https://orcid.org/0000-0003-0264-2536
Figures
Abstract
Zinc plays a crucial role in maintaining immune balance in the human body. Zinc is believed to substantially affect cytokine synthesis and signaling; thus potentially combating viral infections, including Human Papillomavirus infection, through various mechanisms. Several randomized controlled trials (RCTs) have investigated whether oral zinc sulphate can improve viral warts; however, no comprehensive data is currently available. Therefore, we conducted a meta-analysis to evaluate the effectiveness of oral zinc sulphate for the treatment of viral warts. On July 1, 2024, we performed an extensive database search on PubMed, Embase, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov. Initially, 952 studies were identified, and after screening, 7 studies were included in the final analysis. Our findings showed that the total clearance rate of warts was significantly higher in the oral zinc sulphate group than in the control group (risk difference = 0.288; 95% CI = 0.087–0.489; p = 0.005). Subgroup analysis revealed that this therapeutic effect was more pronounced in individuals with low initial plasma zinc levels (risk difference = 0.767; 95% CI = 0.649–0.885; p < 0.001). Additionally, meta-regression showed that rise in zinc ion levels post-treatment were correlated with better treatment outcomes (coefficient = 0.0068; p < 0.001). Furthermore, for patients receiving traditional warts treatment, combining oral zinc sulphate significantly reduced the 6-month recurrence rate (log risk ratio = −1.043; 95% CI = −1.666 – −0.420; p = 0.001). The most common treatment-related side effects were nausea (risk difference = 0.562; 95% CI = 0.088–1.036; p = 0.020) and vomiting (risk difference = 0.205; 95% CI = 0.092–0.317; p < 0.001). Based on this evidence, oral zinc sulphate monotherapy offers notable benefits to those avoiding conventional treatments, and when combined with traditional therapies for viral warts, it can notably reduce recurrence rates over six months.
Citation: Wang C-C, Wang W-X, Wu P-Y (2025) Oral zinc sulphate reduces the recurrence rate and provides significant therapeutic effects for viral warts: A systematic review and meta-analysis of randomized controlled trials. PLoS One 20(5): e0323051. https://doi.org/10.1371/journal.pone.0323051
Editor: Laith Naser Al-Eitan, Jordan University of Science and Technology, JORDAN
Received: August 14, 2024; Accepted: March 31, 2025; Published: May 7, 2025
Copyright: © 2025 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: No authors have competing interests.
Introduction
Nongenital warts can present as common warts, flat warts, and deep palmoplantar warts, and are common and benign diseases caused by Human Papillomavirus (HPV) infection, with a global prevalence of approximately 10%. Warts are twice as common in Caucasians as in Blacks or Asians, with the highest prevalence observed in school-aged children and young adults [1]. External genital warts (condyloma acuminatum) are also caused by HPV infection and are generally considered sexually transmitted diseases, with a prevalence of about 10–20%. [2]. Generally, in individuals with normal immune status, warts are self-limiting diseases; however, the time required for them to disappear varies greatly, ranging from a few months to several years. [3]. One cohort study found that two-thirds of warts resolved without treatment within 2-year period [4].
Zinc is an essential trace element in the human body and is involved in the composition and production of numerous enzymes and transcription factors, respectively. Zinc plays a crucial role in the immune system. Previous studies have shown that zinc deficiency in animals leads to lymphopenia, lymphocyte dysfunction, and thymic atrophy [5]. A previous study reported substantially lower plasma zinc concentrations in patients with verruca vulgaris than in healthy individuals [6]. Another study demonstrated that wart severity was greater in individuals with reduced plasma zinc levels than in those with normal concentrations [7].
