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Background Non-attenders for cervical screening are at increased risk of cervical cancer. Studies offering self-sampling for high-risk Human Papillomavirus (HrHPV) testing have shown greater uptake than sending another invitation for cytology. Objectives To explore whether uptake would increase in a less diverse, more stable population than the previous English study, which demonstrated a lower response rate than other studies. The primary objective was whether non-attenders were more likely to respond to a postal invitation, including kit, to collect a self-sample compared with a further invitation for cytology screening. The secondary objective was whether women with an abnormal result would attend for follow-up. Methods 6000 non-attenders for screening in this pragmatic, randomized (1:1) controlled trial in Newcastle-upon-Tyne were sent an HPV self-sample kit (intervention) or a further invitation for cytology screening (comparator). Results 411(13%) responded to the intervention, returning a self-sample (247(8%)) or attending for cytology (164(5%)), compared with 183(6%) attending for cytology, relative risk 2.25 (95% CI 1.90–2.65) (comparator arm). Of those testing hrHPV positive (32(13%)), 19(59%) subsequently attended cytology screening. Of those in the intervention group who attended for cytology screening without returning an hrHPV self-sample (n = 164), 5% (n = 8) were referred for colposcopy - all attended. In the comparator group eight of the nine referred for colposcopy attended. Conclusion Persistent non-responders to invitations for cervical screening are significantly more likely to respond to a postal invitation to return a self-collected sample for HPV testing than a further invitation for cytology screening. However, just over half followed up on this positive HPV result.

Testing for high-risk (hr) types of human papillomavirus (HPV) is highly sensitive as a screening test of high-grade cervical intraepithelial neoplastic (CIN2/3) disease, the precursor of cervical cancer. However, it has a relatively low specificity. Our objective was to develop a prediction rule with a higher specificity, using combinations of human and HPV DNA methylation. Exfoliated cervical specimens from colposcopy-referral cohorts in London were analyzed for DNA methylation levels by pyrosequencing in the L1 and L2 regions of HPV16, HPV18, HPV31 and human genes EPB41L3, DPYS and MAL. Samples from 1,493 hrHPV-positive women were assessed and of these 556 were found to have CIN2/3 at biopsy; 556 tested positive for HPV16 (323 CIN2/3), 201 for HPV18 (73 CIN2/3) and 202 for HPV31 (98 CIN2/3). The prediction rule included EPB41L3 and HPV and had area under curve 0.80 (95% CI 0.78–0.82). For 90% sensitivity, specificity was 36% (33–40) and positive predictive value (PPV) was 46% (43–48). By HPV type, 90% sensitivity corresponded to the following specificities and PPV, respectively: HPV16, 38% (32–45) and 67% (63–71); HPV18, 53% (45–62) and 52% (45–59); HPV31, 39% (31–49) and 58% (51–65); HPV16, 18 or 31, 44% (40–49) and 62% (59–65) and other hrHPV 17% (14–21) and 21% (18–24). We conclude that a methylation assay in hrHPV-positive women might improve PPV with minimal sensitivity loss.

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved.

BACKGROUND High-risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US). However, no consensus has been reached on the optimal management of low-grade squamous intraepithelial lesions (LSIL). METHODS In this meta-analysis, the diagnostic accuracy of nucleic acid sequence-based amplification (NASBA) detection of messenger ribonucleic acid (mRNA) of 5 hrHPV types (the PreTect HPV-Proofer and NucliSENS EasyQ tests) for detecting grade 2 cervical intraepithelial neoplasia or worse (CIN2+) and CIN3+ was assessed in women who had a diagnosis of ASC-US and LSIL. The results were compared with the Hybrid Capture-2 (HC2) assay, which detects the DNA of 13 hrHPV types. A bivariate random-effect model that incorporated the intrinsic correlation between the true-positive and false-positive rates was used for a pooled meta-analysis. RESULTS Considering underlying CIN2+, the pooled absolute sensitivity of the 10 included studies was 75.4% (95% confidence interval [CI], 68.1%-82.7%) and 76.2% (95% CI, 68.3%-76.9%) for the triage of ASC-US and LSIL, respectively. The pooled absolute specificity to exclude CIN2+ was 77.9% (95% CI, 70.1%-85.7%) and 74.2% (95% CI, 69.5%-78.8%) in women with ASC-US and LSIL, respectively. Five studies allowed direct comparison of the mRNA assays with HC2. Considering CIN2+ in women with ASC-US and LSIL, mRNA testing was substantially more specific than the HC2 assay (ratio: 1.98 and 3.36, respectively; P

ObjectiveWe evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities.MethodsWomen completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions.Results16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age

Cervical cancer is the third most common cancer in women worldwide and often affects women under 40 years with young families. Vaccination against the human papillomavirus (HPV) is a major advance, since it offers primary prevention against the infectious agent that is the main cause of the disease. Two prophylactic vaccines have shown great promise in clinical trials. One of these (Gardasil(®)) contains all four HPV types, offering protection against genital warts (types 6 and 11) as well as cervical cancer (types 16 and 18). The other (Cervarix(®)) contains types 16 and 18, targeting cervical cancer alone, but also has a degree of cross-protection against types 31 and 45, which could significantly increase the level of protection. Adolescent girls remain the primary target of vaccination programmes, but the issues of vaccinating boys and older women are increasingly debated.

