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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.

This review is based on the recent EUROGIN scientific session: “Assessing risk of cervical cancer in the post-vaccination era,” which addressed the demands of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesion (SIL) triage now that the prevalence of vaccine-targeted oncogenic high-risk (hr) human papillomaviruses (HPVs) is decreasing. Change in the prevalence distribution of oncogenic HPV types that follows national HPV vaccination programs is setting the stage for loss of positive predictive value of conventional but possibly also new triage modalities. Understanding the contribution of the latter, most notably hypermethylation of cellular and viral genes in a new setting where most oncogenic HPV types are no longer present, requires studies on their performance in vaccinated women with CIN/SIL that are associated with nonvaccine HPV types. Lessons learned from this research may highlight the potential of cervical cells for risk prediction of all women's cancers.

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer, but the majority of genital HPV infections clear spontaneously. Human leukocyte antigen (HLA) polymorphism influences immune response and genetic susceptibility, and its association with cervical cancer was extensively investigated, but few reports focused on HPV infection.We performed molecular typing of HLA-A, -B, -DQB1, and -DRB1 genes as well as of HPV in 1226 women enrolled in the Ludwig-McGill cohort study and investigated the influence on cumulative HPV positivity. HPV types were grouped according to Alphapapillomavirus subgenera that exhibit similar tissue tropism and biological behavior concerning cancer risk. The associations between HLA polymorphisms and HPV infections were estimated using unconditional logistic regression analysis adjusted for age and race.HLA-B*08 and HLA-DRB1*15:01 were negatively associated with HPV positivity, and similar effects were observed for HPV Subgenus 2 only, which includes HPV16. HLA-DRB1*08:07 was associated with overall HPV infection and Subgenus 2 positivity. The haplotypes HLA-B*08-DRB1*03:01-DQB1*02:01 and HLA-DRB1*08:07-DQB1*04:02 were negatively and positively associated with cumulative HPV positivity, respectively.Our data suggest that HLA class I and II polymorphism can influence HPV natural infection.

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Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Background: Alpha-human papillomavirus (α-HPV) plays a causal role in cervical cancer, but little is known about the epidemiology of genital Beta-human papillomavirus (β-HPV) infection.Methods: We used Luminex and PCR hybridization to detect β- and α-HPVs prevalence at enrollment and 12-month follow-up in cervical samples from 505 women enrolled in the Ludwig-McGill cohort study. We compared epidemiologic correlates of both β- and α-HPVs and compared genotypes between these genera with respect to co-occurrence and association with cervical cytologic abnormalities.Results: Infection with β-HPV types was more prevalent than that with α-HPV types at both visits (cumulative prevalences: 27.3% vs. 21.6%, respectively, P = 0.034). β-HPVs were mostly transient; however, only 1.98% women retained their original positivity at 12 months, whereas persistence was higher for α-HPVs (5.15%; P = 0.007). Age, parity, and sexual activity variables were predictors of α-HPV but not of β-HPV. α- and β-HPV types occurred independently. Increased risk of cervical abnormalities was restricted to women infected with α-9 or α-6 HPV types. We found no epidemiologic correlates for β-HPV infections.Conclusions: Detection of β-HPV types in the cervix tends to occur as random and transient episodes not explained via the sexual-transmission correlates that characterize infections by α-HPVs.Impact: Although it is plausible that β-HPVs may play a direct or indirect carcinogenic role, the lack of epidemiologic correlates for detection episodes of these viruses and lack of association with cervical lesions speak against their ancillary role as sexually transmitted agents in cervical carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(8); 1312–20. ©2017 AACR.

Supplementary Table S1. Positivity at both enrollment and follow-up for selected HPV types in the Ludwig-McGill Cohort Study (n=503)

Supplementary Figure S1. Selection of participants from the Ludwig-McGill Cohort Study for inclusion in the present study. Enrollment and 12-month samples and data were included to permit the analysis of one-year infection persistence.

