Impact of a carrageenan gel on viral load of genital human papillomavirus infections in sexually active women: Findings from the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) trial.

Previous research has shown that women's use of a carrageenan gel reduces the risk of acquiring genital human papillomavirus (HPV) infections but does not help to clear existing ones. Although gel use may not result in complete clearance, it may decrease the viral load of HPV infections. We tested this hypothesis in the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) randomized controlled trial. Participants of the CATCH study were selected for viral load testing if they had completed the first four study visits and tested positive for HPV42 or HPV51 in at least one of these visits. HPV42 and HPV51 were chosen as they were among the most abundant low- and high-risk types, respectively, in the study sample. We measured viral load with a type-specific real-time polymerase chain reaction. Results were displayed using summary statistics. Of 461 enrolled participants, 39 were included in the HPV42 analysis set and 56 in the HPV51 analysis set. The median time between visits 1 and 4 was 3.7 months. The viral load (copies/cell) of HPV42 ranged from <0.001 to 13 434.1, and that of HPV51 from <0.001 to 967.1. The net median change in HPV42 viral load over all four visits was -1.04 copies/cell in the carrageenan and -147 copies/cell in the placebo arm (Wilcoxon rank sum test, p = 0.26). There was no net median change in HPV51 viral load over all four visits in either arm (p = 0.45). The use of a carrageenan-based gel is unlikely to reduce the viral load of HPVs 42 or 51.

Empirical sample-specific approaches to define HPV16 and HPV18 seropositivity in unvaccinated, young, sexually active women.

Given low seroconversion rates following human papillomavirus (HPV) infection, fixed external cutoffs may lead to errors in estimating HPV seroprevalence. We evaluated finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) among unvaccinated, sexually active, HPV-exposed women to determine study-specific HPV16 and HPV18 seropositivity thresholds. We included 399 women (aged 18-24 years) enrolled in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study between 2005 and 2011 in Montreal, Canada. Participants' blood samples from up to six visits spanning 2 years were tested by multiplex serology for antibodies [median fluorescence intensity (MFI)] specific to bacterially expressed HPV16 and HPV18 L1 glutathione S-transferase fusion proteins. We applied FMM and GBTM to baseline and longitudinal antibody titer measurements, respectively, to define HPV type-specific seronegative and seropositive distributions. Study-specific thresholds were generated as five standard deviations above the mean seronegative antibody titers, mimicking cutoffs (HPV16: 422 MFI; HPV18: 394 MFI) derived from an external population of sexually inactive, HPV DNA-negative Korean women (aged 15-29 years). Agreement (kappa) of study-specific thresholds was evaluated against external cutoffs. Seroprevalence estimates using FMM (HPV16: 27.5%-43.2%; HPV18: 21.7%-49.5%) and GBTM (HPV16: 11.8%-11.8%; HPV18: 9.9%-13.4%) thresholds exceeded those of external cutoffs (HPV: 10.2%; HPV18: 9.7%). FMM thresholds showed slight-to-moderate agreement with external cutoffs (HPV16: 0.26%-0.46%; HPV18: 0.20%-0.56%), while GBTM thresholds exhibited high agreement (HPV16: 0.92%-0.92%; HPV18: 0.82%-0.99%). Kappa values suggest that GBTM, used for longitudinal serological data, and otherwise FMM, for cross-sectional data, are robust methods for determining the HPV serostatus without prior classification rules.IMPORTANCEWhile human papillomavirus (HPV) seropositivity has been employed as an epidemiologic determinant of the natural history of genital HPV infections, only a fraction of women incidentally infected with HPV respond by developing significant antibody levels. HPV seropositivity is often determined by a dichotomous fixed cutoff based on the seroreactivity of an external population of women presumed as seronegative, given the lack of evidence of HPV exposure. However, considering the variable nature of seroreactivity upon HPV infection, which arguably varies across populations, such externally defined cutoffs may lack specificity to the population of interest, causing inappropriate assessment of HPV seroprevalence and related epidemiologic uses of that information. This study demonstrates that finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) can be used to independently estimate seroprevalence or serve as the basis for defining study-specific seropositivity thresholds without requiring prior subjective assumptions, consequently providing a more apt internally valid discrimination of seropositive from seronegative individuals.

Use of a carrageenan-based gel had no impact on anal HPVs 16 and 18 viral loads in gay, bisexual, and other men who have sex with men.