“…the prescribing of combined oral contraceptive pills to women with a body mass index >30 kg/m 2 , and particularly those with multiple risk factors for cardiovascular disease, is becoming difficult to justify. ” An increased risk of venous thromboembolism (VTE) was the first serious side effect identified with the combined oral contraceptive pill (COC) in the 1960s. This was quickly realised to be due to the estrogen content of the COC and this has been the main driver behind reductions in estrogen dose seen in the last 50 years [1]. However, in 1995, several studies were published that suggested that COCs containing the progestogens desogestrel and gestodene (‘third-generation’ COCs) increased the risk of VTE more than ‘second-generation’ COCs (containing levon orgestrel). This created a widespread pill-scare, which has never fully been resolved, despite the incongruity that progestogen-only contraceptives do not increase VTE risk and newer evidence showing that prescriber bias and many confounding factors were not taken into account [2].

The National Health Service Cervical Screening Programme (NHSCSP) has announced that from April 2011, human papillomavirus (HPV) testing will be incorporated into the national screening programme in England. Initially, HPV testing will be used for the triage of borderline and mildly dyskaryotic smears, but there are also plans, at a later date, for its use as a ‘test of cure’ following treatment for cervical abnormalities (Figure 1).1 It would have been interesting to see the data underpinning the proposals, but no references were given. Figure 1 National Health Service Cervical Screening Programme (NHSCSP) flow diagram of ‘HPV Triage and Test of Cure Protocol for Women Aged 25 to 64 Years’.1 Figure available at: http://www.cancerscreening.nhs.uk/cervical/hpv-triage-test-flowchart-v2.pdf.1 This flow diagram is reproduced with the kind permission of the NHSCSP. The announcement follows 8 years of pilot projects. The first pilots were completed in 20062 and were followed by the Sentinel Site Implementation Project, which was launched in January 2008, to examine the practical implementation of a national roll-out of HPV testing. A report from the latter does not appear to be publicly available, so it is not possible to tell whether the problems identified in the pilots have been overcome and, if so, how. It is thus impossible to judge the results of the changes. The majority of low-grade cytological abnormalities (at least 70%) will regress without treatment.3 If it was possible to identify those women whose abnormalities were very likely to regress, they could be spared the anxiety of repeat testing and …

Background: A randomised trial to ascertain whether women who do not attend for cervical screening are more likely to respond to the opportunity to collect a self-sample for human papillomavirus (HPV) testing, or to a further invitation to attend for cervical screening. Methods: The study was carried out in a Primary Care Trust (PCT) in London between June 2009 and December 2009. In total, 3000 women were randomly selected from persistent non-responders (i.e., who had not responded to at least two invitations to attend for screening). The women were randomised on a 1 : 1 basis to either receive an HPV self-sampling kit or a further invitation to attend for cervical cytology. The main outcome measures were (1) percentage of women attending for cervical cytology compared with those returning a self-sample HPV test or attending for cytology subsequent to receiving the kit and (2) percentage of those testing positive for HPV who attended further investigation. Results: The total response in the self-sampling group for screening was 10.2%. Of the 1500 women in the control group sent a further invitation for cervical screening, 4.5% attended for cytology screening. This difference is highly statistically significant (P

Since its introduction, there have been concerns regarding the psychological and psychosexual issues associated with cervical screening and the management of abnormal smears. We are now entering a new era in which vaccination against the main cause of cervical cancer, the human papillomavirus, has become possible, and testing for human papillomavirus is likely to become widespread in screening, triage of abnormal smears and the follow-up of women after treatment of cervical intraepithelial neoplasia. It is important that the social and psychological implications of this are understood and that ways of overcoming personal and societal difficulties relating to these issues are found.

This document provides the consensus opinion from an international workshop regarding oral contraceptives and the risk of venous thromboembolism (VTE). It discusses the background and purpose of the workshop the benefits and risks of oral contraceptives describes the serious complication of VTE and assesses the VTE risks of new oral contraceptive products. It also includes information on recently published studies focused on oral contraceptives and VTE.

Background: Several studies have shown that testing for high-risk human papillomavirus (HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with a somewhat lower specificity. Methods: We obtained follow-up results, with at least one smear after participation in the HART study, which compared HPV testing (HC-II) with cytology as a primary screening modality. Results: With a median follow-up of 6 years, 42 additional cases of CIN2+ were identified; women who were HPV positive at baseline were more likely to develop CIN2+ than those who were HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3–31.6)) and the risk increased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU)

Cervical cancer is a major cause of morbidity and mortality worldwide and is common in relatively young women. Cervical screening programs, while successful if properly carried out, are difficult and expensive to implement, and offer secondary, not primary prevention. Vaccination against the human papillomavirus (HPV), which is the major cause of cervical cancer, is a significant step forward.The data on Cervarix, the GSK HPV vaccine, are reviewed and placed in the context of HPV vaccination as a whole. A literature review using PubMed listed publications and official product websites has been carried out.The reader will gain an understanding of the issues involved in HPV vaccination and of the data to date.Cervarix has been shown to have high efficacy against disease associated with both HPV-16 and HPV-18. Its antibody response profile allows for optimism regarding the duration of immunity. The fact that it is a virus-like particle, rather than a live-virus vaccine, is reassuring regarding safety, as are the reasonably extensive safety data for the vaccine preparation so far accrued. Cross protection against oncogenic non-vaccine HPV types, in particular HPV-45, may be important in the prevention of cervical adenocarcinoma, which is currently not well served by screening.

Summary Although we now have many contraceptives, couples still have a negative perception of their personal choices. Many know little about methods other than the combined pill and the condom, and in particular, knowledge of long-acting methods is very poor. Methods that are very safe, such as barriers and natural family planning, are unfortunately not very effective. Meanwhile, the very effective methods—the hormonal contraceptives and intrauterine devices (IUDs)—raise more concerns about health risks and side effects. A woman's choice of contraceptive will be influenced by many factors, and her requirements will change with time. As prescribers, it is our responsibility to ensure that couples are given sufficient and appropriate information to enable them to make decisions.