IntroductionThe Carrageenan-gel Against Transmission of Cervical Human papillomavirus trial’s interim analysis (June 2017, n=277) demonstrated a 36% protective effect of carrageenan against incident human papillomavirus (HPV) infections. We report the trial’s final results on efficacy and safety of a carrageenan-based gel in reducing HPV incidence and prevalence.MethodsA phase IIB randomised, placebo-controlled trial, recruited healthy young women aged ≥18 primarily from health service clinics at two Canadian Universities in Montreal, Canada. Participants were randomised (1:1) to a carrageenan-based or placebo gel to be self-applied every other day for the first month and before/after intercourse. Primary outcomes were HPV type-specific incidence and clearance of prevalent infections. 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). Intention-to-treat analyses were conducted using Cox proportional hazards regression models. Incidence and clearance analyses were restricted to participants with ≥2 visits. Trial registration:ISRCTN96104919.Findings461 participants (enrolled January 16th/2013–September 30th/2020) were randomised to carrageenan (n=227) or placebo (n=234) arm. Incidence, clearance, and safety analyses included 429, 240, 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 [HR] 0·63 [95% CI: 0·49–0·81]). Among participants who tested HPV-positive at baseline, clearance (two consecutive HPV-negative visits following ≥1 positive visit) was comparable between groups; 31·8% (34/107) in carrageenan and 29·3% (39/133) in placebo arm cleared their infections (HR 1·16 [95% CI: 0·73-1·84]). Adverse events were reported by 34·8% (79/227) and 39·7% (93/234) of participants in carrageenan and placebo arm (pInterpretationConsistent with the interim analysis, use of a carrageenan-based gel resulted in a 37% reduction in the risk of incident genital HPV infections in women. A carrageenan-based gel may complement HPV vaccination.FundingCanadian Institute of Health Research (grants MOP-106610 and FDN-143347 to ELF), CarraShield Labs Inc. (St Petersburg, FL) [provided gels in kind].RESEARCH IN CONTEXTEvidence before this studyWe published in 2021 a narrative review summarizing carrageenan’s preventive effect on human papillomavirus (HPV) based on results from 19 experimental research articles that reported on carrageenan’s anti-HPV activity. Since publication and without applying language or date restriction, we identified four additional records based on a PubMed search using the keywords “carrageenan” and “human papillomavirus” or “HPV” up to January 9th, 2023.Altogether, these records consist of tenin vitro(including 4ex vivo), fivein vitroandin vivo, threein vivo, and five clinical studies (including one post-hoc phase III randomised controlled trial [RCT], one observational study, one interim analysis of a phase IIB RCT in women, and two records for the interim analyses of a phase IIB RCT in men). Studies assessed carrageenan alone or in combination with other anti-microbial agents. The results from pre-clinical studies were consistent with a protective effect of carrageenan against HPV.Overall, eight studies were conducted in humans. The samples collected were either 1) cervicovaginal lavage samples to assess anti-HPV activityin vitro(in threeex vivostudies, two being phase I RCTs), or 2) genital samples from women (post-hoc RCT [cervical], observational study [sample type not reported], and RCT phase II [vaginal]) or anal samples from men (one study of incidence and one of clearance). In the threeex vivostudies, intravaginal use of carrageenan-containing gels was associated with strong anti-HPV activity. In a post-hoc sub study of the trial, a lower HPV prevalence in the carrageenan compared to placebo arm was found at the trial end, but only among the most compliant users (adjusted odds ratio [aOR] 0·62 [95% CI 0·41–0·94], n=348). There were, however, no baseline or intermediate measurements to assess HPV status. An observational study reported that a carrageenan-based gel may accelerate clearance of existing HPV infection (aOR 4·9 [95% CI 1·60–15·1], n=75). The interim analysis of the CATCH study found a 36% protective effect of carrageenan against incident HPV infection(s) (HR 0·64 [95% CI 0·45-0·89], n=277). Conversely, a clinical trial conducted in men who have sex with men did not demonstrate a protective effect of carrageenan on incidence (HR 1·21 [95% CI 0·86–1·70]), or clearance (HR 0·84 [95% CI 0·31–2·27]) of anal HPV infections, and reported more adverse events in the carrageenan (59·8%) relative to the placebo (39·8%) arm.Added value of this studyThe CATCH study is the first clinical trial designed to assess the efficacy of a carrageenan-based gel in reducing the risk of incident and prevalent HPV infections in women. Results were consistent when considering HPV subgenera and type-specific analyses. The addition of carrageenan to a lubricant gel does not appear to impact gel tolerability.Implications of all the available evidenceThe results of the CATCH trial indicate that carrageenan-based gels could complement HPV vaccination in protecting against HPV-related diseases. Our findings of the clinical efficacy of carrageenan may encourage future research in this area. It would be important to further examine adherence by looking at determinants of adherence, explore the possibility of the addition of carrageenan to condoms, assess the impact of a carrageenan-based gel on anal HPV infections in women, and continue research in the area of multi-purpose prevention technology for agents against HPV, HIV, and other sexually transmitted infections.

BackgroundUnderstanding 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.MethodsThe 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.ResultsBy 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.ConclusionsOur 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.

BackgroundWe 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.MethodsThe 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.ResultsIn 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%).ConclusionsOur findings suggest many HPV redetections were likely reactivations of latent recurring infections.

IntroductionIncome, 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.MethodsWe 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 household 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.ResultsIndividuals 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, and non-Hodgkin’s lymphoma, breast, uterine, prostate, and testicular cancers. Most differences in site-specific incidence by income quintile remained after adjustment.ConclusionsAlthough 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.

Background: Among women whose cervical specimens tested positive for high-risk human papillomaviruses (hrHPV) via the Hybrid Capture 2 assay in the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed hrHPV genotype concordance between BD Onclarity HPV Assay and Roche's Linear Array, overall and stratified by hrHPV viral load. We also evaluated the performance of cytology, cytology combined with hrHPV genotyping (Onclarity assay) for HPV16/18 and non-HPV16/18 types, and hrHPV genotyping triage strategies for the detection of cervical intraepithelial neoplasia grade 2 or 3 and worse (CIN2+/CIN3+). Methods: Standard measures (expected agreement, agreement, and κ values) were used to compare Onclarity to the reference test, Linear Array. Twenty-four triage strategies were evaluated by calculating their sensitivities, specificities, and positive and negative predictive values for CIN2+ and CIN3+ detection. Results: Among 734 hrHPV+ samples tested, there was near perfect concordance irrespective of viral load between the Onclarity and Linear Array assays for the individual genotypes [human papillomaviruses (HPV) 16, 18, 31, 45, 51, 52] by Onclarity (κ values ranged from 0.92–0.98). Strategies with adequate specificity (>75%) and the highest sensitivities to detect CIN3+ among 617 women positive for hrHPV, were positivity to HPV16 and/or 31 (Sensitivity: 65.2%, Specificity: 76.9%) and HPV16 and/or 18 (Sensitivity: 58.7%, Specificity: 81.6%). Conclusions: While confirming the importance of HPV16, we found that HPV31 was comparable with HPV18 for the detection of CIN2/3+ in the triage of women positive for hrHPV. Impact: HPV31 may be an important genotype in the triage of women positive for hrHPV.