The Lubricant Investigation in Men to Inhibit Transmission of human papillomavirus (HPV) Infection randomized control trial in gay, bisexual, and other men who have sex with men (gbMSM) found that carrageenan use neither reduced acquisition of anal HPV infections nor influenced infection clearance. To investigate carrageenan's lack of protective effect, we compared the change in anal HPV16 and HPV18 viral loads following carrageenan use against placebo. We restricted our analysis to participants who completed the first four study visits and had a valid baseline sample (n = 161, 54 HIV-positive). Samples were tested for HPV detection using the linear array PCR assay. HPV16- and/or HPV18-positive samples were tested for viral load using real-time PCR. For participants who tested HPV16- (n = 29) or HPV18-positive (n = 10) at least once across visits 1-4, we compared the change in type-specific viral load between study arms using the Mann-Whitney U test. Although the median net change in HPV16 and HPV18 viral loads across visits 1-4 was higher in the treatment than placebo arm (HPV16: 0.68 vs. 0.18 copies/cell, p = 0.60; HPV18: 18.32 vs. 10.12 copies/cell, p = 0.52), these differences were not statistically significant. Results were similar by HIV status. Carrageenan use did not impact anal HPV16 or HPV18 viral loads, which may further explain its lack of protective effect in gbMSM.

Epidemiology of genital human papillomavirus infections in sequential male sex partners of young females.

OBJECTIVES: Couple-based studies have considered human papillomavirus (HPV) transmission between current heterosexual partners (male↔female). Using data from young women and their sequential male partners, we analysed HPV transmission from upstream sexual partnerships (male 1↔female) to downstream sex partners (→male 2). METHODS: Among 502 females enrolled in the HPV Infection and Transmission among Couples through Heterosexual activity study (2005-2011, Montréal, Canada), 42 brought one male sex partner at baseline (male 1) and another during follow-up (male 2). Female genital samples, collected at six visits over 24 months, and male genital samples, collected at two visits over 4 months, were tested for 36 HPV types (n = 1512 detectable infections). We calculated observed/expected ratios with 95% CIs for type-specific HPV concordance between males 1 and 2. Using mixed-effects regression, we estimated ORs with 95% CIs for male 2 testing positive for the same HPV type as male 1. RESULTS: Detection of the same HPV type in males 1 and 2 occurred 2.6 (CI 1.9-3.5) times more often than chance (29 instances observed vs. 10.95 instances expected). The OR for male 2 positivity was 4.2 (CI 2.5-7.0). Adjusting for the number of times the linking female tested positive for the same HPV type attenuated the relationship between male 1 and 2 positivity, suggesting mediation. CONCLUSIONS: High type-specific HPV concordance between males 1 and 2 confirms HPV's transmissibility in chains of sequential sexual partnerships. HPV positivity in an upstream partnership predicted positivity in a downstream male when the linking female partner was persistently positive.

Serologic response to human papillomavirus genotypes following vaccination: findings from the HITCH cohort study.

BACKGROUND: Human papillomavirus (HPV) infection contributes to approximately 5% of the worldwide cancer burden. The three-dose HPV vaccine has demonstrated immunogenicity and efficacy. Humoral responses may be critical for preventing, controlling, and/or eliminating HPV infection. Using data from the HITCH cohort, we analysed humoral immune response to HPV vaccination among women in relation to the phylogenetic relatedness of HPV genotypes. METHODS: We included 96 women aged 18-24 years attending college or university in Montreal, Canada. Participants provided blood samples at enrolment and five follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase fusion proteins of multiple Alphapapillomavirus types, and to virus-like particles (VLP-L1) of HPV16 and HPV18 were measured using multiplex serology. We assessed correlations between antibody seroreactivities using Pearson correlations (r). RESULTS: At enrolment, 87.7% of participants were unvaccinated, 2.4% had received one, 3.2% two, and 6.7% three doses of HPV vaccine. The corresponding L1 seropositivity to any HPV was 41.2%, 83.3%, 100%, and 97.0%. Between-type correlations for L1 seroreactivities increased with the number of vaccine doses, from one to three. Among the latter, the strongest correlations were observed for HPV58-HPV33 (Pearson correlation [r] = 0.96; α9-species); HPV11-HPV6 (r = 0.96; α10-species); HPV45-HPV18 (r = 0.95; α7-species), and HPV68-HPV59 (r = 0.95; α7-species). CONCLUSIONS: Correlations between HPV-specific antibody seroreactivities are affected by phylogenetic relatedness, with anti-L1 correlations becoming stronger with the number of vaccine doses received.

Detection and Clearance of Type-Specific and Phylogenetically Related Genital Human Papillomavirus Infections in Young Women in New Heterosexual Relationships.

