Vitamin D status modulates high-risk human papillomavirus infection and persistence: a systematic review and meta-analysis

Vitamin D status modulates high-risk human papillomavirus infection and persistence: a systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Vitamin D status modulates high-risk human papillomavirus infection and persistence: a systematic review and meta-analysis Rupesh Kumar, Aniruddha Sen, Avdhesh Kumar Rai, Abhijit Dutta This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9398917/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract High-risk human papillomavirus (hr-HPV) infection is the principal cause of cervical cancer worldwide. Emerging evidence suggests that serum 25-hydroxyvitamin D [25(OH)D], a key immunomodulatory biomarker, may influence susceptibility to HPV infection and its persistence; however, findings remain inconsistent. In this study, we conducted a systematic review and meta-analysis to evaluate the association between serum 25(OH)D levels and cervicovaginal hr-HPV infection in women. A comprehensive literature search of PubMed, Scopus, Web of Science, and Google Scholar was performed for studies published between 2003 and 2024. Study quality was assessed using Joanna Briggs Institute (JBI) criteria, and pooled odds ratios (ORs) were estimated using a random-effects model. Nine studies comprising 11,401 participants met the inclusion criteria, of which six were included in the quantitative synthesis. Vitamin D sufficiency was associated with significantly reduced odds of hr-HPV infection (OR = 0.15; 95% CI: 0.03–0.70; p = 0.016), although substantial heterogeneity was observed (I² = 98.3%). The pooled prevalence of hr-HPV infection was 27.63%, while vitamin D deficiency was present in 40.03% of participants. These findings suggest a potentially novel, stage-specific role for vitamin D in modulating HPV persistence rather than initial acquisition, possibly through effects on local immune responses and viral clearance. Optimizing vitamin D status may represent a complementary, host-directed strategy to reduce the progression of hr-HPV-related cervical disease; however, further well-designed longitudinal studies are required to confirm causality and clarify underlying mechanisms. Health sciences/Biomarkers Biological sciences/Cancer Health sciences/Diseases Biological sciences/Immunology Health sciences/Medical research Biological sciences/Microbiology 25-hydroxyvitamin D vitamin D deficiency high-risk HPV cervicovaginal infection cervical cancer meta-analysis immunomodulation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Cervical cancer is the fourth most common cancer in women, with approximately 660,000 cases and 350,000 deaths reported worldwide in 2022 [ 1 ]. The majority of cervical cancer cases occur in low- and middle-income countries (LMICs), including Brazil, South Africa, China, and India. According to the World Health Organisation (WHO), more than 90–100% of cervical cancer is due to persistent high-risk human papilloma virus (hr-HPV) infection, particularly in women < 35 years old [ 2 , 3 ]. It is preventable with effective implementation of Papanicolaou smear screening towards early detection of pre-cancerous cervical intraepithelial neoplasia (CIN) lesions, and also with prophylactic vaccination against hr-HPV [ 1 , 4 ]. Human Papilloma Virus (HPV) is one of the most prevalent sexually transmitted infections worldwide, with over 200 types identified. Among these, at least 12 genotypes are considered high-risk due to their oncogenic potential at the cervix [ 5 , 6 ]. Hr- HPV types, particularly HPV-16 and HPV-18, are identified as causative factors for the majority of the cervical cancer cases (70%) [ 6 , 7 ]. Following integration into the host DNA, HPV produces oncoproteins E6 and E7, which inhibit the tumour suppressor proteins p53 and pRb, respectively [ 8 , 9 ]. p53 and pRb genes play a vital role in maintaining genome stability and cellular division, as well as the regulation of cell death [ 8 ]. Loss of function of p53 and pRb results in uncontrolled cell division, genetic mutations, and progression from low-grade CIN to invasive cervical cancer [ 10 ]. In view of significant public health implication of hr-HPV infection, it is pertinent to identify factors that may facilitate in the efficiency/persistence of hr-HPV infection and subsequent carcinoma development [ 8 , 9 , 11 ]. In light of recent advancements in virology, research interest has spiked up in understanding the relationship between vitamin D status, as indicated by serum levels 25(OH)D levels, and HPV infections, especially high-risk HPV types [ 12 ]. In this context, serum 25-hydroxyvitamin D (25[OH]D) concentrations may have role in modulating the host immune response to HPV infections. The level of vitamin D may enhance capabilities of the immune system in preventing viral infections, particularly DNA viruses and HPV, which may be associated with the development of cancer [ 13 ]. Numerous studies suggest that, in addition to genetic, infectious, environmental, and lifestyle factors, deficiency in vitamin D etc. may be linked to an increased risk of developing cervical cancer [ 14 ]. Recent studies have investigated the role of Vitamin D in relation to HPV infections [ 12 , 15 , 16 ]. Vitamin D's immunomodulatory properties are particularly noteworthy as they influence the body's immune responses to viral infections, including HPV [ 12 , 17 ]. A study from Japan has shown an inverse relationship between vitamin D intake and the risk of CINs [ 18 ]. The beneficial effects of vitamin D on protective immunity may be due to its interaction with the constituents of the innate immune system [ 12 ]. Normally, serum levels of 25-hydroxyvitamin D (25[OH]D) are employed as a standard indicator of vitamin D measurement [ 19 ]. Vitamin D deficiency is often illustrated by circulating levels of 25(OH)D falling below 20 ng/ml (50 nmol/L). Vitamin D deficiency is suggested as a biomarker for immune-related diseases and susceptibility to infections, including HPV [ 20 , 21 ]. Low levels of 25-hydroxyvitamin D [25(OH)D] may be associated with a compromised immune system [ 22 – 24 ]. Several observational studies have suggested a potential association between low serum 25(OH)D levels and persistence of hr-HPV infections, although the mechanisms underlying this relationship remain poorly understood. As a result, there is an increasing interest in exploring how Vitamin D supplementation may influence the progression of high-risk HPV infections and whether it could serve as a potential therapeutic strategy in preventing hr-HPV infections. The immunomodulatory properties of vitamin D are hypothesised to play a role in limiting hr-HPV persistence and progression to malignancy [ 25 ]. Vitamin D downregulates pro-inflammatory cytokines by promoting antimicrobial peptides like cathelicidin and defensins which are required for innate immune responses against viral infections [ 26 ]. Vitamin D affects the functional activity of dendritic cells and T-helper cells, thus increasing the specific response to hr-HPV infection [ 27 ]. Sufficient serum 25(OH)D levels may improve disease outcomes in women infected with hr- HPV types [ 28 ]. However, research evidence on the relationship between serum 25(OH)D and hr- HPV infections is inconsistent. Several studies have reported strong relationships between vitamin D deficiency and subsequent hr-HPV infection persistence and/or CINs; however, many didn’t observe such positive associations [ 12 , 14 ]. Variability could be attributed to divergent populations, sample sizes, study techniques, or other factors such as age, sexual behaviour, and smoking. This systematic review and meta-analysis aimed to evaluate the association between serum 25-hydroxyvitamin D levels and the risk of high-risk human papillomavirus (HPV) cervicovaginal infections in women. We investigated whether vitamin D deficiency elevates HPV infection risk and its potential as a modifiable factor for HPV prevention, with implications for reducing cervical cancer incidence. 2. Methods and materials 2.1 Search strategy and selection process A systematic search of the scientific literature was conducted to assess the association between serum 25-hydroxyvitamin D levels and high-risk HPV–related cervicovaginal infection in women. The search covered Google Scholar, PubMed, Web of Science, and Scopus, focusing on studies published between 2023 and 2024. The search terms included a combination of MeSH descriptors and free-text keywords such as “25-hydroxyvitamin D,” “high-risk HPV,” “cervicovaginal infections,” “HPV infection,” and “women.” No language restrictions were applied. Additionally, reference lists of eligible articles and pertinent reviews were screened to identify further relevant studies [29]. 2.2 Inclusion and Exclusion Criteria The inclusion and exclusion of studies were determined according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure methodological transparency and replicability [30]. Inclusion Criteria Studies were included if they met the following criteria: Study design: Observational studies (cross-sectional, case-control, or cohort) that examined the association between serum 25-hydroxyvitamin D [25(OH)D] levels and high-risk human papillomavirus (hr-HPV) cervicovaginal infections in women. Population: Studies involving women of any age group, regardless of geographic region or ethnicity. Exposure measurement: Serum 25(OH)D concentrations reported in ng/mL or nmol/L, with clear definitions of vitamin D sufficiency, insufficiency, or deficiency. Outcome measurement: Detection of hr-HPV DNA using validated molecular techniques such as polymerase chain reaction (PCR), Hybrid Capture 2, Cobas 4800, or equivalent genotyping assays. Data availability: Studies providing sufficient quantitative or qualitative data to estimate the relationship between vitamin D status and hr-HPV infection risk (e.g., prevalence, odds ratios, or raw counts). Publication characteristics: Full-text, peer-reviewed original articles published between 2003 and 2024 in English. Exclusion Criteria Studies were excluded based on the following considerations: Publication type: Reviews, meta-analyses, case reports, editorials, commentaries, letters to the editor, conference abstracts, or animal studies. Data limitations: Studies lacking clearly defined serum 25(OH)D measurements or without hr-HPV infection outcomes. Statistical insufficiency: Studies that did not provide extractable or statistically significant data for meta-analysis. Duplication: Repeated datasets or overlapping data from the same population; in such cases, the most comprehensive or recent study was retained. Accessibility: Studies without available full texts or those published in non-peer-reviewed sources. All included studies were independently reviewed by two investigators. Any discrepancies regarding eligibility were resolved through discussion or consultation with a third reviewer to maintain objectivity and consistency. 