Reduced risk of CIN2+ recurrence in women immunized with a 9-valent HPV vaccine post-excision: Retrospective cohort study.

The main aim of our study was to investigate the specific contribution of a 9-valent human papillomavirus vaccine (9vHPV) to the recurrence risk of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women vaccinated post-excision. Therefore, we conducted a retrospective monocentric cohort study in women aged 22-49 years undergoing conization between 2014 and 2023. The 9vHPV-vaccinated women were matched to unvaccinated women for age and follow-up duration in a 1:2 ratio to eliminate allocation bias. The risk of CIN2+ recurrence was estimated by the incidence rate ratio using Poisson regression with adjustment for comorbidities, smoking status, nulliparity, CIN grade, positive cone margin, and HPV genotypes. The CIN2+ recurrence rates in 147 women enrolled in the analysis were 18 and 2 cases per 100,000 person-days for unvaccinated and vaccinated women, respectively, during a mean follow-up period of 30 months (±22 months). A reduction in CIN2+ recurrences by 90% (95% confidence interval: 12-99%) was documented in 9vHPV-vaccinated participants compared to women undergoing only surgical excision. Moreover, vaccinated women with a positive cone margin showed a 42% (though non-significant) reduction in relapse (p = .661). Full post-conization vaccination with the 9vHPV contributed to an additional reduction in the risk of CIN2+ recurrence. This finding is consistent with current knowledge and suggests a high adjuvant effect of the 9vHPV vaccine.

Prevalence of High-Risk HPV Detection and HPV Vaccination in Cervical Cancer Screening During the HPV Vaccination Era at Siriraj Hospital - Thailand's Largest National Tertiary Referral Center.

OBJECTIVE: To investigate the prevalence of high-risk (HR) human papillomavirus (HPV) detection and HPV vaccination among women undergoing cervical cancer screening during the HPV vaccination era at Siriraj Hospital - Thailand's largest national tertiary referral center. METHODS: This prospective cross-sectional study was conducted at our center's outpatient gynecology clinic during September-December 2021. Women aged ≥18 years with no previous hysterectomy, no history of preinvasive or invasive cervical cancer, and no current pregnancy who visited for cervical cancer screening were eligible for enrollment. Women with abnormal vaginal discharge/bleeding, and specimens with inadequate cellularity were excluded. We collected sociodemographic data, history of HPV vaccination, cervical cytology results, and high-risk HPV testing results. Reverse transcription polymerase chain reaction was used to determine HPV genotype. RESULTS: A total of 216 women (mean age: 41.7 years (range: 25-65), 75.9% premenopausal) were enrolled. Twenty of 216 (9.3%) women tested positive for HR-HPV, and 15 of 216 (6.9%) women had been previously vaccinated for HPV. The most common HPV genotypes detected were Group B infection (HPV 35/39/51/56/59/66/68) (38.9%), followed by HPV16 (27.78%), Group A infection (HPV 31/33/52/58) (27.8%), and HPV18 (5.56%). No HPV45 infection was detected. The detection rate of cytologic abnormalities was 4.16%. Three-quarters (77.8%) of patients with cytologic abnormalities were HR-HPV positive. CONCLUSION: Among the 216 women who underwent cervical cancer screening in this study, there was a 9.3% prevalence of HR-HPV infection, and a 6.9% prevalence of HPV vaccination. Among the 15 vaccinated women, 2 tested positive for HPV16 (1 normal cytology, 1 abnormal cytology).

"Easy women get it": pre-existing stigma associated with HPV and cervical cancer in a low-resource setting prior to implementation of an HPV screen-and-treat program.

