Evidence of decreased long-term risk of cervical pre-cancer after negative primary HPV screens compared to negative cytology screens in a longitudinal cohort study.

BACKGROUND: Growing use of primary HPV cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. METHODS: This longitudinal cohort study (British Columbia, Canada, 2008-2022) recruited women and individuals with a cervix (WIC) who received 1-2 negative HPV screen(s) (HPV1 cohort, N = 5,546, HPV2 cohort, N = 6,624) during a randomized trial and WIC with 1-2 normal cytology result(s) (BCS1 cohort, N = 782,297, BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse (CIN2+) was compared between HPV and cytology cohorts. RESULTS: Cumulative risks of CIN2+ were 3.2/1000 (95% CI: 1.6 to 4.7) in HPV1 and 2.7/1000 (CI: 1.2 to 4.2) in HPV2 after eight years. This was comparable to the risk in the cytology cohorts after 3 years (BCS1: 3.3/1000, [CI: 3.1 to 3.4]; BCS2: 2.5, [CI: 2.4 to 2.6]). The cumulative risk of CIN2+ after 10 years was low in HPV cohorts (HPV1: 4.7/1000, [CI: 2.6 to 6.7]; HPV2: 3.9, [CI: 1.1 to 6.6]). CONCLUSIONS: Risk of CIN2+ eight years after negative screen in HPV cohorts was comparable to risk after 3 years in cytology cohorts (the benchmark for acceptable risk). IMPACT: These findings suggest that primary HPV screening intervals could be extended beyond the current five-year recommendation potentially reducing barriers to screening.

Robotic versus vaginal radical trachelectomy for reproductive-aged patients with early-stage cervical carcinoma: A multi-center cohort study.

BACKGROUND: A randomized non-inferiority trial showed worse survival in women with early-stage cervical cancer treated with radical hysterectomy by minimally invasive approach compared to laparotomy; the impact of surgical approach on survival following radical trachelectomy is unknown. OBJECTIVE: To examine oncologic outcomes in women with early-stage cervical cancer who underwent robotic or vaginal radical trachelectomy at Canadian cancer centers with the highest volumes of radical trachelectomy procedures. STUDY DESIGN: Retrospective multi-centre cohort analysis which includes patients who had surgery between 2006 and 2019. Women with International FIGO 2009 stage IA-IB cervical cancer who underwent radical trachelectomy and lymph node assessment were grouped by surgical approach (vaginal versus robotic surgery). RESULTS: A total of 197 patients were included from 4 regional referral centres. 56 women underwent robotic radical trachelectomy and 141 underwent vaginal radical trachelectomy. All patients had lymph node assessment by a minimally invasive technique. Median age was 32 years, median tumor size was 12 mm, and median depth of invasion was 5 mm. Recurrence-free survival was 97% in both groups at a median follow-up of 57 months. On multivariable analysis, after adjusting for previously chosen confounders (high risk pathologic criteria, tumor size, and LVSI) there was no statistically significant difference in PFS between the 2 groups (HR 2.1, 95%CI 0.3-7.1, p = 0.5). Tumor size larger than 2 cm (HR 9.4, 95%CI 2.8-26, p = 0.003) was the only variable predictive of recurrence. CONCLUSION: Survival outcomes were excellent in both cohorts of patients undergoing robotic vs. vaginal radical trachelectomy. The surgical approach was not significantly associated with risk of recurrence after adjusting for clinically important confounders.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study.

Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Methods: Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N = 6204) or two (HPV2, N = 9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N = 1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10-14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPV positive referred to colposcopy; (2) cytology triage with ASCUS or greater referred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Findings: Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11-12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15-17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR = 0.6, 95% CI: 0.5, 0.7) and HPV2 (HR = 0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Interpretation: Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. Funding: This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).

Age-Specific Trends of Invasive Cervical Cancer Incidence in British Columbia, Canada, 1971-2017.

