key: cord-0746508-r83zgnoa
authors: Shabani, Minoosh; Totonchi, Mehdi; Rezaeimirghaed, Omidvar; Gachkar, Latif; Hajiesmaeili, Mohammadreza; Khoshkar, Ali; Amirdosara, Mahdi; Saffaei, Ali; Shokouhi, Shervin; Mardani, Masoud; Darazam, Ilad Alavi; Karami, Alireza; Sharifi, Milad; Zaman, Mana; Abedheydari, Elham; Sahraei, Zahra
title: Evaluation of the Prophylactic Effect of Hydroxychloroquine on People in Close-Contact with Patients with Covid-19
date: 2021-08-10
journal: Pulm Pharmacol Ther
DOI: 10.1016/j.pupt.2021.102069
sha: 4bb9bf9c107a6a050714aac562c166234d43c822
doc_id: 746508
cord_uid: r83zgnoa

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has caused significant mortality worldwide. The disease attacks the lung tissue and may lead to acute respiratory distress syndrome. An in vitro study showed that hydroxychloroquine (HCQ) has a prophylactic effect against COVID-19 due to its anti-inflammatory effects. The present study aimed to evaluate the prophylactic effect of HCQ on individuals in close contact with patients with COVID-19. METHOD: In this quasi-trial study, we prescribed HCQ for 7 days to all people who had close contact with a patient with COVID-19. All contacts underwent a nasal swab in two steps, and those positive for COVID-19 were excluded from the study. After 14 days of follow-up, the clinical and laboratory manifestations of COVID-19 were evaluated. RESULTS: A total of 113 participants completed the study. The HCQ group comprised 51 (45.13 %) contacts, and 62 (54.86 %) contacts were allocated to the control group. According to the results of clinical examination and real-time polymerase chain reaction test, 8 (12.90%) contacts in the control group were reported to have contracted COVID-19. In the HCQ group, 7 (13.72%) contacts were confirmed to have contracted COVID-19. There was no relationship between HCQ use and age, sex, underlying disorders, and laboratory data (all p >0.05). In terms of HCQ side effects, five participants experienced gastrointestinal and cutaneous side effects that subsided on discontinuation of HCQ. CONCLUSION: The current study showed that HCQ had no prophylactic effect with regard to COVID-19 prevention.

In December 2019, a new member of the Coronoviridae family, called the severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2), was detected in the Wuhan Province of China, and spread globally (1) .

Many efforts have focused on developing preventive strategies against the coronavirus disease 2019 (COVID-19). Frequent hand washing and wearing a face mask are among the essential preventive strategies (2) . However, no specific medication has been found for COVID-19 prevention or prophylaxis. This virus is highly contagious, and recent studies have demonstrated that every patient can infect two other persons on average. The transmission of SARS-CoV-2 by asymptomatic carriers is another vital issue (3) . Healthcare providers and those with a history of close contact with a patient with confirmed COVID-19 are highly at risk of infection (4) . An effective vaccine is a necessary tool to fight the COVID-19 pandemic, but the vaccine development process generally takes years or even decades. Monoclonal antibodies provide an alternative option for the prevention of COVID-19. Passive infusion of monoclonal antibodies as pre-exposure or post-exposure prophylaxis might offer immediate protection from infection that could last weeks or months. Even if a vaccine is available, a few weeks are required to achieve an effective immune response. This emphasizes the benefits of passive immunity in healthcare settings and households (5) . Chloroquine analogs were shown to suppress endosome acidification and to demonstrate at high micromolar concentrations in vitro non-specific antiviral activity against a wide variety of circulating viruses, such as HIV, hepatitis C, influenza, Ebola, severe acute respiratory syndrome, and Middle East respiratory syndrome viruses, and more recently, SARS-CoV-2 (6). A recent report indicated the efficacy of chloroquine against SARS-CoV-2 in vitro. Hydroxychloroquine J o u r n a l P r e -p r o o f (HCQ), which is more soluble than chloroquine, has similar beneficial effects and fewer adverse effects. Similar to chloroquine, HCQ raises the pH and causes antiviral effects. HCQ also has a modulating effect on activated immune cells (7) .

Recent research in China in patients with COVID-19 demonstrated no difference in the rate of virological clearance at seven days and no difference in clinical results (duration of hospitalization, temperature normalization, radiological progression) with or without five days of HCQ use. The above findings are consistent with the lack of virological or therapeutic value of chloroquine in a range of viral infections where it was evaluated for treatment or prophylaxis (8) . In contrast, another study confirmed 100% virus clearance in nasopharyngeal swabs of six patients after 5-6 days of a combination of HCQ and azithromycin. This viral clearance rate was lower with HCQ alone (57.1 %) and 12.5% in patients who did not receive HCQ (9) . No data are available on the efficacy and safety of post-exposure prophylaxis for COVID-19. Post-exposure prophylaxis using HCQ was administered for 14 days in a Korean sample. The follow-up polymerase chain reaction (PCR) test results were negative (10) .

Considering the effects of HCQ against COVID-19, this study aimed to investigate the prophylactic effect of HCQ in individuals in close contact with patients with COVID-19.

This quasi-experimental trial was conducted between April and June 2020 at the Loghman Hakim Hospital, which is affiliated to the Shahid Beheshti University of Medical Sciences, Tehran, Iran. Inclusion criteria were adults who had household exposure to a patient with confirmed COVID-19 at a distance of < 6 ft for > 10 min (11) . At least 48 h, and not > 5 days had passed since their first contact with the patient. This time was based on the incubation period for SARS-CoV-2 (12).