BACKGROUND: Cervical cancer is preventable with vaccination and early detection and treatment programs. However, for these programs to work as intended, stigma related to HPV and cervical cancer must be understood and addressed. We explored pre-existing stigma associated with HPV and cervical cancer in the public healthcare system and community of a low-resource setting prior to implementation of an HPV screen-and-treat program. METHODS: This study conducted thematic analysis of data collected during implementation of a novel HPV screen-and-treat system for cervical cancer early detection and treatment in Iquitos, Peru. We included 35 semi-structured interviews (19 health professionals, 16 women with cervical precancer or cancer), eight focus groups (70 community women), one workshop (14 health professionals), 210 counseling observations (with 20 nurse-midwives), and a document review. We used the Socio-Ecological Model to organize the analysis. RESULTS: We identified three main themes: 1. the implication that women are to blame for their HPV infection through characterizations of being easy or promiscuous, 2. the implication that men are to blame for women's HPV infections through being considered careless or unfaithful, 3. HPV is shameful, embarrassing, and something that should be hidden from others. Consequently, in some cases, women refrained from getting screened for HPV. These themes were seen at the individual level among women, relationship level among women, men, and family members, community level among healthcare staff, and societal level within components of cervical cancer guidelines and male chauvinism. CONCLUSIONS: Cervical cancer early detection and treatment programs in limited resource settings must address stigma entrenched throughout the entire healthcare system and community in order to sustainably and successfully implement and scale-up new programs. Interventions to tackle this stigma can incorporate messages about HPV infections and latency to lessen the focus on the influence of sexual behavior on HPV acquisition, and instead, promote screening and treatment as paramount preventative measures.

Cost-utility and budget impact analyses of cervical cancer screening using self-collected samples for HPV DNA testing in Thailand.

INTRODUCTION: Cervical cancer ranks as the third most prevalent cancer among women in Thailand. However, the effectiveness of cervical cancer screening programs is limited by several factors that impede the screening rate. The utilization of self-collected samples for screening purposes has the potential to alleviate barriers to screening in Thai women. This study assessed the cost-utility and budget impact of implementing cervical cancer screening using self-collected samples for human papillomavirus (HPV) deoxyribonucleic acid (DNA) testing in Thailand. MATERIALS AND METHODS: We employed a decision tree integrated with a Markov model to estimate the lifetime costs and health benefits associated with the cervical cancer screening program for women aged 25-65. The analysis was conducted from a societal perspective. Four screening policy options were compared: (1) additional self-collected samples for HPV DNA testing, (2) clinician-collected samples for HPV DNA testing only, (3) clinician-collected samples for cytology test (i.e., status quo), and (4) no screening. The model inputs were based on unvaccinated women. The screening strategies and management in those with positive results were assumed followed to the Thai clinical practice guideline. Costs were reported in 2022 Thai baht. Sensitivity analyses were conducted. The ten-year budget impacts of the additional self-collected samples for HPV DNA testing were calculated from a payer perspective. RESULTS: All screening policies were cost-saving compared to no screening. When comparing the additional self-collected samples for HPV DNA testing with the clinician-collected samples policy, it emerged as the dominant strategy. The incremental benefit in cervical cancer prevention achieved by incorporating self-collected samples for screening was observed at any additional screening rate that could be achieved through their use. Sensitivity analyses yielded consistently favorable results for the screening policies. The average annual budget impact of the additional self-collected samples for screening policy amounted to 681 million Thai baht. This budget allocation could facilitate cervical cancer screening for over 10 million women. CONCLUSIONS: An addition of self-collected samples for HPV DNA testing into the cervical cancer screening program is cost-saving. The benefits of this screening policy outweigh the associated incremental costs. Policymakers should consider this evidence during the policy optimization process.

Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3.

BACKGROUND: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. METHODS: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. RESULTS: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. CONCLUSION: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. TRIAL REGISTRATION: jRCT2031190034.

Comparative efficacy of human papillomavirus vaccines: systematic review and network meta-analysis.

