Ivermectin, HCQ prophylaxis fall short of reducing COVID-19 infection, mortality

The efficacy of ivermectin in reducing the risk of SARS-CoV-2 infection remains highly uncertain due to serious risk of bias and imprecision of trials, according to the results of a living systematic review and network meta-analysis.

Another prophylactic drug for COVID-19, hydroxychloroquine (HCQ), provides very little to no effect on hospital admission and mortality, potentially increases adverse events, and does not appear to reduce the risk of SARS-CoV-2 infection.

“We are very uncertain if ivermectin with or without iota-carrageenan reduces the risk of SARS-CoV-2 infection and mortality owing to serious risk of bias and very serious imprecision, and the effect estimates are likely to change substantially with additional evidence from ongoing trials,” the researchers said.

“No other drug has been studied in large enough trials to make any inferences about the effects of prophylaxis on COVID-19,” they added.

In this study, the researchers accessed the World Health Organization COVID-19 databases, a comprehensive multilingual source of global COVID-19 literature through 25 March 2021, and six additional Chinese databases through 20 February 2021. Randomized trials of people at risk of COVID-19 who were assigned to receive prophylaxis or no prophylaxis (standard care of placebo) were identified. Pairs of reviewers independently screened potentially eligible studies.

After duplicate data abstraction, the researchers performed random effect Bayesian network meta-analysis. They then assessed eligible studies for risk of bias using a modification of the Cochrane risk of bias 2.0 tool and evaluated certainty of evidence using the grading of recommended assessment, development, and evaluation (GRADE) approach.

Nine randomized trials—six of HCQ (n=6,059), one of ivermectin with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo—were included in the first iteration of this living network meta-analysis. Two trials—one of ramipril and one of bromhexine hydrochloride—failed to meet the sample size requirements for network meta-analysis.

HCQ demonstrated trivial to no effect on hospital admission (risk difference [RD], 1 fewer per 1,000 participants, 95 percent credible interval [CI], 3 fewer to 4 more; high-certainty evidence) or mortality (RD, 1 fewer per 1,000 participants, 95 percent CI, 2 fewer to 3 more; high-certainty evidence). [BMJ 2021;373:n949]

HCQ did not appear to lower the risk of laboratory-confirmed SARS-CoV-2 infection (RD, 2 more per 1,000 participants, 95 percent CI, 18 fewer to 28 more; moderate-certainty evidence) and could even increase adverse effects leading to drug discontinuation (RD, 19 more per 1,000 participants, 95 percent CI, 1 fewer to 70 more; moderate-certainty evidence).

In addition, HCQ seemed to deliver trivial to no effect on suspected, probable, or laboratory-confirmed SARS-CoV-2 infection (RD, 15 fewer per 1,000 participants, 95 percent CI, 64 fewer to 41 more; low-certainty evidence).

On the other hand, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed COVID-19 (RD, 52 fewer per 1,000 participants, 95 percent CI, 58 fewer to 37 fewer), ivermectin alone on laboratory-confirmed infection (RD, 50 fewer per 1,000 participants, 95 percent CI, 59 fewer to 16 fewer) and suspected, probable, or laboratory-confirmed infection (RD, 159 fewer per 1,000 participants, 95 percent CI, 165 fewer to 144 fewer) were very uncertain because of serious risk of bias and very serious imprecision.

“These findings are consistent with those reported in a meta-analysis of HCQ prophylaxis compared with no prophylaxis, which did not find any statistical evidence of a benefit with HCQ prophylaxis for the patient important outcomes of SARS-CoV-2 infection, hospital admission, and mortality,” the researchers said. “The study concluded that HCQ is likely to increase the risk of adverse effects.” [PLoS One 2021;16:e0244778]

Data were also consistent with three meta-analyses and one network meta-analysis evaluating ivermectin as treatment for COVID-19. In contrast with other meta-analyses, certainty in the current study was rated very low owing to serious risk of bias and very serious imprecision. [J Pharm Pharm Sci 2020;23:462-9; medRxiv 2021:2021.01.26.21250420; BMJ 2020;370:m2980]