This study examined invasive cervical cancer (ICC) incidence trends in British Columbia (BC) by age and stage-at-diagnosis relative to World Health Organization ICC elimination targets (4 per 100,000 persons). Incident ICC cases (1971-2017) were obtained from the BC Cancer Registry. Annual age-standardized incidence rates (ASIRs) per 100,000 persons were generated using the direct method. ASIRs were examined among all ages 15+ years and eight age groups using Joinpoint Regression with the Canadian 2011 standard population. Standardized rate ratios (SRRs) compared stage II-IV (late) versus stage I (early) ASIRs by age (2010-2017). ICC ASIRs did not reach the elimination target. ASIRs declined from 18.88 to 7.08 per 100,000 persons (1971-2017). Stronger declines were observed among ages 45+ years, with the largest decline among ages 70-79 years (AAPC = -3.2%, 95% CI = -3.9% to -2.6%). Among ages 25-69 years, varying levels of attenuation in declining trends and stabilization were observed since the 1980s. SRRs indicated higher rates of late-stage ICC among ages 55+ years (SRR-55-69 years = 1.34, 95% CI = 1.08-1.71). Overall, ICC incidence declined in BC since 1971 but did not reach the elimination target. The pace of decline varied across age groups and increased with age. Continued efforts are needed to progress cervical cancer elimination among all age groups.

HSV-2 infection and HPV incidence, persistence, and precancerous lesions in a cohort of HPV-vaccinated women living with HIV.

BACKGROUND: Several co-factors for HPV oncogenesis have been proposed, including co-infection with HSV-2. We assessed the relationship between HSV-2 infection and HPV-related outcomes in quadrivalent HPV-vaccinated (qHPV) women living with HIV (WLWH). METHODS: In this multi-site study of immunogenicity and efficacy of the qHPV vaccine in WLWH, visits took place at months -3, 0, 2, 6, 12, 18, 24, and annually thereafter. Participants provided clinical data and cervico-vaginal swabs for HPV DNA detection; baseline serum was tested for HSV-2 type-specific antibodies. We used non-parametric statistics to compare HPV-related outcomes by HSV-2 serostatus and use of anti-HSV medication. RESULTS: 151 baseline serum samples underwent HSV-2 testing. At baseline, median age was 39 years, median CD4 count was 500 cells/mm3, and 70% had an HIV viral load of <50 copies/mL. Baseline HSV-2 seroprevalence was 76.2%. HSV-2 seropositivity was associated with increased age (p = 0.006). Controlling for age and median CD4 count, HSV-2 seropositivity was not associated with HPV incidence, persistence, and precancerous lesions. The use of anti-HSV medications was associated with higher odds of HSIL cytology (OR = 3.35, 95% CI = 1.03,11.26) and a greater number of HPV types detected (OR = 1.18, 95% CI = 1.00,1.39). Results were similar in sensitivity analyses using an index value of 3.5. The presence of HSV lesions during the study was not associated with HPV outcomes. CONCLUSIONS: HSV-2 seropositivity was common in this cohort of WLWH in Canada but was not associated with multiple measures of HPV incidence, persistence, and precancerous lesions. However, the use of anti-HSV medications was associated with HSIL cytology and number of HPV types detected.

Vaginal microbiota associated with oncogenic HPV in a cohort of HPV-vaccinated women living with HIV.

BACKGROUND: Women living with HIV (WLWH) experience higher rates of human papillomavirus (HPV) infection and cervical cancer than women without HIV. Changes in the vaginal microbiome have been implicated in HPV-related disease processes such as persistence of high-risk HPV infection but this has not been well defined in a population living with HIV. METHODS: Four hundred and 20 girls and WLWH, age ≥9, across 14 clinical sites in Canada were enrolled to receive three doses of quadrivalent HPV vaccine for assessment of vaccine immunogenicity. Blood, cervical cytology, and cervico-vaginal swabs were collected. Cervico-vaginal samples were tested for HPV DNA and underwent microbiota sequencing. RESULTS: Principal component analysis (PCA) and hierarchical clustering generated community state types (CSTs). Relationships between taxa and CSTs with HPV infection were examined using mixed-effects logistic regressions, Poisson regressions, or generalized linear mixed-effects models, as appropriate. Three hundred and fifty-six cervico-vaginal microbiota samples from 172 women were sequenced. Human papillomavirus DNA was detected in 211 (59%) samples; 110 (31%) contained oncogenic HPV. Sixty-five samples (18%) were taken concurrently with incident oncogenic HPV infection and 56 (16%) were collected from women with concurrent persistent oncogenic HPV infection. CONCLUSIONS: No significant associations between taxa, CST, or microbial diversity and HPV-related outcomes were found. However, we observed weak associations between a dysbiotic microbiome and specific species, including Gardnerella, Porphyromonas, and Prevotella species, with incident HPV infection.

