Long-term follow-up results of topical imiquimod for high-grade cervical intraepithelial neoplasia in young women: an original research
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Abstract Background As cervical excisional treatment is associated with adverse pregnancy outcomes, imiquimod has been explored in several studies—such as the TOPIC-3—as an alternative but without success. Therefore, we designed a study focusing on patients aged < 35 years to verify its efficacy. Methods We conducted a retrospective, single-arm cohort study, gathering the medical records of nulliparous women aged < 35 years who had never undergone cervical excisional therapy between October 2021 and March 2024. The primary goal was to identify the rate of histological regression and high-risk Human Papillomavirus (HPV) clearance at 3, 6, and 12 months, as well as beyond, after completing 8 weeks of weekly imiquimod treatment. Results The immediate regression rate from cervical intraepithelial neoplasia (CIN) 2 or 3 lesions to at least CIN 1 was 96.0% after 8 weeks of weekly imiquimod therapy, and the HPV clearance rate at that time was 47.3%. During follow-up, the observed rates of complete remission to normal, regression lower than that of CIN 1, and HPV clearance were 81.6%, 92.9%, and 56.0%, respectively. Notably, the subgroup of patients diagnosed with CIN 2 without HPV16 or 18 achieved the highest regression rate of 96.5%. Among the patients, 7.1% showed persistent disease, and only 1.0% underwent cervical invasive therapies. Conclusions We suggest that topical imiquimod therapies could serve as a potential alternative to postponing cervical excisional therapies for up to 1 year in women < 35 years with CIN2 or 3, who are concerned about future pregnancy outcomes.
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Therefore, we designed a study focusing on patients aged < 35 years to verify its efficacy. Methods We conducted a retrospective, single-arm cohort study, gathering the medical records of nulliparous women aged < 35 years who had never undergone cervical excisional therapy between October 2021 and March 2024. The primary goal was to identify the rate of histological regression and high-risk Human Papillomavirus (HPV) clearance at 3, 6, and 12 months, as well as beyond, after completing 8 weeks of weekly imiquimod treatment. Results The immediate regression rate from cervical intraepithelial neoplasia (CIN) 2 or 3 lesions to at least CIN 1 was 96.0% after 8 weeks of weekly imiquimod therapy, and the HPV clearance rate at that time was 47.3%. During follow-up, the observed rates of complete remission to normal, regression lower than that of CIN 1, and HPV clearance were 81.6%, 92.9%, and 56.0%, respectively. Notably, the subgroup of patients diagnosed with CIN 2 without HPV16 or 18 achieved the highest regression rate of 96.5%. Among the patients, 7.1% showed persistent disease, and only 1.0% underwent cervical invasive therapies. Conclusions We suggest that topical imiquimod therapies could serve as a potential alternative to postponing cervical excisional therapies for up to 1 year in women < 35 years with CIN2 or 3, who are concerned about future pregnancy outcomes. Imiquimod Uterine Cervical Dysplasia Human Papillomavirus Viruses Retrospective Studies Demography Fertility Figures Figure 1 Background Recently released demographic data show that the total incidence of cervical cancer in South Korea has been decreasing. However, the prevalence of cervical cancer among those aged 15–34 years is approximately 4.4 per 100, 000 persons. [ 1 ] As the age at first pregnancy increases, the incidence of high-grade cervical intraepithelial neoplasia (CIN) increases when a person becomes pregnant for the first time. According to the 2019 American Society for Colposcopy and Cervical Pathology guidelines, observation is recommended for women diagnosed with CIN2 who are aged < 25 years. In the patient group diagnosed with CIN3, diagnostic excisional therapy is recommended regardless of their age. [ 2 ] However, observations alone are not always sufficient as alternatives. A recent study involving follow-up of 2,417 women aged 21–39 diagnosed with CIN2 over an average of 4 years showed that 30% were eventually treated during the study because of persistent disease. [ 3 ] Excisional therapy carries an inherent risk of preterm birth, although its influence is controversial. In the 2017 Cochrane review of obstetric outcomes after electrosurgical treatment, the relative risks of preterm birth before 37 weeks, preterm premature rupture of membranes before 37 weeks, and low birth weight (< 2.5 kg) were 1.75, 2.36, and 1.81, respectively. [ 4 – 8 ] Hence, alternative methods more effective than “observation” and less destructive than “excisional therapy are required to treat these women of child-bearing age.” [ 9 ] Because it can preserve the cervix, topical imiquimod treatment has been studied to determine whether it can replace cervical excisional therapy. However, previous trials show that it is not as effective as electrosurgical procedures. [ 10 – 13 ] In a non-randomized multicenter study, TOPIC-3 by Natasja Hendriks, MMK et al., showed that treatment was successful in 60% of women who completed imiquimod treatments and 95% of those treated with large loop excision of transformation zone (LLETZ). [ 14 ] In another phase 3 multicenter randomized controlled trial by Stephan Polterauer et al., the histological regression rate was observed 6 months after imiquimod treatment in 32/51(63%) of patients. [ 15 ] In a systematic review and meta-analysis in 2023 by van de Sande, MK et al., histological regression to less than CIN1 was observed in 55% of patients in the imiquimod group versus 29% and 93% placebo and surgical treatment groups, respectively. [ 16 ] Therefore, we aimed to identify specific age groups and time periods in which the effectiveness of topical imiquimod therapy as an alternative to excisional treatment is enhanced. Methods The study was designed as a non-randomized, retrospective cohort study and was conducted at the participating institution, a single center in the Republic of Korea, between October 2021 and March 2024. Approval was obtained from the Institutional Review Board of this institution (approval number: 2025 − 1093, approval date: 1st September 2025). Informed consent was waived because the study was retrospective in design. We obtained data of patients who were nulliparous, between the ages of 20 and 35 years, had never received cervical excisional therapies, and were concerned about future pregnancy outcomes. All patients were carefully confirmed to have CIN 2 or 3 through multiple cervical punch biopsies performed by gynecologic oncologists. Those who did not complete the 8-week treatment owing to moderate side effects, such as fever and flu-like symptoms, were excluded from the analysis. All patients were fully informed that topical imiquimod application was not the standard treatment for high-grade squamous intraepithelial lesions (HSIL) at this age and had time to consider their decision. All