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Povidone-Iodine for COVID-19: real-time meta analysis of 12 studies
Covid Analysis, January 18, 2022, DRAFT
https://c19pvpi.com/meta.html
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 52% 12 2,549 Improvement, Studies, Patients Relative Risk With exclusions 54% 11 2,478 Mortality 72% 2 872 Hospitalization 84% 2 685 Recovery 42% 2 86 Cases 45% 1 1,354 Viral clearance 71% 9 840 RCTs 56% 10 2,212 RCT mortality 88% 1 606 Peer-reviewed 52% 10 2,460 Prophylaxis 45% 1 1,354 Early 71% 7 878 Late 44% 4 317 Povidone-Iodine for COVID-19 c19pvpi.com Jan 18, 2022 Favors povidone-iodine Favors control
Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 6 studies from 4 different countries show statistically significant improvements in isolation (5 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 52% [36‑64%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment.
Results are robust — in exclusion sensitivity analysis 10 of 12 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ All studies 52% 12 2,549 Improvement, Studies, Patients Relative Risk With exclusions 54% 11 2,478 Mortality 72% 2 872 Hospitalization 84% 2 685 Recovery 42% 2 86 Cases 45% 1 1,354 Viral clearance 71% 9 840 RCTs 56% 10 2,212 RCT mortality 88% 1 606 Peer-reviewed 52% 10 2,460 Prophylaxis 45% 1 1,354 Early 71% 7 878 Late 44% 4 317 Povidone-Iodine for COVID-19 c19pvpi.com Jan 18, 2022 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 17% 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 mortality, morbidity, collateral damage, and endemic risk.
All data to reproduce this paper and sources are in the appendix.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 1271% [46‑84%]44% [19‑61%]45% [20‑62%] 2,549 125
With exclusions 1181% [63‑90%]44% [19‑61%]45% [20‑62%] 2,478 119
Peer-reviewed 1072% [39‑87%]44% [19‑61%]45% [20‑62%] 2,460 100
Randomized Controlled TrialsRCTs 1081% [63‑90%]31% [8‑49%]45% [20‑62%] 2,212 113
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%, p = 0.00011 Early treatment 71% 0.29 [0.16-0.54] 6/440 40/438 71% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Jamir 57% 0.43 [0.27-0.69] death 39/163 62/103 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.05, I​2 = 40.6%, p = 0.0019 Late treatment 44% 0.56 [0.39-0.81] 42/189 64/128 44% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 52% 0.48 [0.36-0.64] 90/1,364 168/1,185 52% improvement 12 povidone-iodine COVID-19 studies c19pvpi.com Jan 18, 2022 Tau​2 = 0.06, I​2 = 33.5%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment 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.
In Vitro Studies
Several in vitro studies show that PVP-I is effective for SARS-CoV-2 at clinically relevant concentrations [Anderson, Bidra, Frank, Hassandarvish, Pelletier, Tucker, Xu].
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 3 4 75.0% 44% improvement
RR 0.56 [0.39‑0.81]
p = 0.0019
Prophylaxis 1 1 100% 45% improvement
RR 0.55 [0.38‑0.80]
p = 0.002
All studies 11 12 91.7% 52% improvement
RR 0.48 [0.36‑0.64]
p < 0.0001
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%, p = 0.00011 Early treatment 71% 0.29 [0.16-0.54] 6/440 40/438 71% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Jamir 57% 0.43 [0.27-0.69] death 39/163 62/103 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.05, I​2 = 40.6%, p = 0.0019 Late treatment 44% 0.56 [0.39-0.81] 42/189 64/128 44% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 52% 0.48 [0.36-0.64] 90/1,364 168/1,185 52% improvement 12 povidone-iodine COVID-19 studies c19pvpi.com Jan 18, 2022 Tau​2 = 0.06, I​2 = 33.5%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment 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%, p = 0.004 Early treatment 88% 0.12 [0.03-0.50] 2/303 17/303 88% improvement Jamir 57% 0.43 [0.27-0.69] 39/163 62/103 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Late treatment 57% 0.43 [0.27-0.69] 39/163 62/103 57% improvement All studies 72% 0.28 [0.08-0.92] 41/466 79/406 72% improvement 2 povidone-iodine COVID-19 mortality results c19pvpi.com Jan 18, 2022 Tau​2 = 0.55, I​2 = 65.6%, p = 0.036 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%, p < 0.0001 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 Jan 18, 2022 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 1 OT: comparison with other treatment 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) 57% 0.43 [0.20-0.94] no recov. 6/27 18/35 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.034 Early treatment 57% 0.43 [0.20-0.94] 6/27 18/35 57% 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%, p = 0.78 Late treatment -27% 1.27 [0.26-6.28] 3/13 2/11 -27% improvement All studies 42% 0.58 [0.23-1.51] 9/40 20/46 42% improvement 2 povidone-iodine COVID-19 recovery results c19pvpi.com Jan 18, 2022 Tau​2 = 0.17, I​2 = 29.2%, p = 0.27 1 OT: comparison with other treatment 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) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement 1 povidone-iodine COVID-19 case result c19pvpi.com Jan 18, 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 1 OT: comparison with other treatment 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%, p = 0.0064 Early treatment 82% 0.18 [0.05-0.62] 12/403 235/396 82% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) 