Background: Apart from the Epstein–Barr virus (EBV), the etiology of the hematologic malignancy Hodgkin lymphoma (HL) is not well defined. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with some lymphoproliferative diseases with similarities to HL. Methods: We performed a systematic review and meta-analysis, by searching Embase, MEDLINE, and Web of Science databases on March 9, 2021, for studies reporting a measure of association for HBV and HL or HCV and HL. We calculated pooled relative risks (RR) and their 95% confidence intervals (CI). Results: Pooling nine HBV studies with 1,762 HL cases yielded an RR of 1.39 (95% CI, 1.00–1.94) and pooling 15 HCV studies with 4,837 HL cases resulted in an RR of 1.09 (95% CI, 0.88–1.35). Meta-analyzing by study design, hepatitis detection method, and region revealed two subgroups with statistically significant associations—HCV studies that used hospital-based controls and/or were conducted in the West Pacific. No included study assessed age or EBV tumor status in relation to HL. Conclusions: Although we did not find an association between HBV or HCV and HL, research assessing the impact of age and EBV tumor status was lacking. Impact: The effect of HBV or HCV infection in the development of HL remains unclear.

Background Infections with human papillomaviruses (HPVs) may enter a latent state, and eventually become reactivated following loss of immune control. It is unclear what proportion of incident HPV detections are reactivations of previous latent infections vs new transmissions. Methods The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) cohort study prospectively followed young newly formed heterosexual partners recruited between 2005 and 2011 in Montréal, Canada. We calculated the fraction of incident HPV detections nonattributable to sexual transmission risk factors with a Bayesian Markov model. Results are the median (2.5th-97.5th percentiles) of the estimated posterior distribution. Results A total of 544 type-specific incident HPV detection events occurred in 849 participants; 33% of incident HPV detections occurred in participants whose HITCH partners were negative for that HPV type and who reported no other sex partners over follow-up. We estimate that 43% (38%–48%) of all incident HPV detections in this population were not attributable to recent sexual transmission and might be potentially reactivation of latent infections. Conclusions A positive HPV test result in many cases may be a reactivated past infection, rather than a new infection from recent sexual behaviors or partner infidelity. The potential for reactivation of latent infections in previously HPV-negative women should be considered in the context of cervical cancer screening.

Background Interplay between vaginal microbiome and human papillomavirus (HPV) remains unclear, partly due to heterogeneity of microbiota. Methods We used data from 546 women enrolled in a cross-sectional study in 5 Brazil. We genotyped vaginal samples for HPV and sequenced V3–V4 region of 16S rRNA gene for vaginal microbiome analysis. We used stepwise logistic regression to construct 2 linear scores to predict high-risk HPV (hrHPV) positivity: one based exclusively on presence of individual bacterial taxa (microbiome-based [MB] score) and the other exclusively on participants’ sociodemographic, behavioral, and clinical (SBC) characteristics. MB score combined coefficients of 30 (of 116) species. SBC score retained 6 of 25 candidate variables. We constructed receiver operating characteristic curves for scores as hrHPV correlates and compared areas under the curve (AUC) and 95% confidence intervals (CI). Results Overall, prevalence of hrHPV was 15.8%, and 26.2% had a Lactobacillus-depleted microbiome. AUCs were 0.8022 (95% CI, .7517–.8527) for MB score and 0.7027 (95% CI, .6419–.7636) for SBC score (P = .0163). Conclusions The proposed MB score is strongly correlated with hrHPV positivity—exceeding the predictive value of behavioral variables—suggesting its potential as an indicator of infection and possible value for clinical risk stratification.

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.

IntroductionWe assessed the incidence of redetection with the same human papillomavirus (HPV) genotype, predictors of first HPV detections and redetections, and prevalence of cytological lesions during HPV redetections.MethodsThe 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 one or more intervening negative visits. Predictors of genotype-specific redetection were assessed using adjusted hazard ratios (aHR) with Cox regression modeling.Results2184 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 7% at 1 year and 15% at 5 years after the loss of positivity of the first detection. Neither age (aHR 0.90, 95%CI 0.54-1.47 for ≥45y vs. ConclusionsOur findings suggest many HPV redetections were likely reactivations of latent recurring infections.

A demonstration project of primary human papillomavirus (HPV) testing was initiated in 2011 among more than 23,000 women attending routine cervical cancer screening. We examined the additional diagnostic performance of HPV genotyping for detecting disease in women with abnormal cytology.Women aged 30 to 65 years were originally screened for HPV using Hybrid Capture II test. Women with positive results were triaged using conventional cytology, and those with atypical squamous cells of undetermined significance or worse (≥ASC-US) were referred to colposcopy. We retrospectively genotyped (Roche cobas 4800 HPV system [Roche Molecular Systems Inc, Pleasanton, CA]) cervical specimens that were HPV + with Hybrid Capture II test and extracted women's medical history postbaseline screening. We calculated positive predictive values (PPVs) and 95% confidence intervals (CIs) of triage tests to detect histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2 + ) within the first year of follow-up among women positive for HPV16, HPV18, and HPV16 and/or HPV18 as well as among those negative for HPVs 16 and 18.Of 1,396 HPV-positive women, 1,092 (78%) were classified as normal, 136 (10%) had CIN1, 80 (6%) had CIN2, 81 (6%) had CIN3, and 7 women had cancer throughout the entire follow-up period. Seventy CIN2 + cases were detected within the first year of follow-up. The PPV for detecting CIN2 + was 20.9% (63/239; 95% CI = 16.4-25.9) for ASC-US + cytology. In women with ASC-US + , PPVs were 31.2% (24/77; 95% CI = 21.1-42.7) for HPV16 + , 27.8% (5/18; 95% CI = 9.7-53.5) for HPV18 + , 30.8% (28/91; 95% CI = 21.5-41.3) for HPV16 + and/or HPV18 + women, and 16.6% (35/211; 95% CI = 11.8-22.3) in women testing negative for HPVs 16 and 18.Partial genotyping as an additional triage strategy to cytology can markedly improve clinical diagnostic performance.

