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Published in Clin Microbiol Infect 2015

Supplementary material

Which high-risk HPV assays fulfil criteria for use in primary cervical cancer screening?

Marc Arbyn1, Peter J.F. Snijders2, Chris J.L.M. Meijer2, Johannes Berkhof3, Kate Cuschieri4, Bostjan J. Kocjan5, Mario Poljak5

1 Unit of Cancer Epidemiology & Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, Belgium2 Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands3 Department of Clinical Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands4 Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK5 Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Contact address: M. Arbyn, Unit of Cancer Epidemiology, Scientific Institute of Public Health, J. Wytsmanstreet 14, B1050, Brussels, Belgium. Tel: 0032 2 6425021; Fax: 0032 2 6425410; Email: [email protected]

Contents

1. PICOS components of the clinical question...........................................................................2

2. Retrieval of references related to HPV-based cervical cancer screening...............................2

3. List of references citing Meijer et al. Int J Cancer 20091, retrieved through

www.scopus.com...................................................................................................................3

4. List of evaluated assays..........................................................................................................9

5. Characteristics of retrieved validation studies.....................................................................10

6. VALGENT protocol.............................................................................................................13

7. Evaluation of the study quality of the included screening studies.......................................14

8. Meta-analysis of the relative cross-sectional sensitivity and specificity of hrHPV DNA or

RNA assays to detect underlying CIN3+ in women attending cervical cancer screening

using HC2 or GP5+/6+ PCR-EIA as comparator................................................................15

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mailto:[email protected]


1. PICOS components of the clinical question

P (population): women attending cervical cancer screening, preferentially those being in the 30-64

years age group.

I (intervention): application of hrHPV assay, other than Hybrid Capture-2 (HC2, Qiagen) or the

GP5+/6+ PCR-EIA to detect nucleic acids of high-risk HPVA.

C (comparator): application of Hybrid Capture-2 (HC2, Qiagen) or the GP5+/6+ PCR-EIA.

O (outcome):

sensitivity and specificity for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), if

possible also CIN3+);

intra- and inter-laboratory reproducibility of finding high-risk HPV nucleic acids (yes or no).

S (study):

validation studies following the protocol of Meijer et al (Int J Cancer 2009)

validation studies following other protocols

primary screening studies (cross-sectional test accuracy studies, baseline results of cohort

studies or randomized trials) reporting sensitivity and specificity of index and comparator

hrHPV assays.

2. Retrieval of references related to HPV-based cervical cancer screening

Box1. Search string used to retrieve relevant literature in http://www.ncbi.nlm.nih.gov/pubmed.

((Uterine Cervical Neoplasms [MeSH Terms] OR Uterine Cervical Dysplasia [MeSH Terms] OR

Cervical Intraepithelial Neoplasia [MeSH Terms] OR ((cervix [tw] OR cervical [tw] OR cervico*

[tw]) AND (cancer* [tw] OR carcinoma OR adenocarcinoma OR neoplas* [tw] OR dysplas* [tw] OR

dyskaryos* [tw] OR squamous [tw] OR CIN [tw] OR CINII* [tw] OR CIN2* [tw] OR CINIII* [tw]

OR CIN3* [tw] OR SIL [tw] OR HSIL [tw] OR H-SIL [tw] OR LSIL [tw] OR L-SIL [tw] OR

ASCUS [tw] OR AS-CUS [tw])))

AND

(papillomaviridae [MeSH:NoExp] OR alphapapillomavirus [MeSH Terms] OR “DNA, viral” [MeSH

Terms] OR Papillomavirus Infections [MeSH Terms] OR Tumor Virus Infections [MeSH Terms] OR

“Cervix Uteri/virology” [MeSH Terms] OR HPV [tw] OR “human papillomavirus” [tw] OR

papillomaviridae [tw] OR PCR OR “hybrid capture*” [tw] OR HC2 [tw] OR HCII [tw] OR “HC 2”

[tw] OR “HC II” [tw] OR ((viral [tw] OR virolog* [tw]) AND (DNA [tw])))

AND

(Screening [tw] OR screen* OR "Early Detection of Cancer"[Mesh])”

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3. List of references citing Meijer et al. Int J Cancer 20091, retrieved through www.scopus.com

Table 1. List of references, indicating those that evaluate HPV assays according to the Meijer guideline included in the current systematic review and those excluded with reason for exclusion (codes for reasons for exclusion are explained on page 6).

Nr Author Year Journal Vol IssueStart page

End Page

In-clude

dReason

exclusion1 Arbyn 2009 Int J Cancer 125 11 2489 2496 02 Braakhuis 2009 Eur J Cancer 45 17 2935 2939 03 Castle 2009 Inf Agents Cancer 4 1 7 04 Castle 2009 J Clin Microbiol 47 10 3344 3347 05 Coupé 2009 Vaccine 27 37 5111 5119 06 Franco 2009 Pub Health Gen 12 5-6 352 361 07 Geraets 2009 J Clin Virol 46 S 3 S21 S26 28 Geraets 2009 J Clin Virol 46 S 3 S16 S20 29 Huang 2009 J Clin Virol 45 S 1 S19 S23 0