2.3 Data Extraction and Validity Assessment The process of data extraction was carried out independently by two reviewers. In the event of a discrepancy regarding any selected article, the matter was discussed and resolved with the support of a non-associated reviewer. The extracted data were the name of the author/study, the year of publication, sample size, country of origin, study site, study design and the participant’s characteristics. The participant’s characteristics included age, their health status, serum 25(OH) D measured in the trial (mean and range) or according to deficiency status: deficient, insufficient, or adequate. Data regarding hr-HPV infection was collected, including information such as whether the woman had hr-HPV infections or how frequently she had such infections, and detection of HPV16 and/or HPV18 through PCR. All the collected data was exported directly into an analysis format in an Excel sheet. Finally, the quality of the evidence was summarised using the GRADE approach with its components, such as heterogeneity, precision, and publication bias, to assess confidence in the meta-analysis outcome [29-31]. 2.4 Risk of bias assessment and quality of studies The assessment of study quality and risk of bias was conducted using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data. This tool evaluates key aspects of study reliability through nine questions, with responses categorised as Yes , No , Unclear , or Not Applicable . Two independent authors (RK and AKR) applied the checklist to the selected studies, and any disagreements were resolved by the first author (RK) through a consensus-based approach or majority decision. The studies were scored based on the number of Yes responses, and their risk of bias was categorised as: Low risk: More than 70% Yes responses, Moderate risk: 50–70% Yes responses, High risk: Less than 50% Yes responses. Studies with a high risk of bias (below 50%) were excluded from further analysis and data synthesis to ensure the reliability of findings related to the prevalence of hr-HPV Cervicovaginal Infections in Women [29, 31, 32]. 2.5 Statistical Analysis The meta-analysis was done using Microsoft Excel software (2013), MedCalc software (Version 19. 3) as well as RevMan software (Version 5. 3). To analyze dichotomised data, odd ratios (ORs) and 95% confidence interval (CI) were used. For continuous data and significance of heterogeneity, we used random effect model and measures of heterogeneity respectively [29]. The primary outcome was the cross-sectional relationship as ORs with 95% CI between serum 25(OH)D level and hr-HPV cervicovaginal infections. A P< 0.05 was considered as statistically significant level. The analysis was also conducted based on the 25(OH)D levels (such as deficiency and sufficiency) and other demographic variables as well according to availability. Based on the data, heterogeneity between studies were evaluated by using Cochran's Q test and also, we used I² statistic as one relevant measure for the degree of heterogeneity. I² statistic denotes the proportion of the variability of effect to be related to heterogeneity instead of sampling errors. I² more than 50% was used to determine whether the values were differing significantly. Furthermore, when there was high level of heterogeneity the source of the heterogeneity was further investigated based on the following subgroups: geographic location, study type, and population. Sensitivity analysis was also performed after removing lower-quality studies (NOS <5). To check the presence of publication bias, Begg funnel plot and Egger's test were used, and the results were considered statistically significant if p < 0. 05 suggested publication bias [29-30, 32]. 3. Results 3.1 Article selection process This meta-analysis included both case-control and cross-sectional studies published between 2003 and 2022, retrieved from major electronic databases including PubMed, Scopus, Web of Science, and Google Scholar. The initial database search yielded 560 records related to the association between serum vitamin D levels and high-risk human papillomavirus (hr-HPV) cervicovaginal infection. After removing 125 duplicate records using automated citation management tools and manual verification, 435 unique studies remained for title and abstract screening. Screening was conducted independently by two reviewers, focusing on study relevance and eligibility criteria. Studies were cross-checked for duplication based on author names, titles, publication year, volume, issue, and methodological parameters, and data were organized in a Microsoft Excel spreadsheet for transparency and reproducibility. During the screening process, 42 studies were excluded for the following reasons: partially overlapping data (n = 11), unrelated topics (n = 16), insufficient information on serum 25-hydroxyvitamin D [25(OH)D] levels (n = 9), and absence of hr-HPV outcome data (n = 6). An additional 33 studies were excluded due to lack of quantitative or extractable data on hr-HPV cervicovaginal infections in women. Ultimately, nine studies (n = 9) met all inclusion criteria and were incorporated into the qualitative synthesis, of which six provided sufficient quantitative data for meta-analysis. The detailed process of study identification, screening, eligibility assessment, and final inclusion is illustrated in the PRISMA flow diagram (Fig. 1 ). 3.2 Characteristics of the study Our meta-analysis included nine articles that had 11,401 participants to evaluate the correlation between serum 25(OH) D level and cervicovaginal hr-HPV infection. The included studies were conducted in several countries and a range of patients, including those with a diagnosed hr-HPV and also those with cervical cancer. The age of participants ranged from 8 to 70 years. Techniques employed in included studies for the detection of hr-HPV were nested polymerase chain reaction, linear array, and the Cobas 4800 test. Serum 25-hydroxyvitamin D level tests were performed using luminescence chemistry chemiluminescence immunoassay (CLIA), radioimmunoassay (RIA), liquid chromatography- mass spectrometry (LC-MS), and mass spectrometry (MS). The selected studies, arranged in order for this meta-analysis, are furnished in (Table 1) (13,19,28,33–38). 3.3 Risk of Bias Assessment: Quality assessment and identification of biases in the reviewed studies were performed using the critical appraisal checklist for cross-sectional studies by the Joanna Briggs Institute (39), and Robvis traffic light plots (Fig. 2 A) and summary (Fig. 2 B) were generated using the modified Rob-2 tool. 3.4 Association of serum 25-hydroxyvitamin D level with hr-HPV infection in Cervicovaginal Infections The present meta-analysis of the 6 studies included 487 hr-HPV-positive and 1,507 HPV negative cases. We employed the association between serum vitamin D levels and HPV infection in cervicovaginal infections in women (Fig. 3 ). We found that in the pooled analysis for all 6 studies, under random-effects modelling, have OR = 0.15 (95% CI: 0.03–0.70), (P = 0.016). This indicates a significant protective association between higher 25(OH)D levels and reduced cervicovaginal hr-HPV infection in the female population. The analysis of studies that observed the association between vitamin D deficiency and HPV showed hr-HPV positivity found in 27.54% of cervicovaginal infection cases. In comparison, HPV negativity was detected in 73.11% of cervicovaginal infection cases with normal serum vitamin D levels. These findings suggest an inverse relationship between serum vitamin D concentration and hr-HPV infection risk (data not shown). However, we found substantial heterogeneity (Q = 301.1526, P < 0.0001, I² = 98.34%). A funnel plot was created to assess publication bias using Egger’s funnel plot. Egger’s funnel plots show no significant asymmetry (Fig. 6 ) and according to Begg's test, there was no significant systematic publication bias. 3.4 Prevalence of smoking, hr-HPV infection, and serum 25-hydroxyvitamin D level status among cervicovaginal infections. The analysis of smoking exposure (including current and ex-smokers) prevalence in 5 included studies revealed a significant association of hr-HPV in cervicovaginal infections (Fig. 4 ). The pooled prevalence across studies was 47.63% (95% CI: 22.42–73.50%) in a random effect. Funnel plot evaluation of publication bias among the pooled and selected studies indicated significant heterogeneity (Q = 370.1874, DF = 4, P < 0.0001, I² = 98.92%). The pooled analysis results of 8 included studies is presented in (Fig. 5 ). The pooled prevalence of hr-HPV-positive cases among cervicovaginal infection in women from the random-effects model was 27.63% (95% CI: 18.21–38.16%). The overall heterogeneity in the meta-analysis was highly significant [(Q = 335.3518, DF = 7, P < 0.0001) and an I² of (97.91%)] indicates substantial variability among the included study outcomes. The meta-analysis of 8 included studies investigating the prevalence of low serum 25(OH)D levels in women with cervicovaginal infections showing pooled proportion of random model was 40.03% (95% CI: 27.72–53.00). The heterogeneity among studies was significantly high [(Q = 361.54, DF = 7, p < 0.0001) and an I² value of 98.06%)] (Fig. 6 ). The prevalence of smoking, hr-HPV positive infection, and low serum levels of 25(OH)D in cervicovaginal patients among women were expressed in the form of a funnel plot (Fig. 6 ). 