The COVID-19 pandemic in Bangladesh is part of the Coronavirus worldwide pandemic disease caused by a newly discovered Coronavirus. Initially, it was called the novel Coronavirus and later named severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) due to its similar characteristics with severe acute respiratory syndrome Coronavirus 1 (SARS-CoV-1).[7–9] The treatment methods for COVID-19 are emerging and rapidly evolving because of ongoing research being done worldwide by a record number of investigators. Due to the uniqueness of each medical and research facility, the approach to the care of patients with COVID-19 varies from institution to institution; in Bangladesh, many patients with mild to moderate disease were being treated with Hydroxychloroquine (HCQ) and Azithromycin. New concerns about HCQ has led us to seek alternatives with shorter recovery time and better tolerability. Thus, we have undertaken a comparative therapeutic analysis, comparing these standard drugs with Ivermectin and Doxycycline.
HCQ, a less toxic derivative of chloroquine, is an antimalarial drug and has decades of treatment use as an immunomodulator.  At present, it has been the topic of discussion concerning its potential use to treat patients with COVID-19. It is thought that the effect of HCQ on antigen cross-presentation may occur, in which a dendritic cell presents the antigen to CD8+Tcells. Thus, improving their priming followed by the activation of CD8+ T-cells through antigen recognition, this results in the induction of selective killing of the infected cells. Therefore, it may accelerate viral clearance in COVID-19. Some studies show that severe deterioration in some patients with COVID-19 has been closely associated with dysregulated and excessive cytokine release termed "cytokine storm" [14, 15] HCQ was found effective in inhibiting SARS-CoV-2 infection in vitro and can significantly decrease the production of cytokines and especially the pro-inflammatory cytokines.
Azithromycin is in the macrolide group of antibiotic drugs used in the treatment of several bacterial infections, including pneumonia. It is known to reversibly bind to the 50S ribosomal subunit of the 70S ribosome to inhibit the translocation step of protein synthesis, but whether it has an antiviral effect or not is not yet known. It has been studied as part of the possible treatment of COVID-19 in combination with HCQ and has been reported to add benefit. [17, 18] However, a recent report failed to establish whether it has any antiviral activity or any synergistic activity with HCQ in the treatment of COVID-19. Therefore, a further comparative study can enhance the significance of the combination therapy of HCQ and Azithromycin.
Ivermectin is a relatively safe and well-tolerated anti-parasitic drug for head lice, scabies, onchocerciasis, and strongyloidiasis that acts by inhibiting nuclear transport activity.  In-vitro studies have shown its function against human immunodeficiency virus (HIV), dengue, influenza, and most recently, against SARS-CoV-2. This effectiveness against SARS-CoV-2 infection is due to its critical interaction of RNA viruses responsible for integrase protein nuclear import.[21, 22] A recent report suggests that Ivermectin reduces mortality rates in hospitalized patients with COVID-19. However, it is not known if antiviral levels are attainable while using known dosing regimens of Ivermectin therapy in patients with COVID-19.[24, 25] Thus, it is vital to investigate the dose regimens of Ivermectin for COVID-19 treatment or to determine if there is appropriate synergism using combination therapy with another drug.
Doxycycline is in the tetracycline class of antibiotics that acts via the inhibition of bacterial ribosomes. It is a well-tolerated bacteriostatic drug that has a long history of clinical use. The efficacy and tolerability of Ivermectin and Doxycycline were established in combination with an earlier study for the treatment of onchocerciasis. Several recent studies have suggested a therapeutic role of Doxycycline against COVID-19.[28, 29]
In this randomized treatment study, we used two different drug combinations, Ivermectin-Doxycycline (Group A) and Hydroxychloroquine-Azithromycin (Group B), for the outpatient therapy of patients with mild to moderate COVID-19 in Bangladesh. The presenting symptoms of the COVID19 patients were fever, cough, sore throat, weakness, chest discomfort, breathing difficulty, diarrhoea, myalgia, and abdominal pain. To avoid the influence in the recovery duration, we solely selected the cases devoid of any severe comorbidities. Only patients with mild to moderate disease that could be treated as outpatients were included. HCQ dosing was decided as per "National guideline for COVID19 management 4.0".
The difference in recovery to negative PCR duration was not significant (P = 0.231) among the two groups. Still, the mean duration of recovery is shorter 8.933days in the case of Ivermectin-Doxycycline (Group A) than that of Hydroxychloroquine-Azithromycin (Group B) 9.33 days. [Figure 1C] Also, the Ivermectin-Doxycycline group had a better outcome ratio of 100% (60/60) recovery to negative PCR compared to that of HCQ 96.36% (54/56).
The difference in recovery to becoming symptom-free was 5.93days (5 to 10 days) in Group A and 6.99days (4 to 12 days) in Group B. This difference was not statistically significant. The Ivermectin group showed a better symptomatic recovery (5.93days) in comparison to the HCQ group (6.99days). [Figure 1G] In the case of Group-A most of the patients gained symptomatic recovery on the 5th (55.50%), 6th (16.32% and 7th (12.24%) day, this is 23.8%, 21.43% and 19.04% in the Group-B.[Figure 1H] In the case of symptomatic and asymptomatic patients the Ivermectin-Doxycycline combination expressed an earlier and faster relief of COVID features and viral clearance than that of HCQ-Azithromycin combination. [Figure: 2 A, C & D] Though the mean recovery duration is not statistically significant in an unpaired t-test. [Figure 2: B] This suggests Ivermectin-Doxycycline may have better efficacy in reducing the COVID-19 symptoms than that of HCQ-Azithromycin therapy.
Additional considerations are tolerability and compliance. In our study, the Ivermectin-Doxycycline group had better patient compliance and fewer adverse effects as compared to the HCQ-Azithromycin group, 31.67%, and 46.42% respectively. [Figure 1D & E] The adverse effects of HCQ in our study are similar to others, with 39.2% of patients complaining of lethargy-dizziness, and with blurred vision and occasional palpitations noted by 23.21% and 17.85% of patients in the HCQ group. In comparison, the adverse effects seen in Group A were also lethargy, nausea, and occasional vertigo but at a lower rate than in Group B, with 23.3% complaining of these adverse effects in Group A.
The sex difference was examined but there were no significant differences in outcome between the males and females in this study. In case of Group A, both male and female had almost the same duration of recovery to negative PCR (8.9 and 9 days) but in Group B (9.45 and 8.78 days), male patients had a longer duration of recovery to negative PCR than the females (9.18 days and 8.92 days).[Figure 1F]
According to this study, both the Ivermectin-Doxycycline and HCQ-Azithromycin treatment regimens were tolerated and may have been an effective treatment for mild to moderate SARS-CoV-2 infection. With regard to time to becoming symptom-free, Ivermectin-Doxycycline combination is superior to HCQ-Azithromycin therapy for mild to moderate degrees of COVID-19 patients. In addition, the Ivermectin-Doxycycline combination is superior to HCQ-Azithromycin in terms of safety, side-effect profile, and compliance. We strongly believe that increasing the duration of Ivermectin treatment to 3days will offer further benefit in reducing the recovery period of COVID beyond that which was seen in our study. This will also prevent disease progression and morbidity to COVID-19 patients.
Our study has limitations; these include relatively small sample size, the dose of Ivermectin, case selection, also the outcome may be biased by additional factors like severity of the disease, lack of cooperation of some participants, and unknown comorbidity.