Willingness to Self-Collect a Sample for HPV-Based Cervical Cancer Screening in a Well-Screened Cohort: HPV FOCAL Survey Results.

Self-collection may provide an opportunity for innovation within population-based human papillomavirus (HPV) cervical cancer screening programs by providing an alternative form of engagement for all individuals. The primary objective was to determine willingness to self-collect a vaginal sample for primary HPV screening and factors that impact willingness in individuals who participated in the Human Papillomavirus For Cervical Cancer (HPV FOCAL) screening trial, a large randomized controlled cervical screening trial. A cross-sectional online survey was distributed between 2017 and 2018 to 13,176 eligible participants exiting the FOCAL trial. Bivariate and multivariable logistic regression assessed factors that influence willingness to self-collect on 4945 respondents. Overall, 52.1% of respondents indicated willingness to self-collect an HPV sample. In multivariable analysis, the odds of willingness to self-collect were significantly higher in participants who agreed that screening with an HPV test instead of a Pap test was acceptable to them (odds ratio (OR): 1.45 (95% confidence interval (CI): 1.15, 1.82), those who indicated that collecting their own HPV sample was acceptable to them (p < 0.001), and those with higher educational ascertainment (OR: 1.31, 95% CI: 1.12, 1.54). The findings offer insight into the intentions to self-collect in those already engaged in screening, and can inform cervical cancer screening programs interested in offering alternative approaches to HPV-based screening.

Human papillomavirus-based screening at extended intervals missed fewer cervical precancers than cytology in the HPV For Cervical Cancer (HPV FOCAL) trial.

While cervix screening using cytology is recommended at 2- to 3-year intervals, given the increased sensitivity of human papillomavirus (HPV)-based screening to detect precancer, HPV-based screening is recommended every 4- to 5-years. As organized cervix screening programs transition from cytology to HPV-based screening with extended intervals, there is some concern that cancers will be missed between screens. Participants in HPV FOr CervicAL Cancer (HPV FOCAL) trial received cytology (Cytology Arm) at 24-month intervals or HPV-based screening (HPV Arm) at 48-month intervals; both arms received co-testing (cytology and HPV testing) at exit. We investigated the results of the co-test to identify participants with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) who would not have had their precancer detected if they had only their arm's respective primary screen. In the Cytology Arm, 25/62 (40.3%) identified CIN2+s were missed by primary screen (ie, normal cytology/positive HPV test) and all 25 had normal cytology at the prior 24-month screen. In the HPV arm, three CIN2+s (3/49, 6.1%) were missed by primary screen (ie, negative HPV test/abnormal cytology). One of these three misses had low-grade cytology findings and would also not have been referred to colposcopy outside of the trial. Multiple rounds of cytology did not detect some precancerous lesions detected with one round of HPV-based screening. In our population, cytology missed more CIN2+, even at shorter screening intervals, than HPV-based screening. This assuages concerns about missed detection postimplementation of an extended interval HPV-based screening program. We recommend that policymakers consider a shift from cytology to HPV-based cervix screening.

Women's acceptability of and experience with primary human papillomavirus testing for cervix screening: HPV FOCAL trial cross-sectional online survey results.

