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Povidone-Iodine for COVID-19: real-time meta analysis of 13 studies
Covid Analysis, May 25, 2022, DRAFT
https://c19pvpi.com/meta.html
0 0.5 1 1.5+ All studies 53% 13 2,749 Improvement, Studies, Patients Relative Risk Mortality 72% 2 872 Hospitalization 84% 3 885 Recovery 25% 3 286 Cases 45% 1 1,354 Viral clearance 71% 10 1,040 RCTs 57% 11 2,412 RCT mortality 88% 1 606 Peer-reviewed 53% 11 2,660 Prophylaxis 45% 1 1,354 Early 72% 8 1,078 Late 44% 4 317 Povidone-Iodine for COVID-19 c19pvpi.com May 2022 Favorspovidone-iodine Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 7 studies from 7 independent teams in 5 different countries show statistically significant improvements in isolation (5 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 53% [37‑65%] 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 11 of 13 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.5 1 1.5+ All studies 53% 13 2,749 Improvement, Studies, Patients Relative Risk Mortality 72% 2 872 Hospitalization 84% 3 885 Recovery 25% 3 286 Cases 45% 1 1,354 Viral clearance 71% 10 1,040 RCTs 57% 11 2,412 RCT mortality 88% 1 606 Peer-reviewed 53% 11 2,660 Prophylaxis 45% 1 1,354 Early 72% 8 1,078 Late 44% 4 317 Povidone-Iodine for COVID-19 c19pvpi.com May 2022 Favorspovidone-iodine Favorscontrol after exclusions
While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 23% 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.
No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. 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.
Highlights
PVP-I reduces risk for COVID-19 with very high confidence for hospitalization, cases, viral clearance, and in pooled analysis, high confidence for mortality, and very low confidence for recovery.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 42 treatments.
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) Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.12, I​2 = 16.9%, p < 0.0001 Early treatment 72% 0.28 [0.16-0.51] 6/540 45/538 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 (ICU) 57% 0.43 [0.27-0.69] death 39/163 62/103 ICU patients 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 53% 0.47 [0.35-0.63] 90/1,464 173/1,285 53% improvement 13 povidone-iodine COVID-19 studies c19pvpi.com May 2022 Tau​2 = 0.06, I​2 = 33.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined 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.
Preclinical Research
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].
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, and 10 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.
0 0.5 1 1.5+ ALL STUDIES MORTALITY HOSPITALIZATION RECOVERY CASES VIRAL CLEARANCE RANDOMIZED CONTROLLED TRIALS RCT MORTALITY PEER-REVIEWED After Exclusions ALL STUDIES All Prophylaxis Early Late Povidone-Iodine for COVID-19 C19PVPI.COM MAY 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 8 8 100% 72% improvement
RR 0.28 [0.16‑0.51]
p < 0.0001
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 12 13 92.3% 53% improvement
RR 0.47 [0.35‑0.63]
p < 0.0001
Table 1. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 1372% [49‑84%]44% [19‑61%]45% [20‑62%] 2,749 133
With exclusions 1281% [65‑90%]44% [19‑61%]45% [20‑62%] 2,678 127
Peer-reviewed 1173% [45‑87%]44% [19‑61%]45% [20‑62%] 2,660 108
Randomized Controlled TrialsRCTs 1181% [65‑90%]31% [8‑49%]45% [20‑62%] 2,412 121
Table 2. Results by treatment stage for all studies and with different exclusions.
