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Povidone-Iodine for COVID-19: real-time meta analysis of 9 studies
DRAFT
PLEASE SUBMIT FEEDBACK
Covid Analysis, December 5, 2021
https://c19pvpi.com/meta.html
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 60% 9 2,256 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 66% 8 2,185 Mortality 88% 1 606 Hospitalization 84% 2 685 Recovery 41% 2 82 Cases 31% 1 1,354 Viral clearance 77% 7 813 RCTs 66% 8 2,185 Peer-reviewed 60% 7 2,167 Prophylaxis 45% 1 1,354 Early 71% 7 878 Late -27% 1 24 Povidone-Iodine for COVID-19 c19pvpi.com Dec 5, 2021 Favors povidone-iodine Favors control
Meta analysis using the most serious outcome reported shows 60% [35‑75%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment shows efficacy while late treatment does not, consistent with expectations for an effective topical nasopharyngeal/oropharyngeal treatment.
Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 4 studies show statistically significant improvements in isolation (3 for the most serious outcome).
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 60% 9 2,256 Improvement, Studies, Patients Relative Risk, 95% CI With exclusions 66% 8 2,185 Mortality 88% 1 606 Hospitalization 84% 2 685 Recovery 41% 2 82 Cases 31% 1 1,354 Viral clearance 77% 7 813 RCTs 66% 8 2,185 Peer-reviewed 60% 7 2,167 Prophylaxis 45% 1 1,354 Early 71% 7 878 Late -27% 1 24 Povidone-Iodine for COVID-19 c19pvpi.com Dec 5, 2021 Favors povidone-iodine Favors control
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 22% of povidone-iodine studies show zero events in the treatment arm.
Multiple treatments are typically used in combination, and other treatments may be more effective.
Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.
All data to reproduce this paper and sources are in the appendix.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 971% [46‑84%]-27% [-528‑74%]45% [20‑62%] 2,256 88
With exclusions 881% [63‑90%]-27% [-528‑74%]45% [20‑62%] 2,185 82
Peer-reviewed 772% [39‑87%]-27% [-528‑74%]45% [20‑62%] 2,167 63
Randomized Controlled TrialsRCTs 881% [63‑90%]-27% [-528‑74%]45% [20‑62%] 2,185 82
Percentage improvement with povidone-iodine treatment
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Baxter (RCT) 65% 0.35 [0.01-8.27] hosp. 0/37 1/42 OT​1 Pablo-Marcos 29% 0.71 [0.32-1.56] viral load 31 (n) 40 (n) Tau​2 = 0.15; I​2 = 22.0% Early treatment 71% 0.29 [0.16-0.54] 6/440 40/438 71% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] severe case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 60% 0.40 [0.25-0.65] 51/1,188 106/1,068 60% improvement 9 povidone-iodine COVID-19 studies c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.16; I​2 = 33.4%; Z = 3.71 Effect extraction pre-specified, see appendix Favors povidone-iodine Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of povidone-iodine for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Results
Figure 3, 4, 5, 6, 7, 8, and 9 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, hospitalization, recovery, cases, viral clearance, and peer reviewed studies. Table 1 summarizes the results by treatment stage.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 7 7 100% 71% improvement
RR 0.29 [0.16‑0.54]
p = 0.00011
Late treatment 0 1 0.0% -27% improvement
RR 1.27 [0.26‑6.28]
p = 0.78
Prophylaxis 1 1 100% 45% improvement
RR 0.55 [0.38‑0.80]
p = 0.002
All studies 8 9 88.9% 60% improvement
RR 0.40 [0.25‑0.65]
p = 0.00023
Table 1. Results by treatment stage.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Baxter (RCT) 65% 0.35 [0.01-8.27] hosp. 0/37 1/42 OT​1 Pablo-Marcos 29% 0.71 [0.32-1.56] viral load 31 (n) 40 (n) Tau​2 = 0.15; I​2 = 22.0% Early treatment 71% 0.29 [0.16-0.54] 6/440 40/438 71% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] severe case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 60% 0.40 [0.25-0.65] 51/1,188 106/1,068 60% improvement 9 povidone-iodine COVID-19 studies c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.16; I​2 = 33.4%; Z = 3.71 Effect extraction pre-specified, see appendix Favors povidone-iodine Favors control
Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Choudhury (RCT) 88% 0.12 [0.03-0.50] 2/303 17/303 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 88% 0.12 [0.03-0.50] 2/303 17/303 88% improvement All studies 88% 0.12 [0.03-0.50] 2/303 17/303 88% improvement 1 povidone-iodine COVID-19 mortality result c19pvpi.com Dec 5, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 2.88 Favors povidone-iodine Favors control
Figure 4. Random effects meta-analysis for mortality results.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Choudhury (RCT) 84% 0.16 [0.09-0.28] hosp. 12/303 77/303 Improvement, RR [CI] Treatment Control Baxter (RCT) 65% 0.35 [0.01-8.27] hosp. 0/37 1/42 OT​1 Tau​2 = 0.00; I​2 = 0.0% Early treatment 84% 0.16 [0.09-0.29] 12/340 78/345 84% improvement All studies 84% 0.16 [0.09-0.29] 12/340 78/345 84% improvement 2 povidone-iodine COVID-19 hospitalization results c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 6.22 Favors povidone-iodine Favors control
Figure 5. Random effects meta-analysis for hospitalization.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Baxter (RCT) 56% 0.44 [0.20-0.94] no recov. 6/25 18/33 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 56% 0.44 [0.20-0.94] 6/25 18/33 56% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement All studies 41% 0.59 [0.23-1.48] 9/38 20/44 41% improvement 2 povidone-iodine COVID-19 recovery results c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.15; I​2 = 27.2%; Z = 1.13 Favors povidone-iodine Favors control
Figure 6. Random effects meta-analysis for recovery.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Seet (CLUS. RCT) 31% 0.69 [0.37-1.01] 338/735 433/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 31% 0.69 [0.37-1.01] 338/735 433/619 31% improvement All studies 31% 0.69 [0.63-0.76] 338/735 433/619 31% improvement 1 povidone-iodine COVID-19 case result c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.00; I​2 = 0.0%; Z = 7.77 Favors povidone-iodine Favors control
Figure 7. Random effects meta-analysis for cases.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 96% 0.04 [0.02-0.07] viral+ 8/303 213/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Pablo-Marcos 29% 0.71 [0.32-1.56] viral load 31 (n) 40 (n) Tau​2 = 1.75; I​2 = 84.4% Early treatment 82% 0.18 [0.05-0.62] 12/403 235/396 82% improvement Zarabanda (RCT) 0% 1.00 [0.19-5.24] viral+ 2/7 2/7 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment 0% 1.00 [0.19-5.24] 2/7 2/7 0% improvement All studies 77% 0.23 [0.07-0.72] 14/410 237/403 77% improvement 7 povidone-iodine COVID-19 viral clearance results c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 1.79; I​2 = 83.6%; Z = 2.52 Favors povidone-iodine Favors control
Figure 8. Random effects meta-analysis for viral clearance.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Improvement, RR [CI] Treatment Control Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Pablo-Marcos 29% 0.71 [0.32-1.56] viral load 31 (n) 40 (n) Tau​2 = 0.33; I​2 = 45.5% Early treatment 72% 0.28 [0.13-0.61] 6/398 36/391 72% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] severe case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 60% 0.40 [0.23-0.69] 51/1,146 102/1,021 60% improvement 7 povidone-iodine COVID-19 peer reviewed trials c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.21; I​2 = 46.6%; Z = 3.28 Effect extraction pre-specified, see appendix Favors povidone-iodine Favors control
Figure 9. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Exclusions
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be easily influenced by potential bias. However, they can also be very high quality.
The studies excluded are as below. Figure 10 shows a forest plot for random effects meta-analysis of all studies after exclusions.