4. Discussion This systematic review and meta-analysis aimed to comprehensively evaluate current evidence on whether vitamin D status influences the risk and persistence of cervicovaginal human papillomavirus (HPV) infection in women. Overall, the findings do not support a simple or consistent linear association between serum vitamin D levels and high-risk HPV (hr-HPV) infection. However, the synthesis of available data provides important insights into a potentially more complex and context-dependent relationship. To the best of our knowledge, this study represents the first meta-analysis to systematically examine the association between low serum vitamin D levels and hr-HPV infection in women, thereby addressing a critical gap in the literature. Previous work has reported no clear association between serum vitamin D levels and cervicovaginal HPV infection [ 12 ]. At the same time, the causal role of oncogenic HPV subtypes in cervical carcinogenesis is well established [ 39 , 40 ], underscoring the importance of identifying modifiable risk factors such as vitamin D status to enhance preventive strategies, particularly among younger women [ 41 , 42 ]. Our meta-analysis indicates a significant association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and increased risk of hr-HPV infection. Notably, the pooled odds ratio of 0.15 suggests a substantial reduction in HPV infection among individuals with higher vitamin D levels. However, considerable heterogeneity across studies suggests that these findings should be interpreted cautiously. Variability in population characteristics, study design, HPV detection methods, and thresholds used to define vitamin D deficiency likely contributed to this heterogeneity. Supporting our findings, Avila E et al. and El-Zein M et al. reported that sufficient vitamin D levels are associated with a reduced risk of HPV infection [ 14 , 19 , 26 ]. Mechanistically, several studies have proposed that vitamin D exerts immunomodulatory effects that may enhance viral clearance and reduce the persistence of HPV infection [ 14 , 41 ]. Nevertheless, other investigations have reported no statistically significant association between vitamin D deficiency and HPV infection, highlighting inconsistencies within the current body of evidence [ 19 , 33 , 34 ]. These conflicting results emphasize the need for further investigation into the complex interplay between vitamin D status and HPV pathogenesis. Biologically, the active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], plays a critical role in regulating immune responses and cellular differentiation [ 33 ]. The vitamin D receptor (VDR) has also been implicated in the development of gynecological malignancies [ 37 ]. Studies by Çakir et al. and Özgü E et al. suggest that vitamin D-mediated immunological mechanisms may influence HPV persistence and the progression of cervical intraepithelial neoplasia [ 37 , 43 ]. Furthermore, vitamin D has been shown to suppress the expression of HPV oncogenes E6 and E7, which are known to inactivate tumor suppressor proteins such as p53 and retinoblastoma (Rb), thereby promoting cervical carcinogenesis [ 26 , 44 ]. These oncoproteins are essential for viral persistence and are strongly associated with the development of cervical cancer [ 45 – 47 ]. Consequently, vitamin D deficiency may impair immune surveillance, facilitating persistent hr-HPV infection and increasing the risk of cervical dysplasia and cancer [ 35 , 37 , 43 , 48 ]. In this meta-analysis of eight studies involving 5,196 participants, the pooled prevalence of hr-HPV infection was 27.63%. A high degree of heterogeneity (I² = 97.91%) was observed, reflecting substantial differences in study populations, methodologies, and diagnostic approaches. Prior studies have highlighted the role of vitamin D in immune regulation, suggesting a potential impact on hr-HPV infection risk. For example, El-Zein M et al. and Çakir AT et al. reported that low serum vitamin D levels are associated with an increased risk of hr-HPV infection [ 19 , 37 ], supporting the hypothesis that vitamin D deficiency may compromise immune responses necessary for viral clearance. Smoking represents an important confounding and modifying factor in this relationship. Extensive evidence indicates that tobacco use contributes to HPV persistence and cervical carcinogenesis [ 49 , 50 ], consistent with findings from previous meta-analyses [ 51 ]. Mechanistically, smoking may promote hr-HPV persistence by reducing the number of Langerhans cells and CD4⁺ lymphocytes, which are critical for local immune defense [ 5 , 50 , 52 , 53 ]. Additionally, smoking impairs macrophage function and reduces natural killer (NK) cell activity, thereby weakening both innate and adaptive immune responses [ 48 , 54 ]. It has also been shown to downregulate key cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), further compromising antiviral immunity [ 55 – 57 ]. However, some studies have not identified a significant association between smoking and hr-HPV infection [ 48 ], contributing to the observed heterogeneity. The high statistical heterogeneity in our pooled analysis (Cochrane Q = 335.3518, I² = 97.91%) suggests that smoking status and other unmeasured confounders may influence the relationship between serum 25(OH)D levels and hr-HPV infection. Future systematic reviews and meta-analyses should incorporate detailed subgroup analyses to better elucidate the combined effects of vitamin D status, smoking, and other behavioral or clinical factors on HPV-related outcomes. From a clinical and public health perspective, our findings suggest that optimizing vitamin D status may represent a promising adjunctive strategy for reducing the burden of hr-HPV infection. Given the high global prevalence of vitamin D deficiency particularly in populations with limited sun exposure or inadequate dietary intake [ 58 ] population-level interventions aimed at improving vitamin D status may have significant preventive potential. Adequate vitamin D levels may reduce the frequency of hr-HPV infection and the risk of HPV-related diseases, including cervical cancer [ 4 , 14 , 19 , 33 – 35 ]. Furthermore, assessing and correcting vitamin D deficiency in women at risk of hr-HPV infection may enhance prevention and management strategies for cervical cancer [ 14 , 59 ]. Vitamin D supplementation, particularly when combined with HPV vaccination, may help reduce the persistence of hr-HPV infections, especially in vitamin D-deficient populations [ 60 ]. Lifestyle interventions, including safe sun exposure and dietary modification, may also contribute to reducing hr-HPV risk [ 14 ]. However, several limitations should be acknowledged. This meta-analysis was restricted to hr-HPV infections, and important variables such as HPV vaccination status, co-infection with other sexually transmitted infections, and longitudinal measures of HPV persistence were not consistently reported across included studies. These factors may significantly influence the observed associations and should be systematically addressed in future research 5. Conclusion This meta-analysis identifies a significant inverse association between serum 25-hydroxyvitamin D levels and high-risk cervicovaginal HPV infection, suggesting that vitamin D sufficiency may reduce susceptibility to hr-HPV, a central driver of cervical cancer. By integrating global evidence, this study provides novel insight into the potential immunomodulatory role of vitamin D in antiviral defence and HPV persistence. However, the observational nature of the included studies and substantial heterogeneity limit causal inference. Large, well-designed randomized controlled trials are required to confirm these findings and clarify clinical relevance. Future work should further elucidate the immunological mechanisms linking vitamin D to viral infections, informing integrated prevention strategies. Collectively, this study highlights vitamin D as a potentially modifiable host factor in HPV infection and offers a new perspective for advancing public health and cervical cancer prevention. Declarations Ethics approval and consent to participate Not applicable. This study is a systematic review and meta-analysis based exclusively on previously published studies and publicly available data. Therefore, ethical approval and informed consent were not required. Consent for publication Not applicable. This manuscript does not contain any individual person’s data in any form. Availability of data and materials All data generated or analyzed during this study are included in this published article and its supplementary information files. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions R.K. conceptualized the study, designed the methodology, supervised the literature search, led data extraction, performed the statistical analyses, and contributed to manuscript drafting and critical revision. A.S. co-developed the study design, conducted literature searching and screening, validated extracted data, performed the risk-of-bias assessment, prepared tables and figures, and wrote major portions of the introduction, discussion, and conclusion while critically refining the manuscript for intellectual accuracy. A.K.R. provided expert guidance on HPV biology and molecular mechanisms, assisted in data interpretation, resolved methodological discrepancies, and contributed to the scientific review of the manuscript. A.D. assisted in data organization, reference management, manuscript formatting, and final proofreading. All authors read and approved the final manuscript. Acknowledgements The authors are grateful to Royal Global University, Guwahati, Assam, India, for providing institutional support for this research. References Bruni, L. et al. Cervical human papillomavirus prevalence in five continents: meta-analysis of 1 million women with normal cytological findings. J. Infect. 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Effect of vitamin D on regression of HPV infection and metabolic parameters: a retrospective study. Eur. J. Gynaecol. Oncol. 42 (2021). Shim, J., Pérez, A., Symanski, E. & Nyitray, A. G. Association between serum 25-hydroxyvitamin D level and cervicovaginal HPV infection in women in the United States. J. Infect. Dis. 213 , 1886–1892 (2016). Troja, C. et al. Serum concentrations of emerging vitamin D biomarkers and detection of prevalent high-risk HPV infection in mid-adult women. Cancer Epidemiol. Biomarkers Prev. 29 , 1468–1474 (2020). Çakir, A. T. & Özten, M. A. Serum vitamin D levels in high-risk HPV-infected patients: is there any relation? J. Clin. Med. Kaz. 19 , 35–39 (2022). Chu, T. W. et al. Vitamin D in gynecological diseases. J. Chin. Med. Assoc. 84 , 1054–1059 (2021). Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16 , 1–17 (2003). IARC. Human papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (IARC, 2011). Pan, T., Banerjee, R., Dasgupta, A. & Paul, B. Vitamin D status among women aged ≥ 40 years in rural West Bengal. J. Fam Med. Prim. Care . 7 , 1263–1267 (2018). AlFaris, N. A. et al. Vitamin D deficiency and associated risk factors in women from Riyadh. Saudi Arabia Sci. Rep. 9 , 20371 (2019). Özgü, E. et al. Could 25-OH vitamin D deficiency explain HPV persistence in cervical premalignant lesions? J. Exp. Ther. Oncol. 11 , 177–180 (2016). Dong, H. et al. Vitamin D and its receptors in cervical cancer. J. Cancer . 15 , 926–938 (2024). Yim, E. K. & Park, J. S. The role of HPV E6 and E7 oncoproteins in cervical carcinogenesis. Cancer Res. Treat. 37 , 319–324 (2005). Di Zazzo, M. P. et al. HPV E6 and E7 oncoproteins cooperatively alter epithelial polarity protein expression. BMC Cancer . 20 , 293 (2020). Pal, A. & Kundu, R. Human papillomavirus E6 and E7: hallmarks and therapeutic targets. Front. Microbiol. 