HPV self-sampling and follow-up over two rounds of cervical screening in Australia - the iPap trial.

OBJECTIVES: Previously, based on 6 months of follow-up, we showed that HPV self-sampling improved participation in cervical screening compared to a reminder letter for Pap testing for never- and under-screened women. Here, we report follow-up and related screening outcomes for women who participated in the initial self-sampling over two screening rounds. SETTING: The randomised controlled trial was conducted in Australia. METHODS: Never- and under-screened women were randomly allocated to the HPV self-sampling or the reminder for Pap test arm and followed at 6 and 36 months since the kits were first mailed. RESULTS: The first round of HPV self-sampling kits were mailed from May-July 2014 to 12 572 women. After 36 months, 19% of never-screened and 9% of under-screened women returned a kit for HPV testing; 2.7% were HPV 16/18 and 5.8% non-16/18 HPV positive. Compliance with first round follow-up was 84% (95% CI: 77.1-89.5%). Non-compliant and cytology triage negative women were mailed another kit at 12 months. Compliance at 12-month follow-up was 59.3% (49.4 to 68.6%). Of 37 women with a 12-month repeat HPV, 70% were positive. Of women who tested negative for HPV in the first round (n = 1573), 25% attended regular screening in the next round and none had CIN2 + detected. The overall prevalence of CIN2 + was 8.5 per 1000 screened (4.8 to 13.9 per 1000). CONCLUSION: While self-sampling can successfully engage women, compliance with repeat testing may require monitoring. The clinician-supported self-collection pathway now in use in Australia will likely improve women's engagement with follow-up.

Pathways to a cancer-free future: A protocol for modelled evaluations to maximize the future impact of interventions on cervical cancer in Australia.

OBJECTIVE: Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence from modelled evaluations of interventions across the cervical cancer spectrum. METHODS: Based on evidence from literature reviews and guidance from a multi-disciplinary Scientific Advisory Committee (SAC), the most relevant evaluations for prevention, diagnosis and treatment were identified. RESULTS: Priority evaluations agreed by the SAC included: increasing/decreasing and retaining vaccination uptake at the current level; vaccinating older women; increasing screening participation; methods for triaging HPV-positive women; improving the diagnosis of cervical intraepithelial neoplasia (CIN) and cancer; treating cervical abnormalities and cancer; and vaccinating women treated for CIN2/3 to prevent recurrence. Evaluations will be performed using a simulation model, Policy1-Cervix previously used to perform policy evaluations in Australia. Exploratory modelling of interventions using idealised scenarios will initially be conducted in single birth cohorts. If these have a significant impact on findings then evaluations with more realistic assumptions will be conducted. Promising strategies will be investigated further by multi-cohort simulations predicting health outcomes, resource use and cost outcomes. CONCLUSIONS: Pathways-Cervix will assess the relative benefits of strategies and treatment options in a systematic and health economic framework, producing a list of 'best buys' for future decision-making in cervical cancer control.

Protocol for Compass: a randomised controlled trial of primary HPV testing versus cytology screening for cervical cancer in HPV-unvaccinated and vaccinated women aged 25-69 years living in Australia.

