CHAPTER 1 1.pdf · Chapter 1. 209130-L-bw-Geraets 1.11.1.111.1 BACKGROUNDBACKGROUND 1.1.11.1.1.1.111.1.1 Short introduction Infection of cervical epithelium with a human papillomavirus

209130-L-bw-Geraets209130-L-bw-Geraets209130-L-bw-Geraets209130-L-bw-Geraets

CHAPTER 1

General introduction and thesis outlineGeneral introduction and thesis outlineGeneral introduction and thesis outlineGeneral introduction and thesis outline

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Chapter 1


1.11.11.11.1 BACKGROUNDBACKGROUNDBACKGROUNDBACKGROUND

1.1.11.1.11.1.11.1.1 Short introductionShort introductionShort introductionShort introduction

Infection of cervical epithelium with a human

papillomavirus (HPV) can lead to the development of

cervical intraepithelial neoplasia (CIN) and ultimately

cervical cancer. Technologies that can detect and

distinguish different human papillomaviruses are

important to determine their involvement in disease, to

evaluate the efficacy of HPV vaccines, to monitor

prevalence of HPV genotypes in immunized cohorts,

and to identity women at risk for having high-grade

CIN within cervical cancer screening programs. Over

125 commercial HPV tests have been developed, with

differences in design and performance. In this thesis we

evaluated the performance of a number of established

and novel technologies for the identification of HPVs in

relation to their intended use.

1.1.21.1.21.1.21.1.2 CCCCervical cancerervical cancerervical cancerervical cancer

Cervical cancer is the fourth most common malignancy

among women worldwide, with 528,000 new cases and

266,000 deaths occurring each year (1). Squamous cell

carcinoma (SCC; 80%) and adenocarcinoma (ADC;

15%) are the main histological types (2), while

adenosquamous and neuroendocrine carcinomas

account for less than 5% of cervical cancers (3).

ADC develops from adenocarcinoma in-situ (AIS).

Precursors of SCC are classified as cervical

intraepithelial neoplasia (CIN) grade 1, 2, and 3

(including carcinoma in-situ). All precursor lesions can

regress, persist or progress. However, the possibility of

regression decreases with increasing CIN grade. The

risk of progression from CIN3 to invasive cervical

cancer (ICC) is estimated between 30-50% (4-7). The

concept of cervical carcinogenesis is summarized in

Figure 1

CIN2 and CIN3 together are referred to as high-

grade CIN (HG-CIN). In the USA, women with HG-

CIN and AIS are treated to prevent cervical cancer. This

approach results in a considerable degree of

overtreatment, since currently progressive and

regressive HG-CIN cannot be distinguished

morphologically. In Europe, small CIN2 localized in a

well-visible transformation zone are often followed by

periodic colposcopy (one year). CIN1 lesions are

considered low-grade CIN (LG-CIN) for which a wait-

and-see policy is advised.

11

General introduction and thesis outline


Figure 1: Figure 1: Figure 1: Figure 1: The concept of HPV-mediated cervical carcinogenesis and the according morphological appearance. HPV

gains access to the basal cells of squamous epithelium, followed by an ordered expression pattern of viral genes leading

to the production and release of new virions. Deregulated expression of E6 and E7 oncoproteins and viral genome

integration are associated with malignant transformation, leading to genomic instability, (epi)genetic changes, and

ultimately invasive cervical cancer. The outcomes of HPV exposure are represented as a transient infection (no

pathology), a productive infection (productive CIN; CIN1 and a subset of CIN2), and a transforming infection

(transforming CIN; remaining subset of CIN2 and CIN3). The majority of transforming CIN and cervical cancers are

suggested to arise from an hrHPV infection of embryonic squamo-columnar junction (SCJ) cells (adapted from (8) and

(9)).

1.1.31.1.31.1.31.1.3 HHHHuman papillomavirusesuman papillomavirusesuman papillomavirusesuman papillomaviruses

PVs are naked viruses with a circular, double-stranded

DNA genome of about 7600-8000 base-pairs (bp)

contained in a protein capsid. The genome is divided

into three regions, i.e., the long control region (LCR),

the early (E) coding region, and the late (L) coding

region. The LCR regulates viral gene expression and

replication. The E region contains six or more early

open reading frames (ORFs), i.e., E1, E2, E4, E5, E6, E7,

which encode proteins required for viral gene

expression, replication and survival. The late (L) region

encodes the two viral structural proteins, i.e., L1 and L2.

By convention, the similarity across the highly

conserved L1 ORF was adapted as the basis for

taxonomic classification of PVs (10). A PV “type” is

defined as a complete PV genome, whose L1 ORF

12

Chapter 1

Squamous epithelium

Superficial zone

Midzone

Basal layer

Basement membraneDermis

Infectious viral particles

Productive CINTransforming CIN Cancer

Cancer

Type of hrHPVinfection

Productive (permissive) infection Transforming (non-permissive) infection

Morphologicalappearance CIN1/2 CIN2/3

20–30 yearshrHPV

SCJ cells

Ectocervix or TZ

Transient (latent) infection

Normal


nucleotide sequence is at least 10% different from that

of any other known PV type (11). PV subtypes share 90

to 98% and variants more than 98% nucleotide

sequence identity in L1.

At higher taxonomy levels, PVs have been grouped

together into species, and species into genera. PV types

within the same genus show less than 60% sequence

identity to types of other genera (12). Different species

within a genus share between 60% and 70% nucleotide

identity, while PVs in the same species share between 71%

and 89% identity in L1 ORF nucleotide sequence (10).

Genera are denominated by a Greek letter and species

by addition of a number to the letter, e.g., species

Alphapapillomavirus 9 (α9) (11).

The family of papillomaviridae currently consists

of 189 classified PVs distributed over 29 genera (12).

Presently, 170 HPV types have been described and are

located in the α, β, γ, μ, and ν genera (13). HPVs are

strictly epitheliotropic and can infect epithelium and/or

mucosal areas of skin, conjunctiva, oropharynx, anus,

penis, vulva, vagina and cervix (11, 14). The β, γ, μ, and

ν genera comprise only cutaneous HPVs, while α genus

contains both cutaneous and mucosal types divided

over 13 species. HPVs within these species branch into

three ancestral clades (15). The phylogenetic

relationship between the different human

papillomaviruses is shown in Figure 2.

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Figure 2:Figure 2:Figure 2:Figure 2: Phylogenetic relationship between human papillomaviruses (from (16)).

14

Chapter 1


The nomenclature for variant lineages of an HPV

type was initially based on the observed association

between the variant and the continent of origin, e.g.,

European, Asian, African 1&2, North-American, and

Asian-American 1&2 variants of HPV16 (17). Recently,

a novel classification and nomenclature system has been

proposed (18). This system is based on full-genome

sequence analysis, and uses an approximate cut-off of

1.0% difference between complete genomes to define

major lineages. Major lineages are named using an

alphanumeric, with the reference genome of each type

always located in the “A” clade. Differences between

0.5–1% are used to designate sublineages (e.g., A1, A2).

The conversion between the novel and initial

nomenclature for HPV16 is shown in Table 1.

Table 1: Table 1: Table 1: Table 1: Novel (18) and initial (17) nomenclature of HPV16 variant (sub)lineages.

Novel (Burk, 2013)Novel (Burk, 2013)Novel (Burk, 2013)Novel (Burk, 2013) Initial (Ho, 1993)Initial (Ho, 1993)Initial (Ho, 1993)Initial (Ho, 1993)

Main lineageMain lineageMain lineageMain lineage SublineageSublineageSublineageSublineage

A A1 European (EUR)

A2 European (EUR)

A3 Asian (As)

B B1 African 1a (AF1a)

B2 African 1b (AF1b)

C C1 African 2a (AF2a)

C2 African 2b (AF2b)

D D1 North-American (NA)

D2 Asian-American 1 (AA1)

D3 Asian-American 2 (AA2)

1.1.41.1.41.1.41.1.4 HPV and cHPV and cHPV and cHPV and cervical cancerervical cancerervical cancerervical cancer developmentdevelopmentdevelopmentdevelopment

The large majority of infections with HPVs are rapidly

cleared by a cell-mediated immune response, and do

not give rise to lesions. About 20% of the remaining

persisting HPV infections cause lesions that are

considered productive infections. These infections lead

to the generation of new virions in the upper epithelial

layers using the host replication machinery under

tightly controlled expression of E6 and E7.

