PVP-I for COVID-19: real-time analysis of all 22 studies

Covid Analysis (Preprint) (meta analysis)

Povidone-Iodine for COVID-19: real-time meta analysis of 9 studies

• Meta analysis using the most serious outcome reported shows 60% [35‑75%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Early treatment shows efficacy while late treatment does not, consistent with expectations for an effective topical nasopharyngeal/oropharyngeal treatment.

• Statistically significant improvements are seen for mortality, hospitalization, cases, and viral clearance. 4 studies show statistically significant improvements in isolation (3 for the most serious outcome).

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 22% of povidone-iodine studies show zero events in the treatment arm.

• Multiple treatments are typically used in combination, and other treatments may be more effective.

• Elimination of COVID-19 is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used, including treatments, as supported by Pfizer [Pfizer]. Denying the efficacy of treatments increases the risk of COVID-19 becoming endemic; and increases mortality, morbidity, and collateral damage.

• All data to reproduce this paper and sources are in the appendix.

	Studies	Early treatment	Late treatment	Prophylaxis	Patients	Authors
All studies	9	71% [46‑84%]	-27% [-528‑74%]	45% [20‑62%]	2,256	88
With exclusions	8	81% [63‑90%]	-27% [-528‑74%]	45% [20‑62%]	2,185	82
Peer-reviewed	7	72% [39‑87%]	-27% [-528‑74%]	45% [20‑62%]	2,167	63
RCTs	8	81% [63‑90%]	-27% [-528‑74%]	45% [20‑62%]	2,185	82
Percentage improvement with povidone-iodine treatment

Covid Analysis et al., 12/5/2021, preprint, 1 author.

Zarabanda et al., Laryngoscope, doi:10.1002/lary.29935 (Peer Reviewed)

The Effect of Povidone-Iodine Nasal Spray on COVID-19 Nasopharyngeal Viral Load in Patients: A Randomized Control Trial

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.

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.

Zarabanda et al., 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.

Pablo-Marcos et al., Enfermedades Infecciosas y Microbiología Clínica, doi:10.1016/j.eimc.2021.10.005 (Peer Reviewed)

Utilidad de los enjuagues con povidona yodada y peroxido de hidrogeno en pacientes con COVID-19

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%.

relative viral load, 29.2% lower, RR 0.71, p = 0.40, treatment 31, control 40, 3rd PCR (mid-recovery).

relative viral load, 9.1% lower, RR 0.91, p = 0.91, treatment 31, control 40, 4th PCR (most patients recovered).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Pablo-Marcos et al., 10/25/2021, prospective, Spain, Europe, peer-reviewed, 6 authors.

Frank et al., Otolaryngology - Head and Neck Surgery, 165:89 (Preprint)

Tolerance of nasal and oral povidone-iodine antisepsis amid COVID-19 pandemic

Prospective study of 42 otolaryngology and dental patients, showing low-dose nasal and oral PVP-I solutions to be well-tolerated.

Frank et al., 10/3/2021, preprint, 6 authors.

Baxter et al., medRxiv, doi:10.1101/2021.08.16.21262044 (Preprint)

Rapid initiation of nasal saline irrigation: hospitalizations in COVID-19 patients randomized to alkalinization or povidone-iodine compared to a national dataset

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.

risk of hospitalization, 65.3% lower, RR 0.35, p = 1.00, treatment 0 of 37 (0.0%), control 1 of 42 (2.4%), relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization/ER, 79.0% lower, RR 0.21, p = 0.50, treatment 0 of 37 (0.0%), control 2 of 42 (4.8%), relative risk is not 0 because of continuity correction due to zero events.

risk of no recovery, 56.0% lower, RR 0.44, p = 0.03, treatment 6 of 25 (24.0%), control 18 of 33 (54.5%).

Baxter et al., 8/17/2021, Randomized Controlled Trial, USA, North America, preprint, 9 authors, this trial compares with another treatment - results may be better when compared to placebo.

Arefin et al., Indian Journal of Otolaryngology and Head & Neck Surgery, doi:10.1007/s12070-021-02616-7 (Peer Reviewed)

Virucidal effect of povidone iodine on COVID-19 in the nasopharynx: an open-label randomized clinical trial

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 [1].

