Neoplasms

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Urogenital Diseases

HPV genotyping

Philip Roelandt, MD PhD

The pathophysiology from anal HPV infection to Anal Intraepithelial Neoplasia is less well understood than cervical HPV infection. In cervical screening programs it is well accepted that the sole presence of a high-risk HPV strain (irrespective of number of viral particles) is sufficient to justify further investigation and treatment. The investigators hypothesize that in anal HPV infection not only the presence but the extent of HPV infection (single genotype viral load) or combination of different HPV genotypes (cumulative viral load) is of importance in determining the risk of anal dysplasia.

Quantitative HPV Genotyping in Screening of Anal Intraepithelial Neoplasia in HIV-positive Patients

Retrieval of 1 anal swab before performing HRA to determine the HPV subtypes at that particular moment

Performing HRA (30 minutes) with or without biopsies, results biopsies up to 10 days

Sciensano

Universitaire Ziekenhuizen KU Leuven

Assistant head of clinic Gastroenterology

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Women in the capital region of Sweden with AGC, a concomitant human papillomavirus (HPV) analysis, and a histopathology.

HPV genotyping of samples classified that were positive for "other HPV"

Joakim Dillner, MD PhD

The purpose of the study is to follow up on cell changes detected in the cervical cancer screening program, to investigate whether they are handled with adequate quality.

The aim of the study is to clarify whether follow-up of cell changes is carried out with sufficiently good quality. It is nationally recommended to perform an HPV test on mild cell changes and only refer to clinical follow-up if you are HPV positive. Descriptive statistics on HPV-testing and follow-up of quality are not available today. If HPV testing has not already been performed, archived samples with glandular cell changes will be HPV-analyzed in Cobas 4800 HPV-polymerase chain reaction (PCR), which shows data on the presence of HPV and Luminex-PCR, which shows which HPV types the samples have. Women with low-grade squamous cell changes (ASCUS and CIN1) with simultaneous HPV analysis will be followed up with data from the Swedish National Cervical Screening Registry (NKCx) from the last ten years. A register linkage with data from NKCx and the National Cancer Registry at the National Board of Health and Welfare will be carried out to determine which women have developed gynecological cancer, cervical cancer and/or pre-cancer (cancer in situ). A follow-up review of reported original cytological (cell samples) and histological (tissue samples) diagnoses will be performed by cytodiagnostics and cytopathologists, to verify the correct diagnosis.

Statistics on collection of non-organized cell samples after a partial negative sample where follow-up is not recommended are produced in aggregated form in the form of an extract from NKCx

Follow-up of Cell Changes in the Cervix

Data available through the Swedish National Cervical Screening Registry and on request from the PI.

Risk for developing CIN3+ or worse depending on HPV type

Karolinska University Hospital

Professor

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Micronutrients

Coagulants

Vitamins

Acetic Acid

Retinol acetate

Iodine

Lugol's solution

Cadexomer iodine

Vitamin A

Retinol palmitate

Anti-Bacterial Agents

Adjuvants, Immunologic

Immunologic Factors

Protective Agents

Retinol

The study intervention will consist in applying HPV genotyping as a triage method of HPV-positive women for cervical cancer screening. After primary screening with the Xpert HPV test, positive women will be sorted according to two groups of genotypes: group 1 (HPV types 16,18,45, 31, 33, 35, 52 and/or 58 obtained from channels 1, 2 and 3) and group 2 (HPV types 51, 59, 39,56, 66 and/or 68 obtained from channels 4 and 5). Women of group 1 will immediately treated, while those of group 2 will not receive immediate treatment and will be followed-up at 12 months. An exception will be made for participants with lesions suspicious of invasive cancer upon examination, which will be referred for further investigations regardless of the HPV type.

The control arm will consist in triage of HPV-positive women by VIA, as currently recommended by the WHO. Women with a positive VIA will be treated immediately, while VIA-negative women will not be treated and will be followed-up at 12 months.