Morphologically, productive infections can appear as

CIN1 and CIN2, but generally do not persist to progress

to advanced precursor lesions (CIN3) and cancer

(Figure 1).

Only a minority of HPV infections become

transforming. Transforming infections are characterized

by deregulated expression of E6 en E7 in the (para)basal

cells, i.e., cells with proliferating capacity. Transforming

infections are associated with CIN2, CIN3 and

ultimately cervical cancer (Figure 1) (8).

The exact mechanism for deregulation of E6 and E7

is not well understood. The majority of cervical

carcinomas contain one or more copies of HPV

integrated into the host genome. Integration occurs

more or less randomly, but viral integration sites often

lie within the ORF of E2, the transcriptional regulator

of E6 and E7 (19, 20). The continuous overexpression of

viral oncoproteins E6 and E7 in proliferating basal cells

of the epithelium leads to genomic instability and

(epi)genetic changes, and ultimately malignant

transformation. Precursor lesions can develop within 2-

3 years after HPV infection (21, 22), while progression

from HG-CIN to cancer may take 10-30 years (21, 23).

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1.21.21.21.2 IMPORTANCE OF HPV GEIMPORTANCE OF HPV GEIMPORTANCE OF HPV GEIMPORTANCE OF HPV GENOTYPINGNOTYPINGNOTYPINGNOTYPING

TESTSTESTSTESTSTESTS

1.2.11.2.11.2.11.2.1 HPVHPVHPVHPV types andtypes andtypes andtypes and disease associationdisease associationdisease associationdisease association

HPV genotyping tests have been very important in

epidemiologic studies towards HPVs and their

association with disease. In a global cervical cancer

case-control study, Munoz et al classified fifteen types

as high-risk (hr) (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,

59, 68, 73, and 82), three as probably high-risk (pr-hr)

(26, 53, and 66), and twelve types as low-risk (lr) (6, 11,

40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108) (Table 2)

(24). This observation correlated with the three

ancestral phylogenetic clades of alpha HPVs (15, 25).

The hrHPVs and pr-hrHPVs were located in α9, α11, α7,

α5, and α6 (“high-risk clade”), while most lrHPVs were

found in α10, α8, α1, and α13 (“low-risk clade 1”) and

α2, α4, α14/15, and α3 (“low-risk clade 2”) (Figure 2).

The most recent carcinogenic classification of

mucosal HPV genotypes by the WHO IARC was based

on the evidence of the epidemiologic risk classification,

supplemented with phylogenetic and biological

evidence when available (26). IARC has classified

mucosal types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,

and 59 as carcinogenic (Class 1), type 68 as probably

carcinogenic (Class 2A), and types 26, 30, 34, 53, 66, 67,

69, 70, 73, 82, 85 and 97 as possibly carcinogenic (Class

2B). HPV6 and HPV11 were not classifiable as to its

carcinogenicity to humans (Class 3), and the remaining

mucosal HPV types were considered probably not

carcinogenic (Class 4) (Table 2).

Table 2: Table 2: Table 2: Table 2: The epidemiologic risk classification (24) and the WHO IARC carcinogenic classification (26) of mucosal

HPV genotypes.

WHO IARC, 2009WHO IARC, 2009WHO IARC, 2009WHO IARC, 2009 Munoz, 2003 Munoz, 2003 Munoz, 2003 Munoz, 2003

HighHighHighHigh----risk typesrisk typesrisk typesrisk types Probably highProbably highProbably highProbably high----

risk typesrisk typesrisk typesrisk types

LowLowLowLow----risk typesrisk typesrisk typesrisk types Types not included inTypes not included inTypes not included inTypes not included in

the studythe studythe studythe study

Class 1 (carcinogenic) 16, 18, 31, 33, 35, 39, 45, 51,

52, 56, 58, 59

- - -

Class 2A (probably

carcinogenic)

68 - - -

Class 2B (possibly

carcinogenic)

73, 82 26, 53, 66 70 30, 34, 67, 69, 85, 97

Class 3 (not

classifiable)

- - 6, 11 -

Class 4 (probably not

carcinogenic)

- - 40, 42, 43, 44, 54, 61,

72, 81, CP6108

All other mucosal

HPVs

The classification of HPVs that pose a high risk for

causing cervical cancer is an evolving process,

particularly for the HPV types in Class 2A/B. These

genotypes have been classified as probably/possibly

carcinogenic mainly based on their close phylogenetic

relation with established carcinogenic HPVs, but

epidemiological and biological evidence is virtually

lacking. Most of these types are not targeted by

commonly used HPV genotyping assays. Additional

research is required to clarify their causal role and

clinical importance. A specific definition of the HPVs

considered (probably/possibly) high-risk is provided in

each individual chapter of this thesis.

16

Chapter 1


Even within the group of established hrHPVs

(Class 1), there appears to be a difference in

carcinogenic potential. Longitudinal studies have

shown an elevated risk of HG-CIN for HPV16 in

particular and to a lesser extent for HPV18, compared

to other high-risk HPV types (27-32). In contrast to

other hrHPV genotypes, these two types show a

proportional increase in prevalence in women having

normal cytology, precancer, and ICC (33, 34).

Technologies that have the resolution to distinguish

intratypic variants were used to investigate differences

in risk associations between variants, in particular for

those of HPV16, the most carcinogenic HPV. Lineages

B, C, and D (Non-European) of HPV16 appear to be

more pathogenic in comparison to isolates from the A

lineage (European) (18). HPV16 lineages B, C and D

persist more frequently (35, 36), are more associated

with precancer and specifically CIN3 (35-40), and have

elevated risks for cancer compared to the HPV16 A

variant lineage. In particular, this increased risk of

cervical cancer is mostly related to the D (Asian-

American) lineage (40-42).

1.2.21.2.21.2.21.2.2 HPV vHPV vHPV vHPV vaccine efficacyaccine efficacyaccine efficacyaccine efficacy trialstrialstrialstrials

HPV genotyping tests targeting a broad range of HPVs

were used to demonstrate the efficacy of two HPV

vaccines. Cervarix® (GlaxoSmithKline Biologicals,

Rixensart, Belgium) and Gardasil® (Merck & Co.,

Whitehouse Station, NJ, USA) are two prophylactic

HPV L1 virus-like particle (VLP) vaccines that have

been licensed to prevent anogenital HPV infections and

their associated neoplasia. Cervarix is a bivalent vaccine

protecting primarily against HPV16 and 18, and

Gardasil is a quadrivalent vaccine that targets besides

HPV16 and 18 also the lrHPV types 6 and 11. Both are

three-dose vaccines composed of HPV L1 proteins self-

assembled into virus-like particles (VLPs), but

produced in different expression systems and

administered with different adjuvants. In contrast to

natural HPV infection, both vaccines induce high titers

of neutralizing anti-L1 VLP antibodies, with virtually

100% seroconversion in vaccinees (43). The AS04

adjuvant system of the bivalent vaccine appears to

induce a stronger, more sustained antibody response

than the conventional adjuvant of the quadrivalent

vaccine (44), although its effect on duration of

protection is unknown.

For both vaccines, HPV genotyping tests targeting

a broad range of HPVs were used to demonstrate high

efficacy against several surrogate endpoints, from

persistent HPV infection to high-grade CIN lesions

(CIN2+) associated with vaccine-targeted HPVs (45).

The quadrivalent vaccine has demonstrated strong

protection against genital warts, of which 90% in men

and women are caused by vaccine targets HPV6 and 11

(46-48). Long-term follow-up of vaccinated cohorts will

determine the duration of protection against vaccine-

targeted types (45).

Cross-neutralization of HPV types related to

HPV16 and 18 confers cross-protection. Both vaccines

provide partial cross-protective efficacy against HPV31

and 33 (49, 50). The bivalent vaccine also offers some

cross-protection against HPV45 (51, 52).

1.2.31.2.31.2.31.2.3 Surveillance of HPV Surveillance of HPV Surveillance of HPV Surveillance of HPV type type type type prevalenceprevalenceprevalenceprevalence

The bivalent and quadrivalent vaccines have been

implemented in vaccination programs in various

countries. Several aspects should be monitored to

evaluate the effects of an HPV vaccination program, i.e.,

1) the occurrence of vaccine-preventable disease, 2) the

concentration of naturally occurring HPV type-specific

antibodies and the prevalence of HPV vaccine-

associated genotypes, 3) the titers of HPV vaccine type-

associated antibody response, 4) vaccine uptake, and 5)

vaccine safety. HPV genotyping tests can be used to

determine the prevalence of HPV genotypes pre- and

post-vaccination. This allows monitoring the effects of

nation-wide vaccination on prevalence of HPV

genotypes (and possibly type replacement) within an

immunized cohort.

