Ensayo Patricia Vac. Vhp Bival2011

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1/11www.thelancet.com/oncology Published online November 9, 2011 DOI:10.1016/S1470-2045(11)70286-8 1

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DOI:10.1016/S1470-

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2045(11)70287-X

*For the HPV PATRICIA Study

Group see webappendix p 11

University of Tampere, School of

Public Health, Tampere, Finland

(Prof M Lehtinen PhD);

Department of Obstetrics and

Gynaecology, University of

Helsinki, Helsinki, Finland

(Prof J Paavonen MD);

Departments of Pathology and

Obstetrics and Gynecology,

University of New Mexico

Health Sciences Center,

Albuquerque, NM, USA

(Prof C M Wheeler PhD);


Gynaecology, Faculty of

Medicine, Chulalongkorn

University, Bangkok, Thailand

(Prof U Jaisamrarn MD);

Department of Microbiology

and Infectious Diseases, Royal

Womens Hospital, Department

of Microbiology, Royal Childrens

Hospital, Murdoch Childrens

Research Institute, and


Gynaecology, University of

Melbourne, Parkville,

VIC, Australia

(Prof S M Garland FRCPA); Unit of

Infections and Cancer, Cancer

Epidemiology Research

Program, Institut Catal

dOncologia, LHospitalet de

Llobregat, IDIBELL, CIBER-ESP,

Catalonia, Spain

(X Castellsagu PhD,

F X Bosch PhD); Vaccines Trials

Group, Telethon Institute for

Child Health Research, Perth, WA

and Sydney University

Overall effi cacy 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

Matti Lehtinen, Jorma Paavonen, Cosette M Wheeler, Unnop Jaisamrarn, Suzanne M Garland, Xavier Castellsagu, S Rachel Skinner, Dan Apter,

Paulo Naud, Jorge Salmern, Song-Nan Chow, Henry Kitchener, Jl io C Teixeira, James Hedrick, Genara Limson, Anne Szarewski,

Barbara Romanowski, Fred Y Aoki, Tino F Schwarz, Willy A J Poppe, Newton S De Carvalho, Maria Julieta V Germar, Klaus Peters, Adrian Mindel,

Philippe De Sutter, F Xavier Bosch, Marie-Pierre David, Dominique Descamps, Frank Struyf, Gary Dubin, for the HPV PATRICIA Study Group*

SummaryBackground Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure

trials of human papillomavirus (HPV) vaccines. Vaccine effi cacy against CIN3+, the immediate precursor to invasivecervical cancer, is more diffi cult to measure because of its lower incidence, but provides the most stringent evidenceof potential cancer prevention. We report vaccine effi cacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults).

Methods Healthy women aged 1525 years with no more than six lifetime sexual partners were included in PATRICIA,irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomlyassigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-basedcentral randomisation system using a minimisation algorithm to account for age ranges and study sites. The patientsand study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reportedpreviously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinicalinterest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at leastone vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319;

control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline,approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered withClinicalTrials.gov, number NCT00122681.

Findings Vaccine effi cacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 855100) in the TVC-naiveand 457% (229622) in the TVC. Vaccine effi cacy against all CIN3+ (irrespective of HPV type in the lesion andincluding lesions with no HPV DNA detected) was 932% (789987) in the TVC-naive and 456% (288587) inthe TVC. In the TVC-naive, vaccine effi cacy against all CIN3+ was higher than 90% in all age groups. In the TVC,vaccine effi cacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 1517 year age group andprogressively decreased in the 1820 year and 2125 year age groups. Vaccine effi cacy against all AIS was 100%(310100) and 769% (160958) in the TVC-naive and TVC, respectively. Serious adverse events occurred in835 (90%) and 829 (89%) women in the vaccine and control groups, respectively; only ten events (01%) and fiveevents (01%), respectively, were considered to be related to vaccination.

Interpretation PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective ofHPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverageof early adolescents might have the potential to substantially reduce the incidence of cervical cancer.

Funding GlaxoSmithKline Biologicals.

IntroductionNearly a decade ago, a proof-of-principle report1 onthe high effi cacy of a prophylactic monovalent humanpapillomavirus (HPV) vaccine against HPV-16 washeralded as the possible beginning of the end forcervical cancer,2 the major disease associated withoncogenic HPV infection. Comprehensive reportsdescribing excellent vaccine effi cacy against precursorsof cervical cancer were subsequently published for the

HPV-16/18 AS04-adjuvanted vaccine (Cervarix,GlaxoSmithKline Biologicals)35 and the HPV-6/-11/-16/-18 vaccine (Gardasil, Merck),68 which are now licensed inmany countries.

Licensure studies focused primarily on prevention ofcervical intraepithelial neoplasia grade 2 or greater (CIN2+;defined as CIN2, CIN3, adenocarcinoma in situ [AIS], orinvasive cervical cancer [ICC]) as the primary endpoint,since regulatory agencies considered CIN2+ to be an


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Articles

2 www.thelancet.com/oncology Published online November 9, 2011 DOI:10.1016/S1470-2045(11)70286-8

Discipline of Paediatrics and

Child Health, Childrens Hospital

Westmead, Sydney, NSW,

Australia (S R Skinner PhD);

Family Federation of Finland,

Sexual Health Clinic, Helsinki,

Finland (D Apter MD);

Department of Gynecology &

Obstetrics, Federal University of

Rio Grande do Sul, UFRGS/HCPA,

Hospital de Clnicas de Porto

Alegre, Brazil (Prof P Naud PhD);

Unidad de Investigacin

Epidemiolgica y en Servicios de

Salud, Instituto Mexicano del

Seguro Social, Morelos, Mexico

(Prof J Salmern PhD);


Gynecology, College of Medicine

and the Hospital, National

Taiwan University, Taipei,

Taiwan (Prof S-N Chow MD);

Manchester Academic Health

Science Centre, Central

Manchester University Hospitals

NHS Foundation Trust, St Marys

Hospital, Manchester, UK

(Prof H Kitchener MD);

Departamento de

Tocoginecologia da Unicamp,

University of Campinas,

Campinas, Sao Paulo, Brazil

(J C Teixeira MD); Kentucky

Pediatric and Adult Research,

Bardstown, KY, USA

(J Hedrick MD); College of

Medicine, University of the

Philippines, Philippine General

Hospital, Makati Medical Centre,

Makati City, Philippines

(Prof G Limson MD); Centre for

Cancer Prevention, Wolfson

Institute of Preventive

Medicine, Queen Mary

University of London, London,

UK (A Szarewski PhD); Division of

Infectious Diseases, Department

of Medicine, Faculty of Medicine

and Dentistry, University of

Alberta, Edmonton, AB, Canada

(Prof B Romanowski MD);

Department of Medical

Microbiology, University of

Manitoba, Winnipeg, MB,

Canada (Prof F Y Aoki MD);

Central Laboratory and

Vaccination Centre, Stiftung

Juliusspital, Academic Teaching

Hospital of the University of

Wuerzburg, Wuerzburg,

Germany (Prof T F Schwarz MD);

Department of Gynaecology,

University Hospital KU Leuven

Gasthuisberg, Leuven, Belgium

(Prof W A J Poppe PhD);

Department of Gynecology and

Obstetrics, Federal University of

Paran, Infectious Diseases in

Gynecology and Obstetrics

Sector, Curitiba, Parana, Brazil

(Prof N S De Carvalho PhD);

acceptable surrogate endpoint for ICC. However, it was

recognised at the time that CIN2+ had limitations,including potential lack of reproducibility9 and the factthat a large proportion of CIN2 cases spontaneouslyregress.10 CIN3 is the immediate precursor of ICC,11 andCIN3+ is generally considered to be a more predictiveendpoint than CIN2+. Moreover, the prevalence ofdifferent HPV types in CIN3 lesions is more similar tothat in ICC than in CIN2 lesions.12 However, the lowerincidence of CIN3+ means that its use as an endpointrequires a large sample size with a long follow-up periodto ensure suffi cient statistical power to make firmconclusions regarding effi cacy.

