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The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov, NCT00090285. Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported. The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. Merck Sharp & Dohme.

Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I2 and χ2 statistics and we did trends analysis to examine the dose–response association between HPV vaccination coverage and each study effect measure. We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19–0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22–0·71) in girls 13–19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54–0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47–0·91]) and in women 20–39 years of age (0·68 [95% CI 0·51–0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34–0·74]) and in anogenital warts (0·86 [95% CI 0·79–0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. The Canadian Institutes of Health Research.

More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+) to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination. In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks. We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+. After 5–8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0·17, 95% CI 0·11–0·25) among girls aged 13–19 years, and decreased significantly by 66% (RR 0·34, 95% CI 0·23–0·49) among women aged 20–24 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0·46, 95% CI 0·33–0·66) among girls aged 13–19 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0·33, 95% CI 0·24–0·46) among girls aged 15–19 years, decreased significantly by 54% (RR 0·46, 95% CI 0.36–0.60) among women aged 20–24 years, and decreased significantly by 31% (RR 0·69, 95% CI 0·53–0·89) among women aged 25–29 years. Among boys aged 15–19 years anogenital wart diagnoses decreased significantly by 48% (RR 0·52, 95% CI 0·37–0·75) and among men aged 20–24 years they decreased significantly by 32% (RR 0·68, 95% CI 0·47–0·98). After 5–9 years of vaccination, CIN2+ decreased significantly by 51% (RR 0·49, 95% CI 0·42–0·58) among screened girls aged 15–19 years and decreased significantly by 31% (RR 0·69, 95% CI 0·57–0·84) among women aged 20–24 years. This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects. WHO, Canadian Institutes of Health Research, Fonds de recherche du Québec – Santé.

Background. Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent. Methods. Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with lowrisk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations. Results. In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74. Conclusions. The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.

Human papillomaviruses are an important cause of genital warts and cervical cancer. In this large, randomized, placebo-controlled trial, a quadrivalent HPV vaccine given at day 1, month 2, and month 6 was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. No beneficial effect was observed on prevalent lesions. The benefit for prevention of incident lesions associated with HPV-16 and HPV-18 appears to increase with time. A quadrivalent HPV vaccine was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. Anogenital infection with the human papillomavirus (HPV) can cause warts, intraepithelial neoplasia, and invasive cancers. 1 – 6 The majority of HPV-associated diseases are caused by HPV types 6, 11, 16, and 18. HPV types 6 (HPV-6) and 11 (HPV-11) cause most anogenital warts, a portion of the cases of low-grade neoplasia, 5 , 7 – 10 and recurrent respiratory papillomatosis, a rare but potentially life-threatening disease. 11 – 13 HPV type 16 (HPV-16) is the most common cause of invasive cancers of the cervix and other anogenital cancers associated with HPV. 4 , 6 , 14 – 19 HPV type 18 (HPV-18), the second most common cause of cervical cancer, . . .

To provide updates for the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines on human papillomavirus (HPV) and anogenital warts (AGWs), a review of the literature was conducted in key topic areas: (1) epidemiology and burden of disease; (2) transmission and natural history; (3) diagnosis and management of AGWs; (4) occupational exposure of healthcare workers; (5) anal cancer screening among men who have sex with men (MSM); and (6) HPV vaccine recommendations. Most sexually active persons will have detectable HPV at least once in their lifetime; 14 million persons are infected annually, and 79 million persons have prevalent infection. HPV is transmitted frequently between partners; more frequent transmission has been reported from females to males than from males to females. A new formulation of imiquimod (3.75% cream) is recommended for AGW treatment. Appropriate infection control, including performing laser or electrocautery in ventilated rooms using standard precautions, is recommended to prevent possible transmission to healthcare workers who treat anogenital warts, oral warts, and anogenital intraepithelial neoplasias (eg, cervical intraepithelial neoplasia). Data are insufficient to recommend routine anal cancer screening with anal cytology in persons living with human immunodeficiency virus (HIV)/AIDS or HIV-negative MSM. An annual digital anorectal examination may be useful for early detection of anal cancer in these populations. HPV vaccine is recommended routinely for 11- or 12-year-olds, as well as for young men through age 21 years and young women through age 26 years who have not previously been vaccinated. HPV vaccine is also recommended for MSM, people living with HIV/AIDS, and immunocompromised persons through age 26 years.

