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BACKGROUND: We assessed if risk of developing cervical intraepithelial neoplasia grade 2/3 (CIN2/3) or adenocarcinoma in situ (AIS) is associated with a short interval between menarche and first sexual intercourse (FSI). METHODS: A total of 1009 Colombian and 1012 Finnish females, aged 16-23, who were enrolled in the phase 3 trials of a quadrivalent human papillomavirus (HPV) 6/11/16/18 vaccine had nonmissing data for age of menarche and FSI. The impact of menarche interval on the odds of developing CIN2-3/AIS was evaluated in placebo recipients who were DNA negative to HPV 6/11/16/18/31/33/35/39/45/51/52/56/58/59 and seronegative to HPV 6/11/16/18 at day 1, and had a normal Pap result at day 1 and month 7, thus approximating sexually naive adolescents (n = 504). RESULTS: The mean age of menarche and FSI was 12.4 and 16.0 years, respectively. Among the women approximating sexually naive adolescents, 18 developed CIN2-3/AIS. Compared with women who postponed FSI beyond 3 years of menarche, those with FSI within 3 years of menarche had a greater risk of cytologic abnormalities (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.02-2.68; P = .04) and CIN2-3/AIS (OR, 3.56; 95% CI, 1.02-12.47; P = .05). CONCLUSIONS: A short interval between menarche and FSI was a risk factor for cytologic abnormalities and high-grade cervical disease. These data emphasize the importance of primary prevention through education and vaccination. CLINICAL TRIALS REGISTRATION: NCT00092521 and NCT00092534. [ABSTRACT FROM AUTHOR]

Introduction: Otitis media (OM) is a common childhood infection. Pneumococcal conjugate vaccines (PCVs) prevent OM episodes, thereby reducing short- and long-term clinical, economic, humanistic, and societal consequences. Most economic evaluations of PCVs focus on direct health gains and cost savings from prevented acute episodes but do not fully account for the broader societal impacts of OM prevention., Areas Covered: This review explores the broader burden of OM on children, caregivers, and society to better inform future economic evaluations of PCVs., Expert Opinion: OM causes a substantial burden to society through long-term sequelae, productivity losses, reduced quality of life for children and caregivers, and contribution to antimicrobial resistance from inappropriate antibiotic use. The effect of PCVs on acute OM has been recognized globally, yet the broader impact has not been consistently quantified, studied, or communicated. Economic evaluations of PCVs must evolve to include broader effects for patients, caregivers, and society from OM prevention. Future PCVs with broader coverage may further reduce OM incidence and antimicrobial resistance, but optimal uptake will depend on increasing the recognition and use of novel frameworks that include broader benefits. Communicating the full value of PCVs to decision makers may result in wider access and positive societal returns.

Introduction: Modeling analyses have attempted to quantify the global impact of pneumococcal conjugate vaccines (PCVs) on pneumococcal disease (PD), however these pediatric models face several challenges in obtaining comprehensive impact measurements., Areas Covered: We present several measurement challenges and discuss examples from recently published pediatric modeling evaluations. Challenges include estimating the number of infants fully or partially vaccinated with PCVs, inclusion of indirect effects of vaccination, accounting for various dosing schedules, capturing effect of PCVs on nonspecific, noninvasive PD, and inclusion of adult PCV use., Expert Opinion: The true impact of PCVs has been consistently underestimated in published analyses due to multiple measurement challenges. Nearly 100 million adults are estimated to have received PCV13 over the last decade globally, potentially preventing up to 662 thousand cases of PD. Approximately 4.1 million cases of invasive PD alone may have been averted through indirect protection. Estimates of PCV impact on noninvasive PD remain a challenge due to altered epidemiology. Program switches, incomplete vaccination, and private market uptake among children also confound PD impact estimates. Taken together, the number of averted PD cases from PCV use in the last ten years may be up to three times higher than estimated in previous studies.

Introduction: Limited changes in serotype 3 invasive pneumococcal disease (IPD) incidence rates after a decade of 13-valent pneumococcal conjugate vaccine (PCV13) introduction into several national immunization programs (NIP) have raised questions about PCV13's effectiveness against this serotype., Methods: We analyzed the impact of pediatric PCV programs on serotype 3 IPD with two approaches. First, we reviewed the publicly available surveillance data from countries identified in two recently published reviews to describe the population impact of pediatric PCV13 or PCV10 vaccination programs on serotype 3 IPD. We then compared the observed trends in PCV10 and PCV13 countries to a previously described dynamic transmission model that simulates the spread of pneumococcal carriage and development of IPD in a population over time., Results: When serotype 3 disease rates are compared from countries that have introduced either a 10-valent (PCV10) vaccine that does not contain serotype 3 in its formulation or PCV13 in their pediatric NIP, over time, serotype 3 incidence rate trends are markedly different. Countries with a PCV10 NIP showed a substantial linear increase in serotype 3 pneumococcal disease among all age groups since the time of PCV10 introduction, whereas countries with a PCV13 NIP experienced a modest decline during the 3-4 years after vaccine introduction followed by an inflection upward in subsequent years., Conclusion: These data suggest that PCV13 provides a certain degree of direct and indirect protection against serotype 3 at the population level and direct adult vaccination with a serotype 3-containing vaccine is likely to provide substantial benefit in the context of a pediatric PCV NIP. Further research around serotype 3 transmission patterns and epidemiology is nonetheless warranted.