OBJECTIVES: Despite their use, differences in human papillomavirus (HPV) vaccine efficacies remain uncertain. This study assesses efficacy differences among bivalent, quadrivalent, and nine-valent HPV (2vHPV, 4vHPV, and 9vHPV) vaccines. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for randomized controlled trials comparing HPV vaccine efficacy against persistent infection (≥6 months) and cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Network meta-analysis yielded direct and indirect comparisons. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were reported, and robustness was evaluated via sensitivity analysis. RESULTS: In 11 randomized controlled trials with 58,881 healthy women, for persistent infection with HPV 16, 9vHPV was most effective at 97% (RR = 0.03, 95% CI: 0.01-0.08); for HPV 18, 2vHPV (Cecolin) was most effective at 98% (RR = 0.02, 95% CI: 0.00-0.29); for CIN2+ associated with HPV 16 and 18, 4vHPV was most effective at 99% (RR = 0.01, 95% CI: 0.00-0.10) and 97% (RR = 0.03, 95% CI: 0.00-0.45), respectively; for persistent infection with HPV 31, 33, 45, 52, and 58, 9vHPV was ≥ 95% effective; both 2vHPV vaccines were cross-effective against HPV 31, 33, and 45; and 4vHPV was cross-effective against HPV 31. CONCLUSIONS: HPV vaccine efficacies differ for different HPV types. Additional data are needed to determine the cross-efficacy of 2vHPV (Cecolin).

HPV vaccination for immunosuppressed women.

Immunocompromised women are at increased risk of having HPV detected and developing HPV-related diseases such as genital warts, anogenital dysplasia, and cancer. This review aims to summarize the current literature regarding the immunogenicity of the HPV vaccine in immunocompromised women and to discuss whether HPV vaccination may be able to reduce the risk of cervical dysplasia and cancer. HPV vaccination induces an immune response in these women; however, it is unknown whether vaccination is effective in reducing the risk of cervical dysplasia and cancer. Further research is needed.

Human papillomavirus vaccination receipt and provider counseling rates among high-risk patients.

OBJECTIVE: We describe provider documented counseling patterns and perception regarding HPV vaccination among patients with a history of cervical dysplasia. METHODS: All patients ages 21-45 who underwent colposcopy at a single academic medical center from 2018 to 2020were sent a self-administered survey through the electronic medical record patient portal to assess their attitudes regarding human papillomavirus (HPV) vaccination. Demographic information, HPV vaccination history, and documented obstetrics and gynecology provider counseling at the time of colposcopy were examined. RESULTS: Of 1465patients, 434 (29.6 %) reported or had documented receipt of at least one dose of the human papillomavirus vaccine. The remainder reported they were not vaccinated or had no documentation of vaccination. Proportion of vaccinated patients was higher among White compared to Black and Asian patients (P = 0.02). On multivariate analysis, private insurance (aOR 2.2, 95 % CI 1.4-3.7) was associated with vaccinated status while Asian race (aOR 0.4, 95 % CI 0.2-0.7) and hypertension (aOR 0.2, 95 % CI 0.08-0.7) were less likely to be associated with vaccination status. Among patients with unvaccinated or unknown vaccination status, 112 (10.8 %) received documented counseling regardingcatch-up human papillomavirus vaccination at a gynecologic visit. Patients seen by a sub-specialist obstetrics and gynecologic provider were more likely to have documented provider counseling regarding vaccination compared to those seen by a generalist obstetric/gynecologist provider (26 % vs 9.8 %, p < 0.001). Patients cited lack of physician discussion (53.7 %) and the belief that they were too old to receive the HPV vaccine (48.8 %) as the main reasons for remaining unvaccinated. CONCLUSION: HPV vaccination and the rate of obstetric and gynecologic provider counseling regarding HPV vaccination among patients undergoing colposcopy remains low. When surveyed, many patients with a history of colposcopy cited provider recommendation as afactor in their decision to undergo adjuvant HPV vaccination, demonstrating the importance of provider counseling in thisgroup.

Invasive cervical cancer, precancerous lesions, and cervical screening participation among women with mental illness in Sweden: a population-based observational study.

