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Pathology and epidemiology of HPV infection in females
Abstract
Human papillomaviruses (HPVs) are a large family of small double-stranded DNA viruses that infect squamous epithelia. It has been established that infection with specific HPV types is a contributing factor to different types of anogenital cancer, including vulval, vaginal, anal, penile, and head and neck cancers. Approximately 4% of all cancers are associated with HPV. HPV infection is the major cause of cervical cancer and genital warts. Genital HPV infections are very common, are sexually transmitted, and have a peak prevalence between ages 18 and 30. Most of these infections clear spontaneously, but in 10-20% of women, these infections remain persistent and are at risk of progression to grade 2/3 cervical intraepithelial neoplasm (CIN) and eventually to invasive cancer of the cervix (ICC). CINs are genetically unstable lesions with a 30-40% risk of progression to ICC. If left untreated, they form a spectrum of increasing cytological atypia, ranging from low-grade CIN1 to high-grade CIN3; the latter are caused almost exclusively by high-risk HPVs, HPV 16 and 18. Infection with HPV requires a microabrasion in the genital epithelium. The oncogenic properties of high-risk HPV reside in the E6 and E7 genes, which if inappropriately expressed in dividing cells deregulate cell division and differentiation. HPV DNA testing has been shown consistently to be superior to cytology in terms of sensitivity and positive predictive value and will become a major tool in cervical cancer screening, at least in the developed countries.
... Embora a maioria das infecções pelo HPV seja assintomática e autolimitada, alguns tipos de HPV estão associados a uma série de doenças clínicas, incluindo verrugas genitais e várias formas de câncer, como o câncer de colo de útero, ânus, garganta, vulva, vagina e pênis. Essas repercussões clínicas podem ser graves e impactar significativamente a qualidade de vida dos afetados (BRASIL, 2016;Stanley, 2010). ...
... Além disso, ter múltiplos parceiros sexuais, início precoce da atividade sexual e tabagismo são considerados fatores de risco. A imunossupressão, como a causada pelo vírus da imunodeficiência humana (HIV), também aumenta a suscetibilidade à infecção pelo HPV e às suas complicações (Stanley, 2010). ...
... Além disso, a educação e a conscientização pública sobre o HPV e suas consequências podem ajudar a prevenir infecções e complicações futuras. Portanto, o estudo contínuo desse tema é fundamental para melhorar a saúde da população e reduzir o impacto das doenças relacionadas ao HPV(BRASIL, 2016;Muñoz et al., 2003;Stanley, 2010). ...
A infecção pelo Papilomavírus Humano (HPV) é um tema de crescente importância na medicina e na saúde pública devido às múltiplas implicações clínicas que apresenta. Esse vírus, que se dissemina principalmente por via sexual, pode resultar em uma variedade de condições clínicas, sendo as mais proeminentes as relacionadas aos tipos de câncer associados ao HPV. Um dos cânceres mais notáveis vinculados ao HPV é o câncer cervical, que afeta principalmente mulheres e é uma das principais causas de morte por câncer em várias partes do mundo. Além disso, o HPV tem sido cada vez mais associado ao câncer de boca e orofaringe, principalmente devido à prevalência do HPV-16 nesses casos, levando a uma mudança na epidemiologia desses cânceres. As verrugas genitais, ou condilomas acuminados, também são uma manifestação clínica comum da infecção pelo HPV. Embora geralmente benignas, essas lesões podem causar desconforto e preocupação para os afetados, e seu tratamento é frequentemente necessário. É importante destacar que as crianças também podem ser afetadas pela infecção pelo HPV, especialmente por transmissão vertical durante o parto. A ocorrência de verrugas virais em crianças é uma manifestação rara, mas é crucial que os profissionais de saúde estejam cientes dessa possibilidade e sejam capazes de fornecer um diagnóstico e tratamento adequados, quando necessário. Dentre os tipos de HPV, alguns são mais oncogênicos, ou seja, têm maior propensão para causar câncer. O HPV-16 e o HPV-18 são amplamente reconhecidos como os tipos mais oncogênicos, devido à sua capacidade de integração do DNA viral no genoma do hospedeiro e à expressão de proteínas virais, como E6 e E7, que interferem na regulação do ciclo celular e contribuem para o desenvolvimento de lesões pré-cancerígenas e câncer. A prevenção é uma abordagem fundamental para reduzir as repercussões clínicas da infecção pelo HPV. A vacinação é uma estratégia eficaz para prevenir a infecção por tipos de alto risco do HPV, incluindo o HPV-16 e o HPV-18, e, assim, reduzir o risco de câncer relacionado ao vírus. Além disso, a conscientização pública sobre práticas sexuais seguras e a importância do rastreamento, por meio do exame de Papanicolaou e de outros métodos de detecção precoce, são componentes essenciais na prevenção e no controle das doenças relacionadas ao HPV.
... Research efforts to understand Human Papillomaviruses (HPVs) often focus on high-risk HPVs (hr-HPVs), particularly the prototypical HPV16, due to their role in cervical and other cancers [1,2]. These investigations have uncovered a universal pattern of viral gene expression that can be extended, with some modification, across different HPV groups [3]. ...
... Of HPV-infected women, approximately 10 % show signs of one of these stages, representing oncogenic transformation of the cervix [27]. However, it is important to note that hr-HPV induced oncogenesis is an uncommon occurrence [2,8]. Oncogenic transformation is predominantly confined to the site of the squamocolumnar junction within a small region of metaplastic squamous epithelium, deemed the "transformation zone", where cells appear to be especially susceptible to hr-HPVs [4,5,28,29]. ...
Infection by Human Papillomaviruses accounts for the most widespread sexually transmitted infection worldwide. Clinical presentation of these infections can range from subclinical and asymptomatic to anogenital cancers, with the latter associated with persistent infection over a significant period of time. Of the over 200 isotypes of the human virus identified, a subset of these has been characterized as high-risk due to their ability to induce oncogenesis. At the core of Papillomavirus pathogenesis sits three virally encoded oncoproteins: E5, E6, and E7. In this review we will discuss the respective roles of these proteins and how they contribute to carcinogenesis, evaluating key distinguishing features that separate them from their low-risk counterparts. Furthermore, we will consider the complex relationship between this trio and how their interwoven functional networks underpin the development of cancer.
... cSCC is the most common form of metastatic skin cancer and its incidence is increasing worldwide. cSCC is an advanced form of premalignant actinic keratosis (AK) that occurs in sun-exposed areas of the body [12]. Chronic exposure to ultraviolet (UV) radiation is known to be the main cause of cSCC development [13]. ...
... Integration HPV DNA integrates into the host cell's genome. For high-risk HPV types, such as HPV 16 s , i 18, this integration can disrupt host genes and initiate carcinogenesis [12] Viral shedding and transport ...
This narrative review provides a comprehensive analysis of skin lesions caused by human papillomavirus (HPV). Human papillomavirus is an infection involving a virus that is omnipresent and can range from benign wart lesions to malignant skin growths. This review includes an analysis of the skin manifestations caused by HPV, and the need for continued successful diagnostic techniques and treatment methods, given the increasing rates of infection among people worldwide. We reviewed all 135 studies related to pathophysiology involving skin, risk factors, and early detection methods like biopsy and molecular testing, from 2000 to 2023. The current treatments, including cryotherapy and laser therapy, are discussed, while the review emphasizes the role of HPV vaccination in preventing infection. Recommendations for the future would involve the improvement of public education and increased vaccine coverage, together with innovative therapies toward better management or control of skin diseases associated with the human papillomavirus (HPV). By advancing these recommendations, we will be in a better position to prevent and treat HPV skin conditions, thus improving the health condition of the general public across the world.
... This process is thought to be mediated by the E1 and E2 HPV oncoproteins [63]. Subsequent to this, the viral DNA enters the productive stage where the DNA is replicated and the viral copy number is amplified to around 50-100 copies per cell; this appears to be independent of the cell cycle [64]. To do this, the machinery responsible for synthesising DNA within the cell must be activated. ...
... The expression of viral genes is low during this period of plasmid or episomal maintenance, and in particular, the expression of the oncogenes E6 and E7 is tightly regulated, with hardly any detectable E6/E7 mRNA transcripts [64]. This is important because these oncoproteins are expressed in the later phase of the lifecycle and are thought to be useful in evading immune responses such as apoptosis and programmed cell death activities [66]. ...
Most cervical cancer cases are a result of persistent high-risk Human papillomavirus (HPV) infections. Cervical cancer is prevalent in LMICs especially in SSA where it is second most prevalent cancer. In South Africa, it is the second most common cancer affecting women aged between 15 and 44 years. The host immune response has been shown as an important factor in controlling the progression or regression of high-risk HPV infection of the cervix to cervical cancer. The risk of cervical cancer is known to be influenced by the host's genetic diversity, particularly by immune response-regulating genes such as the Human Leukocyte Antigen (HLA) class I and II genes. HLA class I genes present viral peptides to CD8+ T cells which are restricted and pre-programmed for cytotoxic functions. There is very little known about the HLA genes of South African women and how these influence outcome of HPV infections. This review aims to understand the role and influence of HLA class I genes in HPV clearance, persistence, and CD8+ T cell mediated immunity in African women by examining existing literature in this area. Understanding this role can influence and inform therapeutic vaccine design that is population specific.
... The PCR master mix contains buffer, dNTPs (U/T), DNase/RNase-free water, biotinylated primers, DNA polymerase, and UNG. Primers included a specific amplification of a fragment of the region L1 of the HPV and 35 HPV genotype primers for high risk (16,18,26,31,33,35,39,45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82) and low risk (6,11,40,42,43,44, 54, 55, 61, 62, 67, 69, 70, 71, 72, 81 and 84) strains and a specific primer for the amplification of a human genomic DNA fragment (betaglobin gene) an internal control to show adequacy of the sample. A specific PCR program cycle was followed by the protocol recommended by the manufacturer (Vitro Mast Diagnostica, Spain). ...
... 35-44 and �45 years) [33]. However, in the developed counties the prevalence of HPV was peak in young women and lowered after 35 years of age [5] and other studies mentioned that there is a second peak in the postmenopausal age groups in some countries [34,35]. ...
Objective
The aim of this study was to explore the prevalence of low and high-risk HPV genotypes in PAP smear samples of women in northern region of the UAE using HPV direct flow CHIP method.
Methods
A cross-sectional retrospective study was conducted between September 2021 to April 2022. A total of 104 liquid-based cervical cytology samples were obtained from women aged 20–59 years attending the Gynaecology out-patient department of Thumbay University Hospital and other hospitals of Northern Emirates of UAE, processed for the routine cytological examination to identify and differentiate morphological changes of the PAP smear samples. HPV genotyping was performed using HPV direct flow CHIP method.
Results
In total, 112 HPV genotypes were detected in 63 women (60.57%) included 18 abnormal cytological and 45 normal epithelial samples. 63 LR and 49 HR HPV genotypes were identified in all the 63 positive samples. Highest rate of infection with multiple LR and HR HPV genotypes were detected in women aged 40–49 years (25.9%) and 20–29 years (23.5%). Infection by HPV6 (13.46%), HPV11 (9.61%), HPV16 (9.61%), HPV62/81 (7.69%) and HPV45 (7.69%) were the most common genotypes. A moderate increase than expected incidence of HPV45 and 62/81 (7.69%) were detected. Co-infection with multiple low and high-risk genotypes is present in 20.2% cases; in that, HPV6 (15.9%) was the most common followed by HPV62/81 (12.7%) and HPV16 (11.11%). The prevalence of HPV18 was found to be 1.6%.
Conclusion
The genotypes 6, 45, 16, 11, 67, 62/81 were the most common HPV infections in the women between the age group of 21 and 59-years-old. A moderate increase of HPV45, 62/81 and much less prevalence of HPV18 were detected in the study population. 43.27% of the normal epithelia were positive to different low and high-risk HPV genotypes. This finding highlights the importance of molecular genotyping of HPV to emphasize the cervical screening triage.
