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The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women. 18 644 women aged 15–25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint—vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18—was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681. Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14·8 (SD 4·9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90·4% (97·9% CI 53·4–99·3; p<0·0001). No clinically meaningful differences were noted in safety outcomes between the study groups. The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.

•HPV is globally prevalent and related to at least 6 different cancer sites in women and men•Prevention of HPV infections and its consequences is now technologically feasible•Novel options for prevention include HPV vaccination and the use of HPV screening methods•Vaccination is cost-effective with high efficacy for HPV infection and disease•International major efforts are needed to extend HPV-related cancer prevention to developing countries Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16INK4a). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. 148 studies were included, contributing data for 12 163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82·2% (95% CI 77·7–86·4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45·8% (95% CI 38·9–52·9) for oropharynx, 22·1% (16·4–28·3) for larynx (including hypopharynx), and 24·2% (18·7–30·2) for oral cavity. The percent positivity of p16INK4a positive cases in HPV-positive oropharyngeal cancer cases was 86·7% (95% CI 79·2–92·9) and of E6/E7 mRNA positive cases was 86·9% (73·2–96·8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39·8% and of p16INK4a was 39·7%. Of subsites, tonsils (53·9%, 95% CI 46·4–61·3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines. European Commission.

The type of human papillomavirus (HPV) in exfoliated cervical cells from almost 2000 women with cervical cancer and a similar number of control women from nine countries was determined by the polymerase chain reaction in 11 studies. Of the 33 types of HPV that were assayed, 18 were classified as high-risk or probable high-risk types and 12 as low-risk types. Odds ratios for cervical cancer that exceeded 200 were associated with HPV 16, 59, 33, and 18. This international study has implications for the design of vaccines against HPV. Cervical cancer is the second most common cancer in women worldwide, and it is the principal cancer of women in most developing countries, where 80 percent of cases occur. 1 Molecular epidemiologic evidence clearly indicates that certain types of human papillomavirus (HPV) are the principal cause of invasive cervical cancer 2 – 4 and cervical intraepithelial neoplasia. 5 , 6 More than 80 HPV types have been identified, and about 40 can infect the genital tract. 7 Genital HPV types have been subdivided into low-risk types, which are found mainly in genital warts, and high-risk types, which are frequently associated with invasive cervical cancer. There is, . . .

► The analyses of human papilloma virus/virus-like particle vaccine phase III efficacy trials in young women are largely completed. ► High efficacy was observed for incident infection and disease by vaccine types. ► Other clinical trials demonstrated protection against genital warts and anal dysplasia in men. ► Immunobridging studies have extended vaccine recommendations to adolescents. End of study analyses of the phase III trials of prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines in young women are now largely completed. Two distinct vaccines were evaluated, Gardasil® (Merck & Co., Whitehouse Station, NJ USA) a quadrivalent vaccine containing VLPs of types 6, 11, 16 and 18 and Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), a bivalent vaccine containing VLPs of types 16 and 18. Both vaccines exhibited excellent safety and immunogenicity profiles. The vaccines also demonstrated remarkably high and similar efficacy against the vaccine-targeted types for a range of cervical endpoints from persistent infection to cervical intraepithelial neoplasia grade 3 (CIN3) in women naïve to the corresponding type at the time of vaccination. However, protection from incident infection or disease from non-vaccine types was restricted, and the vaccines had no effect on prevalent infection or disease. Gardasil® also demonstrated strong protection against genital warts and vulvar/vaginal neoplasia associated with the vaccine types. In other trials, Gardasil® protected mid-adult women from incident infection and CIN caused by the vaccine types and protected men for incident infection, genital warts and anal intraepithelial neoplasia by the vaccine types. Cervarix® protected against vaccine-targeted anal infections in women in an end of study evaluation. For practical reasons, efficacy studies have not been conducted in the primary target populations of current vaccination programs, adolescent girls and boys. However, immunogenicity bridging studies demonstrating excellent safety and strong immune responses in adolescence, coupled with the documentation of durable antibody responses and protection in young adults, leads to an optimistic projection of the effectiveness of the vaccines in adolescent vaccination programs. Taken together, the excellent clinical trial results strongly support the potential of the vaccines as high value public health interventions and justify their widespread implementation to prevent anogenital HPV infections and their associated neoplasia. This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and Related Diseases” Vaccine Volume 30, Supplement 5, 2012.

