INTRODUCTION
Coronaviruses are a large family, which may cause illness in animals or humans. In humans, several coronaviruses are known to cause respiratory infections, ranging from common cold to more severe diseases such as Middle East respiratory syndrome and SARS.1–6 The most recently discovered coronavirus is SARS-CoV-2 which causes COVID-19. As cases of COVID-19 continue to rise in different countries, health systems are facing enormous pressure to manage COVID-19 patients. By August 2, 2020, COVID-19 has been confirmed in about 17,660,523 million individuals worldwide and has resulted in more than 680,894 deaths. These numbers are still increasing. More than 180 countries have reported laboratory-confirmed cases of COVID-19 on all continents, except Antarctica.1–4 In Egypt, the official number of infected patients was 94,316, with 4,834 deaths as of August 2, 2020.1–11
Although many vaccines are in development, effective therapy is needed to treat currently infected patients and prevent mortality. Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used for decades in the treatment and prophylaxis of a number of conditions including malaria. The ability of these drugs to inhibit other coronaviruses, such as SARS-CoV-1, has been explored. Although generally considered safe, there are potential risks associated with taking these medications, including cardiac arrhythmia.7–11
Although an initial study in France found encouraging results for the treatment of COVID-19 with HCQ, the study was later criticized for its methodological problems, leading to skepticism about the validity of its results. Other similar results were not represented in any further subsequent studies, but even reported deleterious clinical outcomes especially cardiac adverse events like prolongation of QT interval.8 On March 28, 2020, the Food and Drug Administration (FDA) granted an emergency use authorization for use of oral formulations of CQ and HCQ in the treatment of COVID-19.7–11 Based on emerging data showing CQ and HCQ as unlikely to be effective in the treatment of COVID-19,12,13 the FDA revoked its previous emergency use authorization for both drugs on June 15, 2020.
In this study, we aimed to evaluate the safety and efficacy of HCQ added to the standard of care versus the standard of care alone in patients with COVID-19.
METHODS
Patients admitted to three tertiary referral centers (n = 194) managing patients with suspected and confirmed COVID-19 in Egypt in the period between March and June 2020 were enrolled. The patients were clinically stratified into mild, moderate, and severe disease according to the WHO interim guidelines published on March 13, 2020. Mild cases represented patients with uncomplicated upper respiratory tract viral infection, moderate cases represented patients with pneumonia but without need for supplemental oxygen, whereas severe disease represented cases with fever or suspected respiratory infection, plus one of the following: respiratory rate > 30 breaths/min, severe respiratory distress, or SpO2 ≤ 93% on room air.14
The Egyptian Ministry of Health (MOH) adopted a standard of care treatment protocol for COVID-19 patients. It included paracetamol, oxygen, fluids (according to assessment), empiric antibiotic (cephalosporins), oseltamivir if needed (75 mg/12 hours for 5 days), and invasive mechanical ventilation with hydrocortisone for severe cases if PaO2 < 60 mmHg, O2 saturation < 90% despite oxygen or noninvasive ventilation, progressive hypercapnia, respiratory acidosis (pH < 7.3), and progressive or refractory septic shock.15
Patients were randomized into two groups using a computerized random number generator using simple randomization with an equal allocation ratio. During randomization, the proportional allocation of each clinical stratum was equalized in both groups.
Study groups.
- 1.Hydroxychloroquine group: This group included 97 patients who received HCQ 400 mg twice daily (in day 1) followed by 200 mg tablets twice daily added to the standard of care treatment adopted by the Egyptian MOH for 15 days.
- 2.Control group: This group included 97 patients who received only the standard of care treatment adopted by the national MOH for 15 days.
All the patients were followed up for 4 weeks.
The study included all patients admitted with SARS-CoV-2 infection and enrolled both genders. Patient who had allergy or contraindication to HCQ, pregnant and lactating females, and patients with cardiac problem (chronic heart failure or prolonged QT interval on electrocardiogram [ECG]) were excluded from the study.
Informed written consent was obtained from each participant, and the study was approved by the Ethics Committee of the Faculty of Medicine, Tanta University. Privacy of the participants and confidentiality of the data were assured. Risks and benefits were explained to the patients. The study was registered on clinicaltrials.gov with registration number NCT04353336.
All the participants were subjected to thorough history taking and full clinical examination including age, gender, weight and height measurements, and calculation of body mass index (BMI); medication history; and investigations in the form of complete blood picture, liver function tests, computed tomography of the chest (CT chest), and SARS-CoV-2 detection in nasopharyngeal swabs using PCR and ECG. Assessment of the studied medication side effects was performed using a questionnaire.