Background In the United States, the 13-valent pneumococcal conjugate vaccine has been recommended for children since 2010 and for adults aged ≥65 years since 2014. We assessed S. pneumoniae antimicrobial nonsusceptibility among adults with suspected pneumonia from hospital settings. Methods Isolates were collected from 105 US sites between 2009 and 2017 in the SENTRY Antimicrobial Surveillance Program. Clinical and Laboratory Standards Institute methods were used for susceptibility testing. Serotypes were determined by cpsB sequence obtained by PCR or whole genome sequencing, plus multiplex PCR and/or Neufeld Quellung reactions as needed. Findings Of 7254 S. pneumoniae isolates analyzed, 63.6% and 36.4% were from patients aged 18‒64 and ≥65 years, respectively. Among all isolates, penicillin and ceftriaxone nonsusceptibility declined by 72.3% and 73.8%, respectively, with smaller changes observed for other antibiotics. Nonsusceptibility patterns were serotype-specific; for example, nonsusceptibility was relatively stable for serotype 19A but declined for 19F. Simultaneously, the percentage of serotype 19A isolates decreased from 17.4% to 3.9%, whereas for serotype 19F this percentage increased from 2.8% to 5.0%. The percentage of serotype 3 isolates that were nonsusceptible increased for select antibiotic classes, and the percentage of serotype 3 among all isolates increased minimally from 10.2% to 11.8%. Interpretation Overall pneumococcal nonsusceptibility patterns were influenced by distinct patterns within serotypes, indicating the likelihood of serotype-specific resistance mechanisms. Serotype 19A observations were consistent with vaccine-induced reductions in circulation with no change in the organism susceptibility, whereas the nonsusceptibility increases for serotypes 3 and 19F may indicate circulation of more antibiotic-resistant clones., Competing Interests: Declaration of Competing Interest JAS, HLS, AGA, LJ, REI, BDG, and RRR are employees of Pfizer Inc and may own stock or stock options. RM is an employee of JMI, which is contracted by Pfizer and other companies to provide surveillance data regarding antimicrobial resistance. JMI was also funded by Pfizer for publication development., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objective: A model was developed to estimate the historical impact (including total societal health and economic benefit) of pneumococcal conjugate vaccine (PCV) programs in the overall Canadian population between 2005 and 2015, inclusively., Methods: Historical incidence of invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) were obtained from epidemiologic databases supplemented with published and unpublished data. Two scenarios were considered: (1) the observed historical incidence from 2005 to 2015 in the setting of PCV use; (2) a hypothetical scenario in which we estimated the number of disease cases assuming no PCV use. Disease cases averted as a result of PCV programs were calculated by subtracting the number of observed historical cases from the number of estimated cases expected in the absence of PCV use., Results: PCV programs were estimated to have saved 6631 lives and averted 14,990 IPD cases, 735,700 pneumonia episodes, and 3,697,993 AOM episodes. Positive clinical outcomes resulted in total cost savings of CAD $1.76 billion over 11 years. Vaccination costs were offset by the direct medical cost savings from fewer cases of IPD, pneumonia, and AOM., Conclusions: Canadian PCV programs have provided significant health benefits and resulted in a substantial value for money. Net savings achieved over the reviewed period would have provided funding for $1.76 billion in other health care costs or public health initiatives. These findings highlight the importance of considering the total value of a vaccination program, rather than vaccine acquisition costs only, when assessing the value of immunization programs.

Introduction : By preventing nasopharyngeal carriage acquisition among vaccinated persons, and thus reducing transmission, pneumococcal conjugate vaccines (PCVs) provide protection against pneumococcal vaccine serotypes among unvaccinated individuals. This systematic review assessed PCVs containing serotype 19A or cross-reactive 19F for 19A carriage effects. Areas covered : Peer-reviewed literature was searched for manuscripts published between 1/1/2000 and 06/18/2018 assessing the impact of PCV on 19A carriage. Expert opinion : Fifty-five, 12, and 32 articles were identified for PCV7, PCV10, and PCV13, respectively. In two of four PCV7 randomized controlled trials (RCTs), 19A carriage was significantly higher in PCV7-vaccinated vs control subjects; in two of two PCV10 RCTs, there was no significant difference in 19A carriage and acquisition between PCV10-vaccinated (2 + 1 schedule) vs control subjects, apart from one timepoint (3 + 1 schedule); and one of one RCTs of PCV13 showed significant decreases in 19A carriage and acquisition in PCV13- vs PCV7-vaccinated (3 + 1 schedule) children. These findings were consistent with observational studies in which an increase or no change in 19A carriage was observed in 91% and 67% of PCV7 and PCV10 studies, respectively, whereas 87% of PCV13 studies documented a decrease. Countries in which serotype 19A transmission is substantial should consider the use of vaccines containing serotype 19A.