BACKGROUND: WHO aims to eliminate cervical cancer. Whether women with mental illness constitute a group at high-risk and require targeted prevention initiatives remains unknown. We aimed to assess whether women with severe mental illness, psychiatric or neurodevelopmental disorders, have an increased risk of invasive cervical cancer, and an increased risk of precancerous lesions and a lower degree of participation in cervical screening compared with women without severe mental illness. METHODS: In this population-based observational study, 4 112 598 women from 1973 to 2018 in Sweden were included to compare the risk of invasive cervical cancer, high-grade precancerous cervical lesions (CIN2+), and degree of participation in cervical screening (defined as the proportion of time covered by screening during a period when cervical screening is recommended) between women with and without mental illness. We focused on severe mental illness (ie, diagnosed in specialised psychiatric care) and also investigated milder mental illness (ie, use of psychotropic medications prescribed in primary care without specialist diagnosis) as secondary exposure. In two nested case-control studies, we defined the cases as women who have a diagnosis of invasive cervical cancer or CIN2+, and randomly selected individually matched controls from women who did not have these diagnoses. FINDINGS: Women with a specialist diagnosis of mental illness had a higher risk of invasive cervical cancer (hazard ratio 2·39, 95% CI 2·22-2·57) and CIN2+ (2·22, 2·18-2·26) and a 5·0% (4·8-5·2) lower cervical screening participation compared with matched controls. The risk increment of invasive cervical cancer and CIN2+ was greatest for substance misuse, whereas the screening reduction was greatest for intellectual disability and autism. In contrast, women who used prescribed psychotropic medications without specialist diagnosis had slightly higher screening participation and higher risk of CIN2+ but lower risk of invasive cervical cancer than women with neither specialist diagnosis nor medication use. INTERPRETATION: Women with severe mental illness participate less in screening and experience a higher risk of cervical neoplasia. Refined approaches are needed to better target these women in the elimination agenda of cervical cancer. FUNDING: Swedish Cancer Society.

Mailing human papillomavirus self-sampling kits to women under-screened for cervical cancer improved detection in cervical cancer screening in a general population study in Japan.

BACKGROUND: One cause of the increase in cervical cancer rates in Japan is the long-term stagnation in the cervical cancer screening consultation rate. Therefore, improving the screening consultation rate is of urgent concern to reduce cervical cancer incidence. Self-collected human papilloma virus (HPV) tests have been successfully adopted in several countries, such as the Netherlands and Australia, as a measure of individuals who have not undergone cervical cancer screening in national programs. This study aimed to verify whether self-collected HPV tests presented an effective countermeasure for individuals who had not undergone the recommended cervical cancer screenings. METHODS: This study was conducted from December 2020 to September 2022 in Muroran City, Japan. The primary evaluated endpoint was the percentage of citizens who underwent cervical cancer screening at a hospital with positive self-collected HPV test results. The secondary endpoint was the percentage of included participants who were diagnosed with cervical intraepithelial neoplasia (CIN) or higher among those who visited a hospital and underwent cervical cancer screening. RESULTS: The included study participants were 7,653 individuals aged 20-50 years with no record of previous cervical cancer examination in the past 5 years. We mailed these participants information on self-administered HPV tests as an alternative screening procedure and sent the kit to 1,674 women who requested the test. Among them, 953 returned the kit. Among the 89 HPV-positive individuals (positive rate, 9.3%), 71 (79.8%) visited the designated hospital for an examination. A closer examination revealed that 13 women (18.3% of hospital visits) had a CIN finding of CIN2 or higher, among whom one each had cervical cancer and vulvar cancer, eight presented with CIN3, and three presented with CIN2; two cases of invasive gynecologic cancer were also identified. CONCLUSIONS: We conclude that the self-collected HPV tests showed a certain efficacy as a measure of individuals who had not undergone the recommended cervical cancer screening. We devised ways to have the unexamined patients undergo HPV testing and ensure that HPV-positive individuals visited the hospital. Despite a few limitations, our findings suggest the effectiveness of this public health intervention.