BACKGROUND: Understanding the natural history of human papillomavirus (HPV) infections is essential to cervical cancer prevention planning. We estimated HPV type-specific infection detection and clearance in young women. METHODS: The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study is a prospective cohort of 502 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at 6 clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness. RESULTS: By 24 months, we detected incident infections in 40.4% (CI, 33.4%-48.4%) of women. Incident subgenus 1 (43.4; CI, 33.6-56.4), 2 (47.1; CI, 39.9-55.5), and 3 (46.6; CI, 37.7-57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections. CONCLUSIONS: Our analyses provide type-specific infection natural history estimates for cervical cancer prevention planning. HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections persist longer than their low oncogenic risk subgenera 1 and 3 counterparts.

Betapapillomavirus natural history and co-detection with alphapapillomavirus in cervical samples of adult women.

Human papillomaviruses (HPV) of the genus Betapapillomavirus can infect both cutaneous and mucosal sites, but research on their natural history at mucosal sites remains scarce. We examined the risk factors and co-detection patterns of HPVs of the Betapapillomavirus and Alphapapillomavirus genera in cervical samples of the Ludwig-McGill cohort study. We assessed a subset of 505 women from the Ludwig-McGill cohort study from São Paulo, Brazil. Cervical samples over the first year of follow-up were tested for DNA of over 40 alphapapillomavirus types and 43 betapapillomavirus types using a type-specific multiplex genotyping polymerase chain reaction assay. We assessed the risk factors for prevalent and incident betapapillomavirus type detection, and whether types were detected more frequently together than expected assuming independence using permutation tests, logistic regression, and Cox regression. We observed significant within-genus clustering but not cross-genus clustering. Multiple betapapillomavirus types were co-detected in the same sample 2.24 (95% confidence interval [CI]: 1.65-3.29) times more frequently than expected. Conversely, co-detections of alphapapillomavirus and betapapillomavirus types in the same sample occurred only 0.64 (95% CI: 0.51-0.83) times as often as expected under independence. In prospective analyses, positivity to one HPV genus was associated with a nonsignificant lower incidence of detection of types in the other genus. Lifetime number of sex partners and new sex partner acquisition were associated with lower risks of prevalent and incident betapapillomavirus detection. Betapapillomaviruses are commonly found in the cervicovaginal tract. Results suggest potentially different mechanisms of transmission for betapapillomavirus genital infections other than vaginal sex.

Cancers Attributable to Infections in the US in 2017: A Meta-Analysis.

Importance: Infections are largely modifiable causes of cancer. However, there remains untapped potential for preventing and treating carcinogenic infections in the US. Objective: To estimate the percentage and number of incident cancers attributable to infections in the US among adults and children for the most recent year cancer incidence data were available (2017). Data Sources: A literature search from 1946 onward was performed in MEDLINE on January 6, 2023, to obtain the data required to calculate population attributable fractions for 31 infection-cancer pairs. National Health and Nutrition Examination Survey data were used to estimate the population prevalence of hepatitis B and C viruses and Helicobacter pylori. Study Selection: Studies conducted in the US or other Western countries were selected according to specific infection-cancer criteria. Data Extraction and Synthesis: Data from 128 studies were meta-analyzed to obtain the magnitude of an infection-cancer association or prevalence of the infection within cancer cells. Main Outcomes and Measures: The proportion of cancer incidence attributable to 8 infections. Results: Of the 1 666 102 cancers diagnosed in 2017 among individuals aged 20 years or older in the US, 71 485 (4.3%; 95% CI, 3.1%-5.3%) were attributable to infections. Human papillomavirus (n = 38 230) was responsible for the most cancers, followed by H pylori (n = 10 624), hepatitis C virus (n = 9006), Epstein-Barr virus (n = 7581), hepatitis B virus (n = 2310), Merkel cell polyomavirus (n = 2000), Kaposi sarcoma-associated herpesvirus (n = 1075), and human T-cell lymphotropic virus type 1 (n = 659). Cancers with the most infection-attributable cases were cervical (human papillomavirus; n = 12 829), gastric (H pylori and Epstein-Barr virus; n = 12 565), oropharynx (human papillomavirus; n = 12 430), and hepatocellular carcinoma (hepatitis B and C viruses; n = 10 017). The burden of infection-attributable cancers as a proportion of total cancer incidence ranged from 9.6% (95% CI, 9.2%-10.0%) for women aged 20 to 34 years to 3.2% (95% CI, 2.4%-3.8%) for women aged 65 years or older and from 6.1% (95% CI, 5.2%-7.0%) for men aged 20 to 34 years to 3.3% (95% CI, 1.9%-4.4%) for men aged 65 years or older. Among those aged 19 years or younger, 2.2% (95% CI, 1.3%-3.0%) of cancers diagnosed in 2017 were attributable to Epstein-Barr virus. Conclusions and Relevance: Infections were estimated to be responsible for 4.3% of cancers diagnosed among adults in the US in 2017 and, therefore, represent an important target for cancer prevention efforts.