Many treatments for warts are available, such as cryotherapy commonly used for nongenital warts, topical podophyllin and imiquimod for external anogenital warts, antiviral medications, and immunotherapies such as zinc supplements [8]. However, cryotherapy can cause pain, blistering, and scarring, while topical podophyllin or imiquimod may lead to local skin irritation and are not safe during pregnancy [9]. Therefore, simply taking seemingly harmless zinc supplements to treat viral warts appears to be an attractive option. Existing literature on oral zinc therapy for viral warts shows mixed findings: one clinical trial reported excellent therapeutic effects, with 86% of patients taking zinc supplements achieving complete wart clearance, while none were cured in the placebo group [10]. Other studies suggest mild to moderate benefits [11,12], while some oppose these findings, stating that zinc supplements neither cure viral warts nor provide additional benefits [13–15]. Since the conclusions of these studies are inconsistent and comprehensive research has been lacking in recent years, we conducted a systematic review and meta-analysis of the efficacy and additional benefits of oral zinc sulphate administration in treating viral warts.
Materials and methods
General guidelines
This meta-analysis was conducted in strict adherence to the latest PRISMA guidelines from 2020 (S1 Table) and has been registered on INPASY, with registration number INPLASY202480037. Ethical approval and written informed consent from the participants were not required because of the nature and methodology of the study.
Eligibility criteria
The population (P), intervention (I), comparison (C), and outcome (O) for this study were as follows: P, human participants with skin or external genital warts; I, either taking oral zinc sulphate alone or a combination of oral zinc sulphate with traditional treatments for viral wart; C, either taking a placebo or using traditional treatments, e.g., topical drugs or cryotherapy, not limited to oral medications, for viral wart; and O, number of patients who achieved viral wart clearance and relapse after completing treatment and treatment-related adverse events.
The inclusion criteria for this study were as follows: 1) randomized controlled trials (RCTs) with human participants; 2) RCTs including the number of individuals who experienced viral wart clearance after treatment in both experimental and control groups; 3) placebo-controlled RCTs (without any age or treatment duration restrictions); 4) RCTs including those administered a dosage of zinc sulphate; and 5) studies on the oral application of zinc ions.
The exclusion criteria were as follows: 1) RCTs involving non-oral zinc sulphate supplementation; and 2) overlapping participants.
Information source, search strategy, and selection process
Two authors independently conducted data searches using electronic databases. Databases used include PubMed, Embase, Web of Science, Cochrane CENTRAL, and ClinicalTrials.gov, and the following keywords were used: [(“wart*” OR “viral wart*” OR “verruca vulgaris” OR “condyloma acuminatum” OR “verruca plana”) AND (“zinc” OR “zinc sulphate” OR “zinc gluconate”)]. The literature search included articles from the earliest available records up to July 1, 2024, without year and language restrictions. Keywords and search results in different databases was listed in “S2 Table”. Additionally, to ensure that all the studies that met the inclusion criteria were included, we manually reviewed the references of the systematic reviews [16] and included them according to the inclusion criteria. If the two authors had different opinions during the search process, a third author was consulted to resolve any disagreements.
Data collection process
Two authors independently extracted data from the screened studies, including demographic information, study design, and intervention methods for both the oral zinc sulphate and control groups, as well as the results of each study. In case of data from different time points after the treatment, we used the final experimental results for our analysis. Data extraction and merging of results from the various study arms were performed according to the instructions in the related chapter of the Cochrane Handbook for Systematic Reviews of Interventions [17,18]. The primary outcome of this study was the total number of patients who achieved clearance of viral warts after treatment. For one study [11] that only provided data on 75% clearance of viral warts, we considered the number of individuals with 75% or more clearance as those who achieved complete disappearance of viral warts. The secondary outcome was defined as the rate of relapse during the follow-up period as well as any treatment-related side effects.
Study risk of bias assessment
In this study, we used the Cochrane risk-of-bias tool for randomized trials (version 2, RoB 2, London, United Kingdom) [19] to evaluate the methodology of the included studies. The items analyzed included the randomization process, adherence to interventions, missing outcome data, outcome measurement, selective reporting, and overall risk of bias. Regarding the standards for reviewing randomization, the allocation sequence must first be kept concealed; for example, the allocation process should be conducted by an external institution or organization. Additionally, the allocation sequence should be unpredictable, with the article mentioning methods such as simple randomization, blocked randomization, or any elements involving random assignment (e.g., computer-generated random numbers or dice rolling). Finally, baseline imbalances need to be assessed.
