NcRNA is an important regulatory pattern of epigenetic modification, which can exert significant effects on HPV-induced tumorigenesis and progression by deregulating downstream genes. However, the knowledge of ncRNAs is still limited, hence, a better understanding of ncRNAs could provide some insights for exploring the carcinogenesis mechanism and identifying valuable biomarkers in HPV-positive HNSCC. Therefore, in this review, we mainly focused on the expression profile of ncRNAs  and explored their regulatory role in HPV-positive HNSCC, aiming to clarify the regulatory mechanism of ncRNAs and identify valuable biomarkers for HPV-positive HNSCC.Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide. Accumulating evidence suggests that persistent HPV infection is closely related to a subset of HNSCC types, and the incidence of human papillomavirus (HPV)-positive HNSCC has been annually increasing in recent decades. Although the carcinogenesis of HPV-positive HNSCC has not been completely elucidated, it has been well confirmed that E6 and E7, the main viral oncoproteins are responsible for the maintenance of malignant transformation, promotion of cell proliferation, and increase in tumor invasion. Moreover, compared with HPV-negative HNSCC, HPV-positive HNSCC shows some special clinical-pathological features, which are possibly related to HPV infection and their specific regulatory mechanisms. Non-coding RNA (ncRNA) is a class of RNA lacking the protein-coding function and playing a critical regulatory role  There aAlthough the pathogenesis of HPV-positive HNSCC has not yet been fully elucidated, it has been well proven that E6 and E7 are the main oncoproteins of high-risk HPVs, which play a crucial role in tumorigenesis and progression of HPV-positive HNSCC , as wellIn the generation of a malignant phenotype, cancer genetics and epigenetics are inextricably linked , 13. EpiNcRNAs are transcripts with nucleotide (nt) length less than 200, which are classified into long non-coding RNA (lncRNA), circular RNA (circRNA), microRNA (miRNA), P-element-induced wimpy testis interacting RNA , small nucleolar RNA (snoRNA), small interfering RNA (siRNA), ribosomal RNA, and tRNA depending on the nucleotide length   mechanism  technology has been used for performing discrepant sequence alignment of genomes, which was developed based on RT-PCR and gene chips technology . The CanThe main significance of differently expressed miRNAs is that they are considered valuable biomarkers in HNSCC . General2.2As mentioned above, miRNAs have been associated with biological behaviors, thus, many researchers have begun to focus on the regulatory roles of miRNAs in HPV-positive HNSCC , 20. Forvia suppressing downstream target genes, such as phosphatase tensin homolog (PTEN) and signal transducer and activator of transcription (STAT)  , 59, 60.n (STAT) , 43, havn (STAT) , and tran (STAT) .Recently, it has been proven that cell autophagy and immune response could influence the prognosis of HNSCC –65. Aranvia their target genes   .2.3Some miRNAs are distinctively expressed in HPV-positive HNSCC, which is regulated by HPV oncoproteins , 69, 73.MYO1B, thereby suppressing tumor progression in HPV-positive HNSCC cells  –88. Thusg et al.  have repg et al. , 87, 89,g et al.  and HaquLncRNAs have been closely associated with some clinical characteristics. Kolenda et al.  have con3.2GRP78 and IRE1  tails, which derived from exons and/or introns of precursor messenger RNA (pre-messenger RNA) . The preAberrant expression of circRNAs is responsible for the clinical behavior of OSCC. Zhao et al.  have conFurthermore, circRNAs may play a regulatory role in tumorigenesis. Zhao et al.  have repDiscrepantly expressed circRNAs have been related to the expression of viral oncoproteins, Zhao et al.  and Yu e5PiRNA is a new class of ncRNAs with a length of 26-30nt , which gThe significance of discrepantly expressed piRNAs is that they can act as prognostic biomarkers , 134. Kr6SnoRNA is a category of ncRNA with a length of 60-300nt that mainly exists in nucleosomes, and is generally used for the synthesis and modification of ribosomal RNA and mRNA . SnoRNAs7NcRNAs include miRNAs, lncRNAs, circRNAs, and piRNAs . Deregulin vitro and in vivo are necessary to explore effective targeted therapies with a view to improving the prognosis of HPV-positive HNSCC.Besides, the discrepant expression of ncRNAs can be distinguished in HPV-positive and HPV-negative HNSCC. Specifically, miRNAs and lncRNAs are different in sample sources (tumor tissues/cell lines), regulation oncoproteins (E6/E7), regulation status (upregulated/downregulated), and effects  in HPV-positive HNSCC. Furthermore, these miRNAs/lncRNAs are involved in different modulation mechanisms, some of them can serve as early molecular markers for the diagnosis and prognosis . Also, nDG and CZ: conception and design. All authors contributed to the article and approved the submitted version.


Uterine Cervical Carcinoma (UCC) is the most prevalent gynecological malignancy globally, with a rising incidence in recent years. Accumulating evidence indicates that specific viral infections, including human papillomavirus (HPV), Epstein-Barr virus (EBV), Hepatitis B and C viruses (HBV and HCV), and human herpesvirus (HHV), may contribute to UCC development and progression. Understanding the complex interplay between viral infections and UCC risk is crucial for developing novel preventative and therapeutic interventions.This comprehensive review investigates the association between viral infections and UCC risk by examining the roles of various viral pathogens in UCC etiology and pathogenesis, and possible molecular mechanisms. Additionally, we evaluate current diagnostic methods and potential therapeutic strategies targeting viral infections for UCC prevention or treatment.The prevention of UCC has been significantly advanced by the emergence of self-sampling for HPV testing as a crucial tool, allowing for early detection and intervention. However, an essential challenge in UCC prevention lies in understanding how HPV and other viral coinfections, including EBV, HBV, HCV, HHV, HIV, or their concurrent presence, may potentially contribute to UCC development. The molecular mechanisms implicated in the association between viral infections and cervical cancer development include: (1) interference of viral oncogenes with cellular regulatory proteins, resulting in uncontrolled cell proliferation and malignant transformation; (2) inactivation of tumor suppressor genes by viral proteins; (3) evasion of host immune responses by viruses; (4) induction of a persistent inflammatory response, contributing to a tumor-promoting microenvironment; (5) epigenetic modifications that lead to aberrant gene expression; (6) stimulation of angiogenesis by viruses; and (7) activation of telomerase by viral proteins, leading to cellular immortalization. Additionally, viral coinfections can also enhance oncogenic potential through synergistic interactions between viral oncoproteins, employ immune evasion strategies, contribute to chronic inflammation, modulate host cellular signaling pathways, and induce epigenetic alterations, ultimately leading to cervical carcinogenesis.Recognizing the implications of viral oncogenes in UCC etiology and pathogenesis is vital for addressing the escalating burden of UCC. Developing innovative preventative and therapeutic interventions requires a thorough understanding of the intricate relationship between viral infections and UCC risk. Uterine cervical carcinoma (UCC) remains a major global health concern, accounting for significant morbidity and mortality in women worldwide. Despite considerable research efforts and advances in screening and prevention strategies, UCC continues to pose a substantial public health challenge, particularly in low- and middle-income countries . A comprViruses, as obligate intracellular parasites, are well-recognized for their ability to manipulate host cellular processes, potentially leading to malignant transformation. Several viruses, such as HPV, Epstein-Barr virus (EBV) , and hepThis review aims to provide a comprehensive overview of the current state of knowledge regarding the relationship between viral infections and UCC risk. We will discuss the evidence supporting the involvement of various viruses in the development of UCC, focusing on their potential roles in oncogenesis, molecular mechanisms, and clinical implications. Furthermore, we will explore the challenges and future directions in the study of viral infections and UCC, emphasizing the need for well-designed epidemiological and molecular studies to better understand the intricate interplay between viruses and UCC malignancy. Ultimately, elucidating the role of viral infections in UCC may lead to novel preventive and therapeutic strategies for this prevalent and life-threatening disease.There are over 100 different types of HPV, which are categorized into three risk groups: high-risk, intermediate-risk, and low-risk, based on their association with UCC . High-riHuman papillomavirus α9 species includes HPV types 16, 31, 33, 35, 52, and 58. HPV α7 species includes HPV types 18, 39, 45, 59, and 68. These species comprise several high-risk HPV types, which are strongly associated with the development of UCC. UCC diagnosis typically involves a combination of screening and testing methods. Regular UCC screening, such as the Papanicolaou (Pap) test or liquid-based cytology, can identify abnormal cell changes in the cervix. If abnormal cells are detected, additional testing, such as HPV DNA testing or colposcopy, may be recommended. HPV