Efficacy of a Carrageenan gel Against Transmission of Cervical HPV (CATCH): interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial.

OBJECTIVES: To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. METHODS: We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. RESULTS: Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9-13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45-0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. CONCLUSIONS: Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

Who's Not Protected in the Herd? Factors Associated with Vaccine-Type HPV in Unvaccinated Women.

STUDY OBJECTIVE: Evidence suggests that vaccine-type human papillomavirus (HPV) prevalence may decrease in unvaccinated women after HPV vaccine introduction, indicating herd protection. The aim of this study was to determine factors associated with vaccine-type HPV (i.e. absence of herd protection) after vaccine introduction. DESIGN: We conducted three cross-sectional studies from 2006-2014 (n = 1180): wave 1 (2006-2007), wave 2 (2009-2010), and wave 3 (2013-2014). SETTING: Participants were recruited from a hospital-based teen health center and a community health department. PARTICIPANTS: We recruited 13-26 year-old young women; those included in this analysis had not received an HPV vaccine. INTERVENTIONS AND MAIN OUTCOME MEASURES: The outcome measure was infection with at least one vaccine-type HPV (HPV6, 11, 16, 18). RESULTS: Multivariable logistic regression demonstrated that in wave 1 (before vaccine introduction), history of anal intercourse (OR = 1.8, 95% CI = 1.1-3.0), age 18-21 vs 13-17 years (OR = 2.1, CI = 1.2-3.6), and Black/multiracial vs White race (OR = 1.8, CI = 1.1-3.0) were associated with vaccine-type HPV in unvaccinated women. In wave 2, no variables were associated with HPV. In wave 3, sexually transmitted infection history (OR = 3.6, CI = 1.3-9.7) was associated with HPV. CONCLUSION: We did not identify a consistent set of modifiable risk factors associated with vaccine-type HPV after vaccine introduction across the three study waves, underscoring the urgency of vaccination for primary HPV prevention and the limitations of relying on herd protection.

The performance of mobile screening units in a breast cancer screening program in Brazil.

PURPOSE: In Brazil, access to breast cancer screening outside of urban centers is limited. This study aims to describe the coverage and performance of a breast cancer screening program implemented with Mobile Screening Units (MSU) in northern São Paulo state. METHODS: This is a retrospective cohort study of a population-based mammography program targeting women ages 40-69 in 108 municipalities from 12/2010 to 07/2015. Screening coverage rates were estimated using the Brazil 2010 census data. We calculated performance measures for the number of exams, recalls, and detected cases of cancer. Screen-detected cases were compared to clinically detected cases using hospital cancer registry data and a propensity-score matching method. The down-staging of screen-detected cases relative to clinically detected cases was assessed using logistic regression to calculate risk ratios (RRs) with 95% confidence intervals. RESULTS: 122,634 women were screened through the MSU program, representing a cumulative coverage rate of 54.8% in the target population. For initial and subsequent rounds, recall rates were 12.25 and 6.10% and cancer detection rates were 3.63 (95% CI 3.23-4.10) and 1.94 (95% CI 1.59-2.41), respectively. 92.51% of referrals were successful. Screen-detected cases had more favorable prognoses than clinically detected cases, including smaller tumor size and a decreased risk of late-stage detection (RR 0.14 95% CI 0.074-0.25). CONCLUSIONS: MSUs are a feasible method for the delivery of mammography services in this setting. Patients who had breast cancer detected on an MSU had favorable prognostic factors when compared with clinically detected cases arising from the same target population.

Assortative mixing as a source of bias in epidemiological studies of sexually transmitted infections: the case of smoking and human papillomavirus.

For studies examining risk factors of sexually transmitted infections (STIs), confounding can stem from characteristics of partners of study subjects, and persist after adjustment for the subjects' individual-level characteristics. Two conditions that can result in confounding by the subjects' partners are: (C1) partner choice is assortative by the risk factor examined and, (C2) sexual activity is associated with the risk factor. The objective of this paper is to illustrate the potential impact of the assortativity bias in studies examining STI risk factors, using smoking and human papillomavirus (HPV) as an example. We developed an HPV transmission-dynamic mathematical model in which we nested a cross-sectional study assessing the smoking-HPV association. In our base case, we assumed (1) no effect of smoking on HPV, and (2) conditions C1-C2 hold for smoking (based on empirical data). The assortativity bias caused an overestimation of the odds ratio (OR) in the simulated study after perfect adjustment for the subjects' individual-level characteristics (adjusted OR 1·51 instead of 1·00). The bias was amplified by a lower basic reproductive number (R 0), greater mixing assortativity and stronger association of smoking with sexual activity. Adjustment for characteristics of partners is needed to mitigate assortativity bias.