... The development of cervical cancer, including precancerous lesions, CIN grades I-III, and early infiltrating cancer, requires a relatively long time (Ren et al., 2021). Most HPV infections are transient and can be spontaneously cleared by the immune system within 1-2 years, while a few persist for many years or even decades (Stanley, 2010). Additionally, HPV detection was able to identify abnormalities in cervicitis and CIN grades I-III during follow-up, but not TCT, suggesting the superior accuracy of HPV detection compared to TCT detection. ...
Objectives
HPV infection and HPV DNA integration can lead to cervical cancer, but the relationship with lesion severity is unclear. This study aimed to investigate the correlation between HPV integration profile and cervical lesion extent.
Materials and methods
Twenty patients representing cervicitis, CIN I, CIN II, and CIN III underwent nanopore sequencing for HPV genotype and integration site analysis. HPV integration profiles were correlated with lesion severity. Gene Ontology (GO) and KEGG analysis were used to identify stage-specific genes and pathways.
Results
HPV integration rates were 60, 60, 100, and 100% for cervicitis, CIN I, CIN II, and CIN III, respectively, with varying numbers of integrated genes. Each group had specific stage-related genes, with 83 shared genes linked to neuron development and cell–cell processes. CIN II and CIN III displayed more cancer-related pathway enrichment than earlier stages.
Conclusion
A positive correlation exists between HPV integration frequency and cervical lesion stage. Late-stage lesions showed heightened enrichment in cancer-related pathways through specific HPV-integrated genes.
... A study in China has shown that in women aged 20-39 years, the incidence of CC has risen from sixth place in 2005 to the third place in 2020, while in women aged 40-79 years, the mortality rate of CC has been continuously increasing since 2005 4 . Persistent human papillomavirus (HPV) infection is a major factor in the development of CC, and approximately 130 HPV types have been detected from clinical biopsies 5,6 . The pathogenicity of HPV of the same type varies greatly and can be divided into high-and low-risk HPV according to the genotype and the risk of carcinogenesis. ...
To analyze the genotype distribution of human papillomavirus (HPV) infection in women in the Huizhou region of China and determine its correlation with age and degree of cervical lesions, with the aim to understand the characteristics of HPV infection in women in the region. A total of 65,127 patients who underwent HPV testing at the Second Maternal and Child Health Hospital of Huizhou City from January 2018 to December 2022 were selected as the research subjects. The polymerase chain reaction-reverse dot blot hybridization technique was used to detect HPV genotypes. The total detection rate of HPV infection was 7.25%, with single infection accounting for 70.94%. The detection rate of high-risk HPV was 6.73%. The top four high-risk types of HPV detected were 16, 52, 18, and 58. The distribution of HPV infection varied greatly among different age groups. The positive rates of HPV were the highest in the < 30-year-old group, followed by the ≥ 60-year-old group, showing a clear bimodal phenomenon. HPV infection in the population of Huizhou is mainly single infection and high-risk type, with higher infection rates in people < 30 and ≥ 60 years old. The local area should pay attention to the prevention and control of HPV.
... HPV (human papillomavirus) is one of the most common sexually transmitted infections (4). Human Papillomavirus (HPV) is the most prevalent sexually transmitted virus (5) and most attributable to cervical cancer (6,7), it (HPV) has around 100 types of HPV, with different variations in their genetic and oncogenic potential (8). ...
Background
Human Papillomavirus (HPV) infection is a potential risk for cervical cancer, the latter is the fourth leading cause of cancer related death worldwide. Effective testing procedures are particularly important in its prevention and management. More accurate HPV tests replace traditional cytology based screening, and they are in line with national and international guidelines that recommend primary HPV testing due to its better efficacy. The purpose of the study was to confirm that these Gynius HPV detection kits were equal in efficiency compared with Roche Cobas HPV assay based testing, which could better facilitate earlier detection and stratification by risk level for cervical lesions.
Methods
The prospective parallel control study recruited 1000 women from the district hospitals of Kibagabaga and Muhima in Rwanda. Participants were tested for HPV DNA tests using both Roche and Gynius kits and then the samples were sent to Rwanda National Reference Laboratory. We analyzed the concordance of two Gynius variants (liquid and lyophilized ) and Roche across for several different HPV subtypes, such as 16, 18 or other high risk types (31,33,35,39,45,51,52,56,58,59,66,68,73,53,82 &26). Statistics like sensitivity, specificity, predictive values and consistency (Kappa) were calculated to compare the concordance of assays.
Results
We found that the Gynius HPV solution is exceptionally easy to implement in laboratory settings within low and middle income countries (LMICs). It offers effective sampling control through color detection, making it highly suitable for self sampling procedures. Additionally, the Gynius HPV solution includes an automated extraction system that completes full plate extraction in under 20 minutes.
The Gynius solution is compatible with various qPCR systems, eliminating the need for costly qPCR machine repurchases. Using lyophilized reagents, which can be stored and transported at room temperature, it bypasses the need for a cold chain and refrigeration.
The Gynius solution also has a high sample processing capacity. For instance, using the BioRad CFX96, it can produce up to 1,200 results per day per machine; with the BioRad CFX384, it can generate up to 4,000 results per day making it ideal for large scale screening.
In a comparison of 987 samples, high risk HPV detection rates were consistent across all three tests: Roche (20%), Gynius liquid (23%), and Gynius lyophilized (21%). Concordance analysis showed high agreement rates, with both Gynius kits achieving over 80% compatibility with Roche for detecting HPV 16, 18, and other virus subtypes.
Conclusion
This study provides compelling evidence for the efficacy of the Gynius HPV kits (both lyophilized and liquid formulations), which demonstrated high concordance rates with established assays for detecting high risk HPV genotypes, particularly HPV 16 and 18. Engineered specifically for low and middle income countries (LMICs), the Gynius HPV kits integrate innovative sampling and detection technologies optimized for resource limited settings, facilitating seamless implementation. These findings indicate that Gynius HPV kits present a viable and scalable solution for cervical cancer screening programs, with the potential to significantly enhance early detection capabilities and broaden preventive care accessibility.
... Preinvasive changes are usually thought to occur in women in their early thirties, although recently they have been more common in the early twenties or even earlier, as was also observed in this study [15,16]. This may be related to the fact that women have sexual intercourse earlier and the most important cause of sexually transmitted cervical intraepithelial neoplasia is human papillomavirus (HPV), as confirmed by numerous studies [17,18]. In addition to the diagnoses of cervical intraepithelial neoplasia, several patients with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells in which a high-grade squamous lesion (ASC-H) cannot be excluded, and several patients with squamous cell carcinoma were included in this study. ...
Objectives: The aim of this study is to investigate the compatibility of pathohistological and Pap findings on material obtained by cervical biopsy and excoalation, and to investigate the compatibility of qualitative histological pattern and diagnosisMaterial and Methods: The study included 152 patients with premalignant lesions of the cervix who underwent Pap testing and targeted cervical biopsy. Archival data on Pap test and histologic diagnosis were collected from available medical records. Information on age and advisable clinical diagnoses was obtained from referrals for pathohistologic examination of tissue. The age of the subjects was determined at the time the tissue samples were collected for analysis. Data on the quality of the material were obtained from microscopic evaluation of the collected materialResults: The largest number of patients was diagnosed with cervical intraepithelial neoplasia type 3 (CIN 3) cytologically (57.2%) and pathohistologically (55.2%). The largest percentage of treated material was rated as very good (46.1%). The majority of respondents (92.4%) had no difference in diagnosis based on Pap test and pathohistological analysis. There was no statistically significant difference in the diagnosis made on the basis of the Pap test and pathohistologic analysis depending on the quality of the materialConclusion: There was a strong positive correlation between the grade established by cytology (Pap test) and the pathohistological diagnosis (PHD). There was no statistically significant difference in the diagnosis made on the basis of the Pap test and pathohistological analysis depending on the quality of the material.M
... The role of healthcare infrastructure in the context of HPV vaccination is multifaceted. The strength of healthcare systems determines the success of vaccination programs, with well-established infrastructure contributing to higher coverage and accessibility [28]. Overcoming infrastructural challenges is essential to ensuring the effective distribution of vaccines, requiring collaborative efforts and public-private partnerships. ...
This study aims to identify the change in the health status of women, particularly in cervical cancer treatment through HPV vaccination. Thus, the research aims to measure the reduction in the incidence of cervical cancer in vaccinated women and evaluate the impact of HPV vaccination on the overall health and well-being of women treated for cervical cancer. The paper uses a research approach that involves reviewing the literature, analysing epidemiological data, and assessing the impact of the vaccination program. Major observations suggest that many developed countries’ campaigns have reduced cervical cancer and enhanced treatment. Further, the study also addresses some additional effects of the intervention, both health-related with an emphasis on the decrease in healthcare costs and an enhancement of the quality of life among women, and social with a focus on the changes in women’s status as a result of vaccination. The research also focusses on the community and economic points of view on HPV vaccination programs, its problems and opportunities regarding socio-economic factors, cultural disparities, and healthcare systems. This study implies that working on those barriers by implementing effective interventions, increasing awareness, and demanding relevant changes in policies could improve vaccination levels as well as outcomes. Hence, this research supports HPV vaccination as vital to the future health status of women. Through the use of survey data and the adoption of a public health perspective, the study can fill existing gaps in the literature on preventive interventions and cervical malignancies and consequently contribute to the enhancement of women’s health, particularly in developing countries.
... Fourthly, genetic factors (9,83). Cervical cancer has been observed to exhibit familial clustering, with a higher susceptibility to HPV infection observed among individuals within particular families (75,84). Fifthly, age, education level and socioeconomic status all play a role in the susceptibility to HPV infection (85,86). ...
Human papillomavirus (HPV) infection plays an important role in cervical cancer. HPV is classified within the Papillomaviridae family and is a non-enveloped, small DNA virus. HPV infection can be classified into two distinct scenarios: i) With or without integration into the host chromosomes. Detection of its infection can be useful in the study of cervical lesions. In the present review, the structural and functional features of HPV, HPV typing, infection and transmission mode, the risk factors for cervical susceptibility to infection and HPV detection methods are described in detail. The development of HPV detection methods may have far-reaching significance in the prevention and treatment of cervical disease. This review summarizes the advantages and limitations of each HPV detection method.
... (Supplementary 2). All participants in this study were women who were positive for hrHPV, and cellular abnormalities caused by hrHPV infection can contribute to cytological abnormalities being more frequently present in cervicitis and CIN1 cases (cytology ≥ ASC-US) [36]. The NPV of PAX1 m in this study was comparable to that of cytology, underscoring the reliability of this alternative triage strategy. ...
Background
In China, the national cervical cancer screening protocol involves initial testing for high-risk human papillomavirus (hrHPV), followed by cytology for hrHPV-positive cases. This study evaluates the effectiveness of PAX1 methylation (PAX1m) analysis in identifying precancerous or cancerous lesions in cervical samples from Chinese women positive for non-16/18 hrHPV strains.
Methods
Between February 2022 and March 2023, 281 cervical samples from non-16/18 hrHPV-positive women underwent cytological examination and PAX1m analysis. The study assessed the statistical relationship between PAX1m levels and the presence of cervical lesions, comparing the diagnostic performance of PAX1m to conventional cytology.
Results
A significant association was found between PAX1 methylation levels and the risk of CIN2 + and CIN3 + lesions, with 47 instances of CIN2 + detected. Odds ratios (ORs) for moderate and high PAX1m levels were 8.86 (95% CI: 2.24–42.17) and 166.32 (95% CI: 47.09-784.97), respectively. The area under the ROC curve for PAX1m in identifying CIN2 + lesions was 0.948 (95% CI: 0.895–0.99). PAX1m demonstrated similar sensitivity and negative predictive value (NPV) to cytology but reduced the colposcopy referral rate from 47.7% with cytology alone to 25.6% with PAX1m, showing superior specificity and positive predictive value across age groups.
Conclusions
PAX1 methylation is a strong indicator of CIN2 + and CIN3 + risk, offering diagnostic performance comparable to cytology with the added benefit of reduced unnecessary colposcopy referrals. These findings support the use of PAX1m analysis as a reliable tool for triaging non-16/18 hrHPV-positive women in outpatient settings.
