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Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. Women aged 29–56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (≥6·5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15–151; p=0·007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28–72; p=0·001). The number of CIN3+ lesions over the two rounds did not differ between groups. The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

AbstractObjectiveTo quantify the effect on cervical disease at age 20 years of immunisation with bivalent human papillomavirus (HPV) vaccine at age 12-13 years.DesignRetrospective population study, 1988-96.SettingNational vaccination and cervical screening programmes in Scotland.Participants138 692 women born between 1 January 1988 and 5 June 1996 and who had a smear test result recorded at age 20.Main outcome measuresEffect of vaccination on cytology results and associated histological diagnoses from first year of screening (while aged 20), calculated using logistic regression.Results138 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.ConclusionsRoutine 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.

Objectives To provide an early risk assessment of extending screening intervals beyond five years for a human papillomavirus (HPV) based cervical screening programme in the Netherlands.Design 14 year follow-up of a population based randomised cohort from the POBASCAM randomised trial. Setting Organised cervical screening in the Netherlands, based on a programme of three screening rounds (each round done every five years).Participants 43 339 women aged 29-61 years with a negative HPV and/or negative cytology test participating in the POBASCAM trial. Interventions Women randomly assigned to HPV and cytology co-testing (intervention) or cytology testing only (control), and managed accordingly.Main outcome measures Cumulative incidence of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+). Associations with age were expressed as incidence rate ratios. In HPV positive women, reductions in CIN3+ incidence after negative cytology, HPV type 16/18 genotyping, and/or repeat cytology were estimated.Results The cumulative incidence of cervical cancer (0.09%) and CIN3+ (0.56%) among HPV negative women in the intervention group after three rounds of screening were similar to the cumulative among women with negative cytology in the control group after two rounds (0.09% and 0.69%, respectively). Cervical cancer and CIN3+ risk ratios were 0.97 (95% confidence interval 0.41 to 2.31, P=0.95) and 0.82 (0.62 to 1.09, P=0.17), respectively. CIN3+ incidence was 72.2% (95% confidence interval 61.6% to 79.9%, P<0.001) lower among HPV negative women aged at least 40 years than among younger women. No significant association between cervical cancer incidence and age could be demonstrated. CIN3+ incidence among HPV positive women with negative cytology, HPV 16/18 genotyping, and/or repeat cytology was 10.4 (95% confidence interval 5.9 to 18.4) times higher than among HPV negative women.Conclusions Long term incidences of cervical cancer and CIN3+ were low among HPV negative women in this study cohort, and supports an extension of the cervical screening interval beyond five years for women aged 40 years and older. HPV positive women with subsequent negative cytology, HPV16/18 genotyping, and/or repeat cytology have at least a fivefold higher risk of CIN3+ than HPV negative women, indicating that HPV based programmes with long intervals (>five years) should be implemented with risk stratification.Trial registration POBASCAM trial number ISRCTN20781131.

AbstractObjectiveTo evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women.DesignUpdated meta-analysis.Data sourcesMedline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review).Review methodsAccuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women.Results56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman’s home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I2>95%).ConclusionsWhen used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.

Australia introduced a human papillomavirus (HPV) vaccination programme with the quadrivalent HPV vaccine for all women aged 12–26 years between 2007 and 2009. We analysed trends in cervical abnormalities in women in Victoria, Australia, before and after introduction of the vaccination programme. With data from the Victorian Cervical Cytology Registry between 2003 and 2009, we compared the incidence of histopathologically defined high-grade cervical abnormalities (HGAs, lesions coded as cervical intraepithelial neoplasia of grade 2 or worse or adenocarcinoma in situ; primary outcome) and low-grade cytological abnormalities (LGAs) in five age groups before (Jan 1, 2003, to March 31, 2007) and after (April 1, 2007, to Dec 31, 2009) the vaccination programme began. Binary comparisons between the two periods were done with Fisher's exact test. Poisson piecewise regression analysis was used to compare incident rate trends. After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0·38% (95% CI 0·61–0·16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1·14, 1·00–1·30, p=0·05). No similar temporal decline was recorded for LGAs or in older age groups. This is the first report of a decrease in incidence of HGAs within 3 years after the implementation of a population-wide HPV vaccination programme. Linkage between vaccination and screening registers is needed to confirm that this ecological observation is attributable to vaccination and to monitor participation in screening among vaccinated women. None.

Screening for cervical cancer is not a component of health care in rural India. This article reports on a trial of cervical-cancer screening by human papillomavirus (HPV) testing, cytologic analysis, or visual inspection of the cervix with acetic acid in rural villages. The results, as compared with those in a group that received no screening, showed that a single round of HPV testing significantly reduced the incidence of invasive cervical cancer and mortality in rural Indian villages. A trial in rural Indian villages of cervical-cancer screening by human papillomavirus (HPV) testing, cytologic analysis, or visual inspection of the cervix with acetic acid showed that a single round of HPV testing significantly reduced the incidence of invasive cervical cancer and mortality. In developing countries, there is a lack of effective screening programs for cervical cancer. In these countries, no clinically significant reduction in the incidence of cervical cancer has occurred during the past three decades. 1 – 4 In developed countries, by contrast, there has been a major decline in cervical-cancer mortality after the introduction of large-scale cytologic testing. The limited success of such screening in developing countries has stimulated evaluation of testing for human papillomavirus (HPV) and visual inspection of the cervix with acetic acid (VIA). In October 1999, we initiated a cluster-randomized, controlled trial to evaluate the effectiveness of a single . . .