Human Papillomavirus Detectability and Cervical Cancer Prognosis: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate whether testing positive for human papillomavirus (HPV) before treatment is associated with cervical cancer recurrence and disease-free, cancer-specific, and overall survival and to report the relationship of HPV to cervical cancer histology, stage, grade, tumor size, lymph node involvement, and treatment response. DATA SOURCES: EMBASE and MEDLINE were searched from inception to January 27, 2022, with the use of MeSH terms and keywords relating to cervical cancer, HPV, and prognosis. ClinicalTrials.gov was not searched because of the nature of our review question. METHODS OF STUDY SELECTION: Studies must have assessed HPV DNA or RNA in cervical pretreatment biopsies or cells from 20 or more patients with invasive cervical cancer followed up for any length of time and reported the effect of testing positive or negative for HPV on cervical cancer recurrence, disease-free survival, cancer-specific survival, or overall survival. We extracted data on HPV-detection methods, patient and tumor characteristics, and clinical outcomes. TABULATION, INTEGRATION, AND RESULTS: Hazard ratios (HRs) and 95% CIs were pooled with a random-effects model. Meta-regression was performed to explore heterogeneity. Of 11,179 titles or abstracts and 474 full-text articles reviewed, 77 studies were included in the systematic review. Among these 77 studies, 30 reported on the relationship of HPV status to histology, 39 to cancer stage, 13 to tumor grade, 17 to tumor size, 23 to lymph node involvement, and four to treatment response. Testing positive for HPV was associated with better disease-free survival (HR 0.38, 95% CI 0.25-0.57; 15 studies with 2,564 cases), cancer-specific survival (HR 0.56, 95% CI 0.44-0.71; nine studies with 1,398 cases), and overall survival (HR 0.59, 95% CI 0.47-0.74; 36 studies with 9,169 cases), but not recurrence (HR 0.59, 95% CI 0.33-1.07; eight studies with 1,313 cases). Meta-regression revealed that the number of cases, tumor grade, specimen type, gene target, and HPV prevalence together explained 73.8% of the between-study heterogeneity. CONCLUSION: This review indicates that HPV detectability in cervical cancer is associated with a better clinical prognosis. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/dtyeb .

Ascertaining asthma status in epidemiologic studies: a comparison between administrative health data and self-report.

BACKGROUND: Studies have suggested that agreement between administrative health data and self-report for asthma status ranges from fair to good, but few studies benefited from administrative health data over a long period. We aimed to (1) evaluate agreement between asthma status ascertained in administrative health data covering a period of 30 years and from self-report, and (2) identify determinants of agreement between the two sources. METHODS: We used administrative health data (1983-2012) from the Quebec Birth Cohort on Immunity and Health, which included 81,496 individuals born in the province of Quebec, Canada, in 1974. Additional information, including self-reported asthma, was collected by telephone interview with 1643 participants in 2012. By design, half of them had childhood asthma based on health services utilization. Results were weighted according to the inverse of the sampling probabilities. Five algorithms were applied to administrative health data (having ≥ 2 physician claims over a 1-, 2-, 3-, 5-, or 30-year interval or ≥ 1 hospitalization), to enable comparisons with previous studies. We estimated the proportion of overall agreement and Kappa, between asthma status derived from algorithms and self-reports. We used logistic regression to identify factors associated with agreement. RESULTS: Applying the five algorithms, the prevalence of asthma ranged from 49 to 55% among the 1643 participants. At interview (mean age = 37 years), 49% and 47% of participants respectively reported ever having asthma and asthma diagnosed by a physician. Proportions of agreement between administrative health data and self-report ranged from 88 to 91%, with Kappas ranging from 0.57 (95% CI: 0.52-0.63) to 0.67 (95% CI: 0.62-0.72); the highest values were obtained with the [≥ 2 physician claims over a 30-year interval or ≥ 1 hospitalization] algorithm. Having sought health services for allergic diseases other than asthma was related to lower agreement (Odds ratio = 0.41; 95% CI: 0.25-0.65 comparing ≥ 1 health services to none). CONCLUSIONS: These findings indicate good agreement between asthma status defined from administrative health data and self-report. Agreement was higher than previously observed, which may be due to the 30-year lookback window in administrative data. Our findings support using both administrative health data and self-report in population-based epidemiological studies.