... 2 Notably, the high-risk genotypes are responsible for nearly 99.7 % of invasive cervical cancers worldwide 5 and emerge as the primary risk factor for the subsequent development of nearly all cervical cancers in women. 6 In fact, HPV is identifiable in 99.7 percent of cervical cancer cases. 7 Additionally, it serves as the predominant cause of and significantly contributes to carcinomas across the anogenital tract in both sexes, and head and neck squamous cell carcinomas. ...
Purpose
Vaccination against HPV plays a crucial role in preventing cervical cancer and related health issues. This study aimed to (1) assess knowledge, awareness, intentions, and attitudes regarding HPV and vaccination among Jordanian parents, and (2) evaluate the efficacy of two intervention strategies in promoting knowledge, awareness, and attitudes towards HPV vaccinations.
Methods
In study one, a web-based survey was used to collect data from Jordanian parents. In study two, participants were allocated into three groups: video-based intervention, lecture-based intervention, and a control group. Pre-post tests were conducted to evaluate the efficacy of the intervention strategies in promoting knowledge, awareness, and attitudes toward HPV vaccination among Jordanian parents.
Results
A total of 572 participants took part in the survey. Knowledge levels about HPV and its vaccine were generally low. Intentions regarding HPV vaccination were uncertain for the majority of participants, with 92 % reported as not receiving any guidance from medical professionals about administering the HPV vaccine to themselves or their children. Only 22 % agreed that their children might get infected with HPV at any time in their lives. The pilot randomized clinical trial revealed an improvement in knowledge, awareness, and attitudes towards HPV vaccination in both intervention groups compared to the control group with large effect sizes (eta squared between 0.29 and 0.68).
Conclusions
Findings highlight the need for increased knowledge and awareness regarding HPV and vaccination. It also supported the potential effectiveness of basic educational efforts in significantly improving knowledge, awareness, and attitudes towards the HPV vaccine.
... Increasing evidence has clearly confirmed that HPV infection leads to the development of cervical intraepithelial neoplasia (CIN), and high-risk HPV infection is the main risk factor for the subsequent evolution of cervical squamous cell carcinoma and adenocarcinoma [22,111]. Although HPV infection is transient in most females, it is not cleared in 10-20% of infected females, resulting in persistent infection and eventually leading to the development of cervical cancer [114]. Given that high plasma antioxidant concentrations appear to be protective against HPV infection in females, several studies have investigated the role of plasma ascorbate concentrations or dietary intake of ascorbate in females with HPV infection [115]. ...
Ascorbate (vitamin C) is an essential vitamin for the human body and participates in various physiological processes as an important coenzyme and antioxidant. Furthermore, the role of ascorbate in the prevention and treatment of cancer including gynecological cancer has gained much more interest recently. The bioavailability and certain biological functions of ascorbate are distinct in males versus females due to differences in lean body mass, sex hormones, and lifestyle factors. Despite epidemiological evidence that ascorbate-rich foods and ascorbate plasma concentrations are inversely related to cancer risk, ascorbate has not demonstrated a significant protective effect in patients with gynecological cancers. Adequate ascorbate intake may have the potential to reduce the risk of human papillomavirus (HPV) infection and high-risk HPV persistence status. High-dose ascorbate exerts antitumor activity and synergizes with chemotherapeutic agents in preclinical cancer models of gynecological cancer. In this review, we provide evidence for the biological activity of ascorbate in females and discuss the potential role of ascorbate in the prevention and treatment of ovarian, endometrial, and cervical cancers.
... While it is well established that PVs are linked to various cancers, the progression from a PV infection to an associated cancer is a rare occurrence (Stanley, 2010). In terms of viral replication, the shift to cancer is typically a nonproductive or 'dead-end' event for the virus. ...
During the last decades, the infection with papillomavirus in domestic cats gained interest from the veterinary community due to its significant impact on the companion's animal's health. Therefore, in this review, we aim to present a concise classification of feline papillomaviruses and their clinical relevance in domestic felines. Initially, the different types of papillomaviruses affecting domestic cats are described. Here, we emphasize the molecular diversity and transmission ways to better understand each virus type and its clinical implications. Furthermore, we explore the clinical importance of papillomavirus infections, analyzing their various manifestations such as skin or oral lesions. We outline the signs and symptoms of these infections, shedding light on the oncogenic mechanisms used by the virus. The knowledge gained from this analysis holds the potential to refine veterinary medical practices, enabling the effective management of this condition and ultimately enhancing the overall quality of life for our feline companions.
... Papillomavirus, a double-stranded DNA virus, is capable of causing infections in mucosal epithelial tissues in various areas of the body, including the vulva, vagina, anus, penis, and head and neck [4,5]. The prevalence of human papillomavirus (HPV) infection is high, with over 200 different types of HPV classified as either high-risk type (HR-HPV) or low-risk type (LR-HPV) based on their carcinogenic potential [6,7]. ...
Background
Increasing evidence suggests that both the vaginal microbiota and human papillomavirus (HPV) may play a role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the relationship between the vaginal microbiome and HPV infection remains poorly understood. The objective of this study was to investigate the association between indicators of the vaginal microbiota and HPV infection.
Methods
From January 2020 to June 2022, clinical data were collected from 5099 outpatients at Beijing Friendship Hospital. These patients underwent simultaneous testing for vaginal microecology and HPV type. A statistical analysis was conducted to examine the relationship between indicators of the vaginal microbiota and HPV infection.
Results
HPV infections were detected in 12.47% (636/5099) of the subjects. Single, double, triple, quadruple, and quintuple infections accounted for 81.29%, 14.62%, 3.14%, 0.94%, and 0.15% of all infections, respectively. A significant disparity in HPV infection prevalence was observed between the vaginitis group and the general population. However, no variation was found among different vaginitis groups. The data indicated that individuals with clue cells and sialidase were more susceptible to HPV infection. Sialidase was identified as an independent risk factor for HPV infection in a multivariable logistic regression model. The most prevalent HPV subtypes were 16 and 52, representing 2.10% and 2.86%, 3.14% and 2.86%, 1.78% and 2.16% in the normal, bacterial vaginitis, and other groups, respectively.
Conclusions
Our findings demonstrate the presence of clue cells and sialidase, which are two diagnostic criteria for bacterial vaginitis, in association with HPV infection. Furthermore, our results suggest that sialidase could potentially serve as a valuable predictor of HPV infection.
... As a result, only persistent high risk HPV infection can lead to cervical cancer [20][21][22][23][24]. The main mechanism of cervical carcinogenesis commences with high-risk HPV infected cervical epithelium through micro-abrasions. ...
Cervical cancer continues to pose a challenge to the health of Thai women, as the second most common cancer after breast cancer. Since high risk human papillomavirus (HPV) type is the main cause for cervical cancer, cervical cancer screening and HPV vaccination is necessary to reduce the incidence of this disease. At present, the World Health Organization hopes to reduce the incidence of cervical cancer to 4 or less cases per 100,000 women per year using 90-70-90% intervention by 2030. The first intervention involves vaccinating 90% of women aged 15 years with the HPV vaccine. The second intervention involves screening 70% of women between the ages of 35 and 45 years using a high-performance screening test. The third intervention involves detecting cervical lesions in 90% of affected women to enable diagnosis and treatment. In this context, this study reviews trends in the incidence and mortality rates of cervical cancer in Thailand, in addition to providing an up to date overview of the causes and necessary risk factors for cervical cancer, as well as reporting on cervical screening and HPV vaccination rates and cervical cancer during the coronavirus disease 2019 (COVID-19) pandemic. This study may prove useful for the formulation of policy aimed at eliminating cervical cancer in Thailand, such as the implementation of a free HPV vaccine service (recommended for women aged 26 or below) and providing at-home kits for cervical cancer screening through clinics and pharmacies. In addition, this review also highlights the need for further research on the effects of the Covid-19 pandemic on cervical cancer screening rates in Thailand.
... They interfere with the host cell's regulatory pathways, promoting cell division and inhibiting natural tumor suppression mechanisms. This aberrant cell behavior culminates in the development of precancerous lesions that, if left unchecked, can evolve into full-fledged anal cancer [10,11]. ...
In this chapter, we present a comprehensive review of anal cancer, focusing on its epidemiology, clinical manifestations (semiology), and therapeutic approaches. We delve into the global incidence and prevalence rates of anal cancer, exploring significant trends and risk factors associated with the disease. We discuss the etiology and pathogenesis of anal cancer, with a particular emphasis on the role of high-risk HPV types and other contributing factors. The chapter provides a detailed analysis of the clinical presentation, diagnosis, and staging of anal cancer, shedding light on the importance of early detection and appropriate screening methods. Furthermore, we thoroughly examine the various treatment modalities available, including surgery, radiation therapy, chemotherapy, and the emerging role of immunotherapy. A multidisciplinary management approach, involving different specialists and tumor boards, is emphasized. The chapter also addresses the follow-up and survivorship care for patients, including potential treatment-related complications and psychosocial support. Finally, we discuss ongoing research efforts and future directions in the field, highlighting the need for continued investigation and optimization of treatment strategies.
... Due to its inconspicuous early onset and prolonged course, understanding the molecular mechanism of CSCC is crucial for diagnosis and clinical therapy. The emergence and development of CSCC are associated with high-risk subtypes of human papillomavirus (HPV) infection, including HPV16 [3][4][5]. Persistent HPV infection leads to low-grade squamous intraepithelial lesion (LSIL), a portion of LSILs eventually develop into high-grade squamous intraepithelial lesion (HSIL), and most HSILs further convert to CSCC [6]. Previous studies have indicated that cholesterol metabolites known as oxysterols have the ability to inhibit the replication of human viral pathogens [7]. ...
Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.
... Genital HPV infection is cleared in most women but remains latent in 10-20% of women. The persistent HPV infections may eventually progress to HSIL and invasive malignancy [17,18]. Of all HPV strains, HPV16 infection is not only more likely to persist but also carried the highest risk of CIN3. ...
Objective:
To introduce HPV self-sampling and out-reach colposcopy clinic as interventions to improve the follow-up of HPV positive women in a community based cervical cancer screening programme.
Methods:
This was a prospective observational study conducted during October 2017 to August 2019 and 2977 women underwent cervical cancer screening using CareHPV test. Follow up colposcopy for HPV positive women were conducted at the rural health center and alternatively as out-reach clinics in their own villages and default rates were compared. HPV positive women were followed up at one-year. They were given an option of either having a follow-up HPV test performed by a health care worker (HCW) or by self-sampling. Compliance to follow up in these two modalities were compared. A validated questionnaire was given to women who had given an HPV self-sample to assess their awareness about HPV and cervical cancer.
Results:
During our initial round of cervical cancer screening using HPV as a primary screening modality, our HPV screen positive rate was 7.05% (210 out of 2977 women screened). Our colposcopy rates following an initial invitation at the rural health centre was only 28.5%. Following this, we initiated out-reach colposcopy clinics at their own villages for HPV positive women and this increased colposcopy rates from 28.5% to 45.2%. The participation rate at one-year follow-up was increased from 40.5% to 60% by the introduction of self-sampling as a follow up option and 16.2% of women who were initially positive remained HPV positive at 12-14 months follow up. All women who were offered the option of self-sampling preferred it over a HCW collected sample.
Conclusion:
Our study showed that self-sampling could also be used effectively in the follow up of HPV positive women in the community. Outreach colposcopy clinics in their own villages enabled better follow up of HPV positive women.
... By the age of 45 years, about four in five males and females will have experienced at least one episode of HPV infection [2]. Most HPV infections can be cleared by the body [3], but in 10-20% of females, these infections remain persistent [4]. Persistent infection with high-risk HPV has been proven to be the cause of cervical cancer and is associated with other cancers such as vulva, vagina, mouth/throat, penis and anus [5]. ...