Genotyping will be obtained by the Xpert system which uses 5 color channels containing primers and probes for the detection of specific genotypes or pooled results as follows: i) HPV 16, ii) HPV 18/45 in pooled result, iii) HPV types 31, 33, 35 52, or 58, in pooled result, iv) HPV types 51 or 59, in pooled result, and v) HPV types 39, 56, 66 or 68 in pooled result.

After application of acetic acid and Lugol's iodine, the cervix will be assessed using simplified "ABCD criteria" (A= acetowhite lesion within the transformation zone, B = spontaneous bleeding or upon slight touch, C (optional) = Lugol-positive coloring of acetowhite lesions, D = diameter \> 5mm of acetowhite lesion).

Visual inspection after application of acetic acid

Patrick Petignat, PD

Bruno Kenfack, Pr

Georges Enow Orock, Prof.

Cervical cancer is the leading cause of cancer death among women in sub-Saharan Africa, despite the existence of effective prevention and screening methods. Because vaccination rates against human papillomavirus (causing nearly all cervical cancers) are still insufficient in some low-resource countries, early detection and treatment of cervical lesions at risk of progressing to cancer are crucial components of cervical cancer control. Therefore, it is essential to find the most reliable and appropriate screening strategy in the context of low-resource countries in order to identify women in need of treatment and thus prevent the development of cervical cancer. The objective of our study is to compare two different methods of cervical cancer screening adapted to low-resource settings, in two study centers in Cameroon.

HPV used as a stand-alone test has a limited specificity and positive predictive value and as a consequence, a significant number of HPV-positive women have no cervical precancerous lesions or cancer and receive unnecessary workup and treatment. For this reason, the WHO has recommended visual inspection with acetic acid (VIA/VILI) as a triage test of HPV-positive women to identify women requiring treatment. Nevertheless, VIA is a highly subjective procedure dependent on the health care provider's experience, with diagnostic accuracy varying from setting to setting. Triage by HPV genotyping has recently emerged as an alternative to triage by VIA, with immediate treatment of women with a subset of high-risk HPV genotypes only, thus reducing overtreatment rates. However, to date, the triage of HPV-positive women by VIA versus HPV genotyping has not yet been compared. This project aims to implement primary HPV-based screening in Cameroon followed by an immediate offer for treatment by thermal ablation after randomization for triage by HPV genotyping or VIA. More specifically, we aim to determine if triage by HPV genotyping (with immediate treatment of women with HPV types 16, 18, 45, 31, 33, 35, 52 or 58) allows better targeting of women needing treatment and allocation of resources to women at-risk than triage by VIA, as recommended by the WHO.

Primary objective: To identify the most efficient screening strategy for cervical cancer in Cameroon, more specifically to determine whether triage by a pool of eight genotypes (HPV types 16, 18, 45, 31, 33, 35, 52 or 58) is more effective than triage by visual inspection with acetic acid for detection of precancerous lesions. ¨

Secondary objectives:

* To determine the overtreatment rate in each screening group (HPV genotyping and VIA/VILI)
* To determine the rate of adverse events (e.g. hemorrhage, infection, hospitalization) in each screening group
* To determine which participant characteristics may be associated with better prediction of CIN2+ for each screening group
* To assess patient and health care provider acceptability of both screening strategies
* To create a sustainable structure for the promotion of women health with a priority made in the prevention of cervical cancer West Region of Cameroon
* To treat all precancerous or cancerous lesions discovered during the screening
* To inform women and their families about gynecological pathologies, including cervical cancer, sexually transmitted diseases (STD) and HIV
* To create a database of cervical images for continuous clinical education
* To develop an Automated VIA/VILI Classifier (AVC) that can help identify cervical precancerous lesions based on a 2-minute video of the cervix during VIA/VILI
* To assess women's, the community's and healthcare providers' acceptability of the AVC test

Study Design: National multicentric open-label two-arm randomized controlled trial

Qualitative and quantitative studies for participants and health care providers will be included during the study period addressing preferences and attitudes toward the screening process and treatment.