10 , 3116 (2020). El Mongy, N. N. et al. Serum vitamin D level in patients with viral warts. J. Egypt. Womens Dermatol. Soc. 15 , 133–138 (2018). Mzarico, E. et al. Relationship between smoking, HPV infection, and cervical cancer risk. Eur. J. Gynaecol. Oncol. 36 , 677–680 (2015). Vaccarella, S. et al. Smoking and human papillomavirus infection: pooled analysis from IARC HPV prevalence surveys. Int. J. Epidemiol. 37 , 536–546 (2008). Nagelhout, G. et al. Smoking as a risk factor for cervical neoplasia and cancer: a systematic review and meta-analysis. Expert Rev. Anticancer Ther. 21 , 781–794 (2021). Poppe, W. A. et al. Tobacco smoking impairs local immunosurveillance in the uterine cervix. Gynecol. Obstet. Invest. 39 , 34–38 (1995). Poppe, W. A. et al. Cervical cotinine and macrophage–Langerhans cell density in the uterine cervix. Gynecol. Obstet. Invest. 41 , 253–259 (1996). Jiang, C., Chen, Q. & Xie, M. Smoking increases the risk of infectious diseases: a narrative review. Tob. Induc. Dis. 18 , 60 (2020). Tollerud, D. J. et al. Association of cigarette smoking with decreased circulating natural killer cells. Am. Rev. Respir Dis. 139 , 194–198 (1989). Mian, M. F. et al. Cigarette smoke impairs natural killer cell cytotoxicity and cytokine release. J. Leukoc. Biol. 83 , 774–784 (2008). Corriden, R. et al. E-cigarette use increases susceptibility to infection via impaired neutrophil function. Am. J. Physiol. Cell. Physiol. 318 , C205–C214 (2020). Raymond-Lezman, J. R. & Riskin, S. I. Benefits and risks of sun exposure to maintain adequate vitamin D levels. Cureus 15 , e38578 (2023). Gholamalizadeh, M. et al. Effects of dietary supplements in patients with cervical cancer: a systematic review. Eur. J. Obstet. Gynecol. Reprod. Biol. X . 19 , 100217 (2023). Mei, Z., Hu, H., Zou, Y. & Li, D. The role of vitamin D in menopausal women’s health. Front. Physiol. 14 , 1211896 (2023). Tables Tabel 1 1Main characteristics of the included studies . Study Year Recruitment Country Sample size Types of Patients Study HPV Detection Technique Age (Year) Serum 25(OH)D Levels Detect Azmi H et al. (2022) 13 2021-2022 Morocco 63 Breast Cancer Case -control nested PCR 18-59 luminescence chemistry technique. García-Carrasco M et al. (2015) 33 2014 Mexico 67 HPV infected cross-sectional PCR and linear array assay - chemiluminescence immunoassay Koc S et al (2021) 34 2016-2018 Turkey 110 HPV infected Retrospective study, cross-sectional - 22-60 - El-Zein M (2021) 19 2005-2011 Canada 490 HPV infected Cross-sectional a Linear Array HPV genotyping assay 8–24 Total vitamin D assay kit Shim J et al. (2016) 35 2003–2006 USA 2353 HPV infected Cross-sectional Linear Array HPV genotyping tests 14–59 Radioimmunoassay kit Troja C, et al. (2020) 36 2011–2012 USA 404 HPV infected Cross-sectional Linear Assay 30–50 Immunoaffinity enrichment-liquid chromatography-tandem mass spectrometry, Çakir AT et al. (2022) 37 2020 Turkey. 143 HPV infected Case-Control Hybrid Capture2 30 -65 - Chu TW et al. (2021) 38 2018-2020 Taiwan 7699 HPV infected Case-Control Cobas 4800 HPV Test 20 -70 above Immunoassays analyze Troja C, et al. (2021) 28 2011–2012 s USA 72 PCRP and Linear Assay 30–50 LC-MS/MS Tabel 2 Assessment of quality evaluation of included studies using JBI criteria Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 %Yes Risk Azmi H et al. (2022) 13 Yes Yes Yes Yes Yes Yes Yes Yes No 88.8 Low García-Carrasco M et al. (2015) 30 Yes Yes Yes Yes Yes Yes Yes No Yes 88.8 Low Koc S et al (2021) 31 Yes No No Yes Yes Yes Yes Yes Yes 77.77 Low El-Zein M (2021) 19 Yes No Yes Yes Yes Yes Yes Yes Yes 100 Low Shim J et al. (2016) 32 No Yes Yes No Yes Yes Yes Yes No 66.66 Moderate Troja C, et al. (2020) 33 Yes Yes Yes No Yes Yes Yes Yes Yes 88.8 Low Çakir AT et al. (2022) 34 Yes Yes Yes Yes Yes Yes Yes No Yes 88.8 Low Chu TW et al. (2021) 35 No Yes Yes Yes Yes Yes Yes Yes Yes 100 Low Troja C, et al. (2021) 28 Yes Yes Yes Yes Yes Yes Yes Yes Yes 100 Low Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9398917","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":621946134,"identity":"b2f7a3c7-3f2d-4bdc-9db2-63c054f0116b","order_by":0,"name":"Rupesh Kumar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYLACxgYGBgMJBoYDHyqAPGbmBmK1MDM+nHEGpIWReC3MxrxtMC4eYD4j9+DDnzsYos2l+49JzpxXG83fDtTyo2IbTi0yN/KSjXnPMOTunHOYTeLjtuO5Mw4zNjD2nLmNU4uERI6ZNGMbQ+6GG8lskjO3HcttAGphZmzDq8X850+oFmneOcdy5xOhxYyBF6IF6P2GmtwNBLXwvEuW5m2TAPnF8OGMYwdyNwK1HMTrF/bcgx9/ttnkbpdufHDgQ01d7rzzhw8++FGBWwsDAw9YJ4x3GEwewKMepgUO6vArHgWjYBSMghEJAN8KXfxXA6ztAAAAAElFTkSuQmCC","orcid":"","institution":"The Assam Royal Global University","correspondingAuthor":true,"prefix":"","firstName":"Rupesh","middleName":"","lastName":"Kumar","suffix":""},{"id":621946135,"identity":"124c51d7-b99e-4d49-86b9-5e5c1df6a889","order_by":1,"name":"Aniruddha Sen","email":"","orcid":"","institution":"The Assam Royal Global University","correspondingAuthor":false,"prefix":"","firstName":"Aniruddha","middleName":"","lastName":"Sen","suffix":""},{"id":621946136,"identity":"6f4e05b2-3ef0-4040-9792-768a99fea9e3","order_by":2,"name":"Avdhesh Kumar Rai","email":"","orcid":"","institution":"Dr. B. Borooah Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Avdhesh","middleName":"Kumar","lastName":"Rai","suffix":""},{"id":621946137,"identity":"39a39409-4da2-4d98-8da7-db57d285e9f6","order_by":3,"name":"Abhijit Dutta","email":"","orcid":"","institution":"The Assam Royal Global University","correspondingAuthor":false,"prefix":"","firstName":"Abhijit","middleName":"","lastName":"Dutta","suffix":""}],"badges":[],"createdAt":"2026-04-13 05:23:02","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9398917/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9398917/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106878023,"identity":"212af436-4d4e-4476-a48e-1c7c72387cc6","added_by":"auto","created_at":"2026-04-14 10:43:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1992711,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of the literature search\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/71c23a65d09c3892200475e0.png"},{"id":106960946,"identity":"651d04ae-9f9e-46f9-9bcc-37323497bcf6","added_by":"auto","created_at":"2026-04-15 09:23:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":616989,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A): Robvis traffic light plots of the risk of bias assessment of the studies according to the modified Rob-2 tool for cross-sectional assessment tool.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(B): Summary of the risk of bias per item from D1 to D9.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/ec4112ff8ce44a1a4bd749ec.png"},{"id":106878025,"identity":"2a114531-548e-48cf-a33b-54251d3e1208","added_by":"auto","created_at":"2026-04-14 10:43:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1237296,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between HPV (+) and level of Vitamin D in cervicovaginal infection. (\u003cstrong\u003eA)\u003c/strong\u003e Meta-analysis of the results association between HPV infection and Vitamin D level in cervicovaginal infection \u003cstrong\u003e(B)\u003c/strong\u003eForest plot of the odds ratio in HPV and vitamin D \u003cstrong\u003e(C\u003c/strong\u003e) funnel plot of studies examining low level of Vitamin D as a risk factor in HPV infection.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/122318d8d9a0428ba9dd0ca7.png"},{"id":106878026,"identity":"e9a9a0fd-f289-4549-9b3c-a42d1f0ad1cd","added_by":"auto","created_at":"2026-04-14 10:43:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1085675,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Results of Prevalence of smoking status in cervicovaginal infection in women \u003cstrong\u003e(B\u003c/strong\u003e). Meta analysis of Forest plot in smoking habits (\u003cstrong\u003eC\u003c/strong\u003e) funnel plot of smoking habits\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/3b237c7f0179f93425d80e1c.png"},{"id":106878027,"identity":"8406a0b4-2132-4745-b9c9-4f944c83dd40","added_by":"auto","created_at":"2026-04-14 10:43:15","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1235248,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Results of Prevalence of HPV status in cervicovaginal infection in women \u003cstrong\u003e(B).\u003c/strong\u003e Meta analysis of Forest plot in HPV infection (\u003cstrong\u003eC)\u003c/strong\u003efunnel plot of HPV status\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/95e0a001964de5ff5da74628.png"},{"id":106878028,"identity":"91690699-d336-45a2-b9ec-7da7e11575a9","added_by":"auto","created_at":"2026-04-14 10:43:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1233064,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003eA\u003c/strong\u003e) Results of Prevalence of Vitamin D level in cervicovaginal infection in women \u003cstrong\u003e(B)\u003c/strong\u003e Meta analysis of Forest plot in vitamin D \u003cstrong\u003e(C)\u003c/strong\u003efunnel plot of vitamin D\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/7d0890e11fff29285cd6e9d3.png"},{"id":108180985,"identity":"893a0be4-c182-4599-a3db-6f2ad3dc6639","added_by":"auto","created_at":"2026-04-30 08:55:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8857284,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9398917/v1/6c7de59a-d6d1-435a-868a-08a510f7b3a4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Vitamin D status modulates high-risk human papillomavirus infection and persistence: a systematic review and meta-analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCervical cancer is the fourth most common cancer in women, with approximately 660,000 cases and 350,000 deaths reported worldwide in 2022 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The majority of cervical cancer cases occur in low- and middle-income countries (LMICs), including Brazil, South Africa, China, and India. According to the World Health Organisation (WHO), more than 90\u0026ndash;100% of cervical cancer is due to persistent high-risk human papilloma virus (hr-HPV) infection, particularly in women\u0026thinsp;\u0026lt;\u0026thinsp;35 years old [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is preventable with effective implementation of Papanicolaou smear screening towards early detection of pre-cancerous cervical intraepithelial neoplasia (CIN) lesions, and also with prophylactic vaccination against hr-HPV [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Human Papilloma Virus (HPV) is one of the most prevalent sexually transmitted infections worldwide, with over 200 types identified. Among these, at least 12 genotypes are considered high-risk due to their oncogenic potential at the cervix [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Hr- HPV types, particularly HPV-16 and HPV-18, are identified as causative factors for the majority of the cervical