participants received imiquimod treatment weekly for 8 weeks. Imiquimod 5% cream was applied by gynecologic oncologists once per week using a brush-type cervical applicator. After administration, a vaginal menstrual cup was inserted to reduce vaginal irritation, which was removed the next morning. We checked the occurrence and severity of side effects at each visit. Adequate contraception was ensured throughout the study period. Pap and HPV co-test with colposcopy (including biopsies) were performed at 1, 3, 6, and 12 months following the last week of treatment. Punch biopsies or endocervical curettages were performed when suspicions of CIN2/3 lesions were observed. If the immediate results, within 1 month after finishing 8 weeks of imiquimod treatment, showed that the patient persistently had HSIL or CIN2/3, the patient was consulted to decide the next step based on the results. The options included four imiquimod treatments or excisional therapy. (Fig. 1 .). Gynecologic pathologists performed histopathological assessment of cervical biopsies following national guidelines and World Health Organization criteria using hematoxylin and eosin staining, as well as p16 and Ki-67 staining. High-risk HPV cases were subtyped with 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, and 82 using real-time polymerase chain reaction/tagging oligonucleotide cleavage and extension, multiple detection temperature, and three cycle threshold methods using Allplex HPV28 Detection Kit (Seegene Inc, Seoul, Korea). Low-risk HPV cases were subtyped as 6, 11, 40, 42, 43, 44, 54, 61, or 70 using the same method. The primary outcomes were the rates of complete remission to normal, regression to lower than LSIL, and HPV clearance within 1 month of weekly imiquimod treatment completion, analyzed based on the initial histology, and the presence of HPV types 16 or 18. Secondary outcomes included the rates of complete remission, regression, and HPV clearance approximately 1 year after treatment, depending on specific factors. Subgroup analysis was performed to determine the differences in treatment outcomes based on the presence or absence of specific HPV types (HPV-16 and HPV-18) and initial histological results using appropriate statistical tools. Statistical Analysis After patient recruitment, the relevant participants were counted to determine the primary and secondary outcomes. Those who underwent cervical excisional treatment for persistent HSIL lesions within a month of weekly imiquimod treatment were excluded from the analysis of the long-term follow-up. All statistical analyses were conducted using the IBM SPSS Software for Windows, version 25 (IBM Corp., Armonk, NY, USA). Results One hundred patients were enrolled in the study between October 2021 and March 2024. Seventy-four (74.0%) patients had CIN2, while the remaining 26 (26.0%) had CIN3. Additionally, 27 (27.0%) patients were positive for HPV types 16 or 18, whereas 66 (66.0%) patients had other high-risk HPV types. The characteristics of the analyzed patients are presented in Table 1 . Table 1 Patient chracteristics Variables No. of Patients (N = 100) Age(years) 20–24 17 (17.0%) 25–35 83 (83.0%) Number of parity after treatments Full-term 4 (4.0%) Pre-term 0 High risk HPV infection 93 (93.0%) with HPV 16 or 18 infection 27 (27.0%) with other high risk HPV infection 66 (66.0%) Initial punch biopsy result CIN2 74 (74.0%) CIN3 26 (26.0%) Abbreviations: HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia In the table, the figures in % in parentheses are the percentage of the total patient population. The immediate outcome was observed one month after treatments. The initial results observed 1 month after completing 8 weeks of treatment are presented in Table 2 . Eighty patients (80.0%) achieved complete remission to normal, whereas 96 of the participants (96.0%) regressed to LSIL or lower. Specifically, the regression rate for patients with HPV 16 or 18 was 88.9%; meanwhile, it was 98.6% for those without HPV 16 or 18. Only four patients consistently had HSIL. Two of these patients received an additional four imiquimod treatments, whereas the other two underwent a loop electrosurgical excision procedure (LEEP) conization; one was confirmed to have normal tissue, and the other had CIN3. Table 2 The immediate outcome observed one month after eight weeks of weekly topical imiquimod applications. Results No. of patients (N = 100) Complete remission 80 (80.0%) Regression(≤ LSIL) 96 (96.0%) Regression with HPV 16 or 18 24 (24/27, 88.9%) Regression without HPV 16 or 18 72 (72/73, 98.6%) Regression from CIN2 71 (71/74, 95.9%) Regression from CIN3 25 (25/26, 96.2%) HPV clearance(to negative) 44 (44/93, 47.3%) with HPV 16 or 18 15 (15/27, 55.6%) with other high risk HPV infection 29 (29/66, 43.9%) Persistent disease 4 (4.0%) who wants more imiquimod treatment 2 who wants LEEP 2* Abbreviations: LSIL, Low-Grade Squamous Intrapithelial Lesion; HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia; LEEP, Loop Electrosurgical Excision procedure In the table, the figures in % in parentheses are the percentage of the total patient population. * The biopsy results of excisional therapy; one was normal and the other was CIN3. Long-term follow-up results Table 3 shows the long-term follow-up results of the imiquimod therapy. The average follow-up duration was 438 days, with a median of 327 days (range: 110–2011 days). Eighty patients (81.6%) showed complete remission, whereas 92.9% showed regression to lower than CIN1. The highest regression rate, 94.5%, was observed in the groups without HPV types 16 and 18. The initial HPV clearance rate after treatment was 47.3%; however, it increased to 56.0% at the long-term follow-up. During the follow-up, 7.1% of patients developed HSIL and received additional treatment. Four of these patients opted for observation and showed regression at the next follow-up (3 months later) without additional treatment. The other two patients regressed after receiving four additional imiquimod applications. One patient required cervical excisional therapy and was confirmed to have CIN3. Table 4 presents the regression rates based on the initial histology and presence of HPV types 16 or 18. The group with CIN2 without HPV type 16 or 18 had the highest regression rate of 96.5%. In the subgroup analysis of 45 patients followed up for more than 360 days, two patients underwent excisional therapy because of persistent high-grade lesions occurring 1 month after topical imiquimod treatment. Among the remaining 43 patients, the complete remission, regression, and HPV clearance rates were 86.05%, 97.67%, and 56.76%, respectively. Table 3 Long-term follow-up of imiquimod strategy. Results No. of patients (N = 98) Complete remission 80 (81.6%) Regression(≤ LSIL) 91 (92.9%) Regression with HPV 16 or 18 22 (22/25, 88.0%) Regression without HPV 16 or 18 69 (69/73, 94.5%) Regression from CIN2 69 (69/73, 94.5%) Regression from CIN3 22 (22/25, 88.0%) HPV clearance(to negative) 51 (51/91, 56.0%) with HPV 16 or 18 16 (16/25, 64.0%) with other high risk HPV infection 35 (35/66, 