Chemoprophylaxis against COVID-19 among health-care workers using Ivermectin in low- and middle-income countries: A systematic review and meta-analysis.

Coronavirus disease-2019 (COVID-19) is a novel viral infectious disease that the World Health Organization (WHO) has announced to be a pandemic. This meta-analysis was aimed at providing evidence for the use of ivermectin to prevent COVID-19 among hospital workers in low-resource countries. Medical databases including African Journals online, Google Scholar, PubMed, Cochrane library, EMBASE, COVID-19 research database (WHO), Clinicaltrials.gov, and SCOPUS were searched for studies on Ivermectin as a chemoprophylactic drug against COVID-19 among hospital personnel in settings with limited resources. Preprint servers such as bioRxiv and medRxiv as well as the gray literature were also searched. Studies adjudged to be eligible were identified using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses algorithm. Statistical analyses were done using Stata version 14.3. Seven studies were selected for the meta-analysis. The total sample size was 2652. There were two randomized controlled trials and five nonrandomized studies. Some studies dosed Ivermectin daily while some dosed it weekly. However, one of the studies dosed it monthly. The studies reported variable clinical benefits. I2 statistic was 92%, and random effect model was used. The pooled odd ratio was 0.11 (95% confidence interval 0.09-0.13). This implies that 89% of the participants benefited from taking Ivermectin as a form of preexposure chemoprophylaxis. Ivermectin has a significant clinical benefit as a preventive drug against COVID-19 for hospital personnel in settings with limited resources.

Introduction

Coronavirus disease-2019 (COVID-19), commonly abbreviated as COVID-19, is a newly documented infectious disease caused by a beta coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[1] It was first reported in Wuhan in China but has now affected all the continents of the world.[2] It has affected several millions of individuals in the world causing significant number of deaths including those of healthcare workers too.[3] The impact of COVID-19 in low- and middle-income countries is unique because there are shortages of health-care workers, well-equipped health facilities, and personal protective equipment.[4]

The World Health Organization (WHO) has defined health-care workers as people whose job is to protect and improve the health of their communities.[5] Ethically, health-care workers cannot refuse to treat patients simply because they are at risk of contracting the patients' diseases.[6] Even during lockdowns when people are expected to stay at home to minimize the spread of infections, health-care workers must still go the health-care facilities to treat infected patients and this put them at high risk of getting infected. Therefore, the safety of health-care workers is of crucial importance especially in low-resource settings where there is background insufficiency of health-care workforce and personal protective equipment.[7]

Studies have shown that there is an increased risk of COVID-19 infection among hospital personnel and the members of their household.[8910] Over 10,000 and 500,000 health-care workers have been infected with COVID-19 in Africa and the Americas, respectively, and similar figures have been estimated in other regions.[111213] Interestingly, a study documented that infection rate among health-care workers was still higher than the general population despite the use of personal protective devices.[9] This suggests that health-care workers need additional protection to reduce the risk of contracting COVID-19.

A number of vaccines to protect against COVID-19 have been approved for usage in various countries, and more vaccines are still undergoing trials.[1415] Statistics have however shown that COVID-19 vaccination has the lowest rate of coverage in nations with low or middle income.[16] This unequitable access to the vaccines has also been emphasized by the WHO with the aim of improving access worldwide.[17] All these shortcomings have heightened the research on suitable candidates for chemoprophylaxis. Currently, there is inadequate evidence to recommend any agent as an ideal chemoprophylactic drug for COVID-19.[18] Chloroquine and hydroxychloroquine were initially suggested as being beneficial for preexposure prophylaxis against COVID-19, but there is a dearth of concrete clinical data to support the initial suggestion.[19] As a result, attention has now been shifted to other drugs such as Ivermectin.

Historically, Ivermectin was discovered by Satoshi Omura and William C. Campbell and this culminated into the award of the 2015 Nobel prize to the two of them for their works.[20] Ivermectin is a semi-synthetic macrocyclic lactone derivative of avermectin with microfilaicidal properties.[21] It was approved for the treatment of river blindness, and it has been extremely beneficial in the control of the disease in sub-Saharan Africa.[22] The widespread human usage derives from the beneficial properties of the drug such as efficacy, broad-spectrum anti-parasitic action, safety profile, ease of administration, and tolerability.[23] Ivermectin inhibits glutamate-gated chloride channels in the filarial worms, thereby paralyzing their muscles, but this effect is not seen in humans.[23] The half-life of Ivermectin in humans is 24–36 h, and some of the active metabolites persist for up to 3–4 days.[23] Although Ivermectin was originally approved for onchocerciasis, it has proven to be effective in the treatment of strongyloidiasis, scabies, leishmaniasis, and myiasis.