10 Huang 2009 J Clin Virol 45 S 1 S13 S17 011 Jeantet 2009 J Clin Virol 45 S 1 S29 S37 212 Kaliterna 2009 J Med Microbiol 58 12 1662 1663 413 Lynge 2009 Eur J Cancer 45 15 2714 2721 014 Meijer 2009 J Clin Virol 46 S 3 S1 S4 015 Overmeer 2009 J Pathol 219 3 327 336 016 Poljak 2009 Acta Dermato Alp Pan Adr 18 3 94 103 417 Poljak 2009 J Clin Microbiol 47 8 2611 2615 018 Sanner 2009 Brit J Cancer 101 5 871 874 019 Sanner 2009 Lakartidningen 106 46 3075 3077 020 Shi 2009 Am J Epidemiol 170 6 708 716 021 Silverloo 2009 Acta Obstet Gynecol Scand 88 9 1006 1010 022 Accetta 2010 J Med Screening 17 4 181 189 023 Agorastos 2010 Ann the NY Acad Sc 1205 51 56 024 Berkhof 2010 Int J Cancer 127 9 2147 2158 025 Bogaards 2010 Am J Epidemiol 171 7 817 825 026 Castle 2010 Am J Epidemiol 171 2 155 163 027 Eklund 2010 J Clin Microbiol 48 11 4147 4155 028 Fagan 2010 J Clin Virol 48 4 251 254 029 Halfon 2010 Cancer Biomarkers 7 3 133 139 030 Halfon 2010 J Clin Virol 48 4 246 250 431 Halfon 2010 J Clin Virol 47 1 38 42 432 Hesselink 2010 J Clin Microbiol 48 3 797 801 yes33 Hillemanns 2010 Best Practice Onkologie 5 4 28 35 034 Jalali 2010 Am J Obstet Gynecol 202 6 581 581 035 Kinney 2010 Am J Clin Pathol 134 2 193 199 036 Lavoué 2010 J Gynecol Obstet Biol Repr 39 2 102 115 037 Poljak 2010 Exp Rev Anti-Inf Ther 8 10 1139 1162 0

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http://www.scopus.com/



End Page

In-clude

dReason

exclusion38 Prétet 2010 J Clin Virol 49 4 286 289 039 Ratnam 2010 J Clin Microbiol 48 8 2779 2785 540 Reuschenbach 2010 Gynecol Oncol 119 1 98 105 041 Rijkaart 2010 Brit J Cancer 103 7 939 946 042 Ronco 2010 Curr Cancer Ther Rev 6 2 104 109 043 Snijders 2010 APMIS 118 6-7 520 528 044 Sotelo-Regil 2010 Gaceta Mex de Oncol 9 5 187 192 045 Valdivia 2010 Rev Chil Infect 27 1 11 16 046 Vince 2010 Medicinski Glasnik 7 1 18 25 047 Zhao 2010 Arch Pathol Lab Med 134 1 103 108 048 Alameda 2011 Rev Espan Patol 44 4 191 194 149 Carozzi 2011 J Clin Microbiol 49 4 1446 1451 yes50 Castle 2011 Am J Clin Pathol 135 3 482 483 051 Castle 2011 J Clin Microbiol 49 8 3029 3032 452 Cuschieri 2011 Exp Rev Obstet Gynecol 6 6 643 653 053 De Bie 2011 J Mol Diagns 13 4 371 376 054 Dobec 2011 J Med Virol 83 8 1370 1376 055 Emmadi 2011 J Mol Diagns 13 6 583 604 056 Estrade 2011 J Clin Microbiol 49 10 3474 3481 557 Geraets 2011 J Clin Virol 50 4 276 280 558 Godínez 2011 Inf Agents Cancer 6 1 23 259 Gravitt 2011 Int J Cancer 129 3 517 527 060 Gyllensten 2011 Brit J Cancer 105 5 694 697 061 Heideman 2011 J Clin Microbiol 49 11 3983 3985 yes62 Jiménez-Ayala 2011 Monographs in Clin Cytol 20 101 106 063 Kang 2011 Med Physics 38 1 107 113 064 Kocken 2011 Gynecol Oncol 122 2 297 302 065 Leemans 2011 Nature Rev Cancer 11 1 9 22 066 Mateos 2011 Enf Infecc Microbiol Clin 29 6 411 414 467 Petry 2011 Best Pr Res: Clin Obstet Gyn 25 5 641 651 068 Pista 2011 J Med Virol 83 2 272 276 469 Poljak 2011 J Clin Microbiol 49 5 1721 1729 yes70 Ratnam 2011 J Clin Microbiol 49 2 557 564 1171 Rebolj 2011 BMJ 342 7808 d2757 072 Rebolj 2011 Exp Rev Anticancer Ther 11 7 1023 1031 073 Sahasrabuddhe 2011 Future Microbiol 6 9 1083 1098 074 Schmeink 2011 Rev in Med Virol 21 3 139 153 075 Shen-Gunther 2011 Gynecol Oncol 123 2 263 271 076 Söderlund-Strand 2011 Am J Obstet Gynecol 205 2 145 145 077 Stoler 2011 Am J Clin Pathol 135 3 468 475 078 Wentzensen 2011 Pathologe 32 6 461 466 079 Wikström 2011 Brit J Cancer 105 3 337 339 080 Wong 2011 J Clin Virol 51 2 136 138 081 Arbyn 2012 Future Virol 7 2 127 133 082 Arbyn 2012 Vaccine 30 S5 F88 F99 083 Barzon 2012 J Clin Virol 55 3 256 261 284 Beldi 2012 Acta Cytologica 56 2 160 165 0