cancer cases (70%) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Following integration into the host DNA, HPV produces oncoproteins E6 and E7, which inhibit the tumour suppressor proteins p53 and pRb, respectively [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. p53 and pRb genes play a vital role in maintaining genome stability and cellular division, as well as the regulation of cell death [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Loss of function of p53 and pRb results in uncontrolled cell division, genetic mutations, and progression from low-grade CIN to invasive cervical cancer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In view of significant public health implication of hr-HPV infection, it is pertinent to identify factors that may facilitate in the efficiency/persistence of hr-HPV infection and subsequent carcinoma development [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In light of recent advancements in virology, research interest has spiked up in understanding the relationship between vitamin D status, as indicated by serum levels 25(OH)D levels, and HPV infections, especially high-risk HPV types [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, serum 25-hydroxyvitamin D (25[OH]D) concentrations may have role in modulating the host immune response to HPV infections. The level of vitamin D may enhance capabilities of the immune system in preventing viral infections, particularly DNA viruses and HPV, which may be associated with the development of cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Numerous studies suggest that, in addition to genetic, infectious, environmental, and lifestyle factors, deficiency in vitamin D etc. may be linked to an increased risk of developing cervical cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have investigated the role of Vitamin D in relation to HPV infections [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Vitamin D's immunomodulatory properties are particularly noteworthy as they influence the body's immune responses to viral infections, including HPV [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A study from Japan has shown an inverse relationship between vitamin D intake and the risk of CINs [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The beneficial effects of vitamin D on protective immunity may be due to its interaction with the constituents of the innate immune system [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Normally, serum levels of 25-hydroxyvitamin D (25[OH]D) are employed as a standard indicator of vitamin D measurement [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Vitamin D deficiency is often illustrated by circulating levels of 25(OH)D falling below 20 ng/ml (50 nmol/L). Vitamin D deficiency is suggested as a biomarker for immune-related diseases and susceptibility to infections, including HPV [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Low levels of 25-hydroxyvitamin D [25(OH)D] may be associated with a compromised immune system [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Several observational studies have suggested a potential association between low serum 25(OH)D levels and persistence of hr-HPV infections, although the mechanisms underlying this relationship remain poorly understood. As a result, there is an increasing interest in exploring how Vitamin D supplementation may influence the progression of high-risk HPV infections and whether it could serve as a potential therapeutic strategy in preventing hr-HPV infections.\u003c/p\u003e \u003cp\u003eThe immunomodulatory properties of vitamin D are hypothesised to play a role in limiting hr-HPV persistence and progression to malignancy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Vitamin D downregulates pro-inflammatory cytokines by promoting antimicrobial peptides like cathelicidin and defensins which are required for innate immune responses against viral infections [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Vitamin D affects the functional activity of dendritic cells and T-helper cells, thus increasing the specific response to hr-HPV infection [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Sufficient serum 25(OH)D levels may improve disease outcomes in women infected with hr- HPV types [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, research evidence on the relationship between serum 25(OH)D and hr- HPV infections is inconsistent. Several studies have reported strong relationships between vitamin D deficiency and subsequent hr-HPV infection persistence and/or CINs; however, many didn\u0026rsquo;t observe such positive associations [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Variability could be attributed to divergent populations, sample sizes, study techniques, or other factors such as age, sexual behaviour, and smoking.\u003c/p\u003e \u003cp\u003eThis systematic review and meta-analysis aimed to evaluate the association between serum 25-hydroxyvitamin D levels and the risk of high-risk human papillomavirus (HPV) cervicovaginal infections in women. We investigated whether vitamin D deficiency elevates HPV infection risk and its potential as a modifiable factor for HPV prevention, with implications for reducing cervical cancer incidence.\u003c/p\u003e"},{"header":"2. Methods and materials","content":"\u003cp\u003e\u003cstrong\u003e2.1 Search strategy and selection process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic search of the scientific literature was conducted to assess the association between serum 25-hydroxyvitamin D levels and high-risk HPV–related cervicovaginal infection in women. The search covered Google Scholar, PubMed, Web of Science, and Scopus, focusing on studies published between 2023 and 2024. The search terms included a combination of MeSH descriptors and free-text keywords such as “25-hydroxyvitamin D,” “high-risk HPV,” “cervicovaginal infections,” “HPV infection,” and “women.” No language restrictions were applied. Additionally, reference lists of eligible articles and pertinent reviews were screened to identify further relevant studies [29].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Inclusion and Exclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion and exclusion of studies were determined according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure methodological transparency and replicability [30].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies were included if they met the following criteria:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eStudy design:\u003c/strong\u003e Observational studies (cross-sectional, case-control, or cohort) that examined the association between serum 25-hydroxyvitamin D [25(OH)D] levels and high-risk human papillomavirus (hr-HPV) cervicovaginal infections in women.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePopulation:\u003c/strong\u003e Studies involving women of any age group, regardless of geographic region or ethnicity.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eExposure measurement:\u003c/strong\u003e Serum 25(OH)D concentrations reported in ng/mL or nmol/L, with clear definitions of vitamin D sufficiency, insufficiency, or deficiency.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOutcome measurement:\u003c/strong\u003e Detection of hr-HPV DNA using validated molecular techniques such as polymerase chain reaction (PCR), Hybrid Capture 2, Cobas 4800, or equivalent genotyping assays.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e Studies providing sufficient quantitative or qualitative data to estimate the relationship between vitamin D status and hr-HPV infection risk (e.g., prevalence, odds ratios, or raw counts).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePublication characteristics:\u003c/strong\u003e Full-text, peer-reviewed original articles published between 2003 and 2024 in English.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies were excluded based on the following considerations:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e\u003cstrong\u003ePublication type:\u003c/strong\u003e Reviews, meta-analyses, case reports, editorials, commentaries, letters to the editor, conference abstracts, or animal studies.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eData limitations:\u003c/strong\u003e Studies lacking clearly defined serum 25(OH)D measurements or without hr-HPV infection outcomes.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eStatistical insufficiency:\u003c/strong\u003e Studies that did not provide extractable or statistically significant data for meta-analysis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDuplication:\u003c/strong\u003e Repeated datasets or overlapping data from the same population; in such cases, the most comprehensive or recent study was retained.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAccessibility:\u003c/strong\u003e Studies without available full texts or those published in non-peer-reviewed sources.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eAll included studies were independently reviewed by two investigators. Any discrepancies regarding eligibility were resolved through discussion or consultation with a third reviewer to maintain objectivity and consistency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data Extraction and Validity Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe process of data extraction was carried out independently by two reviewers. In the event of a discrepancy regarding any selected article, the matter was discussed and resolved with the support of a non-associated reviewer. The extracted data were the name of the author/study, the year of publication, sample size, country of origin, study site, study design and the participant’s characteristics. The participant’s characteristics included age, their health status, serum 25(OH) D measured in the trial (mean and range) or according to deficiency status: deficient, insufficient, or adequate. Data regarding hr-HPV infection was collected, including information such as whether the woman had hr-HPV infections or how frequently she had such infections, and detection of HPV16 and/or HPV18 through PCR. All the collected data was exported directly into an analysis format in an Excel sheet. Finally, the quality of the evidence was summarised using the GRADE approach with its components, such as heterogeneity, precision, and publication bias, to assess confidence in the meta-analysis outcome [29-31].