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1.2.41.2.41.2.41.2.4 HPVHPVHPVHPV----based screeningbased screeningbased screeningbased screening

In the near future, HPV tests that can detect (and

partially identify) a range of hrHPVs (hrHPV DNA

testing) will be implemented in cervical cancer

screening programs. Currently, cervical cancer

screening programs rely on cytology performed on cells

scraped from the transformation zone of the cervix and

collected in a liquid-based medium, e.g., BD SurePath

(BD, Burlington, NC, USA) or ThinPrep PreservCyt

(Hologic, Marlborough, MA, USA). Morphological

changes of cells are graded according to the degree of

abnormality. Different cytology classification systems

are used, e.g., the Bethesda 2001 (USA), BSSC (United

Kingdom), CISOE-A (The Netherlands) and

Papanicolaou (PAP). The different cytology

classification systems are shown in Table 3.

Table 3: Table 3: Table 3: Table 3: Classification systems for cervical cytology (adapted from (53, 54)).

NILM, Negative for intraepithelial lesion or malignancy; ASC-H, atypical squamous cells cannot exclude HSIL; ASC-

US, atypical squamous cells of undetermined significance; AGC, atypical glandular cells; LSIL low grade squamous

intraepithelial lesion; HSIL, high grade squamous intraepithelial lesion; AIS, endocervical adenocarcinoma in situ;

SCC, squamous cell carcinoma; AC, adenocarcinoma; CISOE-A, C composition, I inflammation, S squamous

epithelium, O other abnormalities and endometrium, and E endocervical columnar epithelium

HrHPV DNA tests are an improved primary

cervical cancer screening tool compared to cytology.

Randomized controlled trials have shown that hrHPV

DNA testing detects 30% more CIN2+ and 20% more

CIN3+ in women aged 30 years and older (55-62).

Secondly, trials with longitudinal data on CIN3+ in

subsequent screening rounds (at 3-5 year intervals)

have shown ~50% lower incidence rates of CIN3+

among women with a negative HPV test at baseline

compared to those having normal cytology (56, 60-62).

Moreover, a pooled analysis of these studies

demonstrated that hrHPV-based screening provides

60–70% greater protection against invasive cervical

carcinomas compared to cytology (63).

In general, these hrHPV DNA tests target a range of

13-14 hrHPVs but do not permit individual

identification, or limited only to HPV16 and 18 (partial

genotyping). The clinical use of hrHPV genotyping is

currently unknown, but the separate identification of

HPV16 and 18 might be of use in clinical management,

due to their increased risk for cervical cancer compared

to other hrHPVs.

BETHESDA

2001

Unsatisfactory

for evaluation

Negative

(NILM) Atrophy

ASC-H HSIL SCC

ASC-US LSIL

AGC AGC favor neoplastic AIS AC

BSCC Inadequate Negative

Borderline

nuclear

change

Mild

dyskaryosis

Moderate

dyskaryosis

Severe

dyskaryosis

Severe

dyskaryosis

Invasive

Glandular

neoplasia

CISOE-A C0 S1, E1-2,

O1-2 S2-3, O3, E3 S4, E4-5 S5, O4-5 S6, O6, E6

S7,

E7

S8-9,

O7-8,

E9

PAP PAP0 PAP1 PAP2 PAP3a1 PAP3a2 PAP3b PAP4 PAP5

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Chapter 1


1.31.31.31.3 DESIGN AND PERFORMANDESIGN AND PERFORMANDESIGN AND PERFORMANDESIGN AND PERFORMANCE CE CE CE

ASSESSMENT OF ASSESSMENT OF ASSESSMENT OF ASSESSMENT OF HPV TESTSHPV TESTSHPV TESTSHPV TESTS

1.3.11.3.11.3.11.3.1 Intended useIntended useIntended useIntended use

The design of an HPV DNA test should match its

intended use. HPV tests designed for epidemiologic

purposes, e.g., disease association studies, vaccine

efficacy trials, and surveillance of HPV prevalence,

require a high analytical sensitivity and specificity and

the capacity to individually identify a range of HPVs.

In a clinical setting, HPV tests should detect hrHPV

infections mainly associated with clinically meaningful

disease, i.e., CIN2+ lesions (clinical sensitivity), while

limiting the detection of transient HPV infections not

associated with CIN2+ (clinical specificity). In addition

to primary cervical cancer screening, two other

potential clinical applications of hrHPV testing have

been defined. HrHPV testing can be used as a test-of-

cure for women treated for HG-CIN, and as a triage test

for women with borderline and mild abnormal cytology

(ASC-US/LSIL) (64).

1.3.21.3.21.3.21.3.2 Clinical specimen, collection and Clinical specimen, collection and Clinical specimen, collection and Clinical specimen, collection and

processingprocessingprocessingprocessing

A range of clinical specimens have been used for HPV

analysis, e.g., cervical cells collected by brush and stored

in liquid-based medium (cervical swabs) (64), whole

tissue sections (WTS) of freshly frozen or formalin-

fixed paraffin-embedded (FFPE) cervical biopsies (65,

66), micro-dissected regions of tissue by laser-capture

microscopy (LCM) (67), and cervicovaginal specimens

self-collected by lavage or brush and stored in liquid-

based medium, solid carrier cartridge or dryly (68, 69).

It is important to realize that the yield and quality of the

specimen for HPV testing is influenced by the

methodology used for collection, storage and

processing. Thus, all elements of the diagnostic chain

determine the outcome of the HPV test used and should

be taken into account (68).

1.3.31.3.31.3.31.3.3 Target selection and amplificationTarget selection and amplificationTarget selection and amplificationTarget selection and amplification

Most commercial and in-house tests that have been

developed for HPV detection and genotyping are based

on PCR amplification of HPV DNA. DNA PCR-based

methods will be the focus of this thesis, although some

non-PCR based methods will also be briefly described.

HPV DNA PCR tests do not characterize the

complete HPV genome or the L1 ORF, as is required for

classification of PVs (10). Instead, these assays target

one or more regions within the genome that are

sufficient for accurate viral recognition of one or more

previously classified HPVs. Misrecognition due to

presence of unclassified types or genetic variants is

inherently possible when using any HPV DNA assay.

The size of viral regions that are amplified vary across

HPV tests, but smaller target regions allow more

efficient amplification in specimens with poorly

preserved DNA, e.g., archival FFPE cervical biopsies.

The regions in the viral genome targeted by a selection

of HPV DNA PCR-based assays are shown in Figure 3.

19



Figure Figure Figure Figure 3333: : : : Schematic representation of primer target regions of different type-specific and broad-spectrum DNA PCR-

based assays. The approximate fragment lengths (in nucleotides) are shown in parenthesis. The reference genome of

HPV16 was used.

The degree of heterogeneity of the viral genome enables

two approaches for amplification of viral DNA by PCR

primers, i.e., broad-spectrum (consensus) primers or

type-specific (TS) primers. Broad-spectrum primers

target relatively well-conserved genomic sequences,

enabling the simultaneous amplification of a broad-

spectrum of HPV genotypes in a single test using only a

limited number of primers. By default, these primer sets

are not specifically designed for the amplification of

only a single HPV type. Most broad-spectrum PCR

genotyping assays target well-conserved regions in the

L1 ORF. The likelihood that sequence variations occur

at these positions causing false-negativity is relatively

low. Broad-spectrum amplification can be

accomplished by different approaches: 1) low-

stringency PCR conditions to allow some degree of

mismatch acceptance between primers and target

sequence, 2) degenerate primers with nucleotide

variations at variable base positions, 3) primers with the

non-specific base-analogue inosine at ambiguous base

positions, and 4) sets of multiple, overlapping primers.

A technical limitation of all broad-spectrum PCR-

based assays is the underestimation of the prevalence of

genotypes present in low concentrations within

multiple infections, also known as masking (70). Broad-

spectrum PCR primers do not necessarily have the same

analytical sensitivity and specificity for each genotype

and amplification efficiency might differ among

individual genotypes. Spiking experiments with plasmid

mixtures of different HPV genotypes have shown that a

competitive effect occurs in mixed infections when one

genotype is present in a much lower concentration than

another (PCR competition) (71).