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End Page

In-clude

dReason

exclusion85 Castanon 2012 US Obstet Gynecol 7 1 53 58 086 Chan 2012 Crit Rev in Clin Lab Sc 49 4 117 136 087 Cortés 2012 Progres Obstet Ginecol 55 6 251 258 088 Cruickshank 2012 BJOG 119 6 650 652 089 Deodhar 2012 Clinics in Lab Med 32 2 193 205 090 Depuydt 2012 J Clin Microbiol 50 12 4073 4077 yes91 Dijkstra 2012 J Clin Virol 54 2 147 151 092 Eklund 2012 J Clin Microbiol 50 7 2289 2298 093 Ferreccio 2012 Int J Cancer 132 4 916 923 094 Gök 2012 Int J Cancer 130 5 1128 1135 095 Gyllensten 2012 Gynecol Oncol 125 2 343 345 096 Hwang 2012 Ann Lab Med 32 3 201 205 297 Ikenberg 2012 Monographs in Virol 28 109 119 098 Jentschke 2012 Int J Gynecol Cancer 22 6 1050 1056 499 Kristiansen 2012 Tidsskrift Nor Laegef 132 12-13 1476 1478 0100 Lapierre 2012 J Clin Microbiol 50 4 1240 1244 0

101 Leinonen 2012 BMJ 345 7886 e7789 0

102 Lindell 2012 BJOG 119 2 245 248 0

103 Mateos Lindemann 2012 J Mol Diagns 14 1 65 70 2

104 Micalessi 2012 Clin Chem Lab Med 50 4 655 661 2

105 Monsonego 2012 Vaccine 30 35 5215 5221 0

106 Pinto 2012 Acta Cytologica 56 2 109 121 0

107 Poljak 2012 Vaccine 30 S5 F100 F106 0

108 Rijkaart 2012 The Lancet Oncol 13 1 78 88 0

109 Rodríguez-Iglesias 2012 Enf Infecc Microbiol Clin 30 5 223 224 0

110 Saslow 2012 Am J Clin Pathol 137 4 516 542 0

111 Saslow 2012 CA Cancer J for Clin 62 3 147 172 0

112 Saslow 2012 J Low Genital Tract Dis 16 3 175 204 0

113 Schmeink 2012 J Women's Health 21 12 1295 1301 0

114 Sibley 2012 Inf Genet Evolution 12 3 505 521 0

115 Tropé 2012 J Clin Microbiol 50 6 1927 1935 0

116 Van Baars 2012 J Clin Microbiol 50 12 3937 3943 0

117 Venturoli 2012 J Clin Virol 53 2 121 124 4

118 Von Knebel D 2012 Exp Rev Proteomics 9 2 149 163 0

119 Wiesner 2012 Med Anthropol 31 1 77 92 0

120 Wong 2012 J Clin Microbiol 50 5 1691 1697 2

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End Page

In-clude

dReason

exclusion121 Wright 2012 Best Pr Res: Clin Obstet Gyn 26 2 197 208 0

122 Zhao 2012 Chinese J Pathol 41 12 855 857 0

123 Adefuye 2013 Vaccine 31 0

124 Alaghehbandan 2013 Diagn Cytopathol 41 9 767 775 4

125 Andersson 2013 Oncol Letters 6 1 215 219 0

126 Anonymous 2013 Ginekologia Polska 84 5 395 399 0

127 Berkhof 2013 Vaccine 31 0

128 Carozzi 2013 Lancet Oncol 14 2 168 176 0

129 Castanon 2013 J Med Screening 20 2 99 103 0

130 Castle 2013 Obstet Gynecol Cl N Am 40 2 377 390 0

131 Choi 2013 Handbook on HPV 339 358 0

132 Choi 2013 J Virol Methods 187 1 79 84 2

133 Cubie 2013 Cytopathol 24 5 289 308 0

134 Cuzick 2013 Brit J Cancer 108 4 908 913 11

135 Elkins 2013 Am J Clin Pathol 139 5 605 610 0

136 Geraets 2013 J Clin Virol 57 2 125 129 0

137 Gillio-Tos 2013 J Clin Microbiol 51 9 2901 2907 0

138 Heideman 2013 J Clin Microbiol 51 11 3653 3657 yes

139 Herraez-Hernandez 2013 J Virol Methods 193 1 9 17 2

140 Hesselink 2013 J Clin Microbiol 51 7 2409 2410 yes

141 Jentschke 2013 Gynakologe 46 6 392 396 0

142 Laudadio 2013 Adv Anat Pathol 20 3 158 167 0

143 Léniz 2013 Salud Publ Mex 55 2 162 169 0

144 Lloveras 2013 PLoS ONE 8 3 yes

145 Mouková 2013 Klinicka Onkologie 26 0

146 Oliveira 2013 J Med Virol 85 7 1235 1241 0

147 Picconi 2013 Medicina (Argentina) 73 6 585 596 0

148 Poljak 2013 Acta Dermat Alp Pan Adr 22 2 43 47 0