53.0%) Number of progression 7 (7.1%) who wants observation 4* who wants more imiquimod treatment 2† who wants LEEP 1‡ Abbreviations: LSIL, Low-Grade Squamous Intrapithelial Lesion; HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia; LEEP, Loop Electrosurgical Excision procedure In the table, the figures in % in parentheses are the percentage of the total patient population. * All of them was regressed without any further treatments. † One of them got four more imiquimod treatments, and the other got eight more imiquimod treatments. ‡ The patient progressed to HSIL after 6 months and chose to observe, but the results were persistent HSIL. She eventually got excisional therapy; the biopsy result of LEEP conization was CIN3. Table 4 Regression rate based on HPV and initial histologic type in long-term follow-up period. CIN2 With HPV 16 or 18 Without HPV 16 or 18 87.5% (14/16) 96.5% (55/57) CIN3 88.9% (8/9) 87.5% (14/16) Abbreviations: HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia Discussion This study revealed that topical imiquimod application benefits patients < 35 years old with CIN2 or CIN3 who have never undergone cervical excisional surgery, particularly helping them preserve fertility. The 1-year follow-up data showed an overall regression rate of 93%, which was significantly higher than the rates previously reported. [ 17 ] In the 2022 TOPIC-3 trial by Hendriks, N., et al., and the 2022 study by Polterauer, S., et al., self-application of imiquimod cream three times a week for 16 weeks resulted in a regression rate of approximately 60%. Notably, in our study, we reported a 93% regression rate with clinician-applied imiquimod once a week for only 8 weeks. This finding suggests that even with fewer applications, clinician-administered treatments may provide a sufficient therapeutic effect in this patient group. As this regression rate is comparable to the treatment success rate of LLETZ reported in previous studies, future randomized research is required to establish a robust statistical basis. Additionally, the regression rate and HPV clearance observed in our study surpassed those reported in the observation group of Grimm et al. and Sheth et al. [ 18 – 21 ] . These results indicate that using imiquimod therapy achieved higher regression rates than using natural regression alone in this patient setting, demonstrating an added therapeutic effect beyond spontaneous regression. In this study, the recurrence rate was 7% during the 1-year follow-up period, and only 1% of patients required cervical excisional therapy. Additionally, 4% of patients achieved full-term delivery after imiquimod treatment. In addition, the subgroup analysis showed that the regression rate of 43 of 45 people who were followed up for more than 360 days after completing topical imiquimod treatment was 97.67%. This finding suggests that the treatment effect may be sustained for more than a year. Serati et al., in 2012, investigated the recurrence rate after conization; the median time to recurrence was 12.4 months (range: 2.9–100 months). A second excisional procedure was performed in 39 patients (13.8%): 36 (92.3%) underwent a second LEEP, whereas 3 (7.7%) underwent a total hysterectomy. [ 22 ] Therefore, delaying the first cervical resection procedure by approximately 1 year using the imiquimod method could serve as a bridging therapy that reduces the number of excisional procedures before the first pregnancy, significantly improving fecundity in selected patients. Subgroup analysis based on histology and high-risk HPV types showed the highest regression rate of 96.5% in the CIN2 patient group without HPV types 16 or 18. Nonetheless, further research using randomized subgroup comparisons is necessary to obtain statistically significant results, which is necessary to determine the histological conditions and HPV subtypes that should be treated with topical imiquimod. The study has some limitations. Imiquimod treatment was more effective in those < 35 years. However, owing to the limited number of patients, the treatment effects could not be adequately compared between patients aged < 25 years and those between 25 and 35 years. In addition, conducting randomized prospective studies that include an observation, an imiquimod, and a LEEP conization group would provide stronger evidence regarding the most beneficial treatment for patients in that age group. Our study included 1-year follow-up results; nevertheless, its design did not clarify the comparative impact of treatments on live birth outcomes or other obstetric measures. Therefore, randomized trials with longer follow-up periods are needed to determine whether imiquimod therapy could result in statistically significant improvements in live birth rates and overall reproductive health compared with those of other treatment modalities. Conclusion Based on our study findings, we propose that topical imiquimod application could serve as an alternative to excisional therapy for women < 35 years who have no prior history of excisional treatment and are diagnosed with CIN2 or CIN3, particularly those concerned about future pregnancy outcomes. One-year follow-up data after imiquimod therapy showed a regression rate of 92.9% and a high-risk HPV clearance rate of 56.0%, indicating that patients could safely delay their first excisional procedure. If future studies statistically confirm that imiquimod treatment yields a higher regression rate than that of close observation and better pregnancy outcomes than those of LEEP in this patient population, it could be a reliable alternative for medical professionals and patients. Abbreviations CIN Cervical Intraepithelial Neoplasia HPV Human Papillomavirus LSIL Low–Grade Squamous Intraepithelial Lesion HSIL High–Grade Squamous Intraepithelial Lesion LEEP Loop Electrosurgical Excision Procedure LLETZ Large Loop Excision of the Transformation Zone Declarations Ethics approval and consent to participate This study was conducted in strict compliance with the ethical principles for medical research involving human participants, as outlined in the World Medical Association Declaration of Helsinki (revised at the 75th WMA General Assembly, Helsinki, Finland, October 2024). The study was a non-randomized retrospective cohort conducted at Asan Medical Center, a single center in the Republic of Korea, between October 2021 and March 2024. Approval was obtained from the Institutional Review Board of this institution (approval number: 2025 − 1093; approval date: September 1, 2025). Informed consent was waived because this was a retrospective study, and patient information was anonymized. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Funding This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution J. Kim and D.Y. Kim developed the concept and design of the study, analyzed the patient data, and drafted the manuscript. J.H. and Y.S. provided material support. R. and H.J. revised the manuscript. All authors read and approved the final manuscript. 