Background: The aim of this multicentric study was to identify human papillomavirus (HPV) type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia 2/3 (CIN2/3) in Italy.Methods: Cases were sampled through the electronic databases at the pathology units of eight centers in six regions from central and southern Italy. HPV types were detected from paraffin-embedded tissue samples and cervical specimens through amplification of HPV DNA with GP5+/GP6+ primers, followed by genotyping with reverse line blot (RLB). Untyped HPV-positive samples were sequenced. HPV-negative samples underwent nested PCR, followed by either RLB or sequencing. Finally, the remaining HPV-negative samples were amplified with primers targeting the virus E6 to E7 regions.Results: From 1,162 cases initially selected, 722 samples were further analyzed: 144 CIN2, 385 CIN3, 157 invasive squamous carcinomas, and 36 adenocarcinomas. Samples (6.9%) were HPV negative. The proportion of HPV16/18 was 60.8%, 76.6%, and 78.8% in CIN2, CIN3, and invasive cancers, respectively (P trend = 0.004). There was a significant decreasing trend of HPV16/18 with age in invasive cancers, going from 92% in women <35 years to 73% in women >55 years (P = 0.036). The proportion of coinfections was 16.8%, 15.5%, and 10.0% in CIN2, CIN3, and invasive cancers, respectively (P trend = 0.07).Conclusions: The proportion of invasive cancers caused by HPV16/18 decreases with age at diagnosis. Impact: The absolute risk of an invasive cancer due to non-HPV16/18 in women under 35 is extremely low. This finding might prompt us to rise the age at which public HPV screening for vaccinated women should start. Cancer Epidemiol Biomarkers Prev; 19(9); 2389-400. ©2010 AACR.
The noninferiority score test revealed that the clinical sensitivity and specificity of the Abbott RealTime HR HPV test were not inferior (P ؍ 0.004 and 0.009, respectively) to those of HR HC2. Overall agreement between the two assays was 96.5%, with a k value of 0.86 (CI 95%, 0.82 to 0.91). We evaluated the intralaboratory reproducibility by retesting 521 samples at least 4 weeks after the first test; the crude agreement between the first and second test was 98.5%, with an overall k value of 0.97 (CI 95%, 0.95 to 0.99). This test fully satisfies the requirements of a primary cervical cancer screening test. This assay differentiates between HPV16, HPV18, and non-HPV16/18 types in every specimen, but how to use this information in a screening setting still is unclear.The etiologic link between persistent high-risk human papillomavirus (HR HPV) infections and cervical cancer and its immediate precancerous lesions has been widely demonstrated. A recent IARC classification reports solid evidence for a causal link to cervical cancer for only 12 HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), which are defined as high-risk HPV (2).Large randomized trials produced sound evidence about the efficacy of screening with an HPV DNA test in reducing cervical cancer incidence (19) and mortality (20). According to trial results, an HPV test used as a cervical cancer screening test has three advantages: a higher long-term negative predictive value (NPV) that permits extending the screening interval without increasing the interval risk of cancer, a clinical sensitivity of 90 to 95% for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) (1,3,6,7,13,17,18), and a marked reduction of CIN2/3 and cancer among test-negative women in the subsequent screening round (19).Several studies (12, 21) suggest that infections supported by HPV16 and HPV18 are associated with a higher risk for the progression of cervical cancer. Consequently, the genotyping of HPV16 and HPV18 has been proposed to guide the management of HPV-positive women throughout the follow-up procedures (12). Usually, viral tests are used to understand the etiology of symptomatic diseases. However, the HR HPV test in screening is aimed at preventing cervical cancer in an asymptomatic population, therefore it is useful only when it is able to detect clinically relevant infections. In other words, HPV testing for screening purposes needs optimal balance between clinical sensitivity and specificity. At present, the HPV assays considered clinically validated for screening purposes are the hybrid capture 2 HPV test (HC2) and the GP5ϩ/6ϩ-PCR enzyme immunoassay (EIA) (24). New candidate assays should prove their value in large prospective screening studies or should prove to be noninferior to a validated reference assay in clinical equivalence studies on specimens from a cervical screening cohort. An international consortium recently published guidelines (14) defining the appropriate study design and sample size to measure the sensitivity, specificity, and re...
BackgroundA large free-of-charge quadrivalent HPV (qHPV) vaccination program, covering four cohorts annually (women 11, 14, 17 and 24 years), has been implemented in Basilicata since 2007. This study evaluated vaccine and non-vaccine HPV prevalence 5-7 years post-vaccination program implementation in vaccinated and unvaccinated women.MethodsThis population-based, cross-sectional study was conducted in the public screening centers of the Local Health Unit in Matera between 2012 and 2014. Cervical samples were obtained for Pap and HPV testing (HC2, LiPA Extra® assay) and participants completed a sociodemographic and behavioral questionnaire. Detailed HPV vaccination status was retrieved from the official HPV vaccine registry. HPV prevalence was described overall, by type and vaccination status. The association between HPV type-detection and risk/protective factors was studied. Direct vaccine protection (qHPV vaccine effectiveness [VE]), cross-protection, and type-replacement were evaluated in cohorts eligible for vaccination, by analyzing HPV prevalence of vaccine and non-vaccine types according to vaccination status.ResultsOverall, 2793 women (18-50 years) were included, 1314 of them having been in birth cohorts eligible for the HPV vaccination program (18- to 30-year-old women at enrolment). Among the latter, qHPV vaccine uptake was 59% (at least one dose), with 94% completing the schedule; standardized qHPV type prevalence was 0.6% in vaccinated versus 5.5% in unvaccinated women (P <0.001); adjusted VE against vaccine type infections was 90% (95% CI: 73%-96%) for all fully vaccinated women and 100% (95% CI not calculable) in women vaccinated before sexual debut. No statistically significant difference in overall high-risk HPV, high-risk non-vaccine HPV, or any single non-vaccine type prevalence was observed between vaccinated and unvaccinated women.ConclusionsThese results, conducted in a post-vaccine era, suggest a high qHPV VE and that a well-implemented catch-up vaccination program may be efficient in reducing vaccine-type infections in a real-world setting. No cross-protective effect or evidence of type-replacement was observed a few years after HPV vaccine introduction.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-2945-8) contains supplementary material, which is available to authorized users.
The Hybrid Capture 2 (HC2) test targets 13 human papillomavirus (HPV) types. Here, cross-reactivity with non-HC2-targeted HPV types is described. We aimed to define the proportion of HC2-positive women who had negative results with HC2-targeted HPV types and estimate its determinants and impact on women's health management. The New Technologies for Cervical Cancer (NTCC) trial was followed in two predetermined phases. Women in the experimental arm were tested for the presence of HPV DNA by HC2 following a sample collection in PreservCyt (first phase) or Digene specimen transport medium (STM) (second phase). HPV genotyping was performed on DNA samples from HC2-positive women by PCR with GP5 ؉ /GP6 ؉ primers and reverse line blot (RLB) hybridization. Untyped samples were submitted to direct sequencing or restriction fragment length polymorphism. Multivariate logistic regression analysis estimated the adjusted odds ratios ( C ervical screening has the main purpose of decreasing the burden of cervical cancer by detecting and treating highgrade cervical intraepithelial neoplasia (CIN). Highly sensitive and specific tests have been established to identify the human papillomavirus (HPV) infections that are associated with detectable CIN. Double-testing studies (1) and randomized controlled trials (RCTs) (2-6) have highlighted Hybrid Capture 2 (HC2) as a highly sensitive test (Ͼ95%) (7) for detecting highgrade CIN. Conversely, the HC2 test showed lower clinical specificity than did cytology (90%) (7). Most of the false positives that make the test specificity so low are due to women who are actually infected by a high-risk HPV type but who have not developed high-grade lesions and, in most cases, will never develop cervical lesions (8). To date, this drawback has been overcome by the introduction of triage procedures that limit the referrals of HPV-positive women for unnecessary diagnostic procedures.It has been claimed that HC2 also has analytical false-positive results. HC2 includes a cocktail of probes designed to detect 13 HPV types, which are classified by the International Agency for Research on Cancer (IARC) (9) as carcinogenic with sufficient evidence (group 1), and HPV-68, which is classified as probably carcinogenic (group 2A). Some studies have shown cross-reactivity with other HPV types that are phylogenetically related to the targeted genotypes (10)(11)(12)(13)(14)(15)(16)(17)(18)(19).Increasing analytical false positives were observed with decreasing viral load, as measured by the ratio between the relative light units (RLU) of the specimen and the RLU of a positive cutoff (PC) consisting of 1 pg/ml of HPV DNA (RLU/PC ratio) (11,15,(20)(21)(22). In addition, lower reproducibility of the HC2 results between laboratories (23) and lower agreement between HC2 and PCR with the MY09 to MY11 primers when followed by dot blot hybridization (19) was reported with samples collected in PreservCyt (which is used for liquid-based cytology) than in those collected in the Digene standard transport medium (STM); this su...
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