China started to offer human papillomavirus (HPV) vaccines to females aged 9–45 years in 2016. However, there was a lack of reports about HPV vaccination coverage in a representative sample of females in China. Therefore, this study aimed to examine the current HPV coverage and associated factors among females aged 9–50 years in Shenzhen, China, based on administrative health records kept by community health centers. A multistage random sampling approach was used. The research team randomly selected 18 community health centers in Shenzhen, and 3118 health records of females aged 9–50 years were then randomly selected from these health centers. Among all participants, 18.7% received at least one dose of HPV vaccination. The highest coverage was observed among females aged 18–26 years (23.4%), followed by those aged 27–35 years (22.0%) and 36–45 years (20.2%). Such coverage was very low among females aged 9–17 years (4.6%) and those aged 46–50 years (3.2%). Among females aged 18 years or above, higher education level, having a family doctor, and permanent residency in Shenzhen were associated with higher HPV vaccination coverage, while older age and being married/divorced were negatively associated with coverage. The HPV vaccination coverage in Shenzhen was 18.7% and there is a strong need for improvement.
... Clinical manifestations of HPV infection include anogenital warts, recurrent respiratory papillomatosis, cervical intraepithelial neoplasia, and cancers such as oropharyngeal, cervical, anal, vaginal, vulvar, and penile. Three weeks to eight months is the incubation phase, and two to three months is the clinical manifestation (Stanley, 2010). ...
The human papillomavirus, or HPV, is a virus that can infect both men and women in various body areas. There are more than a hundred varieties of HPV. There are high-risk and low-risk varieties. Infections with the human papillomavirus (HPV) are highly frequent. There are over a hundred varieties of HPV. On the hands and feet, several HPVs can result in warts. Other HPVs can cause genital warts, infections, or malignancies, such as cervical and genital cancer and cancer of the back of the throat. These diseases can also be contracted through sexual activity.
... More than 70% of patients with cervical cancer are caused by HPV16 and HPV18 (Hariri et al. 2011). HPV16 is the main type that causes cervical cancer infiltration, followed by HPV18(de Sanjosé et al. 2007;Stanley 2010). E6 and E7 are the two key viral genes of HPV16, which can activate host DNA synthesis, stimulate cell cycle progression and replicate the viral genome (Peng et al. 2021;von Knebel Doeberitz et al. 1992). ...
The ectopic expression of cellular retinoic acid binding protein 2 (CRABP2) is associated with various tumorigenesis. However, the effects of CRABP2 on the progression of cervical cancer are still unclear. The current study aimed to investigate the role of CRABP2 in the malignant phenotypes of cervical cancer cells. CRABP2 was artificially regulated in CaSki, SiHa, and C-33A cells. CCK-8 assay and flow cytometry were used to assess the cell proliferation and apoptosis abilities, respectively. Wound healing assay and transwell assay were employed to measure the cell migration and invasion abilities, respectively. The results showed that CRABP2 was highly expressed in cervical carcinoma tissues and cell lines, and its high expression was associated with poor overall survival. Knockdown of CRABP2 promoted the cell apoptosis and inhibited cell proliferation, migration, and invasion in cervical carcinoma cells, whereas CRABP2 overexpression exhibited the opposite results. Mechanically, CRABP2 silencing suppressed the Integrin β1/FAK/ERK signaling via HuR. Treatment with siITGB1 or a FAK inhibitor PF-562271 or an ERK inhibitor FR180204 reversed the promoting effects of CRABP2 on cell proliferation, migration, and invasion. Moreover, the overexpression of CRABP2 reverted the HPV16 E6/E7 knockdown-induced inhibition of cell proliferation, migration, and invasion in cervical cancer cells. These results suggested that HPV16 E6/E7 promoted the malignant phenotypes of cervical cancer by upregulating the expression of CRABP2. In conclusion, CRABP2, upregulated by HPV E6/E7, promoted the progression of cervical cancer through activating the Integrin β1/FAK/ERK signaling pathway via HuR.
... The chance of being infected by genital HPV increases when the women are at a younger age, initiate sexual intercourse early, have multiple sexual partners, or have a partner who has multiple partners or an HPV infection and does not use a condom [10,11]. There is no cure for the HPV disease; however, persistent HPV infection can be prevented by completing the HPV vaccine series before the onset of sexual activity [12,13]. ...
Background: Cervical cancer is the leading cause of cancer death in adult women in the developing world including Ethiopia. To combat cervical cancer, the World Health Organization (WHO) recommends that girls aged 9-14 years have to take the human papillomavirus vaccine. However, there is a lack of information regarding the uptake of human papillomavirus vaccine in the study area. Therefore, this study aimed to assess the Human Papilloma Virus vaccine uptake and associated factors among adolescent girls in high schools of Nekemte City, Western Ethiopia, 2020.
Methods: A cross-sectional study design was employed among adolescent girls attending grade 9 and age 15 enrolled at schools in Nekemte City from July 15-30, 2020. Six hundred twenty-six (626) randomly selected adolescent girls were interviewed. The data were entered into Epi Info 7 and analyzed by SPSS 25. Multivariable analysis was computed and a P-value < 0.05 was taken as a cutoff point to declare the statistically significant association.
Result: The uptake of the HPV vaccine was 61.2%, 95%CI (57.2%, 65%). The Place where adolescents grow up (AOR = 3.46, 95%CI [1.95,6.15]), having a mobile phone(AOR = 1.71, 95%CI [1.05, 2.79]), ever heard about HPV (AOR = 5.69, 95%CI [1.33, 24.27]), ever heard about HPV vaccine(AOR = 1.917, 95%CI [1.002, 3.667]), Ever had sexual intercourse (AOR = 3.04, 95% [1.49,6.20]) and Perceived risk of towards HPV(AOR = 4.63 [2.49, 8.63]) has shown statistically significant association with Uptake of the HPV vaccine.
Conclusion: Nearly two-thirds of the study participants had taken at least one dose of the HPV vaccine. It is better if health information on HPV is disseminated considering the available technology like mobile phones and reaching rural girls.
... Las lesiones en el cérvix debidas a la infección por virus de papiloma humano (I-VPH) persistentes, generalmente son previas a las neoplasias intraepiteliales cervicales (NIC), las cuales se clasifican en: NIC-I o lesión de bajo grado, NIC-II y NIC-III, estas últimas también llamadas lesiones de alto grado (Smith, Melendy, Rana, & Pimenta, 2008;Varela & Rojas, 2003). El agente etiológico que se ha asociado al desarrollo del CaCu es el VPH (Stanley, 2010). ...
El cáncer cérvico uterino (CaCu) es un problema de salud pública. Entre los factores asociados a su progresión se encuentran la nutrición inadecuada y la obesidad, aunque esta relación aún no es clara. El objetivo de este trabajo fue evaluar si existe una relación entre el consumo de macronutrientes y el índice de masa corporal (IMC) con lesiones preneoplásicas de cérvix. Se diseñó un estudio transversal y participaron 44 mujeres con las siguientes características: 18% sin lesión (n=8), 41% con infección de virus papiloma humano (I-VPH, n=18) y 41% con neoplasia intraepitelial cervical-I (NIC-I, n=18). Se obtuvo el IMC y una frecuencia de consumo de alimentos. Los resultados mostraron que las mujeres sin y con lesión en cérvix presentaron un IMC que refleja sobrepeso y se encontró un mayor consumo de grasas en las pacientes con NIC-I comparado con las pacientes sin lesión (p=0.023). En conclusión, el consumo alto de grasas y la obesidad podrían estar asociados con un nivel de lesión preneoplásico bajo en el cérvix (NIC-I).
... It has been estimated that high-risk human papillomaviruses (HPVs) are the causal factor in over 5% of all human cancers, including >99.7% of cervical cancers and a growing number of oropharyngeal cancers [1,2]. HPV16 is responsible for the majority of these (around 55% of cervical cancers and almost all HPVpositive (HPV+) head and neck cancers), whilst HPV18 is the cause of another 15% of cervical cancers [3]. As a result of this, cervical cancer is the fourth most prevalent cancer in women and the most common cause of cancer-related death in young women [1]. ...
Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.
... This is why it is critical to get frequent screenings for CC and other HPV-related malignancies, particularly for those with persistent HPV infections (Table 1). (11) There are also various therapies available for HPV infections and associated health issues. Medication to cure genital warts, surgery to remove aberrant tissue, and different medicines to treat cancer caused by HPV are presented in detail in the Advisory Committee on Immunization Practices (ACIP) Recommendations. ...
Human papillomavirus (HPV) in the genital region is a frequently occurring sexually transmitted disease that can result in genital warts and various types of cancer. Most sexually active individuals acquire HPV at a certain point during their lifetime, but fortunately, several of the most harmful HPV types are preventable with vaccinations. All boys and girls aged 9 to 12 should get the HPV vaccine, although it can be given to individuals up to age 45. The HPV vaccine triggers an immune response that helps the body recognize and fight off the virus. There are currently two different HPV vaccines available: Gardasil and Cervarix. Gardasil guards against the two HPV strains that most commonly result in cervical cancer (CC) and various additional strains that can result in genital warts or other types of cancer. Cervarix only offers protection against the two forms of HPV that trigger CC. Mild side effects may occur, but more severe side effects are rare. Despite the availability of HPV vaccination, vaccination rates remain suboptimal in many countries. Raising awareness and expanding access to HPV vaccination are critical steps toward reducing HPV-related diseases. This article explores the basics of HPV and the role of vaccination in preventing its spread.
... [1][2][3] Most HPV infections generally clear with time, but 10-15% of them can be permanent; therefore, CIN and invasive cervical carcinoma can occur if the infection is unclear or untreated. [4,5] According to the American Society of Cervical Colposcopy Pathology (ASCCP) guidelines, women with abnormal cytology are suggested for colposcopic examination. [6] Satisfactory colposcopy is determined by the visualization of the squamocolumnar junction (SCJ), as cervical carcinoma 7 frequently originates from this location and the borders of any visible lesions. ...
Persistent high-risk Human Papillomavirus infection is the primary factor in cervical carcinogenesis. However, other host-related features are believed to play a role as well. Recent research suggests that the vaginal microbiome and the immune microenvironment play a significant role in the acquisition and persistence of Human Papillomavirus infection, as well as in the regression or progression of cervical intraepithelial lesions. Studies in this emerging field describe factors associated with this interaction, though the precise nature remains incompletely understood. In this narrative review, we aim to summarize the current literature on the topic and propose hypotheses and recommendations for future research and treatment strategies.
Background
Men’s involvement in and support for women’s decision-making concerning human papillomavirus (HPV) vaccination is crucial. However, the support provided by men to promote HPV vaccination among women, as a crucial part of intimate relationships has received limited attention. This study examined the behaviors and willingness of young Chinese adult men to support HPV vaccination in women and explored potential factors influencing supportive behaviors and willingness.
Methods
From December 2020 to January 2021, a cross-sectional study was conducted among 1014 young men from eight universities in Zhejiang Province, China. The survey questionnaire assessed behaviors and willingness to support HPV vaccination, HPV-related knowledge, information seeking for male HPV vaccination, attitudes toward women’s vaccination benefits, and sociodemographic variables. Multivariable logistic regression analyses adjusting for all covariates were used to identify factors associated with supportive behaviors and willingness.
Results
Only 48.4% of respondents reported having acquired and shared information about HPV vaccination with loved ones, whereas 41.3% recommended HPV vaccination. Approximately 80% of the participants without supportive behaviors reported a willingness to support the vaccination. Positive attitudes toward the benefits of women’s HPV vaccination, active seeking of information on male HPV vaccination, and relevant sociodemographic and health-related variables were associated with vaccination-supportive behaviors or willingness.
Conclusions
Young men expressed a relatively low level of support for female HPV vaccination. Promoting active information seeking regarding HPV vaccination among men and emphasizing the benefits of HPV vaccination for women could potentially foster more supportive behaviors. Targeted health education should include men to promote their involvement in shared decision-making regarding female HPV vaccinations.
Background The World Health Organization noted a significant rise in global human papillomavirus (HPV) prevalence among women, from 14\% (2019) to 24\% (2024), highlighting the need to understand the transmission dynamics and public health impact. Existing research focuses on single genotype infections and statistical methods, overlooking the effects of co-infection and multi-genotype interactions. Methods Data from HPV nucleic acid tests at two Xiamen hospitals were analyzed using cumulative link models to study symptom severity related to multi-genotype infections. An ordinary differential equation model estimated the reproduction numbers for different infection types. Results Increased risk of HPV-related diseases correlates with age (odds ratio, OR for ages 41–60: 37.07; over 60: 115.7). Multi-genotype infections correlate with greater disease severity (OR for two genotypes: 1.11; three genotypes: 1.21). Co-infections, especially involving high-risk genotypes, show higher transmissibility (median R 0 for two high-risk genotypes: 6.82). Conclusions The findings urge a revision of HPV prevention strategies, focusing on the varying risks across age groups and the enhanced severity and transmissibility of multi-genotype infections. Enhanced surveillance and revised vaccination programs may be crucial to address these challenges.