Statistical analysis.
Data were analyzed using Statistical Package for Social Sciences V. 23 and were expressed in number, percentage (%), mean (x̅) and SD. The variables were tested for normality by the Shapiro–Wilks test. Student’s t-test was used for normally distributed quantitative variables and Mann Whitney’s test for not normally distributed ones. Chi-square test (χ2) was used to study association between qualitative variables, and whenever any of the expected cells were less than five, Fischer’s exact test was used. Binary logistic regression was used to ascertain the effect of the potential risk factors on the patients’ mortality. A two-sided P-value of < 0.05 was considered statistically significant.
Post hoc power analysis.
Considering the percentage of recovery as a primary endpoint and by using G*power program, post Hoc power analysis revealed a sample power of 80.6% with the following input parameters: two-tailed α error 0.05, 54.0% recovery rate in the HCQ group, 34.0% recovery in the control group, and 97 sample size in each group.16
RESULTS
At the time of presentation, interrupted fever was present in 44.6%, continuous fever in 22.3%, headache in 42.9%, sore throat in 25.7%, anorexia in 33.1%, anosmia in 26.9%, pallor in 3.4%, cyanosis in 4.6%, fatigue in 49.0%, vomiting in 13.7%, diarrhea in 35.0%, abdominal pain in 19.4%, cough in 61.3%, and dyspnea in 24.2% of the included patients. Oxygen saturation between 95 and 90 was present in 16.0%, 90–85 in 7.4%, and less than 85 in 6.9% of all the participants.
The computed tomography chest scans were normal in 33.1%, ground-glass opacities in 23.4%, confluent opacities in 25.7%, consolidation in 10.9%, extensive consolidation in 6.3%, and emphysema in only 0.6%.
The two groups were matched for age and gender, with no significant difference between them. They had no significant difference regarding BMI, residence, smoking, pregnant females, or the presence of comorbidities. The patients were randomized equally between the two groups regarding the disease severity (Table 1).
Patients’ characteristics between the two groups
Character | Group 1 (n = 97) | Group 2 (n = 97) | Total (n = 175) | P-value |
---|---|---|---|---|
Age (years), mean ± SD | 40.35 ± 18.65 | 41.09 ± 20.07 | 40.72 ± 19.32 | 0.80 |
Range | 2.0–85.0 | 2.0–83.0 | – | – |
Gender, n (%) | ||||
 Male | 56 (57.7) | 58 (59.8) | 114 (58.8) | 0.77 |
 Female | 41 (42.3) | 39 (40.2) | 80 (41.2) | |
Body mass index, n (%) | ||||
 Normal | 4 (4.1) | 9 (9.3) | 13 (6.7) | 0.46 |
 Overweight | 32 (33.0) | 29 (29.9) | 61 (31.4) | |
 Obese | 40 (41.2) | 35 (36.1) | 75 (38.7) | |
 Morbid obesity | 21 (21.6) | 24 (24.7) | 45 (23.2) | |
Residence, n (%) | ||||
 Rural | 54 (55.7) | 46 (37.4) | 100 (51.5) | 0.25 |
 Urban | 43 (44.3) | 51 (52.6) | 94 (48.5) | |
Smoking, n (%) | 35 (36.1) | 25 (25.8) | 60 (31.4) | 0.12 |
Comorbidities, n (%) | 15 (15.5) | 12 (12.4) | 27 (14.3) | 0.53 |
Liver diseases, n (%) | 0 (0.0) | 2 (2.1) | 2 (1.0) | 0.50 |
Renal impairment, n (%) | 2 (2.1) | 4 (4.1) | 6 (3.1) | 0.68 |
There was no significant difference between the two groups regarding laboratory parameters (Table 2).
