Covid Analysis, May 25, 2022, DRAFT
https://c19pvpi.com/meta.html
•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.
•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.
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.
Figure 3. Overview of results.
| Treatment time | Number of studies reporting positive effects | Total number of studies | Percentage 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 | Patients | Authors | |
| All studies | 13 | 72% [49‑84%] | 44% [19‑61%] | 45% [20‑62%] | 2,749 | 133 |
| With exclusions | 12 | 81% [65‑90%] | 44% [19‑61%] | 45% [20‑62%] | 2,678 | 127 |
| Peer-reviewed | 11 | 73% [45‑87%] | 44% [19‑61%] | 45% [20‑62%] | 2,660 | 108 |
| Randomized Controlled TrialsRCTs | 11 | 81% [65‑90%] | 31% [8‑49%] | 45% [20‑62%] | 2,412 | 121 |
Table 2. Results by treatment stage for all studies and with different exclusions.
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.
Figure 5. Random effects meta-analysis for mortality results.
Figure 6. Random effects meta-analysis for hospitalization.
Figure 7. Random effects meta-analysis for recovery.
Figure 8. Random effects meta-analysis for cases.
Figure 9. Random effects meta-analysis for viral clearance.
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.
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.
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.
Figure 14. Random effects meta-analysis for RCT mortality results.
| Treatment time | Number of studies reporting positive effects | Total number of studies | Percentage 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
[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].
[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.
[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.
[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.
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.
[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.
[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).
[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.
[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.
