Determinants of acquisition and clearance of human papillomavirus infection in previously unexposed young women

Background Global variation in human papillomavirus (HPV) prevalence and persistence may be explained by differences in risk factors, such as sexual activity, oral contraceptive use, and behavioral factors. We evaluated determinants of acquisition and clearance of HPV infection among young women previously unexposed to HPV. Methods Five hundred thirty-four women aged 15 to 25 years who were cytology and HPV DNA negative, and seronegative for anti-HPV-16/18 antibodies, were recruited (July 2000–September 2001) from study centers in Brazil, the United States, and Canada (NCT00689741/NCT00120848). They were followed up for 76 months. Cervical samples were HPV genotyped via polymerase chain reaction. We used multivariable (forward stepwise, P = 0.15) Cox proportional hazards regression to estimate rate ratios (RR) and 95% confidence intervals (CI), separately according to length of follow-up time. Results On short-term follow-up (0–27 months), 257 (48%; 8535.80 person-months; incidence rate = 30.11; 95% CI, 26.64–34.02) incident HPV infections were detected. Marital status, lifetime number of sex partners, history of any sexually transmitted disease, and occasional use of oral contraceptives were strongly associated with acquisition of any HPV. Having 2 or more lifetime sex partners (RR, 2.03; 95% CI, 1.37–3.02) and a history of any sexually transmitted disease (RR, 1.98; 95% CI, 1.19–3.29) were the most important determinants of high-risk HPV (hrHPV) incidence. During the entire follow-up (0–76 months), an increased hrHPV clearance was found among women in North America (RR, 1.38; 95% CI, 1.08–1.78) and black women (RR, 1.64; 95% CI, 1.04–2.60). Greater number of lifetime partners was associated with reduced clearance rates for any HPV (RR, 0.65; 95% CI, 0.43–0.98). Conclusions We identified variation in risk of HPV acquisition and clearance among women unexposed to HPV at baseline

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Long-term Cross-reactivity Against Nonvaccine Human Papillomavirus Types 31 and 45 After 2- or 3-Dose Schedules of the AS04-Adjuvanted Human HPV-16/18 Vaccine

This analysis focused on long-term cross-reactive immunogenicity against nonvaccine human papillomavirus (HPV) types 31 and 45 following 2 doses of AS04-adjuvanted HPV-16/18 vaccine in girls aged 9-14 years or following 3 doses in women aged 15-25 years, for up to 3 years (HPV-070 study) and up to 5 years (HPV-048 study) after the first vaccination. Both schedules elicited antibodies against HPV-31 and HPV-45 up to 5 years after first dose. The antibody concentration was similar in young girls as compared to women. Specific CD4+ T-cell and B-cell responses to HPV-31 and HPV-45 at month 36 were similar across groups. Clinical trials registration: NCT01381575 and NCT00541970

Determinants of acquisition and clearance of human papillomavirus infection in previously unexposed young women

Background Global variation in human papillomavirus (HPV) prevalence and persistence may be explained by differences in risk factors, such as sexual activity, oral contraceptive use, and behavioral factors. We evaluated determinants of acquisition and clearance of HPV infection among young women previously unexposed to HPV. Methods Five hundred thirty-four women aged 15 to 25 years who were cytology and HPV DNA negative, and seronegative for anti-HPV-16/18 antibodies, were recruited (July 2000–September 2001) from study centers in Brazil, the United States, and Canada (NCT00689741/NCT00120848). They were followed up for 76 months. Cervical samples were HPV genotyped via polymerase chain reaction. We used multivariable (forward stepwise, P = 0.15) Cox proportional hazards regression to estimate rate ratios (RR) and 95% confidence intervals (CI), separately according to length of follow-up time. Results On short-term follow-up (0–27 months), 257 (48%; 8535.80 person-months; incidence rate = 30.11; 95% CI, 26.64–34.02) incident HPV infections were detected. Marital status, lifetime number of sex partners, history of any sexually transmitted disease, and occasional use of oral contraceptives were strongly associated with acquisition of any HPV. Having 2 or more lifetime sex partners (RR, 2.03; 95% CI, 1.37–3.02) and a history of any sexually transmitted disease (RR, 1.98; 95% CI, 1.19–3.29) were the most important determinants of high-risk HPV (hrHPV) incidence. During the entire follow-up (0–76 months), an increased hrHPV clearance was found among women in North America (RR, 1.38; 95% CI, 1.08–1.78) and black women (RR, 1.64; 95% CI, 1.04–2.60). Greater number of lifetime partners was associated with reduced clearance rates for any HPV (RR, 0.65; 95% CI, 0.43–0.98). Conclusions We identified variation in risk of HPV acquisition and clearance among women unexposed to HPV at baseline

