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Human Papillomavirus (HPV), Vaccination, and Cervical Cancer

Human papillomavirus (HPV) is a common cause of infection. There are over 100 different sub-types of HPV. HPV types 16 and 18 cause 70% of cervical cancers and are also linked to cancers of the anus, vulva, vagina, penis, as well as the mouth and throat. Over time these can cause cells in the cervix to change, leading to precancerous conditions - cervical intraepithelial neoplasia (CIN), with a higher risk of developing cancer. Vaccination against HPV 16, 18 and other 'high risk' types of HPV reduces the risk of developing cervical and other HPV-related cancers.

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    PubMed Central search for free-access publications about Cervical Cancer, Human Papillomavirus (HPV)
    MeSH term: Uterine Cervical Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Drolet M, Bénard É, Pérez N, et al.
Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis.
Lancet. 2019; 394(10197):497-509 [PubMed] Related Publications
BACKGROUND: More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.
METHODS: In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.
FINDINGS: We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5-8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11-0·25) among girls aged 13-19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23-0·49) among women aged 20-24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33-0·66) among girls aged 13-19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24-0·46) among girls aged 15-19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36-0.60) among women aged 20-24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53-0·89) among women aged 25-29 years. Among boys aged 15-19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37-0·75) and among men aged 20-24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47-0·98). After 5-9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42-0·58) among screened girls aged 15-19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57-0·84) among women aged 20-24 years.
INTERPRETATION: This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects.
FUNDING: WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec - Santé.

Bouchilloux S, Fer F, Lemée F, et al.
Correlation between integration of high-risk HPV genome into human DNA detected by molecular combing and the severity of cervical lesions: first results of the EXPL-HPV-002 study.
Ceska Gynekol. 2019; 84(2):84-92 [PubMed] Related Publications
OBJECTIVES: The aim of the EXPL-HPV-002 study is to evaluate the integration of 14 high-risk HPV as a biomarker of the severity and the progression of cervical lesions. Such a „triage biomarker“ would help to reduce the number of unnecessary colposcopies, to avoid over-treatment of lesions that spontaneously regress and to better target the lesions requiring treatment.
DESIGN: EXPL-HPV-002 is a prospective, open-label, single arm, GCP study conducted at 2 clinical sites in the Czech Republic.
SETTINGS: Investigations centers: Private Gynecology Center, Brno; Gynecological and Obstetrical Clinic, Brno; Genotyping central lab: NRL for Papillomaviruses and polyomaviruses, IHBT, Prague; Histology Central reading: Aeskulab Pathology, Prague; Molecular combing HPV test: Genomic Vision, Bagneux.
METHODS: From June 2016 to May 2018, 688 patients aged 25-65, referred to colposcopy after an abnormal Pap-smear, were enrolled in the study. Among them 60% were found HPV high-risk. The study is divided in two phases: 1. a cross-sectional phase using data collected at first visit (colposcopy images ± histology, pap-smear for HPV genotyping and molecular combing) to study the association between HPV integration status versus colposcopy and histology grades; 2. a longitudinal phase using data collected in follow-up visits: cytology at 6, 18 and 30 months and colposcopy ± histology at 12, 24 and 36 months. A pap-smear collected at 12, 24 and 36 months allows to perform genotyping and molecular combing. HPV integration status is analyzed in comparison with the evolution of lesions, viral clearance and HPV genotype. HPV genotyping and molecular combing were performed on pap-smear samples in central laboratories. Histology data were reviewed by central reading.
RESULTS: The transversal phase of the study is achieved and shows that the HPV integration into the human DNA, monitored by molecular combing, can significantly differentiate normal subjects from women with cervical lesions or cancer.
CONCLUSION: HPV integration into the host genome, monitored by Genomic Visions technology, is a reliable diagnostic biomarker that will greatly help clinicians to improve their medical decision tree.

Baptista AD, Simão CX, Santos VCGD, et al.
Knowledge of human papillomavirus and Pap test among Brazilian university students.
Rev Assoc Med Bras (1992). 2019; 65(5):625-632 [PubMed] Related Publications
OBJECTIVE: Human papillomavirus (HPV) is the most prevalent sexually transmitted virus in the world and is associated with an increased risk of cervical cancer. The most effective approach to cervical cancer control continues to be screening through the preventive Papanicolaou test (Pap test). This study analyzes the knowledge of university students of health science programs as well as undergraduate courses in other areas of knowledge on important questions regarding HPV.
METHOD: Four hundred and seventy-three university students completed a questionnaire assessing their overall knowledge regarding HPV infection, cervical cancer, and the Pap test. A descriptive analysis is presented, and multivariate analysis using logistic regression identified factors associated with HPV/cervical cancer information.
RESULTS: Knowledge was higher for simple HPV-related and Pap test questions but was lower for HPV interrelations with genital warts and cervical cancer. Being from the health science fields and having high income were factors associated with greater knowledge. Only the minority of the participants recognized all the situations that increased the risk of virus infection presented in the questionnaire.
CONCLUSIONS: These findings highlight the need for educational campaigns regarding HPV infection, its potential as a cervical cancer agent and the forms of prevention available.

Zhao J, Lee EE, Kim J, et al.
Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus.
Nat Commun. 2019; 10(1):2300 [PubMed] Free Access to Full Article Related Publications
Single-stranded circular RNAs (circRNAs), generated through 'backsplicing', occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N

Zhang C, Cheng W, Liu Q, et al.
Distribution of human papillomavirus infection: a population-based study of cervical samples from Jiangsu Province.
Virol J. 2019; 16(1):67 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human papillomavirus (HPV) infection may lead to a series of lesions in the cervix. Distributions of HPV genotypes reveal that an increased prevalence of high-risk HPV (HR-HPV) is positively correlated with the severity of cervical lesions. Furthermore, persistent infection of HR-HPV is associated with a risk of cervical cancer. Considering the newly approval of the HPV vaccine in China and the prevalence of HPV distribution, which is meaningful for directing efforts for HPV vaccination, a more detailed understanding of HPV distribution is critical. This study aimed to investigate the overall prevalence of HPV and the age-specific features related to HPV distribution in the Jiangsu population.
METHODS: We collected a total of 62,317 cervical cytological specimens from Xuzhou, Nanjing and Suzhou, which represent the northern, middle and southern regions of Jiangsu Province, respectively. All these samples were assigned to 6 groups based on participant age. HPV genotypes tests were performed by using a commercial kit which is designed for the detection of 17 high-risk HPV genotypes and 6 low-risk HPV genotypes.
RESULTS: The overall prevalence of HPV was up to 26.92% in Jiangsu Province. The most common high-risk genotype was HPV52 (5.09%), followed by HPV16, HPV58, HPV53, HPV51 and HPV68. The most prevalent low-risk genotype was HPV81 (2.70%), followed by HPV43, HPV42, HPV6, HPV11 and HPV83. Most infections were caused by HR-HPV, while single-genotype infection occurred more frequently than multiple-genotype infection. Regarding participant age, the overall infection rate of HPV was distributed in a U-shaped manner, with the highest peak in the younger than 20-year-old cohort. Additionally, significant variations were found between different cities, representing different regions of Jiangsu.
CONCLUSIONS: HPV prevalence is high in Jiangsu Province. The prevention of HPV-related diseases is challenging. Given the variation in HPV prevalence between ages groups and regions, a flexible HPV vaccination program, adjusted base on regional infection features, could have a beneficial effect in Jiangsu Province.