Laboratory parameters between the two groups
Investigation | Group 1 (n = 97), mean ± SD | Group 2 (n = 97), mean ± SD | P-value |
---|---|---|---|
Hemoglobin | 13.20 ± 2.00 | 12.83 ± 1.88 | 0.19 |
Platelets | 280.78 ± 102.12 | 252.08 ± 97.03 | 0.05 |
White blood cells | 5.48 ± 2.82 | 6.07 ± 3.376 | 0.82 |
Lymphocytes | 30.14 ± 21.45 | 31.95 ± 17.00 | 0.07 |
Direct bilirubin | 0.26 ± 0.11 | 0.33 ± 0.26 | 0.09 |
Indirect bilirubin | 0.55 ± 0.20 | 0.58 ± 0.26 | 0.46 |
Albumin | 4.06 ± 0.38 | 3.95 ± 0.45 | 0.07 |
Alanine aminotransferase | 33.07 ± 23.15 | 28.17 ± 18.31 | 0.10 |
Aspartate aminotransferase | 29.52 ± 13.45 | 26.89 ± 179.25 | 0.06 |
International normalized ratio | 1.08 ± 0.14 | 1.06 ± 0.15 | 0.19 |
D-dimer | 26.74 ± 145.03 | 28.17 ± 220.11 | 0.42 |
Median | 0.34 | 0.32 | |
Lactate dehydrogenase | 291.52 ± 149.47 | 282.04 ± 179.25 | 0.07 |
Median | 250.0 | 230.0 | |
Ferritin | 374.75 ± 469.49 | 305.14 ± 357.24 | 0.07 |
Median | 234.0 | 194.0 | |
Creatinine | 0.94 ± 0.29 | 0.98 ± 0.27 | 0.05 |
C-reactive protein | 27.88 ± 48.91 | 35.86 ± 63.60 | 0.38 |
Median | 12.0 | 12.0 |
Mechanical ventilation was needed in four patients (4.1%) in the HCQ group and 5 (5.2%) in the control group, with no significant difference between the two groups (P = 0.75). Six patients (6.2%) died in the HCQ group, and five patients (5.2%) died in the control group without any significant difference between the two groups either (P = 0.76).
Eleven patients (11.3%) in the HCQ group needed intensive care unit (ICU) admission, and 13 patients (13.4%) in the control group needed the same (P = 0.83). The mean duration to negative PCR was 17 ± 3 days in the HCQ group and 18 ± 2 in the control group (P = 0.11). The HCQ group had a mean of 9 ± 2 days to show clinical improvement and 11 ± 3 days to hospital discharge, whereas the control group had a mean of 10 ± 3 to clinical improvement and 11 ± 2 to hospital discharge (P = 0.80 and 0.52, respectively) (Table 3).
Clinical course in both groups
Clinical course | Hydroxychloroquine (n = 97) | Control (n = 97) | P-value |
---|---|---|---|
Disease severity after 28 days, n (%) | |||
 Recovered | 52 (53.6) | 33 (34.0) | 0.06 |
 Mild | 23 (23.7) | 39 (40.2) | |
 Moderate | 8 (8.2) | 11 (11.3) | |
 Severe | 8 (8.2) | 9 (9.2) | |
 Death | 6 (6.1) | 5 (5.1) | |
 Need for ICU | 11 (11.3) | 13 (13.4) | 0.83 |
Duration to negative PCR, mean ± SD | 17.01 ± 2.98 | 17.64 ± 2.45 | 0.11 |
Duration to clinical improvement, mean ± SD | 9.43 ± 1.87 | 9.52 ± 2.94 | 0.80 |
Duration to hospital discharge, mean ± SD | 11.04 ± 2.71 | 11.27 ± 2.19 | 0.52 |
After 28 days, there was no significant difference between the two groups regarding the clinical outcome (P = 0.07). Complete recovery was achieved in 52 cases (53.6%) of the HCQ group, whereas 23 cases (23.7%) were in mild, 8 (8.2%) were in moderate, 8 (8.2%) in severe disease status, and six patients (6.1%) died. Among the control group, 33 patients (34.0%) recovered completely, 39 (40.2%) were in mild, 10 (10.3%) were in moderate, 9 (9.2%) were in severe disease status, and five patients (5.1%) died.
By logistic regression, the overall mortality was not significantly associated with HCQ therapy; however, it was significantly related to the patient’s age, alanine aminotransferase, serum creatinine, serum ferritin, C-reactive protein, oxygen saturation, and the presence of diabetes mellitus (Table 4).
Univariate regression of the potential risk factor of mortality
Variable | Univariate | |||
---|---|---|---|---|
P-value | OR | 95% CI | ||
Lower | Upper | |||
Age | < 0.001 | 1.081 | 1.035 | 1.129 |
Gender | 0.736 | 1.243 | 0.351 | 4.396 |
Smoking | 0.997 | – | – | – |
Alanine aminotransferase | < 0.001 | 1.047 | 1.024 | 1.071 |
Albumin | 0.025 | 0.201 | 0.050 | 0.816 |
Creatinine | < 0.001 | 47.506 | 7.347 | 307.17 |
Ferritin | 0.002 | 1.002 | 1.001 | 1.003 |
C-reactive protein | < 0.001 | 1.029 | 1.017 | 1.040 |
O2 saturation | < 0.001 | |||
 95–90 | 0.035 | 13.739 | 1.198 | 157.62 |
 85–90 | < 0.001 | 632.00 | 51.705 | 7,725.0 |
DM | 0.001 | 9.293 | 2.556 | 33.792 |
Hydroxychloroquine treatment | 0.757 | 0.824 | 0.243 | 2.797 |
OR = odds ratio; DM = diabetes mellitus.
