Better survival is observed in cervical cancer patients positive for specific anti-glycan antibodies and receiving brachytherapy.

OBJECTIVE: To measure anti-glycan antibodies (AGA) in cervical cancer (CC) patient sera and assess their effect on therapeutic outcome. PATIENTS AND METHODS: Serum AGA was measured in 276 stage II and 292 stage III Peruvian CC patients using a high content and throughput Luminex multiplex glycan array (LMGA) containing 177 glycans. Association with disease-specific survival (DSS) and progression free survival (PFS) were analyzed using Cox regression. RESULTS: AGAs were detected against 50 (28.3%) of the 177 glycans assayed. Of the 568 patients, 84.5% received external beam radiation therapy (EBRT) plus brachytherapy (BT), while 15.5% only received EBRT. For stage-matched patients (Stage III), receiving EBRT alone was significantly associated with worse survival (HR 6.4, p < 0.001). Stage III patients have significantly worse survival than Stage II patients after matching for treatment (HR = 2.8 in EBRT+BT treatment group). Furthermore, better PFS and DSS were observed in patients positive for AGA against multiple glycans belonging to the blood group H, Lewis, Ganglio, Isoglobo, lacto and sialylated tetrarose antigens (best HR = 0.49, best p = 0.0008). CONCLUSIONS: Better PFS and DSS are observed in cervical cancer patients that are positive for specific antiglycan antibodies and received brachytherapy.

Improved anal Cytology Sampling: Tush Brush Compared With Dacron Swab.

OBJECTIVE: The objective of this study was to determine the performance characteristics of the Tush brush (TB) compared with a saline moistened Dacron swab (DS) as anal cytology sampling devices. MATERIALS AND METHODS: TB and DS anal cytology tests were randomly collected from 146 patients presenting for anal cytology. High-resolution anoscopy and biopsies were obtained as indicated. Sensitivity and specificity as well as rates of satisfactory specimens were determined for each method using the areas under the receiver operating characteristic curve (AUCROC) and McNemar's test, respectively. Perceived discomfort of each device was determined using a visual analog scale and compared using a paired t test. RESULTS: The adjudicated AUCROC, sensitivity, and specificity were greater, but not significantly different, for the brush (0.63, 85.5, and 40.0, respectively) compared with the swab (0.50, 79.6, and 33.3, respectively) when the anal biopsy results were considered the criterion standard. In the 1 subject diagnosed with anal cancer, the swab cytology result was normal, but the brush result was abnormal. Specimen adequacy was 95.2% for the brush and 93.2% for the swab. Mean discomfort (visual analog scale) scores were swab 28.5 mm versus brush 35.6 mm (p = .0003) with both scores within the minimal to moderate discomfort range. CONCLUSIONS: Anal cytology AUCROC, sensitivity, and specificity in detecting anal neoplasia were greater using the TB when compared with the DS. A novel anal cytology sampling device designed specifically to increase the detection of anal neoplasia would be clinically beneficial.

Reimbursement Incentives to Improve Adherence to Follow-Up of Cervical Cancer Cytology Screening Results in Peru.

OBJECTIVE: The purpose of this study was to determine Peruvian women's attitudes toward novel reimbursement incentives used to improve adherence to obtaining cervical cytology test results. MATERIALS AND METHODS: Women presenting for cervical cancer screening in Peru completed a 34-item Investigational Review Board-approved questionnaire. The questionnaire determined their attitudes toward various reimbursement incentives to improve adherence to obtaining cervical cytology results. Descriptive statistics, generalized linear models, and Kruskal-Wallis tests were used in the analyses. RESULTS: Completed questionnaires were available for 997 women. Most women (51%) would be more likely to return for their Pap result if an incentive was provided, 79% (759/956) agreed that they would pay for the Pap test, and 51% (402/859) would be willing to pay 10 Soles or less. Quechua-speaking women considered follow-up more difficult (p < .0001) but were less likely to return for their Pap results (p < .0001), pay for the Pap test (p < .0001), and afford paying more than 5 Soles (p < .0001) than women who spoke Spanish or both languages. More women who earn 1000 Soles/year or less would likely return if incentivized (p < .0001), felt the incentive would help them remember to return (p = .0047), and would be willing to pay whether there was a rebate (p = .010) as compared with women earning more money. CONCLUSIONS: A reimbursement incentive program designed to improve follow-up of cervical cytology test results was acceptable to most Peruvian women. Such a behavioral-modifying program may improve patient follow-up after cervical cytology testing. Implementation may reduce the morbidity and mortality of cervical cancer in remote regions of the country.

