Michelle I. Silver

Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy.

ObjectiveThe vaginal microbiota helps protect the female genital tract from disease. We sought to describe the composition of the vaginal microbiota in premenopausal, perimenopausal, and postmenopausal women and to explore the association between the microbiota and vulvovaginal atrophy (VVA). MethodsEighty-seven women (aged 35-60 y) were classified as premenopausal (n = 30), perimenopausal (n = 29), or postmenopausal (n = 28) according to Stages of Reproductive Aging Workshop guidelines. Midvaginal bacterial community composition was characterized by 16S ribosomal RNA gene analysis. ResultsBacterial communities clustered into six community state types (CSTs), of which four were dominated by Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, or Lactobacillus jensenii, and two (CST IV-A and CST IV-B) had low relative abundance of Lactobacillus. CST IV-A was characterized by Streptococcus and Prevotella, whereas CST IV-B was characterized by Atopobium. There were significant associations between menopause stage and CST (P = 0.004) and between VVA and CST (P = 0.002). Perimenopausal women were more likely to be classified as CST IV-A or L. gasseri CST, whereas postmenopausal women were often classified as CST IV-A. CSTs dominated by L. crispatus and L. iners were more prevalent in premenopausal women. Nineteen participants had signs of mild or moderate VVA. Compared with women with no VVA, the vaginal microbiota of women with mild or moderate atrophy had 25-fold greater odds of being classified as CST IV-A versus L. crispatus CST (adjusted odds ratio, 25.89; 95% credible interval, 2.98-406.79). ConclusionsA distinct bacterial community state (CST IV-A) with a low relative abundance of Lactobacillus is associated with VVA. Future studies recruiting a larger number of women are needed to replicate the findings. This study provides an impetus for future longitudinal studies designed to manage, modulate, and restore vaginal microbiota homeostasis, which would provide stronger evidence for a causal relationship with VVA and ultimately improve the treatment and prevention of atrophic vaginitis in menopause.

Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women

Understanding the fraction of newly detected human papillomavirus (HPV) infections due to acquisition and reactivation has important implications on screening strategies and prevention of HPV-associated neoplasia. Information on sexual activity and cervical samples for HPV DNA detection using Roche Linear Array were collected semiannually for two years from 700 women ages 35 to 60 years. Incidence and potential fraction of HPV associated with new and lifetime sexual partnerships were estimated using Poisson regression. Cox frailty models were used to estimate hazard ratios (HR) for potential risk factors of incident HPV detection. Recent and lifetime numbers of sexual partners were both strongly associated with incident HPV detection. However, only 13% of incident detections were attributed to new sexual partners, whereas 72% were attributed to 5 or more lifetime sexual partners. Furthermore, 155 of 183 (85%) incident HPV detections occurred during periods of sexual abstinence or monogamy, and were strongly associated with cumulative lifetime sexual exposure [HR: 4.1, 95% confidence interval (CI): 2.0-8.4). This association increased with increasing age. These data challenge the paradigm that incident HPV detection is driven by current sexual behavior and new viral acquisition in older women. Our observation that most incident HPV infection was attributable to past, not current, sexual behavior at older ages supports a natural history model of viral latency and reactivation. As the more highly exposed baby-boomer generation of women with sexual debut after the sexual revolution transition to menopause, the implications of HPV reactivation at older ages on cervical cancer risk and screening recommendations should be carefully evaluated.

A Cohort Effect of the Sexual Revolution May Be Masking an Increase in Human Papillomavirus Detection at Menopause in the United States

BACKGROUND Cohort effects, new sex partnerships, and human papillomavirus (HPV) reactivation have been posited as explanations for the bimodal age-specific HPV prevalence observed in some populations; no studies have systematically evaluated the reasons for the lack of a second peak in the United States. METHODS A cohort of 843 women aged 35-60 years were enrolled into a 2-year, semiannual follow-up study. Age-specific HPV prevalence was estimated in strata defined by a lower risk of prior infection (<5 self-reported lifetime sex partners) and a higher risk of prior infection (≥ 5 lifetime sex partners). The interaction between age and lifetime sex partners was tested using likelihood ratio statistics. Population attributable risk (PAR) was estimated using Levins formula. RESULTS The age-specific prevalence of 14 high-risk HPV genotypes (HR-HPV) declined with age among women with <5 lifetime sex partners but not among women with ≥ 5 lifetime sex partners (P = .01 for interaction). The PAR for HR-HPV due to ≥ 5 lifetime sex partners was higher among older women (87.2%), compared with younger women (28.0%). In contrast, the PAR associated with a new sex partner was 28% among women aged 35-49 years and 7.7% among women aged 50-60 years. CONCLUSIONS A lower cumulative probability of HPV infection among women with a sexual debut before the sexual revolution may be masking an age-related increase in HPV reactivation in the United States.