Synthesis methods
Owing to the heterogeneity among the target groups in the included studies, we applied a random-effects model and used Comprehensive Meta-Analysis software (Biostat, Englewood, NJ, USA) for analysis. Statistical significance was defined as a two-tailed p value < 0.05. Risk difference and its corresponding 95% confidence intervals were used to evaluate the primary outcome. Secondary outcomes, including relapse and treatment-related side effects, are presented as log risk ratios and risk differences with their associated 95% confidence intervals. To assess the heterogeneity of the RCTs included in this study, we calculated the I² value and Cochran’s Q statistic. We categorized the degree of heterogeneity as low, moderate, or high, corresponding to I² values of 25, 50, and 75%, respectively [20]. Additionally, we conducted a subgroup analysis based on the patients’ initial plasma zinc ion concentrations and whether traditional treatments for viral warts were combined. Meta-regression analyses focused on establishing a correlation between the magnitude of the increase in zinc ion levels after treatment and treatment effectiveness, as well as the relationship between disease duration and treatment effectiveness. In the subgroup and meta-regression analyses, treatment efficacy was expressed as a risk difference. To ensure the robustness of this meta-analysis, sensitivity analyses were performed using the “one-study removal method” to assess whether there was a statistically significant change in the summary effect size when each study was sequentially excluded [18]. The assessment of potential publication bias was conducted according to the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions [21]. Funnel plots were constructed and examined using Egger’s regression test.
Results
Study selection and characteristics
The PRISMA flowchart published in 2020 was used for study selection. Initially, we identified 952 studies. We then removed duplicates (n = 298), studies on unrelated topics (n = 554), and non-RCT studies (n = 60), leaving 40 studies. Next, we excluded studies without full-text availability (n = 2), those not administering zinc ions orally (n = 26), and studies with inappropriate experimental or control group designs (n = 5). This resulted in a final selection of 7 studies for analysis. The literature searching process is presented in “Fig 1”, and all non-duplicate studies (n = 654) identified during the search, along with the reasons for their exclusion, are documented in “S3 Table”.
The seven included RCTs comprised 594 participants, 73.6% of whom were female. Based on the available data, the average age was 31.64 ± 12.49 (standard deviation, SD) years. The study duration was mostly eight months [10,13,15], with the shortest study lasting one month [11]. Among the analyzed articles, four were from Iran and the remaining three articles came from Iraq, Egypt, and Mexico. Among these 7 studies, 4 compared the efficacy of oral zinc sulphate to placebo capsule. One study compared the combination of zinc sulphate and cryotherapy with cryotherapy alone [13]. Another study compared the effectiveness of zinc sulphate combined with cryotherapy, imiquimod, or podophyllin to that of cryotherapy, imiquimod, or podophyllin alone [15]. The other study compared the effects of oral zinc sulphate with those of no treatment [11]. Other study details, including initial plasma zinc ion concentrations, the dosages of zinc sulphate, treatment and follow-up durations, are documented in “Table 1”.
Risk of bias in studies
Regarding the overall risk of bias for the seven included RCTs, 42.9% were assessed as having a low risk of bias, 57.1% were rated as having some risk of bias, and none (0%) were classified as having a high risk of bias (Fig 2). Among the evaluated items, three studies were classified as having some risk of bias in the randomization process because they did not describe the concealment of random allocation. For outcome measurement, two studies were rated as having some risk of bias owing to the potential influence of pre-existing knowledge on result interpretation. The detailed scores for each item are recorded in “Table 2”.
Primary outcome
The efficacy of oral zinc sulphate in treating viral warts.
Among the seven RCTs, the number of patients achieving total clearance of viral warts in the experimental groups, including those receiving oral zinc sulphate alone and zinc sulphate combined with traditional treatments, was significantly higher than that in the control group (risk difference = 0.288; 95% CI = 0.087–0.489; p = 0.005; I² = 94.916%) (Fig 3). However, we observed high heterogeneity among the studies; therefore, we performed a sensitivity test, which confirmed the significant results (Fig 4).
Patients taking oral zinc sulphate had significantly greater total clearance rate of warts. The studies are listed in alphabetical order. CI, confidence interval.