Salud es Vida: a Cervical Cancer Screening Intervention for Rural Latina Immigrant Women.

This study examined the feasibility and efficacy of Salud es Vida-a promotora-led, Spanish language educational group session on cervical cancer screening (Pap tests)-self-efficacy (belief in ability to schedule and complete a Pap test), and knowledge among immigrant Hispanic/Latina women from farmworker backgrounds. These women are disproportionately burdened with cervical cancer, with mortality rates significantly higher than non-Hispanic whites. The two-arm, quasi-experimental study was conducted in four rural counties of Southeast Georgia in 2014-2015. Hispanic/Latina immigrant women aged 21-65 years and overdue for a Pap test were included as intervention (N = 38) and control (N = 52) group participants. The intervention was developed in partnership with a group of promotoras to create the toolkit of materials which includes a curriculum guide, a brochure, a flipchart, a short animated video, and in-class activities. Twelve (32 %) intervention group participants received the Pap test compared to 10 (19 %) control group participants (p = 0.178). The intervention group scored significantly higher on both cervical cancer knowledge recall and retention than the control group (p < 0.001). While there was no statistically significant difference in cervical cancer screening self-efficacy scores between the group participants, both groups scored higher at follow-up, adjusting for the baseline scores. The group intervention approach was associated with increased cervical cancer knowledge but not uptake of Pap test. More intensive interventions using patient navigation approaches or promotoras who actively follow participants or conducting one-on-one rather than group sessions may be needed to achieve improved screening outcomes with this population.

Social network characteristics and cervical cancer screening among Quechua women in Andean Peru.

BACKGROUND: Peru has high cervical cancer incidence and mortality rates compared to other Andean countries. Therefore, partnerships between governmental and international organizations have targeted rural areas of Peru to receive cervical cancer screening via outreach campaigns. Previous studies have found a relationship between a person's social networks and cancer screening behaviors. Screening outreach campaigns conducted by the nonprofit organization CerviCusco created an opportunity for a social network study to examine cervical cancer screening history and social network characteristics in a rural indigenous community that participated in these campaigns in 2012 and 2013. The aim of this study was to explore social network characteristics in this community related to receipt of cervical cancer screening following the campaigns. METHODS: An egocentric social network questionnaire was used to collect cross-sectional network data on community participants. Each survey participant (ego) was asked to name six other women they knew (alters) and identify the nature of their relationship or tie (family, friend, neighbor, other), residential closeness (within 5 km), length of time known, frequency of communication, topics of conversation, and whether they lent money to the person, provided childcare or helped with transportation. In addition, each participant was asked to report the nature of the relationship between all alters identified (e.g., friend, family, or neighbor). Bivariate and multivariate analyses were used to explore the relationship between Pap test receipt at the CerviCusco outreach screening campaigns and social network characteristics. RESULTS: Bivariate results found significant differences in percentage of alter composition for neighbors and family, and for mean number of years known, mean density, and mean degree centrality between women who had received a Pap test (n = 19) compared to those who had not (n = 50) (p's < 0.05). The final logistic regression model was statistically significant (χ2 (2) = 20.911, p < .001). The model included the variables for percentage of family alter composition and mean density, and it explained 37.8% (Nagelkerke R(2)) of the variance in Pap test receipt, correctly classifying 78.3% of cases. Those women with higher percentages of family alter composition and higher mean density in their ego networks were less likely to have received a Pap test at the CerviCusco campaigns. CONCLUSIONS: According to this exploratory study, female neighbors more than family members may have provided an important source of social support for healthcare related decisions related to receipt of a Pap test. Future studies should collect longitudinal social network data on participants to measure the network effects of screening interventions in rural indigenous communities in Latin American countries experiencing the highest burden of cervical cancer.

Impact of a Video Intervention for Rural Peruvian Women With Cervical Neoplasia Before Loop Excisional Procedures.