Clinical performance of primary HPV screening cut-off for colposcopy referrals in HPV-vaccinated cohort: Observational study.

OBJECTIVE: To understand the effect of changing from cytology-based to primary HPV screening on the positive predictive value (PPV) of colposcopy referrals for cervical intraepithelial neoplasia (CIN) in a cohort offered HPV vaccination. DESIGN: Retrospective pre/post observational cohort study. SETTING: Scotland. POPULATION OR SAMPLE: 2193 women referred to colposcopy between September 2019 and February 2020 from cytology-based screening and between September 2020 and February 2021 from primary high-risk HPV (hrHPV) screening. METHODS: Calculating positive predictive values (PPVs) for two cohorts of women; one having liquid-based cytology screening and the other, the subsequent hrHPV cervical screening as a pre/post observational study. MAIN OUTCOME MEASURES: Positive predictive values of LBC and hrHPV cut-offs for colposcopy referral for CIN at colposcopy. RESULTS: Three papers fitted our criteria; these reported results only for cytology-based screening. The PPV was lower for women in HPV-vaccinated cohorts indicating a lower prevalence of disease. Vaccination under the age of 17 had the lowest PPV reported. Scottish colposcopy data concerning hrHPV and cytology showed a non-significant difference between PPV (17.5%, 95% CI 14.3-20.7, and 20.6, 95% CI 16.7-24.5, respectively) for referrals with a cut-off of low grade dyskaryosis (LGD); both met the standard set of 8-25%. The hrHPV PPV (66.7, 95% CI 56.8-76.6) was comparable to cytology (64.1, 95% CI 55.8-72.4) for referrals with a cut-off of high grade dyskaryosis (HGD) but neither met the standard set of 77-92%. CONCLUSIONS: Current literature only provides PPVs for LBC and, overall, the vaccinated cohort had lower PPVs. Only LG dyskaryosis met PHE criteria. The PPV for HPV-vaccinated women undergoing either LBC or HR-HPV screening were not statistically different. However, similar to papers in the current literature, HG dyskaryosis (HGD) PPVs of both techniques did not meet the PHE threshold of 76.6-91.6% outlined in the cervical standards data report.

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis.

OBJECTIVE: To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. DESIGN: Systematic review and meta-analysis DATA SOURCES: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. REVIEW METHODS: Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. RESULTS: 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. CONCLUSION: HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021237350.

[Clinical research progress and implications of therapeutic vaccines for cervical cancer and precancerous lesions: a qualitative systematic review].

Objective: To systematically summarize and analyze the clinical research progress of therapeutic vaccines for cervical cancer or precancerous lesions. Methods: English databases (PubMed, Embase, Web of Science, Cochrane library, Proquest, and ClinicalTrails.gov) and Chinese databases (SinoMed, CNKI, WanFang, and VIP Database) were systematically searched to collect literature on therapeutic vaccines for cervical cancer or precancerous lesions from inception to February 18, 2021. After screening, we evaluated the risk of bias of included studies, and combed the basic information of the literature, research designs, information of vaccines, study patients, outcome indicators and so on, qualitatively summarized the clinical research progress. Results: A total of 71 studies were included in this systematic review, including 14 random controlled trials, 15 quasi-random controlled trials, 4 cohort studies, 1 case-control study, 34 case series studies and 3 case reports. The study patients included women aged 15~79 with cervical cancer or precancerous lesions in 18 countries from 1989 to 2021. On the one hand, there were 40 studies on therapeutic vaccines for cervical precancerous lesions (22 867 participants), involving 21 kinds of vaccines in 6 categories. Results showed 3 marketed vaccines (Cervarix, Gardasil, Gardasil 9) as adjuvant immunotherapies were significant effective in preventing the recurrence of precancerous lesions compared with the conization only. In addition, MVA E2 vaccine had been in phase Ⅲ clinical trials as a specific therapeutic vaccine, with relative literature showing it could eliminate most high-grade precancerous lesions. Therapeutic vaccines for precancerous lesions all showed good safety. On the other hand, there were 31 studies on therapeutic vaccines for cervical cancer (781 participants), involving 19 kinds of vaccines in 7categories, with none had been marketed. 25 studies were with no control group, showing the vaccines could effectively eliminate solid tumors, prevent recurrence, and prolong the median survival time. However, the vaccines effectiveness couldn't be statistically calculated due to the lack of a control group. As for the safety of therapeutic vaccines for cervical cancer, 9 studies showed that patients experienced serious adverse events after treatments, where 7 studies reported that serious adverse events occurred in patients couldn't be ruled out as the results of therapeutic vaccines. Conclusions: The literature review shows that the literature evidence for the therapeutic vaccines for cervical precancerous lesions is relatively mature compared with the therapeutic vaccines for cervical cancer. The four kinds of vaccines on the market are all therapeutic vaccines for precancerous lesions, but they are generally used as vaginal infection treatments or adjuvant immunotherapies for cervical precancerous lesions, not used for the specific treatments of cervical precancerous lesions. Other specific therapeutic vaccines are in the early stage of clinical trials, mainly phase Ⅰ/Ⅱ clinical trials with small sample size. The effectiveness and safety data are limited, and further research is still needed.