BackgroundHuman papillomavirus (HPV) infection is a necessary cause of cervical cancer and is associated with anal, penile, vaginal, and vulvar cancers. Previous studies have suggested a protective effect of male circumcision (MC) on HPV infections in males, and that this protection may be conferred to their female sexual partners. We synthesized the available evidence on the association between MC and HPV infections in males and females.MethodsWe performed a systematic review and meta-analysis of the effect of MC on the prevalence, incidence, and clearance of genital HPV infections in heterosexual males and their female sexual partners. We searched multiple databases for studies that assessed MC status and tested for the presence of genital HPV DNA. We used random-effects meta-analysis models to estimate summary measures of effect and 95% confidence intervals (CI) for the prevalence, incidence, and clearance of HPV infections in males and females. We assessed effect modification for prevalence in males using random-effects meta-regression.FindingsWe included 32 publications encompassing 25 unique study populations. MC was associated with decreased odds of prevalent HPV infections (odds ratio 0·45, CI 0·34–0·61), a reduced rate of incident HPV infections (incidence rate ratio 0·69, CI 0·57–0·83), and an increased risk of clearing HPV infections (risk ratio 1·44, CI 1·28–1·61) at the glans penis. Effect modification by sampling site was observed for HPV prevalence in males, with greater protection conferred by MC at the glans than the shaft (OR 0·68, 95% CI 0·48–0·98). Females with circumcised sexual partners were at reduced risk for all outcomes.InterpretationMC protects against various HPV infection outcomes, especially at the glans, and may be a viable prophylactic strategy in regions with a high burden of HPV-associated disease where the HPV vaccine is not commercially available. That the protective effect of MC on HPV infection prevalence varies by penile site has important implications for epidemiologic studies of HPV transmission.FundingFunded by grant FDN-143347 from the Canadian Institutes of Health Research.RESEARCH IN CONTEXTEvidence before this studyPrevious meta-analyses published in 2011, 2012, and 2017 have assessed the impact of MC on genital HPV infections in males, while systematic reviews published in 2017 and 2019 have described the impact of MC on women’s sexual health outcomes. All meta-analyses of males found a protective effect of MC on HPV prevalence, with inconsistent evidence for the association between MC and HPV incidence and clearance. Systematic reviews in females found a protective effect of MC on HPV prevalence.Added value of this studyWe identified an additional 12 publications (including one randomized controlled trial) that were not included in the most recently published systematic review and meta-analysis. We found that in males, MC conferred protection against prevalent HPV infections at the glans and shaft of the penis, protected against the acquisition of HPV infections at the glans, and resulted in increased clearance of HPV infections at the glans and shaft. We also found that MC protected females against various HPV infection outcomes. We considered anatomical site in all analyses and explored effect modification using a meta-regression approach. Our meta-analysis also examined the impact of MC on various HPV infection outcomes in females. To our knowledge, the latter two types of analyses had not been done before.Implications of all the available evidenceCountries with a high burden of HPV-associated diseases, or where the HPV vaccine is not commercially available, may wish to consider male circumcision as a preventive strategy. Both males and their female sexual partners may benefit from MC for protection from HPV infections.

We assessed carrageenan's potential to inhibit human papillomavirus (HPV) DNA extraction and amplification in vaginal swab samples collected in a trial, assessing the efficacy of a carrageenan-based gel against HPV infections. Experiment #1 consisted of adding gel (carrageenan-containing or placebo) to swabs and comparing HPV DNA detection by polymerase chain reaction (PCR) to unmanipulated samples collected from the same participants. For Experiments #2 and #3, we tested vaginal samples for inhibition by addition of an internal control and amplification by real-time PCR. Experiment #4 investigated carrageenan's interference with the extraction process by assessing HPV45 detectability in undiluted and diluted HPV45 positive samples (n = 3) with carrageenan versus no gel. In Experiment #1, there was a loss of HPV positivity with the addition of carrageenan (n = 9), but none with placebo gel (n = 5). In Experiments #2 and #3, the absence of the amplified product was observed in samples from the carrageenan arm: 3.3% (1/30) and 0.5% (1/199) of samples. In Experiment #4, HPV45 was not detected in undiluted carrageenan-containing samples, but after 1/50 dilution, the same HPV45 copy number was detected. Carrageenan does not affect the DNA extraction process, and inhibition of HPV DNA amplification by carrageenan occurs infrequently.

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.