A variety of health professionals will be involved in dealing with issues surrounding human papillomavirus in the near future, but in many cases their own knowledge is insufficient to allow them to comfortably deal with patients’ concerns. Educational initiatives for health professionals are urgently needed. These must take into account attitudes, cultural issues and communication skills, as well as providing facts. The role of the media and advocacy groups should not be ignored.

Gardasil is a quadrivalent human papillomavirus vaccine for the prevention of cervical cancer, cervical and vulvar dysplasia and external genital warts. In our New products review, Steve Chaplin presents the clinical data relating to its efficacy and Dr Anne Szarewski comments on the implications of the proposed immunisation programme. Copyright © 2007 Wiley Interface Ltd

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)

Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages

This study examined attitudes to human papillomavirus (HPV) testing among a purposively selected sample of women from four ethnic groups: white British, African Caribbean, Pakistani and Indian. The design was qualitative, using focus group discussion to elicit women's attitudes towards HPV testing in the context of cervical cancer prevention. The findings indicate that although some women welcomed the possible introduction of HPV testing, they were not fully aware of the sexually transmitted nature of cervical cancer and expressed anxiety, confusion and stigma about HPV as a sexually transmitted infection. The term 'wart virus', often used by medical professionals to describe high-risk HPV to women, appeared to exacerbate stigma and confusion. Testing positive for HPV raised concerns about women's sexual relationships in terms of trust, fidelity, blame and protection, particularly for women in long-term monogamous relationships. Participation in HPV testing also had the potential to communicate messages of distrust, infidelity and promiscuity to women's partners, family and community. Concern about the current lack of available information about HPV was clearly expressed and public education about HPV was seen as necessary for the whole community, not only women. The management of HPV within cervical screening raises important questions about informed participation. Our findings suggest that HPV testing has the potential to cause psychosocial harm to women and their partners and families.

Although adolescent girls are the main population for prophylactic human papillomavirus (HPV) vaccines, adult women who remain at risk of cervical cancer can also be vaccinated. We report data from the interim analysis of the ongoing VIVIANE study, the aim of which is to assess the efficacy, safety, and immunogenicity of the HPV 16/18 AS04-adjuvanted vaccine in adult women.In this phase 3, multinational, double-blind, randomised controlled trial, we randomly assigned healthy women older than 25 years to the HPV 16/18 vaccine or control (1:1), via an internet-based system with an algorithm process that accounted for region, age stratum, baseline HPV DNA status, HPV 16/18 serostatus, and cytology. Enrolment was age-stratified, with about 45% of participants in each of the 26-35 and 36-45 years age strata and 10% in the 46 years and older stratum. Up to 15% of women in each age stratum could have a history of HPV infection or disease. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or higher (CIN1+) associated with HPV 16/18. The primary analysis was done in the according-to-protocol cohort for efficacy, which consists of women who received all three vaccine or control doses, had negative or low-grade cytology at baseline, and had no history of HPV disease. Secondary analyses included vaccine efficacy against non-vaccine oncogenic HPV types. Mean follow-up time was 40·3 months. This study is registered with ClinicalTrials.gov, number NCT00294047.The first participant was enrolled on Feb 16, 2006, and the last study visit for the present analysis took place on Dec 10, 2010; 5752 women were included in the total vaccinated cohort (n=2881 vaccine, n=2871 control), and 4505 in the according-to-protocol cohort for efficacy (n=2264 vaccine, n=2241 control). Vaccine efficacy against HPV 16/18-related 6-month persistent infection or CIN1+ was significant in all age groups combined (81·1%, 97·7% CI 52·1-94·0), in the 26-35 years age group (83·5%, 45·0-96·8), and in the 36-45 years age group (77·2%, 2·8-96·9); no cases were seen in women aged 46 years and older. Vaccine efficacy against atypical squamous cells of undetermined significance or greater associated with HPV 16/18 was also significant. We also noted significant cross-protective vaccine efficacy against 6-month persistent infection with HPV 31 (79·1%, 97·7% CI 27·6-95·9) and HPV 45 (76·9%, 18·5-95·6]) Serious adverse events occurred in 285 (10%) of 2881 women in the vaccine group and 267 (9%) of 2871 in the control group; five (1%) and eight (1%) of these events, respectively, were believed to be related to vaccination.In women older than 25 years, the HPV 16/18 vaccine is efficacious against infections and cervical abnormalities associated with the vaccine types, as well as infections with the non-vaccine HPV types 31 and 45.GlaxoSmithKline Biologicals SA.

Background HR HPV genotypes when assayed collectively, achieve high sensitivity but low specificity for the prediction of CIN2+. Knowledge of the specific genotypes in an infection may facilitate the use of HR HPV detection in routine clinical practice. Objectives To compare the rate of HR HPV detection and the accuracy of CIN2+ prediction between PapType test (Genera Biosystems) and other commercially available HR HPV assays, and to examine the value of full HPV genotyping. Study design PreservCyt samples from 1099 women referred for abnormal cervical cytology were used. CIN2+ was chosen as the primary end-point but CIN3+ was also evaluated. A hierarchy of HR HPV genotypes was created using PPV and this was used to create 3 groups of genotypes with potentially different management. Results The PapType assay has a specificity of 22.4% and a sensitivity of 94.6% for CIN2+ prediction. Classification into Groups A (HPV33 and HPV16, very highly predictive), B (HPV31, 18, 52, 35, 58, 51 highly predictive) and C (HPV68, 45, 39, 66, 56, 59, intermediate predictive) could double the specificity (44.5%) but only slightly reduce the sensitivity for CIN2+ (91.5%) and CIN3+ (94.0%). Conclusions The PapType assay is a simple, reproducible and effective test for HR HPV detection and genotyping. HPV 33 was found to have a very high PPV and should therefore be managed as for HPV16.