149 Preisler 2013 PLoS ONE 8 3 0

150 Rao 2013 J Clin Microbiol 51 5 1478 1484 0

151 Rao 2013 J Clin Virol 58 1 161 167 4

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End Page

In-clude

dReason

exclusion152 Rebolj 2013 Curr Phar Design 19 8 1439 1449 0

153 Rebolj 2013 J Mol Diagns 15 5 670 677 0

154 Reuschenbach 2013 Curr Phar Design 19 8 1358 1370 0

155 Rossi 2013 Curr Phar Design 19 8 1490 1497 0

156 Schmitt 2013 Cancer Epidem Biom Prev 22 3 406 414 5

157 Snijders 2013 Int J Cancer 132 10 2223 2236 0

158 Tornesello 2013 BioMed Res Int 2013 519619 0

159 Van de Ven 2013 Statistics in Med 32 15 2515 2528 0

160 Arbyn 2014 The Lancet Oncol 15 2 172 183 0

161 Boers 2014 J Clin Microbiol 52 12 4391 4393 yes

162 Boers 2014 PLoS ONE 9 7 1

163 Bosgraaf 2014 Exp Rev Anticancer Ther 14 1 75 92 0

164 Bosgraaf 2014 Prev Med 64 108 113 0

165 Castle 2014 Cancer Forum 38 3 209 214 0

166 Chung 2014 J Virol Methods 205 57 60 11

167 Eklund 2014 J Clin Microbiol 52 2 449 459 0

168 Estrade 2014 J Clin Microbiol 52 2 607 612 2

169 Geraets 2014 J Clin Microbiol 52 11 3996 4002 yes†

170 Hesselink 2014 J Clin Microbiol 52 3 890 896 yes

171 Igidbashian 2014 J Low Genital Tract Dis 18 1 87 91 0

172 Isidean 2014 Exp Rev Mol Diagns 14 1 5 16 6

173 Iwasaki 2014 Brazilian J Inf Diss 18 5 469 472 0

174 Kang 2014 J Clin Microbiol 52 6 1954 1961 0

175 Keegan 2014 J Virol Methods 201 93 100 4

176 Kreimer 2014 J Clin Oncol 32 4 361 362 0

177 Kwon 2014 J Clin Virol 59 4 246 249 2

178 Lee 2014 Cancers 6 4 2072 2099 0

179 Leyh-Bannurah 2014 Inf Agents Cancer 9 1 33 0

180 Liao 2014 Int J Cancer 134 7 1715 1724 0

181 Mantzana 2014 Future Virol 9 4 385 395 0

182 Munkhdelger 2014 Diagn Microbiol Inf Dis 79 4 422 427 0

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End Page

In-clude

dReason

exclusion183 Prétet 2014 Indian J Med Res 139 487 489 0

184 Rai 2014 As Pacif J Cancer Prev 15 2 861 865 0

185 Rebolj 2014 Gynecol Oncol 135 3 474 480 4

186 Rodríguez-Carunchio 2014 BJOG 122 1 119 127 0

187 Rodríguez-Salés 2014 Gaceta Sanitaria 28 1 7 13 0

188 Seifert 2014 Bundesgesundheitsblatt 57 3 294 301 0

189 Sultana 2014 BMC Cancer 14 1 207 0

190 Tjalma 2014 Eur J Gynaecol Oncol 35 3 211 218 0

191 Ward 2014 J Virol Methods 207 128 132 3

192 Wentzensen 2014 J Clin Microbiol 52 8 2892 2897 0

193 Zappacosta 2014 Clin Interv Aging 9 683 688 0

194 Alameda 2015 Arch Pathol Lab Med 139 2 241 244 yes

195 Cruickshank 2015 BJOG 122 3 380 386 0

196 Low 2015 J Clin Microbiol 53 2 550 556 3

197 Ngou 2015 JAIDS 68 2 162 168 4

† Validated according to the VALGENT protocol2.

Code Reason for exclusion Number0 Based on title 1461 Secondary publication 22 No CIN2+ outcome 133 No cervical cytological specimen 24 No representative screening population 145 No comparison with HC2 or GP5+/6+ PCR-EIA 46 Review 111 Included in list of 1ary screening studies 3

Total 185

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Figure 1. Flow chart of study selection containing data on the validation of HPV assays for use in primary screening assessed according the criteria defined by Meijer et al (Int J Cancer, 2009)3.

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4. List of evaluated assays

Table 2. List of evaluated assays (full and abbreviated names) and manufacture.