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Risk of\u0026nbsp;bias assessment and\u0026nbsp;quality of\u0026nbsp;studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe assessment of study quality and risk of bias was conducted using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data. This tool evaluates key aspects of study reliability through nine questions, with responses categorised as \u003cem\u003eYes\u003c/em\u003e, \u003cem\u003eNo\u003c/em\u003e, \u003cem\u003eUnclear\u003c/em\u003e, or \u003cem\u003eNot Applicable\u003c/em\u003e. Two independent authors (RK and AKR) applied the checklist to the selected studies, and any disagreements were resolved by the first author (RK) through a consensus-based approach or majority decision. The studies were scored based on the number of \u003cem\u003eYes\u003c/em\u003e responses, and their risk of bias was categorised as: Low risk: More than 70% \u003cem\u003eYes\u003c/em\u003e responses, Moderate risk: 50–70% \u003cem\u003eYes\u003c/em\u003e responses, High risk: Less than 50% \u003cem\u003eYes\u003c/em\u003e responses. Studies with a high risk of bias (below 50%) were excluded from further analysis and data synthesis to ensure the reliability of findings related to the prevalence of hr-HPV Cervicovaginal Infections in Women [29, 31, 32].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe meta-analysis was done using Microsoft Excel software (2013), MedCalc software (Version 19. 3) as well as RevMan software (Version 5. 3). To analyze dichotomised data, odd ratios (ORs) and 95% confidence interval (CI) were used. For continuous data and significance of heterogeneity, we used random effect model and measures of heterogeneity respectively [29]. The primary outcome was the cross-sectional relationship as ORs with 95% CI between serum 25(OH)D level and hr-HPV cervicovaginal infections. A P\u0026lt; 0.05 was considered as statistically significant level. The analysis was also conducted based on the 25(OH)D levels (such as deficiency and sufficiency) and other demographic variables as well according to availability. Based on the data, heterogeneity between studies were evaluated by using Cochran's Q test and also, we used I² statistic as one relevant measure for the degree of heterogeneity. \u0026nbsp;I² statistic denotes the proportion of the variability of effect to be related to heterogeneity instead of sampling errors. I² more than 50% was used to determine whether the values were differing significantly. Furthermore, when there was high level of heterogeneity the source of the heterogeneity was further investigated based on the following subgroups: geographic location, study type, and population. Sensitivity analysis was also performed after removing lower-quality studies (NOS \u0026lt;5). To check the presence of publication bias, Begg funnel plot and Egger's test were used, and the results were considered statistically significant if p \u0026lt; 0. 05 suggested publication bias [29-30, 32].\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Article selection process\u003c/h2\u003e \u003cp\u003eThis meta-analysis included both case-control and cross-sectional studies published between 2003 and 2022, retrieved from major electronic databases including PubMed, Scopus, Web of Science, and Google Scholar. The initial database search yielded 560 records related to the association between serum vitamin D levels and high-risk human papillomavirus (hr-HPV) cervicovaginal infection.\u003c/p\u003e \u003cp\u003eAfter removing 125 duplicate records using automated citation management tools and manual verification, 435 unique studies remained for title and abstract screening. Screening was conducted independently by two reviewers, focusing on study relevance and eligibility criteria. Studies were cross-checked for duplication based on author names, titles, publication year, volume, issue, and methodological parameters, and data were organized in a Microsoft Excel spreadsheet for transparency and reproducibility.\u003c/p\u003e \u003cp\u003eDuring the screening process, 42 studies were excluded for the following reasons: partially overlapping data (n\u0026thinsp;=\u0026thinsp;11), unrelated topics (n\u0026thinsp;=\u0026thinsp;16), insufficient information on serum 25-hydroxyvitamin D [25(OH)D] levels (n\u0026thinsp;=\u0026thinsp;9), and absence of hr-HPV outcome data (n\u0026thinsp;=\u0026thinsp;6). An additional 33 studies were excluded due to lack of quantitative or extractable data on hr-HPV cervicovaginal infections in women.\u003c/p\u003e \u003cp\u003eUltimately, nine studies (n\u0026thinsp;=\u0026thinsp;9) met all inclusion criteria and were incorporated into the qualitative synthesis, of which six provided sufficient quantitative data for meta-analysis. The detailed process of study identification, screening, eligibility assessment, and final inclusion is illustrated in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Characteristics of the study\u003c/h2\u003e \u003cp\u003eOur meta-analysis included nine articles that had 11,401 participants to evaluate the correlation between serum 25(OH) D level and cervicovaginal hr-HPV infection. The included studies were conducted in several countries and a range of patients, including those with a diagnosed hr-HPV and also those with cervical cancer. The age of participants ranged from 8 to 70 years. Techniques employed in included studies for the detection of hr-HPV were nested polymerase chain reaction, linear array, and the Cobas 4800 test. Serum 25-hydroxyvitamin D level tests were performed using luminescence chemistry chemiluminescence immunoassay (CLIA), radioimmunoassay (RIA), liquid chromatography- mass spectrometry (LC-MS), and mass spectrometry (MS). The selected studies, arranged in order for this meta-analysis, are furnished in (Table\u0026nbsp;1) (13,19,28,33\u0026ndash;38).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of Bias Assessment:\u003c/h2\u003e \u003cp\u003eQuality assessment and identification of biases in the reviewed studies were performed using the critical appraisal checklist for cross-sectional studies by the Joanna Briggs Institute (39), and Robvis traffic light plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) and summary (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) were generated using the modified Rob-2 tool.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003e3.4 Association of serum 25-hydroxyvitamin D level with hr-HPV infection in Cervicovaginal Infections\u003c/b\u003e\u003c/h2\u003e \u003cp\u003eThe present meta-analysis of the 6 studies included 487 hr-HPV-positive and 1,507 HPV negative cases. We employed the association between serum vitamin D levels and HPV infection in cervicovaginal infections in women (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We found that in the pooled analysis for all 6 studies, under random-effects modelling, have OR\u0026thinsp;=\u0026thinsp;0.15 (95% CI: 0.03\u0026ndash;0.70), (P\u0026thinsp;=\u0026thinsp;0.016). This indicates a significant protective association between higher 25(OH)D levels and reduced cervicovaginal hr-HPV infection in the female population. The analysis of studies that observed the association between vitamin D deficiency and HPV showed hr-HPV positivity found in 27.54% of cervicovaginal infection cases. In comparison, HPV negativity was detected in 73.11% of cervicovaginal infection cases with normal serum vitamin D levels. These findings suggest an inverse relationship between serum vitamin D concentration and hr-HPV infection risk (data not shown). However, we found substantial heterogeneity (Q\u0026thinsp;=\u0026thinsp;301.1526, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I\u0026sup2; = 98.34%). A funnel plot was created to assess publication bias using Egger\u0026rsquo;s funnel plot. Egger\u0026rsquo;s funnel plots show no significant asymmetry (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e) and according to Begg's test, there was no significant systematic publication bias.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Prevalence of smoking, hr-HPV infection, and serum 25-hydroxyvitamin D level status among cervicovaginal infections.\u003c/h2\u003e \u003cp\u003eThe analysis of smoking exposure (including current and ex-smokers) prevalence in 5 included studies revealed a significant association of hr-HPV in cervicovaginal infections (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The pooled prevalence across studies was 47.63% (95% CI: 22.42\u0026ndash;73.50%) in a random effect. Funnel plot evaluation of publication bias among the pooled and selected studies indicated significant heterogeneity (Q\u0026thinsp;=\u0026thinsp;370.1874, DF\u0026thinsp;=\u0026thinsp;4, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I\u0026sup2; = 98.92%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe pooled analysis results of 8 included studies is presented in (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The pooled prevalence of hr-HPV-positive cases among cervicovaginal infection in women from the random-effects model was 27.63% (95% CI: 18.21\u0026ndash;38.16%). The overall heterogeneity in the meta-analysis was highly significant [(Q\u0026thinsp;=\u0026thinsp;335.3518, DF\u0026thinsp;=\u0026thinsp;7, P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and an I\u0026sup2; of (97.91%)] indicates substantial variability among the included study outcomes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe meta-analysis of 8 included studies investigating the prevalence of low serum 25(OH)D levels in women with cervicovaginal infections showing pooled proportion of random model was 40.03% (95% CI: 27.72\u0026ndash;53.00). The heterogeneity among studies was significantly high [(Q\u0026thinsp;=\u0026thinsp;361.54, DF\u0026thinsp;=\u0026thinsp;7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and an I\u0026sup2; value of 98.06%)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e). The prevalence of smoking, hr-HPV positive infection, and low serum levels of 25(OH)D in cervicovaginal patients among women were expressed in the form of a funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis aimed to comprehensively evaluate current evidence on whether vitamin D status influences the risk and persistence of cervicovaginal human papillomavirus (HPV) infection in women. Overall, the findings do not support a simple or consistent linear association between serum vitamin D levels and high-risk HPV (hr-HPV) infection. However, the synthesis of available data provides important insights into a potentially more complex and context-dependent relationship.