Efficacy and safety of a self-applied carrageenan-based gel to prevent human papillomavirus infection in sexually active young women (CATCH study): an exploratory phase IIB randomised, placebo-controlled trial.

Background: Carrageenan demonstrated potent anti-HPV (human papillomavirus) activity in vitro and in animal models. The Carrageenan-gel Against Transmission of Cervical Human papillomavirus trial's interim analysis (n = 277) demonstrated a 36% protective effect of carrageenan against incident HPV infections. Herein, we report the trial's final results. Methods: In this exploratory phase IIB randomised, placebo-controlled trial, we recruited healthy women aged ≥18 years primarily from health service clinics at two Canadian Universities in Montreal. Participants were randomised (1:1) by the study coordinator (using computer-assisted block randomisation with randomly variable block sizes up to a block size of eight) to a carrageenan-based or placebo gel to be self-applied every other day for the first month and before/after intercourse. Participants, study nurses, and laboratory technicians (HPV testing and genotyping) were blinded to group assignment. At each visit (months 0, 0.5, 1, 3, 6, 9, 12), participants provided questionnaire data and a self-collected vaginal sample (tested for 36 HPV types, Linear Array). The primary outcome was type-specific HPV incidence (occurring at any follow-up visit). Intention-to-treat analyses for incidence were conducted using Cox proportional hazards regression models, including participants with ≥2 visits. Safety analyses included all participants randomised. This trial is registered with the ISRCTN registry, ISRCTN96104919. Findings: Between Jan 16, 2013 and Sept 30, 2020, 461 participants (enrolled) were randomly assigned to the carrageenan (n = 227) or placebo (n = 234) groups. Incidence and safety analyses included 429 and 461 participants, respectively. We found 51.9% (108/208) of participants in carrageenan and 66.5% (147/221) in placebo arm acquired ≥1 HPV type (hazard ratio 0.63 [95% CI: 0.49-0.81], p = 0.0003). Adverse events were reported by 34.8% (79/227) and 39.7% (93/234) of participants in carrageenan and placebo arm (p = 0.27), respectively. Interpretation: Consistent with the interim analysis, use of a carrageenan-based gel compared to placebo resulted in a 37% reduction in risk of incident genital HPV infections in women with no increase in adverse events. A carrageenan-based gel may complement HPV vaccination. Funding: Canadian Institutes of Health Research, CarraShield Labs Inc.

Differences in site-specific cancer incidence by individual- and area-level income in Canada from 2006 to 2015.

Income, a component of socioeconomic status, influences cancer risk as a social determinant of health. We evaluated the independent associations between individual- and area-level income and site-specific cancer incidence in Canada. We used data from the 2006 and 2011 Canadian Census Health and Environment Cohorts, which are probabilistically linked datasets constituted by 5.9 million and 6.5 million respondents of the 2006 Canadian long-form census and 2011 National Household Survey, respectively. Individuals were linked to the Canadian Cancer Registry through 2015. Individual-level income was derived using after-tax household income adjusted for household size. Annual tax return postal codes were used to assign area-level income quintiles to individuals for each year of follow-up. We calculated age-standardized incidence rates (ASIR) and rate ratios for cancers overall and by site. We conducted multivariable negative binomial regression to adjust these rates for other demographic and socioeconomic variables. Individuals of lower individual- and area-level income had higher ASIRs compared to those in the wealthiest income quintile for head and neck, oropharyngeal, esophageal, stomach, colorectal, anal, liver, pancreas, lung, cervical and kidney and renal pelvis cancers. Conversely, individuals of wealthier individual- and area-level income had higher ASIRs for melanoma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast, uterine, prostate and testicular cancers. Most differences in site-specific incidence by income quintile remained after adjustment. Although Canada's publicly funded healthcare system provides universal coverage, inequalities in cancer incidence persist across individual- and area-level income gradients. Our estimates suggest that individual- and area-level income affect cancer incidence through independent mechanisms.