All analyses showed statistically significant effects of oral zinc sulphate in treating viral warts. The studies are listed in alphabetical order. CI, confidence interval.
Subgroup analysis.
In the subgroup analysis, we first categorized patients into two groups based on their initial plasma zinc ion concentration, normal and deficient, using the standard referenced in an article published in 2024 [22]. The results indicated that patients with deficient initial plasma zinc ion levels had significantly better treatment outcomes for viral warts (risk difference = 0.767; 95% CI = 0.649–0.885; p < 0.001) (Fig 5). In contrast, studies involving patients with normal initial plasma zinc ion levels did not show a significant difference in treatment efficacy (risk difference = 0.042; 95% CI = −0.108–0.192; p = 0.579).
The analysis shows that patients with lower initial plasma zinc ion levels have more effective treatment for viral warts when taking zinc sulphate. The studies are listed in alphabetical order. CI, confidence interval.
We further divided the intervention methods into two groups. One group compared oral zinc sulphate with placebo and labeled monotherapy. The other group combined oral zinc sulphate with cryotherapy, imiquimod, or podophyllin, compared with the use of cryotherapy, imiquimod, or podophyllin alone, and was labeled as combined therapy. The chart shows that in the monotherapy group, the efficacy of zinc sulphate was significantly better than that of the placebo (risk difference = 0.522; 95% CI = 0.350–0.695; p < 0.001) (Fig 6). However, in the combined therapy group, the combination of zinc sulphate with traditional treatments did not show significantly better efficacy than traditional treatments alone (risk difference = 0.017; 95% CI = −0.157–0.192; p = 0.848).
The analysis indicates that zinc sulphate alone is more effective for treating viral warts compared to combined treatments. However, this might be due to traditional therapies masking the effects of zinc sulphate in the combined treatment group. The studies are listed in alphabetical order. CI, confidence interval.
Meta-regression.
To examine whether the magnitude of the increase in plasma zinc ion levels in the experimental groups after treatment completion and the disease duration were related to treatment efficacy, we conducted a meta-regression analysis. The plasma zinc ion concentration was measured in μg/dL, and the disease duration was measured in months. The results showed that an increase in both zinc ion levels (coefficient = 0.0068; p < 0.001) (Fig 7) and disease duration (coefficient = 0.0233; p = 0.0001) (Fig 8) were significantly associated with treatment efficacy. The greater the increase in zinc ion levels, the more effective the treatment. Unexpectedly, longer disease duration was associated with better treatment outcomes. Summary of the results of the statistical analyses of the included studies are presented in “Tables 3 and 4”.
The coefficient was 0.0068 with a p value < 0.001.
The coefficient was 0.0233 with a p value was 0.0001.
Secondary outcome
Relapse rate.
We analyzed the studies that provided data on the number of relapsed cases during the follow-up period. Both studies used zinc sulphate in combination with other traditional treatments. We found that the group using zinc sulphate had a lower probability of relapse (log risk ratio = −1.043; 95% CI = −1.666– −0.420; p = 0.001; I² < 0.1%). (Fig 9).
The results show that the group receiving zinc sulphate had significantly lower relapse rates. The studies are listed in alphabetical order. CI, confidence interval.
Treatment-associated adverse event rates.
Among the seven included studies, three provided data on treatment-related adverse effects, encompassing 177 of the 594 participants. Gastrointestinal side effects were the most common, with nausea being the most frequently reported side effect. In all three studies, zinc sulphate use was significantly associated with a higher incidence of nausea (risk difference = 0.562; 95% CI = 0.088–1.036; p = 0.020) (S1 Fig). Vomiting was the second most common side effect and was statistically significant (risk difference = 0.205; 95% CI = 0.092–0.317; p < 0.001) (S2 Fig).
Reporting biases
We created a funnel plot for the seven studies that visually showed slight asymmetry (S3 Fig). However, Egger’s test yielded a two-tailed p value of 0.074, indicating a low likelihood of publication bias. Nonetheless, given the inclusion of fewer than 10 studies, the symmetry should be interpreted with caution.
