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Cryotherapy is standard practice for treating patients with cervical precancer in see-and-treat programmes in low-income and middle-income countries (LMICs). Because of logistical difficulties with cryotherapy (eg, the necessity, costs, and supply chain difficulties of refrigerant gas; equipment failure; and treatment duration >10 min), a battery-operated thermal ablator that is lightweight and portable has been developed. We aimed to compare thermal ablation using the new device with cryotherapy. We report the pilot phase of a randomised controlled trial in routine screen-and-treat clinics providing cervical screening using visual inspection with acetic acid (VIA) in Lusaka, Zambia. We recruited non-pregnant women, aged 25 years or older, who were eligible for ablative therapy. We randomly assigned participants (1:1:1) to thermal ablation, cryotherapy, or large loop excision of the transformation zone (LLETZ), using computer-generated allocation. The randomisation was concealed but the nurses providing treatment and the participants were unmasked. Thermal ablation was achieved using the Liger thermal ablator (using 1–5 overlapping applications of the probe heated to 100°C, each application lasting for 40 s), cryotherapy was carried out using the double-freeze technique (freeze for 3 min, thaw for 5 min, and freeze again for 3 min), and LLETZ (using a large loop driven by an electro-surgical unit to excise the transformation zone) was done under local anaesthesia. The primary endpoint was treatment success, defined as either human papillomavirus (HPV) type-specific clearance among participants who were positive for the same HPV type at baseline, or a negative VIA test at 6-month follow-up, if the baseline HPV test was negative. Per protocol analyses were done. Enrolment for the full trial is ongoing. Here, we present findings from a prespecified pilot phase of the full trial. The final analysis of the full trial will assess non-inferiority of the groups for the primary efficacy endpoint. The study is registered with ClinicalTrials.gov, number NCT02956239. Between Aug 2, 2017, and Jan 15, 2019, 750 participants were randomly assigned (250 per group). 206 (84%) participants in the cryotherapy group, 197 (81%) in the thermal ablation group, and 204 (84%) in the LLETZ group attended the 6-month follow-up examination. Treatment success was reported in 120 (60%) of 200 participants in the cryotherapy group, 123 (64%) of 192 in the thermal ablation group, and 134 (67%) of 199 in the LLETZ group (p=0·31). Few participants complained of moderate to severe pain in any group immediately after the procedure (six [2%] of 250 in the cryotherapy group, four [2%] of 250 in the thermal ablation group, and five [2%] of 250 in the LLETZ group) and 2 weeks after the procedure (one [<1%] of 241 in the cryotherapy group, none of 242 in the thermal ablation group, and two [<1%] of 237 in the LLETZ group). None of the participants reported any complication requiring medical consultation or admission to hospital. Results from this pilot study preliminarily suggest that thermal ablation has similar treatment success to cryotherapy, without the practical disadvantages of providing cryotherapy in an LMIC. However, the study was not powered to establish the similarity between the techniques, and results from the ongoing randomised controlled trial are need to confirm these results. US National Institutes of Health.

