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Background: Cervical cancer screening participation remains insufficient in most countries. Our aim was to evaluate whether offering a HPV self-sampling kit, either mailed directly to the woman's home or using timely opt-in procedures for ordering the kit, increased screening participation compared with a standard second reminder., Methods: In this randomized, controlled effectiveness trial, 9791 Danish women aged 30-64 who were due to receive the second reminder were equally randomized to either: 1) direct mailing of a second reminder and a self-sampling kit (directly mailed group); 2) mailing of a second reminder that offered a self-sampling kit to be ordered by e-mail, text message, phone, or webpage (opt-in group); or 3) mailing of a second reminder to attend regular cytology screening (control group). In an intention-to-treat analysis, we estimated the participation rate at 180 days post intervention, by returning a self-sample or attending regular cytology screening. We calculated the proportion of women with a positive HPV self-sample who attended for cervical cytology triage at the general practitioner within 90 days., Results: Participation was significantly higher in the directly mailed group (38.0%) and in the opt-in group (30.9%) than in the control group (25.2%) (participation difference (PD): 12.8%, 95% CI: 10.6-15.0% and PD: 5.7%, 95% CI: 3.5-7.9%, respectively). Within 90 days, 107 women (90.7%, 95% CI: 83.9-95.3%) with a HPV-positive self-sample attended follow-up., Conclusions: Offering the opportunity of HPV self-sampling as an alternative to regular cytology screening increased participation; the direct mailing strategy was the most effective invitation strategy. A high compliance with follow-up was seen., Trial Registration: Current Controlled Trials NCT02680262 . Registered 10 February 2016.

Human papillomavirus (HPV) infections can have clinical presentations from self-limited benign growth in the skin and mucosal epithelia to malignant growth. HPV infects basal epithelial cells (undifferentiated keratinocytes) of the squamous-columnar junction, especially of the cervix. Although today we understand HPV oncogenesis very well, we have very powerful methods of diagnosis, treatment and prevention of HPV related precancerous lesions, however, more than 270,000 women annually die from cervical cancer worldwide. Integrating HPV vaccination with new, more sensitive, cervical screening assays as part of routine preventive care will improve healthcare for all women. The availability of prophylactic HPV vaccines has provided powerful tools for primary prevention of cervical cancer and other HPV-associated diseases. Secondary prevention through primary high-risk HPV (hr-HPV) testing has the potential to further reduce morbidity and mortality of cervical cancer. However, to achieve the maximum benefit of screening, there is need to continue to identify women who are either unscreened or under-screened. Synergies between HPV vaccination and HPV screening is recommended to improve the effectiveness and cost-effectiveness of prevention HPV-related disease.

Most human papillomaviruses cause inapparent infections, subtly affecting epithelial homeostasis, to ensure genome persistence in the epithelial basal layer. As with conspicuous papillomas, these self-limiting lesions shed viral particles to ensure population level maintenance and depend on a balance between viral gene expression, immune cell stimulation and immune surveillance for persistence. The complex immune evasion strategies, characteristic of high-risk HPV types, also allow the deregulated viral gene expression that underlies neoplasia. Neoplasia occurs at particular epithelial sites where vulnerable cells such as the reserve or cuboidal cells of the cervical transformation zone are found. Beta papillomavirus infection can also predispose an individual with immune deficiencies to the development of cancers. The host control of HPV infections thus involves local interactions between keratinocytes and the adaptive immune response. Effective immune detection and surveillance limits overt disease, leading to HPV persistence as productive microlesions or in a true latent state., (Copyright © 2017. Published by Elsevier Ltd.)

HIV-related immunodeficiency has complex effects on female genital HPV, which include increased risks of infection, multiple types, persistence, reactivation and the risk to develop pre-invasive and invasive disease. Reconstitution of immunity with anti-viral drugs improves cellular immunity, but the risk of HPV-related malignancy remains higher than background incidences and presents at younger ages. Early initiation of antiretroviral therapy (ART) allows improved retention of immune memory through existing antibodies and T-cell clones and improves long-term outcomes. Suggestions of a higher risk to contract HIV if there is existing genital HPV infection are supported and explained by pathophysiological cervical changes, including inflammation. HIV-HPV interactions should influence public health decisions towards prioritising large-scale prepubertal HPV-vaccine roll-out, secondary cervical cancer prevention and early detection programmes for HIV-infected women and early initiation of ART. This chapter will also focus on special considerations for the management of women with co-infection with these two viruses and genital HPV-related diseases., (Copyright © 2017. Published by Elsevier Ltd.)

High-risk human papillomavirus (HPV) infection is known to be a necessary factor for cervical and anogenital malignancies. Cervical cancers account for over a quarter of a million deaths annually. Despite the availability of prophylactic vaccines, HPV infections remain extremely common worldwide. Furthermore, these vaccines are ineffective at clearing pre-existing infections and associated preinvasive lesions. As cervical dysplasia can regress spontaneously, a therapeutic HPV vaccine that boosts host immunity could have a significant impact on the morbidity and mortality associated with HPV. Therapeutic vaccines differ from prophylactic vaccines in that they are aimed at generating cell-mediated immunity rather than neutralising antibodies. This review will cover various therapeutic vaccine strategies in development for the treatment of HPV-associated lesions and cancers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cervical cancer affects women in their reproductive ages. Screening is an important secondary prevention strategy. The long process of carcinogenic transformation from human papillomavirus (HPV) infection to invasive cancer provides ample opportunities to detect the disease at a stage when treatment is highly effective. Suitable screening tests are cytology, visual inspection after acetic acid application and HPV detection tests. Evidence of effectiveness of the tests to reduce cervical cancer mortality and the cost-effectiveness of screening programs have been demonstrated. Cervical intraepithelial neoplasia grade 2 and grade 3 are the high-grade cervical cancer precursors and need to be treated. Treatment is safe and effective with ablative or excisional techniques. The World Health Organization recommends screening women at least once in a lifetime between 30 and 49 years of age and ensuring effective treatment of the detected abnormalities. Combination of HPV vaccination and population-based screening will be instrumental in eliminating cervical cancer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV) is a small double-stranded DNA virus that commonly infects humans. The oncogenic characteristics of HPV derive from the oncoproteins E6 and E7 that act inhibiting p53 and pRB tumor suppressors. About 5% of all cancers worldwide are attributable mainly to those known as high-risk, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Infection with HPV is common after sexual initiation, but the majority of HPV infections do not cause symptoms or disease and are cleared within 12-24 months post-infection. Only a small fraction of those infections that persist or progress to a preneoplastic lesion result in cancer. Persistence of HPV infection is needed to start the oncogenic process. Clearance of infection is common in young adults. Viral load and viral type are the main cofactors for progression from infection to cervical intraepithelial lesions and cancer. Smoking, hormonal exposure, and HIV are additional exposures that increase the risk of progression to cancer. The adverse health effects of HPV infections can be largely controlled through vaccination and screening., (Copyright © 2017. Published by Elsevier Ltd.)