(See the major article by Howell-Jones et al on pages 1397–403.) The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®; GlaxoSmithKline Vaccines) has been demonstrated to have high efficacy against infection and both low- and high-grade cervical intraepithelial neoplasia (CIN; caused by oncogenic HPV types 16 and 18, with substantial cross protection against other high-risk HPV types 31, 33, 45, and 51 [1, 2]. Low-risk HPV types are found in approximately 12% of low-grade CIN, although there is likely to be coinfection with high-risk types [3]. While immunogenicity has been demonstrated in boys [4], the HPV-16/18 AS04-adjuvanted vaccine is not currently licensed for use in boys. Genital warts (GWs) are the most common viral sexually transmitted infection in the Western world, and a 30% increase in new diagnoses was seen in the United Kingdom between 2000 and 2009 [5]. Treatment has a significant morbidity and can be frustrating, and recurrences are common. This causes psychosocial distress to patients and results in substantial financial costs [6, 7]. GWs result from persistent infection with low-risk HPV genotypes, predominantly 6 and 11, although other low-risk types were not evaluated in the former study [8, 9]. It has been suggested that a small proportion of GWs may be caused by HPV types 16 and 18; [10, 11] if true, limited efficacy against warts could occur with a vaccine directed against these types [10, 11]. The HPV-16/18 AS04-adjuvanted vaccine was chosen for the UK national vaccination program, which commenced in September 2008 and has achieved >84% uptake in 12- to 15-year-old girls for all 3 doses. A catch-up program to the age of 18 years achieved between 50% and 70% uptake for all 3 doses [12]. Public Health England (formerly the Health Protection Agency), which monitors rates of sexually transmitted infections in England, has reported a decrease in new diagnoses of GWs in genitourinary medicine clinics among young women since 2008 [13]. By 2011, the overall reduction was 13.3% among 16- to 19-year-olds, with the greatest decline (20.8%) in 17-year-olds, for whom HPV-16/18 AS04-adjuvanted vaccine coverage in 2011 was estimated at 64%. By contrast, rates in the older age groups were generally either static or increasing [14]. Among the potential reasons for this decrease, as discussed by Howell-Jones et al [14], is the possibility of an effect of the HPV-16/18 ASO4-adjuvanted vaccine on low-risk HPV types. A post hoc analysis of the PATRICIA (PApilloma TRIal against Cancer In young Adults) trial was therefore performed to ascertain whether any protection against low-risk HPV types was apparent.

Background: Several new assays have been developed for high-risk HPV testing of cervical samples; we compare six HPV tests in a screening population. Methods: Residual material from liquid-based PreservCyt samples was assayed. Four tests (Hybrid Capture 2, Cobas, Abbott and Becton-Dickinson (BD)) measured HPV DNA while two used RNA (APTIMA and NorChip). Results: Positivity rates ranged from 13.4 to 16.3% for the DNA-based tests with a significantly lower positivity rate for the Abbott assay. The Gen-Probe APTIMA assay was positive in 10.3% of women, which was significantly lower than all the DNA tests; the NorChip PreTect HPV-Proofer test was much lower at 5.2%. 40 CIN2+ cases were identified, of which 19 were CIN3+. All CIN3+ cases were HPV positive by all tests except for one, which was negative by the Abbott assay and five which were negative by the NorChip test. Conclusion: All HPV tests except NorChip showed high sensitivity for high-grade lesions positive by cytology, suggesting co-testing is unnecessary when using HPV tests. Positivity rates in cytology-negative specimens were similar for the DNA-based tests, but lower for the APTIMA test suggesting this maintains the high sensitivity of DNA tests, but with better specificity.

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.

BACKGROUND: The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. METHODS AND FINDINGS: Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. CONCLUSIONS: Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance. ispartof: PLoS One vol:8 issue:11 ispartof: location:United States status: published