Background and aims: The relationship between oral-genital infections caused by human papillomavirus (HPV) in men and women is not well studied. This systematic review and meta-analysis aimed to determine the prevalence of concurrent and concordant oral-genital HPV infection. Methods: This systematic review and meta-analysis was conducted by selecting 89 articles from PubMed, Scopus, and Web of Science databases, exclusively searching for English studies published in international journals up to June 2023. The study summarized the percentages of concurrent (presence of any HPV in both oral and genital sites) and concordant (presence of the same types of HPV in both oral and genital sites) oral-genital HPV infections. The quality of these studies was evaluated using the Quality Assessment Tool for Quantitative Studies (QATQS). Moreover, meta-analysis was done using comprehensive meta-analysis (CMA) software with a random-effects method at a significant level of 0.05. Results: The meta-analysis incorporated a total of 86 articles. Based on QATQS, 83% of these studies achieved ‘Moderate’ ratings. The overall prevalence of concurrent oral-genital HPV infection was 15.5% (95% CI: 11.2–21) in women and 14% (95% CI: 8–23.3) in men. The concordance rate was 41.9% (95% CI: 33.8–50.5) in women and 32.2% (95% CI: 11–64.7) in men. Additionally, the prevalence of genital and oral HPV infections was 61% (95% CI: 21.3–90.6) and 9.5% (95% CI: 7.7–11.7), respectively. Conclusion: This meta-analysis showed that the high prevalence of genital HPV and oral-genital HPV can be a reason for the possibility of self-contamination.
Background and Objective: Human papillomaviruses (HPVs) are a large and diverse group of
double-stranded DNA viruses. HPV infection is one of the most important sexually transmitted
diseases, accounting for over 5% of cancers worldwide. This review aims to investigate the
pathogenicity and effective vaccines against cancers caused by this virus.
Method: In this study, the Research Gate, Scopus, and PubMed scientific databases, as well as the
Google Scholar search engine, were used to search for articles from January 2009 to December
2021. Of the 74 articles, 46 articles that met the study criteria were included in the study cycle.
Articles that were not open-access and were presented as abstracts at conferences were excluded
from the review cycle.
Results: The results of this study show that human papillomavirus (HPV) is the main cause of
cervical cancer and plays a key role in the pathogenesis of this disease. HPV infection can lead to
the development of precancerous lesions that, if left untreated, can develop into cancer. HPV
vaccines are an effective tool in preventing this cancer, but vaccination coverage is low, especially
in developing countries.
Conclusion: This study showed that the human papillomavirus (HPV) is the main cause of cervical
cancer and that complex mechanisms are involved in the development and progression of this
disease. A deep understanding of these mechanisms can help develop more effective strategies for
the prevention, early detection, and treatment of this cancer. Vaccination against HPV is recognized
as an effective preventive strategy, therefore, increasing public awareness and access to vaccines,
especially in developing countries, is essential.
N6‐methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications, as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death (PCD) mechanisms and affecting the tumor microenvironment through various cancer‐associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism‐associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes image .
Background: Human Papilloma virus (HPV) is very common virus in the global population. It is mainly transmitted through sexual contact and can also be transmitted from mother to child during childbirth. There are more than 100 different types of HPV, and most infected individuals do not present symptoms. However, some types of HPV can cause genital warts, while others can lead to change in cervical cells, increasing the risk of cervical cancer development. The best way to prevent HPV infection is through vaccination, along with use of condoms during secual intercourse. It Is essential for women to undergo regular screenings such as Pap test and colposcopy, as they help in the early detection of any cellular changes in the cervix and receiving appropriate treatment if necessary.. Material and methods: This is a retrospective observational study conducted by analyzing the medical records of pregnant women who gave birth in the year 2017 at The Ana Goitia maternal and Child Specialized Hospital. Results: From this research work, we arrived at the result that 24,2%(n=78) of pregnant women underwent the papanicolaou test. Amog them, 71%(n=55) tested negative, 27%(n=21) were classified as PAP class 2 and 2%(n=2) positive for HPV. Conclusion: After analyzing de medical records of the mentioned hospital, it was evident that very few individuals had undergone the papanicolaou test. As consequence, a low number of pregnant women were found to have any abnormalities in the test o tested positive for HPV. This made in challenging to determine the prevalence of this disease In the study population
To analyze the genotype distribution of human papillomavirus (HPV) infection in women in the Huizhou region of China and determine its correlation with age and degree of cervical lesions, with the aim to understand the characteristics of HPV infection in women in the region. A total of 65,127 patients who underwent HPV testing at the Second Maternal and Child Health Hospital of Huizhou City from January 2018 to December 2022 were selected as the research subjects. The polymerase chain reaction-reverse dot hybridization technique was used to detect HPV genotypes. The total detection rate of HPV infection was 7.25%, with single infection accounting for 70.94%. The detection rate of high-risk HPV was 6.73%. The top four high-risk types of HPV detected were 16, 52, 18, and 58. The distribution of HPV infection varied greatly among different age groups. The positive rates of HPV were the highest in the < 30-year-old group, followed by the ≥ 60-year-old group, showing a clear bimodal phenomenon. HPV infection in the population of Huizhou is mainly single infection and high-risk type, with higher infection rates in people < 30 and ≥ 60 years old. The local area should pay attention to the prevention and control of HPV.
Human papillomaviruses (HPVs) are responsible for approximately 5% of all cancers, with high-risk types causing nearly all cervical cancer cases. While cervical cancer is the most recognized outcome of HPV infection, the virus also contributes to vulvar, vaginal, penile, anal, and head and neck cancers. HPV types 16 and 18 are the primary culprits in these malignancies. HPVs exhibit strict host specificity and encompass over 100 types, some linked to benign conditions like genital warts. The viral oncoproteins E6 and E7 play a crucial role in cancer development by inhibiting tumor suppressor genes. HPV-related diseases manifest in various ways, from common conditions like anogenital and plantar warts to rare presentations such as recurrent respiratory papillomatosis, conjunctival papillomas, and middle ear carcinomas. The clinicians must recognize this diversity to ensure the accurate diagnosis and management. Preventive measures, particularly large-scale vaccination, are essential to reduce the incidence and complications of HPV-related diseases.
Cervical cancer is a preventable gynecologic malignancy ranking the fourth most common cancer among women in the world. The association between human papillomavirus (HPV) infection and cervical cancer is proven via the identification of high-risk HPV genotypes in more than 95% of cervical cancer specimens. Persistent high-risk HPV infection is the main risk factor for cervical cancer onset and progression, whereas other factors presumably influence the risk of HPV infection acquisition. While the mechanism associated with HPV-independent cervical cancers is unclear, the pathogenesis of HPV-associated cervical lesions and cancer is well-described. Many host, viral, and environmental factors are involved in the pathogenesis of cervical cancer. For more clarity, the pathogenesis of HPV-related cervical cancer can be presented describing changes on the molecular level, cellular level, and tissue level. As the global incidence of cervical cancer continues to rise, the World Health Organization (WHO) announced and stated the implementation of a cervical cancer elimination plan. According to the WHO initiative, HPV vaccination, cervical cancer screening, and treatment of premalignant cervical lesions have to be reinforced. In the absence of HPV-specific medications, clinical specialists and researchers use various medications to manage HPV infection and related lesions. These are imiquimod, cidofovir, anti-VEGF antibodies, recombinant human IFN α−2b, photodynamic therapy, etc. Moreover, multiple studies are investigating the clinical efficacy of therapeutic HPV vaccines. Diagnosis of cervical cancer is guided by the cancer staging classifications/systems, and management of cervical cancer is directed by international guidelines.
Background: Cervical cancer incidence and mortality have declined substantially in the U.S. over many years, largely due to the decline in squamous cell carcinoma. However, the trend change in recent years is not clear. This study aimed to explore trends in cervical cancer incidence and mortality stratified by demographic and tumor characteristics during 1975-2018.
Methods: Cervical cancer age-adjusted incidence, incidence-based mortality, and relative survival were calculated using the Surveillance, Epidemiology, and End Results-9 database. Trends and the calculation of annual percent change (APC) and average annual percent change (AAPC) were realized by joinpoint software.
Results: A total of 49,658 cases were diagnosed with cervical cancer between 1975-2018 and 17,099 patients died between 1995-2018. Among them, squamous cell carcinoma was the most common histological type (34,169 cases and 11,859 deaths). Cervical cancer incidence rate declined by an average of 1.9% (95% CI, -2.3% to -1.6%) per year over the study period, with the APCs decreased in recent years (-0.5% [95% CI, -1.1% to 0.1%] in 2006-2018). The incidence trend of squamous cell carcinoma was basically consistent with that of the general population, but the incidence of squamous cell carcinoma in distant stage was increasing significantly (1.1% [95% CI, 0.4% to 1.8%] in 1990-2018). During 1995-2018, cervical cancer mortality rate decreased by 1.0% (95% CI, -1.2% to -0.8%) per year overall, but increased by 1.2% (95% CI, 0.3% to 2.1%) per year for distant stage squamous cell carcinoma.
Conclusion: For cases diagnosed with cervical cancer in the United States from 1975 to 2018, the overall incidence and mortality rates decreased significantly, with increase in the incidence and mortality of advanced-stage squamous cell carcinoma. These findings will provide a scientific basis for cervical cancer prevention and management.
Abstract: Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and-18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. In addition, vaccination awareness programs and preventive strategies could help reduce the rate and incidence of HPV infection. In this review, we emphasize HPV infection and its role in cancer progression, molecular and immunopathogenesis, host immune response, immune evasion by HPV, vaccination, and preventive schemes battling HPV infection and HPV-related cancers.
During pregnancy, hormonal and immune adaptations are vital for supporting the genetically distinct fetus during elevated infection risks. The global prevalence of HPV necessitates its consideration during pregnancy. Despite a seemingly mild immune response, historical gestational viral infections underscore its significance. Acknowledging the established HPV infection risks during pregnancy, our review explores the unfolding immunological changes in pregnant women with HPV. Our analysis aims to uncover strategies for safely modulating the immune system, mitigating adverse pregnancy consequences, and enhancing maternal and child health. This comprehensive narrative review delves into the existing knowledge and studies on this topic.
Human papillomaviruses (HPV) cause numerous benign and malignant lesions/tumors of skin and mucosa, including genital warts, recurrent laryngeal papillomatosis (RLP), precancerous lesions, and cancers of the cervix, vulva, vagina, anus, and penis as well as oropharyngeal cancer. Worldwide, 4–5% of all cancers are caused by HPV. Most HPV-associated diseases are vaccine preventable, whereby young age at vaccination or HPV naivety are important. In countries with high HPV vaccination rates among children and adolescents, we are already seeing large reductions in genital warts, high-grade cervical dysplasia (CIN2+), and cervical cancer. Off-label use of HPV vaccination around conization or for present HPV-induced lesions is discussed controversially. Three meta-analyses of HPV vaccination for post-conization prophylaxis show varying degrees of risk reduction for the development of CIN2+ after conization, with only two controlled trials available to date. For RLP, meta-analyses also conclude that off-label HPV vaccination may be useful as adjuvant therapy, but further studies are needed. Elimination of cervical cancer is a World Health Organization (WHO) goal. This requires HPV vaccination rates of 90% in girls up to 15 years of age. Efforts to increase vaccination rates are needed in Germany, where the HPV vaccination rate among 15-year-old girls is only 54%.