Background It is unclear whether sexual transmission rates of human papillomaviruses (HPV) differ between sexes and HPV types. We estimate updated transmission rates from the final HITCH cohort study and propose an estimation method that accounts for interval-censored data and infection clearance. Methods We enrolled young women 18-24 years old and their male sex partners ≥18 years old in Montreal, Canada, between 2005 and 2011. We followed women over 24 months and men over 4 months. We tested genital samples with Linear Array for HPV DNA detection and genotyping. We calculated infection transmission rates between partners using a multistate Markov model via a Bayesian approach. We report the posterior median and 2.5%-97.5% percentile intervals (95% PI). Results We observed 166 type-specific incident HPV transmission events in 447 women and 402 men. The estimated median transmission rate from an HPV-positive to a negative partner was 4.2 (95% PI = 3.1 to 5.3) per 100 person-months. The transmission rate from men-to-women was 3.5 (95% PI = 2.5 to 4.7) and from women-to-men was 5.6 (95% PI = 3.8 to 7.0) per 100 person-months, corresponding to a rate ratio of 1.6 (95% PI = 1.0 to 2.5). Partners reporting always using condoms had a 0.22 (95% PI = 0.05 to 0.61) times lower HPV transmission rate than those reporting never using condoms. HPV16/18 did not have particularly high transmission rates relative to other HPV types. Conclusion Our updated analysis supports previous research suggesting higher women-to-men than men-to-women HPV transmission rates and a protective effect of condoms in heterosexual partnerships. Our results also suggest that crude incidence rates underestimate HPV transmission rates due to interval-censoring. See video abstract at http://links.lww.com/EDE/B794.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

It is unknown whether recently human papillomavirus (HPV)-vaccinated individuals confer protection against vaccine-preventable HPV types to their partners.Participants 18 to 45 years old who were living in Montreal, Canada, and in a heterosexual relationship of 6 months or less were randomly assigned to receive the intervention HPV vaccine, Gardasil or Gardasil 9, or active control (AC), Avaxim, a hepatitis A vaccine. Couples attended a maximum of 6 clinic visits (baseline and at 2, 4, 6, 9, and 12 months) and provided genital samples for detection of 36 HPV genotypes. Participants were vaccinated at baseline and at 2 and 6 months. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between the administered vaccine and infections at the HPV episode level.We restricted analyses to 273 participants (intervention: n = 141, AC: n = 132) who had at least 2 visits with valid HPV data. The HR of becoming positive for a given vaccine-preventable HPV type in the intervention group among those who received at least 1 dose compared with AC was 0.47 (95% CI, 0.23-0.97). Comparing individuals with HPV-vaccinated versus AC-vaccinated partners, there was no difference in risk of becoming positive for a given vaccine-preventable HPV type among those whose partners received at least 1 (HR, 1.46; 95% CI, 0.73-2.94) or 2 (HR, 0.78; 95% CI, 0.31-1.96) doses.Our study provides inconclusive evidence that individuals whose partner recently received an HPV vaccine are protected from vaccine-preventable types but demonstrates that vaccinated individuals are at a lower risk of incident infections.Trial Registration Number: NCT01824537.

Background: Cervical cancer is the fourth leading cause of death among women worldwide, with 85% of the burden falling on low- to middle- income countries. We studied the correlates of cervical cancer incidence and mortality, and case-fatality in Sub-Saharan Africa. Methods: Country-level data on 16 putative cervical cancer correlates for 37 Sub-Saharan African countries were collected from publicly available data sources. We performed univariate and multiple (stepwise) linear regression analyses to identify correlates of cervical cancer incidence and mortality, and case-fatality. Results: In univariate analyses, incidence and mortality rates were significantly correlated with contraceptive use, penile cancer incidence, and human immunodeficiency virus prevalence. Incidence rates were also correlated with literacy rates, whereas mortality rates were correlated with the proportion of rural population and screening coverage. Multiple regression analyses showed contraceptive use (P = 0.009) and penile cancer incidence (P = 0.004) as associated with cervical cancer incidence. Penile cancer incidence (P = 9.77 × 10–5) and number of medical doctors (P = 0.0433) were associated with mortality. The goodness of fit of the incidence and mortality models was moderate at best, explaining 49% and 37% of variability in the data, respectively. However, the case-fatality model had the best fit explaining most of the variation (adjusted R2 = 0.948; P = 6.822 × 10–16). Conclusions: To reduce the burden of cervical cancer in Sub-Saharan Africa, it would be important to design multimodal interventions that not only target screening and HPV vaccination, but also focus on cervical cancer correlates. Impact: Identifying contextual factors associated with cervical cancer in this region could inform targeted interventions.

Anyplex II HPV-28 (HPV-28) can detect individually 28 HPV genotypes. We assessed the agreement between linear array HPV genotyping (LA-HPV) and HPV-28 for detection of 27 HPV genotypes in 410 stored anogenital samples (75 anal samples, 335 physician-collected cervical samples) collected over 5 years from 410 individuals (13 men, 397 women), including 202 HIV-seropositive individuals. HPV DNA was detected in 393 (95.9%, 95% confidence interval [CI]: 93.4-97.4) and 382 (93.2%, 95% CI: 90.3-95.3) samples with HPV-28 and LA-HPV (p = 0.13), respectively, for a good agreement of 96.3% (κ = 0.65). Of the 10503 HPV typing results, 10195 (780 positive, 9577 negative) were concordant, for an agreement of 97.1% (95% CI: 96.7-97.4) and an excellent of κ = 0.82 (95% CI: 0.80-0.84). The mean type-specific concordance for 27 genotypes was 97.0%, 95% CI: 95.8-98.5 (κ = 0.86 ± 0.07, 95% CI: 0.83-0.88). Excellent agreement was obtained individually for all high-risk genotypes (κ = 0.81-0.97) and for most other genotypes except for types 42, 44, 54, 68, and 69. The mean number of types per sample in discordant samples detected with LA-HPV (3.0, 95% CI: 2.7-3.4) was greater than in concordant samples (1.4, 95% CI: 1.3-1.5; p 0.001). In conclusion, HPV-28 compared favorably with LA-HPV, but was more frequently positive for HPV42 and HPV68.