The PApilloma TRIal against Cancer In young Adults(PATRICIA) is the largest trial of HPV-16/18 vaccine

effi cacy so far. Results from event-driven analysesshowed high vaccine effi cacy against CIN2+ lesionsassociated with HPV-16 and HPV-18 infections, andprotection against non-vaccine HPV types (HPV-31,HPV-33, and HPV-45).3,4However, information on CIN3+endpoints was limited because of the follow-up timeaccrued. Here, we report end-of-study results at month48 with roughly 68 000 person-years of follow-up, mostnotably vaccine effi cacy against all CIN3+ and AISlesions irrespective of HPV DNA.

MethodsDetailed methods of the double-blind, randomised,controlled PATRICIA trial, including full inclusion andexclusion criteria, trial locations, and dates, has beenreported previously.3,4 Briefly, healthy women aged1525 years, from 14 countries in Asia Pacific, Europe,Latin America, and North America, and with no morethan six lifetime sexual partners were included in the trial

irrespective of their baseline HPV DNA status, HPV-16/18

serostatus, or cytology. The exclusion criterion of no morethan six lifetime sexual partners was not applied inFinland, in accordance with local regulatory and ethicalrequirements,13 so women with more than six lifetimesexual partners enrolled in Finland were included in thetrial. Written informed consent was obtained from alladult participants. For minors, written informed assentwas obtained from the participant and written informedconsent from their parents. The trial was approved byindependent ethics committees or institutional reviewboards at each location.

ProceduresWomen received either the HPV-16/18 AS04-adjuvanted

vaccine (Cervarix, GlaxoSmithKline Biologicals) or acontrol hepatitis A vaccine (GlaxoSmithKline Biologicals)in a 1:1 ratio at 0, 1, and 6 months (figure 1).3,4 The studyprotocol prescribed that both groups were to beunmasked after the month 48 visit and offered thecrossover vaccine. Long-term follow-up of womenenrolled in Finland is ongoing; these women areparticipating in registry-based follow-up as part of aseparate study (NCT01393470).13 Cervical liquid-basedcytology samples were obtained every 6 months. HPVDNA typing was done on these samples every 6 monthsand cytological examination using the Bethesda systemwas done every 12 months. A prespecified clinicalmanagement algorithm for abnormal cytology resultsand colposcopy referral was used (webappendix p 6, 7).Broad spectrum PCR SPF10-LiPA25 (version 1 based onlicensed Innogenetics SPF10 technology; LaboBiomedical Products, Rijswijk, Netherlands) and type-specific PCR for HPV-16 and HPV-18 DNA were used to

Figure 1: Study design

Person-years of follow-up shown are for the total vaccinated cohort. V=visit. M=month. CIN=cervical intraepithelial neoplasia. HPV=human papillomavirus. *In the

total vaccinated cohort for effi cacy. In the according-to-protocol cohort for effi cacy. End-of-study dataset contains an additional year of follow-up for mostwomen, versus the final event-driven analysis dataset.

Randomisation 1:1V1M0

V2M1

V3M6

V4M7

V5M12

V6M18

V7M24

V10M48

HPV-16/18 vaccine

V8M30

V9M36

Control vaccine

End-of-study analysis

All women remaining in trial completed M48 visit

Person-years of follow-up: 68 032

Final event-driven analysis4

Triggered by detection of 36 CIN2+ cases

associated with HPV-16/18, including

15 associated with HPV-18

Person-years of follow-up: 63 507

Interim event-driven analysis3

Triggered by detection of 23 CIN2+ cases

associated with HPV-16/18* 1 year additional

follow-up


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www.thelancet.com/oncology Published online November 9, 2011 DOI:10.1016/S1470-2045(11)70286-8 3

University of the Philippines

College of Medicine, Philippine

General Hospital, Manila,

Philippines(M J V Germar MD);

Facharzt fr Frauenheilkunde

und Geburtshilfe, Berner

Heerweg 157, Hamburg

Germany (K Peters MD); Sexually

Transmitted Infections Research

Centre, University of Sydney,

Westmead Hospital, NSW,

Australia (Prof A Mindel MD);

Department of Gynaecology,

University Hospital Brussels,

Brussels, Belgium

(P De Sutter MD);

GlaxoSmithKline Biologicals,

Wavre, Belgium (M-P David MSc,

D Descamps MD, F Struyf MD);

and GlaxoSmithKline

Biologicals, King of Prussia, PA,

USA(G Dubin MD)

test cervical samples and biopsy material for HPV DNAfrom 14 HPV oncogenic types (16, 18, 31, 33, 35, 39, 45,51, 52, 56, 58, 59, 66, and 68).3,14

Vaccine effi cacy was assessed against 6-month and12-month persistent infection, CIN1+, CIN2+, CIN3+,and AIS associated with the following: HPV-16; HPV-18;HPV-16 or HPV-18, or HPV-16 and HPV-18 (HPV-16/18).Effi cacy against CIN and AIS was also assessedirrespective of HPV DNA (this includes all lesionssampled and analysed, irrespective of the HPV typeidentified in the lesion, plus lesions in which no HPVDNA was detected). Vaccine effi cacy against abnormalcytology (atypical squamous cells of undeterminedsignificance [ASC-US], low-grade squamous intra-epithelial lesions [LSIL], high-grade intraepithelial lesions[HSIL], ASC cannot exclude HSIL [ASC-H]), colposcopyreferrals, and cervical excision procedures wasalso assessed. Additional categories of cytological

abnormalities were defined as ASC-US positive for high-risk (oncogenic) HPV types (ASC-US HR+) and ASC-USHR+ or greater, which included ASC-US HR+, LSIL,

ASC-H, HSIL, and atypical glandular cells. Persistentinfection was defined as detection of the same HPV typein consecutive samples over a minimum of 5 months(6-month definition) and 10 months (12-monthdefinition). CIN1+ was defined as CIN1, CIN2, CIN3,AIS, or ICC; CIN2+ excluded CIN1, and CIN3+ excludedCIN1 and CIN2. All CIN cases were reviewed by a panelof three pathologists who were masked to vaccineallocation, using a majority rule, and an endpointcommittee made final case assignments.3

Antibodies against HPV-16 and HPV-18 were assessedby ELISA. Seropositivity was defined as an antibody titregreater than or equal to the assay cut off: 8 EU/mL forHPV-16 and 7 EU/mL for HPV-18. Safety assessmentsincluded serious adverse events, new-onset chronic

Figure 2: Participant disposition

HPV=human papillomavirus. TVC=total vaccinated cohort. TVC-naive=total vaccinated cohort of HPV-naive women. ATP-E=according-to-protocol cohort for effi cacy. *One woman in the vaccine

group was classified as having withdrawn for an other reason, but had in fact died. This should have been classified as a serious adverse event and is therefore now shown as such.