DNA testing helps to identify high-risk HPV types, including those within the α9 and α7 species, that are associated with an increased risk of UCC. HPV α9 and α7 species, which encompass several high-risk HPV types, play a crucial role in the development of UCC. Regular screening, early detection, and appropriate follow-up care are vital for preventing the progression of precancerous lesions into invasive UCC. Additionally, HPV vaccination can help protect against the most common high-risk HPV types, including those in the α9 and α7 species, thereby reducing the risk of UCC. Intermediate-risk HPV types have a weaker association with UCC compared to high-risk types. They include HPV strains 68, 73, and 82 . These tThere are several proposed mechanisms by which HPV might contribute to the development of UCC, such as by promoting genomic instability , deregulUnderstanding the molecular biology of HPV infection and UCC development has been crucial in developing prevention and screening strategies, such as HPV vaccines and HPV-based UCC screening tests, to reduce the incidence and mortality of UCC worldwide . HPV vacHowever, it is important to note that HPV vaccines do not protect against all HPV types that can cause UCC, nor do they eliminate the risk entirely. Therefore, even vaccinated individuals should continue to undergo regular UCC screenings as recommended by healthcare professionals. With a reduction in the prevalence of high-risk HPV infections and UCC, there may be a reduced need for frequent UCC screenings  and associated treatments. This can lead to lower healthcare costs and improved quality of life for women. Self-sampling for HPV testing has emerged as a valuable tool in UCC prevention, offering several benefits that can help improve the overall effectiveness of screening programs and facilitate early detection of HPV infections, particularly among high-risk groups . Some keEpstein-Barr virus, also known as human herpesvirus 4 (HHV-4), is a virus that has been associated with various types of cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, and some types of stomach cancer (gastric carcinoma). However, the association between EBV and UCC is not well-established. Some studies have detected EBV DNA or viral proteins in UCC tissues , while on = 22) in their cohort of 99 patients. This is a valuable addition to the existing body of knowledge on EBV and cervical cancer. The authors provide evidence for the prognostic value of EBV status in cervical cancer patients, demonstrating that the 1-year and 5-year OS rates were higher in the EBV-positive group compared to the EBV-negative group. This finding highlights the potential clinical utility of EBV status as a prognostic biomarker  and latent membrane protein 1 (LMP-1), have been implicated in the oncogenic process during EBV infection. EBNA-1 is a multifunctional protein involved in the replication, maintenance, and segregation of the EBV episome in latently infected cells. It is expressed in all EBV-associated malignancies and plays a pivotal role in the persistence of viral episomes within host cells. Additionally, EBNA-1 contributes to the immortalization of infected cells by altering cellular gene expression and promoting genomic instability. During clinical diagnosis, the detection of EBNA-1 expression may serve as a marker of latent EBV infection and its associated cervical malignancies . LMP-1, iomarker . EBV infiomarker , histoneiomarker , and noniomarker . EBV hasiomarker .There have been some studies suggesting that coinfection with EBV and HPV may increase the risk of UCC development. The hypothesis is that the two viruses could act synergistically, with EBV potentially promoting HPV-induced cervical carcinogenesis . Co-infeGiven the current state of research, the direct relationship between EBV and UCC risk remains unclear. Further studies are needed to investigate the potential association between EBV and uterine cancer, as well as the underlying mechanisms involved if such a link exists.Hepatitis B viruses is a DNA virus that primarily infects the liver and can cause both acute and chronic hepatitis. HBV is a well-established risk factor for liver cancer, specifically hepatocellular carcinoma (HCC). However, the association between HBV infection and uterine cancer, particularly UCC, is not well-established. There is limited research on the potential relationship between HBV and uterine cancer, and the available studies do not provide sufficient evidence to establish a clear link between HBV infection and the risk of developing uterine cancer . It is iHepatitis C viruses is a well-known risk factor for liver cancer, particularly hepatocellular carcinoma. However, its association with uterine cancer, particularly UCC, is unclear and not well-established . The preThe clinical importance of EBV, HBV, and HCV in the etiology of cervical cancer has become an area of increasing interest among researchers and clinicians. The exact mechanisms by which EBV may contribute to cervical cancer development remain unclear, but possible explanations include the induction of genomic instability, inhibition of apoptosis, and promotion of cell proliferation . The posHuman cytomegalovirus (HCMV) has been associated with various malignancies, including glioblastoma and prostate cancer. It has been detected in some UCC tissues , but theKaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is a virus primarily associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. While KSHV has been extensively studied in relation to these conditions, its direct association with UCC is not well-established. Although KSHV and HPV are both viruses that can cause cancer, their roles in the development of UCC are distinct. HPV is considered the primary etiological agent for UCC, while KSHV has not been definitively linked to this malignancy. There have been some studies investigating the potential role of KSHV in UCC , but theHuman herpesvirus (HHV), particularly HHV-2, also known as herpes simplex virus type 2 (HSV-2), has been suggested to play a role in the development of UCC . HSV-2 iHuman immunodeficiency virus is a virus that attacks the immune system, specifically the CD4 + T cells, which play a crucial role in immune response. HIV infection can progress to acquired immunodeficiency syndrome (AIDS) when the immune system is severely damaged, leaving the individual vulnerable to various opportunistic infections and cancers. There is a strong association between HIV and UCC. HIV infection weakens the immune system, making it difficult for the body to fight off HPV infections and prevent the progression of pre-cancerous lesions to UCC . HIV-infThe future challenges for the viral etiology of UCC, particularly in relation to HPV, include (1) Improving vaccination coverage, although the HPV vaccine has proven effective in reducing the prevalence of high-risk HPV strains associated with UCC, improving vaccination coverage globally remains a challenge, especially in low- and middle-income countries where the burden of UCC is high; (2) Understanding HPV and other viral coinfections, such as EBV, may potentially play a role in UCC development. Further research is needed to elucidate the mechanisms and significance of these coinfections; (3) expanding screening programs: screening programs using HPV DNA testing have shown promise in detecting precancerous lesions, but implementing and expanding these programs worldwide, particularly in resource-limited settings, remains a challenge; (4) addressing disparities in access to care, disparities in access to preventive care, such as vaccination and screening, contribute to the high burden of UCC in certain populations. Efforts should be made to address socioeconomic, cultural, and logistical barriers to care; (5) developing novel therapeutic approaches, although current treatments for UCC, such as surgery, radiation, and chemotherapy, can be effective, there is a need for novel therapies that target the viral etiology of the disease, such as antiviral drugs and immunotherapies; (6) enhancing public awareness and education, public awareness and understanding of the role of HPV in UCC and the importance of vaccination and screening are essential to reduce the burden of the disease. Educational campaigns targeting various populations can help increase vaccine uptake and participation in screening programs; (7) investigating the role of viral genetic variation, the role of genetic variation within HPV types and its impact on UCC risk and vaccine efficacy needs further investigation; (8) Studying the impact of the HPV vaccine on non-cervical HPV-associated cancers, the HPV vaccine has the potential to prevent other HPV-associated cancers, such as oropharyngeal, anal, and penile cancers. Further research is needed to understand the long-term impact of vaccination on these cancers; (9) Addressing vaccine hesitancy: Vaccine hesitancy remains a challenge in certain populations, and efforts should be made to address misconceptions and promote confidence in the HPV vaccine, and (10) Long-term monitoring and surveillance, continued monitoring and surveillance of HPV prevalence, vaccine efficacy, and UCC incidence are crucial to assess the long-term impact of vaccination and screening programs and inform public health policy.DC and TL: review conception, design, data collection, and quality analysis. TL and YY: the data extraction of the included studies, analysis, and interpretation of results. DC and YY: draft manuscript preparation and the critical revision of the manuscript. All authors reviewed the results and approved the final manuscript.