Pan-Canadian survey on the impact of the COVID-19 pandemic on cervical cancer screening and management: cross-sectional survey of healthcare professionals.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused disruptions to cancer care by delaying diagnoses and treatment, presenting challenges and uncertainties for both patients and physicians. We conducted a nationwide online survey to investigate the effects of the pandemic and capture modifications, prompted by pandemic-related control measures, on cervical cancer screening-related activities from mid-March to mid-August 2020, across Canada. Methods: The survey consisted of 61 questions related to the continuum of care in cervical cancer screening and treatment: appointment scheduling, tests, colposcopy, follow-up, treatment of pre-cancerous lesions/cancer, and telemedicine. We piloted the survey with 21 Canadian experts in cervical cancer prevention and care. We partnered with the Society of Canadian Colposcopists, Society of Gynecologic Oncology of Canada, Canadian Association of Pathologists, and Society of Obstetricians and Gynecologists of Canada, which distributed the survey to their members via email. We reached out to family physicians and nurse practitioners via MDBriefCase. The survey was also posted on McGill Channels (Department of Family Medicine News and Events) and social media platforms. The data were analyzed descriptively. Results: Unique responses were collected from 510 participants (November 16, 2020, to February 28, 2021), representing 418 fully and 92 partially completed surveys. Responses were from Ontario (41.0%), British Columbia (21.0%), and Alberta (12.8%), and mostly comprised family physicians/general practitioners (43.7%), and gynecologist/obstetrician professionals (21.6%). Cancelled screening appointments were mainly reported by family physicians/general practitioners (28.3%), followed by gynecologist/obstetrician professionals (19.8%), and primarily occurred in private clinics (30.5%). Decreases in the number of screening Pap tests and colposcopy procedures were consistently observed across Canadian provinces. About 90% reported that their practice/institution adopted telemedicine to communicate with patients. Conclusions: The area most severely impacted by the pandemic was appointment scheduling, with an important level of cancellations reported. Survey results may inform resumptions of various fronts in cervical cancer screening and management. Funding: The present work was supported by the Canadian Institutes of Health Research (operating grant COVID-19 May 2020 Rapid Research Funding Opportunity VR5-172666 Rapid Research competition and foundation grant 143347 to Eduardo L Franco). Eliya Farah and Rami Ali each received an MSc stipend from the Department of Oncology, McGill University.

Cervical cancer is a common cancer among women caused by infections with certain types of human papillomavirus (HPV). Nearly four in five people are infected with HPV during their lifetime, making it the most common sexually transmitted infection worldwide. Vaccination against the virus can prevent infections and routine screening for precancerous lesions can enable early diagnosis and treatment, improving outcomes. However, the COVID-19 pandemic has disrupted routine cervical cancer screening programs in several countries. This has caused delays in screening, which could result in more women being diagnosed with advanced-stage cancers. El-Zein et al. showed that despite the interrupted screening programmes, about half of practices in Canada were able to catch up on delayed screening by February 2021. Between November 2020 and February 2021, El-Zein et al. surveyed 510 Canadian healthcare professionals involved in cervical cancer screening and treatment. About 64%-75% of the respondents reported canceled or postponed screening appointments. Most appointment delays were less than four months. Fewer than one in ten delays were longer than six months. Most survey respondents said their practices pivoted to using telemedicine for some patient visits, such as cervical cancer screening follow-ups. About 40% of respondents suggested that the pandemic provided support to alternative screening options, such as HPV self-sampling at home. The survey results may help healthcare professionals and policymakers to develop plans that mitigate disruptions to cervical cancer screening during future emergencies.

Association between male circumcision and human papillomavirus infection in males and females: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: Previous studies have suggested a protective effect of male circumcision on human papillomavirus (HPV) infections in males, and that this protection may be conferred to their female sexual partners. OBJECTIVES: To synthesize the available evidence on the association between male circumcision and HPV infections in males and females. DATA SOURCES: We searched MEDLINE, Embase, Scopus, Cochrane, LILACS, and ProQuest Dissertations & Theses Global for records published up to 22 June 2022. STUDY ELIGIBILITY: We considered observational and experimental studies that assessed male circumcision status and HPV prevalence, incidence, or clearance in males or females for inclusion. PARTICIPANTS: Males and their female sexual partners who were tested for genital HPV infection. INTERVENTIONS: Male circumcision compared with no circumcision. THE RISK-OF-BIAS ASSESSMENT: The Newcastle-Ottawa scale was used for observational studies, and the Cochrane risk-of-bias tool was used for randomized trials. DATA SYNTHESIS: We estimated summary measures of effect and 95% CIs for the prevalence, incidence, and clearance of HPV infections in males and females using random-effects meta-analysis. We assessed the effect modification of circumcision on HPV prevalence by the penile site in males using random-effects meta-regression. RESULTS: Across 32 studies, male circumcision was associated with decreased odds of prevalent HPV infections (odds ratio, 0.45; 95% CI, 0.34-0.61), a reduced incidence rate of HPV infections (incidence rate ratio, 0.69; 95% CI, 0.57-0.83), and an increased risk of clearing HPV infections (risk ratio, 1.44; 95% CI, 1.28-1.61) at the glans penis among male subjects. Circumcision conferred greater protection against infection at the glans than the shaft (odds ratio, 0.68; 95% CI, 0.48-0.98). Females with circumcised partners were protected from all outcomes. CONCLUSIONS: Male circumcision may protect against various HPV infection outcomes, suggesting its prophylactic potential. Understanding the site-specific effects of circumcision on HPV infection prevalence has important implications for studies of HPV transmission.

