Comparison of Trials Using Ivermectin for COVID-19 Between Regions With High and Low Prevalence of Strongyloidiasis
MD Avi Bitterman, BS Caitlin Pestana Martins, MD Ahuva Cices, Makarand Prasad Nadendla
JAMA Network Open, doi:10.1001/jamanetworkopen.2022.3079
IMPORTANCE A widely cited meta-analysis of randomized clinical trials has claimed ivermectin as an effective treatment for prevention of mortality in COVID-19. However, an unrecognized interaction variable with the relative risk (RR) of mortality may substantially change the appropriate interpretation of this analysis.
OBJECTIVE To evaluate the association between regional prevalence of strongyloidiasis and ivermectin trial results for the outcome of mortality by testing the hypothesis that strongyloidiasis prevalence interacts with the RR of mortality. DATA SOURCES Original meta-analysis as well as a manual review of all references in a dedicated ivermectin trial database (c19ivermectin) from January 1, 2019, to November 6, 2021. STUDY SELECTION Randomized clinical trials using ivermectin as a treatment for COVID-19 and reporting the outcome of mortality. Studies were excluded in the event of publications revealing suspected trial fraud and/or randomization failure.
DATA EXTRACTION AND SYNTHESIS Study characteristics and RR estimates were extracted from each source. Estimates were pooled using random-effects meta-analysis. Differences by strongyloidiasis prevalence were estimated using subgroup meta-analysis and meta-regression. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed.
MAIN OUTCOMES AND MEASURES Relative risk of mortality in ivermectin trials in regions of high vs low strongyloidiasis prevalence and correlation coefficient of meta-regression analysis between RR of mortality and regional prevalence of strongyloidiasis. RESULTS A total of 12 trials comprising 3901 patients were included in the analysis. Four trials (33%) took place in regions of high strongyloidiasis prevalence and 8 (67%) trials took place in regions of low strongyloidiasis prevalence. Ivermectin trials that took place in areas of low regional strongyloidiasis prevalence were not associated with a statistically significant decreased risk of mortality (RR, 0.84 [95% CI, 0.60-1.18]; P = .31). By contrast, ivermectin trials that took place in areas of high regional strongyloidiasis prevalence were associated with a significantly decreased risk of mortality (RR, 0.25 [95% CI, 0.09-0.70]; P = .008). Testing for subgroup differences revealed a significant difference between the results of groups with low and high strongyloidiasis prevalence (χ 2 1 = 4.79; P = .03). The estimate for τ 2 (the variance of the study effect sizes) was 0 (95% CI, Key Points Question Does prevalence of strongyloidiasis interact with the relative risk (RR) of mortality in ivermectin trials for the treatment of COVID-19? Findings In this meta-analysis of 12 randomized clinical trials involving 3901 patients, favorable mortality results were limited to trials in high-prevalence regions, with no evidence that ivermectin had a mortality benefit in low-prevalence regions. Metaregression found an association between the regional prevalence of..
Source
Risk of bias by item a
Random sequence generation Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data Selective reporting Other bias Abd-Elsalam et al, 29 were not clear for all trials, precluding the inclusion of this variable in the regression model. Third, low event counts in the trials may make the results less reliable. Fourth, varying trial recruitment across urban and rural populations (where strongyloidiasis prevalences often differ) may diminish the reliability of strongyloidiasis trial prevalence estimates. Despite these limitations, the findings warrant concern for ivermectin trials for the treatment of COVID-19 that are not designed to address this interaction.
Conclusions In this meta-analysis of 12 trials comprising 3901 patients, strongyloidiasis prevalence was found to interact with the RR of mortality when ivermectin was used as a treatment for COVID-
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'URL': 'http://dx.doi.org/10.1001/jamanetworkopen.2022.3079',
'relation': {},
'ISSN': ['2574-3805'],
'issn-type': [{'value': '2574-3805', 'type': 'electronic'}],
'subject': ['General Medicine'],
'published': {'date-parts': [[2022, 3, 21]]}}
