Risk factors for human papillomavirus infection and disease: A targeted literature summary.

Adolescents are the primary cohort for routine human papillomavirus (HPV) vaccination, but unvaccinated adults may also benefit. A lack of consensus on which adults to target and the presence of reimbursement barriers likely contribute to the lag in adult vaccinations, highlighting missed prevention opportunities. Understanding factors contributing to risk of HPV infection and disease could help in decision making on vaccination. This review summarizes existing literature on risk factors for HPV infection and disease and includes 153 studies reporting relative risks or odds ratios for factors associated with HPV infection or disease in adults, published between 2009 and 2020. Despite inconsistent design and reporting of risk factors across studies, this review confirmed several risk factors associated with adult infection, including human immunodeficiency virus positivity, number of sex partners, and smoking. These findings can support policymaking, guideline development, and clinical decision making for HPV vaccination and screening of high-risk adult groups.

Prophylactic HPV vaccines in patients with HPV-associated diseases and cancer.

Individuals with human papillomavirus (HPV)-related disease remain at risk for subsequent HPV infection and related disease after treatment of specific lesions. Prophylactic HPV vaccines have shown benefits in preventing subsequent HPV-related disease when administered before or soon after treatment. Based on our understanding of the HPV life cycle and vaccine mechanism of action, prophylactic HPV vaccination is not expected to clear active persistent HPV infection or unresected HPV-associated dysplastic tissue remaining after surgery. However, vaccination may reasonably be expected to prevent new HPV infections caused by a different HPV type as well as re-infection with the same HPV type, whether from a new exposure to an infected partner or through autoinoculation from an adjacent or distant productively infected site. In this review, we describe the evidence for using prophylactic HPV vaccines in patients with HPV-associated disease before, during, or after treatment and discuss potential mechanisms by which individuals with HPV-associated disease may or may not benefit from prophylactic vaccines. We also consider how precise terminology relating to the use of prophylactic vaccines in this population is critical to avoid the incorrect implication that prophylactic vaccines have direct therapeutic potential, which would be counter to the vaccine's mechanism of action, as well as considered off-label. In other words, the observed effects occur through the known mechanism of action of prophylactic HPV vaccines, namely by preventing virus of the same or a different HPV type from infecting the patient after the procedure.

Rate of Involved Endocervical Margins According to High-Risk Human Papillomavirus Subtype and Transformation Zone Type in Specimens with Cone Length ≤ 10 mm versus > 10 mm-A Retrospective Analysis.

The aim of this study was to evaluate the endocervical margin status according to transformation zone (TZ) and high-risk HPV (hr-HPV) subtype in specimens with cone length ≤ 10 mm versus > 10 mm to provide data for informed decision making and patients counseling especially for women wishing to conceive. In this retrospective cohort study, 854 patients who underwent large loop excision of the transformation zone during a nine-year period (2013-2021) for cervical disease were analyzed. The main outcome parameters were excision length, histological result, TZ type, HPV subtype and endocervical margin status. A subgroup analysis was performed according to excision length, with a cut-off value of 10 mm. A two-step surgical procedure was performed in case of an excision length of > 10 mm. The overall rate of positive endocervical margins irrespective of excision length was 17.2%, with 19.3% in specimens with ≤ 10 mm and 15.0% with > 10 mm excision length. Overall, 41.2% of women with a visible TZ and HPV 16/hr infection and 27.0% of women with HPV 18 received an excisional treatment of > 10 mm length without further oncological benefit, respectively. In contrast, assuming that only an excision of ≤ 10 mm length had been performed in women with visible TZ, the rate of clear endocervical margins would have been 63.7% for HPV 16/hr infections and 49.3% for HPV 18 infections. In conclusion, the decision about excision length should be discussed with the patient in terms of oncological safety and the risk of adverse pregnancy events. An excision length > 10 mm increases the number of cases with cervical tissue removed without further oncological benefit, which needs to be taken into account in order to provide an individual therapeutic approach. Furthermore, HPV 18 positivity is related to a higher rate of positive endocervical margins irrespective of TZ.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) Consensus Statement on the Management of Vaginal Intraepithelial Neoplasia.