DISCUSSION
Chloroquine and HCQ are well-known drugs and have been used for decades as antiparasitic and anti-inflammatory drugs to treat malaria and rheumatological disorders. Chloroquine was shown to be effective against SARS-CoV in invitro studies. This may be because of disruption of viral replication, changing immune system activity in addition to its inflammatory effect.17
The two drugs have been tried earlier for the treatment of SARS infection and showed promising efficacy. With the emergence of SARS-CoV-2 pandemic, they have been suggested as potential treatment for the new coronavirus 2019 based on the previous evidence from different coronavirus strains.18
Although cardiac toxicity is a known adverse event requiring monitoring during treatment, HCQ showed promise in treating SARS-CoV-2–infected patients with multiple comorbidities including coronary artery disease. A large trial from India showed that HCQ can decrease time to recovery both in symptomatic and in asymptomatic patients with no effect on mortality.19
At the beginning of the pandemic in Europe, a small series of COVID-19 patients treated in France with HCQ showed improved decline in SARS-CoV-2 viral load compared with controls, which was augmented by the addition of azithromycin.7 However, this study had serious methodological flaws and could not be considered as a good evidence in the favor of HCQ use.8–11
Many other conflicting trials have been published in the past few months leading initially to emergency use authorization for HCQ use in the treatment of COVID-19 and later on withdrawal of this authorization by the FDA. Initial observational trials of HCQ use in hospitalized patients showed that there were no increased risks of mortality or intubation in groups receiving HCQ or the control group who received only standard of care although patients who received HCQ were more critically ill.20 However, many published trials had some methodological flaws and missed important patient outcomes urging the need for properly designed, adequately powered trials to support clinical decisions of HCQ use in treating COVID-19 patients.21
Administration of HCQ did not result in a significantly higher probability of conversion from positive to negative PCR than standard care alone in patients admitted to hospital with nonresponsive mild-to-moderate COVID-19 in China. Adverse events were more frequent in HCQ recipients than in non-recipients.22
A meta-analysis included seven studies with a large number of patients showing that treatment with HCQ was associated with faster improvement of fever, cough, and less radiological progression of lung lesions. However, there was no difference in the virological cure, clinical improvement, or mortality.23
Many subsequent trials did not show benefit for HCQ use in COVID-19, with some of them suggesting more adverse events associated with its use.22–24 A recent clinical trial by Skipper et al.12 studied the change in symptom severity over 14 days in nonhospitalized patients between HCQ and control groups and did not find any significant difference (P = 0.12). Another trial by Cavalcanti et al.13 compared three groups; standard care group, standard care plus HCQ, and standard care plus HCQ and azithromycin. The clinical status at 15 days assessed by a seven-level ordinal scale did not show any significant difference among the three groups. Moreover, elevated liver enzymes and prolonged QT intervals were more frequent among patients who used HCQ.
In our study, adding HCQ to standard care did not add an extra benefit for the patients. Hydroxychloroquine arm was similar in all outcomes. Moreover, HCQ was not effective as postexposure prophylaxis against COVID-19 when administered within 4 days after exposure.25–29
Limitations of the study include small sample size which was not adequately powered for survival endpoint. The number of the included patients was limited because in Egypt, tertiary care hospitals were assigned lately to deal with COVID-19 patients and had many regulations by the Egyptian MOH. The study lacks long-term follow-up which could be addressed in a prospective trial. The utility of HCQ should be evaluated in larger multicenter trials either alone or in combination with other drugs/lines of treatment. The role of HCQ as a prophylaxis against SARS-CoV-2 infection should be among the future trials also.
In conclusion, our trial adds extra evidence from Egypt that HCQ may not be beneficial as a treatment for COVID-19.
Acknowledgment:
Publication charges for this article were waived due to the ongoing pandemic of COVID-19.
REFERENCES
- 1.↑
Zhu N et al. China Novel Coronavirus Investigating and Research Team, 2020. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382: 727–733.
- 2.
Yin Y, Wunderink RG, 2018. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology 23: 130–137.
- 3.
Zhou P et al. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579: 270–273.