It is uncertain whether male circumcision reduces the risk of penile human papillomavirus (HPV) infection and of cervical cancer in a man's female partner. The authors studied women and their male partners enrolled in seven case–control studies of cervical carcinoma in situ and cervical cancer in five countries in Europe, South America, and Asia. Circumcised men were significantly less likely than uncircumcised men to have penile HPV infection. Women whose partners had six or more lifetime sexual partners were less likely to have cervical cancer if their partners were circumcised than if they were uncircumcised. Circumcised men were significantly less likely to have penile human papillomavirus infection. Circumcision may reduce the risk of cervical cancer in female partners. Since Hutchinson reported in 1855 that circumcision might prevent syphilis, 1 studies have suggested that circumcision may reduce the risk of penile cancer, urinary tract infections, and common sexually transmitted diseases, including human immunodeficiency virus (HIV) infection. 2 – 9 Little is known, however, about the effect of male circumcision on the risk of acquiring human papillomavirus (HPV). HPV causes genital warts in men and women, and it has been linked to cancers of the cervix, vulva, vagina, anus, and penis. 10 , 11 Cervical cancer is the second most common cancer among women worldwide, and up to 99 percent of all cases may be . . .

Studies on the role of antibodies produced after infection with human papillomavirus 18 (HPV-18) and subsequent protection from HPV-18 infection have been conflicting, mainly due to inadequate sample size. We pooled data from the control arms of the Costa Rica Vaccine Trial and the PATRICIA trial. Using Poisson regression we compared the risk of newly detected 1-time HPV-18 infection, HPV-18 1-year persistent infection (12MPI), and HPV-18-associated atypical squamous cells of undetermined significance or greater (ASC-US+) lesions between HPV-18 seropositive and seronegative women. High HPV-18 antibodies at enrollment was associated with reduced subsequent HPV-18 detection (P trend = 0.001; relative rate [RR] = 0.69; 95% confidence interval [CI], 0.47-1.01 for the third quartile; RR = 0.63; 95% CI, 0.43-0.94 for the fourth quartile, compared to seronegative). The risk of 12MPI showed a decreasing trend with increasing antibodies (P trend = 0.06; RR = 0.72; 95% CI, 0.29-1.77; RR = 0.42; 95% CI, 0.13-1.32 for the third and fourth quartiles, respectively). Lastly, we observed a significant decreased risk of HPV-18 ASC-US+ with increasing antibody (P trend = 0.01; RR = 0.46; 95% CI, 0.21-0.97 for the fourth quartile). We also observed a significant decreased risk of HPV-16 infection, 12MPI, and ASC-US+ with increasing HPV-16 antibody level. High HPV-18 naturally acquired antibodies were associated with partial protection from future HPV-18 infections and associated lesions. NCT00128661 and NCT001226810.

Background. Baseline information on human papillomavirus (HPV) prevalence and type distribution is highly desirable to evaluate the impact of prophylactic HPV vaccines in the near future. Methods. A meta-analysis was performed of studies published between 1995 and 2009 that used polymerase chain reaction or Hybrid Capture 2 for HPV detection in women with normal cytological findings. Results. The analysis included 194 studies comprising 1,016,719 women with normal cytological findings. The estimated global HPV prevalence was 11.7% (95% confidence interval, 11.6%–11.7%). Sub-Saharan Africa (24.0%), Eastern Europe (21.4%), and Latin America (16.1%) showed the highest prevalences. Age-specific HPV distribution presented with a first peak at younger ages (<25 years) and, in the Americas and Africa, a rebound at older ages (⩾45 years). Among the women with type-specific HPV data (n = 215,568), the 5 most common types worldwide were HPV-16 (3.2%), HPV-18 (1.4%), HPV-52 (0.9%), HPV-31 (0.8%), and HPV-58 (0.7%). Conclusions. Although the prevalence of HPV in women with normal cytological findings is high and variable across world regions, HPV types 16, 18, 31, 52, and 58 are consistently found among the 10 most common types in all of them. These results represent the most comprehensive assessment of HPV burden among women with normal cytological findings in the pre-HPV vaccination era worldwide.