National multicentric open-label two-arm randomized controlled trial

Allocation to the study arm will be concealed until primary HPV screening by the GeneXpert machine has been performed, in order to ensure that the health care provider enrolling the participant into the study and the participant herself have no a priori knowledge of group assignment.

Detected HPV genotypes will only be revealed to the midwife executing the pelvic examination and treatment if the participant is randomized in the intervention arm (triage by genotyping), in order to know whether to treat the participant or not. If the participant is randomized in the control arm (triage by VIA), the midwife will be blinded to the exact HPV genotype channel(s) in order to avoid influence of treatment.

The pathologist performing histological analysis (gold standard) will be blinded to the study arm and the on-site diagnosis.

HPV Screening With Triage by HPV Genotyping Versus Visual Inspection With Acetic Acid

Promoting Comprehensive Cervical Cancer Prevention and Better Women's Health in Low- and Medium Resource Settings HPV Screening With Triage by HPV Genotyping Versus Visual Inspection With Acetic Acid: a Randomized Controlled Trial

Anonymized data may be shared upon reasonable request at the end of the study period.

Sensitivity of triage by HPV genotyping and VIA/VILI for cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) detection at time of screening (first visit), considering histologic results (from cervical biopsy and/or endocervical brushing) as the gold-standard.

Specificity, PPV and NPV of triage by HPV genotyping and VIA/VILI for cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) detection at time of screening (first visit), considering histologic results as the gold-standard.

The percentage of participants who have correctly followed the screening, triage and treatment strategy in each study arm will be measured to assess the feasibility of both triage strategies. This will be measured by study case report forms for both arms.

Overtreatment rate in each screening group, considered as treatment of participants with \<CIN2 on histology

(e.g. hemorrhage, infection, hospitalization)

Odds ratios of correct prediction of CIN2+ for various participant characteristics in each screening group

Estimated number of avoided cases of cervical cancer in each screening group based on identified and treated precancerous lesions and known rate of progression to cervical cancer if no treatment is provided.

Satisfaction with the screening process in both study arms will be measured on a scale from 0 to 10 (on a paper survey) among participants at the end of the first visit, and by a qualitative analysis of data from focus group discussions and individual interviews with health care providers and patients, in order to assess acceptability of both strategies.

Prevalence of HPV infection and cervical pre-cancer and cancer among Cameroonian women, based on HPV results obtained by self-sampling and analysis by the GeneXpert assay and on histological analyses of cervical biopsies and endocervical brushing.

Creation of a database of anonymized cervical images for clinical education, captured by smartphone photography during the VIA/VILI process.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Quantitative HPV Genotyping in Screening of Anal Intraepithelial Neoplasia in HIV-positive Patients	NCT03742375	Human Immunodef...	HPV genotyping	18 Years -	Universitaire Ziekenhuizen KU Leuven
Follow-up of Cell Changes in the Cervix	NCT05709730	Cancer of Cervi...	HPV genotyping	23 Years - 80 Years	Karolinska University Hospital
HPV Screening With Triage by HPV Genotyping Versus Visual Inspection With Acetic Acid	NCT05385406	Cervical Cancer	HPV genotyping Visual inspecti...	25 Years - 49 Years	University Hospital, Geneva
Quantitative HPV Genotyping in Screening of Anal Intraepithelial Neoplasia in HIV-positive Patients	NCT03742375	Human Immunodef...	HPV genotyping	18 Years -	Universitaire Ziekenhuizen KU Leuven
HPV Screening With Triage by HPV Genotyping Versus Visual Inspection With Acetic Acid	NCT05385406	Cervical Cancer	HPV genotyping Visual inspecti...	25 Years - 49 Years	University Hospital, Geneva

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