18 729 enrolled

18 644 TVC9319 HPV-16/18 vaccine 9325 control

16 114 ATP-E8067 HPV-16/18 vaccine 8047 control1252 excluded 1278 excluded

68 administration of forbidden vaccine 9228 randomisation code broken 24

816 vaccine not administered according to protocol 7844 history of vaccination against, or clinical history 3

of, hepatitis A

1 ethics committee request 012 protocol violations 919 administration of forbidden medication 17

64 forbidden underlying medical condition 74190 non-compliance with vaccine schedule 225

47 high-grade or missing cytology 483 two cervices 2

1802 ATP cohort for immunogenicity988 HPV-16/18 vaccine 814 control

8331 excluded 8511 excluded

5941 study site not participating in immunogenicity 4995analysis

68 administration of forbidden vaccine 9228 randomisation code broken 24

816 vaccine not administered according to protocol 7844 history of vaccination against, or clinical history 3

of, hepatitis A1 ethics committee request 0

12 protocol violations 919 administration of forbidden medication 17

64 forbidden underlying medical condition 74176 non-compliance with vaccine schedule 184

1034 intercurrent infection with HPV-16 or HPV-18 2168152 non-compliance with blood sampling schedule 151

16 essential serological data missing 10

HPV-16/18 vaccine Control1521 withdrew 1514 withdrew

251 consent withdrawal 257192 moved from area 215905 lost to follow-up 865

12* SAE 155 non-serious AE 5

10 protocol violation 7146* other 150

HPV-16/18 vaccine Control7798 completed study 7811

85 excluded21 concerns about data integrity64 study vaccine not administered

11 644 TVC-naive5824 HPV-16/18 vaccine 5820 control3495 excluded 3505 excluded

Abnormal cytology, DNA positive for at least one of14 oncogenic HPV types, or seropositive for HPV-16or HPV-18


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diseases (including new-onset autoimmune diseases),

medically significant conditions, and pregnancy out-comes.

Statistical analysisHere, we primarily report data from the total vaccinatedcohort (TVC) and total vaccinated cohort of HPV-naivewomen (TVC-naive). The TVC included all women whoreceived at least one vaccine dose and were evaluable foreffi cacy, irrespective of baseline HPV DNA, cytologicalstatus, and serostatus (webappendix p 8). The TVC-naive included women who received at least one vaccinedose, were evaluable for effi cacy, and at baseline wereHPV DNA negative for all 14 HPV types tested for,seronegative for HPV-16 and HPV-18, and had negative

cytology (webappendix p 8). Data from the according-to-protocol cohort for effi cacy (ATP-E) are shown in thewebappendix p 5.

In the previously published analyses of PATRICIA,3,4which were event-driven, the ATP-E was the primarycohort. Licensure of the vaccine was based on theseanalyses, therefore the ATP-E was the key cohort to fullydescribe the vaccines profile. However, the TVC and theTVC-naive are more relevant from a public healthperspective, so we focused on these cohorts for the end-of-study analysis.

The end-of-study analysis was intended to expand andconfirm the effi cacy results of the previous event-drivenanalysis.4 All end-of-study analyses were descriptive.Vaccine effi cacy and 95% CIs were calculated using aconditional exact method (actual 95% CIs werecalculated for the end-of-study analysis, whereas 979%and 961% CIs were used for the interim and finalevent-driven analyses, respectively3,4). Results wereconsidered to confirm the statistically significant vaccineeffi cacy observed in the final event-driven analysis ifend-of-study estimates of vaccine effi cacy and their95% CIs were higher than zero. All analyses wereprespecified apart from the following, which wereexploratory post-hoc analyses and must therefore beinterpreted with caution: age-stratification of CIN1+,CIN3+, and AIS by 1517 year and 1825 year age groups;

all analyses stratified by 1820 year and 2125 year agegroups; colposcopy referrals; number of cases prevented;and reduction in cytological abnormalities (number ofevents for all abnormalities and number of cases andvaccine effi cacy for ASC-US HR+ or greater, ASC-USHR+, and ASC-H).

Event rates were calculated as the number of casesdivided by the total follow-up in years and were expressedper 100 woman years. Follow-up for the TVC and TVC-naive started the day after the first vaccine dose andended for each outcome at the time the outcome occurred,or at the last sample (up to month 48). Statistical analyseswere done with SAS version 9.1 and Proc StatXact-7 onWindows XP. The trial is registered with ClinicalTrials.gov, number NCT00122681.

Vaccine Control Effi cacy (95% CI)

N Cases Rate N Cases Rate

TVC-naive

CIN1+

All 5466 5 002 5452 141 069 965% (916 to 989)

1517 years 1997 2 003 2022 79 101 974% (905 to 997)

1825 years 3459 3 002 3425 62 049 953% (855 to 991)

1820 years 1096 0 000 1144 35 083 100% (886 to 100)

2125 years 2363 3 003 2281 27 032 894% (655 to 979)

CIN2+

All 5466 1 000 5452 97 047 990% (942 to 100)

1517 years 1997 1 001 2022 53 068 981% (889 to 100)

1825 years 3459 0 000 3425 44 035 100% (914 to 100)

1820 years 1096 0 000 1144 27 064 100% (850 to 100)

2125 years 2363 0 000 2281 17 020 100% (768 to 100)

CIN3+

All 5466 0 000 5452 27 013 100% (855 to 100)

1517 years 1997 0 000 2022 14 018 100% (694 to 100)

1825 years 3459 0 000 3425 13 010 100% (678 to 100)

1820 years 1096 0 000 1144 8 019 100% (395 to 100)

2125 years 2363 0 000 2281 5 006 100% (46 to 100)

AIS

All 5466 0 000 5452 6 003 100% (155 to 100)

TVC

CIN1+

All 8694 121 037 8708 324 101 629% (541 to 701)

1517 years 2882 31 028 2892 155 147 801% (706 to 807)

1825 years 5800 90 042 5806 169 080 470% (312 to 594)

1820 years 1871 32 047 1908 83 121 613% (411 to 751)

2125 years 3929 58 040 3898 86 060 332% (57 to 530)

CIN2+

All 8694 90 028 8708 228 071 607% (496 to 695)

1517 years 2882 21 019 2892 100 090 791% (662 to 876)

1825 years 5800 69 032 5806 128 060 463% (275 to 605)

1820 years 1871 23 034 1908 66 096 650% (430 to 792)

2125 years 3929 46 032 3898 62 043 264% (96 to 509)

CIN3+

All 8694 51 016 8708 94 029 457% (229 to 622)

1517 years 2882 7 006 2892 36 032 805% (556 to 927)

1825 years 5800 44 021 5806 58 027 242% (141 to 500)

1820 years 1871 13 019 1908 30 043 563% (136 to 791)

2125 years 3929 31 021 3898 28 020 101% (905 to 361)AIS

All 8694 3 001 8708 10 003 700% (166 to 947)

Women were infected with at least one of types HPV-16 and HPV-18, and may have been infected with both types.