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) Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.12, I​2 = 16.9%, p < 0.0001 Early treatment 72% 0.28 [0.16-0.51] 6/540 45/538 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 (ICU) 57% 0.43 [0.27-0.69] death 39/163 62/103 ICU patients 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 53% 0.47 [0.35-0.63] 90/1,464 173/1,285 53% improvement 13 povidone-iodine COVID-19 studies c19pvpi.com May 2022 Tau​2 = 0.06, I​2 = 33.1%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 4. 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 (ICU) 57% 0.43 [0.27-0.69] 39/163 62/103 ICU patients 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 May 2022 Tau​2 = 0.55, I​2 = 65.6%, p = 0.036 Favors povidone-iodine Favors control
Figure 5. 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 Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Early treatment 84% 0.16 [0.09-0.28] 12/440 83/445 84% improvement All studies 84% 0.16 [0.09-0.28] 12/440 83/445 84% improvement 3 povidone-iodine COVID-19 hospitalization results c19pvpi.com May 2022 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 6. 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 Elsersy (DB RCT) 15% 0.85 [0.76-0.96] recov. time 100 (n) 100 (n) CT​2 Tau​2 = 0.15, I​2 = 65.5%, p = 0.23 Early treatment 32% 0.68 [0.36-1.28] 6/127 18/135 32% 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 25% 0.75 [0.47-1.18] 9/140 20/146 25% improvement 3 povidone-iodine COVID-19 recovery results c19pvpi.com May 2022 Tau​2 = 0.07, I​2 = 36.5%, p = 0.22 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 7. 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 May 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.002 1 OT: comparison with other treatment Favors povidone-iodine Favors control
Figure 8. 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) Elsersy (DB RCT) 68% 0.32 [0.22-0.49] viral+ 21/100 65/100 CT​2 Tau​2 = 1.08, I​2 = 84.2%, p = 0.00067 Early treatment 80% 0.20 [0.08-0.51] 33/503 300/496 80% 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 [0.14-0.60] 35/523 302/517 71% improvement 10 povidone-iodine COVID-19 viral clearance results c19pvpi.com May 2022 Tau​2 = 0.92, I​2 = 86.1%, p = 0.00099 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 9. 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) Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.29, I​2 = 38.2%, p = 0.00038 Early treatment 73% 0.27 [0.13-0.55] 6/498 41/491 73% 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 (ICU) 57% 0.43 [0.27-0.69] death 39/163 62/103 ICU patients 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 53% 0.47 [0.35-0.64] 90/1,422 169/1,238 53% improvement 11 povidone-iodine COVID-19 peer reviewed trials c19pvpi.com May 2022 Tau​2 = 0.08, I​2 = 41.3%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 10. Random effects meta-analysis for peer reviewed studies. [Zeraatkar] analyze 356 COVID-19 trials, finding no significant evidence that peer-reviewed studies are more trustworthy. They also show extremely slow review times during a pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. 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 11 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 Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Early treatment 81% 0.19 [0.10-0.35] 6/509 45/498 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 (ICU) 57% 0.43 [0.27-0.69] death 39/163 62/103 ICU patients 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 55% 0.45 [0.33-0.61] 90/1,433 173/1,245 55% improvement 12 povidone-iodine COVID-19 studies after exclusions c19pvpi.com May 2022 Tau​2 = 0.07, I​2 = 36.3%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 11. 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 12 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 65% improvement, compared to 43% for other studies. Figure 13 and 14 show forest plots for a random effects meta-analysis of all Randomized Controlled Trials and RCT mortality results. Table 3 summarizes the results.
Figure 12. 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 Elsersy (DB RCT) 91% 0.09 [0.01-1.62] hosp. 0/100 5/100 CT​2 Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001 Early treatment 81% 0.19 [0.10-0.35] 6/509 45/498 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 57% 0.43 [0.28-0.64] 51/1,270 111/1,142 57% improvement 11 povidone-iodine COVID-19 Randomized Controlled Trials c19pvpi.com May 2022 Tau​2 = 0.12, I​2 = 36.7%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment2 CT: study uses combined treatment Favors povidone-iodine Favors control
Figure 13. 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 May 2022 Tau​2 = 0.00, I​2 = 0.0%, p = 0.004 Favors povidone-iodine Favors control
Figure 14. Random effects meta-analysis for RCT mortality results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Randomized Controlled Trials 10 11 90.9% 57% improvement
RR 0.43 [0.28‑0.64]
p < 0.0001
RCT mortality results 1 1 100% 88% improvement
RR 0.12 [0.03‑0.50]
p = 0.004
Table 3. 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]. Figure 15 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 42 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
Figure 15. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 42 treatments. Early treatment is critical.