[1] trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04963-2

risk of no virological cure, 78.9% lower, RR 0.21, p = 0.02, treatment 4 of 27 (14.8%), control 19 of 27 (70.4%), 0.6% nasal irrigation.

risk of no virological cure, 89.5% lower, RR 0.11, p < 0.001, treatment 2 of 27 (7.4%), control 19 of 27 (70.4%), 0.5% nasal irrigation.

risk of no virological cure, 52.6% lower, RR 0.47, p = 0.006, treatment 9 of 27 (33.3%), control 19 of 27 (70.4%), 0.4% nasal irrigation.

risk of no virological cure, 80.0% lower, RR 0.20, p < 0.001, treatment 5 of 27 (18.5%), control 25 of 27 (92.6%), 0.6% nasal spray.

risk of no virological cure, 64.0% lower, RR 0.36, p < 0.001, treatment 9 of 27 (33.3%), control 25 of 27 (92.6%), 0.5% nasal spray.

risk of no virological cure, 73.6% lower, RR 0.26, p < 0.001, treatment 29 of 135 (21.5%), control 44 of 54 (81.5%), all treatment vs. all control.

Arefin et al., 5/18/2021, Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, 9 authors.

Seet et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.04.035 (Peer Reviewed)

Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial

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.

risk of severe case, 44.7% lower, RR 0.55, p = 0.05, treatment 42 of 735 (5.7%), control 64 of 619 (10.3%).

risk of case, 31.1% lower, RR 0.69, p = 0.01, treatment 338 of 735 (46.0%), control 433 of 619 (70.0%), adjusted, OR converted to RR, model 6.

Seet et al., 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.

Arefin, M., Indian Journal of Otolaryngology and Head & Neck Surgery, doi:10.1007/s12070-021-02525-9 (Peer Reviewed)

Povidone Iodine (PVP-I) Oro-Nasal Spray: An Effective Shield for COVID-19 Protection for Health Care Worker (HCW), for all

Report on clinical experience with prophylactic use of PVP-I for COVID-19 in a very high risk environment with no infections, review of the use of PVP-I for the prevention of respiratory infections, and recommendations for use with COVID-19.

Arefin et al., 4/8/2021, peer-reviewed, 1 author.

Elzein et al., Journal of Evidence Based Dental Practice, doi:10.1016/j.jebdp.2021.101584 (preprint 3/17) (Peer Reviewed)

In vivo evaluation of the virucidal efficacy of chlorhexidine and povidone-iodine mouthwashes against salivary SARS-CoV-2. A randomized-controlled clinical trial

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.

inverse relative improvement in Ct value, 88.8% lower, RR 0.11, p < 0.05, treatment 25, control 9.

Elzein et al., 3/17/2021, Double Blind Randomized Controlled Trial, Lebanon, Middle East, peer-reviewed, 7 authors.

Chopra et al., Japanese Dental Science Review, doi:10.1016/j.jdsr.2021.03.001 (Review) (Peer Reviewed)

Can povidone Iodine gargle/mouthrinse inactivate SARS-CoV-2 and decrease the risk of nosocomial and community transmission during the COVID-19 pandemic? An evidence-based update

Review discussing the rationale, safety, recommendations, and dosage of PVP-I gargle/mouthwash as an effective method to decrease the viral load of SARS-CoV-2.

Chopra et al., 3/15/2021, peer-reviewed, 5 authors.

Xu et al., Pathogens, doi:10.3390/pathogens10030272 (Peer Reviewed) (In Vitro)

Differential Effects of Antiseptic Mouth Rinses on SARS-CoV-2 Infectivity In Vitro

In Vitro study showing that PVP-I and other mouthwashes inactivated replication-competent SARS-CoV-2.