This study aims to describe the natural history of and identify the risk factors associated with oral human papillomavirus (HPV) infections in an Australian Indigenous cohort. A longitudinal cohort study design, with baseline (2018), 12-month, and 24-month data obtained from Indigenous Australians aged 18+ years in South Australia, was performed. Face-to-face interviews were conducted, and saliva samples for HPV testing were collected at each time point. Basic descriptive analyses were conducted to calculate prevalence, incidence, persistence, clearance, and incidence proportions of any HPV infection. Multivariable logistic regression analyses with adjusted prevalence ratios (PRs) were conducted to identify risk factors associated with oral HPV infection. Among 993 participants with valid saliva samples, 44 HPV types were identified. The prevalence of infection with any oral HPV infection was 51.3%, high-risk HPV was 11%, and types implicated in Heck’s disease (HPV 13 or 32) was 37.4%. The incidence, persistence, and clearance of any and high-risk HPV infections were 30.7%, 11.8% and 33.3% vs. 9.3%, 2.8%, and 9%, respectively. Our findings indicate that the prevalence, incidence, and persistence of oral HPV infection in a large sample of Indigenous Australians were high, and clearance was low. Oral sex behaviours and recreational drug use were risk factors associated with incident high-risk HPV infection. Human papillomaviruses (HPVs) are the most common, but preventable, sexually transmitted infection in high-income countries  includinThe incidence of HPV-related oropharyngeal cancers (OPCs) has been increasing in some high-income countries and, in some settings , overtaking cervical cancer ,12. TherHeck’s disease, also known as ‘focal epithelial hyperplasia’, is predominately caused by oral HPV types 13 or 32 and has been reported among Indigenous people worldwide ,22,23,24Worldwide, Indigenous populations experience the highest incidence of OPCs due to societal inequality and disparities in health services . The firIt is necessary to estimate the prevalent and incident infection with disease-associated HPV types to better understand the characteristics and pattern of oral HPV infection among Indigenous Australians. However, to date, most studies examining oral HPV infection have been cross-sectional in design. Our previous studies ,30 have This study is reported according to STROBE  guidelines.The project implemented a longitudinal cohort study design. In February 2018 and January 2019 (baseline), a large convenience sample (n = 1011) of Indigenous Australian adults in South Australia aged 18+ years was recruited through Aboriginal Community Controlled Health Organisations (ACCHOs) who were additional key stakeholders in the study. This study had the oversight of ACCHOs and an Indigenous Reference Group (IRG), who advised on all aspects of project staff employment, participant recruitment, data collection, analysis, and feedback.The study received ethical approval from the University of Adelaide Human Research Ethics Committee (H-2016–246) and the Aboriginal Health Council of South Australia (04–17-729). All participants provided written informed consent.The self-reported questionnaire included socio-demographic characteristics, self-rated oral and general health, health related behaviour, HPV vaccination status, and sexual behaviours.Socio-demographic characteristics were ‘Age’, dichotomised two groups (≥37 vs. < 37 years based on the median of 37 years); ‘Gender’ ; ‘Geographic location’ (‘Non-metropolitan’ vs. ‘Metropolitan’); ‘Highest educational attainment’ ; ‘Income’ (defined as ‘Job’ vs. ‘Centrelink-welfare support payments’); Ownership of a government-administered health care card (HCC) ; and Car ownership, from question ‘Do you own a car?’, which had two responses (Yes vs. No).Self-rated general and oral health were assessed from the questions ‘Would you rate your general or oral health as ‘Excellent/Very good/Good’ or ‘Fair/Poor’?Health-related behaviours included ‘Tobacco smoking statuses’, defined as ‘current smoker’, ‘ex-smoker’, and ‘never smoked’. ‘Recreational drug use’ was classified as ‘Currently use’, ‘Don’t now but used to’ and ‘Never used’.Self-reported HPV vaccination status was obtained from the question: ‘Have you ever received a vaccination for HPV?’ and three responses .Sexual behaviours stemmed from two questions: (1) Have you ever given oral sex? and (2) Have you ever received oral sex? and were dichotomised as ‘Yes’  vs. ‘No’ .® AMPure PCR purification kit in a magnetic 96-ring SPRIplate®. Sequencing reactions were performed by containing the purified PCR products together with GP+ primer and BigDye Terminator. Direct sequencing was carried out initially. Samples with multiple HPV types were cloned before sequencing, with at least 5 clones sequenced per sample. Sequence reactions were analysed with an automated DNA sequencer (ABI model 3100) . The DNA sequences were compared with available sequences in GenBank through the BLAST server. The standard PCR method has been used in several projects before by us and others, and it has been proven to be reliable and reproducible [Saliva samples were collected using Omnigene Discover kits  at baseline and 12 and 24 months, from which microbial DNA for genotyping was extracted for analysis. Antonsson and colleagues have evaluated three different kits  for DNA extraction, namely Promega’s Maxwell®-16 Viral Total Nucleic Acid Purification Kit, QIAGEN’s QIAamp Mini Elute Virus Spin Kit and QIAamp Blood DNA Mini Kit (QIAcube) . β-globin polymerase chain reaction (PCR) with the primers PCO3/4 was carried out on all samples to ensure that enough cells to detect human DNA were present and that PCR inhibiting agents were absent. Saliva samples that were β-globin-positive were included in the data analysis. β-globin is a test of DNA integrity; any samples with a negative β-globin were invalid. HPV analysis was performed using a nested PCR system MY09/11 and GP5+/6+ to detect a large spectrum of mucosal HPV type, which included Heck’s-disease-related HPV type and all high-risk HPV types that have oncogenic potential in mucosal tissue. All HPV-DNA-positive samples were sequenced to confirm viral DNA sequences. For the sequencing, HPV-positive PCR products were purified with the Agencourtoducible ,30.Data files were managed and summary variables were computed using SAS software version 9.4 .Analysis began with statistics describing the point prevalence of oral HPV infection, including any type of HPV infection; HPV 13 or 32; HPV16 or 18; and all high-risk HPV (hr-HPV) infections. hr-HPVs were defined as HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82; they were assessed at three time points .After that, the incidence, persistence, and clearance of oral HPV infection at baseline and at 12- and 24-months were calculated. For the incidence, persistence, and clearance analyses, we included only participants who not only supplied three saliva samples but also had valid (β-globin positive) samples at all three time points. Incidence was defined as a negative sample at baseline or negative sample at baseline and 12 months, followed by a positive sample at 24 months; persistence was defined as a positive sample at baseline, 12 months, and 24 months ; and clearance was defined as a positive sample at baseline or a positive sample at baseline and 12 months, followed by a negative sample at 24 months. Two other conditions were defined as ‘fluctuation’: scenario I was defined as a negative sample at baseline, followed by a positive at 12 months, followed by a negative at 24 months; and scenario II  was defined as a positive sample at baseline, followed by a negative sample at 12 months, and then, followed by a positive sample at 24 months. Both scenarios I and II were calculated as incidence and clearance of oral HPV infection. Participants lost to follow-up at 12- and/or 24-months or those that were β-globin-negative at one of three time points  were excluded in this analysis. However, to ensure that the level of missingness or invalid samples did not affect the validity of results, the distribution of baseline characteristics between the two groups was compared.Period prevalence, which refers to prevalence measured over an interval of time, was estimated using the formula:Statistically significant differences were denoted by 95% confidence intervals (CI) that did not overlap.Multivariable logistic regression models with binomial distribution estimation were generated to calculate risk indicators. Unadjusted and adjusted prevalence ratios (PRs) and their 95% CI were calculated for prevalence, incidence, persistent, and clearance of any type of HPV infection, HPV 13 or 32, HPV16 or 18, and all high-risk HPV (hr-HPV) infections. Blocks of covariates were entered into multivariable models in five steps: model 1 was the crude model; the sociodemographic factors  were entered in model 2; health-related behaviours  were added into model 3; self-rated general and oral health were added into model 4; and self-reported HPV vaccination status was added into the final model (full model), which was model 5. It is important to note that the final model was built based on a priori selection of covariates as opposed to covariate selection based upon bivariate statistics.A total of 1009 participants had at least 1 oral HPV test: 993 of which had a valid test result ; 604 of 993 provided saliva samples at all three time points, and 473 of the 604 had valid (β-globin-positive) samples at all three time points. Of the 993 participants with at least one time point with a β-globin-positive saliva sample, 509 were positive for at least one HPV type at one or more time points.The baseline characteristics across three time points of valid and invalid saliva samples are summarised in The incidence, persistence, and clearance of oral HPV infection at baseline, 12-month, and 24-month follow-up among Indigenous Australian adults are presented in Also, The multivariable analyses of any oral HPV infection prevalence are shown in The multivariable analyses of oral HPV 13 or 32, 16 or 18, and hr-HPV infection prevalence are shown in The sociodemographic characteristics, general and oral health, and health-related behaviours of participants (n = 473) who had not or had incidence, persistent, or clearance of any oral HPV infection from baseline to the 24 months follow-up are presented in The multivariable analyses of incidence, persistence, or clearance of any oral HPV infection from baseline to the 24 months follow-up are presented in To the best of our knowledge, this is the first study to provide the natural history of oral HPV infection among Indigenous South Australians across 24 months; it is also the first study to track the incidence and persistence of HPV infections associated with Heck’s disease. This was achieved through the IRG and ACCHOs being actively involved in and supportive of this study, including recruitment and training of research officers.Our findings indicate that current and previous recreational drug use and oral sexual behaviours were positively associated with high-risk HPV infections. Indigenous South Australian adults who reside in non-metropolitan locations had a higher risk of acquiring HPV 13 or 32 infections, but a lower risk of HPV 16 or 18 and hr-HPV infections. Other risk indicators associated with HPV 13 or 32 infections included non-ownership of a car and fair/poor self-rated general health. Meanwhile, we found that the risk indicators associated with incidence of oral HPV infection were lower education levels and non-ownership of a car; risk indicators associated with persistent oral HPV infection were residing in non-metropolitan locations; and a risk indicator associated with clearance of oral HPV infection was also non-ownership of a car.Compared with our previous two studies ,30, a neEvidence has shown that the HPV vaccine is effective in reducing the prevalence of oral HPV infection . In AustOur findings demonstrated that acquisition of oral oncogenic HPV was significantly associated with oral sex. This finding keeps in line with previous studies ,35,36. AThe incidence of HPV types associated with Heck’s disease was much higher among Indigenous Australian adults (16.1%) than non-Indigenous Australian young adults (3.2% HPV 32 and 0% HPV 13) , which mCompared with a study of non-Indigenous Australians , our stuStrengths of this study include: (1) engagement with the Indigenous Australian community through partnerships and involvement of the study’s Indigenous Reference Group; (2) a large representation of the broader South Australian Indigenous population (n = 1011), with the findings potentially having meaning for other Indigenous groups residing in similar socio-economic regions of the world; and (3) a high response rate: 73.5% and 79.4% in the 12- and 24-month follow-ups, respectively. Limitations include (1) lack of oral clinical examination data due to the COVID-19 pandemic: this may not only influence the outcomes of the study, but also meant that we did not have the ability to correlate clinical oral disease statuses, such as Heck’s disease and early stage OPCs; (2) non-representative findings, with a higher proportion of females, those residing in non-metropolitan locations, welfare-based income, health care card holders, and current smokers than in broader Indigenous groups ; (3) losThis study could inform guidelines for the prevention and control of oral HPV infections and help to identify the factors associated with both infection and clearance; it may explore a new potential test for early detection of individuals at risk of developing oropharyngeal cancer. Therefore, oral HPV DNA tests could be considered as a potential screening test for oropharyngeal cancer prevention in the future.Our findings indicated that the prevalence and incidence of oral HPV infection in a large sample of Indigenous Australians were high. Engaging in oral sexual behaviours and recreational drug use are risk factors associated with high-risk HPV infections. Not owning a car and fair/poor self-rated general health are risk indictors associated with oral HPV 13 or 32 infections. These findings support current efforts to increase HPV vaccination uptake amongst Indigenous Australian adolescents.