Women included in the analysis of the TVC-naive cohort were HPV DNA negative for all 14 oncogenic HPV types tested for,

seronegative for HPV-16 and HPV-18, and had negative cytology at month 0. Women were included in the analysis of the

TVC regardless of their HPV DNA or serostatus at month 0. Oncogenic HPV types tested for were HPV-16, HPV-18, HPV-31,

HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. CIN1+ was defined

histologically as CIN1, CIN2, CIN3, AIS, or invasive carcinoma; CIN2+ did not include CIN1, and CIN3+ did not include CIN1

or CIN2. Numbers of patients for the age categories do not add up to the total in the All category, because 26 patients age

14 years or 2633 years were enrolled in the study and included in the All category. CIN=cervical intraepithelial neoplasia.

AIS=adenocarcinoma in situ. HPV=human papillomavirus. TVC-naive=total vaccinated HPV-naive cohort. TVC=total

vaccinated cohort. N=number of evaluable women in each group. Cases=number of evaluable women reporting at least

one event. Rate=number of cases divided by sum of follow-up period (per 100 woman years); follow-up period started on

the day after the first vaccine dose.

Table 1: Vaccine effi cacy against CIN1+, CIN2+, CIN3+, and AI S associated with HPV-16/18 stratified byage (TVC-naive and TVC)


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Correspondence to:

Prof Matti Lehtinen, University

of Tampere, School of Public

Health, Tampere, Finland

[email protected]

See Online for webappendix

Vaccine Control Effi cacy (95% CI) Number of cases prevented

(95% CI)*

N Cases Rate N Cases Rate

TVC-naive

CIN1+

All 5466 174 085 5452 346 171 503% (402 to 588) 860 (640 to 1080)

1517 years 1997 87 114 2022 190 247 538% (402 to 646) 1330 (910 to 1760)

1825 years 3459 87 068 3425 156 124 455% (287 to 586) 560 (330 to 810)

1820 years 1096 38 094 1144 68 164 426% (134 to 625) 700 (210 to 1200)

2125 years 2363 49 056 2281 88 105 469% (238 to 633) 490 (230 to 770)

CIN2+

All 5466 61 030 5452 172 084 649% (527 to 742) 540 (400 to 700)

1517 years 1997 34 044 2022 101 130 659% (493 to 776) 860 (570 to 1160)

1825 years 3459 27 021 3425 71 056 628% (413 to 770) 350 (200 to 510)

1820 years 1096 10 025 1144 38 091 730% (448 to 880) 660 (350 to 1020)2125 years 2363 17 019 2281 33 039 507% (89 to 742) 200 (40 to 370)

CIN3+

All 5466 3 001 5452 44 021 932% (789 to 987) 200 (140 to 270)

1517 years 1997 2 003 2022 24 031 915% (659 to 990) 280 (170 to 430)

1825 years 3459 1 001 3425 20 016 951% (693 to 999) 150 (90 to 240)

1820 years 1096 1 002 1144 11 026 906% (355 to 998) 240 (90 to 440)

2125 years 2363 0 000 2281 9 011 100% (514 to 100) 110 (60 to 200)

AIS

All 5466 0 000 5452 7 003 100% (310 to 100) 30 (20 to 70)

TVC

CIN1+

All 8694 579 183 8708 798 254 277% (195 to 352) 710 (480 to 930)

1517 years 2882 243 227 2892 368 343 339% (221 to 440) 1210 (720 to 1610)1825 years 5800 336 161 5806 430 208 223% (102 to 328) 470 (200 to 720)

1820 years 1871 139 209 1908 184 275 240% (47 to 395) 660 (140 to 1190)

2125 years 3929 197 139 3898 246 176 208% (41 to 347) 370 (80 to 660)

CIN2+

All 8694 287 090 8708 428 134 331% (222 to 426) 440 (280 to 610)

1517 years 2882 112 102 2892 200 183 440% (291 to 560) 810 (490 to 1120)

1825 years 5800 175 083 5806 228 109 235% (65 to 376) 260 (70 to 440)

1820 years 1871 62 091 1908 105 154 406% (180 to 573) 630 (260 to 1010)

2125 years 3929 113 079 3898 123 087 89% (186 to 300) 80 (130 to 290)

CIN3+

All 8694 86 027 8708 158 049 456% (288 to 587) 220 (130 to 320)

1517 years 2882 21 019 2892 61 055 655% (425 to 800) 360 (200 to 530)

1825 years 5800 65 031 5806 97 046 331% (75 to 519) 150 (30 to 270)

1820 years 1871 22 032 1908 44 064 495% (139 to 712) 320 (90 to 560)

2125 years 3929 43 030 3898 53 037 195% (227 to 474) 70 (60 to 210)

AIS

All 8694 3 001 8708 13 004 769% (160 to 958) 30 (10 to 60)

Women included in the analysis of the TVC-naive cohort were HPV DNA negative for all 14 oncogenic HPV types tested for, seronegative for HPV-16 and HPV-18, and had

negative cytology at month 0. Women were included in the analysis of the TVC regardless of their HPV DNA or serostatus at month 0. Oncogenic HPV types tested for were

HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. CIN1+ was defined histologically as CIN1,

CIN2, CIN3, AIS, or invasive carcinoma; CIN2+ did not include CIN1, and CIN3+ did not include CIN1 or CIN2. Numbers of patients for the age categories do not add up to the

total in the All category, because 26 patients age 14 years or 2633 years were enrolled in the study and included in the All category. CIN=cervical intraepithelial neoplasia.

AIS=adenocarcinoma in situ. HPV=human papillomavirus. TVC-naive=total vaccinated HPV-naive cohort. TVC=total vaccinated cohort. N=number of evaluable women in

each group. Cases=number of evaluable women reporting at least one event. Rate=number of cases divided by sum of follow-up period (per 100 woman years); follow-up

period started on the day after the first vaccine dose. *Number of cases prevented per 100 000 woman years of follow-up

Table 2: Vaccine effi cacy and number of cases prevented for CIN1+, CIN2+, CIN3+, and AIS, irrespective of HPV DNA in the lesion, stratified by age

(TVC-naive and TVC)


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Role of the funding sourceThe trial was funded by GlaxoSmithKline Biologicals,who designed the study in collaboration with investigatorsand coordinated collection, analysis, and interpretation

of data. Investigators from the HPV PATRICIA Study

Group collected data for the trial and cared for theparticipants. All authors had full access to all the trialdata and had final responsibility for the decision tosubmit for publication.