Assay (full name) Assay (abbreviated name) Manufacturer

Standard comparator tests

Hybrid Capture 2 High-Risk HPV DNA Test HC2 Qiagen, Gaithersburg, MD, USA

GP5+/6+ PCR-EIA GP5+/6+ EIA Diassay B.V., Rijkswijk, the Netherlands

HPV assays validated according to the Meijer protocol

APTIMA HPV assay APTIMA Hologic, Bedford, MA, USA

Abbott RealTime High Risk HPV test Abbott RT hrHPV test Abbott, Wiesbaden, Germany

BD Onclarity HPV assay BD Onclarity BD Diagnostics, Sparks, MD, USA

Cervista HPV HR Test Cervista Hologic, Bedford, MA, USA

cobas 4800 HPV test cobas 4800 Roche Molecular System (Pleasanton, CF, USA

qPCR (E6/E7) qPCR (E6/E7) Home-brew

HPV-Risk assay HPV-Risk assay Self-Screen BV, Amsterdam, The Netherlands

PapilloCheck HPV-screening test PapilloCheck Greiner Bio-One, Frickenhausen, Germany

HPV assays assessed in cross-sectional studies in a primary screening setting or according to the VALGENT protocol

LMNX genotyping kit HPV GP GP5+/6+-LMNX Diassay B.V., Rijkswijk, the Netherlands

careHPV Test careHPV Test Qiagen, Gaithersburg, MD, USA

MALDI-TOF (matrix-assistedlaser desorption-ionization time-of-flight)

MALDI-TOF Medical Microbiology and Clinical Chemistry, Lund University, Malmö University Hospital, Sweden

Pretect HPV-Proofer Pretect HPV-Proofer NORCHIP, Klokkarstua, Norway

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5. Characteristics of retrieved validation studies

Table 3. Characteristics of the validation studies of HPV assays potentially usable in cervical cancer screening and evaluated according to the Meijer protocol1.

Evaluated Study Study Age Outcomeassay (country) population range Selection criteria verification Medium TimingPapillo-Check

Hesselink, 20104

(NL)

Screening trial, arm with conventional cytology & GP5+/6+ PCR-EIA5,6

40-60y (controls30-60y (cases)

Cases: representative series of 192 women with CIN3+.Controls: 1437 women without CIN2+, negative cytology and no cytological abnormalities within 8 years.

Colposcopy if HSIL+.Repeat cyto & HPV at 6M and 18M if hrHPV+ and or ASCUS/LSIL.At 6M: colposcopy if HSIL+ or ASCUS/LSIL & HPV+.At 18M if hrHPV+ or HSIL+;Coposcopists were aware of cytology and HPV status; histologists were aware of cytology only.

PBS GP5+/6+ PCR-EIA on fresh, new assay on stored samples.

Abbott RThrHPVtest

Carozzi,20117

(IT)

Population-based screening with cytology and HC2

25-64y A random sample of specimen from screened women. Cases: 84 specimen from women with CIN2+.Controls: 914 women without CIN2+.

Immediate colposcopy if ASC-US+ or HC2+. Histology not blinded to cyto or HPV status.

STM HC2 on fresh, new assay on stored samples

Poljak,20118

(SI)

Population-based screening with liquid cytology and HC2 & new HPV assay

30-64y Cases: 38 women with CIN2+.Controls: 3091 without evidence of CIN2+.

Immediate colposcopy if ASC-H+ or AGC, HPV16/18+, other hrHPV+ were recalled for colposcopy 6-12 months later.

Preserv-Cyt

HC2 and new assay on fresh samples

Hesselink, 20139

(NL)

Population-based screening with conventional cytology and GP5+/6+ PCR-EIA.

30-60y Cases, 30 CIN2, 34 CIN3, 4 cancer. Selection of cases not further specified.Controls: 859 consecutive samples form routine screening.

Abnormal cytology or HPV+ triggered diagnostic investigation.Controls: normal cytology and no cytological abnormality within 12 months.

Not specified

GP5+/6+ PCR-EIA on fresh, new assay on stored samples.

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Evaluated Study Study Age Outcomeassay (country) population range Selection criteria verification Medium Timingcobas4800

Heideman, 201110

(NL)

Screening trial with conventional cytology and HC211.

29-60y Cases: 23 CIN2, 33 CIN3, 1 adeno- and 3 squamous carcinoma. Controls: 800 representative scrapes (789 NILM, 11 abnormal cyto) without CIN2+ in follow-up (0-54 months).

Abnormal cytology or HPV+ triggered diagnostic investigation.

UCM HC2 on fresh, new assay on stored samples

Lloveras, 201312

(ES)

Women tested with cytology and HC2.

≥ 30y Cases: 22 CIN2, 38 CIN3 no specific selection criteria.Controls: 898 specimen with no known abnormal cytology in last 5y, selected from consecutive samples.

Not specified. Preserv-Cyt

HC2 & new assay on residual material after cyto processing.

qPCR(E6/E7)

Depuydt,201213

(BE)

Mixed population (mainly screening) tested with cytology RT PCR and HC2.

30-65y Cases: 93 smears from women with CIN2+ (42 CIN2, 45 CIN3, 1 adeno- and 5 squamous carcinoma).Controls: 1,207 representative smears from women without CIN2+ within 28 months.

All women were included in a colposcopy trial. Histology was triggered by baseline colposcopy (all), and repeat colposcopy for cytology and/or HPV+ women.

SurePath Cytology interpretation with knowledge of HPV status (RT PCR).

APTI-MA

Heideman, 201314

(NL)

Screening trial with conventional cytology and HC211.

29-60y Cases: 23 CIN2, 33 CIN3, 1 adeno- and 3 squamous carcinoma. Selection not further specified. Controls: 843 representative scrapes from women (range, 0-54 months) without CIN2+.