Background: Serotype 3 pneumococcal disease has not substantially declined at the population level after the routine introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into pediatric immunization programs across the globe. This epidemiological finding has generated debate regarding the effectiveness of PCV13 against serotype 3 disease. Evaluating PCV13 effectiveness against serotype 3 is especially critical in adults, where serotype 3 makes up an important amount of remaining pneumococcal disease., Methods: We performed a systematic review of the published literature to assess the direct effectiveness of PCV13 against serotype 3 community-acquired pneumonia (CAP) among adults. We then estimated overall vaccine effectiveness (VE) using a pooled analysis of the individual-level, raw data., Results: Two published studies met inclusion criteria. One was a randomized controlled trial conducted in the Netherlands and published in 2014. The other was a recently-published case-control study conducted in Louisville, Kentucky that used a test-negative design (TND). We also identified a third TND study conducted in Argentina that was recently presented as a conference abstract but is not yet published. All three studies were conducted in adults aged ≥65 years. PCV13 VE against serotype 3 hospitalized CAP was 52.5% (95%CI: 6.2-75.9%) from the pooled analysis of individual-level data from all three studies. Results were similar if the unpublished estimate was excluded (serotype 3 VE = 53.6% [95%CI: 6.7-76.9%]). No heterogeneity was observed., Conclusions: Currently-available evidence, although limited to three studies, suggests that PCV13 provides direct protection against serotype 3 hospitalized CAP in adults aged ≥65 years., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We conducted a post-hoc analysis of a double blind, randomized, placebo-controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) among adults aged 65 years or older to assess public health impact., Methods: For all outcomes, we included all randomized subjects, using a modified intention-to-treat (mITT) approach to determine vaccine efficacy (VE), vaccine preventable disease incidence (VPDI) defined as control minus vaccinated group incidence, and numbers needed to vaccinate (NNV) (based on a five-year duration of protection)., Results: Results are reported for, in order, clinical, adjudicated (clinical plus radiologic infiltrate determined by committee), pneumococcal, and vaccine-type pneumococcal (VT-Sp) community-acquired pneumonia; invasive pneumococcal disease (IPD) and VT-IPD. VEs (95% CI) for all hospital episodes were 8.1% (-0.6%, 16.1%), 6.7% (-4.1%, 16.3%), 22.2% (2.0%, 38.3%), 37.5% (14.3%, 54.5%), 49.3% (23.2%, 66.5%), and 75.8% (47.6%, 88.8%). VPDIs per 100,000 person-years of observation (PYOs) were 72, 37, 25, 25, 20, and 15 with NNVs of 277, 535, 816, 798, 1016, and 1342. For clinical CAP, PCV13 was associated with a reduction of 909 (-115, 2013) hospital days per 100,000 PYOs translating to a reduction over 5 years of one hospital day for every 22 people vaccinated. When comparing at-risk persons (defined by self-report of diabetes, chronic lung disease, or other underlying conditions) to not at-risk persons, VEs were similar or lower, but because baseline incidences were higher the VPDIs were approximately 2-10 times higher and NNVs 50-90% lower., Conclusion: A public health analysis of pneumonia and IPD outcomes in a randomized controlled trial found substantial burden reduction following adult PCV13 immunization implemented in a setting with an ongoing infant PCV7-PCV10 program. VPDIs were higher among at-risk adults., Funding: The original study and the current analysis were funded by Pfizer., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Serotype-specific vaccine efficacy (VE) against adult community acquired pneumonia (CAP) remains poorly defined, yet such data are important for assessing the utility of adult pneumococcal conjugate vaccine (PCV) programs., Methods: We evaluated the Community Acquired Pneumonia Immunization Trial in Adults to assess serotype-specific VE for CAP. This parallel-arm randomized clinical trial assessed 13-valent PCV (PCV13) VE among community dwelling persons aged ≥65 years in The Netherlands. In the original analysis, PCV13 VE against first episodes of vaccine-type (VT) chest radiology confirmed CAP was 45.6% (95% confidence interval [CI] 21.8-62.5%). Unlike the original analysis, we included any subject that met a clinical definition of CAP regardless of radiographic findings. VT-CAP was identified by culture (sterile or non-sterile) or serotype-specific urinary antigen detection (SSUAD) test. Only the five serotypes with at least 10 episodes in the control arm, based on the original analysis, were included for VE assessment., Results: Of 272 clinical CAP visits with VT serotypes identified, 253 (93%) were identified by SSUAD including 210 (77%) by SSUAD alone. VE was determined for serotypes 1, 3, 6A, 7F, and 19A, with total first episodes of, respectively, 27, 36, 25, 38, and 48. VE (95%CI) for the five evaluated serotypes against first clinical CAP episodes were: serotype 1, 20.0% (-83.1% to 65.8%); serotype 3, 61.5% (17.6-83.4%); serotype 6A, 33.3% (-58.6% to 73.2%); serotype 7F, 73.3% (40.5-89.4%); and serotype 19A, 45.2% (-2.2% to 71.5%)., Discussion: Statistically significant VE was observed for serotypes 3 and 7F for clinical CAP among elderly community dwelling adults. The VE point estimates and CIs for serotypes 1, 6A, and 19A were lower but consistent with the overall VT-CAP VE of 45.6% previously reported. These findings may be relevant in models to accurately account for the potential impact of adult PCV13 immunization., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The 13-valent pneumococcal conjugate vaccine (PCV13) is the only licensed PCV with serotype 3 polysaccharide in its formulation. Postlicensure PCV13 effectiveness studies against serotype 3 invasive pneumococcal disease (IPD) in children have shown inconsistent results.  We performed a systematic review and meta-analysis of observational studies to assess PCV13 vaccine effectiveness (VE) for serotype 3 IPD in children. We systematically searched PubMed, Embase, and the Cochrane library for studies published before 14 August 2017. We identified 4 published studies and 2 conference posters that provided PCV13 VE estimates stratified by serotype. The pooled PCV13 VE against serotype 3 IPD from the random-effects meta-analysis was 63.5% (95% confidence interval [CI], 37.3%-89.7%). A sensitivity analysis including conference posters gave a pooled VE estimate of 72.4% (95% CI, 56.7%-88.0%). The pooled data from case-control studies with similar methodologies and high quality support direct PCV13 protection against serotype 3 IPD in children., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Following universal recommendation for use of 13-valent pneumococcal conjugate vaccine (PCV13) in US adults aged ≥65 years in September 2014, we conducted the first real-world evaluation of PCV13 vaccine effectiveness (VE) against hospitalized vaccine-type community-acquired pneumonia (CAP) in this population., Methods: Using a test-negative design, we identified cases and controls from a population-based surveillance study of adults in Louisville, Kentucky, who were hospitalized with CAP. We analyzed a subset of CAP patients enrolled 1 April 2015 through 30 April 2016 who were aged ≥65 years and consented to have their pneumococcal vaccination history confirmed by health insurance records. Cases were defined as hospitalized CAP patients with PCV13 serotypes identified via culture or serotype-specific urinary antigen detection assay. Remaining CAP patients served as test-negative controls., Results: Of 2034 CAP hospitalizations, we identified PCV13 serotypes in 68 (3.3%) participants (ie, cases), of whom 6 of 68 (8.8%) had a positive blood culture. Cases were less likely to be immunocompromised (29.4% vs 46.4%, P = .02) and overweight or obese (41.2% vs 58.6%, P = .01) compared to controls, but were otherwise similar. Cases were less likely to have received PCV13 than controls (3/68 [4.4%] vs 285/1966 [14.5%]; unadjusted VE, 72.8% [95% confidence interval, 12.8%-91.5%]). No confounding was observed during adjustment for patient characteristics, including immunocompromised status, body mass index, and history of influenza and pneumococcal polysaccharide vaccination (adjusted VE range, 71.1%-73.3%)., Conclusions: Our study is the first to demonstrate real-world effectiveness of PCV13 against vaccine-type CAP in adults aged ≥65 years following introduction into a national immunization program.

