Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding None.
Abstract Objectives ATHENA evaluated the cobas HPV Test as the primary screen for cervical cancer in women ≥ 25 years. This reports the 3-year end-of-study results comparing the performance of HPV ...primary screening to different screening and triage combinations. Methods 42,209 women ≥ 25 years were enrolled and had cytology and hrHPV testing. Women with abnormal cytology (≥ atypical squamous cells of undetermined significance) and those HPV positive were referred to colposcopy. Women not reaching the study endpoint of CIN2 + entered the 3-year follow-up phase. Results 3-year CIR of CIN3 + in cytology-negative women was 0.8% (95% CI; 0.5–1.1%), 0.3% (95% CI 0.1–0.7%) in HPV-negative women, and 0.3% (95% CI; 0.1–0.6%) in cytology and HPV negative women. The sensitivity for CIN3 + of cytology was 47.8% (95% CI; 41.6–54.1%) compared to 61.7% (95% CI; 56.0–67.5%) for the hybrid strategy (cytology if 25–29 years and cotesting with cytology and HPV if ≥ 30 years) and 76.1% (95% CI; 70.3–81.8%) for HPV primary . The specificity for CIN3 + was 97.1% (95% CI; 96.9–97.2%), 94.6% (95% CI; 94.4–94.8%), and 93.5% (95% CI; 93.3–93.8%) for cytology , hybrid strategy , and HPV primary , respectively. Although HPV primary detects significantly more cases of CIN3 + in women ≥ 25 years than either cytology or hybrid strategy , it requires significantly more colposcopies. However, the number of colposcopies required to detect a single CIN3 + is the same as for the hybrid strategy. Conclusions HPV primary screening in women ≥ 25 years is as effective as a hybrid screening strategy that uses cytology if 25–29 years and cotesting if ≥ 30 years. However, HPV primary screening requires less screening tests.
Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. ...Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+).
This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models.
Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with 5-year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001).
HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia.
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•HPV persistence correlates with an increased risk of 5-year recurrence in women undergoing cervical conization•Patients undergoing laser conization experience a slightly lower risk of recurrence in comparison to LEEP•Further evidence regarding fertility and obstetrical issues is necessary
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.
About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic ...vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8(+) T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNβ), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation.
To estimate the fraction of cervical intraepithelial neoplasia 2 (CIN 2) that might regress if untreated using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous ...Intraepithelial Lesions Triage Study (ALTS).
We compared the cumulative occurrence of CIN 2 (n=397) and CIN 3 or more severe (n=542) diagnosed by the Pathology Quality Control Group in three trial arms-immediate colposcopy, human papillomavirus (HPV) triage, and conservative management-over the 2-year duration of the ALTS trial. A nonparametric test of trend was used to test for differences in the number of CIN 2 cases relative to number of CIN 3 or more severe cases across study arms with an increasing percentage of women referred to colposcopy at baseline.
There were no significant differences in the cumulative 2-year cumulative CIN 3 or more severe diagnoses by study arm (10.9%, conservative management; 10.3%, HPV; 10.9%, immediate colposcopy) (Ptrend=.8), but there was a significant increase in CIN 2 diagnoses (5.8%, conservative management; 7.8%, HPV triage; 9.9%, immediate colposcopy) (Ptrend<.001) in the study arms, with increasing number of women referred to colposcopy at baseline. The relative differences in cumulative CIN 2 by study arm among women who tested HPV-16 positive at baseline were less pronounced (Ptrend=.1) than women who tested positive for other high-risk-HPV genotypes (Ptrend=.01).
There was evidence that approximately 40% of undiagnosed CIN 2 will regress over 2 years, but CIN 2 caused by HPV-16 may be less likely to regress than CIN 2 caused by other high-risk-HPV genotypes.
II.
Specific foods and nutrients help prevent the progression of persistent high-risk human papillomavirus (hrHPV) infection to cervical cancer (CC). The aim of this study was to investigate dietary ...patterns which may be associated with hrHPV status and the risk of high-grade cervical intraepithelial neoplasia (CIN2+). Overall, 539 eligible women, including 127 with CIN2+, were enrolled in a cross-sectional study, and tested for hrHPV infection. Food intake was estimated using a food frequency questionnaire. Logistic regression models were applied. Using the Mediterranean Diet Score, we demonstrated that, among 252 women with a normal cervical epithelium, medium adherence to the Mediterranean diet decreased the odds of hrHPV infection when compared to low adherence (adjOR = 0.40, 95%CI = 0.22-0.73). Using the principal component analysis, we also identified two dietary patterns which explained 14.31% of the variance in food groups intake. Women in the third and fourth quartiles of the "Western pattern" had higher odds of hrHPV infection when compared with first quartile (adjOR = 1.77, 95% CI = 1.04-3.54 and adjOR = 1.97, 95%CI = 1.14-4.18, respectively). Adjusting for hrHPV status and age, women in the third quartile of the "prudent pattern" had lower odds of CIN2+ when compared with those in the first quartile (OR = 0.50, 95%CI = 0.26-0.98). Our study is the first to demonstrate the association of dietary patterns with hrHPV infection and CC and discourages unhealthy habits in favour of a Mediterranean-like diet.
Summary Background We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of ...follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Methods Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov , number NCT00122681. Findings Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7–59·4) in the ATP-E, 56·2% (37·2–69·9) in the TVC-naive, and 34·2% (20·4–45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3–87·9), 91·4% (65·0–99·0), and 47·5% (22·8–64·8). Interpretation Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types—HPV-33, HPV-31, HPV-45, and HPV-51—in different trial cohorts representing diverse groups of women. Funding GlaxoSmithKline Biologicals.
We evaluated the efficacy of the human papillomavirus (HPV)−16/18 AS04‐adjuvanted vaccine in preventing HPV‐related disease after surgery for cervical lesions in a post‐hoc analysis of the PApilloma ...TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15–25 years were randomized (1:1) to receive vaccine or control at months 0, 1 and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV‐16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post‐hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV‐related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post‐surgery. Other outcomes included the incidence of HPV‐related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post‐surgery. Of the total vaccinated cohort of 18,644 women (vaccine = 9,319; control = 9,325), 454 (vaccine = 190, control = 264) underwent an excisional procedure during the trial. Efficacy 60 days or more post‐surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (−21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post‐surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV‐16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+.
What's new?
Persistent infection with oncogenic human papillomavirus (HPV) is a pre‐requisite for cervical cancer, with women who have already undergone treatment for related cervical lesions representing a high‐risk group for the subsequent development of cervical cancer. To date, HPV vaccination is not thought to alter the course of disease in women with prevalent type‐specific infections or pre‐existing lesions at the time of vaccination. This post‐hoc analysis of a randomized controlled trial however shows that women who undergo surgery for cervical lesions after receiving the HPV‐16/18 AS04‐adjuvanted vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent high‐grade cervical disease.
The natural history of human papillomavirus infection de Sanjosé, Silvia; Brotons, Maria; Pavón, Miguel Angel
Best practice & research. Clinical obstetrics & gynaecology,
February 2018, 2018-Feb, 2018-02-00, 20180201, Letnik:
47
Journal Article
Recenzirano
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.
•HPV is a small DNA virus that includes a wide range of types.•Oncogenic types include 12 types that are consistently identified in anogenital tumors in both sexes. E6 and E7 are oncogens.•HPV is a common sexually transmitted infection in the population, and its peak prevalence is early adulthood.•Persistence of infection with high-risk types is the main risk factor for cancer development.
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