Screening histories and contact with physicians as determinants of cervical cancer risk in Montreal, Quebec.

BACKGROUND: Cervical cancer (cca) is largely a preventable disease if women receive regular screening, which allows for the detection and treatment of preinvasive lesions before they become invasive. Having been inadequately screened is a common finding among women who develop cca. Our primary objective was to determine the Pap screening histories of women diagnosed with cca in Montreal, Quebec. Secondary objectives were to determine the characteristics of women at greatest risk of cca and to characterize the level of physician contact those women had before developing cca. METHODS: The Invasive Cervical Cancer Study, a population-based case-control study, consisted of Greater Montreal residents diagnosed with histologically confirmed cca between 1998 and 2004. Respondents to the 2003 Canadian Community Health Survey and a sample of women without cca obtained from Quebec medical billing records served as controls. RESULTS: During the period of interest, 568 women were diagnosed with cca. Immigrants and women speaking neither French nor English were at greatest risk of cca. Most of the women in the case group had been screened at least once during their lifetime (84.8%-90.4%), but they were less likely to have been screened within 3 years of diagnosis. Having received care from a family physician or a medical specialist other than a gynecologist within the 5 years before diagnosis was associated with a greater risk of cca development. CONCLUSIONS: Our findings provide evidence of the need for an organized population-based screening program. They also underscore the need for provider education to prevent missed opportunities for cca screening when at-risk women seek medical attention.

The road ahead for cervical cancer prevention and control.

Since the early 1950s, Papanicolaou ("Pap") cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others-for example, hpv testing followed by genotyping-are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16(INK4a) staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers.

Assessment of the performance of algorithms for cervical cancer screening: evidence from the Ludwig-McGill cohort study.

OBJECTIVE: There are currently multiple tests available for cervical cancer screening and the existing screening policies vary from country to country. No single approach will satisfy the specific needs and variations in risk aversion of all populations, and screening algorithms should be tailored to specific groups. We performed long term risk stratification based on screening test results and compared the accuracy of different tests and their combinations. METHODS: A longitudinal cohort study of the natural history of HPV infection and cervical neoplasia enrolled 2462 women from a low-income population in Brazil. The interviews and cervical screening with cytology and HPV DNA testing were repeated according to a pre-established protocol and the subjects were referred for colposcopy and biopsy whenever high grade lesions were suspected. We compared the specificity, sensitivity and predictive values of each screening modality. Long term risk stratification was performed through time-to-event analyses using Kaplan-Meier analysis and Cox regression. RESULTS: The best optimization of sensitivity and specificity was achieved when using dual testing with cytology and HPV DNA testing, whereby the screening test is considered positive if either component yields an abnormal result. However, when allowing 12months for the detection of lesions, cytology alone performed nearly as well. Risk stratification revealed that HPV DNA testing was not beneficial for HSIL cases, whereas it was for ASCUS and, in some combinations, for negative and LSIL cytology. CONCLUSION: Our results suggest that some high risk populations may benefit equally from cytology or HPV DNA testing, and may require shorter intervals between repeat testing.

Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study.

BACKGROUND: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. METHODS: The three arms are: Control arm - liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm - hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm - hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. RESULTS: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. CONCLUSION: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

Estimating the long-term impact of a prophylactic human papillomavirus 16/18 vaccine on the burden of cervical cancer in the UK.