Kisaakye E, Namakula J, Kihembo C, et al.
Level and factors associated with uptake of human papillomavirus infection vaccine among female adolescents in Lira District, Uganda.
Pan Afr Med J. 2018; 31:184 [PubMed] Free Access to Full Article Related Publications
Introduction: the principal burden of human papillomavirus (HPV) infections is cervical cancer. Cervical cancer ranks as the fourth most common malignancy in women affecting 500,000 women each year with an estimated 266,000 deaths. Uganda has one of the highest cervical cancer incidence rates globally with an age-standardised incidence rate per 100,000 of 47.5. This study assessed the level and the factors associated with uptake of HPV vaccine by female adolescents in Lira district, Uganda.
Methods: a mixed methods approach was employed using a survey among 460 female adolescents. We collected data using an interviewer-administered questionnaire. We interviewed five key informants and conducted ten in-depth interviews. Uptake was defined as completing three doses of the vaccine as per the recommended schedule. Prevalence risk ratios were used as measures of association and were computed using modified poison regression. Content analysis was used for qualitative data.
Results: the mean age of the respondents was 13.97 (SD=1.24). Uptake was at 17.61% (81/460). The factors associated with uptake of HPV vaccine were: attaining ordinary level of education (aPR 1.48, 95%CI 1.11-1.97), positive attitude towards the vaccine (aPR 3.46, 95%CI 1.70-7.02), receiving vaccine doses from different vaccination sites (aPR 1.59, 95% CI 1.10-2.28) and encouragement from a health worker (aPR 1.55, 95%CI 1.15-2.11) or Village Health Team (aPR 3.47, 95%CI 1.50-8.02) to go for the vaccine. Other factors associated with uptake of HPV vaccine included; the existence of community outreaches (aPR 1.47, 95%CI 1.02-2.12), availability of vaccines at vaccination sites (aPR 4.84, 95%CI 2.90-8.08) and receiving full information about the vaccine at the vaccination site (aPR 1.90, 95%CI 1.26-2.85).
Conclusion: HPV vaccine uptake was low in Lira district. Efforts to improve uptake of HPV vaccine should focus on ensuring a consistent supply of vaccines at the vaccination sites, health education aimed at creating a positive attitude towards the vaccine, sensitisation of the adolescents about the vaccine and conducting community outreaches.

Akhtar A, Ghali L, Wang SX, et al.
Optimisation of Folate-Mediated Liposomal Encapsulated Arsenic Trioxide for Treating HPV-Positive Cervical Cancer Cells In Vitro.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO's therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.

Kotowski A, Kotowska M, Warzyszyńska A, et al.
Cervical cancer - causes and prevention of hpv infections in the opinions of young polish women: a cross-sectional survey.
Wiad Lek. 2019; 72(3):327-335 [PubMed] Related Publications
OBJECTIVE: Introduction: Cervical cancer is an important issue of gynecologic oncology. The awareness of this disease, the attitude towards HPV vaccination and cytological screening play an important role in decreasing morbidity and mortality due to cervical cancer. The aim: To assess the various aspects of knowledge regarding cervical cancer, risk factors for this disease, the role of HPV infection and the attitude to primary (vaccination) and secondary (cytological screening) prevention among young women.
PATIENTS AND METHODS: Materials and methods: The study was performed using CAWI method based on original questionnaire in electronic form. Online completing of the survey was voluntary and anonymous.
RESULTS: Results: The study was conducted in a group of 2058 women aged 19-33. In total 98.4% of respondents came across the term "cervical cancer", 84.1% knew that cervical cancer could be prevented and the following were identified as the main risk factors: cervical cancer in closest relatives (85.3%) and HPV infection (81.9%). Although according to 82.0% of women HPV infection can be prevented by vaccination, only 18.4% of respondents were vaccinated. The main reason for non-vaccination was lack of knowledge about the availability of the vaccine (41.2%) and high price (32.0%). Of the unvaccinated people, 63.5% declare their will to be vaccinated in the future. Concerning secondary prevention, 98.6% of the respondents admitted that they knew the term "cytological examination", 89.0% indicated that this examination detected the presence of pre-cancerous lesions, and according to 58.4% of respondents, this test should be performed after sexual initiation. Despite the fact that 80.5% of respondents confirmed the fact of beginning sexual activity (44.4% of them had more than 1 partner), 17.1% of the respondents admitted that they didn't go to gynecologist yet. Approximately 84% of respondents believe that the amount of information on cervical cancer prophylaxis and HPV infections currently providing is insufficient.
CONCLUSION: Conclusions: The basic terms regarding primary (vaccination) and secondary (prophylactic tests) prevention of cervical cancer have been widely known. However, the knowledge about specific risk factors, sexual behaviors contributing to HPV infection and, consequently, the ability to self-identify as belonging to higher risk group is insufficient. It is justified to conduct educational activities regarding the assessment of risks related to cervical cancer addressed to young women. Together with education, HPV vaccination and secondary prevention programs require financial support.