Detection and clearance of type-specific and phylogenetically related genital human papillomavirus infections in young women in new heterosexual relationships.

Background: Understanding the natural history of human papillomavirus (HPV) infections is essential to effective cervical cancer prevention planning. We examined these outcomes in-depth among young women. Methods: The HPV Infection and Transmission among Couples through Heterosexual Activity (HITCH) study is a prospective cohort of 501 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at six clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and liberal clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness. Results: By 24 months, we detected incident infections in 40.4%, CI:33.4-48.4 of women. Incident subgenus 1 (43.4, CI:33.6-56.4), 2 (47.1, CI:39.9-55.5) and 3 (46.6, CI:37.7-57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections. Conclusions: Our woman-level analyses of infection detection and clearance agreed with similar studies. However, our HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections take longer to clear than their low oncogenic risk and commensal subgenera 1 and 3 counterparts.

Site-Specific Cancer Incidence by Race and Immigration Status in Canada 2006-2015: A Population-Based Data Linkage Study.

BACKGROUND: The Canadian Cancer Registry (CCR) does not collect demographic data beyond age and sex, making it difficult to monitor health inequalities. Using data linkage, we compared site-specific cancer incidence rates by race. METHODS: The 2006 and 2011 Canadian Census Health and Environment Cohorts are population-based probabilistically linked datasets of 5.9 million respondents of the 2006 long-form census and 6.5 million respondents of the 2011 National Household Survey. Race was self-reported. Respondent data were linked with the CCR up to 2015. We calculated age-standardized incidence rate ratios (ASIRR), comparing group-specific rates to the overall population rate with bootstrapped 95% confidence intervals (CI). We used negative binomial regressions to adjust for socioeconomic variables and assess interactions with immigration status. RESULTS: The age-standardized overall cancer incidence rate was lower in almost all non-White racial groups than in the overall population, except for White and Indigenous peoples who had higher incidence rates than the overall population (ASIRRs, 1.03-1.04). Immigrants had substantially lower age-standardized overall cancer incidence rates than nonimmigrants (ASIRR, 0.83; 95% CI, 0.82-0.84). Stomach, liver, and thyroid cancers and multiple myelomas were the sites where non-White racial groups had consistently higher site-specific cancer incidence rates than the overall population. Immigration status was an important modifier of cancer risk in the interaction model. CONCLUSIONS: Differences in cancer incidence between racial groups are likely influenced by differences in lifestyles, early life exposures, and selection factors for immigration. IMPACT: Data linkage can help monitor health inequalities and assess progress in preventive interventions against cancer. See related commentary by Withrow and Gomez, p. 876.

Human Papillomavirus Intermittence and Risk Factors Associated With First Detections and Redetections in the Ludwig-McGill Cohort Study of Adult Women.

BACKGROUND: We assessed the incidence and risk factors for first detection and redetection with the same human papillomavirus (HPV) genotype, and prevalence of cytological lesions during HPV redetections. METHODS: The Ludwig-McGill cohort study followed women aged 18-60 years from São Paulo, Brazil in 1993-1997 for up to 10 years. Women provided cervical samples for cytology testing and HPV DNA testing at each visit. A redetection was defined as a recurring genotype-specific HPV positive result after 1 or more intervening negative visits. Predictors of genotype-specific redetection were assessed using adjusted hazard ratios (aHR) with Cox regression modeling. RESULTS: In total, 2184 women contributed 2368 incident HPV genotype-specific first detections and 308 genotype-specific redetections over a median follow-up of 6.5 years. The cumulative incidence of redetection with the same genotype was 6.6% at 1 year and 14.8% at 5 years after the loss of positivity of the first detection. Neither age (aHR 0.90; 95% confidence interval [CI], .54-1.47 for ≥45 years vs < 25 years) nor new sexual partner acquisition (aHR 0.98; 95% CI, .70-1.35) were statistically associated with genotype-specific redetection. High-grade squamous intraepithelial lesion prevalence was similar during first HPV detections (2.9%) and redetection (3.2%). CONCLUSIONS: Our findings suggest many HPV redetections were likely reactivations of latent recurring infections.