As opposed to broad-spectrum PCR, type-specific

(TS) primers target viral sequences that are specific for

a single genotype. These primers permit highly sensitive

and specific identification of HPVs. Although TS PCRs

can be designed to target any region in the HPV

genome, many TS PCR assays amplify regions in the E6

or E7 ORF. These PCR target regions are not

interrupted by viral integration, since over-expression

of E6 and E7 is required for transforming HPV

infections.

An important advantage of TS PCRs is that they are

less prone to underestimate the prevalence of HPV

types that have low viral loads in multiple infections.

20

Chapter 1


However, TS PCRs also have some limitations.

Unknown variations in the primer target sequences

could cause false-negative results (72). In addition, the

performance of a separate type-specific PCR for each

HPV is highly laborious and requires substantial

quantity of clinical specimen. This issue can be

addressed by the development of multiplex type-specific

(MPTS) PCRs, where multiple TS primer sets are

combined in a single PCR reaction for simultaneous

amplification of a defined set of HPVs (72).

1.3.41.3.41.3.41.3.4 ReadReadReadRead----out methodout methodout methodout method

Amplification products generated by broad-spectrum

and by type-specific PCRs can be detected by

hybridization to a mix of oligonucleotide probes in a

DNA enzyme immune-assay (DEIA/EIA) in a

microtiter well plate. In addition, reverse hybridization

(RH) can be done by separate genotype-specific probes

immobilized on carriers such as nylon membrane,

nitrocellulose strips, microsphere beads or DNA chips.

Read-out can also be performed real-time using

fluorochrome-labelled Taqman probes in a quantitative

(q)PCR format as opposed to a conventional end-point

PCR. Read-out systems of PCR products can be

designed to recognize a range of HPV types

simultaneously (detection), individually (full

genotyping), or as a combination of detection and

genotyping (partial genotyping).

The range of HPVs targeted by an HPV test should

be in accordance with its design. Clinically relevant

HPV tests generally target 13 hrHPVs (Class 1 and 2A),

and have often incorporated HPV66 (Class 2B) in

addition. These assays are therefore also referred to as

hrHPV tests. HPV tests designed for epidemiologic

purposes are not necessarily restricted to these hrHPVs

and may also include possibly hr- and lrHPVs.

1.3.51.3.51.3.51.3.5 Assessing HPV test peAssessing HPV test peAssessing HPV test peAssessing HPV test performancerformancerformancerformance and and and and

quality quality quality quality assuranceassuranceassuranceassurance

The non-clinical performance assessment of HPV tests

comprises analytical sensitivity (limit-of-detection),

analytical specificity (interference), precision

(reproducibility) and accuracy (comparison-of-

methods). The analytical accuracy of a novel HPV test

can be evaluated by comparison with an established

“gold standard” or comparator test, using panels of

artificial samples, e.g., plasmids cloned with HPV target

sequences, and/or clinical specimens for which the HPV

test was designed.

However, an analytically validated HPV test

should not be used in clinical practice without prior

clinical validation, since analytical and clinical accuracy

are non-synonymous. The clinical relevance of a novel

hrHPV test for primary cervical cancer screening has to

be supported by data from longitudinal randomized

controlled trials (RCT). Alternatively, a candidate assay

can also be clinically assessed if it shows a clinical

sensitivity and specificity that is non-inferior to a

reference test that has already been validated in

longitudinal RCT. International guidelines for panel

composition and criteria for clinical accuracy and test

reproducibility have been formulated (73).

The laboratories performing hrHPV testing should

comply with quality assurance (QA) measures, such as a

specific infrastructure for nucleic acid amplification,

participation in external quality assessments

(proficiency panels), and accreditation for clinical

molecular testing (73). Some HPV tests have been

equipped with an internal control (IC) to aid

laboratories in assessing specimen quality and/or

monitoring of sample processing, in order to prevent

false-negative HPV results. An IC usually comprises a

spiked exogenous nucleotide sequence or an

endogenous target (e.g., the beta-globin housekeeping

gene) that is simultaneously extracted and amplified

with HPV DNA.

21



1.41.41.41.4 TTTTECHNOLOGIESECHNOLOGIESECHNOLOGIESECHNOLOGIES FOR HPV DETECTION FOR HPV DETECTION FOR HPV DETECTION FOR HPV DETECTION

AND GENOTYPINGAND GENOTYPINGAND GENOTYPINGAND GENOTYPING

1.4.11.4.11.4.11.4.1 Tests for pooled detection of HPVsTests for pooled detection of HPVsTests for pooled detection of HPVsTests for pooled detection of HPVs

HPV DNA detection assays provide a qualitative test

result for a group of HPVs simultaneously (pooled or

grouped detection). These assays generally target 13

hrHPVs (Class1/2A) or 14 hrHPVs (Class1/2A and

HPV66 in addition). Tests not intended for a clinical

setting can detect additional genotypes, including

lrHPVs (e.g., SPF10 DEIA).

Signal amplificationSignal amplificationSignal amplificationSignal amplification

The Hybrid Capture 2 HPV DNA Test (HC2; Qiagen,

Hilden, Germany) is the most frequently used HPV test

in the world. HC2 uses liquid-based chemiluminescent

signal amplification of hybridized target DNA for the

simultaneous detection of 13 hrHPVs. This assay has no

internal control for a human DNA target. The RNA

probes can cross-hybridize with several other (lr)HPVs

(74). The HC2 is intended for primary cervical cancer

screening, management of women with equivocal

cytology results, and test-of-cure. HC2 has been

evaluated in longitudinal randomized, controlled

studies, e.g., NTCC, ARTISTIC, and VUSASCREEN

(59-61, 75). HC2 is therefore considered a reference test

for validation of novel hrHPV assays (73).

The Cervista HPV HR Test (Cervista; Hologic,

Madison, WI, USA) offers simultaneous detection of

DNA from 14 hrHPVs using signal amplification by

Invader chemistry. In a first isothermal reaction, a

probe and an Invader oligonucleotide specifically

anneal to HPV DNA to generate an overlapping

structure. Enzymes specifically cleave and release the

overlapping primary probes. In a second, simultaneous

isothermal reaction, cleaved flaps combine with a

fluorescence resonance energy transfer (FRET) probe,

which generates a fluorescent signal. A region from the

HIST2H2BE gene is also amplified as an internal

control target. The Cervista is indicated for cervical

cancer risk screening combined with cytology and for

management of women with equivocal cytology results.

Cervista has been evaluated in the SHENCCAST II

study (76) and clinically validated by Boers and

colleagues (77). However, concerns have been raised

about the relatively low clinical specificity of this assay

(78), which might be resolved by increasing the assay

threshold for positivity (79, 80).

PCR amplification aPCR amplification aPCR amplification aPCR amplification and enzyme immuno assaysnd enzyme immuno assaysnd enzyme immuno assaysnd enzyme immuno assays

Most endpoint PCR-based methods utilize consensus

primer sets targeting a conserved region of a broad-

spectrum of viral genomes. Detection of amplimers is

performed in a DNA enzyme immuno assay

(designated DEIA or EIA) using a cocktail of specific

probes for a defined set of hrHPVs (e.g., GP5+/6+ EIA)

or a mix of universal probes for a very broad range of

HPVs (e.g., SPF10 DEIA). Presence of HPV is

determined by optical density measurement of labeled

probes hybridized to single-stranded amplimers in a

microtiter plate.

The SPF10-PCR-DEIA (Labo Bio-medical Products,

Rijswijk, The Netherlands) was developed around 15

years ago (81) and is usually combined in a test

algorithm with the LiPA25 reverse hybridization strip

version 1 (Labo Bio-medical Products; described later)

(82). This algorithm was designed to have high

analytical sensitivity and specificity. The SPF10 primers

are non-degenerated and amplify a 65-bp fragment in

the L1 ORF of a broad-spectrum of at least 69 mucosal

and cutaneous HPV types. Qualitative detection of

HPV is performed in a DEIA with conservative,

universal HPV probes. A control target for the

housekeeping gene beta-globin can be separately

amplified and detected. The SPF10 PCR system has been

used in various epidemiologic studies and vaccine trials

for the bivalent vaccine, e.g., PATRICIA and CVT (66,

83-87). The short region of only 65 bp targeted by SPF10

primers is particularly sensitive for amplification in

formalin-fixed paraffin-embedded (FFPE) cervical

biopsy specimens, in which DNA is often poorly

preserved. The sensitivity of the SPF10-PCR-DEIA is too

high for application in a clinical setting (88).