Background Cervical cancer is a common cancer worldwide, with > 85% of deaths occurring in Lower- and Middle-Income Countries where resources for screening programs are limited. Women living with HIV (WLHIV) are at increased risk. HPV test-and-treat is a screening strategy where women with HPV are offered ablative treatment of the cervix to reduce the risk of invasive cancer. WLHIV tend to have more extensive cervical lesions, necessitating more specialised surgical treatments. Method ACTG A5282 was a randomised, open-label, Phase 2 trial conducted in seven countries that compared a cytology-based screening strategy to HPV test-and-treat for cervical cancer prevention in WLHIV. Women with cervical lesions inappropriate for ablative treatment were assigned to Arm C and underwent colposcopy and directed biopsies. Loop electro-excision procedure was performed if high-grade lesions (bHSIL) were present on cervical biopsies. Women were followed 26 weeks later for repeat evaluations. The Clopper-Pearson exact method was used to construct the 95% confidence interval for the proportion of WLHIV with lesions inappropriate for cryotherapy. Logistic regression models were used to assess the factors associated with these lesions. Results Of 1046 women screened, 156 (88%) were Black/Non-Hispanic, with a median age of 36 years; 80% were on ART, and 73% had an HIV-1 RNA < 200 copies/mL. On cervical colposcopy, 17% (179/1046, 95% CI 14.9–19.4%) had cervical lesions inappropriate for cervical ablation. Among 428 (44%) women with High-risk HPV (hrHPV) detected, 112 (26%, 95% CI 22.2%, 30.5%) had cervical lesions inappropriate for ablative therapy. hrHPV was found more commonly among women having lesions inappropriate for ablative therapy as compared to lesions appropriate for ablative therapy (70% vs 54%, p < .001). Among 128 women with extensive cervical lesions undergoing colposcopic biopsies, 43 (34%) had bHSIL detected. Among women undergoing LEEP treatment of bHSIL, 24% had bHSIL detected 26 weeks later. Conclusion Cervical lesions inappropriate for ablative therapy were common among WLHIV. This has implications for cervical cancer programs as these lesions can only be optimally treated with surgical therapies such as loop electroexcision procedures, and the capacity for this procedure should be increased to maximise cervical cancer prevention outcomes.

Human Papillomavirus (HPV) is causally associated with cervical cancer and precancerous lesions (dysplasias) of the cervix. The treatment of choice for low-grade lesions is monitoring with no-treatment, because the majority of them will regress spontaneously. However, this wait-and-see approach can be assisted by nutritional supplements for immune support, like Moducare. The hypothesis of the trial is that Moducare can enhance the natural regression of CIN1. MODUCIN1 is a prospective, open-label, randomized trial where eligible patients will be randomized (1:1) to either the wait-and-see approach (control arm) or to the six months oral administration of Moducare capsules. The main inclusion criterion is newly histologically proven CIN1 and the main exclusion criterion is any previous cervical intraepithelial neoplasia with or without treatment or history of pelvic malignancy. The primary objective is to compare the regression rates of low-grade cervical intraepithelial neoplasia (CIN1) between the two groups: Wait-and-see approach and Moducare. The sample size is estimated at 182 eligible patients, while accrual is expected to last one year. The primary endpoint is expected to be reached after six months from last patient enrollment. The Trial Registration Number is NCT07379905.

The aim of this study was to investigate the capacity of an HPV16 E6/E7 synthetic overlapping long-peptide vaccine to stimulate the HPV16-specific T-cell response, to enhance the infiltration of HPV16-specific type 1 T cells into the lesions of patients with HPV16+ high-grade cervical squamous intraepithelial lesion (HSIL) and HPV clearance. This was a placebo-controlled randomized phase II study in patients with HPV16-positive HSIL. HPV16-specific T-cell responses were determined pre- and post-vaccination by ELISPOT, proliferation assay and cytokine assays in PBMC and HSIL-infiltrating lymphocytes, and delayed-type hypersensitivity skin tests. Motivational problems of this patient group to postpone treatment of their premalignant lesions affected the inclusion rates and caused the study to stop prematurely. Of the accrued patients, 4 received a placebo and 5 received 1–2 vaccinations. Side effects mainly were flu-like symptoms and injection site reactions. A strong HPV-specific IFNγ-associated T-cell response was detected by ELISPOT in all vaccinated patients. The outcome of the skin tests correlated well with the ELISPOT analysis. The cytokine profile associated with HPV16-specific proliferation varied from robust type 1 to dominant type 2 responses. No conclusions could be drawn on vaccine-enhanced T-cell infiltration of the lesion, and there was no HPV clearance at the time of LEEP excision. Thus, vaccination of HSIL patients results in increased HPV16-specific T-cell immunity. Further development of this type of treatment relies on the ability to motivate patients and in the reduction in the side effects.