In a study involving over 3000 patients with onchocerciasis, some of the other beneficial side effects of Ivermectin reported were improved appetite, enhanced libido in men, restoration of menstrual flow in some cases of secondary amenorrhea, and reduced arthritic joint pains.[21] Some of the documented adverse effects of Ivermectin are headache, allergic reactions, postural dizziness, worsened pruritus, chest pain, confusion, seizure, and loss of consciousness.[24] Interestingly, Ivermectin has been documented to have drug–drug interactions with certain medications such as barbiturates, benzodiazepines, and valproic acid. It crosses the placenta and passes into the breast milk making it unsafe in pregnancy and during lactation.[25]

In vitro studies have demonstrated a broad antiviral properties of ivermectin, but there limited clinical studies to justify their antiviral indication in humans.[26] Before COVID-19 pandemic, the various viruses that Ivermectin has been demonstrated to inhibit in vitro include Zika virus, Dengue virus, yellow fever virus, human immunodeficiency virus type 1, and avian influenza virus.[27282930] The suppressive effect of Ivermectin on the replication of these ribonucleic acid viruses lies in its ability to inhibit α/β-importin which is essential for the transport of viral proteins from the cytoplasm to the nucleus.[31]

Caly et al. have demonstrated the potent inhibitory effect of Ivermectin on SARS-CoV-2 replication in vitro.[32] This has led to a lot of clinical trials on the therapeutic effect of Ivermectin on COVID-19, and the results have been impressive.[33343536] The mechanism by which Ivermectin treats COVID-19 is still a subject of intense research. However, the proposed mechanism is the ability of Ivermectin to inhibit transport of viral proteins from the cytoplasm to the nucleus.[37] This hypothesized mechanism is illustrated in Figure 1.

Figure 1

Ivermectin suppresses severe acute respiratory syndrome coronavirus-2 entrance into the nucleus for replication by inhibiting α/β-importin

This meta-analysis was aimed at critically examining the studies on preexposure prophylaxis of COVID-19 with Ivermectin done in low and middle income countries so as to guide its recommendation for health workers in these settings where vaccines are not readily available.

Methods

Search strategy and selection processes.

Relevant studies on preexposure prophylaxis of COVID-19 done in resource-limited settings were searched on medical databases including African Journals online, Google Scholar, PubMed, Cochrane library, EMBASE, COVID-19 research database (WHO), Clinicaltrials.gov, and SCOPUS. Preprint servers such as bioRxiv and medRxiv were also searched. The search terms used were “Ivermectin,” “prophylaxis,” “prevention,” and “COVID-19.” Other terms used in the data search included “Ivermectin use in COVID-19,” “mechanism of action of Ivermectin,” “Pre-exposure prophylaxis of COVID-19,” and “pre-exposure chemoprophylaxis of COVID-19 in resource-limited settings with Ivermectin.” Boolean operators such as “AND” as well as “OR” were also used to enhance the quality and quantity of the available studies. The gray literature was also searched in order to improve the studies available for the meta-analysis. The literature search and selection of studies were done by strictly following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PRISMA flow diagram is shown in Figure 2.

Figure 2

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the literature search and selection

Inclusion criteria

Studies done to demonstrate the chemoprophylactic effect of Ivermectin on COVID-19

Studies done in countries with low or middle income, going by the definition adopted by the World Bank[38] and whose abstracts with or without full text were available at the searched databases or from the gray literature.

Exclusion criteria

Studies on prophylaxis of COVID-19 with Ivermectin outside low- and middle-income countries.[34]

Studies on Ivermectin use in low- and middle-income countries but not focusing on the chemoprophylactic usage.

Data collection and analysis

Abstracts and full texts were carefully examined independently by the authors. Disagreements were resolved by consensus. Data extracted were study designs, interventions and controls, outcome variables, ethical considerations, and reported conflicts of interest. The main outcome variable of interest was the odds of being infected with COVID-19 when taking Ivermectin as chemoprophylaxis compared with placebo (odds ratio [OR] and 95% confidence interval [CI]). CI was calculated for studies where it was not given. Data extracted were initially obtained on a spreadsheet before it was transferred to a statistical tool. The Newcastle-Ottawa scale was used to assess the quality and bias of the nonrandomized studies while the Cochrane Risk of Bias tool was used to assess bias in the randomized trials. Statistical analyses were done using Stata version 14.3 manufactured by Stata Corp LLC, College Station, Texas, USA. DerSimonian and Laird random effect model was used. Heterogeneity was assessed using the I2 statistic.