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.
100% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 50% of prospective studies, consistent with a bias toward publishing positive results. The median effect size for retrospective studies is 57% improvement, compared to 64% for prospective studies, suggesting a potential bias towards publishing results showing lower efficacy. Figure 16 shows a scatter plot of results for prospective and retrospective studies.
Figure 16. Prospective vs. retrospective studies.
Funnel plot analysis.
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 17 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 [Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley]. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Figure 17. Example funnel plot analysis for simulated perfect trials.
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 13 studies compare against other treatments, which may reduce the effect seen. 1 of 13 studies combine treatments. The results of povidone-iodine alone may differ. 1 of 11 RCTs use combined treatment.
Conclusion
PVP-I is an effective treatment for COVID-19. Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 7 studies from 7 independent teams in 5 different countries show statistically significant improvements in isolation (5 for the most serious outcome). Meta analysis using the most serious outcome reported shows 53% [37‑65%] 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 11 of 13 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Study Notes
0 0.5 1 1.5 2+ Viral clearance 79% Improvement Relative Risk Viral clearance (b) 89% Viral clearance (c) 53% Viral clearance (d) 80% Viral clearance (e) 64% Viral clearance (f) 74% c19pvpi.com Arefin et al. NCT04549376 Povidone-Iod.. RCT EARLY 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 0.5 1 1.5 2+ Hospitalization 65% Improvement Relative Risk Hospitalization/ER 79% Recovery 57% Transmission 37% Hospitalization (b) 94% c19pvpi.com Baxter et al. NCT04559035 Povidone-Iod.. RCT EARLY 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 0.5 1 1.5 2+ Mortality 88% Improvement Relative Risk Hospitalization 84% Viral clearance 96% c19pvpi.com Choudhury et al. Povidone-Iod.. for COVID-19 RCT EARLY 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 0.5 1 1.5 2+ Hospitalization 91% Improvement Relative Risk Recovery time 15% Recovery time, smell 49% Recovery time, taste 48% Viral clearance, D7 68% Viral clearance, D10 90% Viral clearance, D4 29% Transmission 92% Transmission (b) 94% c19pvpi.com Elsersy et al. PACTR202101875903773 Povidone-Iod.. RCT EARLY Favors povidone-iodine Favors control
[Elsersy] RCT with 200 patients and 421 contacts in Egypt, with 100 patients and their contacts treated with nasal and oropharyngeal sprays containing povidone-iodine and glycyrrhizic acid, showing significantly faster viral clearance and recovery, and significantly lower transmission.

SOC included vitamin C and zinc. The spray active ingredients included a compound of glycyrrhizic acid in the form of ammonium glycyrrhizate 2.5 mg/ml plus PVI 0.5% for oropharyngeal and dipotassium glycyrrhizinate 2.5 mg/ml plus PVI 0.5% for nasal spray. Patients were advised to concomitantly use oropharyngeal and nasal sprays 6 times per day. They were instructed to abstain from food, drink, and smoke for 20min, particularly after oropharyngeal spray. The oropharyngeal spray bottle contains an atomizer that ends with a long arm applicator to insert inside the mouth cavity and can be directed up, down, right, or left to cover the entire pharyngeal area.
0 0.5 1 1.5 2+ Inverse relative improv.. 89% Improvement Relative Risk c19pvpi.com Elzein et al. Povidone-Iod.. for COVID-19 RCT EARLY 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 0.5 1 1.5 2+ Decrease in log viral l.. 34% Improvement Relative Risk c19pvpi.com Ferrer et al. Povidone-Iod.. for COVID-19 RCT LATE 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 0.5 1 1.5 2+ Improvement in viral ti.. 63% Improvement Relative Risk c19pvpi.com Guenezan et al. Povidone-Iod.. for COVID-19 RCT EARLY 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 0.5 1 1.5 2+ Mortality 57% Improvement Relative Risk c19pvpi.com Jamir et al. Povidone-Iod.. for COVID-19 ICU 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.
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