22

Chapter 1


The GP5+/6+-PCR-EIA has been originally

developed as an in-house test and is now commercially

available (EIA kit GP HR; Diassay, Rijswijk, The

Netherlands). The GP5+/6+ primers amplify a region of

approximately 150 bp in the L1 ORF. Amplification of a

broad-spectrum of HPV genotypes using only two

primers is achieved by a relatively low annealing

temperature. A cocktail of probes specific for 14

hrHPVs hybridizes with the GP5+/6+ amplification

products in an EIA format, providing a qualitative

result (89). A 313-bp fragment of human DNA is

intrinsically co-amplified by the GP5+/6+ primers and

can function as an internal control (90). A specifically

designed probe can detect this fragment in a separate

EIA format. The GP5+/6+-PCR-EIA is intended for

primary cervical cancer screening, management of

women with equivocal cytology results, and test-of-cure.

Similarly to HC2, the GP5+/6+-PCR-EIA has been

evaluated in longitudinal randomized, controlled

studies, e.g., POBASCAM and SWEDESCREEN (56,

62). The GP5+/6+-PCR-EIA is therefore considered a

reference assay for HPV testing in cervical cancer

screening (73).

The AMPLICOR Human Papillomavirus Test

(Amplicor; Roche Diagnostics, Almere, The

Netherlands) has broad-spectrum primers that amplify

a region of 165 bp from L1. Complementary probes can

detect presence of amplification products of 13 hrHPVs

by measuring the optical density in a microtiter plate. A

beta-globin internal control target is amplified in the

same PCR reaction and detected in a separate microtiter

plate. Amplicor has not been clinically validated

according to the international criteria (73). In a triage

population, the clinical sensitivity of Amplicor was only

marginally higher compared to HC2, but its clinical

specificity was significantly lower (91). Two other

studies reported equivalent clinical sensitivity and

specificity for Amplicor and HC2 in triage populations

(92, 93). Roche developed and introduced the Cobas

4800 HPV Test (Cobas; Roche Diagnostics) as an

alternative for Amplicor because it has an improved

clinical specificity.

1.4.21.4.21.4.21.4.2 HPV DNA detection tests with partial HPV DNA detection tests with partial HPV DNA detection tests with partial HPV DNA detection tests with partial

genotypinggenotypinggenotypinggenotyping

A recent generation of HPV tests offers concurrent

identification of a restricted number of HPVs in

addition to pooled hrHPV detection (designated as

partial genotyping). Partial genotyping is usually

limited to HPV16 and 18, with the remaining hrHPVs

detected as a group. Separate identification of HPV16

and 18 might be of use in clinical management, due to

their increased risk for cervical cancer compared to

other hrHPVs.

QuantitaQuantitaQuantitaQuantitatitititive PCR amplificationve PCR amplificationve PCR amplificationve PCR amplification

In HPV tests with quantitative PCR (qPCR) technology,

Taqman probes labeled with a fluorescent dye can

hybridize with the amplimer during every annealing

step. The increase in fluorescence can be monitored

real-time during the exponential increase of amplified

viral target DNA, until limiting reagents, accumulation

of inhibitors or inactivation of the polymerase affect the

PCR efficiency. The first cycle where generated

fluorescence can be distinguished from the background

signal is called the threshold cycle (Ct) or quantification

cycle (Cq). The initial concentration of the measured

target is correlated to the Cq value, and can be

quantified by including a standard curve dilution series.

The Cobas 4800 HPV Test (Cobas) enables the

qualitative, simultaneous detection of 14 hrHPVs using

qPCR amplification of a region in L1. This test provides

individual genotyping of HPV16 and 18, if desired, and

a beta-globin internal control target in the same PCR

reaction. The Cobas is intended for cervical cancer risk

screening in combination with cytology (co-testing) and

for management of women with equivocal cytology

results. In recent years, its clinical value has been

supported by the ATHENA trial (94) and by

comparison with a reference test (95).

Similar to Cobas, the Abbott RealTime High Risk

HPV test (Abbott RealTime HR HPV test; Abbott,

23



Wiesbaden, Germany) provides qPCR-based detection

of 14 hrHPVs, concurrent HPV16/18 genotyping, and a

beta-globin internal control. A modified GP5+/6+

primer mix is used for L1-based viral amplification (96).

The Abbott RealTime HR HPV test has been clinically

validated for HPV-based cervical cancer screening in

women aged 30 years and older in several studies (96-

98).

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

The Netherlands) is an E7-based broad-spectrum qPCR,

which offers detection of 14 hrHPVs and HPV67, with

concurrent HPV16/18 genotyping and sample quality

assessment using an endogenous human beta-globin

internal control target. This assay meets the clinical and

reproducibility criteria of the international guidelines

(73) and is also compatible with specimens that were

self-collected using lavage- and brush-based devices

(99).

The BD Onclarity HPV Assay (Onclarity; Becton

Dickinson, Sparks, MD, USA) is an E6/E7-based qPCR,

enabling detection of 14 hrHPVs in three separate

reactions. Concurrent genotyping is offered for six

types (i.e., HPV16, 18, 31, 45, 51 and 52), while the

remaining hrHPVs are detected as three separate

groups (i.e., HPV33/58, HPV56/59/66, and

HV35/39/68). The test also detects human beta-globin

as an endogenous internal control. The Onclarity has

been clinically validated according to the international

guidelines (100).

Signal amplificationSignal amplificationSignal amplificationSignal amplification

The Cervista HPV 16/18 Test (Cervista HPV16/18;

Hologic) is a reflex test for women that tested positive

by the Cervista HPV HR Test. The Cervista HPV16/18

can determine presence of HPV16 and/or 18 using the

same Invader chemistry as the Cervista.

1.4.31.4.31.4.31.4.3 HPV DNA full genotyping tests using HPV DNA full genotyping tests using HPV DNA full genotyping tests using HPV DNA full genotyping tests using

broadbroadbroadbroad----spectrum PCRspectrum PCRspectrum PCRspectrum PCR

HPV tests with a full genotyping capability for a wide

range of HPV genotypes have great value in estimating

the epidemiological burden of HPV infections and the

efficacy of vaccines, while evidence for the clinical

utility of full genotyping is limited.

BroadBroadBroadBroad----spectrum PCR amplification and reverse spectrum PCR amplification and reverse spectrum PCR amplification and reverse spectrum PCR amplification and reverse

hybridizationhybridizationhybridizationhybridization

The LiPA25 version 1 (Labo Bio-medical Products) is

used for identification of 25 individual HPV genotypes

by reverse hybridization of generated SPF10 amplimers

with genotype-specific probes immobilized on a reverse

hybridization strip. In a combined test algorithm, SPF10

amplimers that are positive by the DEIA (Labo Bio-

medical Products) can be used directly for LiPA25,

eliminating the need for a separate PCR reaction (81,

82). This algorithm has been used in the

aforementioned epidemiological and vaccine efficacy

studies.

The INNO-LiPA HPV Genotyping Extra (INNO-

LiPA; Innogenetics, Gent, Belgium) is another SPF10-

based reverse hybridization strip with similar

technology as the LiPA25 version 1 algorithm, but there

are significant differences. The INNO-LiPA uses

different SPF10 PCR primers and reverse hybridization

probes than LiPA25, does not have a separate DEIA for

detection of a broad-spectrum of HPV types, and offers

a concurrent internal control (HLA-DPB1 gene). The

intended use of INNO-LiPA is currently unclear.

INNO-LIPA has been used in a clinical evaluation (101),

but has not (yet) been fully clinically validated in a

randomized controlled trial or by non-inferiority to a

reference test according to defined guidelines (73). In

addition, it has been used in epidemiologic studies

(102-104), but the analytical sensitivity of INNO-LiPA

remains to be investigated.

The LINEAR ARRAY HPV Genotyping Test (LA;

Roche Diagnostics) is a reverse hybridization strip with

immobilized probes for the recognition of 37 anogenital

HPV (sub)types and an internal control target (beta-

globin) (105). Degenerated PGMY primers are used for

broad-spectrum amplification of a viral DNA fragment

of 450 bp in the L1 ORF (105). LA is intended for the

qualitative in vitro test for detection of HPV in clinical

24

Chapter 1


specimens. LA has been applied in epidemiological

studies (32, 106), but has not been clinically validated.