To predict the public health impact on cervical disease by introducing human papillomavirus (HPV) vaccination in the United Kingdom, we developed a mathematical model that can be used to reflect the impact of vaccination in different countries with existing screening programmes. Its use is discussed in the context of the United Kingdom. The model was calibrated with published data. The impact of vaccination on cervical cancer and deaths, precancerous lesions and screening outcomes were estimated for a vaccinated cohort of 12-year-old girls, among which it is estimated that there would be a reduction of 66% in the prevalence of high-grade precancerous lesions and a 76% reduction in cervical cancer deaths. Estimates for various other measures of the population effects of vaccination are also presented. We concluded that it is feasible to forecast the potential effects of HPV vaccination in the context of an existing national screening programme. Results suggest a sizable reduction in the incidence of cervical cancer and related deaths. Areas for future research include investigation of the beneficial effects of HPV vaccination on infection transmission and epidemic dynamics, as well as HPV-related neoplasms in other sites.

Cervical coinfection with human papillomavirus (HPV) types as a predictor of acquisition and persistence of HPV infection.

Interest in coinfection with multiple types of human papillomavirus (HPV) has increased in response to the possibility of vaccination and the discovery that the host immune response appears to be mainly type specific. This study attempts to document the occurrence of coinfection with multiple HPV types and to determine whether these coinfections predicted acquisition or persistence of other HPV types in a prospective cohort of women in Brazil. Multiple HPV types were detected at the same visit in one-fifth of all women who tested positive for HPV at any time. Acquisition of an HPV infection was more likely among women with any HPV type detected on study entry. Persistence of HPV infection, the true precursor of cervical abnormalities, was independent of coinfection with other HPV types. Given the increasing prominence of HPV vaccination as a potential preventive approach, it is imperative that additional insights on cross-type protection be obtained from longer-term longitudinal investigations.

Oncogenic human papillomavirus infection and cervical lesions in aboriginal women of Nunavut, Canada.

BACKGROUND: The high rate of cervical cancer among aboriginal women of northern Canada has prompted the search for more aggressive methods to augment Papanicolaou (Pap) screening in this population. Nearly all cervical cancers result from oncogenic human papillomavirus (HPV) infections. This has generated interest for incorporating HPV testing into the current screening program. GOALS: To determine the prevalence of oncogenic HPVs in Nunavut, and to assess the association between HPV and squamous intraepithelial lesions (SIL). STUDY DESIGN: A cross-sectional study was conducted on the Pap-screened populations in 19 communities of Nunavut, Canada. Liquid-based cytology was used to screen for SIL. HPV testing was performed using the Hybrid Capture II assay. Correlates of HPV infection and SIL were assessed by logistic regression with control for potential confounders. RESULTS: In 1290 women ages 13 to 79 years, the prevalence rate was 26% for oncogenic HPV and 6.9% for SIL. The odds ratio for the association between HPV and SIL was 37.9 (95% CI, 17.7-80.8) after multivariate adjustment. This association increased markedly with increasing viral load. More than 90% of the women with squamous intraepithelial lesions had positive test results for HPV. More than 75% of the women who had positive test results for HPV but negative test results for SIL were younger than 30 years. CONCLUSION: The results of this study form the basis for further evaluation of the role that liquid-based cytology and HPV testing plays and will contribute to the strategy for cervical cancer prevention in Nunavut.

Effect of type of alcoholic beverage on the risks of upper aerodigestive tract cancers in Brazil.

OBJECTIVES: We investigated the effects of alcohol consumption on the risk of cancers of the upper aerodigestive tract (UADT) in a hospital-based case-control study in Brazil. METHODS: A total of 784 cases of cancers of the mouth, pharynx, and larynx and 1578 non-cancer controls matched on age, gender, hospital area, and admission period provided information on alcohol drinking, smoking, and other characteristics via interview. Using logistic regression, we evaluated the relative risks (RR) of UADT cancer for different beverage types based on cumulative ethanol content exposure and frequency of consumption. RESULTS: Relative to nondrinkers of any alcohol, risks of UADT cancers varied across sites both with increased exposure to ethanol and by alcohol type. RRs at equivalent levels of ethanol consumption were highest for cancers of the mouth for hard liquor (6.9 for > 100 kg lifetime consumption, 95% confidence interval (CI) = 2.8-17.1) and cachaça (4.5 for 101-500 kg, 95% CI = 2.2-9.0). Although RRs increased with frequency of drinks per week, when evaluated against higher proportional alcohol intake, reductions in risk were observed for beer and wine. CONCLUSION: Although methods of measurement can influence the interpretation of the carcinogenic nature of alcohols, increased RRs persisted with continued exposure for all types.

Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection.

Organized screening has contributed to a decline in cervical cancer incidence and mortality over the past 50 years. However, women in developing countries are yet to profit extensively from the benefits of screening programs, and recent trends show a resurgence of the disease in developed countries. The past 2 decades have witnessed substantial progress in our understanding of the natural history of cervical cancer and in major treatment advances. Human papillomavirus (HPV) infection is now recognized as the main cause of cervical cancer, the role of coexisting factors is better understood, a new cytology reporting terminology has improved diagnosis and management of precursor lesions, and specific treatment protocols have increased survival among patients with early or advanced disease. Current research has focused on the determinants of infection with oncogenic HPV types, the assessment of prophylactic and therapeutic vaccines and the development of screening strategies incorporating HPV testing and other methods as adjunct to cytology. These are fundamental stepping stones for the implementation of effective public health programs aimed at the control of cervical cancer.

Sex-specific determinants of HIV infection among injection drug users in Montreal.

BACKGROUND: Sex-specific issues have not been extensively addressed in studies of HIV prevalence, despite the strong implications of differences between men and women in the risk of HIV transmission. The objective of this study was to examine sex-specific behaviours associated with HIV infection among injection drug users in Montreal. METHODS: A total of 2741 active drug users (2209 [80.6%] men) were recruited between 1988 and 1998. Information was sought on sociodemographic characteristics, drug-related behaviour and sexual behaviour, and participants were tested for HIV antibodies. Sex-specific independent predictors of HIV prevalence were assessed by stepwise logistic regression. RESULTS: The overall prevalence of HIV among study subjects was 11.1%; the prevalence was 12.0% among men and 7.5% among women. In multivariate models, a history of sharing syringes with a known seropositive partner (odds ratio [OR] for men 2.44, 95% confidence interval [CI] 1.72-3.46; OR for women 3.03, 95% CI 1.29-7.13) and of sharing syringes in the past 6 months (OR for men 0.61, 95% CI 0.44-0.85; OR for women 0.32, 95% CI 0.14-0.73) were independently associated with HIV infection. Other variables associated with HIV infection were homosexual or bisexual orientation, cocaine rather than heroin as drug of choice, frequency of injection drug use, and obtaining needles at a pharmacy or through needle exchange programs (for men only) and obtaining needles at shooting galleries and being out of treatment (for women only). INTERPRETATION: These results support the hypothesis that risk factors for HIV seropositivity differ between men and women. These sex-related differences should be taken into account in the development of preventive and clinical interventions.

Repeatability of sexual history in longitudinal studies on HPV infection and cervical neoplasia: determinants of reporting error at follow-up interviews.

BACKGROUND: Misclassification of sexual history due to faulty recall or reporting bias may be the reason for variability in the association between sexual history and human papillomavirus (HPV) infection seen in studies conducted in different geographical areas. This study aimed to assess the repeatability of questionnaire information on sexual-history variables and their correlates, using information from repeat interviews by six international prospective cohort studies. METHODS: The pooled dataset included over 14 775 women interviewed on two separate occasions, of whom 5690 returned for a third interview. At each return visit women were re-asked questions on age at first intercourse and number of sexual partners. The six cohorts originated from studies in Denmark, Costa Rica. San Francisco, Toronto, Montreal and São Paulo. RESULTS: Exact agreement between age at first intercourse recalled on separate occasions ranged from 60-85%, whereas exact recall rates for number of sexual partners were substantially lower and more study-dependent, varying between 20% and 77%. The intraclass correlation coefficients gauging the degree of repeatability in responses ranged from 0.68 to 0.97 for age at first intercourse and 0.08 to 0.94 for number of sexual partners. Age, ethnicity, education and cohort membership were the strongest predictors of reporting error for both sexual history markers, although study design characteristics also seemed to play a role. HPV infection status seemed to influence recall of number of partners, but not age at first intercourse. CONCLUSIONS: Information on sexual behaviours is not reliably collected in epidemiological studies of sexually transmitted diseases, which may influence the magnitude of relative risk estimates.