Marie-Hélène Mayrand

Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: Design, methods and preliminary accrual results of the Canadian cervical cancer screening trial (CCCaST)

Since infection with oncogenic human papillomavirus (HPV) has been considered a necessary cause of cervical cancer, tests for oncogenic HPV types have been proposed as adjuncts or replacements to Pap cytology. We designed the Canadian Cervical Cancer Screening Trial (CCCaST) to compare the relative efficacy of HPV DNA testing and Pap cytology in primary screening for cervical cancer and its high‐grade precursors. CCCaST randomized women aged 30–69 years in Montreal (Quebec) and in St. Johns (Newfoundland) to 1 of 2 screening groups: focus on Pap (conventional) or focus on HPV testing (Hybrid Capture 2). Women in both arms received both tests, but were randomized as to their order, the first test being the index test. Women with an abnormal Pap test or a positive HPV test underwent colposcopy and biopsy, as did a random sample of women with a negative index test. CCCaST enrolled 9,667 women between October 2002 and October 2004. At enrolment, 2.8% had an abnormal Pap test, 6.1% had a positive HPV test and 1.1% were abnormal in both tests. ASC‐US was the most frequent cytological abnormality, representing 64% of abnormal Pap results. The frequency of abnormal Pap and HPV results decreased with increasing age and the proportion of HPV‐positive results increased with the severity of Pap abnormality. Efficacy analysis will determine if the extra referrals with HPV DNA testing will translate into a relevant increase in high‐grade cervical cancer precursor detection. Because of its design, CCCaST will provide sound evidence for formulating cervical cancer screening strategies.

Population-Level Impact of the Bivalent, Quadrivalent, and Nonavalent Human Papillomavirus Vaccines: A Model–Based Analysis

BACKGROUND Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines. METHODS We developed an individual-based, transmission-dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada. RESULTS Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers. CONCLUSIONS The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer.

Morphometry of the Pelvic Floor Muscles in Women With and Without Provoked Vestibulodynia Using 4D Ultrasound

INTRODUCTION It has been suggested that pelvic floor muscles (PFMs) play an important role in provoked vestibulodynia (PVD) pathophysiology. Controversy in determining their exact contribution may be explained by methodological limitations related to the PFM assessment tools, specifically the pain elicited by the measurement itself, which may trigger a PFM reaction and introduce a strong bias. AIM The aim of this study was to compare PFM morphometry in women suffering from PVD to asymptomatic healthy control women using a pain-free methodology, transperineal four-dimensional (4D) ultrasound. METHODS Fifty-one asymptomatic women and 49 women suffering from PVD were recruited. Diagnosis of PVD was confirmed by a gynecologist following a standardized examination. All the participants were nulliparous and had no other urogynecological conditions. The women were evaluated in a supine position at rest and during PFM maximal contraction. MAIN OUTCOME MEASURES Transperineal 4D ultrasound, which consists of a probe applied on the surface of the perineum without any vaginal insertion, was used to assess PFM morphometry. Different parameters were assessed in sagittal and axial planes: anorectal angle, levator plate angle, displacement of the bladder neck, and levator hiatus area. The investigator analyzing the data was blinded to the clinical data. RESULTS Women with PVD showed a significantly smaller levator hiatus area, a smaller anorectal angle, and a larger levator plate angle at rest compared with asymptomatic women, suggesting an increase in PFM tone. During PFM maximal contraction, smaller changes in levator hiatus area narrowing, displacement of the bladder neck, and changes of the anorectal and of the levator plate angles were found in women with PVD compared with controls, which may indicate poorer PFM strength and control. CONCLUSION Using a reliable and pain-free methodology, this research provides sound evidence that women with PVD display differences in PFM morphometry suggesting increased tone and reduced strength.

Colposcopic management of abnormal cervical cytology and histology.

OBJECTIVE To provide a guideline for managing abnormal cytology results after screening for cervical cancer, to clarify the appropriate algorithms for follow-up after treatment, and to promote the best possible care for women while ensuring efficient use of available resources. OUTCOMES Women with abnormal cytology are at risk of developing cervical cancer; appropriate triage and treatment will reduce this risk. This guideline will facilitate implementation of common standards across Canada, moving away from the current trend of individual guidelines in each province and territory. EVIDENCE Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in October 2008 using appropriate controlled vocabulary (e.g., colposcopy, cervical dysplasia) and key words (e.g., colposcopy management, CIN, AGC, cervical dysplasia, LEEP, LLETZ, HPV testing, cervical dysplasia triage). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to July 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, and national and international medical specialty societies. Expert opinion from published peer-reviewed literature and evidence from clinical trials is summarized. Consensus opinion is outlined when evidence is insufficient. VALUES The quality of the evidence is rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). VALIDATION This guideline has been reviewed for accuracy from content experts in cytology, pathology, and cervical screening programs. Guideline content was also compared with similar documents from other organizations including the American Society for Colposcopy and Cervical Pathology, the British Society for Colposcopy and Cervical Pathology, and the European Cancer Network.

