European Journal of Cardiovascular Medicine

Coronavirus disease 2019 (COVID-19) is an acute respiratory highly contagious infectious illness with systemic manifestations caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is associated with considerable morbidity and mortality. (1,2) It had a catastrophic effect on the world’s demographics resulting in more than 6 million deaths worldwide as of March 2022, emerging as the most consequential global health crisis since the era of the influenza pandemic of 1918 (Marco Cascella, June 2022). The most common symptoms are fever, tiredness, dry cough and loss of taste or smell. But in more severe cases, acute respiratory distress syndrome (ARDS) develops. While most adults with COVID-19 recover, a few develop ARDS requiring hospitalization. (3,4) Approximately 80% of patients have a mild illness, 15% have moderate to severe disease and 5% have a critical illness. (3,5)

Initially, early in the pandemic, the understanding of COVID-19 and its therapeutic management was limited, creating an urgency to mitigate this new viral illness with experimental therapies and drug repurposing. Since then, due to the intense efforts of clinical researchers globally, significant progress has been made which has led to a better understanding of not only COVID-19 and its management but also has resulted in the development of novel therapeutics and vaccine development at an unprecedented speed.

Hydroxychloroquine, a drug, has generated interest and great debate as a potential treatment for COVID-19. This is due to its widespread availability, low cost, antiviral and immunomodulatory activity and established safety profile from historical use for other ailments such  as  malaria and  some autoimmune diseases.(6,7) In vitro,  hydroxychloroquine limits  entry of SARS-CoV-2 into cells and delays the stage of viral replication.(6-11) Furthermore, hydroxychloroquine reduces the production of several  pro-inflammatory  cytokines  potentially  involved  in the development of ARDS among infected patients.(12-14)

Ivermectin, during in vitro conditions, is an inhibitor of SARS‐CoV‐2 which is able to reduce viral RNA by approximately 5000‐folds in 48 h. This beneficial mechanism of Ivermectin on the COVID‐19 virus was not known until recently and it was thought that it behaved in the same manner as on other viruses. It inhibits the nuclear import of virus and host proteins. Ivermectin may be a safe, affordable, and readily available therapy for COVID‐19. Therefore, the use of Ivermectin warrants the rapid implementation of controlled clinical trials to assess the efficacy against SARS‐CoV‐2. There were observational studies suggesting a beneficial effect of Ivermectin in the treatment of COVID‐19. (15)

Doxycycline is a long-acting, broad-spectrum, semi-synthetic tetracycline antibiotic. It is a bacteriostatic antibiotic and blocks protein biosynthesis. A strong anti-inflammatory effect of this drug has been demonstrated earlier. It is recommended for chronic sinusitis as an immunomodulating and disease-stabilizing medication in the guidelines. It is also an antiviral drug against RNA viruses. For example, it is used in dengue as has been well proven to block a cytokine storm.(16) A hyper inflammatory syndrome or cytokine storm contributes to severe diseases indicating a key role for dysregulated host innate immune mechanisms during advanced stages of COVID-19. (17) Doxycycline has been used as a specific treatment for COVID-19 in India and Brazil; whereas, in the UK, national guidelines recommend doxycycline for suspected COVID-19 pneumonia, in patients at high risk of adverse outcomes in the community, or with bacterial infection. WHO and the US Centre for Disease Control and Prevention, recommend antibiotics for suspected bacterial pneumonia in COVID-19, with doxycycline included in the treatment guidelines for community-acquired pneumonia. Community prescribing data from the USA and the UK suggests that there has been increased use of doxycycline for respiratory tract infections during the COVID-19 pandemic, which could exacerbate antimicrobial resistance. (18) Randomised trials evaluating doxycycline as a treatment for COVID-19 are therefore needed to either provide evidence for its effectiveness, or if it is shown to be ineffective, to prevent its unnecessary use.