The exclusion criteria were age < 18 years, pregnant and/or breastfeeding women, people with underlying disorders such as arrhythmia, favism, chronic kidney diseases, chronic liver diseases, drug allergies, retinopathy, and those with abnormal findings on electrocardiography (which was performed at the beginning of the study). In addition, we excluded people with flu-like symptoms (fever > 37.5 °C, sore throat, cough, dyspnea, myalgia, and diarrhea) during the visit and in the past month or a history of COVID-19. All patients who received other prophylactic medicines, such as ivermectin and convalescent plasma, and those who refused to receive HCQ were also excluded. History and physical examination, including vital signs and oral temperature measurement (°C), was performed for all participants. The researchers evaluated age, sex, weight, smoking status, blood group, underlying disorders, COVID-19 signs and symptoms, and laboratory data (WBC, BUN, Cr, AST, ALT, ALP, albumin, and CRP) for all participants.

Nasopharyngeal swabs were collected for testing for COVID-19 by real-time PCR (RT-PCR) on days 0 and 7.

In this study, a simple sampling method was selected. 

Data were analyzed using SPSS version 16 (IBM, NY, USA). The Kolmogorov-Smirnov test was used, and descriptive results were reported as medians and interquartile ranges. Post-hoc analysis was performed using the Mann-Whitney U test with a pre-per-protocol approach.

Of the 178 participants enrolled in this study, 65 were excluded according to the exclusion criteria.

Fifty-four participants were diagnosed with COVID-19 at the beginning of the study ( Figure 1 shows the CONSORT diagram for the current study. As shown in Table 1 , there were no statistically significant differences between the groups with regard to age, weight, sex, smoking status, blood groups, and underlying disorders (all p ≥0.05).

The hazard ratio for RT-PCR test positivity in the entire patient population after exposure was 1.5

(95 % confidence interval, 1.372-1.642) but no differences were seen between the control group and those treated with hydroxychloroquine [7 (12.90%) vs. 7 (13.72%), p=0.625], respectively.

In addition, clinical evaluations revealed that 2 (3.92%) and 3 (4.83%) contacts in the HCQ and control groups, respectively, developed COVID-19 symptoms. All of these contacts had positive RT-PCR results, except for one patient in the HCQ group. Table 2 shows the results of outcomes according to the group and time of study. Table 3 shows the results of laboratory studies in both groups. Although the mean ALT level was higher in COVID-19-positive participants who took HCQ, there was no statistically significant difference between them. There were no statistically significant differences in laboratory test results between the HCQ and control groups (p ≥0.05).

In terms of adverse effects in the HCQ group, five patients developed an adverse drug reactionthree participants had diarrhea and two developed a maculopapular rash on the trunk and limbs, which was accompanied by swelling of the hands in one participant. All patients recovered after drug discontinuation. No adverse cardiac effects were observed in the HCQ group. None of the patients in the control group experienced adverse effects.

Lastly, of the patients who tested positive for the disease, none required hospitalization, and all recovered after receiving HCQ.

In this study, we aimed to evaluate the prophylactic effects of HCQ after exposure to COVID-19.

There was no statistically significant difference between the HCQ and control groups in the current study involving COVID-19. They found that pre-exposure prophylaxis with HCQ once or twice weekly did not significantly reduce the number of laboratory-confirmed cases. Their study included healthcare workers with continued exposure to COVID-19. Participants were randomized to 400 mg of HCQ once or twice weekly for 12 weeks, which was different from the protocol in the current study (16) .

Boulware et al. investigated post-exposure prophylaxis with HCQ in COVID-19. Participants had close contact with a patient with COVID-19. Their study showed that HCQ had no prophylactic effect on people who had close contact with patients with confirmed COVID-19. HCQ was associated with more side effects, but no serious adverse reactions were reported. These findings are similar to those of the current study (12) .

In comparison with Boulware et al.'s study, the current study evaluated participants with more details, including the nasopharyngeal RT-PCR in two stages, and regular telephonic follow-up. In their study, the participants were divided into high-risk and moderate-risk groups according to the type of exposure to COVID-19. The contacts who did not use face masks were categorized as the high-risk group and those who used face masks were categorized as the moderate group. They included health care providers, and followed their patients entirely through the mail. However, the current study evaluated patients at the office with more details.

The present study had some limitations. One of the significant limitations was the small sample size due to limited resources, such as RT-PCR. However, the researchers believed that the enhanced checkpoints could eliminate, to some extent, the effects of limitations.

In conclusion, the present study found no clinical benefit of HCQ use post exposure to SARS-CoV-2, and it may not help in COVID-19 prophylaxis. However, it is necessary to design trials with larger sample sizes to achieve a definitive conclusion.

The authors have declared that no conflicts of interest exist.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

A pneumonia outbreak associated with a new coronavirus of probable bat origin

The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence

What we know so far: COVID-19 current clinical knowledge and research

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

Monoclonal Antibodies for Prevention and Treatment of COVID-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases

Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines

Self WH; IVY Network Investigators; CDC COVID-19 Response Team. Community and Close Contact Exposures Associated with COVID-19 Among Symptomatic Adults ≥18 Years in 11 Outpatient Health Care Facilities -United States

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

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)

Chloroquine or hydroxychloroquine for prophylaxis of COVID-19

Post-exposure prophylaxis with hydroxychloroquine for the prevention of COVID-19, a myth or a reality? The PEP-CQ Study