Vaginal microecology has a definite influence on human papillomavirus (HPV) infection and clearance, but the specific correlation is still controversial. This research aimed to investigate the differences in the vaginal microenvironment of different types of HPV infection and also provide data supporting clinical diagnosis and treatment.According to strict inclusion and exclusion criteria, the case data of 2,358 female patients who underwent vaginal microecology and HPV-DNA tests at the same time in the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Xi'an Jiaotong University from May 2021 to March 2022 were retrospectively analyzed. The population was divided into two groups: an HPV-positive group and an HPV-negative group. HPV-positive patients were further classified into HPV16/18-positive group and HPV other subtypes positive group. The vaginal microecology of HPV-infected patients was analyzed using the chi-square test, Fisher's exact test, and logistic regression.P < 0.01). The prevalence of mixed vaginitis was 14.37% , with bacterial vaginosis (BV) paired with aerobic vaginitis (AV) accounting for the majority (66.37%). The difference in HPV infection rates among mixed vaginitis was not statistically significant (P > 0.05). The prevalence of single vaginitis was 24.22% , with the most frequent being vulvovaginal Candidiasis , and there was a significant difference in HPV infection rates among single vaginitis (P < 0.001). Patients with BV had a higher risk of being positive for HPV16/18  and other subtypes . Patients with Trichomoniasis were at higher odds of other HPV subtype infections . On the contrary, patients with VVC had lower odds of becoming infected with other HPV subtypes .Among the 2,358 female patients, the HPV infection rate was 20.27% , of which the HPV16/18 infection rate was 25.73% (123/478), and the HPV other subtypes infection rate was 74.27% (355/478). The difference in HPV infection rates between the age groups was statistically significant (Trichomoniasis are linked to HPV infection; hence, restoring the balance of vaginal microecology could assist in the prevention of HPV infection. As a protective factor for other HPV subtype infections, VVC may provide new insights into the development of immunotherapeutic therapies.There were disparities in HPV infection among different age groups; therefore, we should pay attention to the prevention and treatment of susceptible individuals. BV and  Lactobacilli are associated with an increased risk of HPV infection , and other vaginal microdysbiosis and HPV infection are controversial ] age of participants was 35 (28–42) years. The inclusion criteria are as follows: participants who (1) had a sexual history; (2) had no gynecological examination or vaginal ultrasound within 24 h; (3) are at a non-menstrual stage; and (4) had accepted HPV-DNA tests in our hospital. The exclusion criteria are as follows: participants who (1) are pregnant or lactating; (2) had sexual intercourse or used a drug in the vagina within the last 3 days; (3) used antibiotics within 1 month; (4) had accompanying autoimmune diseases or being under immunosuppressive treatment; (5) are complicated with serious medical or surgical diseases; (6) had the history of cervical lesion or HPV infection treatment, including medical and surgical treatments; and (7) had the history of HPV vaccination. The flow chart of the screening process is shown in the Two sterile cotton swabs were used to collect secretions from the upper 1/3 of the vagina; the swabs were placed in test tubes for immediate testing. A special brush for HPV-DNA testing was placed into the cervical canal and rotated 3–5 times; the brush was removed and placed into a specimen tube containing cell preservation solution, then the tube cap was closed and the samples were sent for testing.Trichomoniasis and perform a Donders score using the physiological saline wet sheet method; and the other was used to observe the density and diversity of flora, pseudohyphae, spores, Nugent score, and Lactobacilli grading, as viewed microscopically under oil after drying, fixing, and gram staining. We used the Vaginitis Combined Test Kit provided by Jiangsu Shuoshi Biotechnology Co., Ltd., to detect vaginal microbial function and inflammatory response indicators using the specimens on the second set of cotton swabs, including pH value, leukocyte esterase (LE), neuraminidase (SNA), β-glucuronidase (GUS), and β-N-acetylglucosaminidase (NAG). Evaluation and diagnosis were based on the Vaginal Microecology Evaluation System v.2016  BV: Nugent score ≥7 points; (3) VVC: fungal spores or pseudohyphae could be found microscopically under oil; (4) aerobic vaginitis (AV): according to the clinical manifestations and microscopic Donders score ≥3 points; (5) Trichomoniasis: a large number of white blood cells and active Trichomoniasis under the microscope; (6) Mixed vaginitis: two or more types of vaginitis existing at the same time; and (7) Microbial function and inflammatory response indicators could be determined according to the test kit.One of the sample cotton swabs was used to make two slide preparations, one to microscopically observe m v.2016  as folloDNA from cervical cells was extracted for hybridization and color development. A total of 15 high-risk HPV  and 6 low-risk HPV  types can be detected by HPV-DNA detection kit provided by Jiangsu Shuoshi Biotechnology Co., Ltd. The evaluation and diagnosis results were classified into (1) “HPV-positive”: one or more of the above-mentioned HPV subtypes were detected and divided into “HPV16/18-positive group” and “HPV other subtype positive group”; and (2) “HPV-negative”: none of the above HPV subtypes were detected.P < 0.05 was considered statistically significant.SPSS 25.0 and Origin 2019 software were used for statistical analysis and graphing, respectively. Quantitative data were expressed as median (IQR) and qualitative data were described by absolute and relative indices. The chi-square test, Fisher's exact probability test, or univariate logistic regression analysis were used for the comparison of factors between the groups, the multivariate logistic regression analysis was carried out with significant results, and the OR value and 95% CI were calculated. Statistical tests were two-sided; P < 0.01). The HPV-positive rates of women aged <30, 50–59, and ≥60 years were 24.34%, 24.30%, and 25.33%, respectively, higher than 17.29%−17.98% of women aged 30–49 years . There was a statistically significant difference in HPV infection between the different age groups (49 years .P > 0.05). HPV16/18 infection was most common in women aged ≥60 years, with a positive rate of 36.84%; the lowest positive rate was in the 30–39 years group (22.75%). HPV other subtypes infection was more common in women aged 30–39 years, and the positive rate was 77.25%. On average, the infection rates of HPV other subtypes in different age groups were three times higher than that of HPV16/18 (The incidence of HPV16/18-positive was 25.73% (123/478), while the rate of HPV other subtypes was 74.27% (355/478). The difference in HPV16/18-positive rate between different age groups was not statistically significant (HPV16/18 .P > 0.05). VVC was the most common single vaginitis , and there was a significant difference in HPV infection rates among single vaginitis  in patients with mixed vaginitis. In mixed vaginitis, the difference in HPV infection rates was not statistically significant  and 21.97% (105/478), respectively. BV+AV was the most common mixed vaginitis in HPV-positive patients , and BV was the most common single vaginitis . There was no significant difference in the HPV16/18 infection rate among different types of vaginitis either for mixed vaginitis or single vaginitis . On the multivariable logistic regression, women with BV  had higher odds of being HPV16/18 positive.Trichomoniasis, VVC, BV, AV, abnormal SNA, and Lactobacilli grade between HPV other subtypes positive and HPV-negative groups (P < 0.05). Multivariate logistic regression showed that patients with Trichomoniasis  or BV  had higher odds of being positive for HPV other subtypes; on the contrary, patients with VVC  had lower odds of becoming infected with HPV other subtypes.In a 2021 study of 36 types of cancer in 186 countries, researchers found that cervical cancer was the most common cancer in 23 countries and was the leading cause of cancer death in 36 countries , which mIn this study, HPV16/18 infection rate was 25.73%, and it was more common in women ≥60 years, which was similar to findings in a previous study . Zhang eChlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma, and HPV (Mixed vaginitis is the simultaneous presence of at least two types of vaginitis, contributing to an abnormal vaginal milieu. Nevertheless, the signs and symptoms of mixed vaginitis are often atypical, and treatment is complicated in contrast to single-type vaginitis . Owing t and HPV .Lactobacilli (The novelty of this study is that it investigates the correlation between mixed vaginitis and HPV infection, an area that has limited research. Research considered that mixed vaginitis was related to HPV infection by having higher species diversity and significantly fewer obacilli . HoweverSince AV was first proposed in 2002 , the resLactobacilli in the vagina, increased Gardnerella, and other anaerobic bacteria in BV increases the content of mucinolytic enzymes in the vagina and disrupts the local mucosal barrier, promoting viral adhesion, invasion, and even integration into the host genome, thereby increasing susceptibility to HPV infection. At the same time, anaerobic bacteria can produce ammonia and carcinogenic nitrites, resulting in abnormal lesions of the cervical epithelium (Previous studies have shown that the prevalence of HR-HPV is higher in patients with BV . Furtherithelium .Candida albicans exhibits colonization; it is usually a harmless member of the native microbiota (C. albicans and used as an adjuvant for a new HPV therapeutic vaccine can induce the immune response of HPV-specific CD8+ T cells and Th1 CD4+ T cells and can also induce humoral immunity (C. albicans is a potential immunotherapeutic agent and could be employed in the development of new vaccines or the treatment of HPV infection and even other diseases.The main type of single vaginitis varied widely owing to region, ethnicity, and population origin , 29. VVCcrobiota , and cancrobiota , which gimmunity . This inTrichomoniasis is also a common sexually transmitted disease, associated with multiple health consequences in men and women. Our study found that Trichomoniasis can increase the risk of infection of HPV other subtypes, consistent with previous studies (Trichomoniasis, which reduces the protective mucus layer of the vagina, leading to the development of epithelial cell microlesions, increasing the erosiveness of other subtypes of HPV, and allowing their DNA to integrate into host cells. This inflammatory process can also destroy the basal layer of the cervical epithelium, thus promoting the continued presence of HPV in cervical–vaginal epithelial tissue ( studies . This mal tissue .Lactobacilli in the vaginal microecological environment (Lactobacilli grade and SNA were associated with infection of HPV other subtypes. We believe that the presence of normal Lactobacilli plays an important role in maintaining the acidic environment of the vagina and preventing the invasion of pathogenic microorganisms. Nevertheless, Lactobacilli still cannot produce sufficient protective effect against HPV16/18. As the main pathogen of BV, the detection rate of Gardnerella was significantly increased in HR-HPV-positive women (Gardnerella secretes SNA while elevated SNA concentration was associated with increased risk for cervical lesion and HR-HPV persistent infection (It has been shown that HPV infection is associated with an increase in floral diversity and a decrease in the number of ironment . Our stuve women ; meanwhinfection , 40. A cnfection . Studiesnfection . FurtherThis is a cross-sectional study. To clarify the correlation between vaginal microbiota and different types of HPV infection, it is necessary to expand the sample size in multiple centers and design prospective studies, which is also a common limitation of this study and most other related studies. In addition, we all know that the vaginal microbiome is an intricate and dynamic microecosystem that constantly undergoes fluctuations during the female menstrual cycle and the woman's entire life , 44, whiTrichomoniasis should be alerted to this interaction. Meanwhile, exploring the mechanism of action of VVC may assist in the development of new vaccines or immunotherapeutic agents.In conclusion, our study from a hospital in northwest China found differences in HPV infection rates within different age ranges, which offers insights into the prevention of infection at different ages. Vaginal infectious diseases play an important role in HPV infection, and patients with BV or The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Medical Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.R-fA: study concept and design and critical revision. FF and Y-mH: data acquisition. FF, Y-mH, and L-yW: data analysis and interpretation. YZ, P-pL, and YG: manuscript preparation. All authors contributed to the article and approved the submitted version.