[Pablo-Marcos], unadjusted results with no group details.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Baxter (RCT) 65% 0.35 [0.01-8.27] hosp. 0/37 1/42 OT​1 Tau​2 = 0.00; I​2 = 0.0% Early treatment 81% 0.19 [0.10-0.37] 6/409 40/398 81% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] severe case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 66% 0.34 [0.19-0.61] 51/1,157 106/1,028 66% improvement 8 povidone-iodine COVID-19 studies after exclusions c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.22; I​2 = 35.5%; Z = 3.64 Effect extraction pre-specified, see appendix Favors povidone-iodine Favors control
Figure 10. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Randomized Controlled Trials (RCTs)
Figure 11 and 12 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 2 summarizes the results.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. This is illustrated with the extreme example of an RCT showing no significant differences for use of a parachute when jumping from a plane [Yeh]. RCTs for povidone-iodine are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments. Note that this bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT trials can also provide reliable results. [Concato] find that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. [Anglemyer] summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. [Lee] shows that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see [Deaton, Nichol].
Figure 13. Randomized Controlled Trials. The distribution of results for RCTs and other studies.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mohamed (RCT) 86% 0.14 [0.01-2.21] viral+ 0/5 3/5 Improvement, RR [CI] Treatment Control Choudhury (RCT) 88% 0.12 [0.03-0.50] death 2/303 17/303 Guenezan (RCT) 63% 0.37 [0.06-1.63] viral load 12 (n) 12 (n) Elzein (DB RCT) 89% 0.11 [0.01-1.00] viral load 25 (n) 9 (n) Arefin (RCT) 79% 0.21 [0.08-0.54] viral+ 4/27 19/27 Baxter (RCT) 65% 0.35 [0.01-8.27] hosp. 0/37 1/42 OT​1 Tau​2 = 0.00; I​2 = 0.0% Early treatment 81% 0.19 [0.10-0.37] 6/409 40/398 81% improvement Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] severe case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 66% 0.34 [0.19-0.61] 51/1,157 106/1,028 66% improvement 8 povidone-iodine COVID-19 Randomized Controlled Trials c19pvpi.com Dec 5, 2021 1 OT: comparison with other treatmentTau​2 = 0.22; I​2 = 35.5%; Z = 3.64 Effect extraction pre-specified, see appendix Favors povidone-iodine Favors control
Figure 11. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Choudhury (RCT) 88% 0.12 [0.03-0.50] 2/303 17/303 Improvement, RR [CI] Treatment Control Tau​2 = 0.00; I​2 = 0.0% Early treatment 88% 0.12 [0.03-0.50] 2/303 17/303 88% improvement All studies 88% 0.12 [0.03-0.50] 2/303 17/303 88% improvement 1 povidone-iodine COVID-19 RCT mortality result c19pvpi.com Dec 5, 2021 Tau​2 = 0.00; I​2 = 0.0%; Z = 2.88 Favors povidone-iodine Favors control
Figure 12. Random effects meta-analysis for RCT mortality results. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 7 8 87.5% 66% improvement
RR 0.34 [0.19‑0.61]
p = 0.0003
RCT mortality results 1 1 100% 88% improvement
RR 0.12 [0.03‑0.50]
p = 0.004
Table 2. Randomized Controlled Trial results.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
Treatment delay.
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours [McLean, Treanor]. Other medications might be beneficial for late stage complications, while early use may not be effective or may even be harmful. Figure 14 shows an example where efficacy declines as a function of treatment delay.
Figure 14. Effectiveness may depend critically on treatment delay.
Patient demographics.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in [López-Medina]).
Effect measured.
Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.
Variants.
There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics [Faria, Karita, Nonaka, Zavascki].
Regimen.
Effectiveness may depend strongly on the dosage and treatment regimen.
Treatments.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though the treatment may be very effective when used earlier.
In general, by combining heterogeneous studies, as all meta analyses do, we run the risk of obscuring an effect by including studies where the treatment is less effective, not effective, or harmful.
When including studies where a treatment is less effective we expect the estimated effect size to be lower than that for the optimal case. We do not a priori expect that pooling all studies will create a positive result for an effective treatment. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations.
Discussion
Publication bias.
Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results [Boulware, Meeus, Meneguesso]. For povidone-iodine, there is currently not enough data to evaluate publication bias with high confidence.
Conflicts of interest.
Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. PVP-I for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 povidone-iodine trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all povidone-iodine trials represent the optimal conditions for efficacy.
Early/late vs. mild/moderate/severe.