Favipiravir is a new broad-spectrum antiviral drug, which targets RNA-dependent RNA polymerase. Favipiravir has a wide range of antiviral effects, including those on influenza A and B, viral haemorrhagic fever, etc. In addition, a retrospective study of Ebola virus disease showed that the overall survival rate in the favipiravir group was higher than that in the control group (56.4% [22/39] vs35.3% [30/85], p = 0.027). (19) Based on these mechanisms of action and clinical experience early in the pandemic, so many drugs were used as treatment for COVID-19 in some settings and discussion under guidance of experts regarding its efficacy but no final conclusive best treatment in worldhad come out. It had happened due to availability of a smaller number of studies worldwide.

Our primary aim was to ascertain the best possible regimen that leads to early negativity of RT-PCR. Secondary, is to ascertain the best possible regimen that leads to an early asymptomatic phaseand, thirdly, to ascertain the best possible regimen that leads to decrease in the length of hospital stay. Finally, to ascertain the best possible regimen that leads to decrease in oxygen requirement.

2.1.         Study design and participants:

The present study was a retrospective study in which records of the confirmed COVID -19 patients admitted in the hospital during July 2020 to September 2020, with symptoms of mild COVID as per the guidelines were analyzed. There were four treatment regimens, that were followed in the hospital as per the guidelines. The different treatment regimen was the criteria for grouping of the patient in four groups. Records of all the cases of mild disease admitted to the hospital were screened for the treatment regimen and were grouped as per the treatment given to them. Thirty patients were enrolled in each group, starting from 1^st July 2020. Once 30 patients in a group were enrolled, remaining case records were not screened for that group to remove selection bias. A total of 120 patients were enrolled and categorized in the four groups: G1 (Hydroxychloroquine (HCQS)), G2 (Ivermectin combination with Doxycycline), G3 (Favipiravir) and G4 (Ivermectin in combination with HCQS).

The included patients were first stratified according to their age (≦30, 31-60 and ≧61), then by their gender (inside each stratum into males and females) and then based on their associated co-morbidities (absent and present).

2.2          Procedures:

The treatment regimens followed in the hospital are as under.

Group1 (G1): Hydroxychloroquine (HCQS) group, 30 patients who received 400mg twice daily (on day 1) followed by 200mg twice daily next 5 days added to the standard of care treatment adopted by the Egyptian Ministry of Health (MOH) protocol for 15 days. 

Group2 (G2): Ivermectin in combination with Doxycycline group, 30 patients who received Doxycycline 100mg twice daily for 5 days in combination with single dose of oral Ivermectin tablets (12 mg) every day for 3 days added to the standard of care treatment adopted by the Egyptian Ministry of Health (MOH) protocol for 15 days.

Group 3 (G3): Favipiravir group, 30 patients who received 800mg twice daily (in day 1) followed by 200mg twice daily next 5 days added to the standard of care treatment adopted by the Egyptian Ministry of Health (MOH) protocol for 15 days. 

Group 4 (G4): Ivermectin in combination with HCQS group, 30 patients who received a single dose of oral Ivermectin tablets (12 mg) every day for 3 days with combination HCQS 400mg twice daily (in day 1) followed by 200mg twice daily next 5 days added to the standard protocol of treatment.

2.3.         Outcomes

The primary outcome was the assessment of clinical efficacy of all four-treatment plan in the form of the analysis of all‐cause mortality within 1 month after randomization and the secondary outcomes were the RT-PCR negativity report, length of hospital stay and asymptomatic condition achieved by COVID-19 patient with respect to number of days recorded carefully.  The assessment of the safety of all drug doses was monitored carefully by the physicians or by on duty nursing staff.

2.4.         Ethical considerations

Privacy of participants and confidentially of the data was maintained. The present study was a retrospective study; however, ethical clearance was taken to assess the hospital records.

2.5.         Statistical analysis

Data were analyzed by Statistical Package for Social Sciences (SPSS) Version 26 and were expressed in number (No), percentage, (%) mean (x̅) and standard deviation (SD). One way ANOVA was used to analyze statistical significance level. The regression model (ROC) was also used to compare the different treatment plans/outcomes of all the four groups and to select an optimal cut-off value for determining the presence or absence of a disease. Two‐sided p value of less than 0.05 was considered statistically significant.