Background Cervical cancer is the fourth most common cancer in the world, affecting mainly women residing in low- and middle-income countries. Progression from a pre-invasive phase to that of an invasive phase generally takes years and provides a window of opportunity to screen for and treat precancerous lesions. Methods This study is being conducted at four sites in north Karnataka, India. Community sensitization activities have been organized in the study areas to create awareness among stakeholders, including elected representatives, physicians, health care workers, and potential participants. Organized community based as well as hospital-based screening is being conducted using visual inspection with acetic acid (VIA). Screen positive women are referred to respective study hospitals for colposcopy and directed biopsy. Participants with confirmed high-grade cervical dysplasia (high-grade squamous intraepithelial lesions or HSIL) who fit all other eligibility criteria will be recruited to the study and will receive cryotherapy using CryoPop®, an innovative new cryotherapy device. Discussion There is a need to develop an inexpensive, simple, and effective cryotherapy device for use by frontline health care providers at locations where screening and timely treatment can be given, accelerating access to cervical cancer prevention services and minimizing loss to follow-up of women with precancerous lesions who need treatment. Trial registration Clinical Trial Registry - India CTRI/2019/01/017289 ClinicalTrials.Gov number NCT04154644 . Registered on November 6, 2019.

IntroductionHigh-grade squamous intraepithelial lesions are caused by persistent high-risk human papillomavirus (hr-HPV) infections and are subdivided into cervical intraepithelial neoplasia (CIN) lesions: CIN II (moderate) and CIN III (severe). Current treatment options for CIN II include large loop excision of the transformation zone, imiquimod and expectant management. Each treatment option has its drawbacks, and therefore, a non-invasive treatment is desirable. Preliminary evidence shows that medical-grade honey (MGH) has antiviral activity and might be able to modulate the vaginal microbiome, reduce local inflammation or directly influence the intralesional immune response within cervical tissues. Therefore, this study aims to investigate the possible effect of MGH on hr-HPV clearance and to investigate the possible underlying mechanisms contributing to the regression of CIN II lesions.Methods and analysisThis study is performed in the Zuyderland Medical Centre and Maastricht University Medical Centre+. A total of 60 eligible women with newly histologically confirmed CIN II will receive MGH (L-Mesitran Soft) for intravaginal use for 6 months. The primary objective is to investigate the effect of MGH on the hr-HPV clearance after 6 months. Secondary aims are the effect of MGH on the regression of CIN II lesions, clearance of hr-HPV at 12 and 24 months and the role of the vaginal microbiome, local immune system and intravaginal inflammatory status in response to MGH. Moreover, data on quality of life, side effects and compliance will be collected.Ethics and disseminationEthical approval from the Medical Ethics Review Committee of the Zuyderland Medical Centre Heerlen has been obtained (NL86044.096.24 on 24 April 2024). The results will be presented to researchers and healthcare professionals through conferences, meetings and publications in international journals.Trial registration numberNCT06219018.

Cervical cancer and its precursors (cervical intraepithelial neoplasia (CIN)) represent a current major public health concern. Currently, the treatment of choice for patients with HSILs (high-grade intraepithelial lesions) is surgical treatment—LEEP or cold-knife conization—except for in pregnant women, where it may have significant future consequences. In this paper, we aim to review the current evidence regarding the efficacy of non-surgical approaches for CINs. Therefore, we searched Google Scholar and PubMed for papers on CIN treatments; 91 studies published in English were included in the analysis. The results of the reviewed studies were variable depending on the agent and methodology used. Overall, the remission rates of CIN II ranged from 43 to 93%. However, for some agents, the results were contradictory. Once topical agents have been proven to be effective, they could be used as an alternative to surgical methods in treating HPV-associated CIN, with fewer adverse effects. The use of local agents could allow for more personalized treatments for patients with CINs. Future directions were also sought.