The impact of lag time to cancer diagnosis and treatment on clinical outcomes prior to the COVID-19 pandemic: A scoping review of systematic reviews and meta-analyses.

Background: The COVID-19 pandemic has disrupted cancer care, raising concerns regarding the impact of wait time, or 'lag time', on clinical outcomes. We aimed to contextualize pandemic-related lag times by mapping pre-pandemic evidence from systematic reviews and/or meta-analyses on the association between lag time to cancer diagnosis and treatment with mortality- and morbidity-related outcomes. Methods: We systematically searched MEDLINE, EMBASE, Web of Science, and Cochrane Library of Systematic Reviews for reviews published prior to the pandemic (1 January 2010-31 December 2019). We extracted data on methodological characteristics, lag time interval start and endpoints, qualitative findings from systematic reviews, and pooled risk estimates of mortality- (i.e., overall survival) and morbidity- (i.e., local regional control) related outcomes from meta-analyses. We categorized lag times according to milestones across the cancer care continuum and summarized outcomes by cancer site and lag time interval. Results: We identified 9032 records through database searches, of which 29 were eligible. We classified 33 unique types of lag time intervals across 10 cancer sites, of which breast, colorectal, head and neck, and ovarian cancers were investigated most. Two systematic reviews investigating lag time to diagnosis reported different findings regarding survival outcomes among paediatric patients with Ewing's sarcomas or central nervous system tumours. Comparable risk estimates of mortality were found for lag time intervals from surgery to adjuvant chemotherapy for breast, colorectal, and ovarian cancers. Risk estimates of pathologic complete response indicated an optimal time window of 7-8 weeks for neoadjuvant chemotherapy completion prior to surgery for rectal cancers. In comparing methods across meta-analyses on the same cancer sites, lag times, and outcomes, we identified critical variations in lag time research design. Conclusions: Our review highlighted measured associations between lag time and cancer-related outcomes and identified the need for a standardized methodological approach in areas such as lag time definitions and accounting for the waiting-time paradox. Prioritization of lag time research is integral for revised cancer care guidelines under pandemic contingency and assessing the pandemic's long-term effect on patients with cancer. Funding: The present work was supported by the Canadian Institutes of Health Research (CIHR-COVID-19 Rapid Research Funding opportunity, VR5-172666 grant to Eduardo L. Franco). Parker Tope, Eliya Farah, and Rami Ali each received an MSc. stipend from the Gerald Bronfman Department of Oncology, McGill University.

Serologic Response to Human Papillomavirus Genotypes Among Unvaccinated Women: Findings From the HITCH Cohort Study.

BACKGROUND: Humoral immune responses may be critical for preventing, controlling, and/or eliminating human papillomavirus (HPV) infection. We analyzed humoral response to natural HPV infection considering phylogenetic relatedness among unvaccinated women. METHODS: We included 399 young women attending university/college in Montreal, Canada who were participants of the HITCH cohort. Participants provided blood samples at baseline and 5 follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase (GST) fusion proteins, and virus-like particles (VLP-L1) of Alphapapillomavirus types were measured using multiplex serology. We assessed correlations and associations between HPV types at baseline using Pearson correlation coefficients (r) and univariable linear regressions. RESULTS: At baseline, > 40% were seropositive for GST-L1 antibodies of at least 1 HPV type. Strong correlations between GST-L1 were observed for α9 HPV types: 58-52 (r = 0.86), 58-33 (r = 0.75), 33-52 (r = 0.72), and between GST-E6: 52-11 (r = 0.84), 52-18 (r = 0.79), 58-33 (r = 0.78), 35-11 (r = 0.76). HPV16 VLP-L1 moderately explained variability in HPV16 GST-L1 (regression coefficient [b] = 0.38, R2 = 43.1%), and HPV45 GST-L1 in HPV18 GST-L1 (b = 0.68, R2 = 42.8%). GST-E6 antibodies accounted for a low to moderate proportion of variability in HPV16 and HPV18 GST-E6 (R2 = 6.4%-62.2%). CONCLUSIONS: Associations between naturally induced HPV-specific antibodies depend on phylogenetic relatedness.