Introduction: Pneumococcal conjugate vaccines (PCVs) have provided a significant clinical and economic impact globally. The majority of countries which have implemented an infant PCV program have observed a substantial reduction in the burden of invasive pneumococcal disease (IPD), pneumococcal pneumonia, and acute otitis media (AOM) due to vaccine serotypes. After 17 years of use, many countries have evaluated and re-evaluated the value of their vaccine program using cost-effectiveness analyses; however, many of these analyses do not reflect the current body of evidence., Areas Covered: This literature review summarizes key assumptions used in cost-effectiveness analyses for PCVs and discusses whether these should be refined., Expert Commentary: Many existing models continue to project cost-effectiveness of implementing a PCV program into a naïve population, despite sustained PCV use. Furthermore, many assumptions related to program effectiveness are based on evidence from controlled studies or extrapolated from vaccines that are no longer or were never used. Real world effectiveness data published from nearly 10 years of higher-valet vaccine use should be reflected in key assumptions that drive decision makers to choose one vaccine over another. As data continuously emerges, cost-effectiveness of programs should be evaluated in the context of the most current data.

Introduction: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A. Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies. Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

Streptococcus pneumoniae is a frequent cause of community acquired pneumonia (CAP), with the largest burden of disease attributed to non-bacteremic pneumonia. Due to the high persistent burden of disease, pneumococcal pneumonia, particularly non-bacteremic pneumococcal pneumonia, continues to be a major public health concern. There are currently two pneumococcal vaccines approved for use in adults in the United States (US) and other countries worldwide: a 23-valent pneumococcal simple polysaccharide vaccine (PPV23), and a 13-valent pneumococcal conjugate vaccine (PCV13). The capsular polysaccharides included in PPV23 induce antibodies primarily by a T-cell independent mechanism, thus the immune response is short lived and lacks the ability to elicit an anamnestic response. PCV13, on the other hand, has the bacterial polysaccharides covalently conjugated to an immunogenic carrier protein resulting in the formation of memory B lymphocytes, thus proving long-acting immunologic memory and an anamnestic response. Despite 30years of use, the question of PPV23 vaccine efficacy, particularly with respect to efficacy for non-bacteremic pneumonia, has been extensively debated and investigated; whereas PCV13 efficacy against vaccine-type pneumococcal CAP, both bacteremic and non-bacteremic, was confirmed in a large randomized controlled trial in older adults. PCV13 was approved under the US Food and Drug Administration's accelerated pathway, which allows for earlier approval of products that provide meaningful benefit over existing treatments - in this case, protection of adults from non-bacteremic pneumococcal pneumonia. Its use is now increasingly recommended globally. This article summarizes the history and use of PPV23 and PCV13 in adults and how vaccination of adults with PCV13 addresses an unmet medical need., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region METHODS: Women ages 15-26 and 24-45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus., Results: Predominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81-85%). Types 31/33/45/52/58 accounted for 25-30% of CIN1 in Latin America and Europe, but 14-18% in North America and Asia. Types 31/33/45/52/58 accounted for 33-38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17-18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2-11% of CIN2/3., Conclusions: The 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Streptococcus pneumoniae is a leading cause of illness and death in adults. A polysaccharide vaccine has been available for over 30 years, but despite significant use, the public health impact of this vaccine has been limited. The 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed by the US Food and Drug Administration and other international regulatory authorities with the assumption that induction of a T cell-dependent immune response and noninferior immunogenicity to vaccine antigens when compared with the polysaccharide vaccine would be important to satisfy a significant unmet medical need. PCV13 efficacy against vaccine-type pneumococcal community-acquired pneumonia was confirmed in a large randomized controlled trial in older adults and its use is now increasingly recommended globally.

Background: A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD®) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide., Methods: Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus)., Results: We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates., Conclusions: These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination.

Background: We estimated the prevalence and incidence of 14 human papillomavirus (HPV) types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) in cervicovaginal swabs, and the attribution of these HPV types in cervical intraepithelial neoplasia (CIN), and adenocarcinoma in situ (AIS), using predefined algorithms that adjusted for multiple-type infected lesions., Methods: A total of 10,656 women ages 15 to 26 years and 1,858 women ages 24 to 45 years were enrolled in the placebo arms of one of three clinical trials of a quadrivalent HPV vaccine. We estimated the cumulative incidence of persistent infection and the proportion of CIN/AIS attributable to individual carcinogenic HPV genotypes, as well as the proportion of CIN/AIS lesions potentially preventable by a prophylactic 9-valent HPV6/11/16/18/31/33/45/52/58 vaccine., Results: The cumulative incidence of persistent infection with ≥1 of the seven high-risk types included in the 9-valent vaccine was 29%, 12%, and 6% for women ages 15 to 26, 24 to 34, and 35 to 45 years, respectively. A total of 2,507 lesions were diagnosed as CIN or AIS by an expert pathology panel. After adjusting for multiple-type infected lesions, among women ages 15 to 45 years, these seven high-risk types were attributed to 43% to 55% of CIN1, 70% to 78% of CIN2, 85% to 91% of CIN3, and 95% to 100% of AIS lesions, respectively. The other tested types (HPV35/39/51/56/59) were attributed to 23% to 30% of CIN1, 7% to 14% of CIN2, 3% to 4% of CIN3, and 0% of AIS lesions, respectively., Conclusions: Approximately 85% or more of CIN3/AIS, >70% CIN2, and approximately 50% of CIN1 lesions worldwide are attributed to HPV6/11/16/18/31/33/45/52/58., Impact: If 9-valent HPV vaccination programs are effectively implemented, the majority of CIN2 and CIN3 lesions worldwide could be prevented, in addition to approximately one-half of CIN1., (©2014 American Association for Cancer Research.)

Background: We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine., Methods: Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects ≥ 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease., Results: For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of ≥ 12 months' duration. Acquisition of new sexual partners (among those ≥ 16 years) was ∼1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to ≥ 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders., Conclusions: When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years., (Copyright © 2014 by the American Academy of Pediatrics.)