Prevalence of Human Papillomavirus Among Chinese Han and Mongols Minority Women in Inner Mongolia, China: Reflected by Self-Collected Samples in CHIMUST.

Background: The disparities of hr-HPV infection among races/ethnicities have not been fully discussed. This study aimed to investigate the difference of hr-HPV infection between Chinese Han and Mongols minority women in Inner Mongolia. Methods: Genotyping and histopathology data of Chinese Han and Mongols minority women in Inner Mongolia from Chinese Multi-Center Screening Trial were used to analyze the hr-HPV prevalence, and type-specific distribution in abnormal pathology results. Results: The hr-HPV infection rates of Han women was 15.9% while of Mongols was 21.6% (P < 0.001). The most prevalent genotypes in Han women were ranked as HPV-16,-52,-18/-58,-31/-39, and-59 while in Mongols were-16,-31,-58,-18 and-52. When analyzing the age-specific of hr-HPV infection, two peaks were found at age of 40-44 (20.5%) and 55-59 (23.5%) years in Han women while three peaks were observed at age of 30-34 (22.1%), 45-49 (22.9%), and 55-59 (31.8%) years, respectively, in Mongols. HPV-16 accounting for 62.5 and 53.8% of the CINII+ in Han and Mongols, respectively. Conclusion: The prevalence of hr-HPV was significantly different between the Han and Mongols minority women in Inner Mongolia, races/ethnicities background should be taken into consideration for the refinement of cervical cancer screening strategies and vaccine implementation in China.

Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial.

BACKGROUND: In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT). METHODS: CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation. FINDINGS: Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants. INTERPRETATION: Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer. FUNDING: National Cancer Institute and National Institutes of Health Office of Research on Women's Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Test Performance of Cervical Cytology Among Adults With vs Without Human Papillomavirus Vaccination.

