptomatic COVID-19

Out of 50 COVID-19 cases, 29 (58.0%) were asymptomatic and only 21(42.0%) participants developed symptoms. Though the incidence of new-onset symptoms was higher in the control group [N=15 out of 185, 8.1%] as compared to the PEP group which received HCQ prophylaxis [6 out of 132, 4.5%], but was insignificant (p=0.209) statistically (Table 2).

None of the participants developed moderate to severe COVID-19 needing oxygen replacement or life support. The most common symptom was cough (13 out of 21 participants, 61.9%) and sore throat in 9 (42.8%) participants, followed by fever (7, 33.3%), myalgia (7, 33.3%), and diarrhea in 1 (4.7%) participant with 9 participants had 2 or more symptoms. The new-onset symptoms were not significantly different between the PEP and control groups.

3.4. Secondary outcome

The compliance to HCQ prophylaxis was not adequate in 7 (5.3%) participants, out of whom 6 participants took drugs (800 mg) on day one and thereafter stopped because of the anxiety related to the possible side effect as explained to them during enrollment.

Otherwise, the overall compliance with HCQ prophylaxis was very good. Four participants consumed HCQ (200 mg) daily for 10 days. No serious adverse drug events were noted during the study. The most common adverse drug reaction (ADR) was epigastric abdominal discomfort with a burning sensation, reported by 3 (2.3%) participants which resolved with an antacid.

Itching, low mood, backache, and palpitation were reported by one participant each. The occurrence of palpitation was a single episode and self-limiting for which no specific treatment was required. All the participants reported adequate compliance with the quarantine norm.

Stress and depression were the most common problems felt by 12 (3.8%) participants during the period of quarantine. Getting essentials and foods was difficult for 13 (4.1%) participants. Misbehavior by neighbor and cops were faced by 7 (2.2%) participants.

4. Discussion

Since the arrival of the deadly COVID-19 pandemic, many available drugs have been tried for the treatment or prevention of COVID-19, but none of them succeeded confidently [4], [5], [6]. HCQ is being tried for therapeutic and preventive options against COVID-19 in the view of its in-vitro virucidal action against SARS-CoV-2 [8, 9]. The proposed mechanism for the virucidal effect of HCQ is inhibition of viral fusion to the cell membrane by changing pH of the cell surface, inhibition of viral nucleic acid replication, protein glycosylation, virus assembly, and transportation & release of the new virus particle [89].

The role of HCQ in COVID-19 is still inconclusive and evolving. The study that attracted the attention of the whole world projected the therapeutic potentials of HCQ and Azithromycin combination by decreasing the viral load [7].

A systematic meta-analysis on CoVID-19 patients suggested that HCQ can prevent radiological progression of the lung disease [13]. Interim analysis of the “Solidarity” clinical trial done by WHO, has recommended not to use HCQ for COVID-19 therapy as it doesn’t have any mortality benefit [14]. Boulware et al. concluded that HCQ is not useful for PEP in at-risk individuals for the prevention of COVID-19 [12].

But majorities (66.4%) of the participants in this study were HCW. There is still a lack of clinical trial evaluating HCQ for PEP in a high-risk household contact of laboratory-confirmed COVID-19 cases.

While post-exposure, HCW and non-HCW individuals both have a risk of COVID-19, practically the risk category is completely different. The HCWs are supposed to come in contact with COVID-19 patients after taking all necessary precautions, wearing protective equipment.

But non-HCW individuals are exposed to COVID-19 unknowingly without any precautions or personal protective equipment, as most of the time the patients are their family members or friends or relatives. HCWs usually spend a fixed duration of time with COVID-19 patients and many a time maintains a safe distance but non-HCW individuals live with them for days to weeks without maintaining a safe distance. Post-exposure, non-HCW individuals have a higher risk for COVID-19 as compared to the HCW.

So the incidence of COVID-19 after PEP with HCQ may differ in HCW from non-HCW. In our study, we wanted to evaluate the efficacy of HCQ as PEP for the prevention of COVID-19 in asymptomatic non-HCW individuals at risk for SARS-CoV-2 infection.