3.1. Demographics, epidemiological and clinical characteristics

A total number of 120 patients with a median age of 40.53±11.35 years were included in the study. The mean age was 40.17 ± 10.09 years for Group 1 (HCQS), 41.07 ± 14.92 for Group 2(Ivermectin + Doxy), 40.83 ± 10.63 for Group 3(Favipiravir) and 40.03 ± 09.52for Group 4(HCQS + Ivermectin). Males represented 83% of Group 1, 63% of Group 2, 76% of Group 3 and 80% of Group 4 (Table 1). Most of the patients were in 30-60 years age period in all groups. The most common symptoms i.e. fever was reported frequently in patients of Group 3(Favipiravir) - 80% as compared to other groups. Most of the patient having COVID‐19 symptoms were either fever, cough or sore throat (Table 1).

Table1: Patient Clinico-pathological characteristics

3.2.         Treatments and clinical outcomes

The median interval from illness onset to viral clearance was one of the basic criteria to check efficacy of treatment given to patients. The early negative RT-PCR report was the criteria for predicting the outcome and efficacy of treatment regimen. The RT-PCR negative report was lower in group 1 (HOCQ) 6.8 ± 1.47 days and group 4 (HOCQ + Ivmac) 7.23 ± 0.85 days as compared to group 2 (Ivmac+ doxy) 8.67 ± 1.97 days and group 3 (favipiravir) 9.97±2.773 days.The length of hospital stay was found marginally lower in group1 (HOCQ) (7.13 ± 1.48days) as compared with group 4 (HOCQ + Ivmac) (7.9 ± 0.76days) but when compared with group 2 (Ivmac+ doxy) (9 ± 2.20days) and group 3 (favipiravir) (10.57 ± 2.25 days) there was a significant difference. HOCQ was common in both group1 and group4 which may be one of the reasons for the marginal difference between them and significant difference with other group 2and group 3. Othercriteria used for the assessment of treatment efficacy was the number of days the patient took to become asymptomatic. In this study, group1, had taken much less time, (3.37±2.10 days), to become asymptomatic as compared to other group 2 (4.33 ± 1.47 days), group 3 (5.03 ±2.73 days) and group 4 (3.8 ± 1.65 days). Group 1 and group 4 have shown marginal difference wherein HOCQ was common in both groups which indicate that HOCQ may be one of the reasons of minimal difference. Hydroxychloroquine reduces production of several pro-inflammatory cytokines potentially involved in the development of various infection among infected patients. (Table 2: Figure1)

Table2: Treatments and clinical outcomes

Figure 1: Treatments and clinical outcomes

Receiver Operating Characteristic (ROC) analysis

Evaluation of four different drug treatment plan potency in four different group of patients (no. of patient in each group is same) of COVID‐19 infected.

Receiver Operating Characteristic (ROC) analysis was done to compare the potency of four treatment plans in four different groups of COVID‐19 patient on three different parameters: early RT-PCR test negativity, number of days patient admitted in Hospital and asymptomatic condition achieved by COVID‐19 patient with respect to number of days.

RT-PCR

Sensitivity (66.7%, 86.7%) and specificity (66.7%, 76.7%) of Patient’s RT-PCR negativity testing were checked by ROC analysis. Significant comparison was found with group G1 against the G2 (p=0.001) & G3 (p=<0.0001), respectively. Area under curve (AUC) had also showed fair values in G1 against the G2 (0.749) and good in G1 against the G3 (0.858). Significant data was not found in Group G1 against the G4. The AUC value in G2 against the G3 (0.673) & G4 (0.298) and G3 against the G4 (0.156) were also not found acceptable. (Table: 3a; Figure:2a )

Table 3a: ROC analysis showing comparison between treatment groups with RT-PCR report