For a considerable duration, cervical cancer has posed a significant risk to the well-being and survival of women. The emergence and progression of cervical cancer have garnered extensive attention, with prolonged chronic infection of HPV serving as a crucial etiological factor. Consequently, investigating the molecular mechanism underlying HPV-induced cervical cancer has become a prominent research area. The HPV molecule is composed of a long control region (LCR), an early coding region and a late coding region.The early coding region encompasses E1, E2, E4, E5, E6, E7, while the late coding region comprises L1 and L2 ORF.The investigation into the molecular structure and function of HPV has garnered significant attention, with the aim of elucidating the carcinogenic mechanism of HPV and identifying potential targets for the treatment of cervical cancer. Research has demonstrated that the HPV gene and its encoded protein play a crucial role in the invasion and malignant transformation of host cells. Consequently, understanding the function of HPV oncoprotein is of paramount importance in comprehending the pathogenesis of cervical cancer. E6 and E7, the primary HPV oncogenic proteins, have been the subject of extensive study. Moreover, a number of contemporary investigations have demonstrated the significant involvement of HPV16 E5 oncoprotein in the malignant conversion of healthy cells through its regulation of cell proliferation, differentiation, and apoptosis via diverse pathways, albeit the precise molecular mechanism remains unclear. This manuscript aims to provide a comprehensive account of the molecular structure and life cycle of HPV.The HPV E5 oncoprotein mechanism modulates cellular processes such as proliferation, differentiation, apoptosis, and energy metabolism through its interaction with cell growth factor receptors and other cellular proteins. This mechanism is crucial for the survival, adhesion, migration, and invasion of tumor cells in the early stages of carcinogenesis. Recent studies have identified the HPV E5 oncoprotein as a promising therapeutic target for early-stage cervical cancer, thus offering a novel approach for treatment.
The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various proteins by transferring Ub from E2 Ub conjugating enzymes to the substrate proteins. Several studies indicate that UBE3A regulates the stabilities of key viral proteins in the virus-infected cells and, thereby, the infected virus-mediated diseases, even if it were reported that UBE3A participates in non-viral-related human diseases. Furthermore, mutations such as deletions and duplications in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome (AS) and autism. It is also known that UBE3A functions as a transcriptional coactivator for the expression of steroid hormone receptors. These reports establish that UBE3A is distinguished by its multitudinous functions that are paramount to viral pathology and human diseases. This review is focused on molecular mechanisms for such intensive participation of UBE3A in disease formation and virus regulation.
With over half a million new cases and more than 300,000 deaths per year, cervical cancer is the fourth most common cancer in women worldwide. Higher-grade cervical intraepithelial neoplasia (CIN 2/3) precedes cancer. Early diagnosis and treatment of these lesions can prevent the development of cancer. With the introduction of screening programs based on cytological smears, the incidence and mortality of cervical cancer has decreased by more than half over the last 50 years in high-income countries. It is therefore fair to say that the introduction of cytological screening is one of the most successful preventive medical interventions in medicine. High-risk subtypes of the human papillomavirus (HPV) are almost always the cause of cervical cancer and its precursor lesions. This knowledge has changed the concept of early detection to the extent that HPV testing now plays an important role in screening programs worldwide. In addition to high-risk HPV infection, other virus-independent risk factors must also be considered, albeit to a much lesser extent. These include immunodeficiency, multiparity, long-term use of oral contraceptives, and smoking. The development of cervical cancer is largely preventable. HPV vaccination of girls and boys before their first sexual contact could, with vaccination rates above 70%, make the disease a very rare event. However, because 90% of cervical cancers occur in low- and middle-income countries and due to the absence of opportunities to establish systematic screening programs, the implementation of comprehensive vaccination programs would also be a significant step forward here, as called for by the World Health Organization (WHO).
Most cancers of the uterine cervix are squamous cell carcinomas. Although the incidence of such carcinomas of the uterine cervix has declined over time, that of cervical adenocarcinoma has risen in recent years. The extent to which human papillomavirus (HPV) infection and cofactors may explain this differential trend is unclear.
We pooled data from eight case-control studies of cervical cancer that were conducted on three continents. A total of 167 case patients with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1881 hospital-based control subjects were included. HPV DNA was analyzed in cervical specimens with the GP5+/6+ general primer system followed by type-specific hybridization for 33 HPV genotypes. Blood samples were analyzed for chlamydial and herpes simplex virus 2 (HSV-2) serology. Multivariable unconditional logistic regression modeling was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). All tests of statistical significance were two-sided.
The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients. Cofactors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, and HSV-2 seropositivity. Parity had a weaker association with adenocarcinoma and only among HPV-positive women. Use of an intrauterine device (IUD) had a statistically significant inverse association with risk of adenocarcinoma (for ever use of an IUD compared with never use, OR = .41 [95% CI = 0.18 to 0.93]). Smoking and chlamydial seropositivity were not associated with disease.
HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.
DNA of a new papillomavirus type was cloned from a cervical carcinoma biopsy. Two EcoRI clones of 7.8 and 6.9 kb in length were obtained, the latter contained a 900-bp deletion. The BamHI fragments of both clones were used to characterize the DNA. It represents a distinct type of papillomavirus as determined by its size, its cross-hybridization with DNA of other papillomavirus types under conditions of low stringency only, the co-linear alignment of its genome with HPV 6 and HPV 16 prototypes and its occasional occurrence as oligomeric episomes. We tentatively propose to designate it as HPV 18. DNA hybridizing with HPV 18 under stringent conditions was detected in 9/36 cervical carcinomas from Africa and Brazil, in 2/13 cervical tumors from Germany and 1/10 penile carcinomas. Benign tumors (17 cervical dysplasias, 29 genital warts), eight carcinomata in situ and 15 biopsies of normal cervical tissue were devoid of detectable HPV 18 DNA. HPV 18-related DNA was found, however, in cells of the HeLa, KB and C4-1 lines all derived from cervical cancer. The state of the viral DNA was investigated in four cervical cancer biopsies. The data reveal that the DNA might be integrated into the host cell genome. One tumor provided evidence for head to tail tandem repeats some of which persisted as circular episomes.
Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types.
We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system.
Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500).
We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancer-associated HPV types may be able to prevent most cases of cervical disease in this region.
Human papillomavirus (HPV)—16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development
efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with
other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the
associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly
detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally
associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant
infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the
risk of infection with other types, a theoretical concern with current vaccination efforts.
It is uncertain whether male circumcision reduces the risks of penile human papillomavirus (HPV) infection in the man and of cervical cancer in his female partner.
We pooled data on 1913 couples enrolled in one of seven case-control studies of cervical carcinoma in situ and cervical cancer in five countries. Circumcision status was self-reported, and the accuracy of the data was confirmed by physical examination at three study sites. The presence or absence of penile HPV DNA was assessed by a polymerase-chain-reaction assay in 1520 men and yielded a valid result in the case of 1139 men (74.9 percent).
Penile HPV was detected in 166 of the 847 uncircumcised men (19.6 percent) and in 16 of the 292 circumcised men (5.5 percent). After adjustment for age at first intercourse, lifetime number of sexual partners, and other potential confounders, circumcised men were less likely than uncircumcised men to have HPV infection (odds ratio, 0.37; 95 percent confidence interval, 0.16 to 0.85). Monogamous women whose male partners had six or more sexual partners and were circumcised had a lower risk of cervical cancer than women whose partners were uncircumcised (adjusted odds ratio, 0.42; 95 percent confidence interval, 0.23 to 0.79). Results were similar in the subgroup of men in whom circumcision was confirmed by medical examination.
Male circumcision is associated with a reduced risk of penile HPV infection and, in the case of men with a history of multiple sexual partners, a reduced risk of cervical cancer in their current female partners.
Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.
DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.
To monitor the association between the course of high risk human papillomavirus (HR-HPV) infection and the development of cervical neoplasia over time, from a baseline of normal cervical cytology.
This paper presents the follow up data from a previous cross sectional analysis. Women from a screening population who had normal cytology and who were HR-HPV positive were recalled after two to three years for cytology and HPV genotyping. The development of cervical neoplasia at follow up was related to the course of HPV infection (clearance, persistence, or sequential infection) and the presence of single or multiple HPV infections at baseline. A comparator control group of women who were HPV and cytologically negative at baseline were selected from the same population.
Twelve cases of dyskaryosis were found in women who were HPV positive at baseline; four were high grade. Only three cases of low grade dyskaryosis were found in the control group. Women with type specific persistent infections were significantly more likely to develop cervical neoplasia than women who cleared the infection (p = 0.0001) or were sequentially infected with different types (p = 0.001). Women with multiple HPV infections at baseline were no more likely to develop cervical dyskaryosis than those with a single infection.
Type specific persistent HR-HPV infection as monitored by genotyping can identify women at increased risk of cervical neoplasia more accurately than a single or repeated presence/absence HPV test. The cost effectiveness of such an approach should be investigated by an appropriate, large scale cost-benefit analysis.
To evaluate whether the use of male condoms reduces the risk of male-to-female transmission of human papillomavirus (HPV) infection, longitudinal studies explicitly designed to evaluate the temporal relationship between condom use and HPV infection are needed.
We followed 82 female university students who reported their first intercourse with a male partner either during the study period or within two weeks before enrollment. Cervical and vulvovaginal samples for HPV DNA testing and Papanicolaou testing were collected at gynecologic examinations every four months. Every two weeks, women used electronic diaries to record information about their daily sexual behavior. Cox proportional-hazards models were used to evaluate risk factors for HPV infection.
The incidence of genital HPV infection was 37.8 per 100 patient-years at risk among women whose partners used condoms for all instances of intercourse during the eight months before testing, as compared with 89.3 per 100 patient-years at risk in women whose partners used condoms less than 5 percent of the time (adjusted hazard ratio, 0.3; 95 percent confidence interval, 0.1 to 0.6, adjusted for the number of new partners and the number of previous partners of the male partner). Similar associations were observed when the analysis was restricted to high-risk and low-risk types of HPV and HPV types 6, 11, 16, and 18. In women reporting 100 percent condom use by their partners, no cervical squamous intraepithelial lesions were detected in 32 patient-years at risk, whereas 14 incident lesions were detected during 97 patient-years at risk among women whose partners did not use condoms or used them less consistently.
Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection.
Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent.
We performed a hospital-based, case-control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case-control comparisons.
A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16.
Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use.
The mechanisms of human papillomavirus (HPV) neutralization by antibodies are incompletely understood. We have used HPV16 pseudovirus infection of HaCaT cells to analyze how several neutralizing monoclonal antibodies (MAbs) generated against HPV16 L1 interfere with the process of keratinocyte infection. HPV16 capsids normally bind to both the cell surface and extracellular matrix (ECM) of HaCaT cells. Surprisingly, two strongly neutralizing MAbs, V5 and E70, did not prevent attachment of capsids to the cell surface. However, they did block association with the ECM and prevented internalization of cell surface-bound capsids. In contrast, MAb U4 prevented binding to the cell surface but not to the ECM. The epitope recognized by U4 was inaccessible when virions were bound to the cell surface but became accessible after endocytosis, presumably coinciding with receptor detachment. Treatment of capsids with heparin, which is known to interfere with binding to cell surface heparan sulfate proteoglycans (HSPGs), also resulted in HPV16 localization to the ECM. These results suggest that the U4 epitope on the intercapsomeric C-terminal arm is likely to encompass the critical HSPG interaction residues for HPV16, while the V5 and E70 epitopes at the apex of the capsomer overlap the ECM-binding sites. We conclude that neutralizing antibodies can inhibit HPV infection by multiple distinct mechanisms, and understanding these mechanisms can add insight to the HPV entry processes.
Pseudovirions of human papillomavirus type 16 (HPV16), the principal etiologic agent in 50% of cervical cancers, were used
as a model system to investigate the cell surface interactions involved in the exposure of the broadly cross-neutralizing
papillomavirus L2 epitopes. These neutralizing epitopes were exposed only after cell surface binding and a subsequent change
in capsid conformation that permitted cleavage by the cellular protease furin at a specific highly conserved site in L2 that
is immediately upstream of the cross-neutralizing epitopes. Unexpectedly, binding of L2 antibodies led to the release of the
capsid/antibody complexes from the cell surface and their accumulation on the extracellular matrix. Study of the dynamics
of exposure of the L2 epitopes further revealed that representatives of the apparently dominant class of L1-specific neutralizing
antibodies induced by virus-like particle vaccination prevent infection, not by preventing cell surface binding but rather
by preventing the conformation change involved in exposure of the L2 neutralizing epitope. These findings suggest a dynamic
model of virion-cell surface interactions that has implications for both evolution of viral serotypes and the efficacy of
current and future HPV vaccines.
