{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:27:33Z","timestamp":1786627653321,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human papillomavirus (HPV) infection represents one of the most common sexually transmitted infections worldwide. However, the lack of effective therapeutic strategies to counteract viral infection and its persistence still makes the management of HPV a medical concern. Persistence is indeed a crucial issue in the context of HPV, as it may increase the risk of viral DNA integration into the host genome, thus exposing patients to tumoral progression. This clinical study aims to evaluate the effectiveness of a dietary supplement containing epigallocatechin gallate (EGCG), folic acid (FA), vitamin B12 (B12), and hyaluronic acid (HA) in improving HPV clearance and HPV-induced cervical lesions, and in counteracting viral persistence. A total of 106 patients who tested positive for HPV DNA were enrolled in this study and were treated daily for 6 months with a tablet containing EGCG (200 mg), FA (400 \u03bcg), B12 (1 mg), and HA (50 mg) (Pervistop\u00ae, Lo.Li. Pharma, Rome, Italy). A 6-month treatment with such combined molecules demonstrated a viral clearance in 85.8% of enrolled patients, while 92.3% of participants exhibited no more cervical lesions. Furthermore, 71.8% of patients with persistent infection tested negative to HPV DNA test after 6 months of treatment. The obtained data in this large population strongly support previous evidence on the efficacy of such molecules in the management of HPV infection by improving both viral clearance and related cervical lesions, and by targeting viral persistence.<\/jats:p>","DOI":"10.3390\/ijms26115251","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T06:14:27Z","timestamp":1748585667000},"page":"5251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oral Treatment with EGCG, Folic Acid, Vitamin B12, and Hyaluronic Acid Improves HPV Clearance and Counteracts Its Persistence: A Clinical Study"],"prefix":"10.3390","volume":"26","author":[{"given":"Giuseppina","family":"Porcaro","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics, Women\u2019s Health Centre, 05100 Terni, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Pavone-Cossut","sequence":"additional","affiliation":[{"name":"National HIV\/AIDS Research Center, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Moretti","sequence":"additional","affiliation":[{"name":"National HIV\/AIDS Research Center, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Bilotta","sequence":"additional","affiliation":[{"name":"IVF Clinic, Alma Res Fertility Center, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Aragona","sequence":"additional","affiliation":[{"name":"Systems Biology Laboratory, Department of Experimental Medicine, Sapienza University, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1805-3181","authenticated-orcid":false,"given":"Vittorio","family":"Unfer","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, UniCamillus\u2014Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16086","DOI":"10.1038\/nrdp.2016.86","article-title":"Carcinogenic human papillomavirus infection","volume":"2","author":"Schiffman","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mlynarczyk-Bonikowska, B., and Rudnicka, L. (2024). HPV Infections-Classification, Pathogenesis, and Potential New Therapies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147616"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shanmugasundaram, S., and You, J. (2017). Targeting Persistent Human Papillomavirus Infection. Viruses, 9.","DOI":"10.3390\/v9080229"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"864","DOI":"10.20892\/j.issn.2095-3941.2020.0370","article-title":"Biological and clinical aspects of HPV-related cancers","volume":"17","author":"Szymonowicz","year":"2020","journal-title":"Cancer Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/aje\/kwn036","article-title":"Persistent human papillomavirus infection and cervical neoplasia: A systematic review and meta-analysis","volume":"168","author":"Koshiol","year":"2008","journal-title":"Am. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s10096-020-04073-6","article-title":"Prevalence of genital HPV infection in STI and healthy populations and risk factors for viral persistence","volume":"40","author":"Ciccarese","year":"2021","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.bpobgyn.2017.08.015","article-title":"The natural history of human papillomavirus infection","volume":"47","author":"Brotons","year":"2018","journal-title":"Best. Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1080\/15384101.2016.1191257","article-title":"HPV-mediated inactivation of tumor suppressor p53","volume":"15","author":"Zanier","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.4014\/jmb.2208.08020","article-title":"Dynamics of Viral and Host 3D Genome Structure upon Infection","volume":"32","author":"Friedman","year":"2022","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yap, J.K.W., Kehoe, S.T., Woodman, C.B.J., and Dawson, C.W. (2021). The Major Constituent of Green Tea, Epigallocatechin-3-Gallate (EGCG), Inhibits the Growth of HPV18-Infected Keratinocytes by Stimulating Proteasomal Turnover of the E6 and E7 Oncoproteins. Pathogens, 10.","DOI":"10.3390\/pathogens10040459"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, Y.Q., Lu, J.L., Liang, Y.R., and Li, Q.S. (2018). Suppressive Effects of EGCG on Cervical Cancer. Molecules, 23.","DOI":"10.3390\/molecules23092334"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Song, J.Y., Han, J.H., Song, Y., Lee, J.H., Choi, S.Y., and Park, Y.M. (2021). Epigallocatechin-3-gallate Can Prevent Type 2 Human Papillomavirus E7 from Suppressing Interferon-Stimulated Genes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052418"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8788","DOI":"10.1158\/0008-5472.CAN-04-2402","article-title":"Folate is associated with the natural history of high-risk human papillomaviruses","volume":"64","author":"Piyathilake","year":"2004","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2147\/IJWH.S6522","article-title":"Indian women with higher serum concentrations of folate and vitamin B12 are significantly less likely to be infected with carcinogenic or high-risk (HR) types of human papillomaviruses (HPVs)","volume":"2","author":"Piyathilake","year":"2010","journal-title":"Int. J. Womens Health"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jin, S., Lin, F., Yang, L., and Zhang, Q. (2024). Association between dietary folate intake and HPV infection: NHANES 2005-2016. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0306636"},{"key":"ref_16","first-page":"866","article-title":"[Relationship between serum folate and CIN1 prognosis and its interaction with HR-HPV infection]","volume":"43","author":"Qi","year":"2021","journal-title":"Zhonghua Zhong Liu Za Zhi"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3892\/etm.2020.9316","article-title":"Non-sexual HPV transmission and role of vaccination for a better future (Review)","volume":"20","author":"Petca","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc2050","article-title":"The natural history of cervical HPV infection: Unresolved issues","volume":"7","author":"Woodman","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2221","DOI":"10.1097\/GOX.0000000000002221","article-title":"Hyaluronic Acid Accelerates Re-epithelialization and Alters Protein Expression in a Human Wound Model","volume":"7","author":"Nyman","year":"2019","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Waggett, S., Lyles, E., and Schlesinger, T. (2024). Update on Low-Molecular Weight Hyaluronic Acid in Dermatology: A Scoping Review. EMJ Dermatol., 134\u2013146.","DOI":"10.33590\/emjdermatol\/CCHB4701"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1021\/acsabm.0c01364","article-title":"Role of Hyaluronic Acids and Potential as Regenerative Biomaterials in Wound Healing","volume":"4","author":"Yang","year":"2021","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lagan\u00e0, A.S., Chiantera, V., Gerli, S., Proietti, S., Lepore, E., Unfer, V., Carugno, J., and Favilli, A. (2023). Preventing Persistence of HPV Infection with Natural Molecules. Pathogens, 12.","DOI":"10.3390\/pathogens12030416"},{"key":"ref_23","first-page":"5240","article-title":"Epigallocatechin gallate, folic acid, vitamin B12, and hyaluronic acid significantly increase apoptosis and p53 expression in HeLa cells","volume":"27","author":"Frega","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Aragona, C., Bezerra Espinola, M.S., Bilotta, G., Porcaro, G., and Calcagno, M. (2023). Evaluating the Efficacy of Pervistop((R)), a New Combination Based on EGCG, Folic Acid, Vitamin B12 and Hyaluronic Acid on Patients with Human Papilloma Virus (HPV) Persistent Infections and Cervical Lesions: A Pilot Study. J. Clin. Med., 12.","DOI":"10.3390\/jcm12062171"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tinelli, A., Gustapane, S., Licchelli, M., Coluccia, A.C., Panese, G., Proietti, S., and Gambioli, R. (2024). Treatment with Epigallocatechin Gallate, Folic Acid, Vitamin B12, and Hyaluronic Acid Decreases HPV Positivity in Women Attending Regional Screening in Puglia. Microorganisms, 12.","DOI":"10.3390\/microorganisms12091897"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Calcagno, M., Incocciati, B., Di Fraia, L., and Unfer, V. (2024). Counteracting HPV Cervical and Anal Infection through Dietary Supplementation of EGCG, Folic Acid, Vitamin B12 and Hyaluronic Acid: Clinical Case Reports. J. Clin. Med., 13.","DOI":"10.3390\/jcm13123597"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/IGC.0b013e3181c7ca5c","article-title":"Green tea compound in chemoprevention of cervical cancer","volume":"20","author":"Zou","year":"2010","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Alam, M., Ali, N., Rashid, S., Glowacka, P., Sundaraj, R., Celik, I., Yahya, E.B., Dubey, A., and Zerroug, E. (2023). Epigallocatechin-3-Gallate Therapeutic Potential in Cancer: Mechanism of Action and Clinical Implications. Molecules, 28.","DOI":"10.3390\/molecules28135246"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1093\/jn\/nxx060","article-title":"Folate Deficiency Facilitates Genomic Integration of Human Papillomavirus Type 16 DNA In Vivo in a Novel Mouse Model for Rapid Oncogenic Transformation of Human Keratinocytes","volume":"148","author":"Xiao","year":"2018","journal-title":"J. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E106","DOI":"10.25011\/cim.v31i3.3467","article-title":"Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing","volume":"31","author":"Gao","year":"2008","journal-title":"Clin. Investig. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/LGT.0000000000000525","article-title":"2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors","volume":"24","author":"Perkins","year":"2020","journal-title":"J. Low. Genit. Tract. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e6862","DOI":"10.1002\/cam4.6862","article-title":"A comprehensive narrative review of challenges and facilitators in the implementation of various HPV vaccination program worldwide","volume":"13","author":"Aggarwal","year":"2024","journal-title":"Cancer Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1002\/ijc.29971","article-title":"Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study","volume":"138","author":"Skinner","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Grandi, G., Botticelli, L., Fraia, P.D., Babalini, C., Masini, M., and Unfer, V. (2023). The Association of Four Natural Molecules-EGCG, Folic Acid, Vitamin B12, and HA-To Counteract HPV Cervical Lesions: A Case Report. J. Pers. Med., 13.","DOI":"10.3390\/jpm13030567"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1086\/315086","article-title":"Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer","volume":"180","author":"Franco","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1086\/341782","article-title":"Incidence, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women\u2019s Health Study","volume":"186","author":"Giuliano","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1086\/426867","article-title":"A longitudinal study of genital human papillomavirus infection in a cohort of closely followed adolescent women","volume":"191","author":"Brown","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0022-3476(98)70445-7","article-title":"The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women","volume":"132","author":"Moscicki","year":"1998","journal-title":"J. Pediatr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.2147\/IJWH.S515393","article-title":"The Relationship between Systemic Expression Levels of Immune Cells and Tumor Markers and High-Risk HPV Infection in Patients with Cervical Cancer, Cervical Intraepithelial Neoplasia, and Chronic Cervicitis, and its Clinical Significance","volume":"17","author":"Guo","year":"2025","journal-title":"Int. J. Womens Health"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1001\/jama.287.16.2114","article-title":"The 2001 Bethesda System: Terminology for reporting results of cervical cytology","volume":"287","author":"Solomon","year":"2002","journal-title":"Jama"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.pvr.2016.01.003","article-title":"Clinical and analytical performance of the BD Onclarity\u2122 HPV assay for detection of CIN2+ lesions on SurePath samples","volume":"2","author":"Ejegod","year":"2016","journal-title":"Papillomavirus Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Martinelli, M., Giubbi, C., Sechi, I., Bottari, F., Iacobone, A.D., Musumeci, R., Perdoni, F., Muresu, N., Piana, A., and Fruscio, R. (2022). Evaluation of BD Onclarity\u2122 HPV Assay on Self-Collected Vaginal and First-Void Urine Samples as Compared to Clinician-Collected Cervical Samples: A Pilot Study. Diagnostics, 12.","DOI":"10.3390\/diagnostics12123075"},{"key":"ref_43","first-page":"886","article-title":"[ISO 9001:2015 Certification in Quality Management]","volume":"234","author":"Enders","year":"2017","journal-title":"Klin. Monbl Augenheilkd."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), Younes, M., Aggett, P., Aguilar, F., Crebelli, R., Dusemund, B., Filipic, M., Frutos, M.J., Galtier, P., and Gott, D. (2018). Scientific opinion on the safety of green tea catechins. EFSA J., 16, e05239.","DOI":"10.2903\/j.efsa.2018.5239"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:43:34Z","timestamp":1760031814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/11\/5251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,29]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26115251"],"URL":"https:\/\/doi.org\/10.3390\/ijms26115251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,29]]}}}