Clinical trial experience with prophylactic human papillomavirus 6/11/16/18 vaccine in young black women.

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.

Proximity of first sexual intercourse to menarche and risk of high-grade cervical disease.

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.

Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data.

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.

Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection.

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.

The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials.

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.

Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women.

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.

Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the OPTIMAAL trial.

AIMS: The prevalence, incidence, and prognostic value of anaemia in patients with an acute myocardial infarction (AMI) complicated by heart failure is unclear. METHODS AND RESULTS: We analysed the relationship between haemoglobin (Hb) and outcome in 5010 patients with AMI complicated by heart failure in the OPTIMAAL study. In 3921 patients, follow-up Hb levels were available at 365 (+/-90) days. In a subgroup of 224 patients, iron-related haematinics were assessed at baseline and during follow-up. At baseline, mean Hb was 12.6 +/- 1.3 g/dL in women and 13.7 +/- 1.4 g/dL in men. Hb < 11.5 g/dL was found in 9.3% of patients (women: 18.2%, men: 5.8%). Lower haemoglobin at baseline was clearly associated with female gender and the presence of diabetes, higher age and Killip class, lower body mass index, systolic blood pressure, total cholesterol, and the absence of current smoking (all P < 0.05). Higher Hb [per one standard deviation (SD)] related to lower mortality [adjusted hazard ratios (HR) 0.88; 95% confidence interval (CI) 0.83-0.93], CHF hospitalizations [HR 0.85 (0.77-0.93)], and all-cause hospitalizations [HR 0.96 (0.92-0.99), all P < 0.05]. In patients without anaemia at baseline, the anaemia incidence after 1 year of follow-up was 10.1% in women and 10.0% in men. Of patients with anaemia at baseline, 65% did not have anaemia at 12 months and 46% did not have anaemia at any time during follow-up (median 3.0 years, inter-quartile range, Q1-Q3 = 2.7-3.3 years). At 12 months, an increase in Hb (per SD) was related to lower mortality [HR 0.73 (0.63-0.85; P < 0.0001)] independent of baseline Hb and other clinical characteristics. CONCLUSION: In patients with complicated AMIs, anaemia on admission and/or reductions in haemoglobin during follow-up are independent risk factors for mortality and hospitalization. Studies are warranted to determine whether correcting anaemia after a complicated AMI improves outcome.

Unrecognized glycometabolic disturbance as measured by hemoglobin A1c is associated with a poor outcome after acute myocardial infarction.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) is a measure of the average blood glucose levels over 2 months and is minimally affected by acute hyperglycemia often observed in myocardial infarction (MI). In a large population of high-risk patients with MI, we examined the prognostic impact of HbA1c in patients with and without a history of diabetes. METHODS: In the OPTIMAAL trial, patients with MI complicated with heart failure were randomized to losartan or captopril. Of the 2841 patients who had HbA1c measured at randomization, 495 (17%) reported a history of diabetes. The remaining patients without diabetes history were stratified into 3 categories according to HbA1c level: HbA1c, <4.9% (n = 1642); HbA1c, 4.9% to 5.1% (n = 432); and HbA1c, >5.1% (n = 272). Mean follow-up time was 2.5 years. RESULTS: Mortality rate during follow-up was 18% in patients with a history of diabetes. Increasing HbA1c levels were associated with higher mortality rate among patients without diabetes history (13% in patients with HbA1c <4.9%, 17% in patients with HbA1c 4.9%-5.1%, 22% in patients with HbA1c >5.1%). Among patients with no prior history of diabetes, a 1% absolute increase in HbA1c level at baseline resulted in a 24% increase in mortality, whereas the level of HbA1c had no impact on mortality among the patients with well-known diabetes (multivariate analyses). CONCLUSIONS: In this high-risk MI population, HbA1c level was a potent predictor of mortality in patients without previously known diabetes.

Sex-based short- and long-term survival in patients following complicated myocardial infarction.

AIMS: Mortality in women following an acute myocardial infarction (AMI) is higher than in men, in that women are older and have more co-morbidity at the time of AMI. We evaluated short- and long-term sex-related differences in management and prognosis among high-risk patients following AMI. METHODS AND RESULTS: A total of 1575 women and 3902 men with AMI and heart failure, left ventricular dysfunction, or anterior Q waves, were recruited for participation in the OPTIMAAL trial and followed for 2.7+/-0.9 years in seven European countries. Symptomatic heart failure was more common in women when compared with men. Women were older, with more hypertension and diabetes mellitus. Fewer women were treated with thrombolytics (P<0.001 in all cases). Women had a 1.37-fold higher risks of death (P<0.001) during follow-up, but no differences were observed after adjusting for age. However, in-hospital mortality was significantly higher in women (4.89 vs. 2.54%; P<0.001) and a 1.57-fold higher risk of in-hospital death (P=0.006) persisted after adjusting for age and co-morbidities. CONCLUSION: Among high-risk patients with AMI, age-adjusted long-term survival was similar between sexes. However, adjusted in-hospital mortality was significantly higher in women. Higher short-term risk may warrant more rapid and appropriate management of women with AMI.

The impact of morbid events on survival following hospitalization for complicated myocardial infarction.

BACKGROUND: Little is known about the importance of morbid events with respect to longer term survival following MI hospital discharge. AIMS: Establish the risk of death associated with morbid events following initial discharge from MI hospitalization. METHODS: We examined the rates of morbid events (reinfarction, stroke/TIA, revascularization, heart failure (HF) hospitalization, cardiovascular hospitalization and all-cause hospitalization) and the relationships of these events to subsequent death in patients who survived the initial hospitalization for MI (n = 5301) in the OPTIMAAL trial. Events were classified as Early (< or = 30 days post discharge) and Late (> 30 days post discharge) for an average of 2.7 years follow-up. RESULTS: Death rates were higher in the Early period (0.20 deaths/patient year) than in the Late period (0.05 deaths/patient year). Once a morbid event, excluding revascularization, occurred, the acute hazard ratios (HR, determined by Cox regression) for death on the day of event were higher than at time periods following the event and were highest for reinfarction and stroke/TIA. The acute HRs for death for all 6 morbid events were especially high for events occurring during the Late period. The highest chronic HR for death was associated with HF and all-cause hospitalizations. By contrast, the chronic HR for death from revascularization in both the Early (HR = 0.3) and Late (HR = 0.4) period indicated reduced risk. CONCLUSIONS: The results document event rates following hospitalization for MI, provide quantification of the associated risk for death, and may be useful in designing clinical trials. The serious morbid events examined may serve as potential surrogate endpoints in long-term studies and identify patients that should be targeted for aggressive management.