Some analyses classify treatment based on early/late administration (as we do here), while others distinguish between mild/moderate/severe cases. We note that viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Notes.
3 of the 9 studies compare against other treatments, which may reduce the effect seen.
Conclusion
PVP-I is an effective treatment for COVID-19. Meta analysis using the most serious outcome reported shows 60% [35‑75%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment shows efficacy while late treatment does not, consistent with expectations for an effective topical nasopharyngeal/oropharyngeal treatment. Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 4 studies show statistically significant improvements in isolation (3 for the most serious outcome).
Study Notes
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Virological cure 79% Imp. Relative Risk, 95% CI Virological cure (b) 89% Virological cure (c) 53% Virological cure (d) 80% Virological cure (e) 64% Virological cure (f) 74% Arefin: Virucidal effect of povidone iodine on COVID-19 in the n.. c19pvpi.com/arefin.html Favors povidone-iodine Favors control
[Arefin] RCT with 189 patients showing significantly greater viral clearance with a single application of PVP-I. Authors recommend using PVP-I prophylactically in the nasopharynx and oropharynx. NCT04549376 https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04963-2. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Hospitalization 65% Imp. Relative Risk, 95% CI Hospitalization/ER 79% Recovery 56% Baxter: Rapid initiation of nasal saline irrigation: hospitaliza.. c19pvpi.com/baxter.html Favors povidone-iodine Favors control
[Baxter] Small RCT 79 PCR+ patients 55+ comparing pressure-based nasal irrigation with povidone-iodine and sodium bicarbonate, showing improved recovery with povidone-iodine, and 0/37 COVID-19 related hospitalizations for povidone-iodine compared to 1/42 for sodium bicarbonate. NCT04559035. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 88% Imp. Relative Risk, 95% CI Hospitalization 84% Virological cure 96% Choudhury: Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and.. c19pvpi.com/choudhury.html Favors povidone-iodine Favors control
[Choudhury] RCT 606 patients in Bangladesh for povidone iodine mouthwash/gargle, nasal drops and eye drops showing significantly lower death, hospitalization, and PCR+ at day 7. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Inverse relative impro.. 89% Imp. Relative Risk, 95% CI Elzein: In vivo evaluation of the virucidal efficacy of chlorhex.. c19pvpi.com/elzein.html Favors povidone-iodine Favors control
[Elzein] Small RCT comparing mouthwashing with PVP-I, Chlorhexidine, and water, showing significant efficacy for both PVP-I and Chlorhexidine, with PVP-I increasing Ct by a mean of 4.45 (p < 0.0001) and Chlorhexidine by a mean of 5.69 (p < 0.0001), compared to no significant difference for water. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Improvement in viral t.. 63% Imp. Relative Risk, 95% CI Guenezan: Povidone Iodine Mouthwash, Gargle, and Nasal Spray to Re.. c19pvpi.com/guenezan.html Favors povidone-iodine Favors control
[Guenezan] RCT of PCR+ patients with Ct<=20 with 12 treatment and 12 control patients, concluding that nasopharyngeal decolonization may reduce the carriage of infectious SARS-CoV-2 in adults with mild to moderate COVID-19. All patients but 1 had negative viral titer by day 3 (group not specified). There was no significant difference in viral RNA quantification over time. The mean relative difference in viral titers between baseline and day 1 was 75% [43%-95%] in the intervention group and 32% [10%-65%] in the control group. Thyroid dysfunction occurred in 42% of treated patients, with spontaneous resolution after the end of treatment. Patients in the treatment group were younger. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Virological cure 86% Imp. Relative Risk, 95% CI Mohamed: Early viral clearance among COVID-19 patients when gargl.. c19pvpi.com/mohamed.html Favors povidone-iodine Favors control
[Mohamed] Tiny RCT with 5 PVP-I patients, gargling 30 seconds, 3x per day, and 5 control patients (essential oils and tap water were also tested), showing improved viral clearance with PVP-I. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Viral load 29% Imp. Relative Risk, 95% CI Viral load (b) 9% Pablo-Marcos: Utilidad de los enjuagues con povidona yodada y peroxido.. c19pvpi.com/pablomarcos.html Favors povidone-iodine Favors control