ResultsThe first study participant was enrolled in May, 2004, andthe last study visit took place in November, 2009.Participant disposition is shown in figure 2. In the TVC,mean and median follow-up times were 437 months(SD 117) and 474 months (range 062; 36 and40 years), respectively. The number of person-years offollow-up was 42 942 in the TVC-naive, and 68 032 in theTVC. Demographic and baseline data are shown in the

webappendix p 2.The vaccine had effi cacy against 6-month and 12-month

persistent infection with HPV-16/18, with higher pointestimates in the TVC-naive than in the TVC (webappendixp 3, 4). In the TVC-naive, very high vaccine effi cacy wasnoted against CIN1+, CIN2+, CIN3+, and AIS associatedwith HPV-16/18; estimates were similar in all age strata(table 1). Estimates of vaccine effi cacy for women in theATP-E cohort who were DNA negative for thecorresponding HPV type at baseline and month 6 weresimilar to those in the TVC-naive (webappendix p 5). Inthe TVC, effi cacy against these endpoints was highestin the 1517 year age group and progressively decreasedin the 1820 year and 2125 year age strata (trend testp


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789987); none of the three cases in the vaccine groupwere associated with a vaccine type (figure 3). Thepercentage reduction in CIN2+ cases was lower (649%[527742]), with 61 cases of CIN2+ in the vaccine groupand 172 in the control group. Notably, however, only oneof the 61 cases in the vaccine group (16%) was associated

with HPV-16/18 (figure 3). In the TVC, the percentagereductions in CIN3+ and CIN2+ cases were lower than inthe TVC-naive (456% [288587] and 331%[222426], respectively; figure 4). In the control group,405% of CIN3+ cases were associated with a non-vaccinetype or no HPV DNA, 241% were associated with

Figure 5: Cumulative incidence of CIN2+ (A) and CIN3+ (B) irrespective of HPV DNA in the lesion, in the TVC-naive

Women included in the analysis of the TVC-naive cohort were HPV DNA negative for all 14 oncogenic HPV types tested for, seronegative for HPV-16 and HPV-18, and had negative cytology at month

0. Oncogenic HPV types tested for were HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. Follow-up period started on the

day after the first vaccine dose. CIN2+ was defined histologically as CIN2, CIN3, adenocarcinoma in situ, or invasive carcinoma; CIN3+ did not include CIN2. CIN=cervical intraepithelial neoplasia.

HPV=human papillomavirus. TVC-naive=total vaccinated cohort of HPV-naive women.

Cumulativeincidence

006

004

005

003

001

0

0 2418126 36

Number at risk

Vaccine 5466 5463 5400 5316 5216 5115 4908 4736 1993Control 5452 5445 5367 5264 5172 5068 4849 4650 1983

Number of cases

(cumulative)Vaccine 0 0 1 6 22 24 27 32 43Control 0 0 3 14 28 45 71 104 138

002

4230 48

001

00 2418126 36

Time (months)Time (months)

5466 5463 5401 5322 5237 5136 4931 4764 20205452 5445 5369 5272 5192 5103 4902 4721 2046

0 0 0 0 1 2 3 3 30 0 1 4 6 8 15 26 30

002

4230 48

B TVC-naive CIN3+A TVC-naive CIN2+

VaccineControl

Figure 6: Cumulative incidence of CIN2+ (A) and CIN3+ (B) irrespective of HPV DNA in the lesion, in the TVC

Women were included in the analysis of the TVC regardless of their HPV DNA or serostatus at month 0. Oncogenic HPV types tested for were HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39,

HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. Follow-up period started on the day after the first vaccine dose. CIN2+ was defined histologicall y as CIN2, CIN3,

adenocarcinoma in situ, or invasive carcinoma; CIN3+ did not include CIN2. CIN=cervical intraepithelial neoplasia. HPV=human papillomavirus. TVC=total vaccinated cohort.

Cumulativeincidence

006

004

005

003

001

0

0 2418126 36

Number at riskVaccine 8694 8655 8466 8260 8079 7906 7565 7283 3065Control 8708 8660 8465 8247 8061 7885 7523 7211 3079

Number of cases(cumulative)

Vaccine 0 19 80 125 159 182 203 222 242Control 0 26 81 122 173 212 262 316 368

002

4230 48

A TVC CIN2+VaccineControl

001

00 2418126 36

Time (months)Time (months)

8694 8663 8516 8329 8178 8013 7684 7412 31508708 8671 8513 8313 8160 8008 7676 7390 3203

0 9 27 51 55 66 73 77 810 15 32 51 69 82 98 119 131

002

4230 48

B TVC CIN3+


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HPV-16/18 and were co-infected with a non-vaccine type,

and 354% were associated with HPV-16/18 only(figure 4).Finally, for CIN3+ and CIN2+ irrespective of HPV DNA

in the lesion, the cumulative incidence curves seemed tostart to separate for the vaccine and control groupsat around 12 months post-vaccination in the TVC-naiveand around 18 months post-vaccination in the TVC(figures 5 and 6). Vaccine effi cacy was also observedagainst cytological abnormalities in both the TVC-naiveand TVC (figures 7, 8). Reductions in colposcopy referrals(290% [95% CI 216358] and 148% [89203]) andcervical excision procedures (702% [578793] and332% [208437]) were observed in the TVC-naiveand TVC, respectively (figures 7, 8).

A similar proportion of women in the vaccine andcontrol groups experienced serious adverse events,new-onset chronic diseases, new-onset autoimmunediseases, and medically significant conditions. Pregnancyoutcomes were also similar in both groups (table 3).Anti-HPV-16 and anti-HPV-18 antibody concentrationswere sustained throughout 48 months of follow-up(webappendix p 9,10).

DiscussionThe most important finding of the PATRICIA end-of-study analysis reported here was the high vaccine effi cacyfor HPV-16/18 vaccine against CIN3+ and AISirrespective of HPV DNA in the lesion in women whowere HPV naive at baseline. This represents the estimateof effi cacy against the most stringent ICC precursorlesions in a cohort that approximates adolescents beforesexual debut. The overall effect of the vaccine againstCIN3+ is derived from protection against lesionsassociated with vaccine types (HPV-16/18) and protectionagainst lesions associated with related non-vaccineoncogenic types.

The attributable proportion of HPV-16/18 increases withincreasing lesion severity. Additionally, the prevalence ofnon-vaccine oncogenic HPV types belonging to the A7 andA9 HPV species (for which HPV-18 and HPV-16,respectively, are the prototype viruses) is increased in

more severe lesions, whereas the prevalence of severalother HPV types declines.12 In fact, our observation ofincreasing vaccine effi cacy in increasingly severe lesionsis partly a result of the cross-protective vaccine effi cacyconsistently observed against the non-vaccine typesHPV-31 and HPV-33 (both A9 species), and also apparentagainst HPV-45 (A7 species) and HPV-51 (A5 species).Details of the evaluation of this cross-protection areprovided in a companion article.15 The significantly highervaccine effi cacy against CIN3+ irrespective of HPV DNAcompared with the corresponding CIN2+ endpoint isparticularly important, because CIN3 is a morereproducible and stringent diagnostic endpoint than CIN2and frequently progresses to ICC.911 The very high vaccineeffi cacy against AIS irrespective of HPV DNA is also

Figure 7: Reduction in cytological abnormalities, colposcopy referrals, and cervical excision procedures, in the

TVC-naive

Bars show percent reduction and 95% CIs. Women included in the analysis of the TVC-naive cohort were DNA

negative for all 14 oncogenic HPV types tested for, seronegative for HPV-16 and HPV-16, and had negative cytology

at month 0. Oncogenic HPV types tested for were HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45,

HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. Follow-up period started on the day after the

first vaccine dose. ASC-US, LSIL, ASC-H, HSIL, colposcopy referrals, and cervical excision procedures are irrespective

of HPV DNA. TVC-naive=total vaccinated cohort of HPV-naive women. HPV=human papill omavirus.