Abnormal cytology or HPV+ triggered diagnostic investigation.

UCM HC2 on fresh, new assay on stored samples

Cervista Boers,201415

(CN,NL)

Screening study in China16with liquid cytology and HPV testing with multiple assays on self- & clinician samples, reproducibility study in the NL.

30-59y Cases: 78 randomly selected ASC-US & 31 NILM cytology cases with CIN2+ (45 CIN2, 61 CIN3, 3 carcinoma).Controls: 7,218 samples without CIN2+. No further specification.

Colposcopy if HPV+(Cervista or MALDI-TOF on self- or clinician-sample or HC2 on clinician-sample) or ASCUS+ cytology.Women negative for all tests or being negative at colposcopy or ≤CIN1 histology.

Preserv-Cyt

All tests on fresh samples.

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Evaluated Study Study Age Outcomeassay (country) population range Selection criteria verification Medium Timing

Alameda, 201517

(PT)

Specimen from a large cytopathology laboratory.

17-86y Selected from 1125 consecutive samples:Cases: 64 CIN 2+ with simultaneous/previous cytology (<=3 months before).Controls: 811 specimen (715 NILM, 64 ASC-US, 31 LSIL, 1 ASCH, with <=CIN biopsy.


HC2 & new assay on residual material after cyto processing.

BDOnclarity

Ejegod,201418

(DK,UK)

Screening and referral population19 in UK, reproducibility study in DK.

≥30y Cases: 156 CIN2+ from a colposcopy referral population.Controls: 4,599 women where CIN2+ had not been detected through standard of care.


HC2 and new assay performed simultaneously on archived samples.

HPV-Riskassay

Hesselink, 201420

(NL)

Population-based screening setting

30-60 Cases: 29 CIN2, 37 CIN3, 4 squamous carcinoma (50 ASC-US+ and 20 NILM with + GP5+/6+ PCR-EIA). Controls: 824 consecutive NILM samples without evidence of CIN2+ in follow-up to 2 years.


GP5+/6+ PCR-EIA & new assay performed simultaneously.

PBS: phosphate-buffered saline; STM: Standard Transport Medium (Digene); UCM.ASC-US: atypical squamous cells of undetermined significance; ASCH: atypical squamous cells where high-grade squamous intraepithelial lesions cannot be excluded; CIN: cervical intraepithelial neoplasia; NILM: negative for intraepithelial lesion of malignancyBE: Belgium; DK: Denmark; ES: Spain; IT: Italy; NL: the Netherlands; PT: Portugal; SI: Slovenia; UK: United Kingdom.

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6. VALGENT protocol

VALGENT (Validation of HPV Genotyping Tests) is an international network and forum for validation of HPV genotyping assays. It involves recruitment of 1,300 cervical cytology specimen remnant after cytology processing (1,000 continuous screening samples, enriched with 100 ASC-US, 100 LSIL and 100 HSIL cases). The 1,300 samples are provided from a large European cytopathology laboratory with cervical cytology biobanking capacity. The samples are alliquoted in subparts which are sent to established virology laboratories for genotyping with a given HPV genotyping assay. All the selected cases are linked with clinical outcomes, through local follow-up systems/registries. Within those 1,300 samples about 80-120 cervical precancer can be found, which are used to compute the clinical sensitivity, and ~800 cases with two consecutive normal cytological findings, are used to compute specificity. Two VALGENT studies are completed up hereto, where the series of samples were compiled in Belgium and Scotland, respectively2,23-25. In VALGENT-3 and VALGENT-4/5 sample series will be generated in Slovenia and Denmark. There will always be at least one HPV assay already assessed in a previous VALGENT panel in allow comparison with all tests included in all VALGENT using network comparative statistics. The main outcomes of VALGENT are HPV type concordance, viro-cytological correlation, clinical accuracy in screening and in triage of ASC-US and LSIL, triage by HPV genotyping among women being hrHPV-positive, generation of inter-test matrix allowing comparisons of prevalence estimates from areas where different assays were used. The VALGENT study will be completed with a systematic review of studies where test performance of at least 2 HPV genotyping tests was evaluated in primary cervical cancer screening or in management of screen-positive women. Aggregated data pooled from the literature joined with data from VALGENT studies will be analysed using network meta-analysis. The general outcome will be ranked list of HPV genotyping tests which fulfil and do not fulfil thresholds for clinical practice. VALGENT will enable organisers of screening programmes to make best choices with respect to assay to be used.

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7. Evaluation of the study quality of the included screening studies

Table 4. Evaluation of the quality of the screening studies included in the meta-analysis according to the QUADAS-2 check list2117.