Persistent oncogenic human papillomavirus (HPV) is the cause of cervical cancer, as well as cancers of the anus, penis, vulva, vagina and oropharynx. There is good evidence that prophylactic HPV vaccines are immunogenic and effective against targeted-type HPV infections and type-specific genital lesions, including high-grade cervical intraepithelial neoplasia (CIN), when administered prior to HPV infection. There is good evidence that HPV vaccines are safe in population usage, with the most frequent adverse event being injection-site reactions. There is evidence to support some cross-protection against non-targeted types occurring following the administration of HPV vaccines. There is limited evidence suggesting that HPV vaccines may be beneficial in preventing future disease in women treated for high-grade CIN. This chapter focuses on the accumulated evidence regarding the global use of the three licensed HPV vaccines including safety, immunogenicity, duration of protection, effectiveness, coverage to date and barriers to higher coverage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The long-term effectiveness of the quadrivalent human papillomavirus (qHPV) vaccine was assessed by monitoring the combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18., Methods: Women from Nordic countries of Denmark, Iceland, Norway, and Sweden who received a 3-dose regimen of the qHPV vaccine in the beginning of FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease; V501-015, base study NCT00092534) are followed through different national registries. Effectiveness analyses were conducted approximately 2 years following completion of the base study and occur approximately every 2 years thereafter for 10 years (ie, 14 years from day 1 of the base study). Vaccine effectiveness against HPV16/18-related CIN2 or worse (CIN2+) was estimated by comparing the observed incidence with the expected incidence of CIN2+ in an unvaccinated cohort using historical registry data., Results: In the per-protocol population (2084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9437 person- years of follow-up. Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years. The number of person-years during the follow-up interval of 10-12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period., Conclusion: The qHPV vaccine shows continued protection in women through at least 10 years, with a trend for continued protection through 12 years of follow-up., Clinical Trials Registration: NCT00092534., Study Identification: V501-015., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Human papillomavirus (HPV) is one of the most common sexually transmitted infectious pathogens. Persistent infection has been linked to cancer development, in particular to cervical cancer. This study aims to investigate the epidemiology of HPV infection in women in Inner Mongolia of China and to dissect the disparities between the Han and Mongolian ethnic populations. Cervical cell samples from 5655 women (17-68 years old) were collected during routine gynecologic examination. HPV infection was established using the HPV GenoArray kit detecting 21 HPV genotypes. The overall HPV prevalence was 14.5%. HPV16 (5.0%), HPV58 (2.2%), and HPV52 (1.5%) are the most common genotypes. Of the 21 genotypes investigated, high-risk HPV genotypes dominate in all age groups. HPV16 and HPV58 are the most common genotypes in patients with cervical lesions. HPV prevalence among Han women is 11.5% and the most common genotypes are HPV16 (4%) and HPV58 (2.1%). HPV prevalence is significantly higher in Mongolian women (32.6%), with the most common genotypes being HPV16 (10.7%), HPV31 (7.1%), and HPV52 (4.3%). The multiple infection rate in Mongolian participants (14.9%) is also higher than that of Han participants (4.3%). Urbanization, the number of sex partners, and PAP history appear as risk factors for HPV infection in Han, but not in Mongolian participants. HPV infection is highly prevalent in women in Inner Mongolia, China. HPV16 remains the most common genotype in this area. However, there are clear ethnical disparities in respect to the HPV epidemiology between the Han and Mongolian population., (© 2017 Wiley Periodicals, Inc.)

Cervical cancer is the third most common malignant neoplasm in women worldwide. HPV infection is the necessary factor for the cancer to develop. HPV DNA can be integrated into the genome of squamous epithelium and cause transcription of the viral oncoproteins and development of invasive cancer within 15-20 years. We assessed ICC co-expression of p16/Ki-67 proteins in smears collected from the uterine cervix and the association between p16/Ki-67 co-expression and cytologic and histologic results. Samples were collected from 93 women using liquid based cytology (LBC). Two microscopic slides were prepared: for Papanicolaou staining and ICC staining. Biopsy samples were collected from 43 women. Diagnosis of CIN 2+ was the endpoint of the study. p16/Ki-67 positive cells were found in women with: 1) a cytology result of ASC-US (3.59%), LSIL (2.22%), ASC-H (21.92%), HSIL (33.18%), SCC (72.22%) or NILM (3.44%); 2) a histopathologic result of CIN 1 (2.13%), CIN 2 (19.93%), CIN 3 (23.22%), SCC (69.72%) or normal histology (7.58%). p16/Ki-67 dual staining can increase the efficiency of screening methods and indicate women in whom further diagnostic procedures are required or those with extremely low risk of cancer. Sparing protocols will have a significant role in women of reproductive age.

To evaluate the effectiveness of Human papillomavirus16/18 infection referral to colposcopy in cervical cancer screening for women aged 25 years and older in Chinese northwest region Shaan'xi province. A total of 2224 women were diagnosed with primary high-risk HPV infection by HPV-DNA genotyping technology during August 2014 to August 2015. A total of 1916 cases referred for colposcopy with histological evidence were enrolled, including 1124 women with HPV16/18 genotype and 792 with other High-risk human papillomavirus genotypes. A total of 1916 women aged 25 years and older with HR-HPV positive were referred to colposcopy. The distribution of HPV16, HPV18, and other HR-HPVs infection were 49.22%, 9.45%, and 41.33%, respectively. 71.56% had normal cervical histology, 7.05% had Cervical Intraepithelial Neoplasia1, 8.82% had CIN2, 7.25% had CIN3, and 5.32% had cervical cancer. The percentage of positivity of HPV16 and HPV18 was highly associated with the relative risk of cervical lesion. The sensitivity and specificity of HPV16/18 for detection of CIN2+ (CIN3+) was 82.68% (92.12%) and 47.87% (46.15%), respectively. The positive predictive value and negative predictive value of HPV16/18 for detection of CIN2+ (CIN3+) was 30.16% (19.75%) and 91.03% (97.60%), respectively. HPV16 and HVP18 are the most common genotypes in high grade cervical lesions in Shaan'xi province. Meanwhile, these two types play predominant roles in the progression of high grade cervical lesion. Primary HPV16/18 detection has high sensitivity and negative predictive value in cervical cancer screening and the strategy for women with HPV16 and HPV18 infection referral to colposcopy is efficient and feasible in northwestern region of China., (© 2017 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.)

Two main considerations played roles in creation of new cervical screening system. One was the proven fact that high-risk human papilloma virus infection plays a role in the development of cervical cancer and pre-cancerous lesions. The other was the implementation of the HPV infection's biological behavior in the new screening strategy. The new screening procedure faithfully reflects the cervical carcinogenesis. An organised, population-based and age differentiated screening method could increase attendance of screening and could decrease the possibility of interval cancer rate due to increased sensitivity. Orv Hetil. 2017; 158(52): 2062-2067.