Discussion
In this meta-analysis, oral zinc sulphate was effective in achieving total clearance of viral warts, with a statistically significant risk difference (p = 0.005). This significant difference in risk remained consistent in the sensitivity analysis (p = 0.005). In the analysis of relapse, although the number of studies providing such data was limited, those who received traditional therapy combined with oral zinc sulphate experienced significantly fewer wart recurrences within six months of post-treatment than the control group (p = 0.001). In the subgroup analysis, we found that in the monotherapy group, zinc sulphate showed significantly greater efficacy than the placebo; however, in the combined therapy group, the use of zinc sulphate did not result in a significant difference in therapeutic outcomes. Based on the aforementioned findings, zinc sulphate monotherapy may be an effective option for patients who do not wish to undergo conventional treatments. In patients receiving traditional therapy for viral warts, the addition of zinc sulphate significantly reduces the recurrence rate. We also found that patients with initially low plasma zinc levels showed a greater treatment response than those with normal zinc levels. Further meta-regression analysis confirmed the relationship between changes in zinc concentration and wart clearance, indicating that larger increases in zinc levels after treatment completion predicted better treatment outcomes. Interestingly, we found that longer disease duration was associated with better treatment efficacy, a point discussed later. Demographic data showed a mean patient age of 31.64 ± 12.49 (SD), aligning with real-world epidemiological findings indicating the highest prevalence among young adults. To the best of our knowledge, this is the first meta-analysis to evaluate the efficacy of oral zinc sulphate for viral warts and to investigate the factors influencing its effectiveness.
A previous prospective study comparing the efficacy of oral zinc sulphate and valacyclovir for wart treatment found that valacyclovir was superior [23]. Another open-label study reported a cure rate of 50% in patients treated with oral zinc sulphate [24]. Two systematic review summarized various zinc-related therapies for wart treatment and highlighted the efficacy of oral zinc sulphate [16,25]. However, the methodologies and experimental designs of the first two studies had limitations. Additionally, the two recently published systematic reviews focused primarily on describing the outcomes and limitations of each clinical trial. While we agree with their summaries regarding the efficacy of oral zinc sulfate, they provided limited analysis of the factors influencing treatment outcomes. This is where our paper adds significant value, as these insights can enhance our understanding of patient selection and the prediction of treatment efficacy.
Some studies suggest that zinc can regulate the translation of interferon-γ through gene methylation or affect them at the post-transcriptional level [26]. Other studies have suggested that zinc promotes and inhibits the signaling pathways of interferon receptors through phosphorylation and dephosphorylation [27–30]. Regarding HPVs, zinc appears to influence E6 and E7 proteins. In high-risk HPV types, exogenous zinc supplementation can effectively inhibit the synthesis of E6 and E7 proteins, leading to apoptosis of dysplastic cervical cancer cells by interrupting the viral life cycle. Additionally, zinc can inhibit the enzymatic activity of viral proteases and polymerases and affect the processes of attachment, infection, and uncoating [31]. Similarly, studies have shown that warts are more refractory to treatment and are more likely to recur in patients with zinc deficiency [6,7,32,33].
Notably, a considerable proportion of studies examining the relationship between zinc concentration and viral warts, including the articles incorporated in this meta-analysis, originated from Middle Eastern countries. This may be related to the dietary habits in these regions, especially in rural areas where diets often include a high intake of whole wheat bread. This dietary habit is rich in fiber and phytates, which can reduce zinc absorption efficiency, potentially leading to zinc deficiency [34]. The effect of zinc status on wart treatment efficacy was consistently observed in our subgroup analysis. Three randomized controlled trials [10,12,35] included patients with initial plasma zinc concentrations ranging from to 40–60 µg/dL, indicative of mild zinc deficiency [22]. Following oral zinc sulphate treatment, the proportion of patients with total wart clearance was significantly higher than that in the control group (p < 0.001). In contrast, two other randomized controlled trials [13,14] involved patients with initial zinc levels above 100 µg/dL, and these studies did not show significant treatment efficacy with zinc sulphate (p = 0.579). We further conducted a meta-regression analysis between the mean difference in plasma zinc concentrations before and after treatment and treatment efficacy. A strong positive correlation was found between increased plasma zinc ion concentrations and treatment efficacy (p < 0.001).