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)‐based test which was used. The formerly HPV‐negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV‐negative and a sample of 48 of the 866 cases which were HPV‐positive in the original study. Moreover, 55 of the 66 formerly HPV‐negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR‐negative and ‐positive. Type‐specific E7 PCR for 14 high‐risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV‐negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA‐positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV‐negative on all PCR tests, as against 13 of the 21 that were inadequate ( p < 0·001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99·7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV‐negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright © 1999 John Wiley & Sons, Ltd.
Cervical cancer has been recognized as a rare outcome of a common, sexually transmitted infection whose etiologic association is restricted to a few human papillomavirus (HPV) types. With optimal testing systems HPV DNA can be identified in nearly all specimens of invasive cervical cancer, and it is claimed that infection of the cervix with HPV is a necessary cause of cervical cancer. The evidence is consistent worldwide for squamous cell carcinomas (SCC), adenocarcinomas, and the vast majority (>95%) of the immediate cervical cancer precursors, namely high-grade squamous intraepithelial lesions (HSILs)—also known as cervical intraepithelial neoplasia 3 (CIN 3) or carcinoma in situ. Cofactors that modify the risk for HPV DNA-positive women include the use of oral contraceptives (OCs) for 5 or more years, smoking, high parity (5 or more full-term pregnancies), and previ-ous exposure to other sexually transmitted diseases such as Chlamydia trachomatis and herpes simplex virus type 2 (HSV-2). Women exposed to the human immuno-deficiency virus (HIV) are at high risk for HPV infection, HPV DNA persistence, and progression of HPV lesions to cervical cancer.
To evaluate the association between human papillomavirus (HPV) and cervical cancer, we performed a population-based case-control study in Colombia and Spain, the former country having an incidence rate of cervical cancer about 8 times higher than the latter. It included 436 cases of histologically confirmed invasive cervical cancer and 387 randomly selected population controls. Information on demographic variables, sexual behaviour and other risk factors was obtained by interview. HPV-DNA was measured in cervical-swab specimens with 3 hybridization assays: ViraPap™, Southern hybridization (SH) and polymerase chain reaction (PCR). The presence of HPV-DNA and detection of types 16, 18, 31, 33 and 35 were strongly associated with cervical cancer in each country regardless of the assay used. For both countries combined the adjusted odds ratios and 95% confidence intervals were: ViraPap OR = 25.9 (10.0–66.7); SH OR = 6.8 (3.4–13.4); and PCR OR = 28.8 (15.7–52.6). HPV-16 was the most common type detected in both cases and controls. Our results indicate that there is a very strong association between HPV 16, 18, 31, 33 and 35 and invasive cervical cancer and that this association is probably causal. © 1992 Wiley-Liss, Inc.
By centrifuging total cellular DNA derived from human genital warts (condylomata acuminata) in CsCI-ethidium bromide gradients, supercoiled DNA was isolated. The molecular weight of this DNA was determined by agarose gel electrophoresis and amounted to 5.1 × 106. This DNA isolated from an individual genital wart was annealed to fractions of aqueous supernatants of the same wart after prior centrifugation of this material in CsCI density gradients. Annealing was observed at a density of approximately 1.32 g/ml corresponding to the expected density of papilloma virus particles. Since such particles were also observed in the same preparation by electron microscopy, it was concluded that the supercoiled DNA molecules were derived from papilloma virus nucleocapsids. Positive hybridization was found with six additional preparations from individual genital warts. Therefore, it seems that the isolated DNA prevails in condylomata acuminata. The DNA is different from the other five types of human papilloma viruses described thus far in regard to its restriction endonuclease cleavage patterns. The virus analyzed is tentatively designated as human papilloma virus type 6 (HPV 6).
Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.
The discovery of DNA from a new type of human papillomavirus (HPV) more than three decades ago provided our first glimpse at the agent that causes cervical cancer and served as a catalyst for the explosive growth in HPV-related research that followed. Since then, dozens of new HPV types have been discovered, routes of transmission have been delineated, estimates of prevalence and incidence have been described, carcinogenic properties have been demonstrated, and prophylactic HPV vaccines have been developed and deployed. It is now well-established that certain HPV types, prominently HPV-16 and HPV-18, cause cancers of the uterine cervix, vagina, vulva, penis, anus, oral cavity, and oro-pharynx; cancers that are responsible for significant morbidity and mortality worldwide. More recent findings indicate that widespread adolescent HPV vaccination could substantially reduce the global burden of such HPV-related cancers. Presented below is one epidemiologist's perspective on events that contributed to these scientific achievements.
In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India.
In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment.
In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women.
In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.
Worldwide human papillomavirus (HPV) prevalence in women with normal cytology at any given point in time is approximately 10% indicating that HPV is one of the most common sexually transmitted infections. HPV-16 is consistently the most common type and HPV-18 the second with some minor regional differences. Furthermore, across the spectrum of cervical lesions, HPV-16 is consistently the most common HPV type contributing to 50-55% of invasive cervical cancer cases strongly suggesting that this viral type has a biological advantage for transmission, persistency and transformation. The same phenomenon is observed albeit at a lower level for HPV-18 and HPV-45. Sexual behavioral patterns across age groups and populations are central to the description of the HPV circulation and of the risk of infection. The concept of group sexual behavior (in addition to individual sexual behavior) is important in exploring HPV transmission and has implications for defining and monitoring HPV and cancer prevention strategies. In natural history studies, the pattern of HPV DNA prevalence by age groups is similar to the patterns of HPV incidence. Rates of exposure in young women are high and often include multiple types. There is a spontaneous and rapid decrease of the HPV DNA detection rates in the middle-age groups followed by a second rise in the post-menopausal years. This article reviews: 1) the evidence in relation to the burden of HPV infections in the world and the contributions of each HPV type to the spectrum of cervical cellular changes spanning from normal cytology to invasive cervical cancer; 2) the critical role of the patterns of sexual behavior in the populations; and 3) selected aspects of the technical and methodological complexity of natural history studies of HPV and cervical neoplasia.
Condylomatous lesions, although readily diagnosed on the vulva, are often missed in the vagina and on the cervix by clinical examination alone. The lesions are, however, quite common and may be misdiagnosed as mild dysplasia by cytology, colposcopy and even tissue examination. Condylomatous lesions are presently diagnosed on cytologic evidence in nearly two per cent of asymptomatic patients screened in our program and followed-up by colposcopy and tissue examination, when indicated. The cytologic presentation of these lesions is quite characteristic. The main features are seen in squamous cells: enlargement, bi- or multinucleation, hyperchromasia, peri-nuclear clearing, amphophilia and dyskeratotic changes. Our present experience indicates that a large number of lesions previously classed as mild dysplasias actually represent various stages of condylomatous lesions. When these stages of viral changes are removed from the group of dysplasias, the remaining cases become of much greater significance as the early stages of evolution of carcinomata of the cervix.
Cytogenetic analysis was performed on human papillomavirus (HPV)-immortalized cell lines. Lines were established by co-transfection of primary human keratinocyte cells with HPV type 16 or 18 DNA and pSV2neo. The resulting clonal lines contained integrated HPV DNA and exhibited extended life spans in culture but were non-tumorigenic in nude mice. Two HPV16-immortalized lines (FEPE1L8 and FEPE1L9) and 4 HPV18-immortalized lines (FEA, FEH18L, FEP18-5 and FEP18-11) were established. Two additional lines were derived by subsequent treatment of the FEA line with TPA and by further transfection with HSVII DNA. Cytogenetic analysis revealed that all lines were abnormal, containing a variety of numerical and structural aberrations. Six of the 8 lines were hyper-triploid and 2 were near-diploid. Examination of lines FEA, FEH18L and FEP18-11 at multiple passages in culture revealed that the lines were clonal and chromosomally stable over extended passage in culture. Structural rearrangements were most common in chromosomes 1 and 3 but also occurred in chromosomes 5, 7, 8, 12, 16 and 22. Marker chromosomes were present in all cell lines. A small metacentric marker, possibly an isochromosome for the short arm of chromosome 5, was consistently present in the FEA line and its derivatives (FEAB10 and FEAT) as well as the FEH18L line. A loss or reduction in copy number of chromosome 13 was seen in 5 of the 8 cell lines.
The DNA of human papilloma virus type 6 (HPV 6) has been cloned in Escherichia coli K-12 by using pBR322 as vector. The DNA was cloned at the BamHI and EcoRI cleavage sites. This DNA was mapped by employing further restriction endonucleases and by terminal labeling. No major differences were noted as compared to HPV 6 DNA originating directly from a genital wart. The existence of at least two DNA subtypes (HPV 6a and 6b) became apparent.
DNA from one biopsy sample of invasive cancer of the cervix contained sequences hybridizing with human papillomavirus (HPV) type 11 DNA only under nonstringent conditions. This DNA was molecularly cloned in lambda phage. Under stringent conditions of hybridization it cross-hybridized to a minor extent (less than 0.1%) with HPV types 10, 14, and 15 and showed no homology with DNA of other human HPV types. We therefore propose to designate it tentatively as HPV 16. HPV 16 DNA was used as a probe to test additional cancer biopsy samples from cervical, vulval, and penile cancer, as well as benign genital warts (condylomata acuminata) and cervical dysplasias for the presence of homologous sequences. In 61.1% (11/18) of cervical cancer samples from German patients sequences were found hybridizing with HPV 16 DNA under conditions of high stringency. In contrast, only 34.8% (8/23) of cancer biopsy samples from Kenya and Brazil revealed this DNA. Vulval and penile cancer biopsy samples hybridized to 28.6% (2/7) or 25% (1/4), respectively. Only 2 out of 33 condylomata acuminata contained HPV 16 DNA. Both positive tumors harbored in addition HPV 6 or HPV 11 DNA. The data thus indicate that HPV 16 DNA prevails in malignant tumors, rendering an accidental contamination with papillomavirus DNA from adjacent papillomas rather unlikely. The rare presence in benign genital papillomas in addition to common genital papillomaviruses suggests a dependence of HPV 16 replication on helper virus.
Although it is difficult to estimate the overall prevalence of genital human papillomavirus (HPV) infection, current figures suggest that visible genital warts are present in approximately 1% of sexually active adults in the United States and that at least 15% have subclinical infection, as detected by HPV DNA assays. Genital HPV infection is thus extremely common. The highest rates of genital HPV infection are found in adults 18-28 years of age. Although risk factors for infection are difficult to assess because of the high frequency of subclinical infection, it is clear that major risk factors for acquiring genital HPV infection involve sexual behavior, particularly multiple sex partners. Other possible risk factors for acquisition of genital HPV infection include oral contraceptive use, pregnancy, and impairment of cell-mediated immunity. Strong epidemiologic and molecular data link HPV infection to cervical and other anogenital cancers. The types of HPV most commonly detected in cancers are HPV-16 and HPV-18. In summary, genital HPV infection is common among sexually active populations and causes both benign and malignant neoplasms of the genital tract.
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
Epidemiological studies show that infection with a subset of genital human papillomavirus (HPV) infections is the major risk factor for the subsequent development of cervical cancer. Experimental studies show that that the E6 and E7 genes of these high risk HPVs are oncogenes that deregulate key cell cycle controls. In the normal infectious cycle high level expression of these genes is confined to non-dividing differentiated cells: HPV oncogenesis requires deregulation of viral and cellular genes permitting inappropriate expression of E6 and E7. These are rare events but viral persistence and chronic exposure to steroid hormones increase the probability of this deregulation.
Links between human papillomaviruses (HPVs) and cervical cancer were first suspected almost 30 years ago. DNA of specific HPV types has since been found in almost all cervical cancer biopsies. HPV oncogenes that are expressed in these cells are involved in their transformation and immortalization, and are required for the progression towards malignancy. Epidemiological studies have underlined that HPVs are the main aetiological factor for cervical cancer. But how has this knowledge been translated into the clinic to allow the prevention, screening and treatment of cervical cancer?