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Serati M, Siesto G, Carollo S, Formenti G, Riva C, Cromi A, et al. Risk factors for cervical intraepithelial neoplasia recurrence after conization: a 10-year study. Eur J Obstet Gynecol Reprod Biol. 2012;165:86–90. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 24 Apr, 2026 Reviews received at journal 22 Apr, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviewers agreed at journal 19 Apr, 2026 Reviews received at journal 02 Apr, 2026 Reviewers agreed at journal 02 Apr, 2026 Reviewers invited by journal 02 Apr, 2026 Editor assigned by journal 17 Mar, 2026 Submission checks completed at journal 17 Mar, 2026 First submitted to journal 16 Mar, 2026 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. 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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-9138575","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":616828377,"identity":"e551685f-e24c-43ba-9b53-1aff682bc825","order_by":0,"name":"Jungmi Kim","email":"","orcid":"","institution":"Chungbuk National University Hospital, Chungbuk National University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jungmi","middleName":"","lastName":"Kim","suffix":""},{"id":616828383,"identity":"1420e651-70de-48e6-9683-12acefebca7c","order_by":1,"name":"Ju-Hyun Kim","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ju-Hyun","middleName":"","lastName":"Kim","suffix":""},{"id":616828385,"identity":"5704cfd7-4f64-4caa-b28e-aacd5596ec2a","order_by":2,"name":"Yaesol Kim","email":"","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yaesol","middleName":"","lastName":"Kim","suffix":""},{"id":616828388,"identity":"33c40a74-ffb9-4519-9d50-914bb393b296","order_by":3,"name":"Rumie Lee","email":"","orcid":"","institution":"Chungbuk National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rumie","middleName":"","lastName":"Lee","suffix":""},{"id":616828390,"identity":"873e1cef-2ccf-4b61-8b1d-ddc2fcefc62c","order_by":4,"name":"Hyeonji Choi","email":"","orcid":"","institution":"Chungbuk National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyeonji","middleName":"","lastName":"Choi","suffix":""},{"id":616828394,"identity":"e9ac53be-4127-4395-9be6-30327141ee88","order_by":5,"name":"Dae-Yeon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYBACCYYEEGUDF5Bh4CFKS0IaXICHWC2HSdAi2Z5j+PDrj/Pyuu0HmD98qDgM1HL2AV4t0jxvjI1lEm4bbjuTwCY54wxQC2+7AV4tchI5ZtISCbcZt91gYGPmbQNq4WfD7zColnP2QC3Mn/8So0UaqEXyQ8KBRKAWBmlGkBbeNvxaJHueFRszpCUnbzuT2CbZcyadh43nGH4tEseTNz78YWNnu+344cMfflRYy/HzpOHXwsDAYcAMiQnGBjBFwCcgwP6A8QdhVaNgFIyCUTCSAQBNfkDIhgThsgAAAABJRU5ErkJggg==","orcid":"","institution":"University of Ulsan College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Dae-Yeon","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2026-03-16 13:39:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9138575/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9138575/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106468722,"identity":"2ec90efe-db62-475b-9420-9084e49c6e0b","added_by":"auto","created_at":"2026-04-09 00:43:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":142505,"visible":true,"origin":"","legend":"\u003cp\u003eThe brief summary of treatment course we use in this journal named “imiquimod strategy”\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9138575/v1/e584ce42490bbd21888d43f6.jpg"},{"id":106994066,"identity":"fd942280-0ab1-4ad9-b191-d6f619c2c74e","added_by":"auto","created_at":"2026-04-15 15:03:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":723312,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9138575/v1/b9ff0171-fe75-47b2-a897-4b8e548d4caf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term follow-up results of topical imiquimod for high-grade cervical intraepithelial neoplasia in young women: an original research","fulltext":[{"header":"Background","content":"\u003cp\u003eRecently released demographic data show that the total incidence of cervical cancer in South Korea has been decreasing. However, the prevalence of cervical cancer among those aged 15\u0026ndash;34 years is approximately 4.4 per 100, 000 persons. \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e As the age at first pregnancy increases, the incidence of high-grade cervical intraepithelial neoplasia (CIN) increases when a person becomes pregnant for the first time. According to the 2019 American Society for Colposcopy and Cervical Pathology guidelines, observation is recommended for women diagnosed with CIN2 who are aged\u0026thinsp;\u0026lt;\u0026thinsp;25 years. In the patient group diagnosed with CIN3, diagnostic excisional therapy is recommended regardless of their age. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, observations alone are not always sufficient as alternatives. A recent study involving follow-up of 2,417 women aged 21\u0026ndash;39 diagnosed with CIN2 over an average of 4 years showed that 30% were eventually treated during the study because of persistent disease. \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e Excisional therapy carries an inherent risk of preterm birth, although its influence is controversial. In the 2017 Cochrane review of obstetric outcomes after electrosurgical treatment, the relative risks of preterm birth before 37 weeks, preterm premature rupture of membranes before 37 weeks, and low birth weight (\u0026lt;\u0026thinsp;2.5 kg) were 1.75, 2.36, and 1.81, respectively. \u003csup\u003e[\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e Hence, alternative methods more effective than \u0026ldquo;observation\u0026rdquo; and less destructive than \u0026ldquo;excisional therapy are required to treat these women of child-bearing age.\u0026rdquo; \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBecause it can preserve the cervix, topical imiquimod treatment has been studied to determine whether it can replace cervical excisional therapy. However, previous trials show that it is not as effective as electrosurgical procedures. \u003csup\u003e[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e In a non-randomized multicenter study, TOPIC-3 by Natasja Hendriks, MMK et al., showed that treatment was successful in 60% of women who completed imiquimod treatments and 95% of those treated with large loop excision of transformation zone (LLETZ). \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e In another phase 3 multicenter randomized controlled trial by Stephan Polterauer et al., the histological regression rate was observed 6 months after imiquimod treatment in 32/51(63%) of patients. \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e In a systematic review and meta-analysis in 2023 by van de Sande, MK et al., histological regression to less than CIN1 was observed in 55% of patients in the imiquimod group versus 29% and 93% placebo and surgical treatment groups, respectively. \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e Therefore, we aimed to identify specific age groups and time periods in which the effectiveness of topical imiquimod therapy as an alternative to excisional treatment is enhanced.