- 4.↑
Bhatnagar T, Murhekar MV, Soneja M, Gupta N, Giri S, Wig N, Gangakhedkar R, 2020. Lopinavir/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: protocol for restricted public health emergency use. Indian J Med Res 151: 184–189.
- 5.
Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, Choe KW, Kang YM, Lee B, Park SJ, 2020. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR. J Korean Med Sci 35: e79.
- 6.↑
Cao B, 2020. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 382: 1787–1799.
- 7.↑
Gautret P et al. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 56: 105949.
- 8.↑
Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N, 2020. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 50: 384.
- 9.
Gnegel G, Hauk C, Neci R, Mutombo G, Nyaah F, Wistuba D, Häfele-Abah C, Heide L, 2020. Identification of falsified chloroquine tablets in Africa at the time of the COVID-19 pandemic. Am J Trop Med Hyg 103: 73–76.
- 10.
Xie M, Chen Q, 2020. Insight into 2019 novel coronavirus - an updated interim review and lessons from SARS-CoV and MERS-CoV. Int J Infect Dis 94: 119–124.
- 11.↑
Abena PM et al. 2020. Chloroquine and hydroxychloroquine for the prevention or treatment of COVID-19 in Africa: caution for inappropriate off-label use in healthcare settings. Am J Trop Med Hyg 102: 1184–1188.
- 12.↑
Skipper CP et al. 2020. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med M20–M4207.
- 13.↑
Cavalcanti AB et al. Coalition COVID-19 Brazil I Investigators, 2020. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med. Available at: https://doi.org/10.1056/NEJMoa2019014.
- 14.↑
World Health Organization, 2020. Clinical Management of Severe Acute Respiratory Infection (SARI) When COVID-19 Disease Is Suspected Interim Guidance. Available at: https://apps.who.int/iris/bitstream/handle/10665/331446/WHO-2019-nCoV-clinical-2020.4-eng.pdf?sequence=1&isAllowed=y. Accessed March 13, 2020.
- 15.↑
Egyptian Ministry of Health and Population (MOH), 2020. Diagnosis and Treatment Protocol for COVID-19. Available at: http://www.mohp.gov.eg/QuickServiceDetails.aspx?subject_id=3686. Accessed March 24, 2020.
- 16.↑
Faul F, Erdfelder E, Lang AG, Buncher A, 2007. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39: 175–191.
- 17.↑
Principi N, Esposito S, 2020. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis. doi: 10.1016/S1473-3099(20)30296-6.
- 18.↑
Udwadia ZF, Malu KN, Rana D, Joshi SR, 2020. Hydroxychloroquine for COVID-19: what is our current state of knowledge? J Assoc Physicians India 68: 48–52.
- 19.↑
Bhandari S et al. 2020. Characteristics, treatment outcomes and role of hydroxychloroquine among 522 COVID-19 hospitalized patients in Jaipur city: an epidemio-clinical study. J Assoc Physicians India 68: 13–19.
- 20.↑
Geleris J et al. 2020. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med 382: 2411–2418.
- 21.↑
Alexander PE, Debono VB, Mammen MJ, Iorio A, Aryal K, Deng D, Brocard E, Alhazzani W, 2020. COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine. J Clin Epidemiol 123: 120–126.
- 22.↑
Tang W et al. 2020. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 369: m1849.
- 23.↑
Sarma P et al. 2020. Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic review and meta-analysis. J Med Virol 92: 776–785.
- 24.↑
Horby P et al. 2020. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv. Available at: https://doi.org/10.1101/2020.07.15.20151852.
- 25.↑
Boulware DR et al. 2020. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med 383: 517–525.
- 26.
Khan MS, Butler J, 2020. Hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med 383. Available at: https://doi.org/10.1056/NEJMc2023617.
- 27.
Mohamed AA, Mohamed N, Mohamoud S, Zahran FE, Khattab RA, El-Damasy DA, Alsayed E, Abd-Elsalam S, 2020. SARS-CoV-2: the path of prevention and control. Infect Disord Drug Targets. Available at: https://doi.org/10.2174/1871526520666200520112848.
- 28.
Sarin SK et al. APASL COVID Task Force, APASL COVID Liver Injury Spectrum Study, 2020. Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; the APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study). Hepatol Int 1–11.
- 29.↑
Abd-Elsalam S, Elkadeem M, Glal KA, 2020. Chloroquine as chemoprophylaxis for COVID-19: will this work? Infect Disord Drug Targets. Available at: https://doi.org/10.2174/1871526520666200726224802.