Background & Aims: Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies., Methods: SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial., Results: Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts., Conclusions: The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Human papillomavirus (HPV) is the causative agent of cervical cancer. Black women are disproportionally diagnosed and have higher mortality from cervical cancer in the United States. Here we describe the prophylactic efficacy and safety of a quadrivalent HPV-6/11/16/18 vaccine in black women., Methods: A total of 700 black women from Latin America, Europe, and North America (aged 16-24 years) received the vaccine or placebo in one of two studies. Analyses focused on the efficacy and safety of the vaccine., Results: Baseline rates of Chlamydia trachomatis infection and history of past pregnancy were more than twice as high in black women compared with the non-black women who were enrolled in these trials. HPV-6/11/16 or 18 DNA was detected in 18% of black women versus 14.6% in non-black women at day 1. For black women, vaccine efficacy against disease caused by HPV-6/11/16/18 was 100% for cervical intraepithelial neoplasia (0 vs. 15 cases; 95% confidence interval, 64.5%-100%) and 100% for vulvar and vaginal intraepithelial neoplasia and condylomata acuminata (0 vs. 17 cases; 95% confidence interval, 69.3%-100%). There were no serious vaccine-related adverse experiences. A similar proportion of pregnancies resulted in live births (75.8% vaccine; 72.7% placebo) and fetal loss (24.2% vaccine; 27.3% placebo)., Conclusions: Prophylactic quadrivalent HPV-6/11/16/18 vaccination of young black women demonstrated high efficacy, safety, and tolerability. HPV vaccination has the potential to reduce cervical cancer-related health disparities both in the United States and around the world., (Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use., Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background & Aims: The addition of boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with boceprevir plus peginterferon alfa-2a-ribavirin (PEG2a/R) in patients with identical study entry criteria., Methods: In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended., Results: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P < .0001). Among patients with poor response to interferon therapy (<1-log(10) decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log(10) decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log(10) decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin <10.0 g/dL), compared with 27% in the PEG2a/R group; 43% vs 21%, respectively, developed neutropenia (neutrophil count <750/mm(3))., Conclusions: The addition of boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors., Methods: Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed., Results: In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR., Conclusions: The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In this randomized, double-blind, placebo-controlled trial, 9-15 year old Chinese males (n=100) and 9-45 year old Chinese females (n=500) from Wuzhou, Guangxi, China were randomized (1:1) to receive either quadrivalent HPV vaccine or adjuvant-containing placebo. Blood samples were obtained at day 1 and one month post-dose 3 to determine the level of vaccine-induced antibodies. Among vaccine recipients, high antibody levels were observed for each of the four HPV types and seroconversion was >96%. The vaccine was generally well tolerated, with no vaccine-related serious adverse events. This study demonstrated that the quadrivalent HPV vaccine is highly immunogenic and generally well tolerated among Chinese males and females., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To determine the effect of human papillomavirus (HPV) quadrivalent vaccine on the risk of developing subsequent disease after an excisional procedure for cervical intraepithelial neoplasia or diagnosis of genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia., Design: Retrospective analysis of data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II))., Setting: Primary care centres and university or hospital associated health centres in 24 countries and territories around the world., Participants: Among 17,622 women aged 15-26 years who underwent 1:1 randomisation to vaccine or placebo, 2054 received cervical surgery or were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia., Intervention: Three doses of quadrivalent HPV vaccine or placebo at day 1, month 2, and month 6., Main Outcome Measures: Incidence of HPV related disease from 60 days after treatment or diagnosis, expressed as the number of women with an end point per 100 person years at risk., Results: A total of 587 vaccine and 763 placebo recipients underwent cervical surgery. The incidence of any subsequent HPV related disease was 6.6 and 12.2 in vaccine and placebo recipients respectively (46.2% reduction (95% confidence interval 22.5% to 63.2%) with vaccination). Vaccination was associated with a significant reduction in risk of any subsequent high grade disease of the cervix by 64.9% (20.1% to 86.3%). A total of 229 vaccine recipients and 475 placebo recipients were diagnosed with genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia, and the incidence of any subsequent HPV related disease was 20.1 and 31.0 in vaccine and placebo recipients respectively (35.2% reduction (13.8% to 51.8%))., Conclusions: Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease., Trial Registrations: NCT00092521 and NCT00092534.

The impact of a human papillomavirus (HPV) vaccine on development of cervical intraepithelial neoplasia grade 2-3 or adenocarcinoma in situ (CIN2-3/AIS) in women with ongoing HPV16 or 18 infections prevaccination is reported. Seventeen thousand six-hundred and twenty-two women aged 16-26 were enrolled in 1 of 2 randomized, placebo-controlled, efficacy trials (Protocols 013 and 015). Vaccine or placebo was given at day 1, month 2 and 6. Women were tested for HPV6/11/16/18 DNA and antibodies at day 1. We focus on the subset of women who were seropositive and DNA positive to HPV16 or HPV18 prevaccination. Incidence is expressed as the number of women with an endpoint per 100 person-years-at-risk. In total, 419 vaccine and 446 placebo recipients were both seropositive and DNA positive to HPV16 or HPV18 prevaccination and had at least one follow-up visit. In Protocol 013, the incidence of HPV16/18-related CIN2-3/AIS among these women was 10.9 in the vaccine arm and 7.0 in the placebo arm (vaccine efficacy = -54.9; 95% CI: -181.7, 13.0). In Protocol 015, the incidence of HPV16/18-related CIN2-3/AIS was 5.5 in the vaccine arm and 6.2 in the placebo arm (vaccine efficacy = 12.2%; 95% CI: -29.8, 40.9). These data suggest HPV vaccination neither reduces nor enhances progression to HPV16/18-related high grade cervical lesions, and cervical cytology screening and corresponding management should continue as per local recommendations. Ultimately, population-based surveillance of vaccinated individuals beyond these clinical trials will be required to further address questions regarding the impact of vaccination in women exposed to vaccine HPV types before vaccination., (Copyright © 2011 UICC.)