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e The study was designed as a non-randomized, retrospective cohort study and was conducted at the participating institution, a single center in the Republic of Korea, between October 2021 and March 2024. Approval was obtained from the Institutional Review Board of this institution (approval number: 2025\u0026thinsp;\u0026minus;\u0026thinsp;1093, approval date: 1st September 2025). Informed consent was waived because the study was retrospective in design. We obtained data of patients who were nulliparous, between the ages of 20 and 35 years, had never received cervical excisional therapies, and were concerned about future pregnancy outcomes. All patients were carefully confirmed to have CIN 2 or 3 through multiple cervical punch biopsies performed by gynecologic oncologists. Those who did not complete the 8-week treatment owing to moderate side effects, such as fever and flu-like symptoms, were excluded from the analysis. All patients were fully informed that topical imiquimod application was not the standard treatment for high-grade squamous intraepithelial lesions (HSIL) at this age and had time to consider their decision.\u003c/p\u003e \u003cp\u003eAll participants received imiquimod treatment weekly for 8 weeks. Imiquimod 5% cream was applied by gynecologic oncologists once per week using a brush-type cervical applicator. After administration, a vaginal menstrual cup was inserted to reduce vaginal irritation, which was removed the next morning. We checked the occurrence and severity of side effects at each visit. Adequate contraception was ensured throughout the study period. Pap and HPV co-test with colposcopy (including biopsies) were performed at 1, 3, 6, and 12 months following the last week of treatment. Punch biopsies or endocervical curettages were performed when suspicions of CIN2/3 lesions were observed. If the immediate results, within 1 month after finishing 8 weeks of imiquimod treatment, showed that the patient persistently had HSIL or CIN2/3, the patient was consulted to decide the next step based on the results. The options included four imiquimod treatments or excisional therapy. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.). Gynecologic pathologists performed histopathological assessment of cervical biopsies following national guidelines and World Health Organization criteria using hematoxylin and eosin staining, as well as p16 and Ki-67 staining. High-risk HPV cases were subtyped with 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, and 82 using real-time polymerase chain reaction/tagging oligonucleotide cleavage and extension, multiple detection temperature, and three cycle threshold methods using Allplex HPV28 Detection Kit (Seegene Inc, Seoul, Korea). Low-risk HPV cases were subtyped as 6, 11, 40, 42, 43, 44, 54, 61, or 70 using the same method.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe primary outcomes were the rates of complete remission to normal, regression to lower than LSIL, and HPV clearance within 1 month of weekly imiquimod treatment completion, analyzed based on the initial histology, and the presence of HPV types 16 or 18. Secondary outcomes included the rates of complete remission, regression, and HPV clearance approximately 1 year after treatment, depending on specific factors. Subgroup analysis was performed to determine the differences in treatment outcomes based on the presence or absence of specific HPV types (HPV-16 and HPV-18) and initial histological results using appropriate statistical tools.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAfter patient recruitment, the relevant participants were counted to determine the primary and secondary outcomes. Those who underwent cervical excisional treatment for persistent HSIL lesions within a month of weekly imiquimod treatment were excluded from the analysis of the long-term follow-up. All statistical analyses were conducted using the IBM SPSS Software for Windows, version 25 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOne hundred patients were enrolled in the study between October 2021 and March 2024. Seventy-four (74.0%) patients had CIN2, while the remaining 26 (26.0%) had CIN3. Additionally, 27 (27.0%) patients were positive for HPV types 16 or 18, whereas 66 (66.0%) patients had other high-risk HPV types. The characteristics of the analyzed patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient chracteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of Patients (N\u0026thinsp;=\u0026thinsp;100)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (17.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026ndash;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (83.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of parity after treatments\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFull-term\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-term\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh risk HPV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 (93.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith HPV 16 or 18 infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith other high risk HPV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (66.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial punch biopsy result\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (74.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (26.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eIn the table, the figures in % in parentheses are the percentage of the total patient population.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe immediate outcome was observed one month after treatments.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe initial results observed 1 month after completing 8 weeks of treatment are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Eighty patients (80.0%) achieved complete remission to normal, whereas 96 of the participants (96.0%) regressed to LSIL or lower. Specifically, the regression rate for patients with HPV 16 or 18 was 88.9%; meanwhile, it was 98.6% for those without HPV 16 or 18. Only four patients consistently had HSIL. Two of these patients received an additional four imiquimod treatments, whereas the other two underwent a loop electrosurgical excision procedure (LEEP) conization; one was confirmed to have normal tissue, and the other had CIN3.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe immediate outcome observed one month after eight weeks of weekly topical imiquimod applications.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of patients\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;100)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete remission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (80.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression(\u0026le;\u0026thinsp;LSIL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96 (96.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression with HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (24/27, 88.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression without HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (72/73, 98.