0% 1.00 [0.19-5.24] viral+ 2/7 2/7 OT​1 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.00, I​2 = 0.0%, p = 0.011 Late treatment 32% 0.68 [0.50-0.92] 2/20 2/21 32% improvement All studies 71% 0.29 [0.11-0.75] 14/423 237/417 71% improvement 9 povidone-iodine COVID-19 viral clearance results c19pvpi.com Jan 18, 2022 Tau​2 = 1.54, I​2 = 87.4%, p = 0.011 1 OT: comparison with other treatment 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%, p = 0.0013 Early treatment 72% 0.28 [0.13-0.61] 6/398 36/391 72% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Jamir 57% 0.43 [0.27-0.69] death 39/163 62/103 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.05, I​2 = 40.6%, p = 0.0019 Late treatment 44% 0.56 [0.39-0.81] 42/189 64/128 44% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 52% 0.48 [0.36-0.65] 90/1,322 164/1,138 52% improvement 10 povidone-iodine COVID-19 peer reviewed trials c19pvpi.com Jan 18, 2022 Tau​2 = 0.07, I​2 = 42.4%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment 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%, p < 0.0001 Early treatment 81% 0.19 [0.10-0.37] 6/409 40/398 81% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Jamir 57% 0.43 [0.27-0.69] death 39/163 62/103 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.05, I​2 = 40.6%, p = 0.0019 Late treatment 44% 0.56 [0.39-0.81] 42/189 64/128 44% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 54% 0.46 [0.34-0.62] 90/1,333 168/1,145 54% improvement 11 povidone-iodine COVID-19 studies after exclusions c19pvpi.com Jan 18, 2022 Tau​2 = 0.07, I​2 = 37.1%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment 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 shows the distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results. The median effect size for RCTs is 64% improvement, compared to 43% for other studies. Figure 12 and 13 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 2 summarizes the results.
Figure 11. The distribution of results for Randomized Controlled Trials and other studies, and a chronological history of results.
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%, p < 0.0001 Early treatment 81% 0.19 [0.10-0.37] 6/409 40/398 81% improvement Seneviratne (RCT) 33% 0.67 [0.50-0.91] viral load 4 (n) 2 (n) Improvement, RR [CI] Treatment Control Zarabanda (RCT) -27% 1.27 [0.26-6.28] no recov. 3/13 2/11 OT​1 Ferrer (RCT) 34% 0.66 [0.02-19.0] viral load 9 (n) 12 (n) Tau​2 = 0.00, I​2 = 0.0%, p = 0.013 Late treatment 31% 0.69 [0.51-0.92] 3/26 2/25 31% improvement Seet (CLUS. RCT) 45% 0.55 [0.38-0.80] symp. case 42/735 64/619 OT​1 Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 Prophylaxis 45% 0.55 [0.38-0.80] 42/735 64/619 45% improvement All studies 56% 0.44 [0.30-0.67] 51/1,170 106/1,042 56% improvement 10 povidone-iodine COVID-19 Randomized Controlled Trials c19pvpi.com Jan 18, 2022 Tau​2 = 0.11, I​2 = 37.1%, p = 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment Favors povidone-iodine Favors control
Figure 12. 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%, p = 0.004 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 Jan 18, 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.004 Favors povidone-iodine Favors control
Figure 13. 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 9 10 90.0% 56% improvement
RR 0.44 [0.30‑0.67]
p = 0.0001
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]. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective [Peacock, Willett].
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
Safety.
Safety analysis can be found in [Frank (B), Frank (C), Khan]. [Frank (B)] conclude that PVP-I can safely be used in the nose at concentrations up to 1.25% and in the mouth at concentrations up to 2.5% for up to 5 months.
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.
One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
The median effect size for retrospective studies is 57% improvement, compared to 63% for prospective studies, consistent with a negative publication bias. 100% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 45% of prospective studies, consistent with a bias toward publishing positive results. Figure 15 shows a scatter plot of results for prospective and retrospective studies.
Figure 15. Prospective vs. retrospective studies.
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 12 studies compare against other treatments, which may reduce the effect seen.
Conclusion
PVP-I is an effective treatment for COVID-19. Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 6 studies from 4 different countries show statistically significant improvements in isolation (5 for the most serious outcome). Meta analysis using the most serious outcome reported shows 52% [36‑64%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment is more effective than late treatment. Results are robust — in exclusion sensitivity analysis 10 of 12 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Study Notes
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Virological cure 79% Improvement Relative Risk Virological cure (b) 89% Virological cure (c) 53% Virological cure (d) 80% Virological cure (e) 64% Virological cure (f) 74% 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 [trialsjournal.biomedcentral.com].