Post Hoc Analysis Of The Patricia Randomized Trial Of The Efficacy Of Human Papillomavirus Type 16 (hpv-16)/hpv-18 As04-adjuvanted Vaccine Against Incident And Persistent Infection With Nonvaccine Oncogenic Hpv Types Using An Alternative Multiplex Type-specific Pcr Assay For Hpv Dna

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.).222235244Walboomers, J.M., Jacobs, M.V., Manos, M.M., Bosch, F.X., Kummer, J.A., Shah, K.V., Snijders, P.J., Muñoz, N., Human papillomavirus is a necessary cause of invasive cervical cancer worldwide (1999) J Pathol, 189, pp. 12-19. , http://dx.doi.org/10.1002/(SICI)1096-9896(199909)189:1_12::AID-PATH431_3.0.CO;2-FDe Sanjosé, S., Quint, W.G., Alemany, L., Geraets, D.T., Klaustermeier, J.E., Lloveras, B., Tous, S., Puras, A., Human papillomavirus genotype attribution in invasive cervical cancer: A retrospective cross-sectional worldwide study (2010) Lancet Oncol, 11, pp. 1048-1056. , http://dx.doi.org/10.1016/S1470-2045(10)70230-8Li, N., Franceschi, S., Howell-Jones, R., Snijders, P.J., Clifford, G.M., Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication (2011) Int J Cancer, 128, pp. 927-935. , http://dx.doi.org/10.1002/ijc.25396Guan, P., Howell-Jones, R., Li, N., Bruni, L., De Sanjose, S., Franceschi, S., Clifford, G.M., Human papillomavirus types in 115,789 hpvpositive women: A meta-analysis from cervical infection to cancer (2012) Int J Cancer, 131, pp. 2349-2359. , http://dx.doi.org/10.1002/ijc.27485Tjalma, W.A., Fiander, A., Reich, O., Powell, N., Nowakowski, A.M., Kirschner, B., Koiss, R., Holl, K., Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in europe (2013) Int J Cancer, 132, pp. 854-867. , http://dx.doi.org/10.1002/ijc.27713Descamps, D., Hardt, K., Spiessens, B., Izurieta, P., Verstraeten, T., Breuer, T., Dubin, G., Safety of human papillomavirus (hpv)-16/18 as04- adjuvanted vaccine for cervical cancer prevention: A pooled analysis of 11 clinical trials (2009) Hum Vaccin, 5, pp. 332-340. , http://dx.doi.org/10.4161/hv.5.5.7211Harper, D.M., Franco, E.L., Wheeler, C., Ferris, D.G., Jenkins, D., Schuind, A., Zahaf, T., Dubin, G., Efficacy of a bivalent l1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: A randomised controlled trial (2004) Lancet, 364, pp. 1757-1765. , http://dx.doi.org/10.1016/S0140-6736(04)17398-4Harper, D.M., Franco, E.L., Wheeler, C.M., Moscicki, A.B., Romanowski, B., Roteli-Martins, C.M., Jenkins, D., Dubin, G., Sustained efficacy up to 4.5 years of a bivalent l1 virus-like particle vaccine against human papillomavirus types 16 and 18: Follow-up from a randomised control trial (2006) Lancet, 367, pp. 1247-1255. , http://dx.doi.org/10.1016/S0140-6736(06)68439-0Sustained efficacy and immunogenicity of the human papillomavirus (hpv)-16/18 as04-adjuvanted vaccine: Analysis of a randomised placebo-controlled trial up to 6.4 years (2009) Lancet, 374, pp. 1975-1985. , http://dx.doi.org/10.1016/S0140-6736(09)61567-1De Carvalho, N., Teixeira, J., Roteli-Martins, C.M., Naud, P., De Borba, P., Zahaf, T., Sanchez, N., Schuind, A., Sustained efficacy and immunogenicity of the hpv-16/18 as04-adjuvanted vaccine up to 7.3 years in young adult women (2010) Vaccine, 28, pp. 6247-6255. , http://dx.doi.org/10.1016/j.vaccine.2010.07.007Paavonen, J., Jenkins, D., Bosch, F.X., Naud, P., Salmeron, J., Wheeler, C.M., Chow, S.N., Dubin, G., Efficacy of a prophylactic adjuvanted bivalent l1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: An interim analysis of a phase iii double-blind, randomised controlled trial (2007) Lancet, 369, pp. 2161-2170. , http://dx.doi.org/10.1016/S0140-6736(07)60946-5Paavonen, J., Naud, P., Salmeron, J., Wheeler, C.M., Chow, S.N., Apter, D., Kitchener, H., Greenacre, M., Efficacy of human papillomavirus (hpv)-16/18 as04- adjuvanted vaccine against cervical infection and precancer caused by oncogenic hpv types (patricia): Final analysis of a double-blind, randomised study in young women (2009) Lancet, 