Importance: Current US cervical cancer screening guidelines do not differ by human papillomavirus (HPV) vaccination status. However, as the positive predictive value (PPV) of a screening test decreases, the risk of a false-positive result increases. Objective: To evaluate whether HPV vaccination is associated with decreased PPV for abnormal cervical cytology. Design, Setting, and Participants: This retrospective cohort study conducted via electronic medical record review included eligible patients aged 21 to 35 years who had at least 1 cervical cytology result within a single health system between January 2015 and December 2018. The health system comprises a partnership between an academic health center and a private not-for-profit health center. Patients with abnormal screening cytology and no diagnostic test results were omitted from analysis. Data were analyzed from December 2019 to November 2021. Exposures: HPV vaccination, defined as receiving at least 1 dose of HPV vaccine. Subgroup analyses were performed for those completing all vaccination doses per Advisory Committee on Immunization Practices guidelines and by age at vaccination initiation, dichotomized as younger than 21 years vs 21 years or older. Main Outcomes and Measures: PPV of abnormal cervical cytology for risk of cervical intraepithelial neoplasia (CIN) 2 or more severe diagnosis. Results: A total of 46 988 patients (mean [SD] age, 28.7 [4.5] years; 3058 [6.5%] Asian; 4159 [8.9%] Black or African American; 35 446 [75.4%] White) were included; 15 494 (33.0%) were at least partially vaccinated, and 4289 (9.1%) had abnormal cytology results during the study period. Among the individuals with abnormal cytology, the PPV for CIN 2 or more severe diagnosis was lower among vaccinated individuals (17.4%; 95% CI, 16.4%-18.4%) than unvaccinated individuals (21.3%; 95% CI, 20.4%-22.3%). Among vaccinated individuals, PPV was significantly lower among those completing vaccination (15.9%; 95% CI, 14.9%-17.0%) than those with incomplete vaccination (22.4%; 95% CI, 20.0%-25.0%), especially among those initiating vaccination when younger than 21 years (11.9%; 95% CI, 10.9%-12.9%) vs those initiating at age 21 years or older (30.7%; 95% CI, 27.3%-34.4%). Conclusions and Relevance: Among a population with relatively low HPV vaccine coverage, the PPV of cervical cytology for CIN 2 or more severe diagnosis was significantly lower among vaccinated individuals. PPV will likely further decrease in the future as a population with higher HPV vaccination coverage ages into screening. Confirmation of these results will call for changes in screening strategies, particularly for completely vaccinated individuals who initiated vaccination when younger than 21 years.

The difference in the effectiveness of human papillomavirus vaccine based on smoking status.

AIM: This study aimed to clarify (1) the effectiveness of human papillomavirus (HPV) vaccine against precancerous lesions of uterine cervical cancer and (2) the difference in these effectiveness based on smoking status. METHODS: This retrospective cross-sectional study considered women aged 20-24 who underwent cervical cancer screening in Saga City from April 2014 to March 2020. Cervical cytology and histological diagnosis were compared with or without HPV vaccination and smoking. RESULTS: The study included 7253 women (2467 vaccinated and 4786 unvaccinated). Among the vaccinated women, 462 were smokers, 2003 were nonsmokers: among the nonvaccinated women, the numbers were 1217 and 3554, respectively. 0.28% (7/2467) of participants with vaccination had HSIL+ compared to 0.77% (37/4786) without vaccination (odds ratio [OR] 0.36, 95% confidence interval [CI], 0.16-0.81). About 0.32% (8/2467) with vaccination had cervical intraepithelial neoplasia (CIN) 2+ compared to 0.69% (33/4786) without vaccination (OR 0.46, 95% CI, 0.21-1.00). Four women without vaccination had CIN3+. In nonsmokers, HPV vaccination significantly suppressed the incidence of HSIL+ from 0.42% (15/3554) to 0.1% (2/2003) (OR 0.21, 95% CI, 0.05-0.95), but the suppressive effect was not significant in smokers (OR 0.59, 95% CI, 0.22-1.56). In vaccinated women, the incidence of CIN2+ was 0.20% (4/2003) in nonsmokers and 0.87% (4/462) in smokers (OR 0.22, 95% CI, 0.05-0.89, p = 0.02). CONCLUSIONS: HPV bivalent/quadrivalent vaccination is effective in protecting against CIN but insufficient in smokers. The nine-valent vaccine should be introduced into routine vaccination as soon as possible to prevent high-risk HPV infection other than 6/11/16/18.

Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data.

OBJECTIVES: To provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay. DESIGN: Observational study. SETTING: Real world data from the English HPV screening pilot's first and second rounds (2013-16, follow-up to end of 2019). PARTICIPANTS: 1 341 584 women. INTERVENTIONS: Cervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities. MAIN OUTCOME MEASURES: Detection of CIN3+ and cervical cancer after a negative HPV test. RESULTS: For women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50). CONCLUSIONS: These data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.