In the subgroup analysis of treatment methods, using oral zinc sulphate alone for wart treatment resulted in significantly higher total clearance rate compared to the placebo group. Conversely, in the combined therapy group, zinc ions combined with conventional treatment did not significantly outperform conventional treatment alone. We also created an additional analysis excluding studies that used no-treatment controls or glucose as a control, and the results remained consistent (S4 Fig). This finding should be interpreted cautiously, as the trials included in this review show that viral warts respond well to conventional treatments. Given that conventional therapy is already effective, most warts are likely to be resolved, leaving limited room for additional improvement when applying zinc ions. Thus, no synergistic effect appears between zinc and conventional treatment in our study, though zinc may offer a benefit in reducing recurrence rates.
We found that the longer the wart duration, the better the response to zinc sulphate treatment (p = 0.0001). This finding contrasts with the current knowledge. In one randomized controlled trial [11], the average disease duration for cases classified as having the best and worst cure rates were 7.65 months and 11.1 months, respectively, with a significant intergroup difference (p = 0.013). Another randomized controlled trial from 2018 [13] reported an average disease duration of 16.84 months in the successfully treated group and 24.17 months in the treatment failure group, with a significant difference (p = 0.03). This unexpected result may be due to the limited number of analyzed studies and scarcity of data on disease duration. We hypothesized that patients with recalcitrant viral warts might be in a state of chronic zinc deficiency, rendering them more resistant to conventional treatment [6,7]. Once zinc sulphate supplementation normalized zinc levels, it appeared that the improved immune status might have contributed to a notable therapeutic effect.
Consumption of zinc sulphate is associated a few side effects. Among the studies included in this meta-analysis, the group receiving zinc sulphate experienced significantly more adverse events, with nausea being the most common and statistically significant (p = 0.02). A 2002 study reported that all patients in the experimental group experienced this side effect [10]. Vomiting was the second most common adverse event, occurring significantly more frequently in the experimental group than in the control group (p < 0.001). In the studies included in this review, the highest dosage was 400–600 mg of zinc sulfate per day, equivalent to an effective zinc ion content of approximately 100–150 mg. In fact, for patients with malabsorption syndromes, such as Crohn’s disease or short bowel syndrome, the dose for treating acute zinc deficiency is typically only 50 mg/d [22]. Exceeding this dose can lead to gastrointestinal side effects such as nausea, vomiting, and gastric bleeding [36]. Daily intake of more than 150 mg of zinc can potentially affect lipid profiles and immune function status. Excessive zinc intake may also interfere with copper absorption, leading to copper deficiency [22].
This study had several limitations. First, the number of available studies on this topic was limited, and some were excluded due to their study design. Additionally, some studies had small sample sizes or high dropout rates, which may have contributed to significant heterogeneity and potential bias in the results. To address this, we performed subgroup analyses based on the “initial plasma zinc ion concentration” and “whether combined therapy was used” to examine factors that could contribute to heterogeneity. We also performed a meta-regression to identify the relationship between treatment efficacy and the increase in zinc ion levels as well as the duration of the disease. Secondly, most of the studies included in this meta-analysis originate from the Middle East. Therefore, further research is needed to determine whether this treatment is effective for patients in other regions. While conducting subgroup analyses by ethnicity could be a viable approach to explore differences in treatment efficacy, in this study, the limited number of available articles led to a reduction in power for certain subgroups. As a result, we did not include ethnicity in our subgroup analysis. Third, the sex distribution of the patients included in this study was imbalanced, with only 27.4% of the patients being male. However, whether zinc sulphate is particularly effective in female remains unclear. Most of the existing literature has not analyzed sex as a subgroup. Future studies should address this issue.