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6–12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5–100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

Most cell-based and animal experiments have shown that green tea catechins (GTC) exhibit various health benefits. In human experimental and epidemiological studies, there are conflicting results, and more precise investigations are required. One of the most effective ways to prove beneficial health effects in humans might be clinical intervention studies. Polyphenon®E was developed as a standardized GTC preparation, which was approved by Food and Drug Administration of US in 2006 as a medication to treat genital warts (Veregen® or sinecatechins). Positive efficacy of Polyphenon®E/sinecatechins/Veregen® (PSV) on anogenital warts has been demonstrated in several epidemiological studies and there have been several case reports to show the clinical effectiveness of PSV. In addition, several studies have provided evidence to suggest that PSV is effective in other human papillomavirus (HPV)-related diseases, although some studies failed to show such effects. Since (−)-epigallocatechin gallate (EGCG) is the major component of PSV, the mechanism of the action of PSV might be deduced from that of EGCG. The microarray analysis of the biopsy samples from the patients suggested that apoptosis induction and the downregulation of inflammation are involved in the mechanism of the action of PSV in the clearance of anogenital warts. Cell-based and animal experiments using PSV also demonstrated effects similar to those elicited by EGCG, explaining how PSV works to induce apoptosis and exert anti-inflammatory actions in HPV-related diseases. Future studies would clarify what kinds of diseases respond effectively to PSV, showing health benefits of GTC and EGCG in humans.

Condyloma acuminatum (CA), primarily caused by low-risk HPV6/11, is a benign proliferative disease that is difficult to cure and prone to recurrence. However, the molecular and immune mechanisms underlying relapse remain unclear. We combined metabolomic profiling with single-cell RNA sequencing to investigate recurrence-associated changes. Metabolomics revealed dysregulation of ascorbate and aldarate, glycerophospholipid, purine, and arginine/proline metabolism in recurrent CA. Single-cell analysis identified altered expression of metabolism-related genes (AMD1, GSTM3, ALDH3A1, GPX1, GPX4) in keratinocytes, associated with hyperproliferation, impaired differentiation, and ferroptosis resistance. Immune profiling identified transcriptionally distinct myeloid subpopulations in recurrent CA lesions, including M2 macrophages and dendritic cells. KEGG analysis indicated enrichment of antigen processing, phagosome, and endocytosis pathways in M2 macrophages, and antigen processing and viral carcinogenesis in dendritic cells, suggesting altered immune regulatory states. Notably, the key polyamine biosynthesis regulator AMD1 was downregulated in both M2 macrophages and dendritic cells in recurrent lesions, paralleling metabolic evidence of altered arginine-polyamine pathways. These findings suggest that recurrent CA involves coordinated metabolic dysregulation across keratinocytes and immune cells, highlighting potential targets for immunometabolic intervention.

Background Human papillomavirus (HPV) is a common sexually transmitted infection (STI) known to cause cervical cancer and genital warts. However, making the genital warts aspect explicit may reduce HPV vaccination intention and behaviour due to perceived stigma associated with STIs. Purpose This study investigated the effect of differential information framing on intention to receive the HPV vaccine using the Theory of Planned Behaviour (TPB) and moral norm construct. Method Female university students were randomised to receive a fact sheet describing the HPV vaccine as: (1) preventing cervical cancer only ( n  = 81); or (2) preventing both cervical cancer and genital warts ( n  = 78). A 2-month follow-up investigated relationships between vaccination intention and actual behaviour. Results No effect of information framing was detected on intention to receive the HPV vaccine, or vaccine uptake behaviour at 2-month follow-up. The traditional TPB components predicted 54% of the variance in vaccination intention ( F 3,155  = 61.580, p  < 0.001), and moral norm explained an additional 6.2%. Intention predicted a significant but relatively small proportion of variation (9.6%) in behaviour. Conclusion The HPV vaccine does not seem to be associated with perceptions of stigma related to genital warts, and has broad acceptance among a female university population. This study demonstrates that TPB is suited to investigate HPV vaccination, and has helped clarify the role of moral norm within the TPB.