Determinants of VIA (Visual Inspection of the Cervix After Acetic Acid Application) Positivity in Cervical Cancer Screening of Women in a Peri-Urban Area in Andhra Pradesh, India

Objectives: Visual inspection of the cervix after acetic acid application (VIA) is widely recommended as the method of choice in cervical cancer screening programs in resource-limited settings because of its simplicity and ability to link with immediate treatment. In testing the effectiveness of VIA, human papillomavirus DNA testing, and Pap cytology in a population-based study in a peri-urban area in Andhra Pradesh, India, we found the sensitivity of VIA for detection of cervical intraepithelial neoplasia grade 2 and worse (CIN2+) to be 26.3%, much lower than the 60% to 90% reported in the literature. We therefore investigated the determinants of VIA positivity in our study population. Methods: We evaluated VIA positivity by demographics and reproductive history, results of clinical examination, and results from the other screening methods. Results: Of the 19 women diagnosed with CIN2+, only 5 were positive by VIA (positive predictive value, 3.1%). In multivariate analysis, VIA positivity (12.74%) was associated with older age, positive Pap smear, visually apparent cervical inflammation, and interobserver variation. Cervical inflammation of unknown cause was present in 21.62% of women. In disease-negative women, cervical inflammation was associated with an increase in VIA positivity from 6.1% to 15.5% (P < 0.001). Among the six gynecologists who performed VIA, the positivity rate varied from 4% to 31%. Conclusions: The interpretation of VIA is subjective and its performance cannot be readily evaluated against objective standards. Impact: VIA is not a robust screening test and we caution against its use as the primary screening test in resource-limited regions. Cancer Epidemiol Biomarkers Prev; 19(5); 1373–80. ©2010 AACR.

Differences in the concentration and correlation of cervical immune markers among HPV positive and negative perimenopausal women

INTRODUCTION Women≥45years of age with persistent HPV infections have distinct peripheral circulating immune profiles. Few studies have comprehensively evaluated the cervical immunologic microenvironment in HPV-positive and HPV-negative perimenopausal women. METHODS We collected cervical secretion specimens from 34 high risk HPV (HR-HPV) positive and 44 HR-HPV negative women enrolled in an ongoing prospective cohort assessing the natural history of HPV across the menopausal transition. We used these specimens to quantify concentrations of 27 different immune markers using multiplexed bead-based immunoassays. RESULTS HR-HPV positive women had significantly higher median concentrations of IL-5 (0.11 ng/mgtotal protein vs. 0.08 ng/mgtotal protein), IL-9 (2.7 ng/mgtotal protein vs. 2.1 ng/mgtotal protein), IL-13 (2.1 ng/mgtotal protein vs. 0.9 ng/mgtotal protein), IL-17 (2.9 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), EOTAXIN (4.1 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), GM-CSF (4.3 ng/mgtotal protein vs. 3.3 ng/mgtotal protein), and MIP-1α (3.5 ng/mgtotal protein vs. 1.9 ng/mgtotal protein) compared to HR-HPV negative women. A shift in the correlation of T-cell and pro-inflammatory cytokines (IFN-γ, IL-5, IL-9, IL-10, IL-12, IL-13, IL-15, and TNF-α) from IL-2 to EOTAXIN was observed between HR-HPV negative and positive women. CONCLUSIONS Higher local concentrations of anti-inflammatory and allergy associated markers, with a shift in T-cell associated cytokine correlation from IL-2 to EOTAXIN, are associated with HPV infection among older women.

Patient Concerns About Human Papillomavirus Testing and 5-Year Intervals in Routine Cervical Cancer Screening

OBJECTIVE: To explore attitudes toward new cervical cancer screening options and understand factors associated with those beliefs among women in routine gynecologic care. METHODS: We used an interviewer-administered survey of 551 women aged 36–62 years enrolled in the HPV in Perimenopause Study. Poisson regression with robust error variance was used to estimate prevalence ratios and 95% confidence intervals (CIs) to compare womens preferences for cervical cancer screening methods and frequency. RESULTS: A majority of women (55.6%, 95% CI 51.4–59.8%) were aware that screening recommendations had changed, yet 74.1% (95% CI 70.3–77.7%) still believed women should be screened annually. If recommended by their doctor, 68.4% (95% CI 64.4–72.2%) were willing to extend screening to every 3 years, but only 25.2% (95% CI 21.9–29.2%) would extend screening to 5 years. Most women (60.7%, 95% CI 56.5–65.7%) expressed a strong preference for Pap testing, and 41.4% (95% CI 37.4–45.6%) expressed at least moderate concern over having a human papillomavirus (HPV) test without a Pap test. A desire for more frequent care, higher degree of worry and perceived risk, and abnormal screening history were all associated with reduced willingness to accept HPV testing and longer screening intervals. CONCLUSION: A majority of routinely screened women indicated a willingness to adopt a cervical cancer screening strategy of cytology alone or Pap–HPV cotesting every 3 years if recommended by their physician. However, they remain concerned about HPV testing and extension of screening intervals to once every 5 years. Our results suggest continued reticence to accepting newer HPV-based screening algorithms among routinely screened women older than age 35 years. LEVEL OF EVIDENCE: III

Shedding of Epstein-Barr Virus and Cytomegalovirus from the Genital Tract of Women in a Periurban Community in Andhra Pradesh, India

ABSTRACT We found a large number of false-positive readings by visual inspection with acetic acid (VIA) in a study of cervical cancer screening strategies (VIA, human papillomavirus HPV DNA testing, and Pap cytology) in a periurban community in Andhra Pradesh, India. We evaluated whether these false-positive readings might be occurring as a result of infections with Epstein-Barr virus (EBV) or cytomegalovirus (CMV), prevalent latent herpesviruses known to be shed from the female genital tract. While we found that there was no association between VIA results and the presence of EBV or CMV in the cervix, we did find a high prevalence of both viruses: 20% for EBV and 26% for CMV. In multivariate analyses, CMV prevalence was associated with younger age, lack of running water in the home, and visually apparent cervical inflammation. EBV prevalence was associated with older age and a diagnosis of cervical intraepithelial neoplasia grade 1 or greater. The biological and clinical implications of these viruses at the cervix remain to be determined. The strong association between the presence of EBV and cervical disease warrants future exploration to determine whether EBV plays a causal role in disease development or if it is merely a bystander in the process.

The correlation between human papillomavirus positivity and abnormal cervical cytology result differs by age among perimenopausal women.

Objectives We explored the age-stratified correlates and correlations between high-risk human papillomavirus (HR-HPV) infection and cervical abnormalities in perimenopausal women. Materials and Methods Human papillomavirus testing and Pap smear screening were performed at baseline on 841 routinely screened women age 35 to 60 years in the HPV in perimenopause cohort. Demographic, behavioral, and medical information was collected through telephone-administered questionnaires. Descriptive analyses were used to examine the correlation between HR-HPV infection and cervical abnormalities by age. Logistic regression was used to determine correlates of HPV and abnormalities in women younger and older than 45 years. Results The prevalence of HPV, HR-HPV, and cervical abnormalities decreased significantly with increasing age, as did the correlation between HR-HPV and cervical abnormalities. The prevalence of HR-HPV was 50% among younger women with abnormalities but this decreased steadily to 20% HR-HPV detection among 50- to 54-year-old women, and no abnormalities were detected in 55- to 60-year-old women. Different correlates of HR-HPV infection and abnormalities were observed in women 45 years or older, a pattern not seen in younger women. Conclusions Although the relative proportion of low-grade and high-grade abnormalities did not change with age, we saw a loss of concordance between HR-HPV detection and cytological abnormalities with increasing age. Current guidelines for cervical cancer screening group together all women age 30 years and older. Our data raise important questions about the interpretation of HPV and Pap test results in this age group and suggest that ongoing surveillance of HPV and cytology in cervical cancer screening programs consider a third age stratification among older women.

Evidence-based Consensus Recommendations for Colposcopy Practice for Cervical Cancer Prevention in the United States

The American Society for Colposcopy and Cervical Pathology (ASCCP) Colposcopy Standards recommendations address the role of colposcopy and directed biopsy for cervical cancer prevention in the United States (US). The recommendations were developed by an expert working group appointed by ASCCPs Board of Directors. An extensive literature review was conducted and supplemented by a systematic review and meta-analysis of unpublished data. In addition, a survey of practicing colposcopists was conducted to assess current colposcopy practice in the US. Recommendations were approved by the working group members, and the final revisions were made based on comments received from the public. The recommendations cover terminology, risk-based colposcopy, colposcopy procedures, and colposcopy adjuncts. The ASCCP Colposcopy Standards recommendations are an important step toward raising the standard of colposcopy services delivered to women in the US. Because cervical cancer screening programs are currently undergoing important changes that may affect colposcopy performance, updates to some of the current recommendations may be necessary in the future.

Preparing for the Next Round of Asccp-sponsored Cervical Screening and Management Guidelines

T he American Society for Colposcopy and Cervical Pathology (ASCCP), in collaboration with the National Cancer Institute, has begun to prepare for the next update to its cervical screening and management consensus guidelines. Here, we describe the current plans for this multiyear process. Since 2001, the ASCCP has sponsored several rounds of cervical consensus guidelines; each has made extensive use of epidemiologic data from clinical trials and epidemiologic studies from the National Cancer Institute and other sources. The recommendations have been developed by expert representatives of many cooperating clinical societies after extensive public comment periods. Initially, the ASCCP-sponsored guidelines concentrated on the management of cytologic and histologic abnormalities found during screening. More recently, the ASCCP has cooperated with the American Cancer Society (ACS) and more than 20 other clinical organizations to consider general population screening issues as well. The next round of guidelines might continue to consider both cervical screening and management of abnormal results, pending discussion and in cooperation with other groups. Although it is undesirable to change clinical recommendations unless necessary, revision is needed soon for several reasons. The introduction of human papillomavirus (HPV) testing into US screening programs almost 15 years ago was a major change; initially, it was not possible to judge how repeated rounds of screening would perform. There are now enough data to judge and guide the realistic clinical performance of multiple rounds of “co-testing” combining HPV testing with cytology. We can also estimate howmultiple rounds of primary screening with HPV tests alonewould perform. Second, young women vaccinated prophylactically against HPV have reached the age of screening, and HPV vaccination will increasingly and profoundly affect screening performance. Given the postvaccination prevalence of precancer, cytology and pooled HPV tests perform less effectively (e.g., they are less predictive of cervical precancer) in vaccinated populations than in unvaccinated populations. In addition, new tests and strategies for triage of screen-positive women have been introduced and evaluated sufficiently to consider their role in new recommendations. Finally, the current guidelines are already very complex but still incomplete. As we strive for even greater precision to maximize the benefits andminimize the harms of screening, producing more algorithm trees is not a practical answer. Given available evidence, it is possible, as explained hereafter, to push simultaneously toward greater precision and simplicity, supported by a computer-based decision tool. The risk database will be publicly available, permitting access to those wishing to use it to create such tools. In preparing for the next round of guidelines, we recognize that several groups offer cervical screening and management recommendations, most prominently the US Preventive Services Task Force, ACS, and the American College of Obstetrics and Gynecology. Consistency in recommendations, preferably unanimity regarding the important issues, is very important. Nonetheless, the ASCCP-sponsored guidelines provide a unique perspective in the following ways. The guidelines aim to be as comprehensive as possible, covering such a large number of specific clinical situations that reliance on data from the reference standard of evidence, randomized clinical trials addressing individual questions, are not conceivable for most recommendations. Less emphasis will be on formal review of individual published studies with grading of the published literature provided by a separate group of evaluators. Instead, observational “big data” as well as trial data, pooled from all available sources, will form the basis of the updated recommendations. Epidemiologic research targeted specifically to support the guidelines will be conducted and reviewed by cervical screening and management experts. The most recent set of ASCCP-sponsored consensus guidelines introduced risk of cervical intraepithelial neoplasia (CIN) 2, CIN 3, adenocarcinoma in situ, and cancer as the unifying principle of the many recommendations and algorithm “trees.” Regardless of the screening test or algorithm (e.g., screening followed by triage), there should be equal management of equal risk. A prime example is the equal management of cytologic low-grade squamous intraepithelial lesion (LSIL) and HPVpositive atypical squamous cells of undetermined significance (atypical squamous cells of undetermined significance [ASC-US]). Anticipated improvements planned for the next set of ASCCP-sponsored guidelines will include the following: A) More detailed risk estimates, for greater numbers of test combinations, and for a greater number of clinical scenarios, such that the guidelines better address the variety of clinical situations EDITORIAL