OBJECTIVE: Indigenous Peruvian women have very high rates of cervical cancer. This study assessed the impact of an educational video on impoverished rural Peruvian women seeking loop excision surgery. MATERIALS AND METHODS: Women completed baseline, postvideo and postsurgery questionnaires that assessed knowledge and attitudes about the procedure. Differences between groups were examined using repeated measures analysis of variance. RESULTS: Women who watched the video were significantly more calm (2.6, 2.6, and 2.3, respectively; P = 0.04), relaxed (2.5, 2.5, and 2.1, respectively; P = 0.02), and content (3.4, 3.4, and 2.4, respectively, P < 0.01) at postvideo and postsurgery assessments compared with mean results at the baseline assessment. The same women were also significantly more tense (2.5, 2.0, and 2.0, respectively; P = 0.01), upset (1.6, 1.1, and 1.1, respectively; P = 0.01), and worried (3.0, 2.0, and 2.0, respectively; P = 0.01) at baseline compared with postvideo and postsurgery results. Approximately 93% of women believed that other women scheduled to have loop excision surgery should also watch the video. CONCLUSIONS: Dissemination of culturally sensitive video information minimizes adverse emotional responses associated with loop excision procedures before surgery. Such an intervention quickly improves the psychological well-being of women eventually subjected to surgical management of cervical neoplasia.

The Impact of Accessible Cervical Cancer Screening in Peru-The Día del Mercado Project.

OBJECTIVE: The purpose of this study was to determine the potential impact of accessible secondary cervical cancer prevention efforts in indigenous Peruvian women living in the rural Andes Mountain region of Peru. METHODS: Peruvian women presenting for a Pap test or visiting a local marketplace, clinic, or public facility were asked to complete a questionnaire that assessed their response to the rural Pap screening program. We identified the following: 1) barriers to care, 2) patient knowledge of cervical cancer and Pap tests, and 3) perceptions of and reactions to the market clinic model. Chi-square or Fisher exact tests, t tests and 1-way ANOVA were used to examine differences between locations. RESULTS: Of 4,560 women enrolled, those examined in tents indicated it was easier to get a Pap test (98.7%, P = 0.001) compared with women seen in buildings (96.8%) or CerviCusco (98.0%), and they felt it was more important to have a Pap test close to their home more often (99.3%) than those seen at CerviCusco (97.8%) or buildings (98.8%). Women examined in tents felt the market was a good place to have a Pap test more often (67.0%, P < 0.001) than women who went to buildings (46.0%) or CerviCusco (29.2%). CONCLUSIONS: Many poor indigenous women living in isolated regions are unable to travel to distant health-care facilities. Using a novel mobile clinic model, the "Dia del Mercado Project" successfully reduced barriers to cervical cancer screening by using local marketplaces.

Polarized Light Colposcopy Compared With Standard Colposcopy.

OBJECTIVE: The objective of this study was to determine the potential benefits of polarized light colposcopy compared with standard colposcopy examinations in the evaluation of women with abnormal cervical cytology. MATERIALS AND METHODS: Polarized and standard colposcopy examinations were performed on 330 subjects. Respective images and biopsy annotations were obtained. Sensitivity and specificity; differences in the severity of cervical neoplasia; agreement of colposcopy impression, biopsy intent, and biopsy site; and differences in the number of biopsies were determined using the ROC, Bowker's test of symmetry, kappa statistic, and paired t test, respectively. RESULTS: The sensitivity and specificity for a lesion being seen with nonpolarized light and polarized light colposcopy were 96.8% and 64.5%, and 96.8% and 64.9%, respectively. There was no statistically significant difference in the ROC of the lesion being seen between nonpolarized (80.7) and polarized (80.9) colposcopy. Likewise, there was no statistically significant difference in the ROC of intent to biopsy between nonpolarized (80.2) and polarized colposcopy (78.8). The agreement of cervical histopathology and colposcopy impression for nonpolarized and polarized colposcopy were 0.986 and 0.952, respectively. There was no significant difference between nonpolarized and polarized colposcopy in the mean number of lesions seen or number of sites intended to biopsy. CONCLUSIONS: Polarized light colposcopy was not useful as an adjunct to conventional colposcopy in this study. Further research needs to be performed to determine the overall utility of polarized light colposcopy in clinical practice.

Clinical evaluation of the cartridge-based GeneXpert human papillomavirus assay in women referred for colposcopy.