OBJECTIVE: To study participant's acceptability of and attitudes towards human papillomavirus (HPV) testing compared with cytology for cervical cancer screening and what impact having an HPV positive result may have in future acceptability of screening. DESIGN: Cross-sectional online survey of clinical trial participants. SETTING: Primary care, population-based Cervix Screening Program, British Columbia, Canada. PARTICIPANTS: A total of 5532 participants from the HPV FOCAL trial, in which women received HPV and cytology testing at study exit, were included in the analysis. Median age was 54 years. The median time of survey completion was 3 years after trial exit. OUTCOME MEASURES: Acceptability of HPV testing for primary cervical cancer screening (primary); attitudes and patient perceptions towards HPV testing and receipt of HPV positive screen results (secondary). RESULTS: Most respondents (63%) were accepting of HPV testing, with the majority (69%) accepting screening to begin at age 30 years with HPV testing. Only half of participants (54%) were accepting of an extended screening interval of 4-5 years. In multivariable logistic regression, women who received an HPV positive screen test result during the trial (OR=1.41 95% CI 1.11 to 1.80) or were older (OR=1.01, 95% CI 1.00 to 1.02) were more likely to report HPV testing as acceptable. CONCLUSIONS: In this evaluation of acceptability and attitudes regarding HPV testing for cervix screening, most are accepting of HPV testing for screening; however, findings indicate heterogeneity in concerns and experiences surrounding HPV testing and receipt of HPV positive results. These findings provide insights for the development of education, information and communication strategies during implementation of HPV-based cervical cancer screening. TRIAL REGISTRATION NUMBERS: ISRCTN79347302 and NCT00461760.

Cost-effectiveness analysis of primary human papillomavirus testing in cervical cancer screening: Results from the HPV FOCAL Trial.

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population-based Cervix Screening Program in British Columbia, Canada. We conducted a cost-effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high-grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid-based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co-testing at the 48-month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of -$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC-based testing every 2 years for cervical cancer screening at a lower cost.

Declining rates of cervical intraepithelial neoplasia in British Columbia, Canada: An ecological analysis on the effects of the school-based human papillomavirus vaccination program.

Since 2008, girls in British Columbia (BC), Canada, have been offered HPV vaccination through a school-based, publicly funded immunization program. The oldest birth cohort eligible for the vaccination program was born in 1994 and uptake is on average 63%. To evaluate the impact of the HPV vaccine in BC, ecological trends in cervical intraepithelial neoplasia (CIN) rates were assessed in young women before and after the implementation of the HPV vaccination program. Information on all Pap smears and histopathological abnormalities, in calendar years 2004-2017 in women 16-28 years of age in BC were obtained from the population-based BC Cancer Cervix Screening Program database. Rates of CIN 2 and 3 were calculated as the number of cases divided by the number of cytology specimens for that period. Rate ratios (RR) were calculated by negative binomial piecewise regression. Age-centered incidence rates of CIN 2 and 3 in BC declined significantly among women 16-23 years of age after HPV vaccine introduction compared to before vaccine introduction. The overall reduction postvaccination for CIN2 and 3 in women 16-23 years was respectively 62% (95% CI 54-68%) and 65% (95% CI 58-71%). Age-specific rates for CIN2 significantly declined for those 18-22 years of age and for those 19, 20 and 23 years of age for CIN3. Among women 24-28 years of age no decline in CIN2 and 3 rate over time was observed. The observed reduction in CIN 2 and 3 rates since the introduction of the school-based HPV vaccine program might illustrate the population impact of the BC provincial school-based HPV vaccination program.

Assessing 10-Year Safety of a Single Negative HPV Test for Cervical Cancer Screening: Evidence from FOCAL-DECADE Cohort.

