Species-level characterization of the cervicovaginal microbiota and its role in human papillomavirus-associated cervical carcinogenesis.

The cervicovaginal microbiome may contribute to human papillomavirus (HPV)-associated cervical carcinogenesis, but studies have been limited by low-resolution analysis methods. Using a high-resolution bioinformatics pipeline, we evaluated the relationship of the cervicovaginal microbiome with HPV and cervical intraepithelial neoplasia (CIN). The cervicovaginal microbiome of 186 women was characterized by sequencing 16S rRNA regions (V3-V4 and V5-V6) and annotated with the high-resolution ANCHOR pipeline. Samples were genotyped for HPV using the Roche-Cobas 4800 assay. We fitted logistic regression models using stepwise forward selection to select species (presence/absence) as correlates of CIN1+ and constructed a linear microbiome-based score using the regression coefficients. An HPV-based score was calculated from a separate logistic regression model to detect CIN1+ . Receiver operating characteristic curve analyses were performed; the area under the curve (AUC) and 95% confidence intervals (CI) were compared between scores. Overall, 66.7% of participants were HPV-positive. 77 unique species were identified: 8 using V3-V4, 48 using V5-V6, and 21 shared. Twelve species were retained via stepwise selection. The AUCs for the microbiome-, and HPV-based scores were 0.7656 (95% CI 0.6885-0.8426), and 0.7529 (95% CI 0.6855-0.8204), respectively. Bacterial species may be involved in cervical carcinogenesis as the microbiome- and HPV-based scores performed similarly for CIN1+ detection.

Safety of carrageenan-based gels as preventive microbicides: a narrative review.

BACKGROUND: Carrageenan-containing gels researched for the prevention of sexually transmitted infections (STIs) have shown promising results for human papillomavirus prevention in women, but not in men. We conducted a narrative review to assess the safety of these gels for genital use. METHODS: We searched PubMed using MeSH terms and keywords on 5 November 2023. Title/abstract of articles were screened to identify relevant ones. Full-text screening determined eligibility: empirical study evaluating safety of carrageenan-containing gel(s) for genital use. RESULTS: Of the 125 identified records, 15 were eligible, comprising 14 (10 randomised controlled trials and 4 cohorts) unique study populations. Studies included women only (n=11), men only (n=1) or both (n=3); number of participants ranged from 4 to 6202. Safety was assessed for vaginal (n=13), penile (n=3) and anal use (n=2). Most studies assessed safety of Carraguard (53%), followed by Divine9 (14%), and one each of iota-carrageenan gel, lambda-carrageenan gel, Carvir, PC-6500 (griffithsin and carrageenan) and PC-1005 (MIV-150/zinc acetate/carrageenan). Safety assessment relied on self-report (80.0%), testing for STIs (53.3%), investigator-identified genital findings (93.3%) and/or testing for changes in genital flora (60.0%). Adverse events (AEs) were described by investigators as mostly mild, (mostly) comparable between groups, not observed and/or not significant for vaginal and penile use. Only one study, assessing anal use of carrageenan, reported a significantly higher proportion of AEs in the carrageenan compared with placebo group. CONCLUSIONS: Carrageenan-based gels are generally well tolerated for vaginal and penile, but not anal use. Studies on carrageenan gel's safety for anal use are scarce.

Evidence of Decreased Long-term Risk of Cervical Precancer after Negative Primary HPV Screens Compared with Negative Cytology Screens in a Longitudinal Cohort Study.

BACKGROUND: The growing use of primary human papillomavirus (HPV) cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. METHODS: This longitudinal cohort study (British Columbia, Canada, 2008 to 2022) recruited women and individuals with a cervix who received 1 to 2 negative HPV screens (HPV1 cohort, N = 5,546; HPV2 cohort, N = 6,624) during a randomized trial and women and individuals with a cervix with 1 to 2 normal cytology results (BCS1 cohort, N = 782,297; BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)] was compared between HPV and cytology cohorts. RESULTS: Cumulative risks of CIN2+ were 3.2/1,000 [95% confidence interval (CI), 1.6-4.7] in HPV1 and 2.7/1,000 (95% CI, 1.2-4.2) in HPV2 after 8 years. This was comparable with the risk in the cytology cohorts after 3 years [BCS1: 3.3/1,000 (95% CI, 3.1-3.4); BCS2: 2.5/1,000 (95% CI, 2.4-2.6)]. The cumulative risk of CIN2+ after 10 years was low in the HPV cohorts [HPV1: 4.7/1,000 (95% CI, 2.6-6.7); HPV2: 3.9 (95% CI, 1.1-6.6)]. CONCLUSIONS: Risk of CIN2+ 8 years after a negative screen in the HPV cohorts was comparable with risk after 3 years in the cytology cohorts (the benchmark for acceptable risk). IMPACT: These findings suggest that primary HPV screening intervals could be extended beyond the current 5-year recommendation, potentially reducing barriers to screening.