Background: Human papillomavirus (HPV) bivalent and quadrivalent vaccines have been widely implemented in worldwide organized immunization programs. A nonavalent HPV vaccine is now available in several countries. The objective was to describe the fraction of squamous non-invasive high-grade cervical intraepithelial lesions attributable to genotypes targeted by bi-quadrivalent vaccines and by nonavalent vaccine according to age and diagnosis in women living in the city of Vigo (Galicia, Spain)., Methods: Cervical scrapings (2009-2014) of women with histological diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2, n = 145) and grade 3-carcinoma in situ (CIN3-CIS, n = 244) were tested with Linear Array HPV Genotyping test (Roche diagnostics, Mannheim, Germany). Hierarchical estimation of the fraction attributable to HPV 16/18 or HPV 31/33/45/52/58 detected alone or in combination was calculated. Absolute additional fraction attributable to genotypes targeted by nonavalent vaccine compared to genotypes targeted by bi-quadrivalent vaccines was calculated as the increment of attributable cases with respect to all studied cases. Age group 1, 2 and 3 included women 18 to 34, 35-44 and ≥45 years old, respectively. EPIDAT 3.1 was used., Results: Fraction attributable to genotypes targeted by bi-quadrivalent vaccines was 59% CIN2 vs. 69% CIN3-CIS (p < 0.001). It was 63/51/50% of CIN2 and 78/66/45% of CIN3-CIS in age group 1, 2, 3, respectively. Fraction attributable to genotypes targeted by nonavalent vaccine was 86% CIN2 and 86% CIN3-CIS. It was 87/91/75% of CIN2 and 90/86/76% of CIN3-CIS in age group 1, 2, 3, respectively. Fraction attributable to genotypes targeted by these vaccines tended to decrease as age increased (p-trend <0.05). Globally, absolute additional attributable fraction was 16%, 26% and 29% in age group 1, 2 and 3, respectively (p < 0.005)., Conclusions: Absolute additional fraction of CIN2 and CIN3-CIS attributable to genotypes targeted by nonavalent vaccine was observed in women of any age, especially in those over 35 years old.

Background and Objetive: Human papilloma virus (HPV) is one of the main risk factors associated with the development of cervical cancer and its precursor lesions. It has been reported that HPV16 and 18 types cover approximately 70% of cervical cancer worldwide; however, significant variation in percentages of HPV infections could be related to specific populations., Materials and Methods: Purified DNA of 67 cervical samples were analyzed by Linear Array® HPV genotyping kit. These analyzed samples correspond to 19 cervical tumors, 15 high-grade squamous intraepithelial lesions, 20 low-grade squamous intraepithelial lesions, and 13 cervical samples without injury were studied, all of them previously diagnosed., Results: In general, 16 different HPV types were found with differences in their frequencies, cervical invasive cancer being the richest in HPV sequences, followed by the low-grade squamous intraepithelial lesions and then high-grade lesions. HPV16 was the most frequently distributed type in neoplastic lesions of the cervix, followed by the HPV52, suggesting viral type variability, probably associated to the geographical region studied., Conclusions: The results could indicate variability in HPV presence in Mexico, underlining the important role for HPV52 among others in the Mexican population. This would also potentially have an impact on the current anti-HPV vaccination schemes., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Objective: According to the third cancer plan, organised screening (OS) of cervical cancer (CC) among women aged 25-65 years should be implemented in France in the forthcoming years. The most efficient way to implement OS in the French healthcare system is yet to be determined., Methods: A microsimulation model was developed adopting a collective 'all payers' perspective. A closed cohort of women eligible for CC screening and representative in terms of age and participation in individual screening (IndScr) by annual Papanicolaou (Pap) testing every 3 years was modelled on a lifetime horizon. Different OS strategies, additive to IndScr with a 61.9% participation rate based on mailed invitations to non-participant women to perform OS were assessed. Similar modalities were applied to OS and IndScr participants. Strategies implied different screening tests (Papanicolaou (Pap) test, human papillomavirus (HPV) test and p16/Ki67 double staining) and OS periodicity., Results: Compared with IndScr only, all OS strategies were associated with decreased cancer incidence/mortality (from 14.2%/13.5% to 22.9%/25.8%). Most strategies generated extra costs ranging from €37.9 to €1607 per eligible woman. HPV testing every 10 and 5 years were cost saving. HPV tests every 10 and 5 years were the most efficient strategies, generating more survival at lower costs than Pap-based strategies. Compared to IndScr only, an HPV test every 10 years was cost saving. The most effective strategies were p16/Ki67 as primary or HPV positive confirmation tests, with respective incremental cost-effectiveness ratios of €6 541 250 and €101 391 per life year. Pap-based strategies generated intermediary results., Conclusion: OS strategies based on the HPV test appear highly efficient. However, our results rely on the assumption that women and practitioners comply with the recommended OS periodicities (3, 5, 10 years). Implementing these OS modalities will require major adaptations to the current CC screening organisation. Pap test-based strategies might be simpler to setup while preparing an appropriate implementation of more efficient OS screening modalities., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The Copenhagen Self-Sampling Initiative (CSi) has shown how human papillomavirus (HPV)-based self-sampling can be used to increase screening participation among 23,632 nonattenders in the Capital Region of Denmark. In this study, we describe HPV prevalence and genotype frequency in 4,824 self-samples as determined by three HPV assays (the CLART, Onclarity, and Hybrid Capture 2 [HC2] assays) and compare the results with those for physician-taken follow-up samples. The HPV self-sample findings were also compared to the findings for a reference population of 3,347 routinely screened women from the Horizon study, which had been undertaken in the same screening laboratory. Nonattenders had an HPV prevalence of 11.3% as determined by the CLART assay, which was lower than that for women from the Horizon study (18.5%). One-third of the CSi women who tested HPV positive by self-sampling tested HPV negative on the physician-taken follow-up sample. The CLART and Onclarity assays agreed on 64% (95% confidence interval [CI], 60 to 68%) of the HPV-positive self-taken samples. When the HC2 assay results were added into a three-way comparison, the level of agreement decreased to 27% (95% CI, 24 to 29%). Our findings suggest that further validation of HPV assays on self-taken samples is needed for optimal HPV detection and correct clinical management of HPV-positive women., (Copyright © 2017 Lam et al.)

Objective: To estimate the potential impact of the nonavalent HPV vaccine for high-grade cervical lesions and invasive cervical cancer (ICC) in Portugal., Methods: The present secondary analysis used data collected in the CLEOPATRE II study on the prevalence of HPV 6/11/16/18/31/33/45/52/58 among female patients aged 20-88 years. The prevalence of HPV types in patients with cervical intraepithelial neoplasia (CIN) grades 2/3 and ICC was examined., Results: Data were included from 582 patients. There were 177, 341, and 64 patients with CIN2, CIN3, and ICC, respectively, and 169 (95.5%), 339 (99.4%), and 62 (96.9) of them had HPV infections. Of patients with HPV infections, HPV 16, 18, 31, 33, 45, 52, and 58 infections were identified in 150 (88.8%), 329 (97.1%), and 60 (96.8%) patients with CIN2, CIN3, and ICC, respectively. HPV genotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58 were identified in 540 (94.7%) of the patients with HPV infections., Conclusion: The addition of the five HPV genotypes included in the nonavalent HPV vaccine (HPV 31/33/45/52/58) could result in the new HPV vaccine preventing 94.7% of CIN2/3 and ICC occurrences., (© 2017 International Federation of Gynecology and Obstetrics.)