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression from CIN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (71/74, 95.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression from CIN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (25/26, 96.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPV clearance(to negative)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (44/93, 47.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (15/27, 55.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith other high risk HPV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (29/66, 43.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewho wants more imiquimod treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewho wants LEEP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: LSIL, Low-Grade Squamous Intrapithelial Lesion; HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia; LEEP, Loop Electrosurgical Excision procedure\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eIn the table, the figures in % in parentheses are the percentage of the total patient population.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* The biopsy results of excisional therapy; one was normal and the other was CIN3.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eLong-term follow-up results\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the long-term follow-up results of the imiquimod therapy. The average follow-up duration was 438 days, with a median of 327 days (range: 110\u0026ndash;2011 days). Eighty patients (81.6%) showed complete remission, whereas 92.9% showed regression to lower than CIN1. The highest regression rate, 94.5%, was observed in the groups without HPV types 16 and 18. The initial HPV clearance rate after treatment was 47.3%; however, it increased to 56.0% at the long-term follow-up. During the follow-up, 7.1% of patients developed HSIL and received additional treatment. Four of these patients opted for observation and showed regression at the next follow-up (3 months later) without additional treatment. The other two patients regressed after receiving four additional imiquimod applications. One patient required cervical excisional therapy and was confirmed to have CIN3. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents the regression rates based on the initial histology and presence of HPV types 16 or 18. The group with CIN2 without HPV type 16 or 18 had the highest regression rate of 96.5%. In the subgroup analysis of 45 patients followed up for more than 360 days, two patients underwent excisional therapy because of persistent high-grade lesions occurring 1 month after topical imiquimod treatment. Among the remaining 43 patients, the complete remission, regression, and HPV clearance rates were 86.05%, 97.67%, and 56.76%, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLong-term follow-up of imiquimod strategy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of patients\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete remission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression(\u0026le;\u0026thinsp;LSIL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (92.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression with HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (22/25, 88.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression without HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (69/73, 94.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression from CIN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (69/73, 94.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegression from CIN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (22/25, 88.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHPV clearance(to negative)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (51/91, 56.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith HPV 16 or 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (16/25, 64.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewith other high risk HPV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (35/66, 53.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewho wants observation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewho wants more imiquimod treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewho wants LEEP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAbbreviations: LSIL, Low-Grade Squamous Intrapithelial Lesion; HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia; LEEP, Loop Electrosurgical Excision procedure\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eIn the table, the figures in % in parentheses are the percentage of the total patient population.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* All of them was regressed without any further treatments.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026dagger; One of them got four more imiquimod treatments, and the other got eight more imiquimod treatments.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026Dagger; The patient progressed to HSIL after 6 months and chose to observe, but the results were persistent HSIL. She eventually got excisional therapy; the biopsy result of LEEP conization was CIN3.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRegression rate based on HPV and initial histologic type in long-term follow-up period.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCIN2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWith HPV 16 or 18\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWithout HPV 16 or 18\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87.5% (14/16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96.5% (55/57)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e88.9% (8/9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e87.5% (14/16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: HPV, Human Papillomavirus; CIN, Cervical intraepithelial Neoplasia\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study revealed that topical imiquimod application benefits patients\u0026thinsp;\u0026lt;\u0026thinsp;35 years old with CIN2 or CIN3 who have never undergone cervical excisional surgery, particularly helping them preserve fertility. The 1-year follow-up data showed an overall regression rate of 93%, which was significantly higher than the rates previously reported. \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e In the 2022 TOPIC-3 trial by Hendriks, N., et al., and the 2022 study by Polterauer, S., et al., self-application of imiquimod cream three times a week for 16 weeks resulted in a regression rate of approximately 60%. Notably, in our study, we reported a 93% regression rate with clinician-applied imiquimod once a week for only 8 weeks. This finding suggests that even with fewer applications, clinician-administered treatments may provide a sufficient therapeutic effect in this patient group. As this regression rate is comparable to the treatment success rate of LLETZ reported in previous studies, future randomized research is required to establish a robust statistical basis. Additionally, the regression rate and HPV clearance observed in our study surpassed those reported in the observation group of Grimm et al. and Sheth et al. \u003csup\u003e[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. These results indicate that using imiquimod therapy achieved higher regression rates than using natural regression alone in this patient setting, demonstrating an added therapeutic effect beyond spontaneous regression.