[Pablo-Marcos] Small prospective study with 31 patients gargling povidone-iodine, 17 hydrogen peroxide, and 40 control patients, showing lower viral load mid-recovery with povidone-iodine, without reaching statistical significance. Oropharyngeal only, and only every 8 hours for two days. Results may be better with the addition of nasopharyngeal use, more frequent use, and without the two day limit. Authors are not familiar with the literature, having found only one of the 7 previous trials for PVP-I and COVID-19. Non-randomized study with no adjustments or group details. Some results in Figure 1 appear to be switched compared to the text and the labels in the figure. The viral clearance figures do not match the group sizes - for example authors report 62% PCR- for PVP-I at the 3rd test, however there is no number of 31 patients that rounds to 62%. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Severe case 45% Imp. Relative Risk, 95% CI Case 31% Seet: Positive impact of oral hydroxychloroquine and povidone-.. c19pvpi.com/seetp.html Favors povidone-iodine Favors control
[Seet] Prophylaxis RCT in Singapore with 3,037 low risk patients, showing lower serious cases, lower symptomatic cases, and lower confirmed cases of COVID-19 with all treatments (ivermectin, HCQ, PVP-I, and Zinc + vitamin C) compared to vitamin C. Meta-analysis of vitamin C in 6 previous trials shows a benefit of 16%, so the actual benefit of ivermectin, HCQ, and PVP-I may be higher. Cluster RCT with 40 clusters. There were no hospitalizations and no deaths. NCT04446104. Submit Corrections or Updates.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Recovery -27% Imp. Relative Risk, 95% CI Recovery (b) -50% Virological cure 0% Zarabanda: The Effect of Povidone-Iodine Nasal Spray on COVID-19 Na.. c19pvpi.com/zarabanda.html Favors povidone-iodine Favors control
[Zarabanda] Very late treatment (7 days from onset) RCT comparing 11 & 13 PVP-I (0.5% and 2%), and 11 saline spray patients in the USA, showing no significant differences. There was no control group (saline is likely not a placebo, showing efficacy in other trials). There are large unadjusted differences between groups, e.g. 7.1 days from onset for PVP-I versus 4.8 for saline. Baseline Ct was higher for PVP-I, providing less room for improvement. Authors note that they cannot determine if earlier use is more beneficial. Submit Corrections or Updates.
We performed ongoing searches of PubMed, medRxiv, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Collabovid, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19pvpi.com. Search terms were povidone-iodine, filtered for papers containing the terms COVID-19, SARS-CoV-2, or coronavirus. Automated searches are performed every few hours with notification of new matches. All studies regarding the use of povidone-iodine for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days are used. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms were not used (the next most serious outcome is used — no studies were excluded). For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcome is considered more important than PCR testing status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available (after most or all patients have recovered there is no room for an effective treatment to do better). If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we computed the relative risk when possible, or converted to a relative risk according to [Zhang]. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported including propensity score matching (PSM), the PSM results are used. When needed, conversion between reported p-values and confidence intervals followed [Altman, Altman (B)], and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 [Sweeting]. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.9.9) with scipy (1.7.3), pythonmeta (1.26), numpy (1.21.4), statsmodels (0.13.1), and plotly (5.4.0).
Forest plots are computed using PythonMeta [Deng] with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment, and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective [McLean, Treanor].
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19pvpi.com/meta.html.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
[Arefin], 5/18/2021, Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, 9 authors. risk of no virological cure, 78.9% lower, RR 0.21, p = 0.02, treatment 4 of 27 (14.8%), control 19 of 27 (70.4%), 0.6% nasal irrigation.
risk of no virological cure, 89.5% lower, RR 0.11, p < 0.001, treatment 2 of 27 (7.4%), control 19 of 27 (70.4%), 0.5% nasal irrigation.
risk of no virological cure, 52.6% lower, RR 0.47, p = 0.006, treatment 9 of 27 (33.3%), control 19 of 27 (70.4%), 0.4% nasal irrigation.
risk of no virological cure, 80.0% lower, RR 0.20, p < 0.001, treatment 5 of 27 (18.5%), control 25 of 27 (92.6%), 0.6% nasal spray.
risk of no virological cure, 64.0% lower, RR 0.36, p < 0.001, treatment 9 of 27 (33.3%), control 25 of 27 (92.6%), 0.5% nasal spray.
risk of no virological cure, 73.6% lower, RR 0.26, p < 0.001, treatment 29 of 135 (21.5%), control 44 of 54 (81.5%), all treatment vs. all control.