Background: Cervical cancer disproportionately affects women from lower socioeconomic backgrounds. A human papillomavirus (HPV) vaccination programme was introduced in Scotland in 2008 with uptake being lower and inequitable in a catch-up cohort run for the first three years of the programme compared with the routine programme. The socioeconomic differences in vaccine uptake have the potential to further increase the inequality gap in regards to cervical disease., Methods: Vaccination status was linked to demographic, cytological and colposcopic data, which are routinely collected by the Scottish HPV surveillance system. Incidence rates and relative risk of cervical intraepithelial neoplasia (CIN) 1, 2 and 3 in unvaccinated and vaccinated women were stratified by birth year and deprivation status using Poisson regression., Results: Women who received three doses of HPV vaccine have significantly decreased risk of CIN 1, 2 and 3. Vaccine effectiveness was greater in those women from the most deprived backgrounds against CIN 2 and 3 lesions. Compared with the most deprived, unvaccinated women, the relative risk of CIN 3 in fully vaccinated women in the same deprivation group was 0.29 (95% CI 0.2 to 0.43) compared with 0.62 (95% CI 0.4 to 0.97) in vaccinated women in the least-deprived group., Conclusions: The HPV vaccine is associated with significant reductions in both low-grade and high-grade CIN for all deprivation categories. However, the effect on high-grade disease was most profound in the most-deprived women. These data are welcoming and allay the concern that inequalities in cervical cancer may persist or increase following the introduction of the vaccine in Scotland., Competing Interests: Competing interests: KGP has received travel subsistence for the International Human Papillomavirus conference. KC has received grants from Cepheid, Gene First and Euroimmun outside of the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Human papillomavirus (HPV) is the leading cause of cervical cancer and other malignant and benign neoplastic lesions. HPV vaccination has three potential goals: to prevent transmission, infection, and disease. At present, there are no available data about health consequences of HPV immunization in Italy. The aim of this study is to evaluate the effect of current HPV vaccination strategy in Italy., Methods: A multistate morbidity-mortality model was developed to estimate the infection process in a theoretical cohort of Italian women. The Markov process considered nine health states (health, anogenital warts, grade 1 and grade 2/3 cervical intraepithelial neoplasia, cervical cancer, anal cancer, death due to cervical cancer, anal cancer and other causes), and 26 transition probabilities for each age group. The model was informed with the available data in national and international literature. Effectiveness of immunization was assumed considering a literature review pertaining to models and vaccination coverage rates observed in Italy. Life expectancy (e x ), Quality-Adjusted Life Years (QALYs), Disability-Adjusted Life Years (DALYs), and attributable risk (AR) were estimated for no intervention (cervical cancer screening) and vaccination strategies scenarios., Results: The model showed that in a cohort of 100,000 Italian women the e 0 is equal to 83.1 years. With current HPV vaccination strategy the e 0 achieves 83.2 (+0.1) years. When HPV-related diseases are considered altogether, the QALYs increase from 82.7 to 82.9 (+0.2 QALYs) with no intervention and vaccination strategies respectively. DALYs decrease by 0.6 due to vaccination. Finally, AR is equal to 93 and 265 cases per 100,000 women in population and not vaccinated, respectively., Conclusion: When mortality due to cervical cancer is considered, HPV vaccination seems to have a low impact on health unit gains in the Italian female population. Conversely, when several HPV-related and cancer morbidity conditions are included, the effect of vaccination becomes quite remarkable.

Background: Trends in human papillomavirus (HPV)-associated cervical lesions can provide an indication of vaccine impact. Our purpose was to measure trends in cervical lesions during 2008-2015 and to consider possible explanations including vaccination coverage, changes in screening for cervical cancer, and risk behaviors for acquiring HPV., Methods: Connecticut (CT) implemented mandatory reporting of cervical intraepithelial neoplasia grades 2/3 and adenocarcinoma in situ (cervical intraepithelial neoplasia grade 2 or higher [CIN2+]) in 2008. Trends by age and birth cohort were modeled using negative binomial regression and change-point methods. To evaluate possible explanations for changes, these trends were compared to changes in HPV vaccination coverage, cervical cancer screening, an antecedent event to detection of a high-grade lesion, and changes in sexual behaviors and Chlamydia trachomatis, an infection with similar epidemiology to and shared risk factors for HPV., Results: A significant decline in CIN2+ was first evident among women aged 21 years in 2010, followed by successive declines in women aged 22-26 years during 2011-2012. During 2008-2015, the rates of CIN2+ declined by 30%-74% among women aged 21-26 years, with greater declines observed in the younger women. Birth cohorts between 1985 and 1994 all experienced significant declines during the surveillance period, ranging from 25% to 82%. Ecological comparisons revealed substantial increases in HPV vaccination during this time period, and more modest reductions in cervical cancer screening and sexual risk behaviors., Conclusions: The age and cohort patterns in our data suggest that declines in CIN2+ during 2008-2015 are more likely driven by HPV vaccination, introduced in 2006, than by changes in screening or risk behavior., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

Objective: To evaluate whether quadrivalent human papillomavirus vaccine (4vHPV) administered during the periconceptional period or during pregnancy was associated with increased risks for adverse obstetric events, adverse birth outcomes, or selected major structural birth defects., Methods: We conducted a retrospective, observational cohort study using administrative and health care data from the Vaccine Safety Datalink. Insured women 13-27 years old with singleton pregnancies and a live birth from January 1, 2007, through September 1, 2013, who received 4vHPV during the periconceptional period (2 weeks before to 2 weeks after their last menstrual period), during pregnancy, or during both periods combined were compared with women who had a live birth during the same time period and received 4vHPV 4-18 months before their last menstrual period. We examined risks of gestational diabetes, hypertensive disorders of pregnancy, chorioamnionitis, preterm birth, small-for-gestational-age birth, and selected major structural birth defects in offspring. We estimated relative risks associated with receipt of 4vHPV during the periconceptional period, during pregnancy, and both exposure periods combined using a generalized linear model with Poisson distribution including a propensity score that included relevant maternal demographic and pregnancy characteristics., Results: Of 92,579 potentially eligible pregnant women, 720 received 4vHPV during the periconceptional period, 638 received 4vHPV during pregnancy, and 8,196 received 4vHPV during the comparison period. Administration of 4vHPV during pregnancy was not associated with increased risk of adverse obstetric events, birth outcomes. Preterm birth occurred in 7.9% of pregnancies with vaccine exposures during pregnancy compared with 7.6% of pregnancies with vaccination in the comparison period (adjusted relative risk 0.97, 95% CI 0.72-1.3). Major structural birth defects were diagnosed in 2.0% of pregnancies with vaccine exposure during pregnancy compared with 1.8% of pregnancies with vaccine exposure during the comparison period (adjusted prevalence ratio 1.0, 95% CI 0.52-1.9). Results were similar for 4vHPV exposure during the periconceptional period., Conclusion: Quadrivalent HPV vaccine inadvertently administered in pregnancy or during the periconceptional period was not associated with adverse pregnancy or birth outcomes.

Objective: Due to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+)., Methods: We report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials' end., Results: During the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88)., Conclusions: Ten years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects., Trial Registration Number: NCT01393470., Competing Interests: Competing interests: DA, ML, JP and JD have received grants from GSK group of companies and/or Merck & Co. Inc. through their employers (DA, Family Federation Finland; ML; University of Tampere; JP and PN University of Helsinki; JD and ML, Karolinska Institute) for HPV vaccination studies. GD was and FS is employee of GSK group of companies. FS has received shares and stock options from the GSK group of companies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%-23.8% for LSIL, and 19.0%-32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases.