Misinformation regarding HPV vaccine safety and benefits has resulted in low coverage within the eligible French population. HPV vaccination is safe and efficacious in preventing HPV infections in adolescents. However, reaching optimal coverage in countries such as France is challenging due to misinformation, among other factors. Moreover, disparities exist in cervical cancer screening programs. To support the government health promotion policy aimed at improving prevention and control of HPV-related cancers in France, the Human Papillomavirus Prevention and Control Board (HPV-PCB), in collaboration with local experts, held a meeting in Annecy, France (December 2021).HPV-PCB is an independent, multidisciplinary board of international experts that disseminates relevant information on HPV to a broad array of stakeholders and provides guidance on strategic, technical and policy issues in the implementation of HPV control programs.After a one-and-a-half-day meeting, participants concluded that multi-pronged strategies are required to expand vaccination coverage and screening. Vaccine acceptance could be improved by: 1) strenghtening existing trust in clinicians by continuous training of current and upcoming/pre-service healthcare professionals (HCPs), 2) improving health literacy among adolescents and the public through school and social media platforms, and 3) providing full reimbursement of the gender-neutral HPV vaccine, as a strong signal that this vaccination is essential.The discussions on HPV infections control focused on the need to: 1) encourage HCPs to facilitate patient data collection to support performance assessment of the national cervical cancer screening program, 2) advance the transition from cytology to HPV-based screening, 3) improve cancer prevention training and awareness for all HCPs involved in screening, including midwives, 4) identifying patient barriers to invitation acceptance, and 5) promoting urine or vaginal self-sampling screening techniques to improve acceptability, while establishing appropriate follow-up strategies for HPV-positive women. This report covers some critical findings, key challenges, and future steps to improve the status of HPV prevention and control measures in the country. The HPV Prevention and Control Board is an independent, international, and multidisciplinary group of experts created in 2015 to provide evidence-based guidance and reflection on strategic, technical, and policy issues regarding the implementation and sustainability of human papillomaviruses (HPV) prevention and control programs. The Board aims to multiply and disseminate relevant information on HPV prevention and control to a broad array of stakeholders. It contributes to the control of HPV infection, prevention, and screening strategies of HPV-related cancers by organising two meetings every year; a “technical meeting” covering practical and technological topics such as vaccine characteristics, vaccine safety, screening technologies and landscape, treatment strategies, the role of healthcare providers in vaccination programs, and dealing with anti-vaccine messages ; and a “◦ Review how prevention and control programmes are organised within the French healthcare system◦ To provide a summary of the epidemiology, burden of disease, and surveillance related to HPV and HPV-related cancers in FranceThe healthcare system, prevention and control measures in France◦ To give an overview of the current control measures in France◦ To discuss successes and challenges related to HPV screening and treatment◦ To review the possible implementation of alternative screening methods and strategies, such as self-samplingCervical cancer screening and Treatment in France◦ To give an overview of the evolving HPV vaccination program◦ To discuss successes and challenges related to HPV vaccination◦ To discuss the state of vaccine confidence, associated challenges, and possible solutions to increase vaccine coverage rate◦ To discuss the impact of Covid-19 pandemic on vaccine confidence and review the change in perception, beliefs, and opinions toward vaccination◦ To discuss the efforts and stakeholder participation in social mobilisation and creating awarenessHPV vaccination in FranceThe various stakeholder perspectivesThe way forwardThe eleventh meeting of the HPV Prevention and Control Board (HPV-PCB) was held in December 2021 as a hybrid meeting due to SARS-CoV-2. This report summarises the discussions and lessons learnt from a country meeting that discussed the situation of the HPV prevention and control programmes in France. The objectives of the meeting were:France, which has a population of around 67 million people, has a health expenditure of 4700 US dollars per person, equal to 12.3% of the French GDP. Cardiovascular diseases and cancer are the leading causes of death, whereas, before Covid, infectious diseases accounted for less than 2% of deaths. Regrettably, there is inequality in incidence and mortality rates, with some regions having higher premature mortality. Inequalities in the coverage of the HPV vaccination across departments are attributed to medical density and unemployment rates, among other factors.The Ministry of Solidarity and Health runs various organisations that cover the funding and provision of health services. Among these organisations, the High Council for Public Health (HCSP) provides the authorities with prospective reflection and counselling on public health aspects, contributes to building a global and organised paediatric health policy, and contributes to elaborate and follow-up pluri-annually the national health strategy. In parallel, the National Health Authority  is an independent public authority that provides recommendations on professional practices and is involved in the organisation of care and public health. The HAS has several tasks, including 1) evaluation of health products, medical devices, and medical acts in order to allow their reimbursement, 2) recommendation of best practises and elaboration of public health recommendations, and 3) measurement and improvement of hospitals, clinics, outpatient care, and social and medico-social centres. The National Cancer Institute  is a state agency for health and scientific expertise in oncology, responsible for coordinating actions in the fight against cancer. INCa was created in 2004 and falls under the joint supervision of the Ministry of Solidarity and Health and the Ministry of Higher Education, Research, and Innovation. Its missions are to coordinate actions in the fight against cancer; to initiate and support scientific, medical, technological, and organisational innovation; to contribute to the structuring of the organisation of screening, care, and research; to provide expertise; to produce, analyse and evaluate data; and to promote the application of knowledge and good practices.The National Public Health Plan 2018–2022 aimed to implement a health promotion policy, including prevention, in all settings and throughout life. This aligns well with the ten-year strategy (2021–2030) for the fight against cancers, which emphasizes improved prevention as the first axis in its plan to fight against cancers. One step towards prevention is the introduction of a national cervical cancer screening programme. To increase efficiency, the scale of the organisation has moved from departmental to regional. Despite this, many actors with different missions are involved, which can negatively impact efficiency.The Ministry of Health has the political responsibility for primary prevention through vaccination. However, the organisation falls under the Chief Medical Officer . The French NITAG, the Vaccination Technical Committee , is a consultative body now under the aegis of HAS, acting after a referral from the DGS, works by assessing the strategic need for vaccination and proposing a recommendation supported by a medico-economic assessment. Based on these recommendations, the Ministry of Health will decide whether a vaccine should be integrated into the National Immunization Program.In 2017, the CTV was moved from the HCSP to the HAS. The CTV proposes recommendations on vaccines. Next, the Transparency Committee performs an evaluation of the vaccine in terms of medical benefit at the population level and comparison to previous similar vaccines. Subsequently, the Economic and Product Health Committee decides on the amount to be reimbursed (35% or 65%). It discusses the public price, including negotiation with French public insurance  representatives and the industry, on the acquisition price. The CTV also advises on immunisation schedules and mandatory vaccinations. CTV members are selected by obeying strict rules to prevent conflicts of interest.As an example of the decision-making process for HPV recommendation and advice process, first, as soon as EMA granted the marketing authorisation, CTV analysed in 2007: 1) the incidence of cervical cancer, 2) the average age at first sexual intercourse, 3) the aetiology of HPV in precancerous lesions and cancer 15–25 years after infection, 4) the efficacy of the Gardasil vaccine against HPV infection and cervical lesions, 5) the presence or absence of side effects, 6) cost-effectiveness studies related to its administration, 7) the impact of vaccination on cervical cancer screening by cytology, and finally 8) emphasised the value of screening. The voting members of the CTV proposed a recommendation for girls only with Gardasil (later followed by Cervarix) vaccination before the age of first sexual intercourse (14 years), with a catch-up up to the age of 23. Based on this, the Transparency Committee and the Medico-Economic and Public Health Committee decided on the public price and a reimbursement of 65% of the HPV vaccine by public insurance .In 2019, based on the low coverage of the vaccine in girls and men who have sex with men (MSM), a recommendation was issued to vaccinate boys between 11 and 13 years of age with two doses, boys between 14 and 19 years of age and MSM up to the age of 27 years of age with three doses, without changing the level of reimbursement.Until 2017, three vaccines were mandatory in France: diphtheria (since 1938), tetanus (since 1940) and poliomyelitis (since 1964). Due to various media-divulged myths and rumours, such as hepatitis B vaccine association with multiple sclerosis, pertussis's vaccine association with sudden infant death, and the use of aluminium salt-based adjuvants with macrophage myofascitis, the French population has developed concerns over the years on vaccines safety, and association of vaccines and vaccine components with adverse events. According to a report on vaccine confidence, the vaccine hesitancy rate in France is 45.2%. The overall average rate of vaccine hesitancy in all the countries surveyed (67 countries) was 13% . In anal samples, the prevalence of HPV was 82%, with multiple infections in 58%. In oral samples, the prevalence was 11%, with multiple infections in only 1% of the samples.Technically, the preservation of cervical specimens on FTA cards showed that HPV DNA could be safely recovered after 54 months of storage at room temperature. A concordance of 97% was achieved