Chen H, Wang H, Liu J, et al.
Association of the MUTYH Gln324His (CAG/CAC) variant with cervical carcinoma and HR-HPV infection in a Chinese population.
Medicine (Baltimore). 2019; 98(17):e15359 [PubMed] Related Publications
This study was performed to investigate the relationship between the MUTYH Gln324His (CAG/CAC) genotype and risk of cervical squamous cell carcinoma (CSCC) in a case-control setting. Mismatch amplification-polymerase chain reaction (MA-PCR) was applied to detect the polymorphism in 400 CSCC, 400 CIN III and 1200 control participants. The homozygous His324His (CAC/CAC) genotype of MUTYH was associated with significantly increased risk of CIN III (OR = 1.94) and CSCC (OR = 3.83). Increased risk of CIN III (OR = 1.34) and CSCC (OR = 1.97) was additionally observed with the heterozygous CAG/CAC genotype. Overall, individuals in both CAC/CAC and CAG/CAC genotype groups were at higher risk of cervical carcinoma (CINIII (OR = 1.46) and CSCC (OR = 2.34)). Within the HR-HPV infection-positive group, CAC/CAC and CAG/CAC genotypes were significantly enriched in relation to CIN III and CSCC. Moreover, we observed a positive correlation between the proportion of homozygous CAC/CAC MUTYH genotype and malignant prognostic factors of CSCC, such as cell differentiation grade and lymph node metastasis. These findings clearly highlight associations between the MUTYH Gln324His (CAG/CAC) polymorphism and susceptibility to CSCC, HR-HPV infection and specific prognostic factors, supporting the utility of this variant as an early indicator for patients at high risk of cervical carcinoma.

Gago J, Paolino M, Arrossi S
Factors associated with low adherence to cervical cancer follow-up retest among HPV+/ cytology negative women: a study in programmatic context in a low-income population in Argentina.
BMC Cancer. 2019; 19(1):367 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cervical Cancer is still a major public health challenge in low and middle-income countries. HPV testing has been an innovative approach, which was introduced in Argentina for women aged 30+ through the Jujuy Demonstration Project (JDP) carried out between 2012 and 2014. After a positive HPV-test, cytology is used as triage method. Under this protocol, the group of women with HPV+ and normal cytology are recommended to repeat the test within 12-18 months. Studies have shown that this group has increased risk of CIN2+, however, assuring high levels of repeating test among these women is difficult to achieve. We analyze those factors associated with lower re-test attendance among HPV+/ cytology negative women at a programmatic level in low-middle income settings.
METHODS: We used data of women aged 30+ HPV-tested in the JDP and followed until 2018 (n = 49,565). We performed a set of different adjusted logistic regression models. Primary outcomes were re-test attendance and re-test attendance within recommended timeframe. We assessed as covariates age, health insurance status, year of HPV-testing, Pap testing in the past 3 years, HPV-testing modality (clinician-collected (CC) tests/self-collected (SC) tests), and span between HPV-test collection and report of results.
RESULTS: Forty nine thousand five hundred sixty five women were HPV-tested and 6742 had a positive HPV-test. Among HPV+ women, a total of 4522 were HPV+/Cytology negative (67.1%). In total, 3172 HPV+/Cytology negative women (70.1%) had a record of a second HPV test as of March 2018. Only 1196 women (26%) completed the second test within the timeframe. Women with no record of a previous Pap (OR: 0.46, 95% CI: 0.4-0.53, p < 0.001), aged 64+ (OR: 0.46, 95% CI: 0.31-0.68, p < 0.001) were less likely to be retested; while women with clinician-collected samples had higher odds of being re-tested (OR: 1.42, 95% CI: 1.06-1.91, p < 0.001).
CONCLUSIONS: Low re-test rates were found in HPV +/ normal cytology women. Tailored interventions are needed to increase the effectiveness of the screening in this group, especially for those women with characteristics associated to lower attendance.

Arfi A, Hequet D, Bataillon G, et al.
HPV DNA integration site as proof of the origin of ovarian metastasis from endocervical adenocarcinoma: three case reports.
BMC Cancer. 2019; 19(1):375 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Most endocervical adenocarcinomas are human papillomavirus (HPV)-related cancers associated with p16 immunostaining. Ovarian metastasis from cervical cancer is a rare phenomenon, the mechanism of dissemination remains unclear. The diagnosis of metastasis may be difficult to establish when the ovarian neoplasm presents features consistent with primary tumor. Immunohistochemical expression of p16 in ovarian tumors can guide the diagnosis of metastasis from HPV-related cervical cancer, but p16 positivity is nonspecific. Identical HPV genotype in the paired endocervical and ovarian tumors is a better marker for cervical origin, which may also be confirmed by identical HPV integration site.
CASE PRESENTATION: Two women presented with HPV18 cervical adenocarcinoma. No signs of disease were visible on MRI after treatment. After several years of follow-up, mucinous ovarian tumors were discovered in both patients. Molecular analyses showed that the ovarian lesions were HPV18-positive; indicating a primary cervical origin. A third woman was diagnosed with grade 1 ovarian endometrioid carcinoma with no peritoneal carcinomatosis. Final histological examination and HPV genotyping revealed HPV18-related in situ endometrioid adenocarcinoma in the endocervix and HPV18-related invasive endometrioid adenocarcinoma in the endometrium and both ovaries. Additional molecular analyses performed in two patients identified the same HPV integration sites in both the ovarian and cervical tumors, confirming that the ovarian mass was a metastasis from the cervical adenocarcinoma.
CONCLUSION: We report three new cases of ovarian neoplasia in which the diagnosis of metastasis from cervical cancer was supported by the same HPV genotype and the same integration site in the paired cervical and ovarian tumors. To our knowledge, this is the first report of molecular evidence of the cervical origin of an ovarian metastasis. HPV screening should be performed in ovarian tumors for all patients with history of cervical neoplasia.

Harper DM, Nieminen P, Donders G, et al.
The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up.
Gynecol Oncol. 2019; 153(3):521-529 [PubMed] Related Publications
BACKGROUND: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types.
METHODS: Women 18 years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug.
RESULTS: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, p < 0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, p < 0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (p < 0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions.
CONCLUSIONS: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30 months.