Figure 2a: ROC analysis RT-PCR

Hospital stay

Patient’s stay in terms of number of days in hospital were also checked for sensitivity (76.7%, 76.7%, 73.3%) and specificity (53.3%, 90.0%, 53.3%) by ROC analysis and significant comparison was found in group G1 against the G2 (p=0.001) & G3 (p=<0.0001), respectively. Area under curve (AUC) had also showed fair results in G1 against the G2 (0.743), good in G1 against the G3 (0.915) and poor in G1 against the G4 Group. The AUC, sensitivity and specificity value in G2 against the G3 (0.703; 76.7%; 70.0%) was fair with significant (p=0.007) comparison. G2 against the G4 (0.356) and G3 against the G4 (0.126) were found non acceptable. (Table: 3b; Figure: 2b)

Table 3b: ROC analysis showing comparison between treatment groups with Hospital stay

Figure 2b: ROC analysis Hospital Stay

Asymptomatic

Asymptomatic condition achieved by COVID‐19 patient in term of number of days were studied with sensitivity (66.7%, 63.3%, 76.7%) and specificity (73.3%, 73.3%) by ROC analysis and significant comparison was found with group G1 against the G2 (p=0.020) & G3 (p=0.019), respectively. Area under curve (AUC) had shown poor results in G1 against the G2 (0.674) and G1 against the G3 (0.677). The results for Area under curve (AUC) for G1 against the G4, G2 against the G3 (0.569), G2 against the G4 (0.396) and G3 against the G4 (0.381) were not found acceptable. (Table: 3c; Figure: 2c)

Table 3c: ROC analysis showing comparison between treatment groups with Asymptomatic

Figure 2c: ROC analysis Asymptomatic

Therefore, it is evident from the above results that when ROC analysis was performed in comparison to G1 group against the G2,G3& G4 the AUC, sensitivity and specificity showed the better results in comparison to G2 group against the G3 & G4 and G3 group against G4 for all the three parameters i.e. early RT-PCR test negativity, number of days patient admitted in Hospital and Asymptomatic condition achieved by COVID‐19 patient in term of number of days. However, it may be concluded that G1 group treatment drug is better choice for treating Covid-19 patient as compared to other treatment drugs. 

SARS-CoV-2 coronavirus was first reported in China at the end of 2019 causingenormous losses for global health and economy(21) including the deaths of more than 2 million people (2,886,728) by April 7, 2021,(20).Now, even after a lapse of three years, SARS-CoV-2 viruses are still life threatening. There are still no standard treatment guidelines for curing COVID-19 completely. Furthermore, the WHO has developed a guideline that conforms to reliable standards and methods for the management of this virus. Number of clinical studieshave been conducted to investigate the use of anti-viral drugsfor treatment of SARS-CoV-2 infection. However, in all these studies, the selection of drug dosing regimen was mainly based on previous clinical experiences, which is the first step to discover the effective drug selection with minimum side effects for pandemic disease, like SARS-CoV-2 coronavirus at present.

Many conflicting research articles have been published in the previous years leading initially,fortheemergency use of authorization for HCQ in the treatment of COVID-19. There were no increased risks of mortality or incubation in the initial observational trials of HCQ in hospitalized patients when compared with the control group who received only standard care. Besides, the patients who received HCQ were fallen more critically ill(22). Later on, this authorization was withdrawn by the FDA. 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 (23). The utility of HCQ should be evaluated in larger multicenter trials, either alone or in combination with other drugs/lines of treatment.

Gautret et al treated 20 patients with hydroxychloroquine and compared the results with 16 controls in France. Asymptomatic patients and patients with both lower and upper respiratory tract infections were treated.They used PCR to measure the viral load on day 3, 4, 5 and 6 of post-inclusion and concluded that hydroxychloroquine was effective in viral load reduction (24). This study is giving full support to above Gautret et al study. We also found that hydroxychloroquineisasan ideal drug to treat SARS-CoV-2 infection because it decreases the virus load faster in patientsvia its anti-viral ability and helping out to mediate the cytokine storm via its immunomodulatory effects. We found shorter mean days of RT-PCR negative report (6.8 days), hospital stay (7.13 days) and asymptomatic condition (3.37 days) which were lesser than other treatment plan groups (G2, G3, and G4). In this study, we used one of the unique statistical tool,i.e. ROC curve, for comparing theperformance of different treatment groups. The area under curve, sensitivity and specificity were found significant (P<0.001) in G1 group as compared with other groups(G2, G3, and G4).