between the HPV genotypes detected in the initial cervical samples and on the FTA cards 4.5 years later [Another study estimated the prevalence of the different HPV genotypes in 600 high-grade cervical lesions in patients born between 1972 and 1993. The goal is to determine whether the prevalence of HPV16 and HPV18 is lower in the population born between 1983 and 1993 and potentially exposed to HPV vaccination compared to those born between 1972 and 1982 who were not exposed to vaccination [NCT04167501]. Other studies will evaluate vaccine effectiveness in female students and the HPV genotype distribution in high-grade cervical lesions and cancer in French Guyana.France has had opportunistic screening since the 1980s. A few pilot programmes were organised and launched in the 1990s, but a nationwide organised screening was not launched until 2014 as part of the Third National Cancer Plan. Currently, national screening coverage is around 60% for women between 25 and 65 who have ever been screened, although lower in overseas territories. Even within France, there are important social inequalities in access to screening.The objective of the screening programme is to reduce cervical cancer incidence by 30% through improved coverage, consistent follow-up of screen-positive women, and reduced inequalities in access to screening. The program is coordinated at a regional level by seventeen regional cancer screening coordination centres (CRCDCs) responsible for the invitations, appropriate follow-up, quality assurance and communication. The general practitioner (GP), gynaecologist, or midwife performs spontaneous screenings when women come to the gynaecologist consult. The programme actively invites women who may not naturally seek consultations with their general practitioner/gynaecologist to participate. The invitation stresses that participation is free of charge and allows for opting out. In the event of a positive result without follow-up exams, the healthcare provider (HCP) or the woman herself is contacted. As of June 2021, three years after the program was launched, only 13 of the 17 CRCDCs responded to the INCa activity questionnaire. From this, only seven CRCDCs have invited all eligible women, nine report difficulties in reaching HCPs, and test results are consistently collected in only three CRCDCs. The lack of a national information system hampers implementation, further aggravated by GDPR constraints. Subsequently, INCa started working on a project to collect all test and histology results at a national level. A national committee was formed to create and launch guidelines for self-sampling in women who have yet to respond to previous invitations.France is transitioning from cytology-based to HPV-based screening, as recommended by HAS in 2019. HPV testing has a higher sensitivity and negative predictive value and will facilitate an extended screening interval of five years after an HPV-negative result. After an HPV positive result, reflex cytology will be performed, and when lesions are found, the women will be referred for colposcopy. If cytology does not show lesions, HPV testing is repeated after one year.To move toward a transition, first, a validated screening assay must be selected for the introduction of HPV-based testing. Initially, five tests were selected, which have been approved by the US-FDA , a protoFinally, integrated screening is necessary, including management/follow-up of HPV-positive women, with an organised administration to facilitate call and recall, as most cervical cancer cases occur in women who do not participate in screening, and strategies to increase screening coverage, e.g., by self-sampling as an alternative for pelvic examination. Eventually, screening and vaccination programmes will have to be integrated, as the entry of vaccinated women into the screening age cohort will negatively impact the positive predictive value of cytology.Unfortunately, co-testing is often used in France without a clear benefit; it is more expensive and does not provide additional reassurance relative to an HPV-negative test, with only five cases per million per year based on the cytology addition.The French screening algorithm is in line with the European guidelines for quality assurance in cervical cancer screening , with cyAnother challenge is the obligation to confirm that the woman has agreed to share her data. The gynaecologists miss the opportunity to confirm this on the questionnaire; therefore, the data cannot be shared and is subsequently lost for the screening program's quality assurance (QA).To overcome these challenges, it is necessary to convince HCPs to apply these recommendations. An option would be not to reimburse screening tests after 30 years of age if more than 20% of the users have had two tests (i.e. co-testing). Additionally, it is important that healthcare professionals prioritise the confirmation of patient consent in transmitting anonymous data for program quality assurance. Lastly, it is important to encourage women to participate in screening when invited.While a screening program should theoretically reduce the incidence of cervical cancer by 90%, because of the low coverage in France, this target has not been reached. The third French Cancer Plan aimed to reduce incidence and mortality by increasing coverage and making it more accessible to vulnerable populations through self-sampling. A French study showed that offering vaginal self-sampling is a cost-effective way to increase participation, which was higher in the 'self-sampling' than in the 'no intervention' group and the 'recall' group . FurtherThe cytological results showed nine abnormal Pap smears, including three cases of cervical intraepithelial neoplasia grade III (CINIII) lesions upon histology. A follow-up study proposed urinary HPV testing to 13,535 women aged 35 to 65 years without a recent Pap smear. The participation rate was 15.4%. Of the 1,915 samples analysed, 190 were HPV positive. A satisfactory gynaecological follow-up was observed for 92% of the HPV-positive women . Twenty-Globally, 900,000 new cases of head and neck cancer (HNC) occur each year. The main risk factors for HNC are tobacco and alcohol, betel quid, and viruses, including HPV and EBV, indicating that most cases are preventable. France is among the countries with the highest incidence of HNC in Europe, and the same is true for the subset of oropharyngeal cancer (OPC). Two recent studies, one based on HPV mRNA testing in HPV DNA positives  and one By analysing trends from 1980 to 2012 using an age-period cohort model based on data from 11 French cancer registries, the age-standardised incidence rate of OPC among men decreased slightly. Among women, the age-standardised incidence rate increased . The patThe general lack of awareness of the association between HPV and HNC is a major concern, as it can lead to misdiagnosis and, consequently, delay diagnosis. Considerable efforts are needed to increase awareness among the medical community and the general population.At the end of the session, several points were raised for discussion.Cytology is often used for younger women. Due to increased vaccination coverage, could HPV-based tests not be performed in this age group, as fewer HPV positives are expected in vaccinated women?Are HCPs checking the co-testing box because they are insufficiently informed about reflex cytology testing?They are generally aware of reflex testing but have a financial incentive to request co-testing. The possibility should be considered to remove the box for co-testing completely. A reimbursement policy worked very well in Slovenia to stop HCPs from requesting the wrong tests. This may not work well in France and may be perceived as provocative, as the patient may side with the gynaecologist due to the long-standing relationship.To choose the preferred way to be screened, women must be well informed of the benefits and conditions of self-sampling.With so many private labs, how is quality assurance performed?There is no obligation to have QC/QA, except for clinical pathology, for which accreditation is necessary.Are there differences between HPV-positive and HPV-negative HNC patients? There is a big difference in overall survival, with HPV-positive cancer patients having a much better chance of survival and smaller tumours in the first place, which makes it possible to have robotic surgery. Regrettably, no screening for OPC is possible, making it even more relevant to raise awareness and ensure that cancers are diagnosed at the earliest possible stage. In the longer term, E6/E7 serology might be an option for screening, but this has yet to be confirmed.For anal cancer, which is also HPV related, the incidence of the disease is increasing in France, both in men and women, especially in older women. Screening could focus on high-risk groups such as MSM and people living with HIV. However, anal cytology does not perform well, and high-resolution anoscopy is quite complex and cannot be easily performed. A future session may be needed to discuss this topic in more detail.Many similarities exist between the development of the hepatitis B virus vaccine and the HPV vaccine: the long phase between antigen discovery and industrial production of the vaccine, vaccine hesitancy due to misinformation or debatable decisions by health authorities, and a target age group  which is more prone to autoimmune disorders. For Hep B vaccination in France, this trend was only partially reversed by introducing universal immunisation of infants in 2003, followed by free-of-charge vaccination in 2009. Finally, making the vaccine mandatory in 2017 was the most efficient incentive. The vaccination coverage rate is now around 90%.For the HPV vaccine, the self-assembly of the L1 structural protein into virus-like particles with the same morphology and conformational epitopes as the virus itself and the production of L1 in insect cells or yeast has paved the way for large-scale antigen production. Four vaccines are now commercially available, and effectiveness of these vaccines against cervical cancer has been shown –26. AlthThe initial vaccine recommendation, in 2007, was aimed at 14-year-old girls, with a catch-up vaccination of girls between the ages of 15 and 23 years who had not started sexual activity or were within the first year after initiation of sexual activity. This reference to sexual activity may have confused parents and led to hesitancy. In March 2007, the first recommendation for the HPV vaccine only mentioned the 4vHPV vaccine , which mNevertheless, in 2010, a vaccination coverage rate of 60% was achieved in the 17–20-year age group, receiving at least one dose. As a result of constantly updated messages from health authorities, a media crisis ensued in 2011. Several social media channels claimed that vaccinating with the 4vHPV vaccine (Gardasil) has caused adverse events following vaccination, leading to a 50% drop in the number of vaccinated girls. During that year, French national bodies conducted a study involving 1.8 million French girls. The study provided reassuring information on vaccine safety. The number of autoimmune diseases in vaccinated girls was not higher