Conclusion
Oral zinc sulphate monotherapy can provide significant therapeutic effects in patients unwilling to undergo conventional treatment. For patients using traditional treatments for viral warts, the addition of zinc sulphate can significantly reduce the recurrence rate over the next six months. Future research should focus on the safety of zinc sulphate at higher concentrations, considering cases from other regions or ethnic groups, and explore the relationship between the disease duration and its impact on the treatment efficacy for viral warts.
Supporting information
S1 Fig. This is a forest plot of the risk difference of nausea when taking oral zinc sulphate.
Nausea was significantly more frequent in patients taking zinc sulphate. The studies are listed in alphabetical order. CI, confidence interval.
https://doi.org/10.1371/journal.pone.0323051.s001
(TIF)
S2 Fig. This is a forest plot of the risk difference of vomiting when taking oral zinc sulphate.
Vomiting was significantly more frequent in patients taking zinc sulphate. The studies are listed in alphabetical order. CI, confidence interval.
https://doi.org/10.1371/journal.pone.0323051.s002
(TIF)
S3 Fig. The funnel plot of included trials.
The p value of the Egger’s test was 0.074, indicating probably no evidence of publication bias.
https://doi.org/10.1371/journal.pone.0323051.s003
(TIF)
S4 Fig. This is a forest plot of subgroup analysis conducted based on treatment methods, excluding studies using no-treatment control and glucose as control.
After reanalysis, the results were consistent with the original subgroup analysis.
https://doi.org/10.1371/journal.pone.0323051.s004
(TIF)
References
- 1.
Al Aboud AM, Nigam PK. Wart. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024, StatPearls Publishing LLC; 2024.
- 2.
Leslie SW, Sajjad H, Kumar S. Genital warts. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024, StatPearls Publishing LLC; 2024.
- 3. Loo SK-F, Tang WY-M. Warts (non-genital). BMJ Clin Evid. 2014;2014:1710. pmid:24921240
- 4. Massing AM, Epstein WL. Natural history of warts. A two-year study. Arch Dermatol. 1963;87:306–10. pmid:13933441
- 5. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998;68(2 Suppl):447s–63s.
- 6. Korkmaz S, Şirin FB, Erturan I, Büyükbayram HI, Yildirim M. Coenzyme Q10, Zinc and MDA levels in verruca vulgaris. Turk J Med Sci. 2020;50(5):1387–92. pmid:31999408
- 7. Luong TND, Nguyen CTH, Firas A-N, Van TT. Serum zinc level in patients with severe genital warts: a case-control study in a dermatology hospital. Infect Dis Obstet Gynecol. 2022;2022:7616453. pmid:35959482
- 8. Witchey D J, Witchey N B, Roth-Kauffman M M, Kauffman M K. Plantar warts: epidemiology, pathophysiology, and clinical management. J Am Osteopath Assoc. 2018;118(2):92–105.
- 9. Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1–187.
- 10. Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the treatment of recalcitrant viral warts: randomized placebo-controlled clinical trial. Br J Dermatol. 2002;146(3):423–31. pmid:11952542
- 11. Genedy R, Moniem E, Moussa R. Oral zinc sulfate in the treatment of recalcitrant warts. Egypt J Dermatol Venerol. 2016;36(2):34.
- 12. Yaghoobi R, Sadighha A, Baktash D. Evaluation of oral zinc sulfate effect on recalcitrant multiple viral warts: a randomized placebo-controlled clinical trial. J Am Acad Dermatol. 2009;60(4):706–8. pmid:19293025
- 13. Mahmoudi H, Ghodsi SZ, Tavakolpour S, Daneshpazhooh M. Cryotherapy plus oral zinc sulfate versus cryotherapy plus placebo to treat common warts: a double blind, randomized, placebo-controlled trial. Int J Womens Dermatol. 2017;4(2):87–90. pmid:29872682
- 14. López-García DR, Gómez-Flores M, Arce-Mendoza AY, de la Fuente-García A, Ocampo-Candiani J. Oral zinc sulfate for unresponsive cutaneous viral warts: too good to be true? A double-blind, randomized, placebo-controlled trial. Clin Exp Dermatol. 2009;34(8):e984-5. pmid:20055878
- 15. Akhavan S, Mohammadi SR, Modarres Gillani M, Mousavi AS, Shirazi M. Efficacy of combination therapy of oral zinc sulfate with imiquimod, podophyllin or cryotherapy in the treatment of vulvar warts. J Obstet Gynaecol Res. 2014;40(10):2110–3. pmid:25132143
- 16. Song D, Pan L, Zhang M, Wang S. Clinical use of zinc in viral warts: a systematic review of the clinical trials. J Dermatolog Treat. 2022;33(4):1878–87. pmid:34132162
- 17.