The future of HPV testing in clinical laboratories and applied virology research.

BACKGROUND Human papillomaviruses (HPV) are now considered etiologic agents of cancer of the uterine cervix. Adjunctive diagnostic procedures for the detection of HPV infection could increase the sensitivity of primary and secondary screening of cervical cancer. HPV testing could also improve the specificity of screening programs resulting in avoidance of overtreatment and saving of costs for confirmatory procedures. OBJECTIVES To review the rationale of HPV testing in genital diseases and the potential applications of HPV DNA detection methods for clinical and epidemiological purposes. RESULTS Progression of HPV infection is associated with the persistence of HPV infection, involvement of high-risk HPV types, high HPV viral load in specimens, integration of viral DNA and possibly the presence of cofactors. The design of HPV diagnostic tests will need to take into account these parameters of disease progression. HPV DNA detection techniques based on signal-amplification are standardized, commercially available and detect several high-risk HPV types. They increase the sensitivity of screening for high-grade and low-grade lesions. Although they may yield false-negative results in the presence of significant HPV-related disease, new test formats could resolve this weakness. Amplification techniques are ideal instruments for epidemiologic purposes since they minimize misclassification of HPV infection status and allow for the detection of low viral burden infections. They are currently not readily applicable to diagnostic laboratories. CONCLUSIONS Before recommending HPV testing, prospective trials of untreated LSIL with HPV testing as well as the determination of the efficacy and cost-effectiveness of novel HPV tests, need to be completed.

Human Papillomavirus (HPV) DNA Triage of Women with Atypical Squamous Cells of Undetermined Significance with cobas 4800 HPV and Hybrid Capture 2 Tests for Detection of High-Grade Lesions of the Uterine Cervix

ABSTRACT The triage of women with high-risk (HR) human papillomavirus (HPV)-positive smears for atypical squamous cells of undetermined significance (ASC-US) to colposcopy is now an integrated option in clinical guidelines. The performance of cobas 4800 HPV and that of Hybrid Capture 2 (HC2) for HR HPV DNA detection in cervical samples in PreservCyt were compared in 396 women referred to colposcopy for ASC-US. Of these, 316 did not have cervical intraepithelial neoplasia (CIN), 47 had CIN1, 29 had CIN2 or CIN3 (CIN2+), and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 149 (37.6%) samples with HC2 and cobas 4800 HPV, respectively (P = 0.15). The clinical sensitivities and specificities for detecting CIN2+ were 89.7% (95% confidence interval [CI], 72.8 to 97.2%) and 66.7% (95% CI, 61.7 to 71.3%) with cobas 4800 HPV and 93.1% (95% CI, 77.0 to 99.2%) and 72.2% (95% CI 67.4 to 76.5%) with HC2. The performance of cobas 4800 HPV was similar to that of HC2 for identifying women with ASC-US who would benefit the most from colposcopy.

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial

BACKGROUND Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsors study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING Merck & Co, Inc.

Prevalence of human papillomaviruses in semen: a systematic review and meta-analysis

STUDY QUESTION What is the prevalence of human papillomavirus (HPV) in semen? SUMMARY ANSWER HPV is present in the semen of asymptomatic men, with a pooled prevalence in a random effects meta-analysis of populations seeking fertility evaluation/treatment of 16%, versus 10% in other populations. WHAT IS KNOWN ALREADY The main risk of donor insemination (DI) is known to be contamination with an infectious agent. HPV is the necessary cause of cervical cancer, and plays an etiologic role in other anogenital cancers. Although it is known to be prevalent and sexually transmitted, donor semen specimens are not tested for the presence of HPV. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis of studies published between January 1980 and June 2013 were performed. Variables collected included characteristics of study populations, method of semen preparation, HPV DNA detection and genotyping, HPV types targeted and proportion of HPV positivity. PARTICIPANTS/MATERIALS, SETTING, METHODS Two investigators independently assessed the studies for inclusion in the review and abstracted the data, while others reviewed the extracted data in detail. Studies were included if they provided data on HPV DNA prevalence in semen and PCR-based methods were used. For the meta-analysis, reports were separated according to the study populations, creating two distinct subgroups: populations seeking fertility evaluation/treatments, and other populations. Data were analysed using a random effects model for each subpopulation. MAIN RESULTS AND THE ROLE OF CHANCE The literature search identified 285 studies, and in the 27 studies that were included the HPV DNA prevalence in 4029 semen samples varied from 0 to 100%. The three studies focusing on sperm donors identified HPV DNA in 26.3, 7.5 and 16.0% of semen samples. HPV-16 was the most common type overall. The pooled prevalence in a random effects meta-analysis of seven studies focusing on infertile populations was 16% [95% confidence interval (CI): 10-23%] versus 10% (95% CI: 7-14%) in 11 reports focusing on other populations. LIMITATIONS, REASONS FOR CAUTION First, despite defining clinically relevant subgroups, substantial heterogeneity remained. Secondly, although we retrieved data from reports in English or French only, after reviewing the five reports in other languages only two more could have been added and, as their prevalence estimates were similar to those of studies included in our review, we do not believe that exclusion of these reports biased our results or conclusions. WIDER IMPLICATIONS OF THE FINDINGS HPV DNA can be found in donor semen and preliminary studies confirm genome activity. For this reason, and although the exact consequences of insemination with HPV-infected semen (cervical infections/lesions, impact on success rate of DI) remain to be clarified, we believe that HPV-infected sperm should be considered a health risk unless well-designed studies prove otherwise. The development and validation of adequate sperm washing techniques before DI appears to be a promising option. STUDY FUNDING/COMPETING INTEREST(S) C.L. and P.M. have no conflicts of interests relevant to the submitted work. H.T. has served as a consultant and on advisory boards and has received speaker fees and travel assistance from Merck-Frosst Canada, Glaxo SmithKline Pharmaceuticals, Belgium and Gilead Sciences. F.C. has received grants through his institution from Merck and Roche, as well as honoraria from Merck and Roche for lectures on HPV. M.-H.M. has received grants though her institution from Merck and Qiagen and lecture honoraria from Merck and GSK for conferences on HPV and best practices in cervical cancer prevention. TRIAL REGISTRATION NUMBER N/A.