High-risk human papillomavirus (hrHPV) testing is now being introduced as a potential primary screening test for improved detection of cervical precancer and cancer. Current U.S. Food and Drug Administration-approved tests are batch tests that take several hours to complete. A rapid, non-batch test might permit point-of-care (POC) testing, which can facilitate same-day screen and management strategies. For a non-batch, random-access platform (GeneXpert; Cepheid, Sunnyvale, CA), a prototype hrHPV assay (Xpert) has been developed where testing for 14 hrHPV types can be completed in 1 h. In the first clinical evaluation, Xpert was compared to two validated hrHPV tests, the cobas HPV test (cobas, Roche Molecular Systems) and Hybrid Capture 2 (hc2, Qiagen), and to histologic outcomes using specimens from colposcopy referral populations at 7 clinical sites in the United States (n = 697). The sensitivity of Xpert for cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) (n = 141) was equal to that of cobas (90.8% versus 90.8%, P = 1) and greater than that of hc2 (90.8% versus 81.6%, P = 0.004). Xpert was more specific than cobas (42.6% versus 39.6%, P = 0.02) and less specific than hc2 (42.6% versus 47.7%, P < 0.001). Similar results were observed for cervical intraepithelial neoplasia grade 3 or higher (CIN3+) (n = 91). HPV16 detection by Xpert identified 41.8% of the CIN2+ specimens with a positive predictive value (PPV) of 54.6%. By comparison, HPV16 detection by cobas identified 42.6% of the CIN2+ specimens with a PPV of 55.0%. hrHPV detection by the Xpert demonstrated excellent clinical performance for identifying women with CIN2+ and CIN3+ that was comparable to that of currently available clinically validated tests.

Multimodal hyperspectroscopy as a triage test for cervical neoplasia: pivotal clinical trial results.

OBJECTIVE: To prospectively evaluate a new non invasive device that combines fluorescence and reflectance spectroscopy in a population in women at risk for cervical dysplasia. METHODS: A total of 1607 women were evaluated with multimodal hyperspectroscopy (MHS), a painless test with extremely high spectral resolution. Subjects who were referred to colposcopy based on abnormal screening tests or other referral criteria underwent the MHS test and also had a sample taken for additional cytology and presence of high risk human papilloma virus (HPV) prior to undergoing biopsy. RESULTS: Sensitivity of MHS for cervical intraepithelial neoplasia (CIN) 2+ was 91.3% (252/276). Specificity, or the potential reduction in referrals to colposcopy and biopsy, was 38.9% (222/570) for women with normal or benign histology and 30.3% (182/601) for women with CIN1 histology. Two year follow-up data, collected for a subgroup of 804 women, revealed 67 interval CIN2+ that originally were diagnosed at enrollment as normal or CIN1. MHS identified 60 of these (89.6%) as positive for CIN2+ prior to their discovery during the two year follow-up period. CONCLUSIONS: MHS provides an immediate result at the point of care. Recently, the limitations of cytology have become more obvious and as a consequence greater emphasis is being placed on HPV testing for cervical cancer screening, creating a need for an inexpensive, convenient and accurate test to reduce false positive referrals to colposcopy and increase the yield of CIN2+ at biopsy. MHS appears to have many of the attributes necessary for such an application.

Impact of pap test compliance and cervical cancer screening intervals on human papillomavirus vaccine acceptance.

OBJECTIVES: The objective of this study was to determine the impact of Pap test compliance and cervical cancer screening intervals on human papillomavirus (HPV) vaccination acceptance. MATERIALS AND METHODS: A convenience sample of 499 women 21 to 65 years old completed a 37-question survey in Augusta and Savannah, GA. The survey assessed their knowledge about HPV, cervical cancer, and the HPV vaccine. The questionnaire also determined their Pap test compliance and how longer Pap test intervals would influence their willingness to receive the HPV vaccine. Differences between categorical variables and knowledge scores were examined using χ test and unequal-variance t tests, respectively. RESULTS: Pap test-noncompliant women were more likely to get the HPV vaccine if they only needed a Pap test every 10 years compared with Pap test-compliant women (27.6% vs 14.6%, p = .02). A greater number (83.5%) of Pap test-noncompliant women preferred the HPV vaccine plus every 10-year Pap test option compared with Pap test-compliant women (31.3%, p < .0001). Most women (87%) responded that they would likely get the HPV vaccine if it would safely reduce the frequency of Pap testing. CONCLUSIONS: Women are receptive to getting the HPV vaccine in exchange for longer cervical cancer screening intervals. Moreover, Pap test-noncompliant women are more likely to get the HPV vaccine if Pap testing was needed less frequently. Increasing the Pap testing interval may be an excellent method to improving HPV vaccine acceptance in women at highest risk for cervical cancer.