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this study represents the first meta-analysis to systematically examine the association between low serum vitamin D levels and hr-HPV infection in women, thereby addressing a critical gap in the literature. Previous work has reported no clear association between serum vitamin D levels and cervicovaginal HPV infection [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. At the same time, the causal role of oncogenic HPV subtypes in cervical carcinogenesis is well established [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], underscoring the importance of identifying modifiable risk factors such as vitamin D status to enhance preventive strategies, particularly among younger women [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur meta-analysis indicates a significant association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and increased risk of hr-HPV infection. Notably, the pooled odds ratio of 0.15 suggests a substantial reduction in HPV infection among individuals with higher vitamin D levels. However, considerable heterogeneity across studies suggests that these findings should be interpreted cautiously. Variability in population characteristics, study design, HPV detection methods, and thresholds used to define vitamin D deficiency likely contributed to this heterogeneity.\u003c/p\u003e \u003cp\u003eSupporting our findings, Avila E et al. and El-Zein M et al. reported that sufficient vitamin D levels are associated with a reduced risk of HPV infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Mechanistically, several studies have proposed that vitamin D exerts immunomodulatory effects that may enhance viral clearance and reduce the persistence of HPV infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Nevertheless, other investigations have reported no statistically significant association between vitamin D deficiency and HPV infection, highlighting inconsistencies within the current body of evidence [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These conflicting results emphasize the need for further investigation into the complex interplay between vitamin D status and HPV pathogenesis.\u003c/p\u003e \u003cp\u003eBiologically, the active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], plays a critical role in regulating immune responses and cellular differentiation [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The vitamin D receptor (VDR) has also been implicated in the development of gynecological malignancies [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Studies by \u0026Ccedil;akir et al. and \u0026Ouml;zg\u0026uuml; E et al. suggest that vitamin D-mediated immunological mechanisms may influence HPV persistence and the progression of cervical intraepithelial neoplasia [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Furthermore, vitamin D has been shown to suppress the expression of HPV oncogenes E6 and E7, which are known to inactivate tumor suppressor proteins such as p53 and retinoblastoma (Rb), thereby promoting cervical carcinogenesis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. These oncoproteins are essential for viral persistence and are strongly associated with the development of cervical cancer [\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Consequently, vitamin D deficiency may impair immune surveillance, facilitating persistent hr-HPV infection and increasing the risk of cervical dysplasia and cancer [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this meta-analysis of eight studies involving 5,196 participants, the pooled prevalence of hr-HPV infection was 27.63%. A high degree of heterogeneity (I\u0026sup2; = 97.91%) was observed, reflecting substantial differences in study populations, methodologies, and diagnostic approaches. Prior studies have highlighted the role of vitamin D in immune regulation, suggesting a potential impact on hr-HPV infection risk. For example, El-Zein M et al. and \u0026Ccedil;akir AT et al. reported that low serum vitamin D levels are associated with an increased risk of hr-HPV infection [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], supporting the hypothesis that vitamin D deficiency may compromise immune responses necessary for viral clearance.\u003c/p\u003e \u003cp\u003eSmoking represents an important confounding and modifying factor in this relationship. Extensive evidence indicates that tobacco use contributes to HPV persistence and cervical carcinogenesis [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], consistent with findings from previous meta-analyses [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Mechanistically, smoking may promote hr-HPV persistence by reducing the number of Langerhans cells and CD4⁺ lymphocytes, which are critical for local immune defense [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Additionally, smoking impairs macrophage function and reduces natural killer (NK) cell activity, thereby weakening both innate and adaptive immune responses [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. It has also been shown to downregulate key cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), further compromising antiviral immunity [\u003cspan additionalcitationids=\"CR56\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. However, some studies have not identified a significant association between smoking and hr-HPV infection [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], contributing to the observed heterogeneity.\u003c/p\u003e \u003cp\u003eThe high statistical heterogeneity in our pooled analysis (Cochrane Q\u0026thinsp;=\u0026thinsp;335.3518, I\u0026sup2; = 97.91%) suggests that smoking status and other unmeasured confounders may influence the relationship between serum 25(OH)D levels and hr-HPV infection. Future systematic reviews and meta-analyses should incorporate detailed subgroup analyses to better elucidate the combined effects of vitamin D status, smoking, and other behavioral or clinical factors on HPV-related outcomes.\u003c/p\u003e \u003cp\u003eFrom a clinical and public health perspective, our findings suggest that optimizing vitamin D status may represent a promising adjunctive strategy for reducing the burden of hr-HPV infection. Given the high global prevalence of vitamin D deficiency particularly in populations with limited sun exposure or inadequate dietary intake [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] population-level interventions aimed at improving vitamin D status may have significant preventive potential. Adequate vitamin D levels may reduce the frequency of hr-HPV infection and the risk of HPV-related diseases, including cervical cancer [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, assessing and correcting vitamin D deficiency in women at risk of hr-HPV infection may enhance prevention and management strategies for cervical cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Vitamin D supplementation, particularly when combined with HPV vaccination, may help reduce the persistence of hr-HPV infections, especially in vitamin D-deficient populations [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Lifestyle interventions, including safe sun exposure and dietary modification, may also contribute to reducing hr-HPV risk [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, several limitations should be acknowledged. This meta-analysis was restricted to hr-HPV infections, and important variables such as HPV vaccination status, co-infection with other sexually transmitted infections, and longitudinal measures of HPV persistence were not consistently reported across included studies. These factors may significantly influence the observed associations and should be systematically addressed in future research\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis meta-analysis identifies a significant inverse association between serum 25-hydroxyvitamin D levels and high-risk cervicovaginal HPV infection, suggesting that vitamin D sufficiency may reduce susceptibility to hr-HPV, a central driver of cervical cancer. By integrating global evidence, this study provides novel insight into the potential immunomodulatory role of vitamin D in antiviral defence and HPV persistence. However, the observational nature of the included studies and substantial heterogeneity limit causal inference. Large, well-designed randomized controlled trials are required to confirm these findings and clarify clinical relevance. Future work should further elucidate the immunological mechanisms linking vitamin D to viral infections, informing integrated prevention strategies. Collectively, this study highlights vitamin D as a potentially modifiable host factor in HPV infection and offers a new perspective for advancing public health and cervical cancer prevention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable. This study is a systematic review and meta-analysis based exclusively on previously published studies and publicly available data. Therefore, ethical approval and informed consent were not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This manuscript does not contain any individual person’s data in any form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eR.K. conceptualized the study, designed the methodology, supervised the literature search, led data extraction, performed the statistical analyses, and contributed to manuscript drafting and critical revision.\u003c/p\u003e\n\u003cp\u003eA.S. co-developed the study design, conducted literature searching and screening, validated extracted data, performed the risk-of-bias assessment, prepared tables and figures, and wrote major portions of the introduction, discussion, and conclusion while critically refining the manuscript for intellectual accuracy.\u003c/p\u003e\n\u003cp\u003eA.K.R. provided expert guidance on HPV biology and molecular mechanisms, assisted in data interpretation, resolved methodological discrepancies, and contributed to the scientific review of the manuscript.\u003c/p\u003e\n\u003cp\u003eA.D. assisted in data organization, reference management, manuscript formatting, and final proofreading.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Royal Global University, Guwahati, Assam, India, for providing institutional support for this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBruni, L. et al. 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Soc.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 133\u0026ndash;138 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMzarico, E. et al. Relationship between smoking, HPV infection, and cervical cancer risk. \u003cem\u003eEur. J. Gynaecol. Oncol.\u003c/em\u003e \u003cb\u003e36\u003c/b\u003e, 677\u0026ndash;680 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaccarella, S. et al. Smoking and human papillomavirus infection: pooled analysis from IARC HPV prevalence surveys. \u003cem\u003eInt. J. Epidemiol.\u003c/em\u003e \u003cb\u003e37\u003c/b\u003e, 536\u0026ndash;546 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagelhout, G. et al. Smoking as a risk factor for cervical neoplasia and cancer: a systematic review and meta-analysis. \u003cem\u003eExpert Rev. Anticancer Ther.