Human papillomavirus (HPV) infection causes cervical cancer, a significant portion of anal, genital, and oropharyngeal cancers, genital warts, and recurrent respiratory papillomatosis. In June 2006, a quadrivalent HPV-6/11/16/18 vaccine (Gardasil/Silgard) was licensed in the United States, and subsequently in the European Union (September 2006). It has since been approved in 121 countries, with >74 million doses distributed globally as of March 2011. As the incidence of HPV infection peaks 5-10 years after the onset of sexual activity, preadolescents and adolescents represent an appropriate target group to implement HPV vaccination programs so as to achieve the maximal public health benefit. In this article, we provide an overview of the prophylactic efficacy of the vaccine in young women who were found to be negative to at least one of the four vaccine HPV types, thus approximating sexually naive adolescents. Because adolescents are also at high risk for other infections which are preventable by currently available vaccines, the development of concurrent immunization strategies may lead to better compliance, thereby contributing to the overall goal of protection against preventable diseases. We also summarize concomitant administration studies with meningococcal, diphtheria, tetanus, and pertussis vaccines, which were conducted in adolescents aged 9-15 years. Prophylactic efficacy in other populations (males aged 16-26 years) is also summarized along with long-term safety and efficacy studies., (Copyright © 2011 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: High-risk human papillomavirus (hrHPV) is the primary cause of cervical cancer. As Chlamydia trachomatis is also linked to cervical cancer, its role as a potential co-factor in the development of cervical intraepithelial neoplasia (CIN) grade 2 or higher was examined., Methods: The placebo arms of two large, multinational, clinical trials of an HPV6/11/16/18 vaccine were combined. A total of 8441 healthy women aged 15-26 years underwent cervicovaginal cytology (Papanicolaou (Pap) testing) sampling and C trachomatis testing at day 1 and every 12 months thereafter for up to 4 years. Protocol-specified guidelines were used to triage participants with Pap abnormalities to colposcopy and definitive therapy. The main outcome measured was CIN., Results: At baseline, 2629 (31.1%) tested positive for hrHPV DNA and 354 (4.2%) tested positive for C trachomatis. Among those with HPV16/18 infection (n = 965; 11.4%) or without HPV16/18 infection (n = 7382, 87.5%), the hazard ratios (HRs) associated with development of any CIN grade 2 according to baseline C trachomatis status were 1.82 (95% CI: 1.06 to 3.14) and 1.74 (95% CI 1.05 to 2.90), respectively. The results were comparable when only the 12 most common hrHPV infections were considered, but the excess risk disappeared when the outcome was expanded to include CIN grade 3 or worse., Conclusion: Further studies based on larger cohorts with longitudinal follow-up in relation to the C trachomatis acquisition and a thorough evaluation of temporal relationships of infections with hrHPV types, C trachomatis and cervical neoplasia are needed to demonstrate whether and how in some situations C trachomatis sets the stage for cervical carcinogenesis. Trial registration NCT00092521 and NCT00092534.

Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment., Methods: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks., Results: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls., Conclusions: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

We evaluated the overall agreement between colposcopically directed biopsies and the definitive excisional specimens within the context of three clinical trials. A total of 737 women aged 16-45 who had a cervical biopsy taken within 6 months before their definitive therapy were included. Per-protocol, colposcopists were to also obtain a representative cervical biopsy immediately before definitive therapy. Using adjudicated histological diagnoses, the initial biopsies and the same day biopsies were correlated with the surgically excised specimens. The overall agreement between the biopsies taken within 6 months of definitive therapy, and the definitive therapy diagnoses was 42% (weighted kappa = 0.34) (95% CI: 0.29-0.39). The overall underestimation of cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ (CIN2-3/AIS) and CIN3/AIS was 26 and 42%, respectively. When allowing for one degree of variance in the correlation, the overall agreement was 92% for CIN2-3/AIS. The overall agreement between the same day biopsy and definitive therapy specimen was 56% (weighted kappa = 0.41) (95% CI: 0.36-0.47), and the underestimation of CIN2-3/AIS was 57%. There were significant associations in the agreement between biopsies and excisional specimen diagnoses when patients were stratified by age, number of biopsies, lesion size, presence of human papillomavirus (HPV)16/18 and region. Of 178 diagnostic endocervical curettages performed, 14 (7.9%) found any HPV disease. Colposcopic accuracy improved when CIN2 and CIN3/AIS were grouped as a single predictive measure of high-grade disease. Colposcopy functioned well when allowed a one-degree difference between the biopsy and the surgical histologic interpretations, as done in clinical practice. Taking more than one biopsy improved colposcopic accuracy and could improve patient management., (Copyright © 2010 UICC.)

The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma., (Copyright © 2011 UICC.)