\u003c/p\u003e \u003cp\u003eIn this study, the recurrence rate was 7% during the 1-year follow-up period, and only 1% of patients required cervical excisional therapy. Additionally, 4% of patients achieved full-term delivery after imiquimod treatment. In addition, the subgroup analysis showed that the regression rate of 43 of 45 people who were followed up for more than 360 days after completing topical imiquimod treatment was 97.67%. This finding suggests that the treatment effect may be sustained for more than a year. Serati et al., in 2012, investigated the recurrence rate after conization; the median time to recurrence was 12.4 months (range: 2.9\u0026ndash;100 months). A second excisional procedure was performed in 39 patients (13.8%): 36 (92.3%) underwent a second LEEP, whereas 3 (7.7%) underwent a total hysterectomy. \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e Therefore, delaying the first cervical resection procedure by approximately 1 year using the imiquimod method could serve as a bridging therapy that reduces the number of excisional procedures before the first pregnancy, significantly improving fecundity in selected patients.\u003c/p\u003e \u003cp\u003eSubgroup analysis based on histology and high-risk HPV types showed the highest regression rate of 96.5% in the CIN2 patient group without HPV types 16 or 18. Nonetheless, further research using randomized subgroup comparisons is necessary to obtain statistically significant results, which is necessary to determine the histological conditions and HPV subtypes that should be treated with topical imiquimod.\u003c/p\u003e \u003cp\u003eThe study has some limitations. Imiquimod treatment was more effective in those\u0026thinsp;\u0026lt;\u0026thinsp;35 years. However, owing to the limited number of patients, the treatment effects could not be adequately compared between patients aged\u0026thinsp;\u0026lt;\u0026thinsp;25 years and those between 25 and 35 years.\u003c/p\u003e \u003cp\u003eIn addition, conducting randomized prospective studies that include an observation, an imiquimod, and a LEEP conization group would provide stronger evidence regarding the most beneficial treatment for patients in that age group. Our study included 1-year follow-up results; nevertheless, its design did not clarify the comparative impact of treatments on live birth outcomes or other obstetric measures. Therefore, randomized trials with longer follow-up periods are needed to determine whether imiquimod therapy could result in statistically significant improvements in live birth rates and overall reproductive health compared with those of other treatment modalities.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on our study findings, we propose that topical imiquimod application could serve as an alternative to excisional therapy for women\u0026thinsp;\u0026lt;\u0026thinsp;35 years who have no prior history of excisional treatment and are diagnosed with CIN2 or CIN3, particularly those concerned about future pregnancy outcomes. One-year follow-up data after imiquimod therapy showed a regression rate of 92.9% and a high-risk HPV clearance rate of 56.0%, indicating that patients could safely delay their first excisional procedure. If future studies statistically confirm that imiquimod treatment yields a higher regression rate than that of close observation and better pregnancy outcomes than those of LEEP in this patient population, it could be a reliable alternative for medical professionals and patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCIN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCervical Intraepithelial Neoplasia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Papillomavirus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLSIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLow\u0026ndash;Grade Squamous Intraepithelial Lesion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHSIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHigh\u0026ndash;Grade Squamous Intraepithelial Lesion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLEEP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLoop Electrosurgical Excision Procedure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLLETZ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLarge Loop Excision of the Transformation Zone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was conducted in strict compliance with the ethical principles for medical research involving human participants, as outlined in the World Medical Association Declaration of Helsinki (revised at the 75th WMA General Assembly, Helsinki, Finland, October 2024). The study was a non-randomized retrospective cohort conducted at Asan Medical Center, a single center in the Republic of Korea, between October 2021 and March 2024. Approval was obtained from the Institutional Review Board of this institution (approval number: 2025\u0026thinsp;\u0026minus;\u0026thinsp;1093; approval date: September 1, 2025). Informed consent was waived because this was a retrospective study, and patient information was anonymized.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ. Kim and D.Y. Kim developed the concept and design of the study, analyzed the patient data, and drafted the manuscript. J.H. and Y.S. provided material support. R. and H.J. revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets analyzed during this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKang MJ, Won YJ, Lee JJ, Jung KW, Kim HJ, Kong HJ, et al. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2019. Cancer Res Treat. 2022;54:330\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Lower Genit Tract Dis. 2020;24:102\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilver MI, Gage JC, Schiffman M, Fetterman B, Poitras NE, Lorey T, et al. Clinical Outcomes after Conservative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in Women Ages 21\u0026ndash;39 Years. Cancer Prev Res (Phila). 2018;11:165\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyrgiou M, Athanasiou A, Kalliala IEJ, Paraskevaidi M, Mitra A, Martin-Hirsch PP, et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database Syst Rev. 2017;11:Cd012847.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367:489\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyrgiou M, Athanasiou A, Kalliala IE, Paraskevaidi M, Mitra A, Martin-Hirsch PP et al. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database of Systematic Reviews. 1996;2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu R, Liu C, Ding X. Association between loop electrosurgical excision procedure and adverse pregnancy outcomes: a meta-analysis. J Maternal-Fetal Neonatal Med. 2023;36:2183769.