Abstract Background Vaginal dysbiosis characterized by depleted lactobacilli is usually correlated with human papillomavirus (HPV) infection and cervical carcinogenesis, but the effect of the Lactobacillus genus and represented species on this process remains unclear. Methods PubMed, EMBASE, and CENTRAL databases were searched up to February 15, 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effect model and Review Manager (version 5.3) for Mac. Results Eleven studies comprising 1230 cases were included. Lactobacillus spp. was associated with the decreased detection of high-risk subtype (hr)HPV infection (OR = 0.64, 95% CI = 0.48–0.87, I2 = 6%), cervical intraepithelial neoplasia (CIN) (OR = 0.53, 95% CI = 0.34–0.83, I2 = 0%), and cervical cancer (CC) (OR = 0.12, 95% CI = 0.04–0.36, I2 = 0%). At the level of Lactobacillus species, Lactobacillus crispatus, but not Lactobacillus iners, was correlated with the decreased detection of hrHPV infection (OR = 0.49, 95% CI = 0.31–0.79, I2 = 10%) and CIN (OR = 0.50, 95% CI = 0.29–0.88, I2 = 0%). Conclusions Cervicovaginal Lactobacillus spp. is associated with the decreased detection of hrHPV infection, CIN, and CC; L. crispatus may be the critical protective factor.

Background Human papillomavirus (HPV) vaccination is predicted to lower the positive predictive value (PPV) of cytology. Methods We included 153,250 girls born between 1989 and 1993, resident in Sweden since the introduction of HPV vaccines (October 2006) and attending cervical screening at age 23 years. We assessed their first cytology and following histopathological diagnosis using Swedish National Cervical Screening Registry (NKCx). By linkage with the national Swedish HPV vaccination registry, we determined PPV of abnormal cytology for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the differences with 95% confidence intervals (CIs) according to vaccination status. Results The PPV of high-grade cytology for CIN2+ was 69.9% (95% CI, 67.9–71.9), 64.9% (95% CI, 59.8–69.8) and 57.4% (95% CI, 50.9–63.7) among women unvaccinated, initiating vaccination at age 17–22 years and initiating vaccination before age 17 years, corresponding to reduction in PPV by 8% (95% CI, 0–15%) and 17% (95% CI, 7–26%) in vaccinated groups after adjustment for birth cohort, respectively. Conclusion The PPV of cytology for CIN2+ decreased among vaccinated women, and the decrease was stronger for girls vaccinated at younger ages. A switch from cytology to HPV testing might potentially improve the screening performance.

Background We studied the cases of single and multiple HPV infection and analyzed the correlation with negative cases, and preneoplastic and neoplastic lesions of the uterine cervix with the aim of making a contribution to the prognostic factor under discussion. Methods Nine hundred nine women undergoing second level screening because they had been positive at cervical cytology were enrolled. All the patients underwent colposcopy and cervical biopsy with viral genotyping. We divided mHPV infection based on the number of genotypes present: infections with 2 strains, 3 strains, 4 strains and 5 or more strains. Statistical analysis The analysis of the data was made using the χ2 test. Contingency tables were created to evaluate the correlation between single, multiple and CIN2+ infections. Values with p  < 0.05 were considered statistically significant. Results The presence of genotype HPV16 in our study was associated with a 12 times greater risk of developing a high-grade lesion, OR = 12.70. The patients with single infections had the highest incidence of CIN2+ (34.1%) with respect to those with multiple infections (10.6%).When we studied in the mHPV infection the prevalence of the combinations between the genotypes, we found that in mHPV16 infections, the combinations HPV16, 18 and HPV16, 31 were the most frequent (55.5%) in CIN3 lesion. Conclusions Our results suggest that single HPV infections have a greater risk of developing SCC with respect to multiple infections. Multiple HPV infections are relevant only in the first phase of the lesion (CIN1-CIN2), while they are absent in carcinomas, where infections are of a single genotype. In particular, among multiple infections, HPV16 infection with 2 HR genotypes is associated significantly with CIN2 / CIN3 (21/30) and has 4 times greater risk of developing a high-grade lesion. Thus, it is probable that only specific combinations of HPV (HPV16,18 - HPV 16,31) can be associated with a clinically significant impact, while other combinations can simply be correlated because of a common infection or diagnostic method used. Therefore, multiple HPV16 infections with two high-risk genotypes is a major risk of CIN2/CIN3.

ObjectiveDue 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+).MethodsWe 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.ResultsDuring 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).ConclusionsTen 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 numberNCT01393470.