Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING: Merck & Co, Inc.

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

Importance: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01984697.

Fabric-based exocervical and endocervical biopsy in comparison with punch biopsy and sharp curettage.

OBJECTIVES: Fabric-based endocervical and exocervical biopsy tools were compared with exocervical punch biopsy and sharp endocervical curettage. We compared the level of pain reported by the patient and the amount of bleeding rated by the physician relative to the type of biopsy used. MATERIALS AND METHODS: This was a 2-center institutional review board-approved study of patients undergoing colposcopy. One center randomized patients to undergo either conventional (punch biopsy, sharp endocervical curettage) or fabric-based biopsy of the endocervix and exocervix, and a second center enrolled nonrandomized controls. The patient and physician subjectively rated bleeding (exocervical) and pain (endocervical and exocervical) from the biopsy procedure(s), which were compared using the nonparametric Wilcoxon test. RESULTS: Exocervical and endocervical biopsies from 55 patients were compared. Fabric-based biopsies were abundant full-thickness curettage and showed statistically significant less pain and bleeding than the conventional biopsy methods (p < .0001). CONCLUSIONS: Fabric-based biopsies are significantly less traumatic than conventional biopsies. The benefits of a less-invasive biopsy could increase the willingness to perform multiple biopsies, increase disease detection, and improve patient satisfaction, which could impact future gynecologic health-seeking behavior and compliance with colposcopy recall.

Optical detection of high-grade cervical intraepithelial neoplasia in vivo: results of a 604-patient study.

OBJECTIVE: The purpose of this study was to assess the in vivo optical detection of high-grade cervical intraepithelial neoplasia (2/3+) on the whole cervix with a noncontact, spectroscopic device. STUDY DESIGN: Cervical scanning devices collected intrinsic fluorescence and broadband white light spectra and video images from 604 women during routine colposcopy examinations at 6 clinical centers. A statistically significant dataset was developed of intrinsic fluorescence and white light-induced cervical tissue spectra that was correlated to expert histopathologic determination. On the basis of a retrospective analysis of the acquired data, a classification algorithm was developed, validated, and optimized. RESULTS: Intrinsic fluorescence, backscattered white light, and video imaging each contribute complementary information to diagnostic algorithms for high-grade cervical neoplasia. More than 10000 measurements that were made on colposcopically identified tissue from >500 subjects were the basis for algorithm training and testing. Algorithm performance demonstrated a sensitivity of approximately 90%. This performance was confirmed by various training methods. With the use of a multivariate classification algorithm, optical detection is predicted to detect 33% more high-grade cervical intraepithelial neoplasia (2/3+) than colposcopy alone. CONCLUSION: Full cervix optical interrogation for the detection of high-grade cervical intraepithelial neoplasia is feasible and appears capable of detecting more high-grade cervical intraepithelial neoplasia than colposcopy alone. With the use of this classification algorithm, a multisite, randomized controlled trial is underway that compares the combination of optical detection and colposcopy versus colposcopy alone.

A stiff bristled, spiral-shaped ectocervical brush: a device for transepithelial tissue biopsy.

OBJECTIVE: To compare a new spiral-shaped tissue-sampling brush with a standard cervical punch biopsy. METHODS: Before large loop excision of the transformation zone, women with cervical intraepithelial neoplasia underwent a transepithelial brush biopsy of a portion of a colposcopically identified lesion, followed by a punch biopsy of the remaining portion. Brush biopsy samples were processed using liquid-based cytology and cell block techniques. Diagnoses were made using a consensus of three pathologists. Brush biopsy samples without basal cells were considered inadequate. The histological diagnosis was compared with the brush biopsy and punch biopsy samples. Patient-reported pain and physician-reported bleeding for punch and brush biopsies were compared. RESULTS: Fifty-two women were enrolled in the study; 47 successfully completed the study protocol. Eight brush biopsy specimens were inadequate. Thirty-nine women showed abnormal pathology (human papillomavirus/cervical intraepithelial neoplasia I or worse) on large loop excision of the transformation zone, and 32 women had high-grade (or worse) lesions. The punch biopsy correlated with high-grade disease in 53.1% of these women. The brush biopsy result correlated with high-grade disease in 79.3% of these women using a cell block technique and 76.7% using liquid cytology. There was significantly less pain (P <.001) and significantly less bleeding (P <.001) with the brush biopsy. CONCLUSION: When an adequate sample is collected, spiral brush biopsy is as good as a standard punch biopsy for detecting cervical pathology, with substantially less pain and bleeding. User training and guidelines for sampling are needed to assure that an adequate sample is collected.

Efficient triage of the "screen-positive" at-risk patient.

At this time little, if any, of the vast knowledge base being generated by current research is available for practical application within screening programs, although the path is opening for the development of future methodologies that might someday lead to the successful eradication of cervical cancer. Current efforts to develop a vaccine against HPV are rapidly progressing and are promising. In the meantime, a better understanding and utilization of the technologies at hand will result in a successful, organized approach to the detection of early cervical cancer and its precursors [56]. The adoption of any new screening technologies must result in a documented reduction in the incidence of cervical cancer. Until then, colposcopy and HPV DNA testing when indicated appears to remain as the undisputed gold standard in the evaluation of the patient at risk.