Dowrloaded from jfprhc,bmj.corn on November 7,2013 - Punished by grouytnni com =.::'«l SVVIU E ‘ME WT For nurnbened affiliations see end of article. Correspondence to Professor Dr Johan res Bitzer. Chief Physician and Chairman Department of Obnettics and Gynaecology. University Hospital Basel. Basel. Switzerland; JohartnesBitzer@usb.cl‘. Received IS March 2013 Accepted 18 March 2013 To cite: Bitzer J Amy J-J. Beerttmizer R. et al. Joumai of Fanfly Planning and Reproductive Health C are Published Online First lnlease include Day Month Year] doi: 10. l l36lifptl1(-20l3- 100624 Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism Johannes Bitzer Cosignatories Jean-Jacques Amy,‘ Rob Beerthuizen,2 Martin Birkhauser,3 Teresa Bombas,“ Mitchell Creinin,5 Philip D Darney,5 Lisa Ferreira Vicente,’ Kristina Gemzell-Danielsson,° Bruno lmthurn,9 Jeffrey T Jensen,” Andrew M Kaunitz,“ Ali Kubba,” Medlard M Lech,” Diana Mansour,” Gabriele Merki,” Thomas Rabe,‘6 Katarina Sedlecki,” David Serfaty,‘8Jact1ues Seydoux,” Lee P Shu|man,2° Regine Sitruk-Ware, ‘ Sven O Skouby,” Anne Szarewski, James Trussell,” Carolyn Westhoffzs A NEW PILL SCARE? HOW DID IT COME ABOUT AND HOW SHOULD WE TACKLE IT? The cotttroversy around the combined hormonal contraceptives ((IH(,'s) of the so-called third (containing gestodene or desogestrel) and fourth generation (cott- raining drospirenone. DRSP) lt-as reached .1 highly emotional political dimension in which all those who “are prol'essionall_v responsible for women's health are involved: the national health authorities, the pltarrnaceutical companies, the pro- fessional orgartis-ations, the prescrihers. the media and the public (i.e. the current or potential users of CH(Is). The — initially scientific — controversy has now led to a ptthlic health dispute that culminated in the decision of the Frenelt '.1tltht)ritlc's to withdraw the com hination containing etltinylestradiol (EE) and cyproterone acetate (CPA) from the market. The potential impact of this measure, namely the loss of confidence in .1/I (Ill(.'s. could be quite serious. WHAT TRIGGERED THIS CRISIS? Several re;.',is‘tr_v~hasei.l studies published in the Britr'.~‘l2 .\ledic.tl Irirrrmtl. partictilarlv 23 the one based on the Danish Registry. indicated that there is an increased risk of venous thrombiternholism (VTE) asso- ciated with the intake of third- and liounh-generation combined oral contra- ceptives ((ZO('.s) compared to prepara- tions containing the progestogen le\'onorges‘trel (I-.\l(§).q5 The relative risk (RR) was around 2. and the absolute attributable risk was estimated to be (dependent on the background preva- lence rate) between .2 to 8 per ll) llllll users per year.q A very recent systentatic review and meta-anal_vsis of the possible link between treatment with CHCs and VTF. con- cluded that. in this regard. (I) (3H(Zs cort- taining I.N(} or norgestimate were the safest. (.1) those containing desogestrel. DRSI’ or (IPA were associated with a sig- ttillC.‘tI1tl_\' ltiglter risk than (IH(Is contain- ing LNG, and (3) the aup,ntented risk of VTE found for pills containing gestodene compared to (l(.)(Ls with L\'(; appeared to be smaller than in earlier s'tttcllcs.7 These resultsq contrast with those of published prospective cohort studies. sponsored by It’-a_ver He-altlt(.are. at the request of the European Medicitte Bitzer J et J Journal offamily Planting and Reolodzcme Health (.19 20‘~3;0:'-at doizt 0.’ ’-36Ii?prh: 2073 ‘0062-1 1

Sidney et al. report a large database analysis which purports to show an increased risk of venous and arterial thromboembolism (VTE and ATE) in users of the 30 mcg ethinyl-estradiol (EE)/3 mg drospirenone (DRSP) preparation compared to several older combined pills (COCs). It is a recurring problem that databases do not contain important information necessary for such analyses. In this case there was no information at all regarding body mass index (BMI) smoking or family history. The European Active Surveillance (EURAS) study showed that obesity was more common (1.6-fold higher) among users of DRSP containing COCs compared to users of levonorgestrel (LNG) and other progestogen containing COCs. The EURAS study showed that adjustment for age BMI duration of current use family history of VTE and the interaction between age and BMI reduced the VTE relative risk by 27% as compared with an analysis that adjusted only for age. The analysis published here included women between 2001 and 2007. The comparator pills had been already been available for many years while DRSP containing COCs entered the market in 2001. New users were defined as not having a prescription for a COC in the 6 months preceding entry to the study. However so-called ‘new users’ could simply have had a break and in fact have been using COC for years. Women starting COCs for the first time are more likely to be given a newer pill and thus the DRSP group would certainly have contained more real “new starters” than the comparison group. We are aware that there has been a great deal of publicity in the USA regarding the risk of VTE with DRSP containing pills over the last 10 years; this will certainly have led to detection bias. Women who developed any symptoms were more likely to be referred if they were taking a pill that had recently been in the news associated with a higher risk. Indeed this is suggested by the data in Table 4 where the total mortality in users of DRSP COCs appears to be (nonsignificantly) reduced despite the fact that at the same time they are supposed to increase the risk of both VTE and ATE. When several studies all with the same flaws show similar results this does not mean they are correct. It is simply a repetition of the same incorrect conclusion. (full-text) Copyright © 2013 Elsevier Inc. All rights reserved.

High-risk human papillomavirus (HPV) DNA/RNA testing provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). Several new HPV tests are now available for this purpose, and a direct comparison of their properties is needed. Seven tests were evaluated with samples in liquid PreservCyt transport medium from 1,099 women referred for colposcopy: the Hybrid Capture 2 (Qiagen), Cobas (Roche), PreTect HPV-Proofer (NorChip), Aptima HPV (Gen-Probe), and Abbott RealTi m e assays, the BD HPV test, and CINtec p16 INK4a cytology (mtm laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology found on either the biopsy or the treatment specimen after central review. Three hundred fifty-nine women (32.7%) had CIN grade 2+ (CIN2+), with 224 (20.4%) having CIN3+. For detection of CIN2+, Hybrid Capture 2 had 96.3% sensitivity, 19.5% specificity, and 37.4% PPV. Cobas had 95.2% sensitivity, 24.0% specificity, and 37.6% PPV. The BD HPV test had 95.0% sensitivity, 24.2% specificity, and 37.8% PPV. Abbott RealTi m e had 93.3% sensitivity, 27.3% specificity, and 38.2% PPV. Aptima had 95.3% sensitivity, 28.8% specificity, and 39.3% PPV. PreTect HPV-Proofer had 74.1% sensitivity, 70.8% specificity, and 55.4% PPV. CINtec p16 INK4a cytology had 85.7% sensitivity, 54.7% specificity, and 49.1% PPV. Cytology of a specimen taken at colposcopy (mild dyskaryosis or worse) had 88.9% sensitivity, 58.1% specificity, and 50.7% PPV. Our study confirms that, in a referral setting, HPV testing by a number of different tests provides high sensitivity for high-grade disease. Further work is needed to confirm these findings in a routine screening setting.