The impact of intolerance of uncertainty on anxiety after receiving an informational intervention about HPV: A randomised controlled study

This study examined the impact of intolerance of uncertainty (IU) and an informational intervention about human papillomavirus (HPV) infection on perceived uncertainty about ones HPV testing status (referred to as ‘HPV uncertainty’) and anxiety. IU, HPV uncertainty and other pre-intervention measures were assessed through mailed questionnaires. Participants were then randomly assigned to receive either a long (N = 125) or short (N = 124) HPV-specific information pamphlet or a long (N = 131) or short (N = 115) control pamphlet about cancer prevention. Participants subsequently completed measures of HPV uncertainty and anxiety. Providing a lot of HPV information increased HPV uncertainty more than providing little HPV information and cancer prevention information. Among women who received the long HPV or the short control pamphlet, those with higher IU were more anxious than those with lower IU. Women with higher IU are more likely to seek HPV information, but they may also be at risk for experiencing higher anxiety because factual uncertainties about HPV cannot be resolved through the provision of more information.

A comparison of cognitive-behavioral couple therapy and lidocaine in the treatment of provoked vestibulodynia: study protocol for a randomized clinical trial

BackgroundProvoked vestibulodynia (PVD), a frequent form of chronic genital pain, is associated with decreased sexual function for afflicted women, as well as impoverished sexual satisfaction for women and their partners. Pain and sexuality outcomes for couples with PVD are influenced by interpersonal factors, such as pain catastrophizing, partner responses to pain, ambivalence over emotional expression, attachment style and perceived relationship and sexual intimacy. Despite recommendations in the literature to include the partner in cognitive-behavioral therapy targeted at improving pain and sexuality outcomes, no randomized clinical trial has tested the efficacy of this type of intervention and compared it to a first-line medical intervention.MethodsThis bi-center, randomized clinical trial is designed to examine the efficacy of cognitive-behavioral couple therapy compared to topical lidocaine. It is conducted across two Canadian university-hospital centers. Eligible women diagnosed with PVD and their partners are randomized to one of the two interventions. Evaluations are conducted using structured interviews and validated self-report measures at three time points: Pre-treatment (T1: prior to randomization), post-treatment (T2), and 6-month follow-up (T3). The primary outcome is the change in reported pain during intercourse between T1 and T2. Secondary outcomes focus on whether there are significant differences between the two treatments at T2 and T3 on (a) the multidimensional aspects of women’s pain and (b) women and partners’ sexuality (sexual function and satisfaction), psychological adjustment (anxiety, depression, catastrophizing, self-efficacy, and quality of life), relationship factors (partner responses and dyadic adjustment) and self-reported improvement and treatment satisfaction. In order to detect an effect size as small as 0.32 for secondary outcomes, a sample of 170 couples is being recruited (27% dropout expected). A clinically significant decrease in pain is defined as a 30% reduction.DiscussionThe randomized clinical trial design is the most appropriate to examine the efficacy of cognitive-behavioral couple therapy, a recently developed and pilot-tested psychosocial intervention for couples coping with PVD, in comparison to a frequent first-line treatment option, topical lidocaine. Findings from this study will provide important information about empirically supported treatment options for PVD, and inform future treatment development and research for this patient population.Trial registrationClinicaltrials.gov NCT01935063; registration date: 27 August 27 2013.