Comparison of knowledge and attitudes toward human papillomavirus, HPV vaccine, pap tests, and cervical cancer between US and Peruvian women.

OBJECTIVES: The purpose of this study was to determine and compare the knowledge and attitudes toward human papillomavirus (HPV), HPV vaccine, Pap tests, and cervical cancer among US and Peruvian women. MATERIALS AND METHODS: A convenience sample of 275 US women in Augusta, GA, and 702 Peruvian women living in or near Cusco, Peru, completed 22- or 21-item questionnaires, respectively. These questionnaires determined their knowledge about HPV, the HPV vaccine, Pap tests, and cervical cancer. Simple logistic regression was used to determine the relationship between location and language on the correct responses. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: US Spanish- (OR = 0.02), Quechua- (OR = 0.05), and Peru Spanish-speaking women (OR = 0.03) were significantly less likely to know that HPV causes cervical cancer compared with US non-Spanish-speaking women. US Spanish- (OR = 10.61, OR = 5.74), Quechua- (OR = 11.08, OR = 9.89), and Peru Spanish-speaking women (OR = 17.25, 14.43) were significantly more likely to be embarrassed and afraid, respectively, to get a Pap test compared with US non-Spanish-speaking women. US Spanish- (OR = 0.11), Quechua- (OR = 0.14), and Peru Spanish-speaking women (OR = 0.11) women were significantly less likely to know the HPV vaccine is safe and effective compared with US non-Spanish-speaking women. CONCLUSIONS: Education must be implemented to address serious misconceptions and worrisome attitudes toward Pap tests and the HPV vaccine to decrease the rate of cervical cancer in Peru and US Spanish-speaking women.

External genital human papillomavirus prevalence and associated factors among heterosexual men on 5 continents.

BACKGROUND: We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. METHODS: We tested serum samples from 3463 HM aged 16-24 years with 1-5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. RESULTS: The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having >3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1-4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3-6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. CONCLUSION: Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.

Prevalence of and risk factors for human papillomavirus (HPV) infection among HIV-seronegative men who have sex with men.

BACKGROUND: We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM). METHODS: Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA. RESULTS: The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence. CONCLUSIONS: The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection.

The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials.

We evaluated the overall agreement between colposcopically directed biopsies and the definitive excisional specimens within the context of three clinical trials. A total of 737 women aged 16-45 who had a cervical biopsy taken within 6 months before their definitive therapy were included. Per-protocol, colposcopists were to also obtain a representative cervical biopsy immediately before definitive therapy. Using adjudicated histological diagnoses, the initial biopsies and the same day biopsies were correlated with the surgically excised specimens. The overall agreement between the biopsies taken within 6 months of definitive therapy, and the definitive therapy diagnoses was 42% (weighted kappa = 0.34) (95% CI: 0.29-0.39). The overall underestimation of cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ (CIN2-3/AIS) and CIN3/AIS was 26 and 42%, respectively. When allowing for one degree of variance in the correlation, the overall agreement was 92% for CIN2-3/AIS. The overall agreement between the same day biopsy and definitive therapy specimen was 56% (weighted kappa = 0.41) (95% CI: 0.36-0.47), and the underestimation of CIN2-3/AIS was 57%. There were significant associations in the agreement between biopsies and excisional specimen diagnoses when patients were stratified by age, number of biopsies, lesion size, presence of human papillomavirus (HPV)16/18 and region. Of 178 diagnostic endocervical curettages performed, 14 (7.9%) found any HPV disease. Colposcopic accuracy improved when CIN2 and CIN3/AIS were grouped as a single predictive measure of high-grade disease. Colposcopy functioned well when allowed a one-degree difference between the biopsy and the surgical histologic interpretations, as done in clinical practice. Taking more than one biopsy improved colposcopic accuracy and could improve patient management.

Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection.