Higgins J, Li T. Chapter 6: choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane handbook for systematic reviews of interventions version 6.4 (updated August 2023). Cochrane; 2023. Available from: www.training.cochrane.org/handbook
- 18.
Deeks J, Higgins J. Chapter 10: analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane handbook for systematic reviews of interventions version 6.4 (updated August 2023). Cochrane; 2023. Available from: www.training.cochrane.org/handbook
- 19. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. pmid:31462531
- 20. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. pmid:12958120
- 21.
Page M, Higgins J, Sterne J. Chapter 13: assessing risk of bias due to missing results in a synthesis. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane handbook for systematic reviews of interventions version 6.4 (updated August 2023). Cochrane; 2023. Available from: www.training.cochrane.org/handbook
- 22.
Maxfield L, Shukla S, Crane JS. Zinc deficiency. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024, StatPearls Publishing LLC; 2024.
- 23. Rai R, Jamale V. Comparative evaluation of oral valacyclovir versus oral zinc sulfate in the treatment of cutaneous verruca: a hospitalbased, prospective clinical study. Iran J Dermatol. 2021;24(3):179–85.:
- 24. Mun J-H, Kim S-H, Jung D-S, Ko H-C, Kim B-S, Kwon K-S, et al. Oral zinc sulfate treatment for viral warts: an open-label study. J Dermatol. 2011;38(6):541–5. pmid:21352302
- 25. Simonart T, de Maertelaer V. Systemic treatments for cutaneous warts: a systematic review. J Dermatolog Treat. 2012;23(1):72–7. pmid:21054194
- 26. Rodenkirchen V, Schettgen T, Rink L. Zinc deficiency impairs interferon-γ production on post-transcriptional level. J Trace Elem Med Biol. 2020;62:126598. pmid:32645654
- 27. Brautigan DL, Bornstein P, Gallis B. Phosphotyrosyl-protein phosphatase. Specific inhibition by Zn. J Biol Chem. 1981;256(13):6519–22. pmid:6165721
- 28. Shanker V, Trincucci G, Heim HM, Duong HTF. Protein phosphatase 2A impairs IFNα-induced antiviral activity against the hepatitis C virus through the inhibition of STAT1 tyrosine phosphorylation. J Viral Hepat. 2013;20(9):612–21. pmid:23910645
- 29. You M, Yu DH, Feng GS. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol Cell Biol. 1999;19(3):2416–24. pmid:10022928
- 30. David M, Chen HE, Goelz S, Larner AC, Neel BG. Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol. 1995;15(12):7050–8. pmid:8524272
- 31. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr. 2019;10(4):696–710. pmid:31305906
- 32. Raza N, Khan DA. Zinc deficiency in patients with persistent viral warts. J Coll Physicians Surg Pak. 2010;20(2):83–6. pmid:20378032
- 33. Ghanem AH, Esawy AM, Khalifa NA, Kamal HM. Evaluation of serum interleukin 17 and zinc levels in recalcitrant viral wart. J Cosmet Dermatol. 2020;19(4):954–9. pmid:31410973
- 34. Hunt JR, Beiseigel JM, Johnson LK. Adaptation in human zinc absorption as influenced by dietary zinc and bioavailability. Am J Clin Nutr. 2008;87(5):1336–45. pmid:18469257
- 35. Sadighha A. Oral zinc sulphate in recalcitrant multiple viral warts: a pilot study. J Eur Acad Dermatol Venereol. 2009;23(6):715–6. pmid:19298490
- 36. Skalny A, Aschner M, Tinkov A. Zinc. Adv Food Nutr Res. 2021;96:251–310.