BACKGROUND: Long-term safety of a single negative human papillomavirus (HPV) test for cervical cancer screening is unclear. The HPV FOr cerviCAL Cancer Trial (FOCAL) was a randomized trial comparing HPV testing with cytology. The FOCAL-DECADE cohort tracked women who received one HPV test during FOCAL, and were HPV negative, for up to 10 years to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) detected through a provincial screening program. METHODS: FOCAL participants who received one HPV test, were negative, and had at least one post-FOCAL cervix screen were included (N = 5,537). We constructed cumulative incidence curves of CIN2+/CIN3+ detection, analyzed cumulative risk of detection at intervals post-HPV test, calculated average incidence rates for detection, and compared hazard across ages. RESULTS: Ten years after one negative HPV test, the probability of CIN2+ detection was lower than 1%, with most lesions detected 7 years or later. Average incidence rates of CIN2+/CIN3+ lesions over follow-up were 0.50 [95% confidence interval (CI), 0.31-0.78] and 0.18 (95% CI, 0.07-0.36) per 1,000 person-years, respectively. Hazards were higher for younger ages (nonsignificant trend). CONCLUSIONS: Among women with a single negative HPV test, long-term risk of CIN2+ detection was low, particularly through 7 years of follow-up; thus, one negative HPV test appears to confer long-term protection from precancerous lesions. Even 10-year risk is sufficiently low to support extended testing intervals in average-risk populations. IMPACT: Our findings support the safety of screening policies using HPV testing alone at 5-year or longer intervals.

Prevalent and persistent oncogenic HPV types in a cohort of women living with HIV prior to HPV vaccination.

OBJECTIVE: To describe prevalent and persistent oncogenic human papillomavirus (HPV) types detected in women living with HIV (WLWH) in Canada, including women with cervical dyskaryosis, and to determine predictors of type-specific HPV persistence. METHODS: Women and girls living with HIV, recruited from 14 sites of HIV care across Canada, were included in a sub-analysis of a prospective vaccine immunogenicity cohort study (two HPV DNA results, at least one cervical cytology result pre-vaccination). Demographic and clinical data were collected alongside cervical samples for cytology and HPV DNA typing between November 25, 2008, and May 19, 2015. RESULTS: Pre-vaccination, HPV16 and HPV52 were the most prevalent oncogenic HPV types. Of the 252 women and girls who met the eligibility criteria, 45% were infected with at least one oncogenic HPV type and one-third of participants had a persistent oncogenic infection. HPV16, 45, and 52 were the most frequently persistent types. Seventeen percent of women had persistent infections with oncogenic HPV types not within currently available vaccines (HPV35/39/51/56/59/68/82). Lower CD4 count significantly predicted HPV persistence (P=0.024). Cervical cytology results were normal for 82.9% of participants, atypical squamous cells of undetermined significance for 2.4%, low-grade squamous intraepithelial lesions for 11.5%, and high-grade squamous intraepithelial lesions for 2.8%. CONCLUSION: Unvaccinated WLWH were infected with a wide range of oncogenic HPV types. The findings highlighted the importance of optimal treatment of HIV and continued cervical cancer screening as key steps toward the global elimination of cervical cancer.

Brief Report: Persistence of Non-Vaccine Oncogenic HPV Genotypes in Quadrivalent HPV-Vaccinated Women Living With HIV.

BACKGROUND: Human papillomavirus (HPV) vaccines have promising safety and immunogenicity data in women living with HIV (WLWH). However, it is critical to understand the residual burden of oncogenic HPV within WLWH to inform postvaccination cervical screening needs. We assessed rates of persistent infection with nonquadrivalent HPV (qHPV) oncogenic types in a cohort of qHPV-vaccinated WLWH. SETTING: Multicentre, longitudinal cohort across Canada. METHODS: WLWH were scheduled to receive 3 doses of qHPV vaccine. Participants provided health data and HPV DNA samples. Persistent cases of HPV were defined as new HPV in samples from ≥2 consecutive visits or as HPV present in the last sample. HPV31/33/35/39/45/51/52/56/58/59/68/82 were considered to have oncogenic potential. Median follow-up time was 4 years after initial vaccine dose. RESULTS: A total of 284 participants were eligible for this analysis with 1205 person-years (PY) of follow-up (≥1 dose of vaccine, ≥1 HPV DNA result after vaccination). The highest incidence of persistent infection was with HPV51 (1.38/100 PY), followed by HPV52 (1.18/100 PY), and HPV39 (1.06/100 PY). The incidence of persistent infection with pooled HPV types added in the nonavalent vaccine (HPV31/33/45/52/58) was lower than the incidence of persistent oncogenic HPV types not contained within available vaccines (HPV35/39/51/56/59/68) (2.4/100 PY versus 3.6/100 PY, respectively). CONCLUSIONS: qHPV-vaccinated WLWH continue to face a burden of persistent oncogenic HPV infection. Although the nonavalent vaccine could alleviate some of this burden, 2 of the top 3 persistent oncogenic HPVs in this cohort are not contained within any available vaccine. This highlights the need for ongoing cervical screening in HPV-vaccinated WLWH.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Screening for Anal Cancer in Women With a History of Vulvar High-Grade Squamous Intraepithelial Lesions.