ABSTRACT: The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the management of vaginal intraepithelial neoplasia.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

HPV screening in the urine of transpeople - A prevalence study.

Background: There is limited data on human papillomaviruses (HPV) prevalence in transpeople due to low acceptance rate of screening methods. HPV tests from self-collected urine are gender-neutral, have a high acceptance, and have a comparable accuracy in females to clinician-collected samples. The aim of this study was to evaluate both the HPV prevalence in the urine in a large cohort of 200 transpeople with common risk profiles and the acceptability of such screening method. Methods: The study was conducted at the outpatient clinic for transpeople at the Department of Obstetrics and Gynaecology, Medical University of Vienna, Austria. 200 transpeople have been enrolled between May and October 2021. Inclusion criteria were gender identity dysphoria, age over 18 years, and adequate language skills.Subjects were asked to answer a survey concerning gender identity, established risk factors for HPV infections as well as their preference regarding urine or provider-collected cytology-/HPV-based screening, and to provide a urine sample. Five patients not able to provide urine were excluded. HPV genotyping was performed using a validated multiplex real-time PCR assay, which simultaneously detects 28 HPV genotypes. This trial is registered at ClinicalTrials.gov, NCT04864951. Findings: Overall HPV positivity was 19·0% (37/195), 24·2% in female to male, 11·8% in male to female, 26·3% in genderqueer/non binary/other subjects, 27·9% in subjects currently having a cervix, and 26·0% in subjects born with cervix. Independent of gender reassignment surgery, being born with a cervix was associated with a higher risk of HPV infections (p = 0·008), yet 42·3% (44/104) have never attended cervical cancer screening. Overall, 79·0% (154/195) of transpeople would prefer urine HPV tests to provider-collected HPV screening. Interpretation: HPV testing in self-collected urine samples provides a unique opportunity for screening of this hard-to-reach population and should be evaluated in further studies. Funding: None.

Effectiveness, immunogenicity, and safety of the quadrivalent HPV vaccine in women and men aged 27-45 years.

Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-invasive Vulvar Lesions.

ABSTRACT: The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vulvar squamous intraepithelial neoplasia, vulvar Paget disease in situ, and melanoma in situ. For differentiated vulvar intraepithelial neoplasia (dVIN), an excisional procedure must always be adopted. For vulvar high-grade squamous intraepithelial lesion (VHSIL), both excisional procedures and ablative ones can be used. The latter can be considered for anatomy and function preservation and must be preceded by several representative biopsies to exclude malignancy. Medical treatment (imiquimod or cidofovir) can be considered for VHSIL. Recent studies favor an approach of using imiquimod in vulvar Paget's disease. Surgery must take into consideration that the extension of the disease is usually wider than what is evident in the skin. A 2 cm margin is usually considered necessary. A wide local excision with 1 cm free surgical margins is recommended for melanoma in situ. Following treatment of pre-invasive vulvar lesions, women should be seen on a regular basis for careful clinical assessment, including biopsy of any suspicious area. Follow-up should be modulated according to the risk of recurrence (type of lesion, patient age and immunological conditions, other associated lower genital tract lesions).

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) consensus statements on pre-invasive vulvar lesions.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vulvar squamous intraepithelial neoplasia, vulvar Paget disease in situ, and melanoma in situ. For differentiated vulvar intraepithelial neoplasia (dVIN), an excisional procedure must always be adopted. For vulvar high-grade squamous intraepithelial lesion (VHSIL), both excisional procedures and ablative ones can be used. The latter can be considered for anatomy and function preservation and must be preceded by several representative biopsies to exclude malignancy. Medical treatment (imiquimod or cidofovir) can be considered for VHSIL. Recent studies favor an approach of using imiquimod in vulvar Paget's disease. Surgery must take into consideration that the extension of the disease is usually wider than what is evident in the skin. A 2 cm margin is usually considered necessary. A wide local excision with 1 cm free surgical margins is recommended for melanoma in situ. Following treatment of pre-invasive vulvar lesions, women should be seen on a regular basis for careful clinical assessment, including biopsy of any suspicious area. Follow-up should be modulated according to the risk of recurrence (type of lesion, patient age and immunological conditions, other associated lower genital tract lesions).

Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial.

BACKGROUND: The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL. METHODS: This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4-6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535. FINDINGS: 110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion -0·016, 95% CI -0·15 to -0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups. INTERPRETATION: Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment. FUNDING: Austrian Science Fund and Austrian Gynaecological Oncology group.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines.

INTRODUCTION: Studies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58). METHODS: PubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58. RESULTS: Eighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time. CONCLUSIONS: The cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

BACKGROUND: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age. METHODS: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. RESULTS: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. CONCLUSIONS: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence.

BACKGROUND: The extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies. METHODS: PubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts. RESULTS: Data from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3-66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines. CONCLUSIONS: RCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.

Surgical Treatment of Vulvar HSIL: Adjuvant HPV Vaccine Reduces Recurrent Disease.

Data suggest that adjuvant human papillomavirus (HPV)-vaccination in women treated for cervical HPV diseases reduces recurrent disease. This study investigates adjuvant HPV-vaccination and the rate of recurrence in women undergoing surgery for vulvar high-grade squamous intraepithelial lesions (HSIL). From January 2013 to April 2020, we enrolled 149 women in a prospective case-control study. The control group (NV-group) was treated by standard surgery alone, while the study group received adjuvant vaccination soon after surgery (V-group). A follow-up was performed by vulvoscopy and HPV test. Statistical analysis was performed by Fisher's exact test. HSIL recurrence was observed in 24/76 (32%) patients in NV-group and in 8/42 patients (19%) of the vaccinated group. By analysing the recurrence rate related to the incident and reactivated latent HPV infection, we found a significant difference between (17/76) 22.3% in NV-group and (2/42) 4.8% in V-group (p = 0.01). A reduction of 78.5% in incident/reactivated HPV infections was demonstrated. Data results add to the current knowledge about the mechanism of post-surgical adjuvant HPV vaccination. Our prospective study is the first to document the vaccine clinical effectiveness in preventing "reactivation" of latent HPV infections. Quadrivalent HPV vaccine administered after the surgical treatment for vulvar HSIL appears to be useful in preventing recurrent disease.

The status of human papillomavirus vaccination recommendation, funding, and coverage in WHO Europe countries (2018-2019).

Background: There is a need to better understand HPV vaccination (HPVv) implementation in WHO Europe Region (WHO/ER), including recommendations, funding, and vaccination coverage rates (VCR). Methods: A targeted literature review (up to 31 January 2020) was conducted using national health ministry websites, WHO database, and published studies from WHO/ER countries (n = 53). HPVv recommendations and funding data (target age, gender, schedule, setting, target and monitored VCR) for primary and catch-up cohorts were collected. Results: National recommendations for HPVv exist in 46/53 (87%) countries, of which 38 (83%), 2 (4%), and 6 (13%) countries provided full, partial, or no funding, respectively, for the primary cohort. Fully or partially funded HPVv was provided for girls only in 25/53 (47%) countries and for both boys and girls in 15/53 (28%) countries. HPVv catch-up was fully or partially funded in 14/53 (26%) countries. Among 40 countries with a national immunization program (NIP), monitored VCRs ranged from 4.3% to 99% (n = 30). Of the 10 countries reporting VCR targets, only Portugal exceeded its target. Conclusion: Of the 53 WHO/ER countries, 40 have funded HPVv NIPs, among which 30 report VCRs. Additional efforts are required to ensure HPVv NIPs are fully funded and high VCRs maintained.