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 781\u0026ndash;794 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoppe, W. 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Respir Dis.\u003c/em\u003e \u003cb\u003e139\u003c/b\u003e, 194\u0026ndash;198 (1989).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMian, M. F. et al. Cigarette smoke impairs natural killer cell cytotoxicity and cytokine release. \u003cem\u003eJ. Leukoc. Biol.\u003c/em\u003e \u003cb\u003e83\u003c/b\u003e, 774\u0026ndash;784 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorriden, R. et al. E-cigarette use increases susceptibility to infection via impaired neutrophil function. \u003cem\u003eAm. J. Physiol. Cell. Physiol.\u003c/em\u003e \u003cb\u003e318\u003c/b\u003e, C205\u0026ndash;C214 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaymond-Lezman, J. R. \u0026amp; Riskin, S. I. Benefits and risks of sun exposure to maintain adequate vitamin D levels. \u003cem\u003eCureus\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, e38578 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGholamalizadeh, M. et al. Effects of dietary supplements in patients with cervical cancer: a systematic review. \u003cem\u003eEur. J. Obstet. Gynecol. Reprod. Biol. X\u003c/em\u003e. \u003cb\u003e19\u003c/b\u003e, 100217 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMei, Z., Hu, H., Zou, Y. \u0026amp; Li, D. The role of vitamin D in menopausal women\u0026rsquo;s health. \u003cem\u003eFront. Physiol.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, 1211896 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTabel 1\u0026nbsp;\u003c/strong\u003e1Main characteristics of the included studies\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eRecruitment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTypes of Patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHPV Detection Technique\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(Year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum 25(OH)D Levels Detect\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAzmi H et al. (2022) \u003csup\u003e13\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2021-2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMorocco\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eBreast Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCase -control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003enested PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e18-59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eluminescence chemistry technique.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGarc\u0026iacute;a-Carrasco M et al. (2015) \u003csup\u003e33\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMexico\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003ecross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePCR and linear\u003c/p\u003e\n \u003cp\u003earray assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003echemiluminescence immunoassay\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKoc S et al (2021) \u003csup\u003e34\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2016-2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eTurkey\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eRetrospective\u003c/p\u003e\n \u003cp\u003estudy, cross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e22-60\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEl-Zein M\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(2021) \u003csup\u003e19\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2005-2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e490\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCross-sectional a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eLinear Array HPV genotyping assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e8\u0026ndash;24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eTotal vitamin D assay kit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eShim J et al. (2016) \u003csup\u003e35\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2003\u0026ndash;2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e2353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eLinear Array HPV genotyping tests\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e14\u0026ndash;59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eRadioimmunoassay\u003c/p\u003e\n \u003cp\u003ekit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTroja C, et al. (2020) \u003csup\u003e36\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2011\u0026ndash;2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eLinear Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30\u0026ndash;50\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eImmunoaffinity enrichment-liquid chromatography-tandem mass spectrometry,\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Ccedil;akir\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;AT et al. (2022) \u003csup\u003e37\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eTurkey.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCase-Control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eHybrid Capture2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30 -65\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChu TW et al. (2021) \u003csup\u003e38\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2018-2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eTaiwan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e7699\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eHPV infected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCase-Control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eCobas 4800 HPV Test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e20 -70 above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eImmunoassays analyze\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTroja C, et al. (2021) \u003csup\u003e28\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2011\u0026ndash;2012 s\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePCRP and\u0026nbsp;Linear Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003e30\u0026ndash;50\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eLC-MS/MS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTabel 2\u003c/strong\u003e Assessment of quality evaluation of included studies using JBI criteria\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%Yes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAzmi H et al. (2022) \u003csup\u003e13\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e88.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGarc\u0026iacute;a-Carrasco M et al. (2015) \u003csup\u003e30\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e88.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKoc S et al (2021) \u003csup\u003e31\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e77.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEl-Zein M (2021) \u003csup\u003e19\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eShim J et al. (2016) \u003csup\u003e32\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e66.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTroja C, et al. (2020) \u003csup\u003e33\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e88.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Ccedil;akir AT et al. (2022) \u003csup\u003e34\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e88.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChu TW et al. (2021) \u003csup\u003e35\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTroja C, et al. (2021) \u003csup\u003e28\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"25-hydroxyvitamin D, vitamin D deficiency, high-risk HPV, cervicovaginal infection, cervical cancer, meta-analysis, immunomodulation","lastPublishedDoi":"10.21203/rs.3.rs-9398917/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9398917/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHigh-risk human papillomavirus (hr-HPV) infection is the principal cause of cervical cancer worldwide. Emerging evidence suggests that serum 25-hydroxyvitamin D [25(OH)D], a key immunomodulatory biomarker, may influence susceptibility to HPV infection and its persistence; however, findings remain inconsistent. In this study, we conducted a systematic review and meta-analysis to evaluate the association between serum 25(OH)D levels and cervicovaginal hr-HPV infection in women. A comprehensive literature search of PubMed, Scopus, Web of Science, and Google Scholar was performed for studies published between 2003 and 2024. Study quality was assessed using Joanna Briggs Institute (JBI) criteria, and pooled odds ratios (ORs) were estimated using a random-effects model. Nine studies comprising 11,401 participants met the inclusion criteria, of which six were included in the quantitative synthesis. Vitamin D sufficiency was associated with significantly reduced odds of hr-HPV infection (OR\u0026thinsp;=\u0026thinsp;0.15; 95% CI: 0.03\u0026ndash;0.70; p\u0026thinsp;=\u0026thinsp;0.016), although substantial heterogeneity was observed (I\u0026sup2; = 98.3%). The pooled prevalence of hr-HPV infection was 27.63%, while vitamin D deficiency was present in 40.03% of participants. These findings suggest a potentially novel, stage-specific role for vitamin D in modulating HPV persistence rather than initial acquisition, possibly through effects on local immune responses and viral clearance. Optimizing vitamin D status may represent a complementary, host-directed strategy to reduce the progression of hr-HPV-related cervical disease; however, further well-designed longitudinal studies are required to confirm causality and clarify underlying mechanisms.\u003c/p\u003e","manuscriptTitle":"Vitamin D status modulates high-risk human papillomavirus infection and persistence: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 10:43:08","doi":"10.21203/rs.3.rs-9398917/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33c2ec46-d30e-41c4-afee-042db8498b21","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66180156,"name":"Health sciences/Biomarkers"},{"id":66180157,"name":"Biological sciences/Cancer"},{"id":66180158,"name":"Health sciences/Diseases"},{"id":66180159,"name":"Biological sciences/Immunology"},{"id":66180160,"name":"Health sciences/Medical research"},{"id":66180161,"name":"Biological sciences/Microbiology"}],"tags":[],"updatedAt":"2026-04-16T18:24:50+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 10:43:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9398917","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9398917","identity":"rs-9398917","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}