The clearly higher sensitivity and reproducibility of human papillomavirus (HPV) DNA testing for high-grade cervical intraepithelial neoplasia (CIN) has led to widespread calls to introduce it as the primary screening test. The main concern has been its lower specificity, due to the fact that it cannot separate transient from persistent infections, and only the latter are associated with an increased risk of high-grade CIN and cancer. Thus, even proponents of HPV testing generally only recommend it for women over the age of 30 years (or in some cases 35 years). If HPV testing is to reach its full potential, new approaches with better specificity are needed, either as triage tests for HPV positive women or, if the high sensitivity of HPV DNA testing can be maintained, as alternate primary screening modalities. Approaches that may useful in this regard, especially as triage tests, include HPV typing, methylation (and consequent silencing) of host and viral genes, and new cytologic methods, such as p16(INK4a) staining, which attempt to identify proliferating cells. At an earlier stage of development are direct methods based on detection of HPV E6 or E7 proteins. Recent progress and current status of these methods is discussed in this chapter. The current status of visual inspection (VIA and VILI) methods is also surveyed and progress on self-sampling is reviewed. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

The past 50 years have seen great advances in combined oral contraceptives (COCs) that have resulted in reduced risks of adverse events and improved cycle control. The most important changes in COCs over time include repeated lowering of the estrogen dose, development of new progestogens, and the reduction or elimination of the pill-free interval. Most recently, formulations that deliver estradiol in lieu of ethinylestradiol have been introduced. The advantages of COCs generally far outweigh the disadvantages. Current options in oral contraception include a wide spectrum of products that enable clinicians to choose the most appropriate formulation for individual women. This article summarises the advances in oral contraceptives over time and describes the most current clinical data regarding the use of COCs.

HPV DNA testing is known to be much more sensitive than cytology, but less specific. A range of HPV and related tests in 858 women referred for colposcopy because of an abnormal smear were evaluated to compare the performances of these tests. This article compared the Abbott test to other tests which had been previously evaluated. This test was a real true test for 14 high-risk HPV types. The Abbott test was found to be highly sensitive for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) (98.9%) with a specificity of 31.5%. These numbers were comparable with the Qiagen HC2 test, the Roche Linear Array and Amplicor tests, and the Gen-Probe APTIMA test. Differences between these tests appeared to be related mostly to the choice of cutoff level. An added feature of the Abbott test was the provision of type specific results for HPV 16 and 18. J. Med. Virol. 82: 1186–1191, 2010. © 2010 Wiley-Liss, Inc.

The types of oral contraception available, their risks and benefits and alternative options.

The cervicography and concurrent endocervical brush smear results obtained in 1162 women screened at the Marie Stopes Clinic were analysed. Colposcopy and biopsy results were obtained for positive cases. A comparison was made with a group of 1007 women attending the same clinic for routine cytology only. Nearly 10% of women who were screened by cervicography had a technically defective cervicogram, the main single reason being that the view was obscured by blood. Routine cytology was positive in 1%, while cervicography was positive in 13%, where positivity was defined as a result leading to a recommendation for colposcopy. The false positive rate for cervicography was 26%. Even after adjustment, this difference was highly significant (P less than 0.0001).

Background: The detection of high-risk human papillomavirus (HPV) DNA provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). This study compared the sensitivity and specificity of several adjunctive tests for the detection of high-grade CIN in a population referred to colposcopy because of abnormal cytology. Methods: 953 women participated in the study. Up to seven tests were carried out on a liquid PreservCyt sample: Hybrid Capture II (Digene), Amplicor (Roche), PreTect HPV-Proofer (NorChip), APTIMA HPV assay (Gen-Probe), Linear Array (Roche), Clinical-Arrays (Genomica), and CINtec p16INK4a Cytology (mtm Laboratories) immunocytochemistry. Sensitivity, specificity, and positive predictive value (PPV) were based on the worst histology seen on either the biopsy or the treatment specimen after central review. Results: 273 (28.6%) women had high-grade disease (CIN2+) on worst histology, with 193 (20.2%) having CIN3+. For the detection of CIN2+, Hybrid Capture II had a sensitivity of 99.6%, specificity of 28.4%, and PPV of 36.1%. Amplicor had a sensitivity of 98.9%, specificity of 21.7%, and PPV of 33.5%. PreTect HPV-Proofer had a sensitivity of 73.6%, specificity of 73.1%, and PPV of 52.0%. APTIMA had a sensitivity of 95.2%, specificity of 42.2%, and PPV of 39.9%. CINtec p16INK4a Cytology had a sensitivity of 83.0%, specificity of 68.7%, and PPV of 52.3%. Linear Array had a sensitivity of 98.2%, specificity of 32.8%, and PPV of 37.7%. Clinical-Arrays had a sensitivity of 80.9%, specificity of 37.1%, and PPV of 33.0%. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3033–42)