The impact of a human papillomavirus (HPV) vaccine on development of cervical intraepithelial neoplasia grade 2-3 or adenocarcinoma in situ (CIN2-3/AIS) in women with ongoing HPV16 or 18 infections prevaccination is reported. Seventeen thousand six-hundred and twenty-two women aged 16-26 were enrolled in 1 of 2 randomized, placebo-controlled, efficacy trials (Protocols 013 and 015). Vaccine or placebo was given at day 1, month 2 and 6. Women were tested for HPV6/11/16/18 DNA and antibodies at day 1. We focus on the subset of women who were seropositive and DNA positive to HPV16 or HPV18 prevaccination. Incidence is expressed as the number of women with an endpoint per 100 person-years-at-risk. In total, 419 vaccine and 446 placebo recipients were both seropositive and DNA positive to HPV16 or HPV18 prevaccination and had at least one follow-up visit. In Protocol 013, the incidence of HPV16/18-related CIN2-3/AIS among these women was 10.9 in the vaccine arm and 7.0 in the placebo arm (vaccine efficacy = -54.9; 95% CI: -181.7, 13.0). In Protocol 015, the incidence of HPV16/18-related CIN2-3/AIS was 5.5 in the vaccine arm and 6.2 in the placebo arm (vaccine efficacy = 12.2%; 95% CI: -29.8, 40.9). These data suggest HPV vaccination neither reduces nor enhances progression to HPV16/18-related high grade cervical lesions, and cervical cytology screening and corresponding management should continue as per local recommendations. Ultimately, population-based surveillance of vaccinated individuals beyond these clinical trials will be required to further address questions regarding the impact of vaccination in women exposed to vaccine HPV types before vaccination.

Adenocarcinoma in situ and associated human papillomavirus type distribution observed in two clinical trials of a quadrivalent human papillomavirus vaccine.

The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma.

Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia.

OBJECTIVES: High-risk human papillomavirus (hrHPV) is the primary cause of cervical cancer. As Chlamydia trachomatis is also linked to cervical cancer, its role as a potential co-factor in the development of cervical intraepithelial neoplasia (CIN) grade 2 or higher was examined. METHODS: The placebo arms of two large, multinational, clinical trials of an HPV6/11/16/18 vaccine were combined. A total of 8441 healthy women aged 15-26 years underwent cervicovaginal cytology (Papanicolaou (Pap) testing) sampling and C trachomatis testing at day 1 and every 12 months thereafter for up to 4 years. Protocol-specified guidelines were used to triage participants with Pap abnormalities to colposcopy and definitive therapy. The main outcome measured was CIN. RESULTS: At baseline, 2629 (31.1%) tested positive for hrHPV DNA and 354 (4.2%) tested positive for C trachomatis. Among those with HPV16/18 infection (n = 965; 11.4%) or without HPV16/18 infection (n = 7382, 87.5%), the hazard ratios (HRs) associated with development of any CIN grade 2 according to baseline C trachomatis status were 1.82 (95% CI: 1.06 to 3.14) and 1.74 (95% CI 1.05 to 2.90), respectively. The results were comparable when only the 12 most common hrHPV infections were considered, but the excess risk disappeared when the outcome was expanded to include CIN grade 3 or worse. CONCLUSION: Further studies based on larger cohorts with longitudinal follow-up in relation to the C trachomatis acquisition and a thorough evaluation of temporal relationships of infections with hrHPV types, C trachomatis and cervical neoplasia are needed to demonstrate whether and how in some situations C trachomatis sets the stage for cervical carcinogenesis. Trial registration NCT00092521 and NCT00092534.

The humoral response to Gardasil over four years as defined by total IgG and competitive Luminex immunoassay.

Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies.

Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies.

OBJECTIVE: To evaluate if new imiquimod formulations using a shorter treatment duration are safe and efficacious to treat anogenital warts. METHODS: In two studies 534 women ≥12 years of age (mean 33.4) with 2-30 warts (mean 7.9) and total wart area ≥10 mm(2) (mean 166.3) were randomized (1:2:2) to placebo (106), imiquimod 2.5% (212) or 3.75% (216) creams applied once daily until complete clearance or a maximum of 8 weeks. RESULTS: For placebo, imiquimod 2.5% and 3.75%, respectively, complete clearance of all warts was achieved in 14.2%, 28.3%, and 36.6% of women (intent-to-treat, P = 0.008 imiquimod 2.5%, and P < 0.001 3.75% versus placebo). Mean changes in wart counts were -10.7%, -50.9%, and -63.5% (per-protocol, P < 0.001 each active versus placebo) and safety-related discontinuation rates 0.9%, 1.4%, and 2.3%. CONCLUSIONS: Imiquimod 3.75% applied daily for up to 8 weeks was well tolerated and superior to placebo in treating women with external anogenital warts.