Boulware et al. defined COVID-19 cases as, symptomatic illness confirmed by a positive molecular assay or COVID-19 related symptoms [12]. Whereas fever, cough, sore throat, respiratory difficulty, and diarrhea are the common presentation of COVID-19, up to 80% of cases may be asymptomatic also [3,15]. Radiological pictures may be normal in mild cases and interstitial pneumonia with ARDS in severe cases.

H1N1 and Influenza-A infections can also present with similar clinical and radiological pictures, causing diagnostic difficulty for COVID-19 with the concurrence of seasonal viral pneumonia. As per Boulware et al. only 16 out of 107 symptomatic cases were PCR-confirmed [12].

Molecular diagnostic assay of nasopharyngeal/BAL samples is the investigation of choice for definitive diagnosis and differentiation of COVID-19 from other seasonal viral pneumonia. So the only PCR-positive cases should be leveled as definite COVID-19 and PCR-negative symptomatic cases may be leveled as probable COVID-19 in the view of ongoing pandemic and variable sensitivity of RTPCR to detect SARS-CoV-2 in different specimen [16].

Similarly, all asymptomatic high-risk contact should be tested with molecular diagnostic assay within the incubation period of 2 weeks, as about 80% of cases COVID-19 can be asymptomatic [15]. There was a possibility of missing asymptomatic COVID-19 in the study by Boulware et al. as molecular testing for SARS-CoV-2 was done only for the symptomatic individuals, contrary to the present study where asymptomatic individuals samples were also tested with RTPCR for SARS-CoV-2.

That’s why the present study was able to detect the asymptomatic COVID-19 cases in individuals at risk for SARS-CoV-2 infection. As per our study, 58.0% of the COVID-19 cases were asymptomatic. Regarding the “Solidarity” clinical trial showing no mortality benefit in COVID-19 patients treated with HCQ [14], we would like to reemphasize that prevention is better than cure. As nearly 80% of CoVID-19 patients are asymptomatic and hardly require any specific therapy, prevention of COVID-19 in high-risk individuals is of utmost importance to contain this deadly pandemic.

Safety concern has been raised against the use of HCQ, as it can cause life-threatening cardiac arrhythmias, QT-prolongation, hypoglycemia, vision loss from irreversible retinopathy and hemolysis in G6PD deficient.

But these side effects are not common in routine practice and HCQ seems to be safe for prolonged use [10,13]. Fortunately, none of the study participants complained of any serious adverse events. The drug was tolerable to most of the participants and compliance was good. Only 3 participants complained of mild epigastric abdominal discomfort with a burning sensation after the first dose which was self-limiting thereafter. The incidence of side effects was more in Boulware et al. which maybe because of the higher dose (3800 mg) of HCQ used as compared to the present study (2000 mg) [12].

The household direct contacts of the COVID-19 patients are at the highest risk for SARS-CoV-2 infection. To date, there is no clinical trial available regarding PEP with HCQ for the prevention of COVID-19 in asymptomatic high-risk household direct contact of laboratory-confirmed COVID-19 patients.

Recently published studies are also supporting the role of HCQ for the prevention and treatment of COVID-19 [17], [18], [19]. As per Boulware et al. also there was an absolute risk reduction of -2.4% points in the participants received HCQ prophylaxis, but it did not reach statistical significance [12]. Looking at the disastrous nature of this gigantic pandemic even a 2.4% risk reduction may have a significant impact in preventing further spread when millions of people are infected or will be infected. As per the present study, the absolute risk reduction for the incidence of COVID-19 in participants received PEP with HCQ was – 8.8% points which were statistically significant (p=0.033). With this open level clinical trial, we absolutely don’t claim or recommend PEP with HCQ for the prevention of COVID-19 in asymptomatic direct contact.

Nevertheless, based upon one or two studies we should not completely disregard or reject the potential of HCQ as PEP in asymptomatic high-risk contact for the prevention of COVID-19. Based upon the safety profile of HCQ and as definitive therapy is still awaited, even a few percentages of risk reduction for CoVID-19 will have a huge impact against this global pandemic of worst nature.