©FSRH J Fam Plann Reprod Health Care 2008: 34(4) Background The UK’s human papillomavirus (HPV) vaccination programme should now be underway: vaccination of 12–13year-old girls against HPV was due to begin in September 2008, with a recent announcement that 17–18-year-olds will also be vaccinated in this academic year.1 From September 2009, a further catch-up programme for girls up to the age of 18 years will commence. The Department of Health (DH) has decided that the HPV vaccine to be used for the programme will be Cervarix® (GlaxoSmithKline), which is the bivalent vaccine against the cervical cancer-causing HPV types 16 and 18. This decision has surprised many, in view of the fact that the other available vaccine, Gardasil® (Merck), would protect against genital warts (HPV types 6 and 11) as well as cervical cancer. It is unfortunate that there has not been a proper disclosure of the factors that led to the decision, resulting in widespread speculation amongst health professionals and the media, particularly relating to the cost of the vaccine. A list of the pre-agreed evaluation criteria against which the bids were evaluated has recently been released (Table 1), and includes many factors, which have been weighted, though details of cost are still not given. When questioned, the Secretary of State for Health stated that both published and unpublished data were considered.2 The suggestion in the media that girls in the UK will receive an inferior vaccine may undermine the success of the vaccination programme, as parents become unsure whether it is worth vaccinating their daughter with such a product.3,4 Adding fuel to this debate is a mathematical model published in the BMJ, which was considered by the DH when making its decision.5 This suggests that Cervarix must be £13–£21 cheaper than Gardasil in order to be cost effective. However, it should be noted that a number of assumptions were made in this model; it was assumed both vaccines were identical in terms of efficacy, duration of immunity, cross-protection against nonvaccine HPV types, and that uptake amongst girls would be at least 80%. This last assumption is the least likely to be correct; a pilot study in a primary care trust (PCT) in Manchester found uptake was only 70% overall, and significantly lower in schools with a greater proportion of girls from ethnic minority groups and poorer families. In addition, the Catholic schools in the PCT refused to participate in the pilot.6 One could speculate that another factor influencing the DH decision might have been the possibility of greater acceptability of a ‘cervical cancer vaccine’ (without the need to mention genital warts) in certain ethnic and religious groups.7

OBJECTIVE: To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). DESIGN: Multinational cohort study with joint database analysis. SETTING: Seven primary HPV screening studies in six European countries. PARTICIPANTS: 24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. MAIN OUTCOME MEASURE: Long term cumulative incidence of CIN3+. RESULTS: The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. CONCLUSIONS: A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Several studies have shown that HPV testing is substantially more sensitive than cytology for primary cervical screening. However, less data exist concerning the duration of protection afforded by a negative HPV test compared to a normal cytological outcome. Here we report the long-term findings from the Hammersmith study in women aged 35 or more. HPV testing by Hybrid Capture II was performed on all available samples from the baseline screening visit. Passive surveillance of subsequent cytology screening results for the 2,982 women in the study was undertaken using a national registry. Histological outcomes were sought for all women with abnormal smears. The primary outcome was duration of protection against histologically confirmed CIN2+ afforded by a negative HPV test compared to normal cytology. 2,516 women had at least one further smear at least 1 year after entry and 20 new cases of CIN2+ were identified during a median follow-up of 6.4 years. Including disease identified at baseline, the risk of developing CIN2+ at 1, 5 and 9 years after a normal cytology was 0.33%, 0.83% and 2.20% respectively whereas it was 0.19%, 0.42% and 1.88% after a negative HPV test. HPV testing offered excellent protection from CIN2+ for at least 6 years after a negative test, whereas the protection from cytology began to wane after about 3 years. Substantially more CIN2+ lesions were found in the follow-up period in those initially HPV positive compared to those HPV negative (HR = 6.52, p = 0.001), whereas there was little difference according to initial cytology (HR = 1.64, p = 0.51).

Objective To provide health professionals involved in cervical cancer screening with an insight into the complex issues relating to communication about screening and to provide a framework for a more effective communication strategy. Methods This paper has been compiled by a multidisciplinary pan-European group of health professionals and cancer advocates from several European screening programmes. European surveys on screening communication, literature reviews and group discussion were used for this purpose. Results Information on cervical screening must be accessible, relevant, comprehensible, comprehensive, client-centred, phase-specific and multilevel. An effective communication strategy should consider health professionals’ screening knowledge and their communication skills, consumers’ health literacy skills and the communication needs of specific sub-groups in the target population. Co-operation between screening professionals, advocacy groups and journalists should be promoted. Conclusion To communicate effectively and appropriately is a complex task which can be influenced by a number of factors. Screening workers need better information themselves and must take into account the needs and characteristics of the target population. Practice implications This document should provide a useful tool to help screening professionals in designing and developing good quality and effective communication strategies.

Vaccines against cervical cancer are being developed but screening is still needed.