Palmer T, Wallace L, Pollock KG, et al.
Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study.
BMJ. 2019; 365:l1161 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To quantify the effect on cervical disease at age 20 years of immunisation with bivalent human papillomavirus (HPV) vaccine at age 12-13 years.
DESIGN: Retrospective population study, 1988-96.
SETTING: National vaccination and cervical screening programmes in Scotland.
PARTICIPANTS: 138 692 women born between 1 January 1988 and 5 June 1996 and who had a smear test result recorded at age 20.
MAIN OUTCOME MEASURES: Effect of vaccination on cytology results and associated histological diagnoses from first year of screening (while aged 20), calculated using logistic regression.
RESULTS: 138 692 records were retrieved. Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 showed an 89% reduction (95% confidence interval 81% to 94%) in prevalent cervical intraepithelial neoplasia (CIN) grade 3 or worse (from 0.59% (0.48% to 0.71%) to 0.06% (0.04% to 0.11%)), an 88% reduction (83% to 92%) in CIN grade 2 or worse (from 1.44% (1.28% to 1.63%) to 0.17% (0.12% to 0.24%)), and a 79% reduction (69% to 86%) in CIN grade 1 (from 0.69% (0.58% to 0.63%) to 0.15% (0.10% to 0.21%)). Younger age at immunisation was associated with increasing vaccine effectiveness: 86% (75% to 92%) for CIN grade 3 or worse for women vaccinated at age 12-13 compared with 51% (28% to 66%) for women vaccinated at age 17. Evidence of herd protection against high grade cervical disease was found in unvaccinated girls in the 1995 and 1996 cohorts.
CONCLUSIONS: Routine vaccination of girls aged 12-13 years with the bivalent HPV vaccine in Scotland has led to a dramatic reduction in preinvasive cervical disease. Evidence of clinically relevant herd protection is apparent in unvaccinated women. These data are consistent with the reduced prevalence of high risk HPV in Scotland. The bivalent vaccine is confirmed as being highly effective vaccine and should greatly reduce the incidence of cervical cancer. The findings will need to be considered by cervical cancer prevention programmes worldwide.

Bruno MT, Coco A, Di Pasqua S, Bonanno G
Management of ASC-US/HPV positive post-menopausal woman.
Virol J. 2019; 16(1):39 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of our study was to determine which diagnostic course is best to identify women at risk of CIN2+ among post-menopausal women with cytological diagnosis of ASCUS METHODS: We selected women who had been post-menopausal for at least one year , and who had completed the entire diagnostic-therapeutic course that they had undertaken. The sample was divided into two arms: in the first arm, we considered 146 ASCUS positive women who had undergone the HPV test, colposcopy and then underwent more detailed diagnostics by means of LEEP or a scraping of the cervical canal. The second arm was made up of 124 ASCUS positive women who had undergone a vaginal administration of estriolo, the HPV test and colposcopy. Estriol was administered for 5 weeks: the first week one vaginal suppository every evening, the other four weeks the administration was twice a week. Then, the patients underwent colposcopy. In cases of positivity a biopsy was carried out, the patients positive for CIN2+ at the biopsy underwent excisional therapy using LEEP and were followed up. The patients, who were negative at colposcopy or with histological diagnosis of CIN1, were examined again at 1 year.
RESULTS: In the first arm the HPV test had an SE of 94%, an SP of 68%, NPV of 99%, and PPV of 28%. The PPV is very low because of the elevated percentage of false positives that the HPV test gave (71%). In the second arm the HPV test maintained its high SE (100%), an SP of 74%, a NPV of 100%, and a PPV of 43%. The use of estrogen increased the specificity of the test.
CONCLUSION: It is important to say that the second arm indicates the use of local estrogen therapy only for ASCUS/HPV positive postmenopausal women. Therefore, the HPV test should be used as the first diagnostic possibility in cases of ASCUS in post-menopausal women, associating local estrogen therapy only with HPV positive women.

Frayle H, Gori S, Rizzi M, et al.
HPV testing for cervical cancer screening: technical improvement of laboratory logistics and good clinical performance of the cobas 6800 in comparison to the 4800 system.
BMC Womens Health. 2019; 19(1):47 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: European guidelines for cervical cancer screening now recommend the use of clinically validated assays for high-risk HPV-DNA sequences as primary test in women older than 30 years, performed in centralized laboratories, and run on systems providing automated solutions for all steps.
METHODS: We conducted a comparison study, according to the international guidelines, nested within the organized population-based cervical screening program, between the cobas 4800 and 6800 systems (Roche Diagnostics), to evaluate accuracy and reproducibility of HPV test results and laboratory workflow. In Italy implementation of HPV cervical screening is under way on a regional basis; in Veneto it started in June 2015, following a piloting phase; the assay in use in the three centralized laboratories is the cobas 4800 HPV test, run on the cobas 4800 system. Comparison of HPV results with a new version of the assay (cobas 6800/8800 HPV) run on the cobas 6800 system, and intra- and inter-reproducibility analyses have been conducted in samples collected in PreservCyt medium (Hologic) from women without and with a subsequent diagnosis of high-grade lesion.
RESULTS: Samples from women older than 30 years attending organized cervical cancer screening were used. Clinical sensitivity and specificity were evaluated on 60 cases and 925 controls, respectively; intra-laboratory reproducibility and inter-laboratory agreement by the 6800 system were evaluated on 593 and 460 specimens, respectively. Our results showed a very high agreement (> 98%) for overall qualitative results between the two systems; clinical sensitivity and specificity of the HPV assay run on 6800 were non-inferior to those of the HPV assay run on 4800 (p = 0,0157 and p = 0,0056, respectively, at the recommended thresholds of 90 and 98%); kappa values of 0.967 and 0.969 were obtained for intra- and inter-laboratory reproducibility analyses in the 6800 system. The 6800 platform displayed several technological improvements over the 4800 system, with higher throughput and laboratory productivity, and lower operator's hands-on time.
CONCLUSIONS: The new cobas 6800/8800 HPV assay run on the 6800 instrument is suitable for use in large centralized laboratories included within population-based cervical cancer screening programs.

Hall MT, Smith MA, Lew JB, et al.
The combined impact of implementing HPV immunisation and primary HPV screening in New Zealand: Transitional and long-term benefits, costs and resource utilisation implications.
Gynecol Oncol. 2019; 152(3):472-479 [PubMed] Related Publications
BACKGROUND: In response to emergent evidence, many countries are transitioning from cytology-based to HPV screening. We evaluated the impact of an upcoming transition on health outcomes and resource utilisation in New Zealand.
METHODS: An extensively validated model of HPV transmission, vaccination, natural history and cervical screening ('Policy1-Cervix') was utilised to simulate a transition from three-yearly cytology for women 20-69 years to five-yearly HPV screening with 16/18 genotyping for women 25-69 years, accounting for population growth and the impact of HPV immunisation. Cervical cancer rates, resources use (test volumes), costs, and test positivity rates from 2015 to 2035 were estimated.
FINDINGS: By 2035, the transition to HPV screening will result in declines in cervical cancer incidence and mortality rates by 32% and 25%, respectively, compared to 2018. A potentially detectable 5% increase in cervical cancer incidence due to earlier detection is predicted for the year of transition. Annual numbers of women screened will fluctuate with the five-year screening interval. Cytology volumes will reduce by over 80% but colposcopy volumes will be similar to pre-transition rates, and program costs will be reduced by 16%. A 9% HPV test positivity rate is expected in the first round of HPV screening (2019-2023), with 2.7% of women referred for colposcopy. Transitioning from cytology to primary HPV cervical screening could avert 149 cancer cases and 45 deaths by 2035.
CONCLUSION: Primary HPV screening and vaccination will reduce cervical cancer and resources use. A small transient apparent increase of invasive cancer rates due to earlier detection may be detectable at the population level, reflecting the introduction of a more sensitive screening test. These findings can be used to inform health services planning and public communications surrounding program implementation.