than in unvaccinated girls, except for some increase in Guillain–Barre syndrome. The absence of association between the incidence of any autoimmune disorders was confirmed in a study with a slightly different design . This leHPV vaccination coverage is steadily increasing; however, it is far from WHO's 90% vaccination target to eliminate cervical cancer as a public health concern by 2030. Additionally, geographic disparity has been brought to attention in regions with low coverage scattered across the map, including overseas departments.The French population trusts doctors more than any other profession. Hence, physicians play a pivotal role in the population’s vaccination, as their support of the official recommendations strongly influences the acceptance or refusal of the vaccine.Qualitative interviews with French physicians  showed that two-thirds (19/28) of the participants were favourable to HPV vaccination; some opposed it (4), while others were reluctant to recommend it . Three dInitial and continuous training of medical students is essential to enable them to fulfil their role as vaccinators. A nationwide cross-sectional online survey was conducted among students from 27 medical schools in France regarding their vaccination education . The surTo conclude, the perspective of other healthcare professionals  in the vaccination process in France has to be considered, as is already the case for several other vaccines for individuals 18 years of age and older. The HAS recommended in June 2022 that this be expanded to people under 18 years of age.In all countries, resistance to vaccination is as old as vaccination itself. After the inoculation against smallpox, Edward Jenner introduced the first proper vaccine, immunisation with a viral strain of bovine origin. Soon after, rumours claimed that vaccinated humans risked developing cow-like body parts. This shows that social media is not needed to develop fake news and vaccine hesitancy, though they are powerful facilitators. Louis Pasteur, who developed the rabies vaccine, also faced fierce opposition from scientific colleagues  and the media .The Universal League of Anti-Vaccinators started in England in the late nineteenth century, but still exists today and is active in France: the Ligue Nationale pour la Liberté des Vaccinations.Anthroposophy, founded by Rudolf Steiner at the beginning of the twentieth century, still has many followers in Europe and is opposed to vaccinations. Many Steiner-Waldorf schools still exist, mainly in Europe, where more than 70% of all these schools can be found.Another force against vaccination is libertarianism, a form of ultraliberalism, especially regarding economy, anarchism, individualism, and isolationism. This movement denies the authority and power of the state and calls for the dissolution of the coercive social institution. For libertarians, mandatory vaccination is a violation of the body.One of the main tools used to spread vaccine misinformation is false publication, with the 1998 Lancet publication on the association of autism and the measles vaccine as a prime example. After this publication, vaccination coverage decreased significantly, especially in the UK, causing measles outbreaks worldwide and returning vaccination coverage to levels before this publication took several years.Another infamous example is the paper that suggested that the HPV vaccine causes cervical cancer. The author of this paper claimed to work at the Karolinska Institute, but no one with this name worked at this institute. In fact, this institute was among the first to show that the vaccine prevents cervical cancer .In 2019, the WHO declared vaccine hesitancy one of the top ten threats to global health. Distrust and rejection of authority have been described as the main reasons for the reluctance towards vaccines . TherefoAlthough HPV infection is one of the most common sexually transmitted infections in Europe, HPV vaccination remains highly controversial in many countries, including France. Participants in European studies most commonly reported issues with the quantity and quality of information available about HPV vaccination, followed by concerns about potential side effects of the vaccine and mistrust of health authorities, healthcare workers, and new vaccines. Studies have found that low HPV vaccine uptake in France can partly be explained by concerns about the risks associated with the vaccines, their safety, effectiveness, and importance .To explore HPV vaccination decision-making among mothers and adolescent girls in France, a study was set up in Paris, recruiting vaccinated and unvaccinated girls and their mothers for interviews and focus groups –36.The main themes found to be associated with the decision-making process of adolescents and mothers for HPV vaccination were maturity, the influence of risk–benefit perceptions and trust of vaccines and stakeholders involved in the exercise of vaccination: 1) Maturity was shown to have an important role in HPV decision-making: Most adolescents felt not included in HPV decision making, as most of the time communication strategies are aimed at the caregivers or parents. In contrast, they can have the maturity to make informed decisions. This shows the need for individualised communication approaches with adolescents themselves to strengthen discussions and information on HPV vaccination . 2) RiskA project was set up in French Guyana to train local vaccinators and organise a school-based HPV immunisation campaign. French Guyana is in South America, with 90% of its area covered with forests, leaving a narrow coastline with all the infrastructure. Nevertheless, 20% of the population lives along the border of two rivers and can only be reached by pirogue. Cervical cancer is the second most common cancer among women and HPV prevalence rates are high, with limited access to cervical screening. Hence, immunisation is the prioritised line of prevention. As a first step, an information campaign was started to inform parents and pupils about cervical cancer prevention through immunisation and parental consent. Alongside this, professional training on HPV vaccination, including safety, effectiveness, and dealing with vaccine hesitancy. This training was provided to doctors, nurses, and midwives and was accredited by the National Agency for continuing professional development. On the first day of the campaign, 86 of the 246 registered girls were vaccinated. However, resistance emerged from local and church leaders, and in combination with the Covid pandemic, the campaign had to be stopped. The continuation of the project is planned for the first quarter of 2022, still with the objective of performing a vaccination program in all middle schools.At the end of the session, several points were raised for discussion.What is the role of fathers in the decision process?Mothers are more important in decision-making, but fathers are also involved. Although it is generally felt that fathers do not actively participate in decision-making, they seem increasingly keen to do so.How should trust be defined?It is essential to highlight that results from proximity, therefore, at different levels, such as trust in the product, the HCP (associated with closer proximity), and the authorities (associated with distance proximity).Recent data indicate a break in the slope of a decrease in cervical cancer incidence and mortality, possibly caused by more aggressive tumours, which are not detected by screening, occurring in young unvaccinated women.Treatment of cervical cancer is discussed in multidisciplinary teams and depends on tumour size (as observed by MRI) and lymphovascular space invasion status . For women eligible for conisation (stage IA1), those who are LVSI negative, treatment is based on the histologic margins. Those with negative or wide histologic margins can be followed up with HPV detection, while women with positive or small margins undergo radical hysterectomy type A. Women who are LVSI positive undergo pelvic lymphadenectomy of the sentinel nodes. If the nodes are negative, the woman is treated with radical hysterectomy type B. If the lymph nodes are positive, the case is considered advanced stage, with treatment schedules selected accordingly. This is also the case for stages IA2 and IB1. Radical hysterectomy is no longer an option for larger tumours , and women with negative lymph nodes are treated with brachytherapy . For stages IB3 and IVA, concomitant radiochemotherapy is proposed, except stage IVA with the risk of fistula, in which pelvic exenteration is performed.In case of recurrence, detected with magnetic resonance imaging (MRI) and positron emission tomography (PET) scan, radiotherapy can be applied . Otherwise, surgery (pelvectomy) is necessary. Chemotherapy for recurrences, e.g., using Bevacizumab or anti-PD-1, is currently under investigation.Radical hysterectomy is performed according to the Querleu-Morrow classification , in whicIn the case of pregnancy at the time of diagnosis, the length of pregnancy is important for the approach; after 24 weeks, treatment is postponed until fetal maturity for those stages that allow waiting (IA1/IB1).A proportion of women with cervical cancer are confronted at an age where they still may want to have children, in which case they must be treated conservatively, however, without increased risk of recurrence compared to traditional treatment. Furthermore, the treatment must increase the chance of having healthy babies afterwards. The experience at the hospital of Lyon over the period 1986 – 2011 included 160 cases of radical trachelectomy in women with a mean age of 31.5 years . The iniRegarding safety, nine recurrences occurred, leading to six deaths, while two patients were disease-free after further treatment. The risk of recurrence was closely associated with lesion size, with a ten times greater risk if the diameter of the tumour exceeded 20 mm . PregnanIt is still debated whether radical trachelectomy is safe in the case of LVSI; however, LVSI is not a prognostic factor for recurrence. Ultrastaging the sentinel nodes may help to find micrometastases that are contraindications to fertility preservation. Finally, to offer fertility preservation for more advanced cervical carcinomas, a study used neoadjuvant chemotherapy before radical trachelectomy in 19 women with a tumoral diameter of 29 to 51 mm (mean = 37 mm). After a median follow-up of 79 months, two early recurrences were observed and four healthy babies were born . StudiesAt the end of the session, several points were raised for discussion.How can the observation that the decrease in incidence and mortality of cervical cancer in France have slowed down be explained?This is mainly due to very aggressive tumours in younger women, with such a short period between infection and full-blown cancer that the screening programme cannot find them. These cancers are treated in the same way as other less aggressive cancers. Perhaps treatment needs to be tailored more accurately. The use of neoadjuvant chemotherapy can be important here. It may also be helpful in low- and middle-income countries, where surgery and radiation therapy resources are