ASC-US=atypical squamous cells of undetermined significance. ASC-US HR+=ASC-US which were positive for

high-risk (oncogenic) HPV DNA by Hybrid Capture II test. ASC-US HR+ or greater=ASC-US HR+, LSIL, ASC-H, HSIL,

and atypical glandular cells. LSIL=low-grade squamous intraepithelial lesions. ASC-H=atypical squamous cells,

cannot exclude HSIL. HSIL=high-grade intraepithelial lesions.

0

10

20

30

40

50

60

70

80

90

100

Reduction(%)

Vaccine: numberof cases (events) 679 (791) 400 (465) 650 (926) 16 (16) 17 (17) 43 (43)672 (672)907 (1428)

Control: number

of cases (events)831 (1005) 554 (663) 847 (1248) 34 (34) 41 (42) 143 (143)933 (933)1215 (1999)

Vaccine efficacy 197% 290% 246% 533% 588% 702%290%273%

95% CI 110275 191377 164320 130759 259781 578793216358207333

ASC-US ASC-USHR+

LSIL ASC-H HSIL Cervicalexcision

Colposcopyreferral

ASC-USHR+ orgreater

Figure 8: Reduction in cytological abnormalities, colposcopy referrals, and cervical excision procedures, in the TVC

Bars show percent reduc tion and 95% CIs. Women were included in the analysis of the TVC regardless of their HPV

DNA or serostatus at month 0. Oncogenic HPV types tested for were HPV-16, HPV-18, HPV-31, HPV-33, HPV-35,

HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-66, and HPV-68. Follow-up period started on

the day after the first vaccine dose. ASC-US, LSIL, ASC-H, HSIL, colposcopy referrals and cervical excision procedures

are irrespective of HPV DNA. TVC=total vaccinated cohort. HPV=human papillomavirus. ASC-US=atypical

squamous cells of undetermined significance. ASC-US HR+=ASC-US which were positive for high-risk (oncogenic)

HPV DNA by Hybrid Capture II test. ASC-US HR+ or greater=ASC-US HR+, LSIL, ASC-H, HSIL, and atypical glandular

cells. LSIL=low-grade squamous intraepithelial lesions. ASC-H=atypical squamous cells, cannot exclude HSIL.HSIL=high-grade intraepithelial lesions.

20

0

20

40

60

80

100

Reduction(%)

Vaccine: number

of cases (events)1475 (1996) 991 (1312) 1406 (2306) 61 (66) 71 (77) 230 (230)1634 (1634)2029 (3935)

Control: number

of cases (events)1622 (2150) 1155 (1499) 1650 (2693) 79 (82) 102 (107) 344 (344)1908 (1908)2368 (4557)

Vaccine efficacy 95% 148% 155% 228% 304% 332%148%155%

95% CI 28157 72218 93214 92 to 456 49494 20843789203103204

ASC-US ASC-USHR+ LSIL ASC-H HSIL CervicalexcisionColposcopyreferralASC-USHR+ orgreater


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noteworthy. Roughly 50% of adenocarcinoma is caused by

HPV-16, 32% by HPV-18, and 12% by HPV-45.

16

Incidenceand mortality from adenocarcinoma, which is morediffi cult to detect than squamous cell carcinoma,17 arerising in many countries,18 and adenocarcinoma mightcomprise up to 25% of ICC.16

Vaccine effi cacy in the overall study population (ie, theTVC) was substantially less than that observed in theTVC-naive. Similar findings have been reported inthe FUTURE trials of HPV-6/-11/-16/-18 vaccine.8 This isnot surprising, since the overall populations enrolled inthese studies include women with pre-existing infectionsor lesions that are not affected by prophylactic vaccines. 4,8,19 The observation of progressively decreasing vaccineeffi cacy in the 1517, 1820, and 2125 year age groups in

the TVC is most likely due to the higher exposure to HPVat baseline among older women in PATRICIA, as hasbeen reported elsewhere;20 in PATRICIA, around 80% ofwomen in the TVC aged 1517 years were HPV-16/18DNA-negative and seronegative compared with around70% of those aged 1825 years. This difference in effi cacyby age group was absent in the TVC-naive, in whichvaccine effi cacy against CIN3+ irrespective of HPV DNAexceeded 90% for all age groups.

Estimates of the numbers of CIN1+, CIN2+, and CIN3+lesions prevented in the youngest age group (1517 years)were considerably higher than in the older age group(1825 years and when further stratified as 1820 and2125 years) in both cohorts. This observation probablyreflects the higher rate of new infections in the youngerage group compared with the older age group in bothcohorts. Overall, the number of lesions prevented wassimilar in both cohorts, as has been reported for theHPV-6/11/16/18 vaccine.8 The TVC-naive is a selectedsubset of the TVC, identified on the basis of being HPV-16and HPV-18 seronegative and having no prevalentinfection at baseline. This selection might introduce biasfor comparisons of case prevention between the twocohorts, because of potential differences with regard toepidemiological factors that affect the rate of infectionand lesion development during follow-up. Indeed, ourdata show that the lesion attack rate is higher in the TVC

than in the TVC-naive. This might explain why thenumber of lesions prevented is similar in both cohorts,despite higher vaccine effi cacy in the TVC-naive.

Overall, our results support the notion that maximumpopulation benefit from immunisation of women willmost likely be achieved if girls in early adolescence arevaccinated before sexual debut, since the risk of HPVinfection starts from sexual debut and infection is highin adolescents.21,22 Additionally, the HPV-16/18 vaccineproduces the highest immune response, sustained overthe long-term, in adolescent girls compared with youngadult women,23 further supporting immunisation ofyoung adolescents. Our data also suggest that catch-upvaccination programmes that include sexually activewomen aged 1520 years will provide a benefit against

high-grade cervical lesions, albeit reduced benefitcompared with vaccination of early adolescents. Althoughthe age-stratified results we report here must beconsidered with caution, they are consistent withanalyses suggesting reduced effectiveness and cost-effectiveness of vaccination programmes in women aged18 or 21 years and older.24,25 Indeed, recent data fromAustralia show that the introduction of the HPVvaccination programme was followed by a decrease in

incidence of high-grade cervical lesions in womenyounger than 18 years but not in older age groups.26

Construction of a risk model to assess whether or notthere is a subgroup of women aged 2125 years whocould benefit from catch-up vaccination might bepossible, but is beyond the scope of this report.