Results

Seven studies were eventually selected, having met the eligibility criteria, for the meta-analysis. Table 1 shows the locations and sample size of each study. There were two randomized controlled trials and five nonrandomized studies. Two of the studies were done in Africa and Asia, respectively, and three studies were conducted in South America. Table 2 shows the protocol used in each study to administer Ivermectin. Some studies dosed Ivermectin daily while some dosed it weekly. However, one of the studies dosed it monthly. Table 3 shows the ORs and the pooled OR. The total sample size in this meta-analysis was 2652. I2 statistic was 92% which suggests significant heterogeneity in the selected studies. Using random effect model, on account of the significant heterogeneity, the pooled odd ratio was 0.11 (95% CI 0.09–0.13). This implies that 89% of the participants benefited from taking Ivermectin as a form of preexposure chemoprophylaxis. The forest plot is shown in Figure 3.

Table 1

Studies, types and locations

Study	Location	Study type
Alam et al.[39]	Bangladesh	Observational study
Elgazzar et al.[40]	Egypt	Matched case-control study
Behera et al.[41]	India	Matched case-control study
Shouman et al.[42]	Egypt	Randomized controlled trial
Chala ER[43]	Argentina	Randomized controlled clinical trial
Carvallo et al., (pilot)[44]	Argentina	Observational study
Carvallo et al., (multicentric)[44]	Argentina	Observational study

Table 2

Studies and ivermectin doses

Study	Dose of ivermectin
Alam et al.[39]	12 mg monthly for 4 months
Elgazzar et al.[40]	300 µg/kg weekly for 2 weeks
Behera et al.[41]	300 µg/kg on day 1 and day 3
Shouman et al.[42]	15 mg, 18 mg, 24 mg on day 1 and day 3
Chala ER[43]	12 mg weekly for 4 weeks
Carvallo et al., (pilot)[44]	3 mg daily for 14 days
Carvallo et al., (multicentric)[44]	12 mg weekly for 8 weeks

Table 3

The sample size, odds ratio of each study

Study	Sample size	OR	95% CI (lower limit-upper limit)
Alam et al.[39]	118	0.03	0.01-0.06
Elgazzar et al.[40]	200	0.18	0.12-0.24
Behera et al.[41]	372	0.27	0.15-0.51
Shouman et al.[42]	304	0.06	0.03-0.09
Chala ER[43]	234	0.13	0.03-0.40
Carvallo et al., (pilot)[44]	229	0.00	0.00-0.01
Carvallo et al., (multicentric)[44]	1195	0.00	0.00-0.01
Pooled effect	Total=2652	0.11	0.09-0.13

OR=Odds ratio, CI=Confidence interval

Figure 3

Forest plot of the meta-analysis

Discussion

There were limited numbers of studies available for this meta-analysis. Camprubí et al.[45] have also highlighted the dearth of clinical studies on the possible repurposing of Ivermectin as a therapeutic or prophylactic drug against COVID-19.[44] All the studies showed variable benefit of using Ivermectin as chemoprophylaxis against COVID-19. However, most of the studies were not randomized controlled trials. Bonsu et al.,[46] have reported the logistic and financial hurdles encountered in conducting drug trials in resource limited settings, thereby limiting the number of published randomized clinical trials from such settings. There was significant heterogeneity in the studies. This could be due to the differences in demographics and study designs. Six of the studies involved health-care workers while a study involved relatives of COVID-19 patients who were caring for their infected relatives.

This meta-analysis shows that 89% of the individuals in the various studies, when pooled together, would benefit from the usage of Ivermectin to prevent COVID-19 infection. The findings in this study are similar to that of another meta-analysis that looked at the clinical benefit of Ivermectin as either a therapeutic or prophylactic agent across all settings, both resource-limited and developed nations.[47] In that study, 90% of the individuals (both health workers and the general population) who took various doses of Ivermectin as chemoprophylaxis benefited from it. This is quite significant for hospital personnel in settings where the resources are inadequate. Such settings are characterized by high incidence of COVID-19 infections among the limited health workers, yet protective wears are in limited supply and approved vaccines are still not readily available.

Limitations

The available articles selected for this study were few and highly heterogeneous. In addition, most of the studies were not randomized controlled drug trials and the risk of bias was quite high. Furthermore, the doses of Ivermectin varied across studies

Conclusion

Our study has demonstrated the effectiveness of Ivermectin in preventing the transmission of the SARS-CoV-2 among health-care workers in low- and middle-income countries. In addition, the various doses were all found to be effective, but the most effective was the 12 mg weekly doses administered over a period of 8 weeks. With the limited access to COVID-19 vaccines and sustainable supplies of infection prevention commodities, we recommend that Ivermectin may be used as a prophylactic drug against COVID-19 among hospital workers practicing in developing countries. Notwithstanding the need for further randomized studies on the use of Ivermectin as preventive therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.