INTRODUCTION: Australia's National Cervical Screening Program (NCSP) currently recommends 2-year cytology in women aged 18-69 years. Following a review of the NCSP prompted by the implementation of human papillomavirus (HPV) vaccination, the programme will transition in 2017 to 5-year primary HPV screening with partial genotyping for HPV16/18 in women aged 25-74 years. Compass is a sentinel experience for the renewed NCSP and the first prospectively randomised trial of primary HPV screening compared with cytology to be conducted in a population with high uptake of HPV vaccination. This protocol describes the main Compass trial, which commenced after a pilot study of ~5000 women completed recruitment. METHODS AND ANALYSIS: Women aged 25-69 years will be randomised at a 1:2 allocation to (1) 2.5-year image-read, liquid-based cytology (LBC) screening with HPV triage of low-grade smears (active control Arm A) or (2) 5-year HPV screening with partial genotyping and referral of HPV16/18-positive women to colposcopy (intervention Arm B). Women in Arm B positive for other oncogenic HPV (not 16/18) will undergo secondary randomisation at a 1:1 allocation to either LBC or dual-stained (p16INK4a and Ki-67) cytology testing (dual-stained cytology). The primary outcome is cumulative CIN3+ (CIN3, adenocarcinoma in situ and invasive cervical cancer) following a 5-year HPV exit testing round in both arms, in women randomised to the HPV arm versus women randomised to the LBC arm, based on an intention-to-treat analysis. The primary outcome will first be tested for non-inferiority and if declared, the primary outcome will be tested for superiority. A total of 36 300 women in birth cohorts not offered vaccination and 84 700 women in cohorts offered vaccination will be recruited, bringing the final sample size to 121 000. The trial is powered for the secondary outcome of cumulative CIN3+ in screen-negative women, adjusted for censoring after CIN2+ treatment and hysterectomy. ETHICS AND DISSEMINATION: Approved by the Bellberry Ethics Committee (2014-11-592). Findings will be reported in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT02328872; Pre-results.

Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: Results of the Compass pilot randomised trial.

BACKGROUND: Using primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia's HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%-77%). METHODS AND FINDINGS: Compass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25-64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology ('LBC screening'), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types ('HPV+LBC triage'), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types ('HPV+DS triage'). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%-3.9%]) and 1/995 (0.1% [95% CI 0.0%-0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%-4.7%]) and 20/1,992 (1.0% [95% CI 0.6%-1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%-4.9%]) and 24/2,008 (1.2% [95% CI 0.8%-1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women's vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available. CONCLUSIONS: In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%-44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613001207707.

Home-based HPV self-sampling improves participation by never-screened and under-screened women: Results from a large randomized trial (iPap) in Australia.

We conducted a randomized controlled trial to determine whether HPV self-sampling increases participation in cervical screening by never- and under-screened (not screened in past 5 years) women when compared with a reminder letter for a Pap test. Never- or under-screened Victorian women aged 30-69 years, not pregnant and with no prior hysterectomy were eligible. Within each stratum (never-screened and under-screened), we randomly allocated 7,140 women to self-sampling and 1,020 to Pap test reminders. The self-sampling kit comprised a nylon tipped flocked swab enclosed in a dry plastic tube. The primary outcome was participation, as indicated by returning a swab or undergoing a Pap test; the secondary outcome, for women in the self-sampling arm with a positive HPV test, was undergoing appropriate clinical investigation. The Roche Cobas® 4800 test was used to measure presence of HPV DNA. Participation was higher for the self-sampling arm: 20.3 versus 6.0% for never-screened women (absolute difference 14.4%, 95% CI: 12.6-16.1%, p < 0.001) and 11.5 versus 6.4% for under-screened women (difference 5.1%, 95% CI: 3.4-6.8%, p < 0.001). Of the 1,649 women who returned a swab, 45 (2.7%) were positive for HPV16/18 and 95 (5.8%) were positive for other high-risk HPV types. Within 6 months, 28 (62.2%) women positive for HPV16/18 had colposcopy as recommended and nine (20%) had cytology only. Of women positive for other high-risk HPV types, 78 (82.1%) had a Pap test as recommended. HPV self-sampling improves participation in cervical screening for never- and under-screened women and most women with HPV detected have appropriate clinical investigation.

HAVE YOU HAD THE HPV VACCINE? YOU STILL NEED TO BE SCREENED FOR CERVICAL CANCER.

Nearly all cervical cancer is caused by one or more oncogenic strain of Human Papilloma Virus (HPV) (Walboomers et al. 1999). There are about 40 anogenital HPV types and approximately 15 are associated with cancer of the cervix.