Objective: To determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy., Design: A two-centre observational study including vaccinated and unvaccinated women., Setting: Colposcopy clinics serving two health regions in Scotland, UK., Population: A total of 361 women aged 20-25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening., Methods: Cervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi-square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features., Main Outcome Measures: Colposcopic features, HPV genotypes, mRNA expression, and cervical histology., Results: The prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated)., Conclusions: In this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch-up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines., Tweetable Abstract: Reduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Background: Dysplasia may progress because of a loss to follow-up after an abnormal cervical cytology. Approximately 18% of Danish women postpone the recommended follow-up, which depends on the cytology results., Aim: To investigate if a reminder to the GP about missed follow-up could reduce the proportion of women who fail to act on a recommended follow-up, and to analyse the effect on sociodemographic and general practice variations., Design and Setting: A national electronic GP reminder system was launched in Denmark in 2012 to target missed follow-up after screening, opportunistic testing, or surveillance indication. The authors compared follow-up proportions in a national observational before-after study., Method: From national registries, 1.5 million cervical cytologies (from 2009 to 2013) were eligible for inclusion. Approximately 10% had a recommendation for follow-up. The proportion of cervical cytologies without follow-up was calculated at different time points. Results were stratified by follow-up recommendations and sociodemographic characteristics, and changes in practice variation for follow-up were analysed., Results: Fewer women with a recommendation for follow-up missed follow-up 6 months after a GP reminder. Follow-up improved in all investigated sociodemographic groups (age, ethnicity, education, and cohabitation status). Interaction was found for age and cohabitation status. Variation between practices in loss to follow-up was significantly reduced., Conclusion: An electronic GP reminder system showed potential to improve the quality of cervical cancer screening through reduced loss to follow-up., (© British Journal of General Practice 2017.)

Pre-adolescent girls (9-15years) have the option of receiving a two dose HPV vaccine series at either a six month or one year interval to provide protection from HPV 16, the most prevalent type associated with cervical cancers, as well as several other less prevalent types. This series of vaccinations is highly likely to protect her from HPV infection until she enters the routine screening program, whether that be primary HPV testing or a combination of HPV testing and cytology. The two dose program has been recommended by the World Health Organization (WHO) since 2015. For women 15years and older, the three dose vaccine schedule is still recommended. The past ten years of Gardasil use has provided evidence of reduced HPV 16/18 infections in countries where there has been high coverage. Gardasil9 has replaced Gardasil. Gardasil9 has the same rapid anti-HPV 18 and HPV45 titer loss as Gardasil did. Cervarix remains equivalent to Gardasil9 in the prevention of HPV infections and precancers of any HPV type; Cervarix also has demonstrated sustained high antibody titers for at least 10years. One dose of Cervarix provides protection against HPV 16/18 infection with robust antibody titers well above natural infection titers. This may offer the easiest and most cost effective vaccination program over time, especially in low and lower middle income countries. Cervical cancer screening must continue to control cancer incidence over the upcoming decades. Future studies of prophylactic HPV vaccines, as defined by the WHO, must demonstrate protection against six month type specific persistent infections, not actual cervical cancer precursor disease endpoints, such as cervical intraepithelial neoplasia grade 3 (CIN 3) or adenocarcinoma in situ (AIS). This simplifies and makes less expensive future comparative studies between existing and new generic vaccines., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

The problem of cervical cancer in low- and lower-middle-income countries (LLMICs) is both urgent and important, and calls for governments to move beyond pilot testing to population-based screening approaches as quickly as possible. Experiences from Zambia, Bangladesh, Guatemala, Honduras, and Nicaragua, where scale-up of evidence-based screening strategies is taking place, may help other countries plan for large-scale implementation. These countries selected screening modalities recommended by the WHO that are within budgetary constraints, improve access for women, and reduce health system bottlenecks. In addition, some common elements such as political will and government investment have facilitated action in these diverse settings. There are several challenges for continued scale-up in these countries, including maintaining trained personnel, overcoming limited follow-up and treatment capacity, and implementing quality assurance measures. Countries considering scale-up should assess their readiness and conduct careful planning, taking into consideration potential obstacles. International organizations can catalyze action by helping governments overcome initial barriers to scale-up., (© 2017 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: To evaluate the cost-effectiveness of human papillomavirus (HPV) DNA testing (versus Papanicolaou (Pap)-based screening) for cervical cancer screening in Nicaragua., Design: A previously developed Monte Carlo simulation model of the natural history of HPV infection and cervical cancer was calibrated to epidemiological data from Nicaragua. Cost data inputs were derived using a micro-costing approach in Carazo, Chontales and Chinandega departments; test performance data were from a demonstration project in Masaya department., Setting: Nicaragua's public health sector facilities., Participants: Women aged 30-59 years., Interventions: Screening strategies included (1) Pap testing every 3 years, with referral to colposcopy for women with an atypical squamous cells of undetermined significance or worse result ('Pap'); (2) HPV testing every 5 years, with referral to cryotherapy for HPV-positive eligible women (HPV cryotherapy or 'HPV-Cryo'); (3) HPV testing every 5 years, with referral to triage with visual inspection with acetic acid (VIA) for HPV-positive women ('HPV-VIA'); and (4) HPV testing every 5 years, with referral to Pap testing for HPV-positive women ('HPV-Pap')., Outcome Measures: Reduction in lifetime risk of cancer and incremental cost-effectiveness ratios (ICER; 2015 US$ per year of life saved (YLS))., Results: HPV-based screening strategies were more effective than Pap testing. HPV-Cryo was the least costly and most effective strategy, reducing lifetime cancer risk by 29.5% and outperforming HPV-VIA, HPV-Pap and Pap only, which reduced cancer risk by 19.4%, 12.2% and 10.8%, respectively. With an ICER of US$320/YLS, HPV-Cryo every 5 years would be very cost-effective using a threshold based on Nicaragua's per capita gross domestic product of US$2090. Findings were robust across sensitivity analyses on test performance, coverage, compliance and cost parameters., Conclusions: HPV testing is very cost-effective compared with Pap testing in Nicaragua, due to higher test sensitivity and the relatively lower number of visits required. Increasing compliance with recommended follow-up will further improve the health benefits and value for public health dollars., Competing Interests: Competing interests: JJ was the director of the START-UP demonstration projects and received all tests used in the study as a donation from Qiagen; no other relationships or activities that could appear to have influenced the submitted work. JJ was the co-owner and Deputy Manager of Onco Prev International, a Peruvian company, from 2012 through March 2017. Onco Prev International offers cervical cancer screening services and in 2016 also began positioning for distribution of medical devices including colposcopes and the Liger thermocoagulator. Onco Prev International did not commercialize any medical instrument during the time JJ was part of the company., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: To evaluate clinician and patient attitudes toward home self-collected human papillomavirus (HPV) testing for cervical cancer screening., Methods: Women aged 21-65 years were recruited for a randomized trial comparing home self-collected HPV testing to standard clinician-collected Pap screening. Participants were surveyed about their attitudes toward self-collected HPV testing. Clinicians performing cervical cancer screening in University of Washington medical clinics were also surveyed to determine their acceptability of self-collected HPV testing., Results: Over half (59.1%) of the 1,769 women surveyed preferred self-collected HPV testing to clinician-collected tests. Reasons most often cited were convenience or time saving (82.7%), and avoiding embarrassment or discomfort associated with pelvic exam (38.1%). Women who did not prefer self-collected HPV testing reported greater faith in clinician-collected samples (56.7%) or a desire for a clinic visit to address other issues (42.4%). One hundred eighteen (49.6%) of 238 physicians and midlevel providers surveyed completed the survey. The majority (78.0%) reported that they would recommend a self-collected HPV test if the test had qualities such as high sensitivity and cost effectiveness. Provider concerns mirrored those of patients, namely ensuring adequate sample collection and the opportunity to address other health concerns., Conclusion: Patients and clinicians are supportive of self-collected HPV testing. However, concerns regarding adequacy of samples that are self collected and the desire to see a provider in a clinic setting for other health needs highlight areas that need to be addressed if self collection proves to be a viable option for cervical cancer screening.