The Reverse Line Blot (RLB) is an in-house assay

for the identification of 37 HPVs using the same

GP5+/6+ amplification products as the EIA (89, 107).

Oligonucleotide probes are attached to a nylon

membrane in parallel lines, and PCR products are

hybridized perpendicularly using a miniblotter. Hybrids

are visualized by a conjugate-substrate reaction. The

RLB has been used in a case-control study by WHO

IARC to define the risk-classification of individual

genotypes (24), but also in a screening setting, to

identify the respective HPV type(s) in women testing

positive for hrHPV by EIA (108).

Two commercially available alternative assays for

the genotyping of GP5+/6+ amplimers have been

recently developed, using the same probes as the RLB

with minor modifications. The Genotyping Kit HPV GP,

version 1 (GP5+/6+ strip, Diassay, Rijswijk, The

Netherlands; previously marketed as digene HPV

Genotyping RH Test) is a strip-based reverse

hybridization assay for identification of 14 hrHPVs and

4 probably hrHPVs. This assay was designed as an easy-

to-use alternative for RLB and could be used for reflex

genotyping following hrHPV positivity by HC2 or EIA.

The LMNX Genotyping Kit HPV GP (GP5+/6+ LMNX,

Diassay; previously marketed as digene HPV

Genotyping LQ Test) provides identification of the

same HPVs, but read-out is performed using bead-

based xMAP technology on a Luminex platform. This

platform is more suitable for high-throughput testing,

enabling the GP5+/6+ LMNX to be used as a reflex

genotyping test but also as a stand-alone test for hrHPV

detection and concurrent genotyping, if desired.

The PapilloCheck HPV-Screening (PapilloCheck;

Greiner Bio-One GmbH, Frickenhausen, Germany) is a

PCR-microarray and allows identification of 24 types,

including 14 hrHPVs. Broad-spectrum primers amplify

a 350 bp region from the E1 ORF. A region in the

human ADAT1 gene is amplified to confirm presence

of human DNA and a control-template is present in the

PCR master mix to rule out inhibition of amplification.

Fluorescently labeled amplification products hybridize

with specific DNA probes fixed on a DNA chip and are

measured. PapilloCheck has been clinically validated for

simultaneous detection of 14 hrHPVs according to the

requirements for clinical sensitivity and specificity (109).

1.4.41.4.41.4.41.4.4 HPV DNA full genotyping tests usiHPV DNA full genotyping tests usiHPV DNA full genotyping tests usiHPV DNA full genotyping tests using typeng typeng typeng type----

specific specific specific specific (q)PCR(q)PCR(q)PCR(q)PCR

TypeTypeTypeType----specific PCR amplificationspecific PCR amplificationspecific PCR amplificationspecific PCR amplification

Separate type-specific (TS) PCRs for HPV16 and 18 have

been developed (71) and incorporated into the HPV

testing algorithm that was used in the two largest

efficacy trials of the bivalent vaccine, PATRICIA and

CVT. These assays utilize TS primers targeting short

regions in the E6/E7 ORF (HPV16; 92 bp) and in the L1

ORF (HPV18; 126 bp) for endpoint PCR amplification,

followed by read-out using DEIA technology, as

described before (71). The combination of the L1-based

SPF10 broad-spectrum PCR algorithm followed by TS

HPV16/18 PCRs provided a higher analytical accuracy

than both assays alone (71).

Recently, two novel assays for multiplex type-

specific (MPTS) amplification of regions in E6, were

introduced, i.e., MPTS12 and MPTS123 (Labo Bio-

medical Products). In MPTS12 amplification is

performed in two separate TS PCRs, and pooled

amplification products are genotyped by strip-based

reverse hybridization targeting 9 hrHPVs, i.e., HPV16,

18, 31, 33, 35, 45, 52, 58, and 59 (110). MPTS123

requires performance and pooling of three separate

PCRs, and utilizes bead-based xMAP technology for

identification of 14 hrHPVs and 2 lrHPVs (HPV6 and

11) on a Luminex platform (72). These assays were

designed to be used in conjunction with the SPF10

LiPA25 system and improved the analytical accuracy for

a broader range of HPVs, similar to the TS16/18 assays.

This is particularly important when investigating the

cross-protection of the bivalent vaccine against other

types than HPV16/18 (86).

25



TypeTypeTypeType----specific qspecific qspecific qspecific quantitauantitauantitauantitatitititive PCR amplificationve PCR amplificationve PCR amplificationve PCR amplification

TS HPV qPCR assays were internally developed at

Merck Research Laboratories (MRL) and used for

efficacy determination in the Phase III trials of the

quadrivalent vaccine, e.g., the FUTURE I and II (111,

112). Merck TS HPV qPCR assays are a set of type-

specific PCRs for amplification of multiple sequences

simultaneously, i.e., in the L1, E6, and E7 ORFs (of

HPV6, 11, 16, 18, 31, 45, 52, and 58) or in the E6 and E7

ORFs (of HPV33, 35, 39, 51, 56, and 59) (113-115). The

triplex or duplex qPCR is performed for each HPV type

individually. These assays appeared to have a higher

analytical sensitivity than INNO-LiPA HPV

Genotyping Extra in a direct analytical comparison,

with a limit of detection (LOD) that was below 50

copies/test for all HPVs targeted (114).

An in-house method comprising a set of E6/E7-

based type-specific qPCRs for 13 hrHPVs and 4

additional HPVs was developed at the RIATOL

laboratory in Antwerpen, Belgium. A separate beta-

globin qPCR is performed as an endogenous internal

control to assess specimen quality. A density

sedimentation method has been implemented in the

processing of clinical specimens (116). The clinical

validation of the RIATOL qPCRs was reported by

Depuydt et al (117).

1.4.51.4.51.4.51.4.5 HPV mRNA detection testsHPV mRNA detection testsHPV mRNA detection testsHPV mRNA detection tests

The detection of hrHPV mRNA encoding viral

oncoproteins E6 and E7 instead of DNA might allow

better distinction between productive (low expression

of E6/E7) and transforming (high expression of E6/E7)

infections (118). Overexpression of E6 and E7 is

required for malignant transformation in HPV-related

cancers.

The Aptima HPV assay (Aptima; Hologic Gen-

Probe, San Diego, CA, USA) is an HPV assay designed

for pooled detection of E6/E7 mRNA from 14 hrHPVs.

Aptima is based on target capture after cell lysis, with

subsequent transcription-mediated amplification (TMA)

and probe hybridization protection for detection of

E6/E7 mRNA expression (119, 120). Aptima met the

cross-sectional clinical and reproducibility criteria of

the international guidelines for HPV test requirements

for cervical screening (121). It was noted that these

requirements for cross-sectional equivalence were

formulated for HPV DNA tests and may not necessarily

be valid for other molecular markers, e.g., E6/E7 mRNA.

Longitudinal data are needed to ensure that the long-

term negative predictive value of this mRNA assay is

similar to those of validated HPV DNA tests and allows

for the same screening intervals (121).

1.4.61.4.61.4.61.4.6 HPV16 intratyHPV16 intratyHPV16 intratyHPV16 intratypic variant analysispic variant analysispic variant analysispic variant analysis

Sanger sequence analysis of parts of the HPV16 genome,

e.g., E6, L1 and the long control region (LCR) (17, 122)

was used to identify different HPV16 variants, which

were associated with human population migrations and

continent of origin (18) (Table 1). More recently, a

novel HPV16 variant reverse hybridization assay (RHA)

was developed and evaluated for simple and accurate

recognition of these HPV16 variant lineages (123). This

assay uses E6-based PCR amplification of a large, single

region (570 bp) for clinical specimens of sufficient

quality, or uses primer sets that generate four smaller,

overlapping regions for samples in which DNA is

poorly preserved. The generated amplification products

encompass variant-specific single nucleotide

polymorphisms (SNPs) that are targeted by

oligonucleotide probes in a strip-based RHA. This assay

can differentiate between the four main lineages A

(European&Asian), B (African 1), C (African 2) and D

(North-American&Asian-American), and has the

resolution to distinguish some sublineages, i.e., A1&A2

(European) from A3 (Asian) within the main lineage A,

and D1 (North-American) from D2&D3 (Asian-

American) within the main lineage D.

The characteristics of HPV tests described in

this chapter are summarized in Table 4.