Women's experience with home-based self-sampling for human papillomavirus testing.

BACKGROUND: Increasing cervical screening coverage by reaching inadequately screened groups is essential for improving the effectiveness of cervical screening programs. Offering HPV self-sampling to women who are never or under-screened can improve screening participation, however participation varies widely between settings. Information on women's experience with self-sampling and preferences for future self-sampling screening is essential for programs to optimize participation. METHODS: The survey was conducted as part of a larger trial ("iPap") investigating the effect of HPV self-sampling on participation of never and under-screened women in Victoria, Australia. Questionnaires were mailed to a) most women who participated in the self-sampling to document their experience with and preference for self-sampling in future, and b) a sample of the women who did not participate asking reasons for non-participation and suggestions for enabling participation. Reasons for not having a previous Pap test were also explored. RESULTS: About half the women who collected a self sample for the iPap trial returned the subsequent questionnaire (746/1521). Common reasons for not having cervical screening were that having Pap test performed by a doctor was embarrassing (18 %), not having the time (14 %), or that a Pap test was painful and uncomfortable (11 %). Most (94 %) found the home-based self-sampling less embarrassing, less uncomfortable (90 %) and more convenient (98%) compared with their last Pap test experience (if they had one); however, many were unsure about the test accuracy (57 %). Women who self-sampled thought the instructions were clear (98 %), it was easy to use the swab (95 %), and were generally confident that they did the test correctly (81 %). Most preferred to take the self-sample at home in the future (88 %) because it was simple and did not require a doctor's appointment. Few women (126/1946, 7 %) who did not return a self-sample in the iPap trial returned the questionnaire. Their main reason for not screening was having had a hysterectomy. CONCLUSIONS: Home-based self-sampling can overcome emotional and practical barriers to Pap test and increase participation in cervical screening despite some women's concerns about test accuracy. Mailing to eligible women and assuring women about test accuracy could further optimize participation in screening.

A pilot study to compare dry cervical sample collection with standard practice of wet cervical samples for human papillomavirus testing.

BACKGROUND: For human papillomavirus (HPV) DNA detection, specimen collection and transportation using a dry swab without transport medium has advantages, in various situations, over liquid media. OBJECTIVE: In this pilot study we evaluated whether a dry cervical sample taken with a flocked swab (dry sample) is a valid alternative for HPV DNA testing compared with the standard practice of a wet sample taken with a cyto-broom placed directly into liquid media (wet sample). STUDY DESIGN: Women attending the dysplasia clinic at the Royal Women's Hospital, Melbourne Australia between November 2013 and February 2014 were enrolled. During colposcopic examination, a practitioner collected wet and dry cervical samples, with the order of collection randomised. In the laboratory both samples were left for a week before being tested for 14 high-risk HPV types using the Roche Cobas 4800 test. RESULTS: Overall, 209 had valid HPV results from both samples. The observed agreement for HPV detection between wet and dry samples was 92.8% and kappa was 0.85 (95% confidence interval (95% CI): 0.78-0.92). There was no statistical difference in the percent HPV positive for each sample (p = 0.30). HPV testing of the dry sample had an 88.5% (95% CI: 79.9-94.3%) sensitivity for HPV detected using the wet specimen. For the HPV results categorized hierarchically, there was 92.8% overall agreement and a kappa of 0.87 (95% CI = 0.80-0.93) for the paired results. CONCLUSION: Using dry flocked swabs to collect cervical cells is a valid alternative to collecting wet samples for HPV DNA testing using a PCR based test.

Women's views on human papillomavirus self-sampling: focus groups to assess acceptability, invitation letters and a test kit in the Australian setting.