Made available in DSpace on 2020-12-12T02:16:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-08-01 Background Composition of the vaginal microbiome is strongly related to a woman's reproductive health and risk of sexually transmitted infections. Ethnoracial, behavioral, and environmental factors can influence microbiome. The Brazilian population is unique in terms of miscegenation of ethnic groups and behavioral characteristics across different regions. We aimed to characterize the vaginal microbiome of women from 5 geographical regions of Brazil. Methods We sequenced V3-V4 regions of 16S rRNA gene in vaginal samples of 609 reproductive-aged women. We performed logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between sociodemographic and behavioral factors with Lactobacillus-depleted microbiome (community state type [CST] IV). Results Vaginal samples were grouped into 5 CST: CST I (L. crispatus predominant, 30.5%), CST II (L. gasseri predominant, 4.4%), CST III (Lactobacillus iners predominant, 36.5%), CST IV (Lactobacillus-depleted, 27.4%), and CST V (L. jensenii predominant, 1.2%). Several factors were independently associated with CST IV, such as smoking (OR, 1.80; 95% CI, 1.02-3.18), number of partners (OR, 2.11; 95% CI, 1.20-3.70), and vaginal douching (OR, 2.24; 95% CI, 1.34-3.74). A protective effect was observed for milk/dairy intake (OR, 0.47; 95% CI, 0.27-0.82) and sitz bathing (OR, 0.43; 95% CI, 0.19-0.98). Conclusions Nearly two thirds of Brazilian women may be at an increased risk for adverse outcomes associated with a vaginal microbiota characterized by the depletion of Lactobacillus or dominance by L. iners, whose protective role has been widely questioned. Several factors related to sexual behavior and intimate hygiene were associated with CST IV. Department of Basic Pathology Federal University of Paraná (UFPR) Department of Pathology Botucatu Medical School Sao Paulo State University (UNESP) Division of Cancer Epidemiology McGill University Institute of Genomic Science University of Maryland School of Medicine Department of Gynecology and Obstetrics Federal University of Paraíba (UFPB) Department of Gynecology and Obstetrics Federal University of Paraná (UFPR) Department of Gynecology and Obstetrics Federal University of Goiás (UFG) Department of Nursing Botucatu Medical School Sao Paulo State University (UNESP) Department of Gynecology and Obstetrics State University of Pará (UEPA) Department of Gynecology and Obstetrics Faculty of Medicine State University of Campinas (UNICAMP) Department of Gynecology and Obstetrics Faculty of Medicine Federal University of Rio Grande Do Norte (UFPR) Department of Pathology Botucatu Medical School Sao Paulo State University (UNESP) Department of Nursing Botucatu Medical School Sao Paulo State University (UNESP)

Background Limited evidence indicates greater female-to-male (F–M) transmission of genital infection with human papillomavirus (HPV) relative to male-to-female (M–F). We verified the hypothesis of a differential transmission rate in couple-based studies by conducting a systematic review and meta-analysis. Methods We searched MEDLINE, EMBASE, Scopus, and Cochrane Library databases for studies published until December 2019. We calculated pooled estimates of F–M and M–F transmission rates and their rate differences per 100 person-months, with 95% confidence intervals (CI), using a random-effects model. We counted occurrences of directionality preponderance for each HPV type. Results We identified 7 eligible studies published between 2008 and 2019, providing data for 752 couples. Pooled estimates for F–M and M–F transmission rates were 3.01 (95% CI, 1.19–7.64; I2 = 97%) and 1.60 (95% CI, 0.86–2.98; I2 = 89%), respectively. The overall rate difference was 0.61 (95% CI, −0.27 to 1.49; I2 = 75%). Three studies provided rates by sex and HPV genotype; 2 favored a preponderance of F–M and 1 favored M–F transmission. Conclusions There was slight evidence for a differential transmission rate favoring higher F–M than M–F transmission with substantial statistical heterogeneity across studies.

Most women positive for human papillomavirus (HPV) are cytology normal. The optimal screen-management of these women is unclear given their risk of developing precancer. We performed a systematic review and meta-analysis of progression rates to precancer and cancer for HPV-positive, cytology normal women. We searched MEDLINE, EMBASE and Scopus for prospective studies measuring the cumulative incidence of precancer and cervical cancer in HPV-positive, cytology/histology normal women. Record screening was performed independently by two reviewers. We modeled the cumulative incidence over time using a multilevel random-effects meta-regression model. We used the model to predict HPV type-specific risks of precancer and cancer over follow-up. Data from 162 unique records were used in our analysis. The average incidence rate of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in high-risk HPV positive but cytology/histology normal women was 1.0 per 100 women-years (95% CI: 1.0-1.1). This corresponds to an average cumulative risk at 1, 3 and 5 years of 2.1% (95% prediction interval 0.0-9.5), 4.3% (95% prediction interval 0.0-11.5) and 6.4% (95% prediction interval 0.0-13.5). HPV type was a strong predictor of the risk of oncogenic progression. There was substantial heterogeneity in the background precancer risk across studies (P-value < .0001). Our HPV type-specific progression risk estimates can help inform risk-based cervical cancer screening guidelines for HPV-positive women. However, precancer and cervical cancer risks are highly variable and may not be generalizable between populations.