not always available.Will new chemotherapeutic agents  be a game changer in the field of cervical cancer treatment?Currently, these agents are only used in trials, and we are awaiting long-term follow-up results, but the early results look promising. In Switzerland, where there is more experience with anti-PD-1, the drug is active initially, but after 6–8 months, progression is observed again, making the drug applicable to a limited number of cases.For women living with HIV, should high-grade lesions be treated more aggressively?HIV is not an indication to treat more aggressively. Control of the HIV infection is more important than how lesions are treated. However, vaccination and screening for women living with HIV remain extremely important, as that may prevent the development of cancer in these women and in non-HIV-positive women.Political decisions on health issues are generally slow, and, usually, the decision process is not linear, making it often difficult for HCPs to understand the reasoning. Often, yearly changes in the vaccination schedule contribute to misunderstanding and a difficult follow-up of the recommendations. Recommendations for vaccination schedules are often aimed at both the general population and specific groups. However, healthcare professionals must handle each case individually and address practical questions on the spot. As a result, it is crucial for these professionals to stay up-to-date with the latest information continuously. Unfortunately, health authorities have been inactive in providing continuous support to HCPs after the initial recommendations were made. Additionally, vaccine companies are unable and unwilling to fill this gap, as it could lead to perceived conflicts of interest and further mistrust.Infovac-France was set up in 2003 to fill this void, as a platform of expertise in vaccinology, following the Swiss example. Initially, the focus of Infovac was on paediatricians, but this was expanded to GPs, pharmacists, nurses, and midwives. Though Infovac has an internet site open to the public, the platform of expertise itself is for HCPs only. The platform is independent and unpolitical, providing one-on-one advice but not recommendations on specific queries or questions regarding any aspect of vaccines and vaccination with shares valid documents and references if necessary. The platform receives around 8000 questions per year, and on average, 10 min are spent per question to provide evidence-based answers within 24–48 h. Infovac is open throughout the year, including weekends and bank holidays. Infovac acts as a finger on the pulse regarding any aspects of vaccines and vaccination because of the questions that are received, including hesitancy in HCPs and, through them, the general public. During annual meetings, the Infovac experts gather to receive activity feedback and discuss uncertainties, grey areas, or topics requiring consensus. The number of questions has steadily increased from 30–50 per week in the early years to 100–150 per week in 2021, making it a heavy burden for the experts who generally do this next to their regular job. However, experts are compensated for the work they have performed. As many experts have been active since the start of Infovac, new members are needed, and the total number of members may have to be increased to reduce the workload.The most frequently visited topics on the Infovac website are the frequently asked questions list and the pages dedicated to vaccine availability (shortage) and vaccine hesitancy.Several issues still need to be resolved to optimise information and communication on the HPV vaccine with adolescents: whether to preferentially speak about cancer or genital warts; how to address HPV vaccine safety, given the suggested link with GBS in France (which is not reproduced in other countries); whether and how to address herd protection; how to present information on vaccine coverage; how to address currently insufficient vaccine coverage in France; and whether to present HPV as a sexually transmittable infection.Discrete choice experiments can be performed to quantify the weight of these determinants in vaccine acceptance. Participants can be asked to decide for or against vaccination in hypothetical scenarios containing various levels of attributes described, as previously shown in university students  and healWhen the conversation focused on the cancer prevention benefits of the HPV vaccine, the participants were more willing to accept it. However, when the conversation focused on protection against genital warts, it did not motivate the participants. Girls were more likely to accept the vaccine for indirect protection, but this was not the case for boys. It was also observed that positive reporting phrasing, such as reporting that "more than 80% of young people in other countries got vaccinated", motivated vaccine acceptance compared to using "insufficient coverage,". Finally, the notion of sexual transmission did not influence acceptance . This stImplementing the HBV and HPV vaccines in France faced similar challenges, such as hesitancy driven by misinformation or controversial decisions and targeting young adults aged 10–20. Although universal infant immunisation followed by free vaccination improved the low coverage of the HBV vaccine, mandatory vaccination in 2017 was the most effective measure, leading to 90% coverage. Despite the introduction of a free HPV vaccine for girls aged 11–14 in 2013, the coverage rate remained low at under 30% in 2020. Leveraging strategies seen as successful in other vaccine programs may help France achieve higher coverage rates for HPV vaccinations.The initial recommendation for HPV vaccination in France in 2007 targeted 14-year-old girls, with catch-up vaccination for girls aged 15–23 who had not started sexual activity or were within the first year after initiation of sexual activity. The reference to sexual activity may have caused confusion among parents and led to hesitancy. Additionally, the first recommendation focusing only on 4vHPV vaccine was perceived as preference, over the 2vHPV vaccine. This may have cast doubt on the general preference for HPV vaccination, and the update of this recommendation in 2010 only added to the doubt and reluctance to vaccinate. However, the vaccination coverage rate increased to 60% in the 17–20 age group that received at least one dose in 2010. In 2011, a media crisis occurred due to unclear messages from health authorities, with several social media channels claiming that the 4vHPV vaccine (Gardasil) had caused adverse events following vaccination, resulting in a 50% drop in the number of vaccinated girls. However, studies conducted by national bodies, including 1.8 million French girls, showed that the number of autoimmune diseases in vaccinated girls was not higher than in unvaccinated girls, leading to the conclusion that data from the international and French literature did not show an increase in the incidence of autoimmune diseases or multiple sclerosis after vaccination with Gardasil. Despite steadily increasing HPV vaccination coverage, it is far from the WHO 90% vaccination target to eliminate cervical cancer as a public health concern by 2030, and geographical disparities have been identified in regions with low coverage.Physicians play a crucial role in the vaccination of the French population, as their support of official recommendations strongly influences vaccine acceptance or refusal. A study of French physicians  showed that two-thirds (19/28) of the participants were favourable to HPV vaccination, some opposed it (4), while others were hesitant about recommending it. The physicians' judgment was influenced by their trust in the stakeholders involved in designing and implementing the HPV vaccination strategy which further reinforces the importance of HPV awareness at this level. To enable physicians to fulfil their role as vaccinators, strong training of stakeholders involved in vaccination  is essential. Practical training was associated with better perceived preparedness, and methods based on practical learning are likely to produce the best results and should be favoured to improve student preparedness. Lastly, in February 2023 French authorities announced reimbursed recommendation of HPV vaccination for adolescents (boys and girls) between the ages of 11 and 14 and up to 19 years of age for catch-up vaccination. Thus, further strengthening the overall importance of HPV vaccination in preventing HPV-related cancers.Cervical cancer screening is undergoing a paradigm shift from a cytology-based approach to an HPV-based approach in women aged 30–65 years. The successful implementation of this transition requires the participation of all stakeholders involved in the screening process, including healthcare authorities, medical societies, and healthcare professionals. Co-testing does not improve HPV-based testing alone, and thus it is essential to apply the screening algorithm recommended by the relevant regulatory bodies . Furthermore, the use of clinically validated HPV tests and continuous quality assurance laboratories accreditation with international standards ISO15189 is necessary to ensure the best performance of the screening process.Regional Cancer Screening Coordination Centers (CRCDC) have a crucial role to play in organising and coordinating the screening process. The next step in cervical cancer screening is to consider how to screen vaccinated women. It remains unclear whether women below 30 years of age should still be screened by cytology, given the decreasing prevalence of HPV-positive cases. Innovative molecular tests, including viral load, genotyping, and methylation, may prove useful in triaging HPV-positive women more accurately than cytology. However, more large-scale studies are needed to evaluate the efficacy of these tests.Guidelines for the use of self-sampling for non-respondent women are now available. Self-sampling has the potential to increase screening coverage, and it is imperative to involve regional CRCDC in its implementation and follow-up. Large-scale communication campaigns are necessary to encourage women's participation in the organised cervical cancer screening program, which, combined with vaccination, is key to eliminating cervical cancer.This manuscript provides a comprehensive overview of France's HPV prevention and control programs up to December 2021, the date when the meeting took place. We acknowledge that the situation in France has changed since the meeting. However, the overview of the HPV prevention and control history in France up to December 2021 encompasses many lessons learned, which have the potential to contribute to and leverage opportunities for countries and regions that are optimising their prevention and control programs. Specifically, the events leading up to and following the implementation of 11 mandatory vaccinations are unique. This meeting report emphasises the importance of political determination, the power of stakeholder consensus (and the mobilisation process to obtain this consensus), and the subsequent outcomes as significant lessons learned that can serve as blueprints for other countries.