A small randomized controlled trial in 72 adults hospitalized with COVID-19 in Bangladesh was compared using doxycycline for 5 days plus single-dose Ivermectin, Ivermectin alone for 5 days and placebo.(25) The primary outcome of mean time to negative SARS-CoV-2 PCR was 12·7 days (95% CI 11·3–14·2) in the placebo group and a similar 11·5 days (9·8–13·2; p=0·27) in the Doxycycline plus Ivermectin group and was shorter in the Ivermectin alone group (9·7 days [7·8–11·8]; p=0·02) than in the placebo group. (26) There were no differences in hospitalization duration in both cases. Similar results were found in this study also when used the combination of Ivermectin and Doxycycline (group 2 treatment plan).  The primary outcome of negative SARS-CoV-2 RT- PCR report was 8·67 days (SD =1.971), hospital stay was 9 days (SD=2.19) and 4.33(SD= 1.47) days of asymptomatic condition which was not significant with other treatment plan of groups (G1, G3 and G4).  This study also supports the combination of ivermectin plus doxycycline for not showing the significant outcome either clinically or faster patient recovery in comparison to other treatment plan.

Severalstudieson use of Favipiravirsuggested that there were no significant differences in clinical parameters, eg, length of hospitalizations, clinical recovery etc. There is no evidence that favipiravir reduces mortality or the use of mechanical ventilation among moderate and severe COVID-19 patients.(27) The existing literature on the effectiveness of these antivirals (Remdesivir, Lopinavir/Ritonavir, and Favipiravir) have several limitations. Firstly, in most of the studies these antiviral agents were used in combination with other drugs, therefore, their results cannot be drawn solely from the antiviral that was administered. Furthermore, the sample size used in some studies was small, limiting the generalization of the findings and not representing the population. Present study has shownthat patient who were given this plan of treatment (G3) took long duration of hospital stay (10.57±2.25days), longer mean time of RT-PCR negative report (9.97±2.77 days) and accordingly, long time in becoming the asymptomatic condition (5.03±2.73 days) in comparison to other plan of treatment (G1, G2, G4). As this study has also not found any significant result in patients either clinically or physically, therefore, not giving the confidence to thetreatingdoctor for recommending drug Favipiravir.

HCQ behaves as a first-level barrier by inhibiting the entry of the virus into the host cell, while Ivermectin reduces viral replication if the virus did get in. Based on all such evidences, we hypothesize that HCQ and Ivermectin could act in a consequential and synergistic manner. However, we found that HCQ individually provides better results as compared to use in combination with Ivermectin to patient. G1 plan of treatment, i.e., HCQwasfound lesser days of RT-PCR negative report (6.8+1.47 days), hospital stay (7.13+1.48 days) and days of asymptomatic(3.37+2.10days) as compared to use of HCQ in combination with Ivermectin i.e. 7.23 days, 8.65 days and 3.8 days, respectively in G4 plan to treatment. As per previous literature no one has used such combination either in vitro or in vivo studies on SARS-CoV-2 infection

Our results are helpful for decision-makers to fight this emerging viral infection in present condition.  Further, based on our study it is evident to recommend use of low-dose hydroxychloroquine drug to help in diminishing the viral load in critically ill patients with COVID‐19. We encourage the ongoing investigations on this area to make clear guidelines to prevent and treat this disease.

Conflict of Interest: No conflict of interest found between authors. This is ensure that “All authors have contributed to, seen, and approved the final, submitted version of the manuscript.”

Author contributions: SS: Experiment design, manuscript review; AS: provide thing required for experiments; MKN:  manuscript writing, provide thing required for experiments; RU: review experiments data; PJ: help in data collection; RG: provide facility for research; AKG: arranging data; KB: writing manuscript, arranging data, statically analysis; AB: help in statically analysis.

Acknowledgements, details of funding sources: NA

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