DNA methylation analysis may improve risk stratification in cervical screening. We used a pan-epigenomic approach to identify new methylation markers along the continuum of cervical intraepithelial neoplasia (CIN) to cervical cancer. Physician-collected samples (54 normal, 50 CIN1, 40 CIN2 and 42 CIN3) were randomly selected from women at a single-center colposcopy clinic. Extracted DNA was subjected to Illumina Infinium EPIC array analysis, and methylation was assessed blinded to histopathological and clinical data. CpG sites whose state of methylation correlated with lesion grade were assessed (Spearman correlation), and a weighted methylation score was calculated comparing normal to CIN3. Validation of the top selected genes was performed in an independent cohort (100 normal, 50 CIN1, 50 CIN2, 50 CIN3 and 8 cervical cancers) of new patients, referred for colposcopic examination at three hospitals, using targeted DNA methylation Illumina amplicon sequencing. The relationship between a combined weighted marker score and progression from normal through precancerous lesions and cervical cancer was compared using one-way ANOVA. Our analyses revealed 7,715 CpGs whose methylation level correlated with progression (from normal to CIN1, CIN2 and CIN3), with a significant trend of increased methylation with lesion grade. We shortlisted a bigenic (hyaluronan synthase 1, HAS1 and ATPase phospholipid transporting 10A, ATP10A corresponding to cg03419058 and cg13944175 sites) marker set; r = 0.55, p < 0.0001. Validation of the four most discriminating genes (CA10, DPP10, FMN2 and HAS1) showed a significant correlation between methylation levels and disease progression (p-value < 2.2 × 10-16 , adjusted R2 = 0.952). Translational research of the identified genes to future clinical applications is warranted.

Background: Vaccination against human papillomaviruses (HPV) prevents HPV infections and, consequently, cervical lesions. However, the effect of vaccination on HPV transmission within couples is unknown. Methods: We used data from HITCH, a prospective cohort study of heterosexual couples (women ages 18–24 years) in Montreal, 2005 to 2013. Vaccination history was self-reported. Genital samples were tested for HPV DNA by PCR (linear array). Type-specific viral loads were quantified using real-time PCR. OR and HR were estimated using multilevel mixed-effects logistic regression and a parametric model for interval- censored survival-time data, respectively. Differences in viral loads were evaluated using the Friedman ANOVA test. Results: Among 497 couples, 12, 16, and 35 women received 1, 2, or 3 vaccination doses at baseline, respectively. Median age at vaccination was 18 years. Most women (92.1%) had their first coitus before vaccination. At baseline, partner concordance of persistent HPV6/11/16/18 infections was lower in vaccinated than unvaccinated women [adjusted OR = 0.10; 95% confidence interval (CI), 0.01–0.65] but not for non α7/α9/α10-HPV types (adjusted OR = 1.00; 95% CI, 0.44–2.29). Incidence of persistent α7/α9/α10 HPV types in women was inversely associated with vaccination status at baseline (adjusted HR = 0.12; 95% CI, 0.03–0.47). Likewise, male partners of vaccinated women had a lower incidence of α7/α9/α10 HPV infections (adjusted OR = 0.22; 95% CI, 0.05–0.95). Vaccinated women with HPV 6/11/16/18 infections had lower viral loads (P = 0.001) relative to unvaccinated women. Conclusions: Vaccination of sexually active women significantly reduced transmission of α7/α9/α10 HPV types in heterosexual couples. Impact: These results underscore and quantify the positive effect of HPV vaccination on HPV transmission within heterosexual couples.

While launching a campaign to eliminate cervical cancer, the World Health Organization called to halt human papillomavirus (HPV) gender-neutral vaccination (GNV) because of limited vaccine supply, raising ethical and legal questions about female-only vaccination versus GNV. We identified ethical and legal aspects of HPV GNV by searching MEDLINE for records up to February 19, 2021. We also provided an overview of HPV vaccines, the evolution of HPV vaccine recommendations in North America, and a timeline of male HPV vaccination introduction by searching PubMed, Google, and government websites. Four HPV vaccines are available: Cervarix, Gardasil, Gardasil9, and Cecolin. Vaccine recommendations in North America evolved from female only to eventually include males. Following the FDA's approval of the first HPV vaccine for males (2009), 35 countries began vaccinating males (2011–2020). On the basis of 59 eligible records out of 652, we identified the following constructs: lower male awareness of HPV and vaccination (n = 13), limited economic resources (n = 5), shared social responsibility (n = 18), unprotected groups from female-only HPV vaccination (n = 10), limited screening for HPV-associated noncervical cancers (n = 6), consideration of ethical principles (n = 17), and HPV vaccine mandates (n = 5). Ethical and legal aspects must be considered when recommending vaccination for females only or GNV.