Objective To examine the psychosocial impact of testing positive for high risk human papillomavirus (HPV) among women attending primary cervical screening.Design Cross sectional survey.Measures were taken at baseline and one week after the receipt of HPV and cytology screening results.Setting Well women's clinic in London, UK.Population or Sample Four hundred and twenty-eight women aged 20-64 years.Methods Postal questionnaire survey.Main outcome measures Psychosocial and psychosexual outcomes were anxiety, distress and feelings about current, past and future sexual relationships.Results Women with normal cytology who tested positive for HPV (HPVdivided by) were significantly more anxious and distressed than women who were negative (HPV-) using both a state anxiety measure [F(1,267)=29, P

91% of low-grade abnormalities on Pap smears in adolescents and young women regress within 36 months and only 3% progress to high-grade disease. This is the main finding from the cohort study in today’s Lancet by Anna- Barbara Moscicki and colleagues from the University of California at San Francisco. These findings are similar to those of a smaller study from Brazil. In the Brazil study which was not restricted to young women an estimated 92.5% of cases regressed within 24 months and 6.5% progressed. The protocol in Moscicki and colleagues’ study called for women with a colposcopic high-grade lesion to be randomly assigned to biopsy or no biopsy. We are told that 17 women were excluded because they had highgrade squamous intraepithelial lesions (HSIL) on histological examination and that 67 of the 187 women included had biopsies taken. If 17 of the 84 (20%) women who had a biopsy had HSIL we can infer that a number of HSILs were missed in the 120 women who did not have a biopsy. Thus Moscicki’s study provides strong indirect evidence that HSIL regresses in adolescents and young women in accord with the findings from another study. (excerpt)

AIM--To investigate the distribution of cytokeratins 10, 13, 14 and 19 in biopsy specimens taken from acetowhite and non-acetowhite areas of the cervix. METHOD--Cervical biopsy specimens were taken from both acetowhite and non-acetowhite areas from 44 patients who presented with abnormal cervical cytology. The specimens were snap frozen in liquid nitrogen and multiple sections taken from each specimen. Staining was performed for cytokeratins 10, 13, 14, 19 and NADPH diaphorase enzyme. The areas of each section positive for the various markers were measured. RESULTS--Cytokeratin 10 positive cells were greatly increased in number in acetowhite biopsy specimens compared with non-acetowhite samples (45.1% v 2.8%; p < 0.0001). Cytokeratin 19 was also increased, but to a lesser extent (17.8% v 5.5%; p < 0.0001). In contrast, the almost universal expression of cytokeratin 13 was reduced in acetowhite biopsy specimens (86.2% v 96.9%; p < 0.0001). Cytokeratin 14 was found diffusely in the basal region of the stratified squamous epithelium and was marginally more apparent in the acetowhite biopsy specimens (p = 0.04). CONCLUSION--It is suggested that the presence of cytokeratin 10 may be an essential requirement for the formation of acetowhite change in association with the cellular swelling caused by acetic acid.

The paper by Stephenson et al. claims that it is the largest RCT of an extended combined oral contraceptive pill (COC) regimen apart from that of Anderson et al. However with 503 recruits it is half the size of an RCT published in April 2012 and and less than a third of the size of an RCT published in August 2012 in your journal both of which also showed that the conventional regimen and the flexible extended regimens were well tolerated. I am surprised that these trials were not mentioned in the discussion. I am also interested in the fact that at the largest recruiting site approximately 47% of women declining to take part did not wish to change their COC-I am assuming this since the authors state that 90% of all participants were taking the COC at the time of recruitment. Were any reasons given for example had the women had a previous negative experience with Microgynon and therefore changed to a different COC? This might explain such a high level of reluctance to participate. (full text) Copyright © 2013 Elsevier Inc. All rights reserved.

Tailoring the length of combined oral contraceptive (COC) pill use to the individual woman is an effective solution to problems associated with the 7-day pill-free interval (PFI).

Anne Szarewski,1 Cecilia Moeller2 1Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom; 2Bayer HealthCare Pharmaceuticals, Global Market Research General Medicine, Berlin, Germany Background: Monthly bleeding can have a negative impact on daily life and, given the choice, many women would reduce the frequency of bleeding. While some women choose to occasionally postpone or reduce bleeding frequency with an oral contraceptive (OC), most women have no or limited experience of regularly reducing the frequency of scheduled bleeding with OCs, ie, the extended OC regimen. Study design: An online survey of 4039 women aged 15–49 years who were currently using, had used, or would consider using any form of hormonal contraception was conducted in Brazil, Canada, Czech Republic, France, Germany, Italy, UK, and USA to assess awareness of and the reasons for and against reducing bleeding frequency. Results: Overall, 51.1% and 30.7% of women surveyed were aware that they could occasionally or regularly reduce bleeding frequency with an OC. Moreover, 27.6% and 9.9% of previous/current OC users had occasionally or regularly reduced bleeding frequency with an OC. The main reasons for reducing bleeding frequency were convenience, physician recommendations, special events, and relief of problems associated with bleeding. Many women mistakenly believed that reducing bleeding frequency would have a negative health impact. Conclusion: Additional efforts are needed to educate women about the possibility and potential health benefits of reducing bleeding frequency and to dispel misconceptions about the use of extended OC regimens. Keywords: extended regimen, menstruation, oral contraceptive, withdrawal bleeding, scheduled bleeding

O Lidegaard, LH Nielson, CW Skovlund. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001–10. BMJ 2012;344:e2990 This is basically a companion paper to the one published last year in the British Medical Journal,1 which concentrated on the pill and was comprehensively criticised in the January 2012 issue of this Journal,2 to which readers are referred. This analysis, also from the Danish registry, looks at the Evra® patch, NuvaRing®, Implanon® and the levonorgestrel-releasing intrauterine system (Mirena® IUS). All the previous issues of confounding, lack of information regarding smoking, body mass index and family history, and not comparing like with like, apply here. It is important to compare new users with new users, as a well-established fact is that the …

The papers on venous thromboembolism in oral contraceptive users have similar faults to earlier database studies.1 2 These include lack of validation of venous thromboembolism (VTE) cases and lack of information on, or control of, important potential confounders such as duration of use, especially short duration use; family history; body mass index (BMI); and smoking.3 Jick and Hernandez’s …