The present study will make the researchers around the globe to recognize the potentials of HCQ as a virucidal agent and will encourage the researchers for further study to prove the virucidal effect of HCQ in-vivo as well as to reconsider further randomized clinical trials with a larger sample size for better evaluation of the efficacy of HCQ as PEP for the prevention of COVID-19 in asymptomatic at-risk individuals.

4.1. Limitation

The limitation of our study is being an open level clinical trial and not randomized [20]. We could not conduct a randomized double-blind clinical trial because of ethical issues as the off-level use of HCQ was not completely safe for conducting a double-blind study.

Randomization and blinding were not permissible, as HCQ prophylaxis was recommended for all individuals at risk for COVID-19 by the ICMR [11]. HCQ is approved as an anti-malarial and immunomodulator in rheumatic diseases and the in-vitro virucidal effect of HCQ is yet to be proven in the in-vivo study [9].

The use of HCQ is not completely safe, as it can cause life-threatening complications. It was very difficult to get a preliminary workup done before starting HCQ in high-risk contacts of COVID-19, to restrict the spread of highly contagious SARS-CoV-2 in HCW and it was also difficult to follow-up physically due to lock-down factors. This study, which to our knowledge is the only clinical trial dedicated to evaluating the efficacy of HCQ as a PEP to prevent COVID-19 in asymptomatic, high risk, household contacts of the laboratory-confirmed COVID-19 cases.

4.2. Conclusion

Post-exposure prophylaxis with HCQ has the potential for the prevention of COVID-19 in asymptomatic individuals at risk for SARS-CoV-2 infection, as there was significant risk reduction for the incidence of COVID-19 in participants who received PEP with HCQ. Till definitive therapeutic drugs or preventive vaccines are available, there is no harm in continuing PEP with HCQ in suitable at-risk individuals for the prevention of COVID-19, as endorsed by many national/international health authorities.

Better pharmacovigilance is required for monitoring ADR and the prevention of misuse of HCQ. Further randomized clinical trials with a larger sample size are encouraged for better evaluation of the efficacy of HCQ as PEP for the prevention of COVID-19 in asymptomatic high risk direct contacts of the COVID-19 patients.

List of authors & contributions

1 Dr. Deba Prasad Dhibar: Concept, design, contact tracing, recruitment, data analysis, data interpretation, protocol & manuscript writing

2 Dr. Navneet Arora: Plan Execution, screening, contact tracing, recruitment, data collection, Case record form

3 Dr. Arpit Kakkar: Plan Execution, screening, contact tracing, recruitment, data collection, Case record form,

4 Dr. Neeraj Singla: Screening data collection

5 Dr. Ritin Mohindra: Participant management, isolation and diagnosis

6 Dr. Vikas Suri: Participant management, isolation and diagnosis

7 Dr. Ashish Bhalla: Participant management, isolation and diagnosis, expert guidance

8 Dr. Navneet Sharma: Expert guidance and facility availability

9 Dr. Mini P Singh: SARS-CoV-2 RTPCR processing, interpretation, reporting

10 Dr. Ajay Prakash: Data analysis, statistical analysis, ADR monitoring

11 Dr. Lakshmi PVM: Epidemiological analysis and interpretation

12 Dr. Bikash Medhi: Guidance and ADR monitoring

Acknowledgement

We thank and acknowledge the all the participants for sparing their valuable time and participation in this study to generate some knowledge regarding the unknowns about the COVID-19.

Declarations

Funding: Nothing to disclose

Competing Interests: Nothing to disclose

Ethical Approval: Institutional ethics committee approval ID: IEC-04/2020-1624

(Study protocol submitted to IEC added as supplemental file)

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Study site: Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

clinicaltrials.gov PRS ID: CT04408456

Principal investigator statement: The authors confirm that the principal investigator for this paper is Dr. Deba Prasad Dhibar and that he had direct clinical responsibility for patients.

Data sharing: All data requests should be submitted to the corresponding author (DPD) for consideration.View Abstract








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