ObjectiveHigh-risk human papillomavirus (HR-HPV) infection is the chief cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. The Erhuang suppository (EHS) is a traditional Chinese medicine (TCM) prepared from realgar (As2S2), Coptidis rhizoma, alumen, and borneolum syntheticum and has been used for antiviral and antitumor purposes. However, whether EHS can efficiently alleviate HR-HPV infection remains unclear. This study was conducted to evaluate the efficacy of EHS for the treatment of persistent HR-HPV infection in the uterine cervix.MethodsIn this study, we evaluated the therapeutic efficacy of EHS in a randomized controlled clinical trial with a 3-month follow-up. Totally, 70 patients with persistent HR-HPV infection were randomly assigned to receive intravaginal administration of EHS or placebo. HPV DNA, ThinPrep cytologic test (TCT), colposcopy, and safety evaluation were carried out after treatment. Microarray analysis was performed to compare transcriptome profiles before and after EHS treatment. A K14-HPV16 mouse model was generated to confirm the efficiency of EHS.ResultsAfter 3 months, 74.3% (26/35) of the patients in the treatment group were HPV negative, compared to 6.9% (2/29) in the placebo group. High-throughput microarrays revealed distinct transcriptome profiles after treatment. The differentially expressed genes were significantly enriched in complement activation, immune response, and apoptotic processes. The K14-HPV16 mouse model also validated the remarkable efficacy of EHS.ConclusionThis study demonstrated that EHS is effective against HR-HPV infection and cervical lesions. Additionally, no obvious systemic toxicity was observed in patients during the trial. The superior efficacy and safety of EHS demonstrated its considerable value as a potential cost-effective drug for the treatment of HPV infection and HPV-related cervical diseases.

: Persistent infection of cervical epithelium with “high risk” human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX™ adjuvant (HPV16 Immunotherapeutic) for patients with CIN. : Patients with CIN ( n = 31) were recruited to a randomised blinded placebo controlled dose ranging study of immunotherapy. : Immunotherapy was well tolerated. Immunised subjects developed HPV16 E6E7 specific immunity. Antibody, delayed type hypersensitivity, in vitro cytokine release, and CD8 T cell responses to E6 and E7 proteins were each significantly greater in the immunised subjects than in placebo recipients. Loss of HPV16 DNA from the cervix was observed in some vaccine and placebo recipients. : The HPV16 Immunotherapeutic comprising HPV16E6E7 fusion protein and ISCOMATRIX™ adjuvant is safe and induces vaccine antigen specific cell mediated immunity.

Background Cervical dysplasia (cervical intraepithelial neoplasia (CIN)) is caused by Human Papillomavirus (HPV) and is most common in women of reproductive age. Current treatment of moderate to severe CIN is surgical. This procedure has potential complications, such as haemorrhage, infection and preterm birth in subsequent pregnancies. Moreover, 15% of women treated for high grade CIN develop residual/recurrent CIN or cervical cancer after surgical excision. Finally, 75–100% of patients with a residual and recurrent CIN 2–3 lesion are still HPV positive. They could possibly benefit from an alternative medical treatment, which aims to eliminate HPV. The primary study objective is to evaluate the effectivity of imiquimod 5% cream compared to treatment with Large Loop Excision of the Transformation Zone (LLETZ) for recurrent/residual CIN. Methods/design This study is a multicentre, non-inferiority randomized single blinded study. The study population consists of female patients with histological proven residual/recurrent CIN after previous surgical treatment. Four hundred thirty-three patients will be included in the Netherlands. The first 35 patients will be included in a pilot study to prove non-futility. Included patients will be randomized to receive either 5% imiquimod cream or LLETZ treatment. Imiquimod will be inserted three times a week intravaginally for a period of 16 weeks using a vaginal applicator. Ten weeks after the end of imiquimod treatment a biopsy will be taken for treatment response. In case of progressive or stable disease a LLETZ will be performed. At 12 and 24 months after the start of treatment cytology will be taken for follow up. The LLETZ group will be treated according to the current guidelines. Throughout the study, HPV typing and quality of life will be tested. Discussion Repeated LLETZ in women with residual/recurrent CIN lesions has complications. We would like to possibly offer alternative treatment in a selected group to avoid these risks. Moreover, we monitor treatment efficacy, side effects and long-term recurrence rates. Trial registration Medical Ethical Committee approval number: NL 53792.078.15. Affiliation: Erasmus Medical Center. Registration number ClinicalTrials.gov : NCT02669459 , date of registration: 27th January 2016.