UNLABELLED: Background The study evaluated acceptability, invitation letters and the test kit for a trial of human papillomavirus (HPV) self-sampling among never- and under-screened women in Australia. METHODS: Victorian women, 30-69 years, who had never had a Pap test or were overdue for one, participated. Four focus groups including eight to nine participants segmented by age (30-49 and 50-69 years) and screening history (never- and under-screened) were conducted in August 2013. Discussions were recorded and transcribed verbatim and data analysed using thematic content analysis. RESULTS: The response to the concept of HPV self-sampling was positive. Decision-making was largely influenced by the content of a pre-invitation letter. Appealing features of self-sampling were cost (free), convenience (home-based) and anticipated less discomfort (with a swab) than a Pap test. Small kits that fit in mailboxes were preferred over post office parcel collection. The perceived barriers include concerns about test accuracy and lack of confidence that a home-based test would give the same results as a physician administered test. Women wanted information on the timing of receipt of the results and information about the organisation providing the test. CONCLUSION: HPV self-sampling is a possible alternative for Australian women who are reluctant to have a Pap test and may increase the likelihood of participation in cervical cancer screening if women's concerns about it can be addressed. The findings of this study are relevant for researchers, policymakers and practitioners implementing self-sampling for under-screened women as part of cervical screening programs.

Rationale and design of the iPap trial: a randomized controlled trial of home-based HPV self-sampling for improving participation in cervical screening by never- and under-screened women in Australia.

BACKGROUND: Organized screening based on Pap tests has substantially reduced deaths from cervical cancer in many countries, including Australia. However, the impact of the program depends upon the degree to which women participate. A new method of screening, testing for human papillomavirus (HPV) DNA to detect the virus that causes cervical cancer, has recently become available. Because women can collect their own samples for this test at home, it has the potential to overcome some of the barriers to Pap tests. The iPap trial will evaluate whether mailing an HPV self-sampling kit increases participation by never- and under-screened women within a cervical screening program. METHODS/DESIGN: The iPap trial is a parallel randomized controlled, open label, trial. Participants will be Victorian women age 30-69 years, for whom there is either no record on the Victorian Cervical Cytology Registry (VCCR) of a Pap test (never-screened) or the last recorded Pap test was between five to fifteen years ago (under-screened). Enrolment information from the Victorian Electoral Commission will be linked to the VCCR to determine the never-screened women. Variables that will be used for record linkage include full name, address and date of birth. Never- and under-screened women will be randomly allocated to either receive an invitation letter with an HPV self-sampling kit or a reminder letter to attend for a Pap test, which is standard practice for women overdue for a test in Victoria. All resources have been focus group tested. The primary outcome will be the proportion of women who participate, by returning an HPV self-sampling kit for women in the self-sampling arm, and notification of a Pap test result to the Registry for women in the Pap test arm at 3 and 6 months after mailout. The most important secondary outcome is the proportion of test-positive women who undergo further investigations at 6 and 12 months after mailout of results. DISCUSSION: The iPap trial will provide strong evidence about whether HPV self-sampling could be used in Australia to improve participation in cervical screening for never-and under-screened women. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12613001104741; UTN: U1111-1148-3885.

HPV testing in the National Cervical Screening Program--when is it recommended?

BACKGROUND: Women with high grade cervical squamous intraepithelial lesions (HSILs) have traditionally had annual smears after treatment. This recommendation however, changed in 2005. Since then, testing for high risk types of human papillomavirus (HPV) has been an integral part of the follow up of these women. Despite this, health practitioners are failing to perform HPV tests on all women eligible for testing. OBJECTIVE: This article highlights the recommendation for HPV testing after treatment of HSILs. By testing appropriately, a significant number of these women will be able to return to routine cervical screening. DISCUSSION: Persistent infection with high risk HPV types is known to cause high grade cervical changes which, if left untreated, can progress to cervical cancer. Following treatment, high grade changes have been shown to regress in the majority of women and ongoing risk can be assessed using HPV testing. Cervical cytology accompanied by HPV testing should commence 12 months after treatment, and continue annually until the woman has tested negative for both tests on two consecutive occasions. When all four tests are negative, the woman can safely return to the recommended routine Pap screening interval (currently 2-yearly).