Chen P, Zhang W, Yang D, et al.
Human Papillomavirus Status in Primary Lesions and Pelvic Lymph Nodes and Its Prognostic Value in Cervical Cancer Patients with Lymph Node Metastases.
Med Sci Monit. 2019; 25:1894-1902 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The aim of this study was to assess the presence of HPV DNA in cervical tissues and lymph nodes in patients who have uterine cervical neoplasms with lymphatic metastases and who underwent surgery for invasive cervical cancer and pelvic lymphadenectomy, to establish the utility of HPV type and viral load in predicting disease progression. MATERIAL AND METHODS We retrospectively assessed 88 patients with uterine cervical neoplasms with lymph node metastases. All 88 patients were in FIGO stage IA-IIB. A total of 316 paraffin-embedded archival tissues (88 cervical samples and 228 pelvic lymph node specimens) were acquired. All the samples were analyzed using real-time PCR to determine HPV DNA presence/type and to quantify viral load. RESULTS In total, 17 HPV genotypes were detected in the cervical lesions and pelvic lymph nodes of the patients. The most common HPV type in all samples was HPV16, followed by HPV18. The existence of HPV16 DNA and low HPV16 viral load in cervical lesions were also significantly associated with disease recurrence. Furthermore, lymphovascular space involvement was also correlated with worse disease outcome. CONCLUSIONS HPV16 DNA presence and low viral load in primary lesions can be used to predict disease recurrence. HPV DNA is a favorable prognostic indicator in patients with uterine cervical neoplasms who have lymphatic metastases.

Wright TC, Parvu V, Stoler MH, et al.
HPV infections and cytologic abnormalities in vaccinated women 21-34 years of age: Results from the baseline phase of the Onclarity trial.
Gynecol Oncol. 2019; 153(2):259-265 [PubMed] Related Publications
OBJECTIVES: Countries with school-based human papillomavirus (HPV) vaccination have seen significant reductions in vaccine-targeted HPV infections, cytologic abnormalities, and high-grade cervical intraepithelial neoplasia (≥CIN2). However, the impact of HPV vaccination in the United States (where vaccination is largely opportunistic) may be less due to lower coverage rates and vaccination in patients at ages beyond the recommended routine vaccination age.
METHODS: The Onclarity trial enrolled 33,858 subjects ≥21 years who were screened with cytology and the BD Onclarity HPV Assay. HPV positive women or those with cytologic abnormalities underwent colposcopy and biopsy. The prevalence of HPV, cytologic abnormalities, and ≥CIN2 was compared in a subset of 14,153, vaccinated and unvaccinated women, 21-34 years. Results were compared by vaccination status; Mantel-Haenszel analysis was performed to determine the association between vaccination status and prevalence, adjusting for age.
RESULTS: The prevalence of overall HPV, HPV16, 18, 31, and 33/58 were all lower in vaccinated women for each age group; a significant difference (p < 0.001) was observed in vaccinated women for all ages combined. Cytologic low-grade squamous intraepithelial lesion (LSIL) or worse was lower in vaccinated women (p = 0.021), as was ≥CIN2 prevalence associated with HPV 16 or 18 (p = 0.011).
CONCLUSIONS: Women with a prior history of HPV vaccination have a lower prevalence of any high-risk HPV, HPV 16, 18, 31, and 33/58; a cytology result of ≥LSIL, and ≥CIN2 associated with HPV 16/18 compared to unvaccinated women. A lower HPV prevalence in older, vaccinated women suggests that "catch-up" vaccination provides benefit.

Li S, Zhang W, Jiang K, et al.
Nanobody against the E7 oncoprotein of human papillomavirus 16.
Mol Immunol. 2019; 109:12-19 [PubMed] Related Publications
The persistent infection of high-risk human papillomavirus (HPV) is one of the most common causes of cervical cancer. It is well documented that expression of two oncogenes (E6/E7) plays a key role in tumor progression. HPV16E7 -targeting via nanobody (Nb) therefore could be beneficial for HPV16-associated cancer diagnosis and therapy. In this work, phage-display approach was employed to select the high affinity HPV16E7-specific Nb. Firstly; a high-quality immune library was constructed. After three round of biopanning, high-affinity HPV16 E7-specific nanobodies were retrieved. By phage ELISA and sequencing, four different sequences of anti- HPV16E7 nanobodies were selected. Then recombinant nanobody Nb2 was cloned and expressed in E. coli, and the specificity and thermal stability of purified Nb2 was evaluated. To examine the potential of Nb2 as an inhibitor of E7 function, Nb2 was expressed within HPV16 positive cells. Proliferation assay showed that the intracellular expressed Nb2 as an intrabody can decrease the growth of HPV16-positive cells. The results indicate that Nb2 as an intracellular antibody directed towards HPV oncoprotein E7 has great promise in applications for the therapy of HPV16-associated disease.

Zhang X, Zhi Y, Li Y, et al.
Study on the relationship between methylation status of HPV 16 E2 binding sites and cervical lesions.
Clin Chim Acta. 2019; 493:98-103 [PubMed] Related Publications
BACKGROUND: The aim of this study was to investigate the methylation status of E2BSs in the HPV 16 long control region (LCR) in clinical cervical samples.
METHODS: Methylation status of the four E2BSs in 43 clinical cervical samples with HPV 16 infection was quantitatively detected using pyrosequencing. Meanwhile, Quantivirus® HPV E6/E7 RNA 3.0 assay (bDNA) was used to detect E6/E7 mRNA levels in the corresponding specimens.
RESULTS: Our results showed that methylation status of E2BS1, 2 and 4 sites in high-grade squamous intraepithelial lesions (HSIL) and cervical cancer were significantly higher than that of asymptomatic HPV 16 infection and low-grade squamous intraepithelial lesions (LSIL) (all P < .05). Furthermore, methylation status of HPV 16 E2BS1 and 2 was positively correlated with E6/E7 mRNA levels (r
CONCLUSIONS: The methylation status of E2BS1 and 2 may have utility as diagnostic markers for the severity of cervical lesions in the future.