26

Chapter 1


Ta

ble

4:

Ta

ble

4:

Ta

ble

4:

Ta

ble

4:

Bri

ef o

verv

iew

of

a s

elec

tio

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f H

PV

tes

ts,

sum

mar

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g th

eir

tech

nic

al

cha

ract

eris

tics

(H

PV

s ta

rget

ed,

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gen

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cap

ab

ilit

y, t

ech

nol

ogy,

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ma

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nd

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Inte

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In

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Inte

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end

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chap

ter:

chap

ter:

chap

ter:

chap

ter:

HC

2 13

hrH

PV

s N

on

e Si

gnal

am

pli

fica

tio

n

by

hyb

rid

cap

ture

DN

A

No

/n.a

. Sc

reen

ing

Tri

age

afte

r cy

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gy

Tes

t-of

-cu

re

NT

CC

AR

TIS

TIC

VU

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RE

EN

3, 4

Cer

vist

a 14

hrH

PV

s N

on

ec

Sign

al a

mp

lifi

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on

by

inva

der

ch

emis

try

DN

A

Yes

/n.a

. Sc

reen

ing

(wit

h c

yto

logy

)

Tri

age

afte

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tolo

gy

Bel

inso

n, 2

011

(76)

Bo

ers,

201

4 (7

7)

-

Ap

tim

a 14

hrH

PV

s N

on

e T

ran

scri

pti

on-

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iate

d

amp

lifi

cati

on

an

d

pro

be

hyb

rid

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ion

mR

NA

, E6/

E7

d

No

/yes

Sc

reen

ing

(wit

h c

yto

logy

,

amo

ng

>30

yrs

)

Tri

age

afte

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gy

(am

on

g >

21yr

s)

Wu

, 201

0 (1

19)

Mon

son

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, 201

2 (1

20)

Hei

dem

an, 2

013

(121

)

-

Co

bas

14

hrH

PV

s H

PV

16&

18

BS-

qP

CR

D

NA

, L1,

~20

0 bp

Y

es/n

o

Scre

enin

g (w

ith

cyt

olo

gy)

Tri

age

afte

r cy

tolo

gy

AT

HE

NA

Hei

dem

an, 2

011

(95)

-

Ab

bot

t

Rea

lTim

e H

R

HP

V

14 h

rHP

Vs

HP

V16

&18

B

S-q

PC

R

DN

A, L

1, ~

150

bp

Yes

/no

N

ot

spec

ifie

d. C

lin

ical

ly

vali

dat

ed

Car

ozz

i, 20

11 (

96)

Po

ljak

, 201

1 (9

7)

Hes

seli

nk,

201

3 (9

8)

-

HP

V-R

isk

assa

y 15

hrH

PV

s H

PV

16&

18

BS-

qP

CR

D

NA

, E7,

~15

0 bp

Y

es/n

o

Scre

enin

g

Tri

age

afte

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gy

Tes

t-of

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re

Hes

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4 (9

9)

-

On

clar

ity

14 h

rHP

Vs

HP

V16

&18

&3

1&45

&51

&52

e

Th

ree

sep

arat

e B

S-

qP

CR

s

DN

A, E

6/E

7d

Yes

/no

N

ot

spec

ifie

d. C

lin

ical

ly

vali

dat

ed

Eje

god

, 201

3 (1

00)

-

Ria

tol

(in

-

hou

se)

13 h

rHP

Vs

and

4 o

ther

HP

Vs

Fu

ll

TS-

qP

CR

s fo

r ea

ch

typ

e se

par

atel

y

DN

A, E

6/E

7d

Yes

f /no

N

ot

spec

ifie

d. C

lin

ical

ly

vali

dat

ed

Dep

uyd

t, 2

012

(117

) -

Pap

illo

Ch

eck

14 h

rHP

Vs

and

10 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, E

1, ~

350

bp

Yes

/yes

N

ot

spec

ifie

d. C

lin

ical

ly

vali

dat

ed

Hes

seli

nk,

201

0 (1

09)

-

GP

5+/6

+-E

IA

14 h

rHP

Vs

No

ne

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

150

bp

Yes

f /no

Sc

reen

ing

Tri

age

afte

r cy

tolo

gy

Tes

t-of

-cu

re

PO

BA

SCA

M

SWE

DE

SCR

EE

N

10, 1

1

27



HP

V t

est

HP

V t

est

HP

V t

est

HP

V t

est

HP

Vs

det

ecte

dH

PV

s d

etec

ted

HP

Vs

det

ecte

dH

PV

s d

etec

ted

a aaa C

on

curr

ent

Co

ncu

rren

t C

on

curr

ent

Co

ncu

rren

t

gen

oty

pin

gge

no

typ

ing

gen

oty

pin

gge

no

typ

ing

Tec

hn

olo

gyT

ech

no

logy

Tec

hn

olo

gyT

ech

no

logy

T

arge

tT

arge

tT

arge

tT

arge

t In

tern

al c

on

tro

l:

Inte

rnal

co

ntr

ol:

In

tern

al c

on

tro

l:

Inte

rnal

co

ntr

ol:

end

oge

no

us/

end

oge

no

us/

end

oge

no

us/

end

oge

no

us/

exo

gen

ou

sex

oge

no

us

exo

gen

ou

sex

oge

no

us

Ma

Ma

Ma

Mai

n i

nd

icat

ed u

sein

in

dic

ated

use

in i

nd

icat

ed u

sein

in

dic

ated

use

S

up

po

rtin

g S

up

po

rtin

g S

up

po

rtin

g S

up

po

rtin

g tr

ials

an

d/o

r tr

ials

an

d/o

r tr

ials

an

d/o

r tr

ials

an

d/o

r

stu

die

sst

ud

ies

stu

die

sst

ud

iesb bbb

Th

is

Th

is

Th

is

Th

is

thes

is,

thes

is,

thes

is,

thes

is,

chap

ter:

chap

ter:

chap

ter:

chap

ter:

GP

5+/6

+

LM

NX

(L

Q

Tes

t)g

14 h

rHP

Vs

and

4 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

150

bp

Yes

/no

Sc

reen

ing

Tri

age

afte

r cy

tolo

gy

Tes

t-of

-cu

re

- 4,

5, 1

0, 1

1

GP

5+/6

+ R

LB

(in

-hou

se)

14 h

rHP

Vs

and

23 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

150

bp

No

/no

E

pid

emio

logy

an

d r

efle

x

gen

oty

pin

g af

ter

hrH

PV

po

siti

vity

by

EIA

Van

den

Bru

le, 2

002

(107

)

Mu

no

z, 2

003

(24)

Rij

kaar

t, 2

012

(108

)

3, 4

GP

5+/6

+ s

trip

(v1)

(R

H T

est)

h

14 h

rHP

Vs

and

4 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

150

bp

No

/no

R

efle

x ge

no

typ

ing

afte

r

hrH

PV

po

siti

vity

by

EIA

- 3,

5

PG

MY

Lin

ear

Arr

ay

14 h

rHP

Vs

and

23 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

450

bp

Yes

/no

N

ot

spec

ifie

d. U

sed

in

epid

emio

logi

cal

and

surv

eill

ance

stu

die

s. N

ot

clin

ical

ly v

alid

ated

Co

utl

ee, 2

006

(105

)

Wh

eele

r, 2

014

(32)

Tra

biz

i, 2

014

(106

)

-

Am

pli

cor

13 h

rHP

Vs

No

ne

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, ~

165

bp

Yes

f /no

N

ot

spec

ifie

d. N

ot

clin

ical

ly

vali

dat

ed (

rep

lace

d b

y C

ob

as)

Car

ozz

i, 20

07 (

92)

Mo,

200

8 (9

3)

Wen

tzen

sen

, 200

9 (9

1)

5

SFP

10 D

EIA

(ver

sio

n 1

)

14 h

rHP

Vs

and

at l

east

55

oth

er

HP

Vs

No

ne

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, 6

5 b

p

No

/no

V

acci

ne

tria

ls, s

urv

eill

ance

and

ep

idem

iolo

gy

Kle

ter,

199

8 (8

1)

PA

TR

ICIA

CV

T

Tja

lma,

201

2 (6

6)

2, 6

, 7, 8

, 9,

11

SPF

10 L

iPA

25

(ver

sio

n 1

)

14 h

rHP

Vs

and

11 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, 6

5 b

p

No

/no

V

acci

ne

tria

ls, s

urv

eill

ance

and

ep

idem

iolo

gy

Kle

ter,

199

9 (8

2)