The distribution of women from different countriesacross the different cohorts might weaken thegeneralisability of our study. For example, Finlandenrolled only women aged 16 or 17 years, who made upa large proportion of the TVC-naive. The exclusion ofwomen with more than six lifetime sexual partners alsoweakens the generalisability of the findings, especiallyin the 2125 year age group in the TVC, where some ofthe excluded women most likely had multiple HPV

Vaccine Control

Safety outcomes

Number of women assessed 9319 9325

Serious adverse event 835 (90%) 829 (89%)

Vaccine-related serious adverse event 10 (01%) 5 (01%)

Medically significant condition* 3298 (354%) 3378 (362%)

New-onset chronic disease 285 (31%) 307 (33%)

New-onset autoimmune disease 99 (11%) 95 (10%)

Deaths 10 (01%) 13 (01%)

Pregnancy and pregnancy outcomes

Number of pregnancies 2257 2257

Ongoing pregnancies 12 (05%) 11 (05%)

Normal infant 1642 (728%) 1671 (740%)

Abnormal infant 26 (12%) 22 (10%)

Congenital anomaly 18 (08%) 13 (06%)

Medically significant condition|| 8 (04%) 9 (04%)

Spontaneous abortion 205 (91%) 195 (86%)

Elective termination 212 (94%) 228 (101%)

Data are number (%) of women reporting event. TVC=total vaccinated cohort. *Medically significant conditions were

defined as adverse events prompting emergency room visits, physician visits that are not routine or related to

common diseases, or serious adverse events that are not related to common diseases. A predefined list of potential

new-onset chronic diseases (NOCDs) was reviewed by the Independent Data Monitoring Committee (IDMC). Based on

this list, the clinical database was searched for all potential NOCDs and reviewed in a masked manner by a

GlaxoSmithKline (GSK) physician before data analysis. An event was considered to be a potential NOCD if it had not

been recorded in the participants previous medical history or if symptoms were characteristic of an NOCD. A separate

list, restricted to potential autoimmune events, was also reviewed by the IDMC and was used by the GSK safety

physician to identify new-onset autoimmune diseases. No deaths were considered possibly related to vaccination in

either the vaccine group or control group. Some less frequent pregnancy outcomes are not listed. Congenital

anomalies were defined as structural-morphological, chromosomal, and genetic anomalies. ||Medically significant

conditions in the infant were defined as all other reports of abnormal outcomes considered to be medically significant(eg, congenital infectious conditions, neonatal death).

Table 3: Safety and pregnancy outcomes throughout the study (TVC)


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infections. Unfortunately, we do not have country-specific data on the relative proportions of the excludedwomen.

The main strengths of our 4-year end-of-study analysiswere the size and diversity of the study population andthe study duration, which resulted in roughly68 000 person-years of follow-up and a considerablyhigher number of lesion cases than were available atthe final event-driven analysis reported previously. 4 Atthe time of the final event-driven analysis, only around3000 women had completed the month 48 visit, whereasat the end-of-study analysis, 15 600 women had

completed this visit. Thus, the present end-of-studydataset contains an extra year of follow-up for mostwomen. Furthermore, the colposcopy algorithm led to amuch higher referral rate in the later part of the study,most notably in the HPV-naive population, whose firstpossible colposcopy would have occurred after themonth 12 or month 18 visit. Thus, even though thestudy was powered to assess vaccine effi cacy againstCIN2+ associated with HPV-16/18, the large number ofcases in the end-of-study analysis enabled us to verifyvaccine effi cacy against CIN3+ irrespective of HPVDNA, and expand our observations to AIS. Safety,immunogenicity, and effi cacy against persistentHPV-16/18 infections were in line with our previousobservations.4

The high effi cacy of the vaccine against CIN3+

irrespective of HPV type in the lesion in HPV-naivewomen suggests that the target population for vaccin-ation might benefit from substantial protection againstcervical cancer. If the broad protection offered by HPVvaccination is durable in ongoing long term follow-up13and high population coverage can be achieved, modifi-cations of cervical cancer screening programmes mightbe possible (panel). Screening programmes have beenvery effective in reducing cervical cancer,27 but aredependent on attendance rates.28 For developed anddeveloping countries choosing whether to direct resourcestowards comprehensive screening, opportunistic formsof screening, or HPV vaccination, the present data provideimportant information for health economic analyses.

In conclusion, provided that organised vaccinationprogrammes achieve high coverage in early adolescentsbefore sexual debut, HPV vaccination has the potential tosubstantially reduce the incidence of cervical cancer,perhaps allowing modification of screening programmes.Appropriate effectiveness and implementation studiesassessing the combination of vaccination and newscreening strategies are warranted.

Contributors

ML, JP, CMW, UJ, SMG, XC, SRS, DA, M-PD,DD, FS, and GD formedthe core writing team for the manuscript. All authors reviewed andcommented on a draft of the manuscript and gave final approval tosubmit for publication. All authors contributed to the study design,acquisition of data or statistical analyses, and interpretation of data.See webappendix p 11 for the HPV PATRICIA Study Group.

Conflicts of interest

DD, GD, FS, and M-PD are employees of GlaxoSmithKline Biologicals.DD, GD, and FS own stock in GlaxoSmithKline Biologicals, and GDholds a relevant patent. All investigators at study clinical sites werefunded through their institutions to do the study protocol. CMW, DA, JP,PN, HK, PDS, FYA, FXB, JH, SRS, SMG, ML, TFS, AS, XC, JCT, and BRhave received funding through their institutions to do HPV vaccinestudies for GlaxoSmithKline Biologicals or Merck Sharp & Dohme(Sanofi Pasteur MSD). JP received a research grant through the HelsinkiUniversity Hospital Research Institute to conduct clinical trials on HPVvaccination. SRS has also received funding through her institution fromCSL to do research on school-based adolescent HPV vaccination.Through the University of New Mexico, CMW has received equipmentand reagents for HPV genotyping from Roche Molecular Systems andfunding for HPV vaccine studies from GlaxoSmithKline (in addition tothe present study) and Merck & Co. FXB is an editor of the international

newsletter (HPV TODAY) and guest editor of the journal Vaccine toprepare international reviews on topics related to HPV. WAJP, NSDC,FXB, XC, SMG, PN, BR, TFS, and AS have received consulting fees.SMG, SRS, FYA, PN, and TFS have received honoraria; TFS, BR, andFXB have been paid for expert testimony; BR, FYA, SRS, JCT, NSDC,PDS, and WAJP have received payment for board membership; JCT,FYA, NSDC, XC, PDS, PN, FXB, BR, and TFS have received payment forlectures, including service on speakers bureau; AS, FYA, NSDC, PDS,FXB, and BR have received payment for development of educationalpresentations; and NSDC, JS, WAJP, JCT, SRS, PN, XC, FXB, UJ, FYA,JH, SMG, AM, AS, and CMW have received travel reimbursements fromGlaxoSmithKline Biologicals or Merck Sharp & Dohme (Sanofi PasteurMSD), or both. DA has received support for travel from Vestliitto.S-NC, KP, MJVG, and GL declare that they have no conflicts of interest.

Acknowledgments

This study (NCT00122681/580299/008) was funded and coordinated byGlaxoSmithKline Biologicals. We thank study participants and theirfamilies. We thank Mary Greenacre for writing and editorial assistance,

Panel: Research in context

Systematic review

The present study is part of a development programme for prophylactic HPV vaccine.

Studies were done to achieve licensure of the vaccine and to examine how the vaccine

might be best used in real-world settings, and were developed in conjunction with

leading experts in HPV vaccine research and with regulatory bodies. Literature related to

HPV vaccination studies was systematically followed before the start of the study, during

the trial, and during the development of the publication (1997 to June, 2011). The volume

of literature has now increased, and we used our knowledge and expertise to select trials

we thought were most relevant for the present report.