Patient selection

Index & compara-tor tests

Reference test Flow & timing Concerns of applicability

Author, year P1 P2 T1 T2 R1 R2 R

3 F1 F2 F3 F4 F5 F6 Patient selection Test Reference

testQiao, 2008 Y U Y Y Y Y Y Y Y Y Y Y Y Low Low Low

Wu, 2010 Y Y Y Y Y Y Y Y N Y Y Y N Low Low Moderate

Belinson, 2011 U U Y U Y U Y Y N Y Y N Y Moderate Low Low

Monsonego, 2011 Y Y Y Y Y N Y Y Y Y Y Y Y Low Moderate LowPoljak, 2011 Y Y Y Y Y N Y Y Y Y U Y Y Low Moderate LowRatnam, 2011 Y U Y Y Y Y Y U Y Y U U Y Low Low Moderate

Iftner, 2012 Y Y Y Y Y Y Y U* U* U* U* U

* U* Low Low Moderate

Cuzick, 2013 Y Y Y Y Y Y Y Y N Y Y Y U Low Low ModerateNieves, 2013 Y Y U Y Y N Y U Y Y Y Y Y Low Low Moderate

Lin, 2014 Y Y Y Y Y U Y Y Y Y Y U Y Low Low Low

QUADAS items21: (P1) acceptable enrolment method, (P2) inappropriate exclusions avoided, (T1) pre-specified test cut-off, (T2) results of index and comparator tests blinded towards each other and reference test, (R1) acceptable reference test, (R2) results of reference test blinded towards index and comparator tests, (R3) incorporation bias avoided, (F1) acceptable delay between triage tests and reference test, (F2) partial verification avoided, (F3) differential verification avoided, (F4) withdrawals explained, (F5) uninterpretable results reported for tests, (F6) uninterpretable results reported for reference test. Each quality item is judged with: Y (fulfilled, green), U (unclear, yellow), N (not fulfilled, red).* The quality of the study flow in Iftner 2012 et al22 could not be assessed since based on data presented a conference proceeding.

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8. Meta-analysis of the relative cross-sectional sensitivity and specificity of hrHPV DNA or RNA assays to detect underlying CIN3+ in women attending cervical cancer screening using HC2 or GP5+/6+ PCR-EIA as comparator

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Figure 2. Relative sensitivity of hrHPV DNA or RNA assays compared to the validated standard comparator tests (HC2 or GP5+/6+ PCR-EIA) to detect CIN3+ in cervical cancer screening, by study design.

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APTIMAWu, 2010Monsonego, 2011Iftner, 2012Nieves, 2013Cuzick, 2013Subtotal (I-squared = 0.0%, p = 0.804)

Abbott RT hrHPV testPoljak, 2011Cuzick, 2013Subtotal (I-squared = 0.0%, p = 0.714)

BD OnclarityCuzick, 2013Subtotal (I-squared = .%, p = .)

CervistaBelinson, 2011Subtotal (I-squared = .%, p = .)

GP5+/6+-LMNXGeraets, 2014Subtotal (I-squared = .%, p = .)

MALDI-TOFBelinson, 2011Subtotal (I-squared = .%, p = .)

PapilloCheckHesselink, 2010Subtotal (I-squared = .%, p = .)

Pretect HPV-ProoferCuzick, 2013Subtotal (I-squared = .%, p = .)

careHPVQiao, 2008Subtotal (I-squared = .%, p = .)

cobas 4800Cuzick, 2013Subtotal (I-squared = .%, p = .)

Study

1ary screening1ary screening1ary screening1ary screening1ary screening

Meijer protocol1ary screening

1ary screening

1ary screening

VALGENT protocol

1ary screening

Meijer protocol

1ary screening

1ary screening

1ary screening

Design

HC2HC2HC2HC2HC2

HC2HC2

HC2

HC2

GP5/6+ EIA

HC2

HC2

HC2

HC2

HC2

Comparator

1.04 (0.91, 1.19)1.00 (0.92, 1.09)0.95 (0.88, 1.01)1.00 (0.91, 1.10)1.00 (0.92, 1.09)0.98 (0.95, 1.02)

1.00 (0.92, 1.08)0.97 (0.87, 1.08)0.99 (0.93, 1.05)

1.00 (0.92, 1.09)1.00 (0.92, 1.09)

0.97 (0.94, 1.01)0.97 (0.94, 1.01)

1.00 (0.96, 1.04)1.00 (0.96, 1.04)

0.96 (0.93, 1.00)0.96 (0.93, 1.00)

0.99 (0.96, 1.03)0.99 (0.96, 1.03)

0.71 (0.53, 0.94)0.71 (0.53, 0.94)

0.91 (0.78, 1.06)0.91 (0.78, 1.06)

1.00 (0.92, 1.09)1.00 (0.92, 1.09)

RR (90% CI)

1.04 (0.91, 1.19)1.00 (0.92, 1.09)0.95 (0.88, 1.01)1.00 (0.91, 1.10)1.00 (0.92, 1.09)0.98 (0.95, 1.02)

1.00 (0.92, 1.08)0.97 (0.87, 1.08)0.99 (0.93, 1.05)

1.00 (0.92, 1.09)1.00 (0.92, 1.09)

0.97 (0.94, 1.01)0.97 (0.94, 1.01)

1.00 (0.96, 1.04)1.00 (0.96, 1.04)

0.96 (0.93, 1.00)0.96 (0.93, 1.00)

0.99 (0.96, 1.03)0.99 (0.96, 1.03)

0.71 (0.53, 0.94)0.71 (0.53, 0.94)

0.91 (0.78, 1.06)0.91 (0.78, 1.06)

1.00 (0.92, 1.09)1.00 (0.92, 1.09)

RR (90% CI)

1.5 .75 1 1.5 2

Relative sensitivity

Outcome CIN3+


document.docx 18

.