Xu et al., 3/1/2021, peer-reviewed, 7 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Jayaraman et al., medRxiv, doi:10.1101/2021.02.25.21252488 (Preprint)

Povidone iodine, hydrogen peroxide and chlorhexidine mouthwashes reduce SARS-CoV2 burden in whole mouth fluid and respiratory droplets

Study of SARS-CoV2 burden in whole mouth fluid and respiratory droplets with povidone iodine, hydrogen peroxide, and chlorhexidine mouthwashes in 36 hospitalized COVID-19 patients using PCR and rapid antigen testing. There were significant reductions in SARS-CoV2 burden with all treatments in both respiratory droplets and whole mouth fluid.

Jayaraman et al., 3/1/2021, prospective, India, South Asia, preprint, 12 authors.

Guenezan et al., JAMA Otolaryngol Head Neck Surg., doi:10.1001/jamaoto.2020.5490 (Peer Reviewed)

Povidone Iodine Mouthwash, Gargle, and Nasal Spray to Reduce Nasopharyngeal Viral Load in Patients With COVID-19: A Randomized Clinical Trial

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.

relative improvement in viral titer reduction between baseline and day 1, 63.2% lower, RR 0.37, p = 0.25, treatment 12, control 12.

Guenezan et al., 2/4/2021, Randomized Controlled Trial, France, Europe, peer-reviewed, 7 authors.

Tucker et al., bioRxiv, doi:10.1101/2021.01.31.426979 (Preprint) (In Vitro)

In vitro inactivation of SARS-CoV-2 with 0.5% povidone iodine nasal spray (Nasodine) at clinically relevant concentrations and timeframes using tissue culture and PCR based assays

In Vitro study showing that PVP-I eliminated the viability of SARS-CoV-2 with short exposure times. Authors find that PCR alone may not be adequate for viral quantification and recommend incorporating cell culture to assess viral viability.

Tucker et al., 2/1/2021, preprint, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Khan et al., American Journal of Otolaryngology, doi:10.1016/j.amjoto.2020.102880 (Peer Reviewed)

Tolerability and usability of 0.5% PVP-I gargles and nasal drops in 6692 patients: Observational study

Study of the use of PVP-I gargles and nasal drops before and after ENT examinations with a total of 6,692 patients, finding high usability and good tolerance for use.

21 patients (0.76%) reported an itching sensation in the nose on the first day of use of 0.5% PVP-I nasal drops and discontinued its further use. However, none of the patients reported any serious side effects or allergic reaction to 0.5% PVP-I nasal drops and gargles.

The 0.5% PVP-I gargles and nasal drops were used by healthcare workers about three to four times in a day for 5 months. None of them developed any COVID-19 symptoms.

Khan et al., 1/3/2021, peer-reviewed, 2 authors.

Seneviratne et al., Infection, doi:10.1007/s15010-020-01563-9 (Peer Reviewed)

Efficacy of commercial mouth-rinses on SARS-CoV-2 viral load in saliva: randomized control trial in Singapore

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.

Seneviratne et al., 12/14/2020, peer-reviewed, 12 authors.

Choudhury et al., Bioresearch Communications, Volume 7, Issue 1, January 2021 (Peer Reviewed)

Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient

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.

risk of death, 88.2% lower, RR 0.12, p < 0.001, treatment 2 of 303 (0.7%), control 17 of 303 (5.6%).

risk of hospitalization, 84.4% lower, RR 0.16, p < 0.001, treatment 12 of 303 (4.0%), control 77 of 303 (25.4%).

risk of no virological cure, 96.2% lower, RR 0.04, p < 0.001, treatment 8 of 303 (2.6%), control 213 of 303 (70.3%), day 7.

Choudhury et al., 12/3/2020, Randomized Controlled Trial, Bangladesh, South Asia, peer-reviewed, 6 authors.

Frank et al., JAMA Otolaryngol Head Neck Surg, doi:10.1001/jamaoto.2020.3053 (Peer Reviewed) (In Vitro)

In Vitro Efficacy of a Povidone-Iodine Nasal Antiseptic for Rapid Inactivation of SARS-CoV-2

In Vitro study showing povidone-iodine nasal antiseptics at concentrations (0.5%, 1.25%, and 2.5%) completely inactivated SARS-CoV-2 within 15 seconds of contact. No cytotoxic effects on cells were observed after contact with each of the nasal antiseptics tested.