Although condoms most likely prevent HIV infection, evidence of their effectiveness against other sexually transmitted diseases is mixed.
The goal of the study was to determine whether condom use prevents genital human papillomavirus (HPV) infection and HPV-related conditions.
We conducted a literature review and meta-analysis of the effect of condom use on the prevention of genital warts, subclinical HPV infection, cervical intraepithelial neoplasia (CIN), and invasive cervical cancer (ICC).
Among 27 estimates from 20 studies, there was no consistent evidence that condom use reduces the risk of becoming HPV DNA-positive. However, risk for genital warts, CIN of grade II or III (CIN II or III), and ICC was somewhat reduced.
Available data are too inconsistent to provide precise estimates. However, they suggest that while condoms may not prevent HPV infection, they may protect against genital warts, CIN II or III, and ICC.
Penile HPV-associated lesions are frequently seen in male sexual partners of women with CIN. The natural course and clinical significance of these lesions are unclear. Women with CIN and their male sexual partners were randomized for condom use (condom group n = 68, noncondom group n = 68). Males were screened for the presence of penile lesions, i.e., flat lesions, papular lesions and condylomata acuminata, and of HPV in their penile swabs by PCR testing. Median follow-up time was 13.1 months (range 2.9-57.4). The outcome of our study was clinical regression of penile lesions defined as disappearance of lesions at penoscopy. Potentially prognostic factors, i.e., HPV status, lesion type and age, were studied as well. Outcomes were assessed in 57 men of the condom group and in 43 men of the noncondom group. Condom use shortened the median time to regression of flat penile lesions (7.4 months condom group vs. 13.9 months noncondom group; HR = 2.1, 95% CI 1.2-3.7). This effect was not found for papular lesions (HR = 0.5, 95% CI 0.1-2.8). HPV-negative men showed a significantly shorter median time to regression of flat lesions (3.8 months) compared to men with either HPV-positive status (8.5 months; HR = 0.4, 95% CI 0.2-0.9) or inconsistent HPV status (13.1 months; HR = 0.2, 95% CI 0.1-0.6). Regression of flat penile lesions is HPV-dependent and accelerated by condom use. This effect is probably the result of blocking viral transmission between sexual partners.
Papillomaviruses infect epithelial cells, and depend on epithelial differentiation for completion of their life cycle. The expression of viral gene products is closely regulated as the infected basal cell migrates towards the epithelial surface. Expression of E6 and E7 in the lower epithelial layers drives cells into S-phase, which creates an environment that is conducive for viral genome replication and cell proliferation. Genome amplification, which is necessary for the production of infectious virions, is prevented until the levels of viral replication proteins rise, and depends on the co-expression of several viral proteins. Virus capsid proteins are expressed in cells that also express E4 as the infected cell enters the upper epithelial layers. The timing of these events varies depending on the infecting papillomavirus, and in the case of the high-risk human papillomaviruses (HPVs), on the severity of neoplasia. Viruses that are evolutionarily related, such as HPV1 and canine oral papillomavirus (COPV), generally organize their productive cycle in a similar way, despite infecting different hosts and epithelial sites. In some instances, such as following HPV16 infection of the cervix or cottontail rabbit papillomavirus (CRPV) infection of domestic rabbits, papillomaviruses can undergo abortive infections in which the productive cycle of the virus is not completed. As with other DNA tumour viruses, such abortive infections can predispose to cancer.
The proportion of women infected with human papillomavirus (HPV) varies greatly across populations, as might the distribution of HPV types. We aimed to compare HPV-type distribution in representative samples of women from different world regions.
Women were randomly selected from the general population of 13 areas from 11 countries (Nigeria, India, Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy, and Spain). A standardised protocol was used for cervical specimen collection. All HPV testing was by GP5+/6+ PCR-based EIA. The proportion of HPV-positive women infected with different HPV types was compared by study area and between pooled regions with age-adjusted odds ratios (ORs) with corresponding 95% floating CIs.
15 613 women aged 15-74 years without cytological abnormalities were included in a pooled analysis. Age-standardised HPV prevalence varied nearly 20 times between populations, from 1.4% (95% CI 0.5-2.2) in Spain to 25.6% (22.4-28.8) in Nigeria. Although both overall HPV prevalence and HPV16 prevalence were highest in sub-Saharan Africa, HPV-positive women in Europe were significantly more likely to be infected with HPV16 than were those in sub-Saharan Africa (OR 2.64, p=0.0002), and were significantly less likely to be infected with high-risk HPV types other than HPV16 (OR 0.57, p=0.004) and/or low-risk HPV types (OR 0.44. p=0.0002). Women from South America had HPV-type distribution in between those from sub-Saharan Africa and Europe. Heterogeneity between areas of Asia was significant.
Heterogeneity in HPV type distribution among women from different populations should be taken into account when developing screening tests for the virus and predicting the effect of vaccines on the incidence of infection.
HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.
This chapter provides an overview of the epidemiology of human papillomavirus (HPV) infection, with a focus on the dynamics of sexual transmission. We explore concepts related to the spread of sexually transmitted infections, including population prevalence, duration of infectivity, patterns of sexual contacts, and transmissibility, including modifiers of susceptibility and infectivity. HPV prevalence and incidence are high in most studies, particularly amongst young women. There is strong evidence that transmission occurs primarily via sexual activity, most commonly vaginal and anal intercourse. Although the duration of infectivity may be short, current evidence suggests that HPV is highly transmissible. The implications of transmission dynamics for the success of future HPV vaccines are discussed.
The major steps in cervical carcinogenesis include infection of the metaplastic epithelium of the cervical transformation zone with one or more of the 12-18 carcinogenic types of human papillomavirus (HPV) infection, viral persistence, clonal progression of the persistently-infected epithelium to cervical precancer, and invasion. Although these fundamental steps are established, several new epidemiologic studies have shed light on the factors that influence each of these transitions. The importance of the transformation zone in cervical cancer has been extended to other HPV-induced cancers such as anal or tonsillar cancers. Natural history studies show that HPV with normal cervical cytology and cervical intraepithelial neoplasia (CIN) grade 1 behave similarly, with the majority of both showing regression. Although these studies have demonstrated the importance of HPV persistence in the development of precancer CIN-3, the timing from infection to evidence of CIN-3 varies from 1 to 10 years. Whether equivalent lesions diagnosed later differ in their natural history remains unknown. Several factors have been implicated in enhancing persistence and/or progression. However, none are consistently associated with both except age: young women are less likely to show persistence and older women with persistence are more likely to be at risk of invasive cancer. Recent studies have also underscored the importance of the host immune response in clearance of established infections. Finally, data on non-cervical HPV infections, such as penile infections are limited to date compared to cervical infections. Several ongoing cohort studies should give us further insight into male infections in the near future.
On the basis of current evidence regarding human papillomavirus (HPV) and cancer, this chapter provides estimates of the global burden of HPV-related cancers, and the proportion that are actually "caused" by infection with HPV types, and therefore potentially preventable. We also present trends in incidence and mortality of these cancers in the past, and consider their likely future evolution.
The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of the vagina and anus are likewise caused by HPV, as are a fraction of cancers of the vulva, penis, and oropharynx. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina, and anus and for about 30-40% of cancers of the vulva, penis, and oropharynx. Other cancers causally linked to HPV are non-melanoma skin cancer and cancer of the conjunctiva. Although HPV is a necessary cause of cervical cancer, it is not a sufficient cause. Thus, other cofactors are necessary for progression from cervical HPV infection to cancer. Long-term use of hormonal contraceptives, high parity, tobacco smoking, and co-infection with HIV have been identified as established cofactors; co-infection with Chlamydia trachomatis (CT) and herpes simplex virus type-2 (HSV-2), immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified.
An important occurrence in cervical carcinogenesis is deregulated expression of the high-risk human papillomavirus (HR-HPV) oncogenes E6 and E7. Several risk factors for cervical neoplastic progression are likely to contribute to viral oncogene deregulation, particularly integration of HR-HPV into the host genome. Integration represents a by-product of viral infection that is detected in almost 90% of cervical carcinomas. The mechanism of integration is not fully understood, although there is a clear predilection for chromosomal common fragile sites, most likely due to their accessibility for insertion of foreign DNA. Recent work has suggested that an important intermediate stage in cervical carcinogenesis is characterized by transcriptionally silent HR-HPV integrants, which co-exist with viral episomes in infected cells. As episome-derived E2 protein inhibits integrant transcription, clearance of episomes (eg by host innate immunity) is associated with loss of integrant silencing and integrant selection. The process of integration and subsequent clonal selection of integrants can therefore be considered as two independent and biologically distinct events. Indeed, integrated HPV may be viewed as selectable because it represents a form of the virus that is resistant to host mechanisms of viral clearance, enabling infected cells to maintain viral oncogene expression and avoid cell death. Care should be taken in interpreting studies of HPV integration frequency in clinical samples, as the techniques used have assessed either the presence of integrated viral DNA or evidence of transcriptional activity from integrants, but not both.
We set out to estimate the age and genotype-specific prevalence of cervical human papillomavirus (HPV) DNA in women with normal cervical cytology worldwide by meta-analysis of a systematic literature review. Reports on HPV prevalence published between January, 1995, and January, 2005, were retrieved. To be included, studies required information on cervical cytology, plus detailed descriptions of study populations, methods used to collect cervical samples, and assays used for HPV DNA detection and typing. Final analyses included 78 studies that could be separated into women with normal cytology, and of which subsets of 44 and 48 studies had data on age and type-specific HPV prevalence, respectively. Overall HPV prevalence in 157 879 women with normal cervical cytology was estimated to be 10.4% (95% CI 10.2-10.7). Corresponding estimates by region were Africa 22.1% (20.9-23.4), Central America and Mexico 20.4% (19.3-21.4), northern America 11.3% (10.6-12.1), Europe 8.1% (7.8-8.4), and Asia 8.0% (7.5-8.4). In all world regions, HPV prevalence was highest in women younger than 35 years of age, decreasing in women of older age. In Africa, the Americas, and Europe, a clear second peak of HPV prevalence was observed in women aged 45 years or older. On the basis of these estimates, around 291 million women worldwide are carriers of HPV DNA, of whom 32% are infected with HPV16 or HPV18, or both. The HPV types most commonly detected are similar to those most commonly described in pre-neoplastic and cancer cases, although the relative contribution of HPV16 and HPV18 is substantially lower in cytologically normal women.
Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection, and virtually all cases of cervical cancer are attributable to infection by a subset of HPVs (reviewed in ref. 1). Despite the high incidence of HPV infection and the recent development of a prophylactic vaccine that confers protection against some HPV types, many features of HPV infection are poorly understood. It remains worthwhile to consider other interventions against genital HPVs, particularly those that target infections not prevented by the current vaccine. However, productive papillomavirus infection is species- and tissue-restricted, and traditional models use animal papillomaviruses that infect the skin or oral mucosa. Here we report the development of a mouse model of cervicovaginal infection with HPV16 that recapitulates the establishment phase of papillomavirus infection. Transduction of a reporter gene by an HPV16 pseudovirus was characterized by histology and quantified by whole-organ, multispectral imaging. Disruption of the integrity of the stratified or columnar genital epithelium was required for infection, which occurred after deposition of the virus on the basement membrane underlying basal keratinocytes. A widely used vaginal spermicide, nonoxynol-9 (N-9), greatly increased susceptibility to infection. In contrast, carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection even in the presence of N-9, suggesting that carrageenan might serve as an effective topical HPV microbicide.
The invasive potential of cervical intraepithelial neoplasia 3 (CIN3; also termed stage 0 carcinoma) has been poorly defined. At the National Women's Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. The resulting variation in management allows comparison of the long-term risk of invasive cancer of the cervix in women whose lesion was minimally disturbed with those who had adequate initial treatment followed by conventional management. We aimed to estimate the long-term risk of invasive cancer in these two groups of women. A judicial inquiry referred for independent clinical review in 1988 all women for whom there remained doubt about the adequacy of their management.
Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update
- Smith
Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis
- de Sanjosé
Human papillomavirus is a necessary cause of invasive cervical cancer worldwide
- Walboomers
Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis
- Clifford
Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study
- McCredie