Selected bits from the PDF:

PATIENTS AND GROUPS

All patients who presented at JMCH outpatient clinics with strong clinical suspicion of mild-to-moderate COVID-193, 15between March and August 2020, who were not hospitalized, were included. Briefly, patients presenting with a varying combination of fever, cough, fatigue, anorexia, shortness of breath, myalgia, diarrhea, nausea and vomiting, anosmia or ageusia, but no signs of severe pneumonia, including SpO2 ≥ 90% on room air, were defined as mild-to-moderate COVID-19. The diagnostic investigations included PCR testing for SARS-CoV-2, immunoglobulin titers against SARS-CoV-2, pulmonary radiological features (plain radiography and/or CT scan) blood inflammatory markers, such as CRP, and additional investigations depending upon the presenting clinical picture and comorbidities. Being a developing country, there are financial and logistic constraints along with limited availability of public testing facilities because of which not every patient could be tested for COVID-19 through PCR or antibody titers. Therefore, a strong clinical suspicion remained the major diagnostic parameter as described above.

Covid was not confirmed by PCR for a subset of subjects.

TREATMENTS:

The patients who received azithromycin (AZI) 500 mg PO daily and hydroxychloroquine (HCQ) 200 mg PO twice daily, both for seven days, were considered as control group(Group-A) while the cases (Group-B) comprised of all those patients who received ivermectin (IVM) 12mg PO daily for six days in addition to AZI+HCQ.

For 6 days!

RESULTS:

A total of 95 patients, including 36 females (38%) and 59 males (62%) diagnosed with COVID- 19 with mild to moderate illness were included in this study, who had received azithromycin and hydroxychloroquine (AZI+HCQ) as part of the treatment. Out of those, 41 (Group-B) had also received ivermectin (IVER+AZI+HCQ), while remaining 54 received AZI+HCQ only (Group-A). Majority (n=68; 72%) had no comorbidity.

Mild to moderately ill.

The baseline characteristics are given in Table-2. The majority of patients presented with fever, body ache, lethargy and respiratory complaints although gastrointestinal symptoms were not uncommon. The total leukocyte count showed significant difference between the two groups, however no clinical significance could be suggested as the values fell well within normal limits. Loss of weight was also common. The most striking difference was whether both groups differed in presence of fever on day 5, 7, 10 and 14. Group-B had a consistently and significantly shorter span of fever at each time-point mentioned above. The odds ratio (OR) suggested that Group-B had much higher odds to have a shorter span of febrile illness. The drugs were well-tolerated in the doses used as shown by lack of any reported side effects.

DISCUSSION:

This study shows that ivermectin use is associated with reduced duration of the febrile illness in an outpatient setting, thus promoting early recovery from COVID-19 infection, especially when started early in the course of the illness. There are several advantages of this study. This study included COVID-19 patients suffering from febrile illness who had presented most frequently on the 3rd day of febrile illness (unimodal distribution). The severity of illness and treatment was uniform and suggested an effective, feasible and very affordable method of treatment at community level. There are some limitations of this study such as a case-control design, and exclusion of severely ill or hospitalized patients. Many patients were diagnosed on the basis of the clinical syndrome rather than the molecular testing, as it was neither widely available nor within reach of the majority of the population within the country.

Earlier the antimalarial drugs chloroquine and hydroxychloroquine were claimed to possess antiviral activity, however, such studies were mainly in vitro and needed clinical trials to validate their efficacy and safety in humans. This was even more concerning when chloroquine or hydroxychloroquine in combination with another potentially cardiotoxic drug azithromycin was considered to treat COVID-19. However, recent studies do not support chloroquine or hydroxychloroquine for the treatment of COVID-19 as follows. A comparative observational study involving COVID-19 patients reported that hydroxychloroquine was not superior to control group in terms of worsening of symptoms, respiratory distress, or overall survival, all by the end of 3 weeks of treatment. A clinical trial found no difference in seroconversion rate at 28th day of COVID-19 illness among those receiving hydroxychloroquine compared to control group. Thus, AZI+HCQ does not impart any beneficial effect in COVID-19 and is as good as placebo, albeit with an increased risk of cardiotoxicity.

Above: Argument why AZT + HCQ = placebo

The adequate safety profile of any drug is pivotal to consider it as a potential drug to treat different diseases and ivermectin certainly possesses this quality. Its safety profile is established in adults on fixed daily doses of up to 36 mg without producing any significant adverse effects.24 Apart from the antiparasitic effect, ivermectin is known for its antimicrobial, antiviral, and anticancer potential. In this study ivermectin was used in a fixed dose of 12 mg once a day for six days without any reported side effect, thus confirming other similar studies where ivermectin has been used safely in a variety of conditions. With its good safety profile, ability to produce beneficial effects against many RNA and DNA viruses, and effects on various biological mechanisms, they can be considered as a potential treatment of COVID-19 infection.12 In this study, a dose of 12 mg once daily was used for six days leading to a highly feasible cost of under three dollars for the entire course of ivermectin over six days.

A recent study suggested that ivermectin used in hospitalized patients suffering from severe pulmonary complications would reduce mortality among COVID-19 patients.29 However, it was a retrospective study, conducted among hospitalized patients many of whom required a combination of various drugs, had multiple confounders requiring statistical adjustments, the administration of ivermectin did not follow a consistent dosing regimen and many of the patients were given ivermectin later in the course of the disease. The primary and secondary end-points were also different as compared to our study. Another study conducted among healthcare personnel suggested a beneficial role of ivermectin in COVID-19 patients.30 However it was a cross-sectional study conducted on COVID-19 patients presenting with a wide range of severity including asymptomatic patients as well as severely ill. Further, the study included mixed treatment regimens. In this study, the group taking ivermectin showed a much quicker recovery from the febrile illness at all time-points consistently with an odds ratio being highly significant as discussed below. The most drastic difference was seen within the first 5 days, suggesting the potential of ivermectin to bring about a sharp improvement among COVID-19 patients. To complement our observation, logistic regression analysis shows ivermectin being the only significant factor underlying the shorter duration of febrile illness among patients. Similarly, the survival analysis further supports this inference as the Kaplan-Meier curve showed a clear and highly significant advantage of using ivermectin among COVID-19 patients presenting with febrile illness. Interestingly, like other drugs being tried and used for COVID-19, this study suggests that the sooner the treatment is started, the better the magnitude of benefit in terms of a shorter duration of febrile illness. Recently, it has been postulated 31 that hydroxychloroquine may act synergistically with ivermectin to improve recovery in patients infected with SARS-CoV-2, however, we were not able to explore this in our study. An adequately designed randomized trial should provide the evidence for this hypothesis

To conclude, ivermectin used in COVID-19 infection seems to be a safe and well-tolerated drug which could shorten the duration of febrile illness in outpatient setting. The mechanism of action of ivermectin in COVID-19 needs further investigation stepping further in the direction of a direct antiviral as well as immunomodulatory effects. It is recommended that a double-blinded, placebo controlled trial should be carried out to establish the efficacy of ivermectin in coronavirus infections among patients who have various level of disease severity and ivermectin doses administered.

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