BackgroundInfections with human papillomaviruses (HPV) may enter into a latent state in epithelial basal cells, and eventually become reactivated following loss of immune control. It is unclear what proportion of incident detections of HPV are due to reactivation of previous latent infections versus new transmissions.MethodsThe HITCH cohort study prospectively followed young newly-formed heterosexual partners recruited between 2005-2011 in Montréal, Canada. We calculated the fraction of incident HPV detections non-attributable to sexual transmission risk factors with a Bayesian Markov state transition model. Results are the median (2·5-95·5th percentiles) of the estimated posterior distribution.Findings544 type-specific incident HPV detection events occurred in 849 participants; 32·5% of all incident HPV detections occurred in participants whose HITCH partners were negative for that HPV type and who did not report having sex with anyone else over follow-up. We estimate that 42·7% (38·4-47·2%) of all incident HPV detections in this population might be attributable to reactivation of latent infections, not transmission.InterpretationA positive HPV test result in many cases may be a reactivated past infection, rather than a new infection from recent sexual behaviors or partner infidelity. The potential for reactivation of latent infections in previously HPV-negative women should be considered in the context of cervical cancer screening.FundingCanadian Institutes of Health Research, National Institutes of Health, Merck-Frosst Canada Ltd, Merck & Co Ltd, Fonds de la Recherche en Santé du Québec.Research in ContextEvidence before this studyPrevious studies assessing the proportion of HPV infections attributable to reactivation in women have been conducted in individual-based studies. Determining this estimate using a couple-based study design could account for the partner’s HPV status and rule out sexual transmission. Authors from this current study recently published a systematic review that aimed to identify all published couple-based studies measuring HPV transmission. They searched MEDLINE, EMBASE, Scopus, and Cochrane Library from database inception to December 1, 2019, with no language restrictions using the keywords and MeSH terms “HPV,” “papillomavirus infections,” “papillomaviridae,” “transmission,” “heterosexuality,” “couples,” and “sexual partners”. Studies were included if the study population was heterosexual couples, genital samples were collected from each partner, and HPV transmission rates were reported. The search yielded 834 records, of which seven couple-based studies were eligible to be included in the systematic review. None of the identified studies measured the proportion of HPV infections attributable to reactivation.Added value of this studyThis study presents the first analysis assessing reactivation of HPV infections using a couple-based study design. We recruited young heterosexual couples and collected genital HPV data from both partners, allowing us to control for the sexual partner’s HPV status. We estimate that 57% of the newly detected incident HPV infections in women could be attributed to sexual transmission while the remaining 43% is most likely due to reactivation of latent infections.Implications of all the available evidenceIn the context of cervical cancer screening, our findings suggest that women who have previously tested HPV negative may not remain HPV-negative, even with no new sexual partners, due to reactivation of a latent infection. This underscores the importance for HPV-negative women to undergo multiple screenings in their lifetime. In addition, the sizeable proportion of newly detected HPV infections attributable to reactivation suggests that a positive HPV test is not necessarily due to recent sex or partner infidelity, which may help de-stigmatize a positive HPV test result.

Background: Self-sampling has become an attractive proposition now that human papillomavirus (HPV) primary testing is being incorporated into cervical cancer screening programs worldwide. We compared predictive values of HPV testing based on self- and physician-collected samples, and cytology, in detecting high-grade cervical intraepithelial neoplasia (CIN). Methods: The Cervical And Self-Sample In Screening (CASSIS) study enrolled 1,217 women ages 16–70 years prior to scheduled colposcopies. Vaginal specimens were self-collected using the validated HerSwab device. Cervical specimens were collected by gynecologists. Specimens were tested for presence of high-risk HPV (hrHPV) by the Cobas 4800 HPV test. We estimated positive predictive values (PPV) and negative predictive values (NPV) and 95% confidence intervals (CI) for a subset of women (n = 700) who underwent cervical biopsy and cytology at the actual CASSIS visit. Results: hrHPV was detected in 329 women (47%) with HerSwab and in 327 (46.7%) with physician sampling. Respective values for HPV16/18 were 119 (17%) and 121 (17.3%). On histology, 134 women had CIN1, 49 had CIN2, 48 had CIN3, 5 had CIN2/CIN3, and 3 had cancers. PPVs for CIN2+ of any hrHPV were 28% (95% CI, 23.2–33.1) and 29.7% (95% CI, 24.8–34.9) for HerSwab and physician samples, respectively. Corresponding values for HPV16/18 were 43.7% (95% CI, 34.6–53.1) and 43.8% (95% CI, 34.8–53.1). PPV of cytology (ASC-US+) was 26.6% (95% CI, 21.6–32.0). Corresponding NPVs (same order as PPVs) were 96.4% (95% CI, 93.9–98.1), 97.8% (95% CI, 95.6–99), 90.9% (95% CI, 88.2–93.1), 91% (95% CI, 88.4–93.2), and 94.7% (95% CI, 91.8–96.8). Conclusions: Our results confirm that HPV self-sampling has comparable performance with a physician-collected sample in detecting cervical lesions. Impact: HPV self-sampling has the potential to increase coverage in cervical cancer screening.

BackgroundWe studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance.MethodsThe HITCH cohort study included young, heterosexual, recently formed, sexually active couples. Questionnaires and genital samples were collected at 0 and 4 months. Samples were tested for HPV DNA by polymerase chain reaction (PCR; Linear Array). VLs of HPV6/11/16/18/31/42/51 were quantified using type-specific real-time PCR. Correlations between VL and type-specific HPV prevalence and incidence were evaluated using multilevel, mixed-effects linear/logistic regression models.Results We included 492 couples. VLs were higher in penile than vaginal samples. VL at subsequent visits correlated significantly within men (r, 0.373), within women (r, 0.193), and within couples (r range: 0.303–0.328). Men with high VL had more type-specific persistent HPV infections (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0–10.5]). High VL in men was associated with prevalent (OR, 5.3 [95% CI, 2.5–11.2]) and incident (OR, 6.7 [95% CI, 1.5–30.7]) type-specific HPV infections in their partner. Women’s VL was associated with type-specific HPV prevalence in their partner at the same (OR, 5.9) and subsequent (OR, 4.7) visit.ConclusionsPersistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes.