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Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus- dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies. Persistent infection with human papillomavirus can lead to cervical intraepithelial neoplasia (CIN). Here, the authors profile the vaginal microbiota in a cohort of non-pregnant young women diagnosed with CIN2 and find that absence of Lactobacillus spp. and presence of a diverse population of strict anaerobes associates with a decreased regression of untreated CIN2 lesions.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections. [PUBLICATION ABSTRACT]

► Development of CIN3 is rare in women aged 30 years who test HPV DNA-negative. ► Heterosexual transmission is extremely common. ► Transmission between the anus and cervix and vice versa are common in a woman. ► Prevalence of penile HPV is greater than cervical HPV but persistence is less likely. ► Persons with HIV, MSM, and women with cervical cancer are at risk for anal cancer. This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70–90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women, prevalence rates are steady across all ages, suggesting that men do not develop protection against reinfection. This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012.

Persistent human papillomavirus (HPV) infections is necessary for the development of cervical cancers. Consequently, understanding the biologic mechanisms resulting in clearance is key in cancer prevention. Similar to other mucosal sites, it is expected that the local microbiome plays a significant role in shaping the immune response responsible for HPV clearance. Using cervical wash repository samples from a prospective study of HPV in women, this study investigates the microbiome and its associated inflammatory milieu during HPV 16 pre-acquisition, persistence and clearance states. For comparison, samples from women with no history of HPV ever during the study period were selected. We showed that 9 of 13 inflammatory cytokines were found to be significantly increased in the immediate post-clearance visit compared to the pre-acquisition or infection visits. was associated with higher levels of inflammatory cytokines. Women with no history of HPV infection had similar cytokine profiles as those with HPV 16 post-clearance. This study documented an immune response shortly after HPV 16 clearance. appeared to be involved in shaping this immune response. The appearance of may have resulted from a shift from anti-microbial to anti-viral immune response with loss of bacterial control. The similar high levels of cytokines seen in women with no history of HPV suggest that a certain level of inflammatory surveillance is required to maintain an HPV negative state. This data may inform therapies such as probiotics or pro-inflammatory agents for treatment of persistent HPV.

The global supply of human papillomavirus (HPV) prophylactic vaccines has been constrained since 2020.Vaccine manufacturers have increased capacity and new HPV vaccines are now available. Vaccine supply is now able to meet the full HPV vaccine demand which has been achieved earlier than predicted. •Global supply of human papillomavirus (HPV) prophylactic vaccines has been constrained since 2020.•Vaccine manufacturers have increased capacity and new HPV vaccines are now available.•Vaccine supply is now able to meet the full HPV vaccine demand which has been achieved earlier than predicted.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

The major steps in cervical carcinogenesis include infection of the metaplastic epithelium of the cervical transformation zone with one or more of the 12–18 carcinogenic types of human papillomavirus (HPV) infection, viral persistence, clonal progression of the persistently-infected epithelium to cervical precancer, and invasion. Although these fundamental steps are established, several new epidemiologic studies have shed light on the factors that influence each of these transitions. The importance of the transformation zone in cervical cancer has been extended to other HPV-induced cancers such as anal or tonsillar cancers. Natural history studies show that HPV with normal cervical cytology and cervical intraepithelial neoplasia (CIN) grade 1 behave similarly, with the majority of both showing regression. Although these studies have demonstrated the importance of HPV persistence in the development of precancer CIN-3, the timing from infection to evidence of CIN-3 varies from 1 to 10 years. Whether equivalent lesions diagnosed later differ in their natural history remains unknown. Several factors have been implicated in enhancing persistence and/or progression. However, none are consistently associated with both except age: young women are less likely to show persistence and older women with persistence are more likely to be at risk of invasive cancer. Recent studies have also underscored the importance of the host immune response in clearance of established infections. Finally, data on non-cervical HPV infections, such as penile infections are limited to date compared to cervical infections. Several ongoing cohort studies should give us further insight into male infections in the near future.

Background Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. Methods We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls. Results Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1β and IL-8 remained significantly elevated pre- ( p < 0.0001 and p = 0.0014, respectively) and post-treatment ( p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision ( p < 0.0001); however, their levels remained lower than controls post-treatment. Conclusions Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high-diversity VMB composition, and higher levels of proinflammatory cytokines and AMPs compared to normal controls. Surgical excision of the disease reduces levels of vaginal AMPs but does not alter VMB composition or cytokine levels. These findings suggest that women with CIN have an inherent predisposition to a high-diversity proinflammatory environment that is not corrected by disease excision. The failure to re-establish a Lactobacillus -enriched CST may explain why women remain at high risk of pre-invasive and invasive disease recurrence.

PurposeCurrent cervical cancer screening guidelines recommend 3-year screening intervals, in contrast to the previous recommendation of annual screening, to prevent over screening and overtreatment. We evaluated the impact of viewing a tablet-based educational tool prior to seeing a clinician on young women’s knowledge and understanding of cervical cancer screening, HPV vaccination follow-up of abnormal pap smears, and comfort in communicating with their providers.MethodsThis cross-sectional study was part of a cluster-randomized study of fourteen primary care clinics from January 2015 to December 2016. We developed the cervical cancer education tool in English and Spanish using a community-based approach that included formative work and cognitive interviewing. Clinics were randomized to use the intervention (tablet-based patient education tool) or to participate as a control group. We administered surveys to a convenience sample of 229 English- or Spanish-speaking women aged 19 to 35 years in these clinics. We used descriptive analyses and logistic regression models with cluster-robust standard errors to compare differences among the two groups.ResultsCompared to women seen in control clinics, women seen in intervention clinics demonstrated greater knowledge regarding human papilloma virus (HPV (p = 0.004) and understanding (p < 0.001) of cervical cancer screening. Comfort in communicating with providers was not statistically different (p = 0.053). Women in the intervention group felt that the tool helped them understand that an abnormal Pap smear does not require immediate treatment (61.5%).ConclusionInnovative online patient education that is offered prior to patients’ interaction with their clinicians can improve their knowledge about cervical cancer prevention and treatment.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical neoplasia and cancer, based on recommendations from a formal review and recent workshop, is presented. The new screening recommendations address when to begin screening, when screening may be discontinued, whether to screen women who have had a hysterectomy, appropriate screening intervals, and new screening technologies, including liquid-based cytology and HPV DNA testing.