The incidence of genital warts in Australian women prior to the national vaccination program.

The quadrivalent human papillomavirus (HPV) vaccine currently being delivered to Australian women aged 12-26 years under the National HPV Vaccination Program promises to substantially reduce the incidence of genital warts. We review what is known about the burden of genital warts among Australian women. Incidence appears to peak among women aged 20-24 years, of whom 1.4% report genital warts in the previous year and who are hospitalised for treatment at a rate of 26 per 100,000. A surveillance system capable of documenting any decrease in the incidence of genital warts and recurrent respiratory papillomatosis after vaccination is urgently required.

Abnormal Pap tests after the HPV vaccine.

BACKGROUND: Worldwide, cervical cancer affects 500 000 women and causes 275 000 deaths annually. Persistent infection with one of 13 oncogenic types of human papillomavirus (HPV) is now known to be the cause of both squamous and adenocervical carcinomas of the cervix. The Pap test involves the examination of exfoliated cells from the cervix and has been shown to be an effective way of detecting the precursors of squamous cell carcinoma. In Australia, commencing in 2007, a free quadrivalent HPV vaccine was offered to all females aged 12-26 years. OBJECTIVE: This article looks at why a substantial number of young women who have been vaccinated with the HPV vaccine will still have Pap test abnormalities. DISCUSSION: Prophylactic efficacy of the two HPV vaccines against specific HPV types is almost 100%. This knowledge has created an expectation of the demise of both cervical cancer and Pap test abnormalities. Efficacy of the vaccine is dependent upon the recipient not having been infected with that HPV type. It is likely that most of the women aged 18-26 years who have had the HPV vaccine were already sexually active and therefore exposed to one or more HPV types. We can still expect to see a substantial number of young vaccinated women with Pap test abnormalities, due to both HPV exposure before vaccination and to the many HPV types not covered by the vaccine. A noticeable reduction in cancers and Pap test abnormalities will not be seen for some years.

Pap test update.

BACKGROUND: 2006 was an eventful year in the area of screening to prevent cervical cancer. New screening guidelines were introduced nationally in July, and in November the Australian Government agreed to fund one of the human papillomavirus (HPV) vaccines, Gardasil, under the National Immunisation Program. OBJECTIVE: This article discusses the cervical screening program and the Pap test in the era of HPV vaccination. DISCUSSION: With the introduction of a vaccine to prevent the acquisition of significant genital HPV types, many practitioners will be questioning the continuing need for the Pap test. But for those women who have missed out on the vaccine, the Pap test will still play a crucial role in preventing the development of cervical cancer, and the vaccinated cohort will need to continue screening in some form as the vaccine does not cover all the HPV types responsible for anogenital cancer.

Human papillomavirus: beware the infection you can't see.

BACKGROUND: Genital human papillomavirus (HPV) is a common sexually transmitted infection. In the first 10 years of sexual activity, point prevalence rates approach 25% and the lifetime risk of acquisition of this infection may be as high as 80%. There are over 200 types of HPV, of which approximately 50 infect the genital area. OBJECTIVE: This article aims to discuss HPV detection and its role in cervical cancer development. DISCUSSION: The HPV types that cause genital warts do not cause cervical cancer. The subclinical types (especially types 16 and 18) are most frequently found in high grade epithelial abnormalities and therefore can potentially cause anogenital cancers. Human papillomavirus is a 'necessary but not sufficient cause for cervical cancer'. Most genital HPV infection is transient. Cervical cancer is actually a rare outcome of HPV infection. However, only 5% of women in developing countries have had a Pap smear in the past five years, and worldwide approximately 250 thousand women die of this disease every year. The role of HPV DNA testing has not yet been defined, but is no doubt a potential tool for the future. Meanwhile, international vaccine trials using HPV virus-like particles are taking place, and look promising.