Human papillomavirus vaccination in women undergoing excisional treatment for cervical intraepithelial neoplasia and subsequent risk of recurrence: A systematic review and meta-analysis.

INTRODUCTION: In this review and meta-analysis we aimed to investigate whether human papilloma virus (HPV) vaccination administered after excisional treatment of cervical intraepithelial neoplasia (CIN) is associated with a reduced risk of recurrence of CIN grade 2 or worse (CIN2+). MATERIAL AND METHODS: We performed a systematic literature search in three online databases through June 2021. Observational studies and randomized controlled trials (RCTs) were eligible for inclusion if the prophylactic HPV vaccine was administered after excisional treatment for histologically verified CIN. Only English language literature was included. The primary outcome measure was recurrence of CIN2+ after treatment. A meta-analysis was performed using fixed and random-effects models, and results were reported as pooled odds ratios (OR) with 95% confidence intervals (95% CI). Quality assessment was performed using ROB2-tool for RCTs and ROBINS-I for observational studies. The protocol was registered in PROSPERO (CRD42021238257). RESULTS: A total of 1561 studies were identified, of which nine, including 19 971 women, were included. Two studies were RCTs and seven were observational studies. Using the fixed-effect model on the two RCTs, the OR for recurrence of CIN2+ was 0.29 (95% CI 0.16-0.53). Due to considerable heterogeneity in observational studies, the random-effects model was used to estimate pooled OR for CIN2+ recurrence in these studies. Thus, using unadjusted data from observational studies, the OR for CIN2+ recurrence was 0.35 (95% CI 0.18-0.67), whereas when using adjusted data, the OR for CIN2+ recurrence was 0.54 (95% CI 0.21-1.35). However, quality assessment revealed a serious risk of bias for the majority of the studies included. CONCLUSIONS: HPV vaccination post-treatment was associated with a significantly reduced risk of CIN2+ recurrence when using unadjusted estimates from observational studies and RCTs. We found no significant effect of HPV vaccination on risk of CIN2+ recurrence when using the outcome measure from observational studies with the least risk of bias. Large, well-designed randomized placebo-controlled trials are needed to determine whether post-treatment HPV vaccination should be recommended to all women undergoing excisional treatment for CIN.

The eight-year long-term follow-up on the effectiveness of the quadrivalent human papillomavirus vaccine in Chinese women 20-45 years of age.

The quadrivalent human papillomavirus (4vHPV) vaccine has shown confirmative effectiveness in preventing HPV-related diseases among women and men around the globe. The phase III, randomized, double-blind efficacy study (Base study, NCT00834106) conducted in China showed 100% efficacy against HPV 16/18-related cervical intraepithelial neoplasia and efficacy against HPV persistent infection for 78 months. Participants aged 20-45 years who received three doses of 4vHPV vaccine or placebo during the base study were selected and invited for this long-term follow-up (LTFU) study to assess the long-term effectiveness of the 4vHPV vaccine in preventing HPV-related diseases. A total of 368 participants were included in this LTFU study with a median follow-up of 94 months. Among 27 participants (Vaccine vs. Placebo: 8 vs. 19) who underwent colposcopy and biopsy due to cervical cytological abnormalities or HPV infection, no HPV-16/18-related cases of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN) was observed in the vaccine group while two HPV-16-related cases (CIN1/VaIN) were observed in the placebo group. There were another two HPV-related cases (non-vaccine HPV types) found in the placebo group. Consistent with the findings from global studies that suggested long-term efficacy of 4vHPV vaccine, our study showed continued protective effect of 4vHPV vaccine against HPV-related precancerous diseases through a median follow-up time of 94 months with the longest follow-up time of 125 months after completing three doses of vaccination among Chinese women 20-45 years of age.