374, pp. 301-314. , http://dx.doi.org/10.1016/S0140-6736(09)61248-4Lehtinen, M., Paavonen, J., Wheeler, C.M., Jaisamrarn, U., Garland, S.M., Castellsague, X., Skinner, S.R., Dubin, G., Overall efficacy of hpv-16/18 as04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind patricia trial (2012) Lancet Oncol, 13, pp. 89-99. , http://dx.doi.org/10.1016/S1470-2045(11)70286-8Wheeler, C.M., Castellsague, X., Garland, S.M., Szarewski, A., Paavonen, J., Naud, P., Salmeron, J., Lehtinen, M., Cross-protective efficacy of hpv-16/18 as04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic hpv types: 4-year endof- study analysis of the randomised, double-blind patricia trial (2012) Lancet Oncol, 13, pp. 100-110. , http://dx.doi.org/10.1016/S1470-2045(11)70287-XTota, J.E., Ramanakumar, A.V., Jiang, M., Dillner, J., Walter, S.D., Kaufman, J.S., Coutlee, F., Franco, E.L., Epidemiologic approaches to evaluating the potential for human papillomavirus type replacement postvaccination (2013) Am J Epidemiol, 178, pp. 625-634. , http://dx.doi.org/10.1093/aje/kwt018Van Doorn, L.J., Molijn, A., Kleter, B., Quint, W., Colau, B., Highly effective detection of human papillomavirus 16 and 18 dna by a testing algorithm combining broad-spectrum and type-specific pcr (2006) J Clin Microbiol, 44, pp. 3292-3298. , http://dx.doi.org/10.1128/JCM.00539-06Quint, W.G., Scholte, G., Van Doorn, L.J., Kleter, B., Smits, P.H., Lindeman, J., Comparative analysis of human papillomavirus infections in cervical scrapes and biopsy specimens by general spf(10) pcr and hpv genotyping (2001) J Pathol, 194, pp. 51-58. , http://dx.doi.org/10.1002/path.855Wheeler, C.M., Kjaer, S.K., Sigurdsson, K., Iversen, O.E., Hernandez-Avila, M., Perez, G., Brown, D.R., Barr, E., The impact of quadrivalent human papillomavirus (hpvTypes 6, 11, 16, and 18) l1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine hpv types in sexually active women aged 16-26 years (2009) J Infect Dis, 199, pp. 936-944. , http://dx.doi.org/10.1086/597309Van Alewijk, D., Kleter, B., Vent, M., Delroisse, J.M., De Koning, M., Van Doorn, L.J., Quint, W., Colau, B., A human papilloma virus testing algorithm comprising a combination of the l1 broad-spectrum spf10 pcr assay and a novel e6 high-risk multiplex type-specific genotyping pcr assay (2013) J Clin Microbiol, 51, pp. 1171-1178. , http://dx.doi.org/10.1128/JCM.02831-12Kleter, B., Van Doorn, L.J., Ter Schegget, J., Schrauwen, L., Van Krimpen, K., Burger, M., Ter Harmsel, B., Quint, W., Novel short-fragment pcr assay for highly sensitive broad-spectrum detection of anogenital human papillomaviruses (1998) Am J Pathol, 153, pp. 1731-1739. , http://dx.doi.org/10.1016/S0002-9440(10)65688-XKleter, B., Van Doorn, L.J., Schrauwen, L., Molijn, A., Sastrowijoto, S., Ter Schegget, J., Lindeman, J., Quint, W., Development and clinical evaluation of a highly sensitive pcr-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus (1999) J Clin Microbiol, 37, pp. 2508-2517Tjalma, W.A., Depuydt, C.E., Cervical cancer screening: Which hpv test should be used-l1 or e6/e7? (2013) Eur J Obstet Gynecol Reprod Biol, 170, pp. 45-46. , http://dx.doi.org/10.1016/j.ejogrb.2013.06.027Palmroth, J., Merikukka, M., Paavonen, J., Apter, D., Eriksson, T., Natunen, K., Dubin, G., Lehtinen, M., Occurrence of vaccine and non-vaccine human papillomavirus types in adolescent finnish females 4 years postvaccination (2012) Int J Cancer, 131, pp. 2832-2838. , http://dx.doi.org/10.1002/ijc.27586Pagliusi, S.R., Aguado, M.T., Efficacy and other milestones for human papillomavirus vaccine introduction (2004) Vaccine, 23, pp. 569-578. , http://dx.doi.org/10.1016/j.vaccine.2004.07.046(2011) Fifty-seventh Report World Health Organization Technical Report Series 962, , http://apps.who.int/medicinedocs/documents/s19540en/s19540en.pdf, World Health Organization Expert Committee on Biological Standardization. World Health Organization, Geneva, Switzerlan