Thompson B, Barrington WE, Briant KJ, et al.
Educating Latinas about cervical cancer and HPV: a pilot randomized study.
Cancer Causes Control. 2019; 30(4):375-384 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
INTRODUCTION: The purpose of this study was to assess effects of three different educational intervention arms on knowledge of and intention to receive Pap testing and HPV co-testing.
METHODS: Three active educational intervention arms were developed: a fotonovela, a radionovela, and a digital story. A pilot randomized controlled trial of 160 Latinas was conducted to assess the effectiveness of the intervention arms in increasing knowledge of cervical cancer and HPV and intention to be screened for cervical cancer compared to an attention control group (flu vaccination).
RESULTS: Women in all three treatment arms significantly increased knowledge about cervical cancer compared to control arm (p = 0.02). Knowledge about cervical cancer screening also increased in the active arms compared to control (p = 0.0003). Knowledge of HPV risk also increased relative to the control (p = 0.0001). There were no significant differences between the intervention arms in increased knowledge of cervical cancer or cervical cancer screening (p = 0.57 and 0.16, respectively).
DISCUSSION: This study supported the use of small media interventions in narrative education form as effective in increasing knowledge and intention to be screened for cervical cancer. The three culturally relevant interventions, built on qualitative data, were all successful in increasing knowledge.

Budukh A, Maheshwari A, Palayekar V, et al.
Prevalence and nonsexual transmission of human papilloma virus (HPV) in the adolescence girls from rural area of Maharashtra state, India.
Indian J Cancer. 2018 Oct-Dec; 55(4):336-339 [PubMed] Related Publications
OBJECTIVE: To find out the prevalence of human papilloma virus (HPV) in adolescent girls and to access the nonsexual transmission of HPV from their mother by using the same old cloth used by their mother.
METHOD: Menstrual pads were collected from the women of age group years to find out the presence of HPV and whether it can be used as a cervical cancer screening tool. The results of the said study have been published in the European Journal of Cancer Prevention. During this study, menstrual pads of the daughters of participating women were collected to see the nonsexual transmission of HPV. After conducting the health education and obtaining the informed consent, we interviewed 57 mothers (age group 30-50, married, sexually active) and daughters [age group 12-18, unmarried (not exposed to sex)] from the rural area of Pune district of Maharashtra state, India. The menstrual pads were collected and transported to Mumbai for polymerase chain reaction (PCR) testing. HPV testing was carried out by PCR.
RESULTS: Out of 57, 28 (49%) daughters and 23 (40.4%) mothers provided menstrual pad. Out of 23 mothers, one was HPV positive [4.3%: 95% confidence interval (CI) 0.2-23.0] and out of 28 girls, 3 (10.7%: 95% CI 2.0-33.0) were HPV positive. The daughter, whose mother was HPV positive, had negative result for HPV.
CONCLUSION: The HPV prevalence in adolescence girls was 10.7%. There may be other nonsexual medium that might have caused HPV in adolescence girls, which needs further research.

Pista A, Costa C, Saldanha C, et al.
Budget impact analysis of cervical cancer screening in Portugal: comparison of cytology and primary HPV screening strategies.
BMC Public Health. 2019; 19(1):235 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Primary Human Papilloma Virus (HPV) testing is the currently recommended cervical cancer (CxCa) screening strategy by the Portuguese Society of Gynecology (SPG) clinical consensus. However, primary HPV testing has not yet been adopted by the Portuguese organized screening programs. This modelling study compares clinical benefits and costs of replacing the current practice, namely cytology with ASCUS HPV triage, with 2 comparative strategies: 1) HPV (pooled) test with cytology triage, or 2) HPV test with 16/18 genotyping and cytology triage, in organized CxCa screenings in Portugal.
METHODS: A budget impact model compares screening performance, clinical outcomes and budget impact of the 3 screening strategies. A hypothetical cohort of 2,078,039 Portuguese women aged 25-64 years old women is followed for two screening cycles. Screening intervals are 3 years for cytology and 5 years for the HPV strategies. Model inputs include epidemiological, test performance and medical cost data. Clinical impacts are assessed with the numbers of CIN2-3 and CxCa detected. Annual costs, budget impact and cost of detecting one CIN2+ were calculated from a public healthcare payer's perspective.
RESULTS: HPV testing with HPV16/18 genotyping and cytology triage (comparator 2) shows the best clinical outcomes at the same cost as comparator 1 and is the most cost-effective CxCa screening strategy in the Portuguese context. Compared to screening with cytology, it would reduce annual CxCa incidence from 9.3 to 5.3 per 100,000, and CxCa mortality from 2.7 to 1.1 per 100,000. Further, it generates substantial cost savings by reducing the annual costs by €9.16 million (- 24%). The cost of detecting CIN2+ decreases from the current €15,845 to €12,795. On the other hand, HPV (pooled) test with cytology triage (comparator 1) reduces annual incidence of CxCa to 6.9 per 100,000 and CxCa mortality to 1.6 per 100,000, with a cost of €13,227 per CIN2+ detected with annual savings of €9.36 million (- 24%). The savings are mainly caused by increasing the length of routine screening intervals from three to five years.
CONCLUSION: The results support current clinical recommendations to replace cytology with HPV with 16/18 genotyping with cytology triage as screening algorithm.