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Aring;str\u0026ouml;m E, Turkmen S. Obstetric outcomes after cervical loop electrosurgical excision procedure. Cancer Treat Res Commun. 2023;34:100668.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoeneman MM, Essers BA, Gerestein CG, van de Sande AJM, Litjens RJNTM, Boskamp D, et al. Treatment of Cervical Intraepithelial Neoplasia: Patients Preferences for Surgery or Immunotherapy with Imiquimod. J Immunother. 2017;40:148\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesravines N, Miele K, Carlson R, Chibwesha C, Rahangdale L. Topical therapies for the treatment of cervical intraepithelial neoplasia (CIN) 2\u0026ndash;3: A narrative review. Gynecol Oncol Rep. 2020;33:100608.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, et al. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012;206:42. e1-. e7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026ouml;derlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol. 2014;86:634\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHecken JM, Rezniczek GA, Tempfer CB. Innovative Diagnostic and Therapeutic Interventions in Cervical Dysplasia: A Systematic Review of Controlled Trials. Cancers (Basel). 2022;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHendriks N, Koeneman MM, van de Sande AJM, Penders CGJ, Piek JMJ, Kooreman LFS, et al. Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study. J Immunother. 2022;45:180\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolterauer S, Reich O, Widschwendter A, Hadjari L, Bogner G, Reinthaller A, et al. Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial. Gynecol Oncol. 2022;165:23\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan De Sande A, Kengsakul M, Koeneman M, Jozwiak M, Gerestein C, Kruse A-J, et al. The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: a systematic review and meta‐analysis. Int J Gynecol Obstet. 2024;164:66\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFonseca BO, Possati-Resende JC, Salcedo MP, Schmeler KM, Accorsi GS, Fregnani JHTG, et al. Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix: A Randomized Controlled Trial. Obstet Gynecol. 2021;137:1043\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheth SS, Oh JE, Bellone S, Siegel ER, Greenman M, Mutlu L, et al. Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147). Clin Cancer Res. 2024;30:1768\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Lu CX. Spontaneous Regression of Cervical Intraepithelial Neoplasia 2: A Meta-analysis. Gynecol Obstet Invest. 2019;84:562\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrimm C, Polterauer S, Natter C, Rahhal J, Hefler L, Tempfer CB, et al. Treatment of Cervical Intraepithelial Neoplasia With Topical Imiquimod: A Randomized Controlled Trial. Obstet Gynecol. 2012;120:152\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEhret A, Bark VN, Mondal A, Fehm TN, Hampl M. Regression rate of high-grade cervical intraepithelial lesions in women younger than 25 years. Arch Gynecol Obstet. 2023;307:981\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerati M, Siesto G, Carollo S, Formenti G, Riva C, Cromi A, et al. Risk factors for cervical intraepithelial neoplasia recurrence after conization: a 10-year study. Eur J Obstet Gynecol Reprod Biol. 2012;165:86\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Imiquimod, Uterine Cervical Dysplasia, Human Papillomavirus Viruses, Retrospective Studies, Demography, Fertility","lastPublishedDoi":"10.21203/rs.3.rs-9138575/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9138575/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAs cervical excisional treatment is associated with adverse pregnancy outcomes, imiquimod has been explored in several studies\u0026mdash;such as the TOPIC-3\u0026mdash;as an alternative but without success. Therefore, we designed a study focusing on patients aged\u0026thinsp;\u0026lt;\u0026thinsp;35 years to verify its efficacy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective, single-arm cohort study, gathering the medical records of nulliparous women aged\u0026thinsp;\u0026lt;\u0026thinsp;35 years who had never undergone cervical excisional therapy between October 2021 and March 2024. The primary goal was to identify the rate of histological regression and high-risk Human Papillomavirus (HPV) clearance at 3, 6, and 12 months, as well as beyond, after completing 8 weeks of weekly imiquimod treatment.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe immediate regression rate from cervical intraepithelial neoplasia (CIN) 2 or 3 lesions to at least CIN 1 was 96.0% after 8 weeks of weekly imiquimod therapy, and the HPV clearance rate at that time was 47.3%. During follow-up, the observed rates of complete remission to normal, regression lower than that of CIN 1, and HPV clearance were 81.6%, 92.9%, and 56.0%, respectively. Notably, the subgroup of patients diagnosed with CIN 2 without HPV16 or 18 achieved the highest regression rate of 96.5%. Among the patients, 7.1% showed persistent disease, and only 1.0% underwent cervical invasive therapies.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe suggest that topical imiquimod therapies could serve as a potential alternative to postponing cervical excisional therapies for up to 1 year in women\u0026thinsp;\u0026lt;\u0026thinsp;35 years with CIN2 or 3, who are concerned about future pregnancy outcomes.\u003c/p\u003e","manuscriptTitle":"Long-term follow-up results of topical imiquimod for high-grade cervical intraepithelial neoplasia in young women: an original research","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-09 00:43:18","doi":"10.21203/rs.3.rs-9138575/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-24T07:41:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T08:51:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10970842876135115980259549998094761606","date":"2026-04-20T06:43:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29218762033053523069479067056200823642","date":"2026-04-20T00:44:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-02T20:41:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186184378769590057321076168565853021325","date":"2026-04-02T16:25:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-02T07:38:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-17T06:22:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-17T06:22:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2026-03-16T13:29:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7bbd71d4-0e35-46ac-826b-47d8df23cd30","owner":[],"postedDate":"April 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-19T00:38:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-09 00:43:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9138575","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9138575","identity":"rs-9138575","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
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