OBJECTIVES: The primary obkective was to determine the prevalence of (a) a positive anal cancer screen and (b) histological anal high-grade squamous intraepithelial lesion (HSIL) in women undergoing surveillance for previously diagnosed and treated human papillomavirus (HPV)-associated vulvar HSIL. The secondary objective was to determine the patients' acceptability of the screen. MATERIALS AND METHODS: This is a single-institution, cross-sectional pilot study. Women, aged 30 to 80 years, with a history of biopsy-proven vulvar HSIL were invited to undergo screening for anal cancer. Positive screen characterized by abnormalities in any of the following: anal high-risk HPV (HR-HPV); anal cytology; and digital anorectal examination. All women with an abnormal screen were referred for high-resolution anoscopy. All women completed a postscreen questionnaire. RESULTS: Fifty-seven patients were recruited. The median (interquartile range) age was 61.5 (51.0-68.0) years. The prevalence of a positive screen was 56.1% (95% CI = 43.3%-68.2%). Of the 32 screen-positive patients, 12 had both abnormal cytology and HR-HPV, 3 had positive HR-HPV alone, and 17 had abnormal cytology alone. Of the 29 patients with a positive screen who went on to anoscopy, the prevalence of anal HSIL was 33.3% (95% CI = 19.2%-51.2%). The prevalence of anal HSIL among all of those who had screening (N = 57) was 18.2% (95% CI = 10.2%-30.3%). The examination was well tolerated with 100% of patients, indicating that they would have the screening again. CONCLUSIONS: Women with vulvar HSIL have an increased risk of developing anal HSIL. Larger studies are needed to define optimal screening protocols as well as algorithms for management in high-risk populations.

Cervical Cancer Screening in Immunocompromised Women.

In the context of changing recommendations for cervical cancer screening, differing recommendations in each province, and a lack of guidance for cervical screening of immunocompromised women, this article provides specific recommendations for cervical cancer screening of immunocompromised women in Canada.

The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living With Human Immunodeficiency Virus.

BACKGROUND: Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. METHODS: We enrolled 420 females aged ≥9 years (range, 9-65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. RESULTS: Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1-4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2-4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3-2.6) and of genital warts was 1.0/100PY (95% CI, 0.3-2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02-0.03), 1.5 (95% CI, 1.1-2.0), and 1.2 (95% CI, 0.2-3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). CONCLUSIONS: Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH.

Identifying Barriers to Treatment for Women With Cervical Dysplasia in Rural Northern British Columbia.

OBJECTIVE: This study seeks to identify barriers to colposcopy examination faced by patients living in Northern BC to improve outcomes for women at risk of developing cervical cancer. METHODS: A retrospective chart review (n = 309) was conducted in the four colposcopy clinics in Northern BC to collect information regarding patients who were referred for colposcopy after abnormal cytology. Demographic factors associated with non-attendance were identified as barriers to accessing care. Aggregate data from the Cervical Cancer Screening Program (n = 4265) were used to calculate wait times by health region across BC. RESULTS: The odds of having missed an appointment was highest for women who were pregnant (OR 4.0) or attending site D vs. site A (OR 6.0); however, only clinic location remained significant in a multivariable model. Wait times were longer for women who had ever missed appointments, and varied among the sites, with site A and D having significantly longer wait times than the remaining sites. The Northern Health Authority had the longest overall median colposcopy wait time for high-grade cytology in the province at 41 days longer than the provincial average of 62 days. CONCLUSION: The Northern Health Authority faces unique challenges associated with geography and patient population that are associated with longer wait times for colposcopy when compared with other health authorities in the province.

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.