Skoulakis A, Fountas S, Mantzana-Peteinelli M, et al.
Prevalence of human papillomavirus and subtype distribution in male partners of women with cervical intraepithelial neoplasia (CIN): a systematic review.
BMC Infect Dis. 2019; 19(1):192 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Human Papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection. The present systematic review summarizes data regarding the prevalence of HPV and the distribution of subtypes in heterosexual male partners of women, who were diagnosed with any grade of cervical intraepithelial neoplasia (CIN).
METHODS: We conducted a systematic review of the literature by Medline and Google Scholar databases using the terms "Human Papillomavirus" or "HPV" plus "men" or "male partners" or "women with CIN". We included original published English-language articles published from 1/1/2000 until 1/1/2018 that had screened male partners of women with CIN using HPV DNA testing. We excluded studies that they overlapped with other included studies or were unrelated to the study subject.
RESULTS: We included a total of 12 publications, which reported the prevalence of HPV in free-clinical signs male partners of women with CIN. The largest proportion of the studies were from South America (seven studies), and the rest from Europe. The mean age of participants was 35.18 + - 3.47 years. HPV prevalence ranged from 12.9 to 86%; the total HPV prevalence among the studies was 49.1%, while ten out twelve studies (83.3%) demonstrated prevalence > 20%. Between the studies, the distribution of HPV subtypes varied on the basis of the method used, on the population and on the geographic region. A great variety of subtypes were detected, including 6, 11, 16, 18, 31, 33, 40, 42, 45, 51, 52, 53, 54, 56, 57, 58, 59, 61, 62, 66, 68, 81 and 83. In six studies the HPV 16 was the most frequent, while in two others the HPV 6 and HPV 83.
CONCLUSIONS: Until now, there are not precise screening or surveillance guidelines for the management of partners of women with CIN. This population is frequently colonized by various HPV subtypes and therefore need to be screened in an effort to reduce the infection in both sexes. The screening test could include detection/identification of HPV subtypes by a molecular assay, followed by peniscopy only in the positive cases.

Fitzpatrick MB, Dube Mandishora RS, Katzenstein DA, et al.
hrHPV prevalence and type distribution in rural Zimbabwe: A community-based self-collection study using near-point-of-care GeneXpert HPV testing.
Int J Infect Dis. 2019; 82:21-29 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
OBJECTIVES: High-risk human papilloma viruses (hrHPV) are the causative agents of cervical cancer, the leading cause of cancer deaths among Zimbabwean women. The objective of this study was to describe the hrHPV types found in Zimbabwe for consideration in cervical cancer screening and vaccination efforts.
DESIGN AND METHODS: To determine hrHPV prevalence and type distribution in Zimbabwe we implemented a community-based cross-sectional study of self-collected cervicovaginal samples with hrHPV screening using near-point-of-care Cepheid GeneXpert HPV.
RESULTS: The hrHPV prevalence was 17% (112/643); 33% (41/123) vs. 14% (71/520) among HIV-1-positive and -negative participants, respectively (p=2.3E-07). Typing via Xpert HPV showed very good overall agreement (77.2%, kappa=0.698) with the Seegene Anyplex II HPV HR Detection kit. The most common types were HPV16, HPV18, HPV35, HPV52, HPV58, HPV68, HPV18, and HPV51, each of which appeared in 14-20% of infections. 37% (28/76) of women with positive cytology results (ASCUS+) had a type not included in the basic vaccine and 25% (19/76) had a type not currently in the nine-valent vaccine.
CONCLUSIONS: hrHPV type distribution includes less common high-risk types in rural Zimbabwe. The distribution and carcinogenicity of hrHPV type distribution should be considered during screening assay design, program development, as well as vaccine distribution and design.

Ghosh D, Roy AK, Murmu N, et al.
Risk Categorization with Different Grades of Cervical Pre-Neoplastic Lesions - High Risk HPV Associations and Expression of p53 and RARβ
Asian Pac J Cancer Prev. 2019; 20(2):549-555 [PubMed] Related Publications
Objective: To identify high risk HPV associations by evaluating linked p16 overexpression and also the expression of p53 and RARβ together with histopathology for risk categorization of cervical pre-neoplastic lesions. Materials and Methods: Immunohistochemical staining was performed on 100 cases of cervical pre- neoplastic lesions for expression of biomarkers like p16, p53 and RARβ for comparison with haematoxylin/eosin (HE) findings. All the experimentally generated data were statistically analyzed. Results: In this study 70% cases showed overexpression of p16INK4A increasing progressively from CIN I to CIN II but reduced in CIN III (p <0.01). p53 oncoprotein expression was seen in 51% cases, again with increments from CIN I to CIN II with slight reduction in CIN III (p<0.01). Some 24% cases showed negative immunoreactivity for the putative tumor suppressor gene RARβ (p>0.05). Conclusion: Our study provides support for the idea that p16 can be used to identify associations with HPV , as well as having potential along with p53 and RARβ for categorizing cervical pre-neoplastic cases having a higher risk of neoplastic conversion. Thus it may be concluded that accurate risk categorization can be achieved with the help of genetic markers as well as histopathology.

Lee H, Hur S, Jang H, et al.
Cost-Utility of a Two-Dose Human Papillomavirus Vaccination Programme Added to Cervical Cancer Screening Compared with Cervical Cancer Screening Alone in Korea
Asian Pac J Cancer Prev. 2019; 20(2):425-435 [PubMed] Related Publications
Background: Cervical cancer is caused by the human papillomavirus and is a leading cause of cancer death among young Korean women. Current screening programmes could benefit from the addition of HPV vaccination into their schedule to help reduce disease burden. Two-dose vaccination schedules targeting HPV types 16 and 18, which are responsible for most cervical cancer cases, have recently been approved. Of the two available vaccines, AS04-adjuvanted HPV16/18 vaccine (AS04-HPV16/18v) provides greater protection against non-vaccine oncogenic HPV, while HPV-6/11/16/18 vaccine (4vHPVv) provides protection against genital warts. Methods: The health and economic consequences of introducing a two-dose HPV vaccination programme in 12-year-old girls together with screening were assessed in the Korean healthcare setting using a previously-published Markov model. Results: Compared with screening alone, AS04-HPV16/18v was cost-effective (incremental cost-effectiveness ratio below and within the Korean Won [KRW] 20-30 million treshold). When comparing the two vaccines, at 3% discount rate, AS04-HPV16/18v dominated 4vHPVv (i.e., provided 174 more quality-adjusted life-years (QALYs), 304 more life-years (LYs) and cost-savings of KRW 980 million). At a 5% discount rate, AS04-HPV16/18v provided comparable QALYs (albeit 5 fewer), 105 more LYs and cost-savings of KRW 292 million compared with 4vHPVv. Results were particularly sensitive to the discount rate used, as the health benefits of preventing cervical cancer are observed much later than those of preventing genital warts. Conclusion: For the Korean setting, HPV vaccination with a two-dose schedule is a cost-effective option, and AS04-HPV16/18v is likely to offer better health outcomes at a cost-saving compared with 4vHPVv.

Aydoğmuş H, Aydoğmuş S
Comparison of Colposcopic Biopsy Results of Patients Who have Cytomorphological Normal but HPV 16-18 or Other High-Risk HPV Subtypes Positive
Asian Pac J Cancer Prev. 2019; 20(2):417-420 [PubMed] Related Publications
Objective: Current guidelines suggest annual co-test follow-up in non-16/18 high-risk HPV positive patients without abnormal cytologic findings. Considering the relatively high false-negative rates of cervical cytology, a follow-up period of one year might constitute an additional risk for development of cervical malignancies in these patients. The current study aims to evaluate colposcopic biopsy results of cytologically normal patients detected to carry high risk HPV by screening tests. Materials and Methods: A total of 160 patients with normal cervical cytology and high-risk HPV subtypes who underwent colposcopic examination were included in the study. Patients were divided into two groups according to their HPV results: HPV 16-18 and other types (non-16/18 high-risk subtypes). ECC, cervical biopsy, LEEP/ conization results were analyzed for both groups. Histopathological results of the groups were compared in terms of ≤LSIL, HSIL and cervical cancer rates. Results: Cervical biopsy results in the “16-18” group were assessed as HSIL in 40 (48.2%) patients, LSIL in 6 patients (7.2%) and normal in 37 (44.6%) patients. ECC results revealed HSIL in 9 (10.8%) patients and LSIL in 1 (1.2%) patient. Nineteen out of 42 patients who underwent LEEP/conization had HSIL (surgical margin positivity was reported in 4 cases), while 3 patients had LSIL. None of the cases had cervical carcinoma. Conclusion: The present study detected that 15.6% of women infected with non-16/18 high-risk HPV subgroups developed ≥HSIL lesions. Although this rate seems lower than HPV 16-18 group, it is still too high to be overlooked. In conclusion, we suggest further clinical trials with larger number of patients to be conducted on this topic.

Cassani B, Soldano G, Finocchiaro D, et al.
Detection and genotyping of HPV-DNA through different types of diagnostic platforms in liquid-based cervical-cytology samples.
Pathologica. 2018; 110(4):294-301 [PubMed] Related Publications
Background: At present cervical cancer represents the second most common cancer in women worldwide and it reaches a global mortality rate of 52%. Only the early detection and the adequate treatment of pre-neoplastic lesions and early-stage cervical cancer decrease the mortality rate for this type of cancer. Cervical carcinoma screening, as a method of second prevention, is currently feasible through molecular research of high-risk HPV genotypes and in lots of organized screening programs the Pap-test is performed only in women with positive HPV-test. Currently, there are various diagnostic platforms detecting and molecular genotyping HPV, which are based on different procedures, determining uneven viral genotypes panels and using diverse type of vials to collect and store the samples. Previous studies have pointed out that DNA-HPV test can be negative in pre-neoplastic lesions, even of high grade, or in presence of cervical cancer. Therefore, it's important to assess the risk of false negative diagnoses using DNA-HPV molecular test, because in this circumstance women do not undergo immediately Pap-test, but they are submitted to second round screening with DNA-HPV test after 5 years: this protocol could increase the incidence of "interval cancers". The present study aims at comparing the results of HPV detection and genotyping on liquid based cervical cytology, using some of the most relevant diagnostic platforms in commerce.
Methods: The study is based on a group of patients which went to their private gynecologist in a contest of opportunistic screening. The vial used in the examined population has been EASYPREP
Results: We have examined 1284 samples of women aged 16 to 73 years: 1125 have been tested using HC2 procedure, 272 samples with Onclarity method, 159 with Xpert
Discussion: The present study highlights the following: 1) Positive results' percentage for high-risk HPV-DNA genotypes, deriving from the three diagnostic platforms used and with the same vial to collect and store samples, does not significantly vary on the basis of the type of equipment and it is congruent with the Italian percentage already detected during organized screening programs. 2) Even the molecular diagnostic approach could give false negative results, preventing the detection in the screened population of cervical HPV-related lesions and theoretically endangering women to develop "interval cancer". 3) In the population examined, genotype 16 has been the most expressed, whereas genotype 18 was among the less frequently detected. Other genotypes often noticed have been: 56-59-66 (Onclarity P3 group), 31, 51 and 35-39-68 (Onclarity P2 group). This remark emphasizes the importance of HPV infection and genotypes distribution's continuous monitoring, considering that HPV-vaccines planned in Italy in the "National vaccination prevention program 2017-2019" are not specific for the majority of these genotypes. 4) The necessity to improve the screening program to identify cervical carcinomas and pre-neoplastic cervical lesions is remarked by the detection during HPV-test of possible coinfection (present at least in 8,76% of our records). In fact, the risk of development of cervical cancer might be associated with type-specific interactions between genotypes in multiple infections and, in addition, other genotypes, not targeted by quadrivalent HPV-vaccine, can increase the risk of cervical carcinoma. 5) As there's a different combination of HPV-genotypes in diagnostic categories used by the HPV screening platforms, it's important that anyone who is in charge of this diagnostic analysis promotes among clinicians the adequate rendition of the laboratory's data in the patient records, reporting both the diagnostic result and the method through which it has been obtained.

Kovacevic G, Milosevic V, Knezevic P, et al.
Prevalence of oncogenic Human papillomavirus and genetic diversity in the L1 gene of HPV16 HPV 18 HPV31 and HPV33 found in women from Vojvodina Province Serbia.
Biologicals. 2019; 58:57-63 [PubMed] Related Publications
The main purpose of this paper is to estimate the pre-vaccination prevalence of 12 hrHPV types among 564 women from Vojvodina province (Serbia). The corrected contingency coefficient (Ccorr) was used to estimate the importance of association of examined HPV types and cytological diagnosis. The highest association with the abnormal cytology was observed for HPV 16 (Ccorr = 0.493) in all age groups of participants. The effect of HPV 16 was especially clear within the group of women older than 35 years (Ccorr = 0.691), compared with women younger than 35 (Ccorr = 0.333). The molecular characterization at the level of L1 gene of HPV 16, 18, 31 and 33 variants was for the first time assessed in our region. Nearly all HPV 16 isolates cluster with variant lineage A (96.4%) the remaining isolates clustering with variant lineage D. All of HPV 18 and HPV 33 isolates are clustering within the lineage A while isolates of HPV 31 group with lineages A and C. This contributes to understanding of intrinsic geographical and biological differences of examined HPV types and could be useful for development of cervical cancer screening strategies in Vojvodina (Serbia) and diagnosis of HPV related cervical cancer in general.

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