Objectives: Multinational phase III trials of a human papillomavirus vaccine, Gardasil, have shown the vaccine to be generally well-tolerated, efficacious, and immunogenic. We evaluated the immunogenicity and safety of Gardasil administered concomitantly with Menactra and Adacel., Methods: In this open-label study, boys (n = 394) and girls (n = 648) aged 10 to 17 were randomly assigned in a 1:1 ratio as follows: group A (concomitant administration) received a 0.5-mL dose of Gardasil at day 1, month 2, and month 6 and a 0.5-mL dose of Menactra and Adacel on day 1; group B (nonconcomitant administration) received Gardasil at day 1, month 2, and month 6 and Menactra and Adacel at month 1. Antibody levels for all vaccine components were measured. Systemic, injection-site, and serious adverse experiences (AEs) were monitored., Results: Immune responses after concomitant administration of the 3 vaccines were noninferior to nonconcomitant administration. Seroconversion for Gardasil was > or = 99% in both groups A and B. For Menactra and Adacel, concomitant administration of the vaccines was demonstrated to be noninferior to nonconcomitant administration. Concomitant administration was generally well-tolerated. No participants withdrew because of an AE. One serious AE of transient muscular weakness of <24 hours' duration after the third Gardasil injection was reported in group B and was deemed possibly vaccine-related by the investigator., Conclusions: Overall, concomitant administration was generally well-tolerated and did not interfere with the immune response to the respective vaccines. Concomitant administration should minimize the number of visits required to deliver each vaccine individually, leading to increased compliance and more effective disease prevention.

Background: The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group)., Methods: This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk., Results: The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type., Conclusions: High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.

Background: We describe the safety of the human papillomavirus (HPV)-6/11/16/18 vaccine using updated clinical trial data (median follow-up time of 3.6 years) and summarize up to 3 years of post-licensure surveillance., Methods: In 5 clinical trials, 21,480 girls/women aged 9 to 26 years and boys aged 9 to 16 years received >or=1 dose of HPV-6/11/16/18 vaccine or placebo. All serious and non-serious adverse experiences (AEs) and new medical conditions were recorded for the entire study period(s). As of June 2009, >25 million doses of HPV-6/11/16/18 vaccine had been distributed in the United States with >50 million doses globally. Post-licensure safety as summarized by the Centers for Disease Control and Prevention using the United States Vaccine Adverse Event Reporting System database is also reported., Results: Eight subjects experienced a treatment-related serious AE (0.05% vaccine; 0.02% placebo). Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients. Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placeboaluminum; 45% placebo-saline). No differences were seen in the incidence of the most common non-serious AEs-headache and pyrexia. The Vaccine Adverse Event Reporting System has received 14,072 reports for the HPV-6/11/16/18 vaccine since licensure, with only 7% being serious AEs, about half the average reported for licensed vaccines in general., Conclusions: HPV-6/11/16/18 vaccination was associated with more injection-site pain than placebo but similar incidences of systemic and serious AEs and new medical conditions potentially consistent with autoimmune phenomena. Based on review of post-licensure safety information, the benefits of vaccination to prevent the majority of genital tract precancers and cancers continue to far outweigh its risks.

Objective: A comprehensive questionnaire designed to assess the full spectrum of potential human papillomavirus (HPV)-related psychosocial effects in women does not exist. The HPV Impact Profile (HIP) was developed to determine the psychosocial impact of HPV infection and related interventions., Research Design and Methods: Draft instrument items and domains were developed using a literature review and cognitive debriefing interviews with women who had experienced HPV-related conditions. An importance rating questionnaire guided item ranking and reduction. A draft questionnaire was pilot-tested for comprehension and ease of completion. Psychometric evaluation of the final HIP was conducted in a survey of 583 women. Data quality, item acceptability, scale acceptability, reliability, and discriminate construct validity were assessed., Outcome Measure: The final HIP contained 29 items rated on a 0-10 point discretized visual analog scales grouped into seven hypothesized domains., Results: Total HIP scores ranged from 0 (no impact) to 100 (worst impact). Data quality was high, with missing data for items ranging from 0 to 0.7% and over 99% of the scores were computable. Cronbach's alpha ranged from 0.64 to 0.90 and was > or =0.7 for 5/7 domains. Discriminant construct validity was demonstrated. Appropriate modifications could potentially be made to improve some aspects of the HIP, including modification to include other HPV diseases such as head and neck, anal, and vulvovaginal cancers and HPV disease in men., Conclusions: The disease-specific HIP has favorable reliability and construct validity and a good ability to discriminate among disease severity.

Introduction: As limited data among German women exist about HPV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae, we report the prevalence of these genital infections and general baseline demographics of the young German women enrolled in the phase III trials of the quadrivalent HPV vaccine., Materials and Methods: German females (n = 437; 9-23 years) were recruited among 3 international phase 3 studies of an HPV-6/11/16/18 vaccine. We present baseline characteristics, prevalence of HPV-6/11/16/18 and, for women aged 16-23, abnormal cervical cytology and sexually transmitted diseases., Results: Chlamydia trachomatis and Neisseria gonorrhoeae prevalence was 5 and 0.3%, respectively. Approximately 17% of participants had HPV-6, 11, 16, or 18 DNA or antibodies. All subjects <17 years were naïve to the four vaccine types., Discussion: The results of the vaccine trials have demonstrated that it is worth administering prophylactic HPV vaccines before sexual debut; however, none of these sexually active German women were positive to all four types and most were positive to only one type. Thus, all women had the potential to benefit from vaccination with a quadrivalent HPV vaccine.