Background We conducted a systematic review and meta-analysis to assess efficacy and safety of prophylactic HPV vaccines against cervical cancer precursor events in women. Methods Randomized-controlled trials of HPV vaccines were identified from MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts and references of identified studies, and assessed by two independent reviewers. Efficacy data were synthesized using fixed-effect models, and evaluated for heterogeneity using I 2 statistic. Results Seven unique trials enrolling 44,142 females were included. The fixed-effect Relative Risk (RR) and 95% confidence intervals were 0.04 (0.01-0.11) and 0.10 (0.03-0.38) for HPV-16 and HPV 18-related CIN2+ in the per-protocol populations (PPP). The corresponding RR was 0.47 (0.36-0.61) and 0.16 (0.08-0.34) in the intention-to-treat populations (ITT). Efficacy against CIN1+ was similar in scale in favor of vaccine. Overall vaccines were highly efficacious against 6-month persistent infection with HPV 16 and 18, both in the PPP cohort (RR: 0.06 [0.04-0.09] and 0.05 [0.03-0.09], respectively), and the ITT cohorts (RR: 0.15 [0.10-0.23] and 0.24 [0.14-0.42], respectively). There was limited prophylactic effect against CIN2+ and 6-month persistent infections associated with non-vaccine oncogenic HPV types. The risk of serious adverse events (RR: 1.00, 0.91-1.09) or vaccine-related serious adverse events (RR: 1.82; 0.79-4.20) did not differ significantly between vaccine and control groups. Data on abnormal pregnancy outcomes were underreported. Conclusions Prophylactic HPV vaccines are safe, well tolerated, and highly efficacious in preventing persistent infections and cervical diseases associated with vaccine-HPV types among young females. However, long-term efficacy and safety needs to be addressed in future trials.

Background Human papillomavirus (HPV) vaccines were designed to prevent cervical cancer in women and their provision remains a major public health need. However, HPV is also a major cause of non-cervical anogenital and oropharyngeal cancers and the potential benefit of vaccination likely extends beyond cervical cancer. Methods A systematic literature search of PubMed (1995–2014) identified publications assessing the incidence, persistence, and clearance of non-cervical anogenital/oral HPV infections. Comparability with cervical HPV was assessed by identifying articles assessing the same or similar populations. Results Available data suggest high incidence rates of non-cervical HPV infection in men and women, with HPV-16 predominating in all sites. The incidence of high risk HPV per 100 person-years ranged from 11.4 to 72.9 for penile infections, 6.7–47.9 at other male genital sites, and 4.4–36.7 and 5.3–23.4 for anal infections in men and women, respectively. The incidence per 100 person-years of oral infection with any HPV type ranged from 5.7 to 6.7 in men and 6.8–39.6 in women. Within the limitations of the data, there was a general pattern of higher incidence and clearance of non-cervical genital HPV infections, compared to cervical infections. HIV status, circumcision, number of sex partners and partner HPV status significantly influenced high-risk HPV incidence/clearance at male anogenital sites. Few studies assessed risk factors for oral HPV. Conclusions Parallels appear to exist between the epidemiology of cervical and non-cervical HPV infections in terms of incidence, HPV-type distribution, and risk factors for infection. Available data suggest that non-cervical genital HPV infections may occur more frequently, with higher clearance rates, than cervical infections. More extensive studies could provide useful information for estimating vaccine impact, the wider cost-benefit of HPV vaccination, and guiding vaccination policy. Trial registration Not applicable, as systematic review of the literature.