[Baxter], 8/17/2021, Randomized Controlled Trial, USA, North America, preprint, 9 authors, this trial compares with another treatment - results may be better when compared to placebo. risk of hospitalization, 65.3% lower, RR 0.35, p = 1.00, treatment 0 of 37 (0.0%), control 1 of 42 (2.4%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of hospitalization/ER, 79.0% lower, RR 0.21, p = 0.50, treatment 0 of 37 (0.0%), control 2 of 42 (4.8%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of no recovery, 56.0% lower, RR 0.44, p = 0.03, treatment 6 of 25 (24.0%), control 18 of 33 (54.5%).
[Choudhury], 12/3/2020, Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, 6 authors. risk of death, 88.2% lower, RR 0.12, p < 0.001, treatment 2 of 303 (0.7%), control 17 of 303 (5.6%).
risk of hospitalization, 84.4% lower, RR 0.16, p < 0.001, treatment 12 of 303 (4.0%), control 77 of 303 (25.4%).
risk of no virological cure, 96.2% lower, RR 0.04, p < 0.001, treatment 8 of 303 (2.6%), control 213 of 303 (70.3%), day 7.
[Elzein], 3/17/2021, Double Blind Randomized Controlled Trial, Lebanon, Middle East, peer-reviewed, 7 authors. inverse relative improvement in Ct value, 88.8% lower, RR 0.11, p < 0.05, treatment 25, control 9.
[Guenezan], 2/4/2021, Randomized Controlled Trial, France, Europe, peer-reviewed, 7 authors. relative improvement in viral titer reduction between baseline and day 1, 63.2% lower, RR 0.37, p = 0.25, treatment 12, control 12.
[Mohamed], 9/9/2020, Randomized Controlled Trial, Malaysia, Europe, preprint, 16 authors. risk of no virological cure, 85.7% lower, RR 0.14, p = 0.17, treatment 0 of 5 (0.0%), control 3 of 5 (60.0%), relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 12.
[Pablo-Marcos], 10/25/2021, prospective, Spain, Europe, peer-reviewed, 6 authors, excluded in exclusion analyses: unadjusted results with no group details. relative viral load, 29.2% lower, RR 0.71, p = 0.40, treatment 31, control 40, 3rd PCR (mid-recovery).
relative viral load, 9.1% lower, RR 0.91, p = 0.91, treatment 31, control 40, 4th PCR (most patients recovered).
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
[Zarabanda], 11/1/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 13 authors, this trial compares with another treatment - results may be better when compared to placebo. risk of no recovery, 26.9% higher, RR 1.27, p = 1.00, treatment 3 of 13 (23.1%), control 2 of 11 (18.2%), 2%.
risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 11 (27.3%), control 2 of 11 (18.2%), 0.5%.
risk of no virological cure, no change, RR 1.00, p = 1.00, treatment 2 of 7 (28.6%), control 2 of 7 (28.6%), day 5, minus strand PCR.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
[Seet], 4/14/2021, Cluster Randomized Controlled Trial, Singapore, Asia, peer-reviewed, 15 authors, this trial compares with another treatment - results may be better when compared to placebo. risk of severe case, 44.7% lower, RR 0.55, p = 0.05, treatment 42 of 735 (5.7%), control 64 of 619 (10.3%).
risk of case, 31.1% lower, RR 0.69, p = 0.01, treatment 338 of 735 (46.0%), control 433 of 619 (70.0%), adjusted per study, odds ratio converted to relative risk, model 6.
References
Please send us corrections, updates, or comments. Vaccines and treatments are both extremely valuable and complementary. All practical, effective, and safe means should be used. Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. Denying the efficacy of any method increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. Treatment protocols for physicians are available from the FLCCC.
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