Frank et al., 9/17/2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Mohamed et al., medRxiv, doi:10.1101/2020.09.07.20180448 (Preprint)

Early viral clearance among COVID-19 patients when gargling with povidone-iodine and essential oils: a pilot clinical trial

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.

risk of no virological cure, 85.7% lower, RR 0.14, p = 0.17, treatment 0 of 5 (0.0%), control 3 of 5 (60.0%), relative risk is not 0 because of continuity correction due to zero events, day 12.

Mohamed et al., 9/9/2020, Randomized Controlled Trial, Malaysia, Europe, preprint, 16 authors.

Anderson et al., Infectious Diseases and Therapy, doi:10.1007/s40121-020-00316-3 (Peer Reviewed) (In Vitro)

Povidone-Iodine Demonstrates Rapid In Vitro Virucidal Activity Against SARS-CoV-2, The Virus Causing COVID-19 Disease

In Vitro study showing rapid and effective virucidal activity of PVP-I
against SARS-CoV-2. All four products tested [antiseptic solution (PVP-I 10%), skin cleanser (PVP-I 7.5%), gargle and mouth wash (PVP-I 1%) and throat spray (PVP-I 0.45%)] achieved C 99.99% virucidal activity against SARS-CoV-2, corresponding to C 4 log10 reduction of virus titre, within 30s of contact.

Anderson et al., 7/8/2020, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Martínez Lamas et al., Oral Diseases, doi:doi.org/10.1111/odi.13526 (Peer Reviewed)

Is povidone iodine mouthwash effective against SARS‐CoV‐2? First in vivo tests

Small study analyzing the impact of PVP-I mouthwash on the salivary viral load of SARS‐CoV‐2 in 4 patients with COVID‐19. In 2 of the 4 patients (those with a higher initial viral load), PVP‐I resulted in a significant drop in viral load, which remained after 3 hours.

Martínez Lamas et al., 7/2/2020, peer-reviewed, 9 authors.

Hassandarvish et al., British Dental Journal volume, doi:10.1038/s41415-020-1794-1 (Peer Reviewed) (In Vitro)

Povidone iodine gargle and mouthwash

In Vitro study showing undiluted PVP-I (1% w/v) achieved >5 log10 reduction in SARS-CoV-2 virus titres at 15, 30 and 60 seconds treatment exposure under both clean and dirty conditions. In contrast, when PVP-I was tested at 1:2 dilution a >4 log10 kill at 15 seconds and >5 log10 kill at 30 and 60 seconds in comparison to control was seen in both clean and dirty conditions.

Hassandarvish et al., 6/26/2020, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Khan et al., Am J Otolaryngol, doi:10.1016/j.amjoto.2020.102618 (Peer Reviewed)

Repurposing 0.5% povidone iodine solution in otorhinolaryngology practice in Covid 19 pandemic

Study of the use of PVP-I gargles and nasal drops before ENT appointments finding good tolerability.

Khan et al., 6/18/2020, peer-reviewed, 3 authors.

Frank et al., Ear, Nose & Throat Journal, doi:10.1177/0145561320932318 (Peer Reviewed)

Povidone-Iodine Use in Sinonasal and Oral Cavities: A Review of Safety in the COVID-19 Era

Review of povidone-iodine finding that it 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.

Frank et al., 6/10/2020, peer-reviewed, 4 authors.

Bidra et al., Journal of Prosthodontics, doi:10.1111/jopr.13209 (Peer Reviewed) (In Vitro)

Rapid In‐Vitro Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) Using Povidone‐Iodine Oral Antiseptic Rinse

In Vitro study showing PVP‐I rapidly inactivated SARS‐CoV‐2. Viricidal activity was present at the lowest concentration and contact time tested (0.5% PVP‐I and 15 seconds).

Bidra et al., 6/8/2020, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Mendoza et al., SSRN, doi:10.2139/ssrn.3589404 (Preprint)

Prevention of COVID-19 Infection with Povidone-Iodine

Review of the antiviral efficacy of PVP-I and its potential use as a prophylactic on the oropharyngeal and nasopharyngeal mucosa for COVID-19.

Mendoza et al., 5/7/2020, preprint, 1 author.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychloro..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption