This study shows that the clinical performance and reproducibility of the cobas 4800 HPV test for high-risk human papillomavirus (HPV) detection fulfill the criteria as formulated in international guidelines of HPV test requirements for cervical screening purposes. Accordingly, the cobas 4800 HPV test can be considered clinically validated for cervical screening.A critical feature for high-risk human papillomavirus (hrHPV) tests used for cervical screening is their clinical accuracy for detection of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (CIN2ϩ). For primary screening, an hrHPV test should have a balanced clinical sensitivity and specificity to allow effective detection of CIN2ϩ and minimize follow-up procedures of HPV test-positive women without CIN2ϩ. Furthermore, high intra-and interlaboratory reproducibility is required to ensure reliable performance of the test in clinical practice. Both the high-risk HPV Hybrid Capture 2 method (HC2) and GP5ϩ/6ϩ-PCR-enzyme immunoassay (EIA) fulfill these specifications and are considered clinically validated for screening purposes (4). In order to facilitate the validation procedure of any novel, candidate hrHPV assay without the necessity of performing large, prospective screening trials, specific criteria have recently been outlined by an international consortium based on clinical equivalence analysis (3, 4). Here, we evaluated the recently FDA-approved cobas 4800 HPV test (1) according to this validation strategy. The cobas 4800 HPV test features automated sample preparation combined with real-time PCR technology to detect 14 hrHPV genotypes. PCR amplification and detection occur in a single tube, where probes with four different reporter dyes track the different targets in the multiplex reaction: (i) HPV16, (ii) HPV18, (iii) 12 hrHPV types (i.e., HPV31, as a pool, and (iv) -globin as the control for extraction and amplification adequacy.The clinical performance of the cobas 4800 HPV test was assessed relative to HC2, which detects 13 hrHPV types (i.e., HPV16,, in a cohort of screening participants originally screened by cytology and HC2 cotesting (intervention group of the VUSA-Screen trial) (5, 6). A detailed description of the VUSA-Screen trial, including the referral policy and follow-up procedure, has been published previously (6). Informed consent was obtained from all study participants, and this study followed the local ethical guidelines of the medical center.A total of 860 archived cervical scrapings were selected comprising (i) a set for clinical sensitivity analysis of 60 representative scrapes from women (median age of 35 [range, 29 to 60] years) who had histologically confirmed CIN2ϩ (i.e., 23 with CIN2, 33 with CIN3, 1 with adenocarcinoma, and 3 with squamous cell carcinoma) diagnosed within a median follow-up time of 3.3 (range, 0 to 32.6) months and detected through either HC2 or cytology or both (hereafter referred to as cases) and (ii) a set for clinical specificity analysis of 800 representative scrapes from women (m...
A user-friendly self-sampling method for collecting representative cervical cell material would lower the threshold for women to respond to the invitation for cervical screening. In the present article, we introduce such a device; we have evaluated its sensitivity and specificity to detect high-grade cervical intraepithelial neoplasia (CIN), via high-risk human papillomavirus (hrHPV) detection and liquid-based cytology (LBC), compared to endocervical brush samples obtained by gynecologists. Women who had a cervical smear reading of moderate dyskaryosis or worse or a repeat equivocal Pap smear result in the cervical screening program (n ؍ 64) and healthy volunteers (n ؍ 32) took a self-obtained sample at home prior to their visit to the gynecological outpatient department. At the outpatient department, an endocervical brush smear was taken, followed by colposcopy and biopsy whenever applicable. Both self-obtained samples and endocervical brush samples were immediately collected in Surepath preservation solution and used for LBC and hrHPV testing (by general primer-mediated GP5؉/6؉ PCR). hrHPV test results showed a good concordance between the two sample types (87%; ؍ 0.71), with sensitivities for prevalent high-grade CIN that did not differ significantly (92% and 95%; P ؍ 1.0). The hrHPV test on self-obtained samples proved to be at least as sensitive for high-grade CIN as cytology on endocervical brush samples (34/37 versus 31/37; P ؍ 0.5). LBC showed a poor concordance between self-obtained and endocervical brush samples (60%; ؍ 0.27). In conclusion, selfobtained samples taken by this novel device are highly representative of the hrHPV status of the cervix. In combination with hrHPV testing, the use of this device may have implications for increasing the attendance rate for cervical screening programs.Population-based screening for cervical cancer at present is based on exfoliative cytology that allows early detection of the premalignant stages. The premalignant lesions can be treated fairly easily and without major side effects. However, two major problems need to be overcome. Firstly, the specificity and sensitivity of cytological screening are subject to improvement. Given the causal relation between a persistent infection with high-risk human papillomavirus (hrHPV) and the development of cervical cancer (33) and its precursor lesions, additive testing for hrHPV is being considered for increasing the sensitivity and specificity of population-based cervical screening (8,22).Secondly, the compliance rate of current population-based cervical screening programs is not optimal. Annually, in The Netherlands, 30% of the invited women do not participate in the cervical screening program, and as is the case in the United Kingdom and the United States (23,25,26), half of the cervical cancers are diagnosed in this group of women (1, 30). A userfriendly self-sampling method for collecting representative cervical cell material at home would lower the threshold for women to participate in the screening. Recent...
We studied harms related to cervical cancer screening and management of screen-positive women in the United States (US) and the Netherlands. We utilised data from four US integrated health care systems (SEARCH), the US National Health Interview Survey, New Mexico state, the Netherlands national histopathology registry, and included studies on adverse health effects of cervical screening. We compared the number of Papanicolaou (Pap) smear tests, abnormal test results, punch biopsies, treatments, health problems (anxiety, pain, bleeding, and discharge), and preterm births associated with excisional treatments. Results were age-standardized to the 2007 US population. Based on SEARCH, an estimated 36 million Pap tests were performed in 2007 for 91 million US women aged 21–65 years, leading to 2.3 million abnormal Pap tests, 1.5 million punch biopsies, 0.3 million treatments for precancerous lesions, 5 thousand preterm births, and over 8 million health problems. Under Netherlands screening practice, fewer Pap tests (58%), abnormal test results (64%), punch biopsies (75%), treatment procedures (40%), preterm births (60%), and health problems (63%) would have occurred. The SEARCH data did not differ much from other US data for 2007 or from more recent data up to 2013. Thus compared with the less intensive screening practice in the Netherlands, US practice of cervical cancer screening may have resulted in two- to three-fold higher harms, while the effects on cervical cancer incidence and mortality are similar. The results are also of high relevance in making recommendations for HPV screening. Systematic collection of harms data is needed for monitoring and for better incorporation of harms in making screening recommendations.
Similar CIN2+ sensitivity for HPV testing in first-void urine, physician-taken smear and brush-based self-sample.
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