Interpretation

The primary target population for HPV vaccination is adolescent girls before sexual debut,

and the most stringent endpoints currently measurable in HPV vaccine trials are CIN3+

and AIS, irrespective of HPV DNA in the lesion. Here, the end-of-study analysis ofPATRICIA reports for the first time the effi cacy of the HPV-16/18 vaccine against these

endpoints in a population that approximates adolescents before sexual debut. Very high

vaccine effi cacy was shown in this population, supporting the notion that vaccination of

girls in early adolescence will probably achieve maximum population benefit. We also

noted substantial vaccine effi cacy in a population approximating a general population of

sexually active women, suggesting that catch-up vaccination will also provide some

benefit. The study provides data to substantiate the benefits of HPV vaccination

programmes, and health-care professionals should be encouraged to aim for a high

vaccine uptake. Moving forward, if protection from HPV vaccines is shown to be durable,

and high vaccination coverage can be achieved, public health bodies might want to

consider whether cervical cancer screening programmes can be modified when conducted

alongside vaccination strategies.


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h l / l bli h d li b 6/ ( ) 86 8

and Jenny Andersson (Cromsource) for editorial assistance andmanuscript coordination on behalf of GlaxoSmithKline Biologicals,

Wavre, Belgium.

References1 Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of

a human papillomavirus type 16 vaccine. N Engl J Med2002;347: 164551.

2 Crum CP. The beginning of the end for cervical cancer?N Engl J Med2002; 347: 170305.

3 Paavonen J, Jenkins D, Bosch FX, et al, for the HPV PATRICIAStudy Group. Effi cacy of a prophylactic adjuvanted bivalent L1virus-like-particle vaccine against infection with humanpapillomavirus types 16 and 18 in young women: an interimanalysis of a phase III double-blind, randomised controlled trial.Lancet2007; 369: 216170.

4 Paavonen J, NaudP, J Salmern J, et al, for the HPV PATRICIAStudy Group. Effi cacy of human papillomavirus (HPV)-16/18AS04-adjuvanted vaccine against cervical infection and precancercaused by oncogenic HPV types (PATRICIA): final analysis of a

double-blind, randomised study in young women. Lancet2009;374: 30114.

5 GlaxoSmithKline Vaccine HPV-007 Study Group. Sustainedeffi cacy and immunogenicity of the human papillomavirus(HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomisedplacebo-controlled trial up to 64 years. Lancet2009; 374: 197585.

6 Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalentvaccine against human papillomavirus to prevent anogenitaldiseases. N Engl J Med2007; 356: 192843.

7 FUTURE II Study Group. Quadrivalent vaccine against humanpapillomavirus to prevent high-grade cervical lesions. N Engl J Med2007; 356: 191627.

8 Muoz N, Kjaer SK, Sigurdsson K, et al. Impact of humanpapillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associatedgenital diseases in young women.J Natl Cancer Inst2010;102: 32539.

9 Carreon JD, Sherman ME, Guilln D, et al. CIN2 is a much

less reproducible and less valid diagnosis than CIN3: resultsfrom a histological review of population-based cervical samples.Int J Gynecol Pathol2007; 26: 44146.

10 Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence forfrequent regression of cervical intraepithelial neoplasia-grade 2.Obstet Gynecol2009; 113: 1825.

11 Hakama M, Luostarinen T, Hakulinen T. Survival of in situcarcinoma of cervix uteri: a 50-year follow-up in Finland.Int J Cancer2004; 112: 107274.

12 Schiffman M, Herrero R, DeSalle R, et al. The carcinogenicity ofhuman papillomavirus types reflects viral evolution. Virology2005;337: 7684.

13 Lehtinen M, Apter D, Dubin G, et al. Enrolment of22,000 adolescent women to cancer registry follow-upfor long-term human papillomavirus vaccine effi cacy:guarding against guessing. Int J STD AIDS 2006; 17: 51721.

14 van Doorn L-J, Molijn A, Kleter B, Quint W, Colau B. Highlyeffective detection of human papillomavirus 16 and 18 DNA bya testing algorithm combining broad-spectrum and type-specificPCR.J Clin Microbiol2006; 44: 329298.

15 Wheeler CM, Castellsagu X, Garland SM, et al, for the HPVPATRICIA Study Group. Cross-protective effi cacy of HPV-16/18

AS04-adjuvanted vaccine against cervical infection and precancercaused by non-vaccine oncogenic HPV types: 4-year end-of-studyanalysis of the randomised, double-blind PATRICIA trial.Lancet Oncol2011; published online Nov 9. DOI:10.1016/S1470-2045(11)70287-X.

16 de Sanjos S, Quint WGV, Alemany L, et al, on behalf of theRetrospective International Survey and HPV Time Trends StudyGroup. Human papillomavirus genotype attribution in invasivecervical cancer: a retrospective cross-sectional survey. Lancet Oncol2010; 11: 104856.

17 Gunnell AS, Ylitalo N, Sandin S, Sparn P, Adami HO, Ripatti S.A longitudinal Swedish study on screening for squamous cellcarcinoma and adenocarcinoma: evidence of effectiveness andovertreatment. Cancer Epidemiol Biomarkers Prev2007; 16: 264148.

18 Bray F, Carstensen B, Mller H, et al. Incidence trendsof adenocarcinoma of the cervix in 13 European countries.Cancer Epidemiol Biomarkers Prev2005; 14: 219199.

19 Hildesheim A, Herrero R, Wacholder S, et al. Effect of humanpapillomavirus 16/18 L1 viruslike particle vaccine among youngwomen with preexisting infection.JAMA 2007; 298: 74353.

20 Szarewski A, Poppe WAJ, Skinner SR, et al. Effi cacy of the humanpapillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in womenaged 15 to 25 years with and without serological evidence ofprevious exposure to HPV-16/18. Int J Cancer2011; published onlineAug 19. DOI:10.1002/ijc.26362.

21 Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirusinfection in female university students as determined by aPCR-based method.JAMA 1991; 265: 47277.

22 Brown DR, Shew ML, Qadadri B, et al. A longitudinal study ofgenital human papillomavirus infection in a cohort of closelyfollowed adolescent women.J Infect Dis 2005; 191: 18292.

23 Petj T, Pedersen C, Poder A, et al. Long-term persistence ofsystemic and mucosal immune response to HPV-16/18AS04-adjuvanted vaccine in preteen/adolescent girls and youngwomen. Int J Cancer2010; published online Dec 28. DOI:10.1002/

ijc.25887.24 French KM, Barnabas RV, Lehtinen M, et al. Strategies for the

introduction of human papillomavirus vaccination: modelling theoptimum age- and sex-specific pattern of vaccination in Finland.Br J Cancer2007; 96: 51418.

25 Kim JJ, Goldie SJ. Health and economic implications of HPVvaccination in the United States. N Engl J Med2008; 359: 82132.

26 Brotherton JML, Fridman M, May CL, Chappell G, Savile AM,Gertig DM. Early effect of the HPV vaccination programme oncervical abnormalities in Victoria, Australia: an ecological study.Lancet2011; 377: 208592.

27 Lr E, Day NE, Hakama M. Trends in mortality from cervicalcancer in the Nordic countries: association with organisedscreening programmes. Lancet1987; 1: 124749.

28 Harper DM, Nieminen P, Paavonen J, Lehtinen M. Cervical cancerincidence can increase despite HPV vaccination. Lancet Infect Dis2010; 10: 59495.

Ensayo Patricia Vac. Vhp Bival2011

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