.

.

.

.

.

.

.

.

.

APTIMAWu, 2010Monsonego, 2011Iftner, 2012Nieves, 2013Cuzick, 2013Subtotal (I-squared = 96.2%, p = 0.000)

Abbott RT hrHPV testPoljak, 2011Cuzick, 2013Subtotal (I-squared = 0.0%, p = 0.693)

BD OnclarityCuzick, 2013Subtotal (I-squared = .%, p = .)

CervistaBelinson, 2011Subtotal (I-squared = .%, p = .)

GP5+/6+-LMNXGeraets, 2014Subtotal (I-squared = .%, p = .)

MALDI-TOFBelinson, 2011Subtotal (I-squared = .%, p = .)

PapilloCheckHesselink, 2010Subtotal (I-squared = .%, p = .)

Pretect HPV-ProoferCuzick, 2013Subtotal (I-squared = .%, p = .)

careHPVQiao, 2008Subtotal (I-squared = .%, p = .)

cobas 4800Cuzick, 2013Subtotal (I-squared = .%, p = .)

Study

1ary screening1ary screening1ary screening1ary screening1ary screening

Meijer protocol1ary screening

1ary screening

1ary screening

VALGENT protocol

1ary screening

Meijer protocol

1ary screening

1ary screening

1ary screening

Design

HC2HC2HC2HC2HC2

HC2HC2

HC2

HC2

GP5/6+ EIA

HC2

HC2

HC2

HC2

HC2

Comparator

1.08 (1.06, 1.10)1.06 (1.05, 1.08)1.01 (1.00, 1.01)1.01 (1.00, 1.03)1.06 (1.04, 1.07)1.04 (1.02, 1.07)

1.02 (1.00, 1.03)1.02 (1.01, 1.03)1.02 (1.01, 1.03)

0.99 (0.97, 1.00)0.99 (0.97, 1.00)

1.03 (1.02, 1.04)1.03 (1.02, 1.04)

1.00 (0.97, 1.04)1.00 (0.97, 1.04)

1.02 (1.01, 1.03)1.02 (1.01, 1.03)

0.99 (0.98, 1.00)0.99 (0.98, 1.00)

1.12 (1.10, 1.13)1.12 (1.10, 1.13)

1.02 (1.00, 1.05)1.02 (1.00, 1.05)

0.99 (0.98, 1.00)0.99 (0.98, 1.00)

RR (90% CI)

1.08 (1.06, 1.10)1.06 (1.05, 1.08)1.01 (1.00, 1.01)1.01 (1.00, 1.03)1.06 (1.04, 1.07)1.04 (1.02, 1.07)

1.02 (1.00, 1.03)1.02 (1.01, 1.03)1.02 (1.01, 1.03)

0.99 (0.97, 1.00)0.99 (0.97, 1.00)

1.03 (1.02, 1.04)1.03 (1.02, 1.04)

1.00 (0.97, 1.04)1.00 (0.97, 1.04)

1.02 (1.01, 1.03)1.02 (1.01, 1.03)

0.99 (0.98, 1.00)0.99 (0.98, 1.00)

1.12 (1.10, 1.13)1.12 (1.10, 1.13)

1.02 (1.00, 1.05)1.02 (1.00, 1.05)

0.99 (0.98, 1.00)0.99 (0.98, 1.00)

RR (90% CI)

1.5 .75 1 1.5 2

Relative specificity

Outcome CIN3+


Figure 3. Relative specificity of hrHPV DNA or RNA assays compared to the validated standard comparator tests (HC2 or GP5+/6+ PCR-EIA) to detect CIN3+ in cervical cancer screening, by study design.

document.docx 19


8. References

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10. Heideman DA, Hesselink AT, Berkhof J, van KF, Melchers WJ, Fransen DN, Verkuijten M, Meijer CJ, Snijders PJ. Clinical validation of the cobas(R)4800 HPV Test for cervical screening purposes. J Clin Microbiol 2011;49: 3983-5.

11. Rijkaart DC, Berkhof J, van Kemenade FJ, Rozendaal L, Verheijen RH, Bulk S, Herreilers ME, Verweij WM, Snijders PJ, Meijer CJ. Comparison of HPV and cytology triage algorithms for women with borderline or mild dyskaryosis in population-based cervical screening (VUSA-screen study). Int J Cancer 2009;126: 2175-81.

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18. Ejegod DM, Serrano I, Cuschieri K, Nussbaumer WA, Vaughan LM, Ahmad AS, Cuzick J, Bonde J. Clinical Validation of the BD Onclarity™ HPV Assay Using a Non-Inferiority Test. J Med Microbiol Diagn 2014;S3: 003: 1-4.

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24. Schmitt M, Depuydt CE, Benoy I, Bogers J, Antoine J, Pawlita M, Arbyn M. Viral load of high-risk human papillomaviruses as reliable clinical predictor for the presence of cervical lesions. Cancer Epidemiol Biomarkers Prev 2013;22: 406-14.

25. Schmitt M, Depuydt C, Benoy I, Bogers J, Antoine J, Arbyn M, Pawlita M. Prevalence and viral load of 51 genital human papillomavirus types and 3 subtypes. Int J Cancer 2013;132: 2395-403.

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