Epidemiology of HPV-associated cancers past, present and future: towards prevention and elimination.

Cervical cancer is the first cancer deemed amenable to elimination through prevention, and thus lessons from the epidemiology and prevention of this cancer type can provide information on strategies to manage other cancers. Infection with the human papillomavirus (HPV) causes virtually all cervical cancers, and an important proportion of oropharyngeal, anal and genital cancers. Whereas 20th century prevention efforts were dominated by cytology-based screening, the present and future of HPV-associated cancer prevention relies mostly on HPV vaccination and molecular screening tests. In this Review, we provide an overview of the epidemiology of HPV-associated cancers, their disease burden, how past and contemporary preventive interventions have shaped their incidence and mortality, and the potential for elimination. We particularly focus on the cofactors that could have the greatest effect on prevention efforts, such as parity and human immunodeficiency virus infection, as well as on social determinants of health. Given that the incidence of and mortality from HPV-associated cancers remain strongly associated with the socioeconomic status of individuals and the human development index of countries, elimination efforts are unlikely to succeed unless prevention efforts focus on health equity, with a commitment to both primary and secondary prevention.

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.

Naturally developed HPV16 antibodies and risk of newly detected cervical HPV infection outcomes.

Little is known about the protection conferred by antibodies from natural human papillomavirus (HPV) infection. Our objective was to evaluate the association between HPV16 seroreactivity and HPV16 redetection, newly detected HPV infections, and loss of HPV DNA detection during follow-up. We analyzed data from 2462 unvaccinated Brazilian women. HPV16 IgG and neutralizing antibodies at baseline were assessed by enzyme-linked immunosorbent assay (n = 1975) and by the pseudovirus-based papillomavirus neutralization assay (n = 487). HPV detection, genotyping, and viral load were assessed by PCR-based methods. The associations were analyzed by Cox proportional hazards models. We observed a positive association between HPV16 IgG seroreactivity and redetection of HPV16 infections. Age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) ranged from 2.45 (1.04-5.74) to 5.10 (1.37-19.00). Positive associations were also observed between HPV16 IgG antibodies and (1) newly detected HPV infections by genotypes unrelated to HPV16 (age-adjusted HR [95% CI] = 1.32 [1.08-1.2]) and (2) loss of detection of HPV infections by genotypes unrelated to HPV16 (age-adjusted HR [95% CI] = 1.24 [1.03-1.50]). Naturally developed HPV16 antibodies do not prevent recurrent HPV infections. Overall HPV16 IgG and neutralizing antibodies seem to be serological markers for latent or past infections.

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.

Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

Scientific approaches toward improving cervical cancer elimination strategies.

At the 2023 EUROGIN workshop scientific basis for strategies to accelerate the elimination of cervical cancer and its causative agent, human papillomavirus (HPV) were reviewed. Although some countries have reached key performance indicators toward elimination (>90% of girls HPV vaccinated and >70% of women HPV screened), most are yet to reach these targets, implying a need for improved strategies. Gender-neutral vaccination, even with moderate vaccination coverage was highlighted as a strategy to achieve elimination more rapidly. It is more resilient against major disturbances in vaccination delivery, such as what happened during the coronavirus pandemic. Further, an analysis of ethical/legal issues indicated that female-restricted vaccination is problematic. Extended catch-up of vaccination with concomitant screening, and outreach to vulnerable groups were highlighted. Although birth cohorts with high coverage of HPV vaccination at school are protected against HPV, and HPVs have a very low reproductive rate in women above age 35, adult women below age 30 have inadequate direct protection. In addition to herd protection from gender-neutral vaccination, this group can be protected by offering concomitant catch-up HPV vaccination and HPV screening. Furthermore, hepatitis B vaccination experiences indicate that elimination cannot be achieved without prioritizing vulnerable/migrant populations. The long-lasting durability of vaccination-induced antibody responses suggests prolonged protection with HPV vaccines when adequately administrated. Finally, cost-effectiveness modelling suggests that high-coverage HPV vaccination in multiple population segments will be resource-saving due to reduced need for screening. In summary, the workshop found that strategically optimal deployment of vaccination will accelerate elimination of HPV and cervical cancer.

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.

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.

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.

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.

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

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

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.