Importance: A substantial effect of human papillomavirus (HPV) vaccines on reducing HPV-related cervical disease is essential before modifying clinical practice guidelines in partially vaccinated populations., Objective: To determine the population-based cervical intraepithelial neoplasia (CIN) trends when adjusting for changes in cervical screening practices that overlapped with HPV vaccination implementation., Design, Setting, and Participants: The New Mexico HPV Pap Registry, which captures population-based estimates of both cervical screening prevalence and CIN, was used to compute CIN trends from January 1, 2007, to December 31, 2014. Under New Mexico Administrative Code, the New Mexico HPV Pap Registry, a statewide public health surveillance program, receives mandatory reporting of all cervical screening (cytologic and HPV testing) and any cervical, vulvar, and vaginal histopathological findings for all women residing in New Mexico irrespective of outcome., Main Outcome Measures: Prespecified outcome measures included low-grade CIN (grade 1 [CIN1]) and high-grade CIN (grade 2 [CIN2] and grade 3 [CIN3])., Results: From 2007 to 2014, a total of 13 520 CIN1, 4296 CIN2, and 2823 CIN3 lesions were diagnosed among female individuals 15 to 29 years old. After adjustment for changes in cervical screening across the period, reductions in the CIN incidence per 100 000 women screened were significant for all grades of CIN among female individuals 15 to 19 years old, dropping from 3468.3 to 1590.6 for CIN1 (annual percentage change [APC], -9.0; 95% CI, -12.0 to -5.8; P < .001), from 896.4 to 414.9 for CIN2 (APC, -10.5; 95% CI, -18.8 to -1.2; P = .03), and from 240.2 to 0 for CIN3 (APC, -41.3; 95% CI, -65.7 to 0.3; P = .05). Reductions in the CIN2 incidence were also significant for women 20 to 24 years old, dropping from 1027.7 to 627.1 (APC, -6.3; 95% CI, -10.9 to -1.4; P = .02)., Conclusions and Relevance: Population-level decreases in CIN among cohorts partially vaccinated for HPV may be considered when clinical practice guidelines for cervical cancer screening are reassessed. Evidence is rapidly growing to suggest that further increases in raising the age to start screening are imminent, one step toward integrating screening and vaccination.

Objective: To investigate the clinical and economic impacts of school-based administration of the quadrivalent HPV vaccine., Methods: A retrospective health-economic analysis was conducted using data collected in Singapore between 2004 and 2005. A dynamic transmission model was adapted for universal vaccination that provided 80% coverage among students aged 11-12 years. Strategy 1 involved only girls, with a 5-year catch-up vaccination to provide 50% coverage among those aged 13-17 years. Strategy 2 included both girls and boys with no catch-up vaccination. Outcomes included the predicted incidence of HPV-related disease over 100 years., Results: Current coverage was assumed to be 5%. Strategy 1 would reduce cervical intraepithelial neoplasia grade 1 (CIN1) by 63.8%, cervical intraepithelial neoplasia grade 2-3 (CIN2-3) by 62.9%, cervical cancer by 50.9%, and genital warts by 78.0% (female individuals) and 73.6% (male individuals). Strategy 2 would reduce CIN1 by 64.0%, CIN2-3 by 63.1%, cervical cancer by 50.7%, and genital warts by 79.9% (female individuals) and 80.1% (male individuals). The incremental cost-effectiveness ratio was S$12 464 for strategy 1 and $27 837 for Strategy 2. These values decreased to $7477 and $22 574, respectively, if a two-dose regimen was adapted., Conclusion: School-based quadrivalent HPV vaccination offered clinical and economic benefits, and is cost-effective in Singapore., (© 2017 International Federation of Gynecology and Obstetrics.)

Cervical cancer is a serious public-health problem in Asian countries. Since human papillomavirus (HPV) infection is the main risk factor for cervical cancer, HPV vaccination is considered a promising strategy to prevent cervical cancer. However, comprehensive immunogenicity and safety information for Asian populations is lacking. We searched four electronic databases including PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov. We reviewed selected manuscripts and extracted the pooled relative risk (RR) from immunogenicity and safety information on HPV vaccination among women in Asian countries. We identified two quadrivalent-vaccine studies and eight bivalent-vaccine studies conducted in Asian countries. Analysis across these studies suggested that the HPV vaccines significantly enhanced HPV16- and HPV18-specific antibody among both uninfected (RR 85.69; 95% confidence interval (CI) 31.51-233.04 and 62.77; 95% CI 37.4-105.51) and infected individuals (RR 8.60; 95% CI 6.95-10.64 and RR 8.13; 95% CI 5.96-11.11). Furthermore, HPV vaccination among Asian populations has a favorable safety profile, with only slightly higher risks of local (RR: 1.89; 95% CI 1.65-2.17) and systemic (RR: 1.33; 95% CI 1.18-1.50) adverse events in vaccinated individuals compared with controls. For Asian populations, HPV vaccines enhance the level of HPV16- and HPV18-specific antibodies for both uninfected and infected individuals. Also, the risk of adverse events related to vaccination are acceptable. More data are needed to establish vaccine efficacy with regard to prevention of HPV infection and further outcomes including cervical intraepithelial neoplasia (CIN) and cervical cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: The aim of this study is to determine the impact of visual inspection with acetic acid (VIA) plus immediate cryotherapy on the prevalence of VIA-detected cervical squamous intraepithelial lesion (SIL)., Methods: Women in four rural communities in Southeast Nigeria were screened with VIA. Women who tested positive to VIA were offered either immediate cryotherapy or large loop excision of the transformation zone based on predetermined eligibility criteria. Cervical biopsies were taken before cryotherapy and examined by consultant histopathologists. All participants were rescreened 1 year later. The main outcome measures were population prevalence of cervical precancers before and after intervention, cure rates, and over-treatment rates., Results: A total of 653 women participated in the study. The prevalence of cervical SIL before the intervention was 8.9% (58/653). The prevalence 1 year later was 1.4% (9/649). This gave an 84.3% reduction in the population prevalence of SIL. The reduction in cervical SIL prevalence was statistically significant (P = 0.0001). The prevalence of high-grade SIL reduced significantly from 4.1% (27/653) preintervention to 0.5% (3/649) 1 year postintervention (P = 0.0001). This gave an 87.8% reduction in the population prevalence of high-grade SIL. Cryotherapy provided a cure rate of 87.9% (95% confidence interval: 76.82-94.33)., Conclusion: Population cervical cancer prevention using VIA plus immediate cryotherapy leads to significant reduction in the population prevalence of cervical SIL. This has the potential of being an acceptable supplement to cervical cytology for cervical cancer prevention in low-income populations.

Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs)., Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided., Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70., Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.)

We conducted a cross-sectional study on the occurrence of a specific type of genital human papillomavirus (HPV) among long-term monogamous male partners of women with cervical dysplasia and genital warts. The purpose of the study was to improve knowledge with regards to the management of these couples. The presence of genital HPV-DNA was detected by PCR with broad spectrum primers followed by hybridization. 82 males met the study criteria, 41 in each group. Genital HPV-DNA prevalence was 67.5% in the genital warts group and 72.2% in the cervical dysplasia group. The prevalence of high risk HPVs was higher in the cervical dysplasia group, while low risk HPVs were more prevalent in the genital warts group (p < .05). The prevalence of HPV in males was independent of the duration of the relationship (73.5% for 6-24 months and 66.7% for longer relationships). In conclusion, our results suggest that the prevalence of the genital HPV infection in both groups of male partners is comparable and very high, but the spectrum of HPV types varies significantly. The presence of the genital HPV infection in male sexual partners seems to be independent of the duration of the relationship. Applying the HPV vaccination to boys may prevent this phenomenon., (© 2016 Wiley Periodicals, Inc.)

Two groundbreaking reports were published in Acta Cytologica at the transition of 1976 to 1977. One appeared in the last issue of 1976 [Meisels and Fortin: Acta Cytol 1976;20:505-509] and the other in the first issue of 1977 [Purola and Savia: Acta Cytol 1977;21:26-31]. Today, 40 years later, it is not an overstatement to conclude that these are the two most influential studies ever published in this journal. Two reports with a similar content being published so close together (in the same journal) raised the question "Which of the two reports was truly submitted first?" In this commentary, this enigma is clarified beyond reasonable doubt, based on the well-considered testimonial of Prof. Leopold G. Koss, the reviewer of one of the two papers. To fully appreciate the significance of the novel discovery made in these two reports, it is essential to align them in the right context, both retrospectively and prospectively. This commentary will assist the reader by summarizing the existing knowledge on human papillomavirus (HPV) before these two milestone papers appeared, and describe the incredibly rapid progress that they evoked during the subsequent decades, which made HPV the single most important human tumor virus. As the final proof of virus-cancer causality, prophylactic HPV vaccines have been effective in preventing (a) virus transmission and HPV infection, (b) benign HPV-induced tumors (genital warts), and (c) cervical intraepithelial neoplasia (CIN). Formal evidence of the prevention of cervical cancer by these HPV vaccines still awaits confirmation, and the same applies to the eventual prevention of human cancers at other anatomic sites, part of the global burden of oncogenic HPVs., (© 2017 S. Karger AG, Basel.)

The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16-26years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To provide a scientific basis for the prevention and treatment of cervical intraepithelial neoplasia grade 1 (CIN1). This study evaluated the impact of human papillomavirus (HPV) infection on the natural history of CIN1., Methods: Electronic databases of Cochrane Library, EMBASE, PubMed, CNKI, CBM, and Wanfang were searched in April 2016. The eligibility criteria were documented by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We used the Newcastle-Ottawa scale (NOS) to assess study quality., Results: Thirty-eight studies out of 3,246 identified papers were eligible for inclusion. The risk of CIN1 progression (relative risk [RR]: 3.04; 95% confidence interval [CI]: 2.41-3.83; P < 0.00001) and persistence (RR: 1.48; 95% CI: 1.17-1.87; P = 0.001) was higher in the HPV-positive group than HPV-negative group. Specifically, the risk of CIN1 progression (RR: 13.91; 95% CI: 3.46-55.90; P = 0.000) was higher among persistent high-risk HPV-positive patients and the ratio of CIN1 regression (RR: 0.65; 95% CI: 0.59-0.71; P < 0.00001) was lower in the HPV-positive group than HPV-negative group., Conclusion: HPV infection resulted in an increased risk of CIN1 progression and decreased disease reversibility. Persistent high-risk HPV infection resulted in a further increased risk of CIN1 progression.

We examined spatial variations in the frequencies of women who had not heard of human papillomavirus vaccination (NHrd-Vac) and who had not had Pap testing (NHd-Pap) among Colombian administrative divisions (departments), before and after considering differences in socio-demographic factors. Following global and local tests for clustering, Bayesian Poisson hierarchical models identified department factors associated with NHrd-Vac and NHd-Pap, as well as the extent of the spatially structured and unstructured heterogeneity. Models of spatial variations for both outcomes included the department percentage of women with subsidised health insurance. The relative risks of NHrd-Vac and NHd-Pap were highest in several departments adjacent to the Colombian border. Our finding that the risk of not having adequate access to cervical cancer (CC) prevention programmes in Colombia was location-dependent, could be used to focus resources for CC prevention programmes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Objectives: A randomized trial was conducted in Tuscany, Italy, to evaluate the effectiveness of HPV vaccination for 25year old (yo) women who attend at the first time cervical cancer screening. The trial also evaluated immune response after vaccination, reductions of cytological abnormalities and the impact of vaccination on screening activity., Study Design: During 2010-2011, all 25 yo women who were invited to the Florence cervical cancer screening programme were also asked to participate in the trial. Enrolled women were randomized into study and control groups. Those in the study group were offered HPV vaccination after the usual Pap test. The cytology distribution and prevalence for any high risk (hr) HPV type were compared at the subsequent screening round in an intention-to-treat analysis. The impact of HPV vaccination was evaluated per protocol comparing vaccinated women with the control group., Results: Our results showed a reduction in HPV prevalence at recall for any hr-HPV type but it was not statistically significant, being 17.1% vs 21.4%, p=0.20 in the study and control groups, respectively. If we restricted the analysis to vaccinated women, strong reductions of the HPV 16,18,31,33,45 and HPV 31,33,45 infections were observed, being 5.3% vs 12.8%, p<0.01 and 2.1% vs 6.5%, p=0.02, respectively. Significant reductions for any hr-HPV infection and for HPV 16 infection were also observed in women HPV 16/18 negative at enrolment, being 12% vs 21.4%, p<0.01 and 0.6% vs 6.7%, p-value<0.01, respectively. In women hr-HPV negative at enrolment no infections due to HPV 16 or HPV 18 were observed and there was a big reduction for any hr-HPV infection (7.1% vs 21.4% p<0.01). A strong antibody response was observed not only for HPV 16 & 18 but also for their related types., Conclusions: Our findings suggest that HPV vaccination at the age 25 is beneficial if it is offered to hr-HPV negative women. Our data will assist in developing a cost effectiveness model for choosing the best strategy to integrate screening and vaccination for the coming years. Clinical trial registration number is NCT02296255., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: The incidence of cervical cancer is up to 20-fold higher among First Nations women in Canada than the general population, probably due to lower participation in screening. Offering human papillomavirus (HPV) self-sampling in place of Papanicolaou (Pap) testing may eventually increase screening participation and reduce cervical cancer rates in this population., Design: A community-randomised controlled screening trial., Setting: First Nations communities in Northwest Ontario, Canada., Participants: Women aged between 25 and 69, living in Robinson Superior Treaty First Nations. The community was the unit of randomisation., Interventions: Women were asked to complete a questionnaire and have screening by HPV self-sampling (arm A) or Pap testing (arm B)., Primary Outcome Measures: The number of women who participated in cervical screening., Randomisation: Community clusters were randomised to include approximately equivalent numbers of women in each arm., Results: 6 communities were randomised to arm A and 5 to arm B. One community withdrew, leaving 5 communities in each group (834 eligible women). Participation was <25%. Using clustered intention-to-treat (ITT) analysis, initial and cumulative averaged uptakes in arm A were 1.4-fold (20% vs 14.3%, p=0.628) and 1.3-fold (20.6% vs 16%, p=0.694) higher compared to arm B, respectively. Corresponding per protocol (PP) analysis indicates 2.2-fold (22.9% vs 10.6%, p=0.305) and 1.6-fold (22.9% vs 14.1%, p=0.448) higher uptakes in arm A compared to arm B. Screening uptake varied between communities (range 0-62.1%). Among women who completed a questionnaire (18.3% in arm A, 21.7% in arm B), the screening uptake was 1.8-fold (ITT; p=0.1132) or 3-fold (PP; p<0.01) higher in arm A versus arm B., Conclusions: Pap and HPV self-sampling were compared in a marginalised, Canadian population. Results indicated a preference for self-sampling. More research on how to reach underscreened Indigenous women is necessary., Trial Registration Number: ISRCTN84617261., Competing Interests: The ACCSS team received support from Roche Diagnostics (RD) for the HPV analyses of the self-collected samples. However, RD was not involved with the study design, the analyses or the writing of the manuscript., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening. In 1975, the rate was 14.8 per 100,000 women. By 2011, it decreased to 6.7 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.3 per 100,000 women in 2011 (1). The American Cancer Society (ACS) estimated that there would be 12,900 new cases of cervical cancer in the United States in 2015, with 4,100 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 527,624 new cases of the disease and 265,672 resultant deaths each year (3). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (4, 5).New technologies for cervical cancer screening continue to evolve, as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. In 2011, the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) updated their joint guidelines for cervical cancer screening (6), as did the U.S. Preventive Services Task Force (USPSTF) (7). Subsequently, in 2015, ASCCP and the Society of Gynecologic Oncology (SGO) issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening for cervical cancer that was approved in 2014 by the U.S. Food and Drug Administration (FDA) (8). The purpose of this document is to provide a review of the best available evidence regarding the prevention and early detection of cervical cancer.

The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening. In 1975, the rate was 14.8 per 100,000 women. By 2011, it decreased to 6.7 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.3 per 100,000 women in 2011 (1). The American Cancer Society (ACS) estimated that there would be 12,900 new cases of cervical cancer in the United States in 2015, with 4,100 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 527,624 new cases of the disease and 265,672 resultant deaths each year (3). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (4, 5).New technologies for cervical cancer screening continue to evolve, as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. In 2011, the ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) updated their joint guidelines for cervical cancer screening (6), as did the U.S. Preventive Services Task Force (USPSTF) (7). Subsequently, in 2015, ASCCP and the Society of Gynecologic Oncology (SGO) issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening for cervical cancer that was approved in 2014 by the U.S. Food and Drug Administration (FDA) (8). The purpose of this document is to provide a review of the best available evidence regarding the prevention and early detection of cervical cancer.

Human papillomavirus (HPV) is a common infection in kidney transplant recipients. HPV causes cervical, anal, vulvar, vaginal, penile and head and neck cancers. Kidney transplant recipients have a disproportionate burden of disease given prolonged immunosuppression. Given the long pre-invasive state of precancer lesions such as cervical intraepithelial neoplasia (CIN) and anal intraepithelial neoplasia (AIN) most HPV-cancers are preventable with screening and targeted treatment of disease. Pre-transplant vaccination of age-eligible kidney transplant recipients is otherwise ideal., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Human papillomavirus (HPV) vaccination within a nonorganized setting creates a poor cost-effectiveness scenario. However, framed within an organized screening including primary HPV DNA testing with lengthening intervals may provide the best health value for invested money. To compare the effectiveness and cost-effectiveness of different cervical cancer (CC) prevention strategies, including current status and new proposed screening practices, to inform health decision-makers in Spain, a Markov model was developed to simulate the natural history of HPV and CC. Outcomes included cases averted, life expectancy, reduction in the lifetime risk of CC, life years saved, quality-adjusted life years (QALYs), net health benefits, lifetime costs, and incremental cost-effectiveness ratios. The willingness-to-pay threshold is defined at 20 000&OV0556;/QALY. Both costs and health outcomes were discounted at an annual rate of 3%. A strategy of 5-year organized HPV testing has similar effectiveness, but higher efficiency than 3-year cytology. Screening alone and vaccination combined with cytology are dominated by vaccination followed by 5-year HPV testing with cytology triage (12 214&OV0556;/QALY). The optimal age for both ending screening and switching age from cytology to HPV testing in older women is 5 years later for unvaccinated than for vaccinated women. Net health benefits decrease faster with diminishing vaccination coverage than screening coverage. Primary HPV DNA testing is more effective and cost-effective than current cytological screening. Vaccination uptake improvements and a gradual change toward an organized screening practice are critical components for achieving higher effectiveness and efficiency in the prevention of CC in Spain.

Background: Screening reduces cervical cancer incidence and mortality., Objective: To describe cervical cancer epidemiology and screening guidelines in six low- and middle-income countries (LMICs) participating in the Study on global AGEing and adult health (SAGE)., Search Strategy: Incidence, mortality, and screening-rate data were obtained for six LMICs and three higher-income comparator countries (Australia, USA, and UK). SCOPUS and PubMed were used to identify literature published after 2000 in English, using several screening-linked terms., Selection Criteria: Literature describing the use of cervical cancer screening guidelines in China, Ghana, India, Mexico, Russia, and South Africa were included., Data Collection and Analysis: Incidence, mortality trends, and screening rates were graphed and screening recommendations were summarized., Main Results: Higher rates of cervical cancer incidence, mortality, and 5-year prevalence were found in LMICs compared with the comparator countries. LMICs with absent or newly implemented screening guidelines had the lowest rates of crude and effective cervical cancer screening, with high cancer incidence and mortality. Countries with established guidelines had higher screening rates and lower disease burden. Cost, inadequate knowledge, geographical location, and cultural views were common barriers to effective screening coverage., Conclusion: Work must continue to improve the implementation of affordable, relevant, and achievable methods to improve screening coverage in LMICs., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood., Objectives: To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions., Study Design: We included 1711 women (18-25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated., Results: Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively., Conclusion: We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies., (Published by Elsevier Inc.)