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Hospitalization 65% Improvement Relative Risk Hospitalization/ER 79% Recovery 57% Transmission 37% Hospitalization (b) 94% c19pvpi.com/baxter.html Favors povidone-iodine Favors sodium bicar..
[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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 88% Improvement Relative Risk Hospitalization 84% Virological cure 96% 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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Inverse relative impro.. 89% Improvement Relative Risk 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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Decrease in log viral .. 34% Improvement Relative Risk c19pvpi.com/ferrer2.html Favors povidone-iodine Favors control
[Ferrer] Small very late (>50% 7+ days from symptom onset, 9 PVP-I patients) RCT testing mouthwashing with cetylpyridinium chloride, chlorhexidine, povidone-iodine, hydrogen peroxide, and distilled water, showing no significant differences. Over 30% of patients show >90% decrease in viral load @2 hrs with all 5. Authors note that a trend was observed for viral load decrease with PVP-I @2h for patients <6 days from onset (p=0.06, Wilcox test).
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Improvement in viral t.. 63% Improvement Relative Risk 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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Mortality 57% Improvement Relative Risk c19pvpi.com/jamirp.html Favors povidone-iodine Favors control
[Jamir] Retrospective 266 COVID-19 ICU patients in India, showing significantly lower mortality with PVP-I oral gargling and topical nasal use, and non-statistically significant higher mortality with ivermectin and lower mortality with remdesivir.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Virological cure 86% Improvement Relative Risk 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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Viral load 29% Improvement Relative Risk Viral load (b) 9% 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%.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Symptomatic case 45% Improvement Relative Risk Case 31% c19pvpi.com/seetp.html Favors povidone-iodine Favors vitamin C
[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.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Fold change 33% Improvement Relative Risk c19pvpi.com/seneviratne.html Favors povidone-iodine Favors control
[Seneviratne] Small mouthwash RCT with 4 PVP-I patients and 2 water patients concluding that PVP-I may have a sustained effect on reducing the salivary SARS-CoV-2 level in COVID-19 patients. ISRCTN95933274.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Recovery -27% Improvement Relative Risk Recovery (b) -50% Virological cure 0% c19pvpi.com/zarabanda.html Favors povidone-iodine Favors saline spray
[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.
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 (3.9.10) with scipy (1.7.3), pythonmeta (1.26), numpy (1.21.4), statsmodels (0.14.0), 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%), NNT 1.8, 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%), NNT 1.6, 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%), NNT 2.7, 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%), NNT 1.4, 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%), NNT 1.7, 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%), NNT 1.7, all treatment vs. all control.
[Baxter], 8/17/2021, Randomized Controlled Trial, USA, North America, preprint, 9 authors, average treatment delay 4.0 days, 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%), NNT 42, 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%), NNT 21, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of no recovery, 56.8% lower, RR 0.43, p = 0.03, treatment 6 of 27 (22.2%), control 18 of 35 (51.4%), NNT 3.4.
risk of transmission, 36.9% lower, RR 0.63, p = 0.51, treatment 4 of 37 (10.8%), control 6 of 35 (17.1%), NNT 16.
[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%), NNT 20.
risk of hospitalization, 84.4% lower, RR 0.16, p < 0.001, treatment 12 of 303 (4.0%), control 77 of 303 (25.4%), NNT 4.7.
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%), NNT 1.5, 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% better, 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%), NNT 1.7, 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% better, RR 0.71, p = 0.40, treatment 31, control 40, 3rd PCR (mid-recovery).
relative viral load, 9.1% better, 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.
[Ferrer], 12/22/2021, Randomized Controlled Trial, Spain, Europe, peer-reviewed, 19 authors. relative decrease in log viral load, 34.0% better, RR 0.66, p = 0.82, treatment 9, control 12, calculated from Supplementary Table 1.
[Jamir], 12/13/2021, retrospective, India, South Asia, peer-reviewed, 6 authors, study period June 2020 - October 2020. risk of death, 57.0% lower, RR 0.43, p < 0.001, treatment 39 of 163 (23.9%), control 62 of 103 (60.2%), NNT 2.8, adjusted per study, multivariable Cox regression.
[Seneviratne], 12/14/2020, Randomized Controlled Trial, Singapore, Asia, peer-reviewed, 12 authors. relative fold change, 32.9% better, RR 0.67, p < 0.01, treatment 4, control 2, PVP-I vs. water, 6 hours.
[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 symptomatic case, 44.7% lower, RR 0.55, p = 0.002, treatment 42 of 735 (5.7%), control 64 of 619 (10.3%), NNT 22.
risk of case, 31.1% lower, RR 0.69, p = 0.01, treatment 338 of 735 (46.0%), control 433 of 619 (70.0%), NNT 4.2, adjusted per study, odds ratio converted to relative risk, model 6.
Supplementary Data
References