PA

TR

ICIA

CV

T

Tja

lma,

201

2 (6

6)

2, 6

, 7, 8

, 9,

11

SPF

10 I

NN

O-

LiP

A e

xtra

14 h

rHP

Vs

and

14 o

ther

HP

Vs

Fu

ll

BS-

PC

R a

nd

pro

be

hyb

rid

izat

ion

DN

A, L

1, 6

5 b

p

Yes

/no

N

ot

spec

ifie

d. U

sed

in

epid

emio

logi

cal

stu

die

s. N

ot

clin

ical

ly v

alid

ated

Bar

zon

, 201

2 (1

01)

Dar

tell

, 201

3 (1

02)

Co

lon

-Lo

pez

, 201

4 (1

03)

Kja

er, 2

014

(104

)

2

Mer

ck T

S

qP

CR

s

13 h

rHP

Vs

and

two

oth

er H

PV

s

Fu

ll

TS-

qP

CR

s fo

r ea

ch

typ

e se

par

atel

y

DN

A, L

1&E

6&E

7

or E

6&E

7d,i

Yes

f /no

V

acci

ne

tria

ls

Els

e, 2

011

(114

)

FU

TU

RE

I

FU

TU

RE

II

-

28

Chapter 1


HP

V t

est

HP

V t

est

HP

V t

est

HP

V t

est

HP

Vs

det

ecte

dH

PV

s d

etec

ted

HP

Vs

det

ecte

dH

PV

s d

etec

ted

a aaa C

on

curr

ent

Co

ncu

rren

t C

on

curr

ent

Co

ncu

rren

t

gen

oty

pin

gge

no

typ

ing

gen

oty

pin

gge

no

typ

ing

Tec

hn

olo

gyT

ech

no

logy

Tec

hn

olo

gyT

ech

no

logy

T

arge

tT

arge

tT

arge

tT

arge

t In

tern

al c

on

tro

l:

Inte

rnal

co

ntr

ol:

In

tern

al c

on

tro

l:

Inte

rnal

co

ntr

ol:

end

oge

no

us/

end

oge

no

us/

end

oge

no

us/

end

oge

no

us/

exo

gen

ou

sex

oge

no

us

exo

gen

ou

sex

oge

no

us

Ma

Ma

Ma

Mai

n i

nd

icat

ed u

sein

in

dic

ated

use

in i

nd

icat

ed u

sein

in

dic

ated

use

S

up

po

rtin

g S

up

po

rtin

g S

up

po

rtin

g S

up

po

rtin

g tr

ials

an

d/o

r tr

ials

an

d/o

r tr

ials

an

d/o

r tr

ials

an

d/o

r

stu

die

sst

ud

ies

stu

die

sst

ud

iesb bbb

Th

is

Th

is

Th

is

Th

is

thes

is,

thes

is,

thes

is,

thes

is,

chap

ter:

chap

ter:

chap

ter:

chap

ter:

TS1

6/18

H

PV

16 a

nd

18

F

ull

T

S-P

CR

s an

d p

rob

e

hyb

rid

izat

ion

sep

arat

ely

DN

A, E

6/E

7, 9

2 b

p

and

L1,

126

bp

No

/no

V

acci

ne

tria

ls

Van

Do

orn

, 200

6 (7

1)

PA

TR

ICIA

CV

T

-

MP

TS1

2

HP

V16

, 18,

31,

33, 3

5, 4

5, 5

2,

58, a

nd

59

Fu

ll

Tw

o se

par

ate

TS-

PC

Rs

and

on

e p

robe

hyb

rid

izat

ion

DN

A, E

6, 5

5-13

9

bp

No

/no

V

acci

ne

tria

ls

Van

Ale

wij

k, 2

013

(72)

Skin

ner

, 201

4 (1

10)

-

MP

TS1

23

14 h

rHP

Vs

and

2 o

ther

HP

Vs

Fu

ll

Th

ree

sep

arat

e T

S-

PC

Rs

and

on

e p

robe

hyb

rid

izat

ion

DN

A, E

6, 5

5-13

9

bp

No

/no

V

acci

ne

tria

ls

Van

Ale

wij

k, 2

013

(72)

2

HP

V16

var

ian

t

RH

A

HP

V16

mai

n

vari

ant

lin

eage

s

n.a

.T

S-P

CR

an

d p

rob

e

hyb

rid

izat

ion

DN

A, E

6, 5

70 b

pj

No

/no

N

atu

ral h

isto

ry a

nd

epid

emio

logi

cal

stu

die

s o

f

HP

V16

var

ian

t in

fect

ion

s

San

chez

, 201

1 (1

23)

9

a Un

less

oth

erw

ise

spec

ifie

d,

13

hrH

PV

s re

fers

to

type

s 1

6,

18

, 3

1, 3

3, 3

5, 3

9, 4

5,

51,

52,

56,

58

, 5

9,

an

d 6

8;

14

hrH

PV

s re

fers

to

afo

rem

enti

oned

typ

es p

lus

HP

V6

6;

15

hrH

PV

s re

fers

to

afo

rem

enti

on

ed t

ypes

plu

s H

PV

66 a

nd

67

. b T

he

clin

ica

l tr

ials

are

: N

TC

C (

61);

AR

TIS

TIC

(6

0);

VU

SASC

RE

EN

(7

5);

PO

BA

SCA

M (

56);

SW

ED

ESC

RE

EN

(6

2);

AT

HE

NA

(9

4);

PA

TR

ICIA

(85

); C

VT

(8

3);

FU

TU

RE

I (

11

1);

FU

TU

RE

II

(112

).

c Cer

vist

a of

fers

no

con

curr

ent

gen

otyp

ing.

Par

tial

gen

otyp

ing

for

HP

V1

6 a

nd

18

is p

ossi

ble

th

rou

gh r

efle

x te

stin

g u

sin

g a

sep

ara

te a

ssa

y (C

ervi

sta

HP

V 1

6/1

8 T

est)

. dSi

ze o

f re

gio

n(s

) ta

rget

ed b

y p

rim

ers

not

sp

ecif

ied

in

kit

man

ua

l or

lit

era

ture

e O

ncl

ari

ty d

etec

ts a

dd

itio

na

l h

rHP

Vs

as t

hre

e gr

oups

, i.

e.,

33/5

8, 5

6/59

/66

, an

d 3

5/3

9/6

8.

f Inte

rnal

con

trol

an

alys

is i

s p

erfo

rmed

in

a s

epar

ate

ass

ay

in p

ara

llel

wit

h H

PV

an

aly

sis.

g Th

e L

MN

X G

enot

ypin

g ki

t H

PV

GP

(G

P5

+/6

+ L

MN

X; D

iass

ay B

V)

was

pre

viou

sly

mar

ket

ed a

s th

e d

igen

e H

PV

Gen

oty

pin

g L

Q T

est

(LQ

Tes

t, Q

iage

n).

hT

he

Gen

otyp

ing

kit

HP

V G

P,

vers

ion

1 (

GP

5+

/6+

str

ip; D

iass

ay

BV

) w

as

pre

vio

usl

y m

ark

eted

as

the

dig

ene

HP

V G

enot

ypin

g R

H T

est

(RH

Tes

t, Q

iage

n).

i A

tri

ple

x q

PC

R t

arg

ets

seq

uen

ces

in L

1,

E6

, an

d E

7 f

or H

PV

6,

11,

16,

18,

31,

45,

52,

an

d 5

8;

A d

upl

ex q

PC

R t

arg

ets

sequ

ence

s in

E6

an

d E

7 f

or H

PV

33,

35,

39,

51,

56,

an

d 5

9.

j In c

ase

of

spec

imen

s w

ith

poo

rly

pre

serv

ed D

NA

, fo

ur

sma

ller

, ov

erla

ppi

ng

fra

gmen

ts o

f 1

04,

109

, 65

, an

d 6

9 bp

, re

spec

tive

ly,

can

be

am

plif

ied

.

29



1.51.51.51.5 THESIS OUTLINETHESIS OUTLINETHESIS OUTLINETHESIS OUTLINE

In this thesis we aimed to evaluate a number of

established and novel PCR-based technologies for the

identification of HPVs, and apply these in

epidemiologic and clinical studies in accordance with

their intended use. These novel technologies comprise

additions and improvements to two established PCR-

based (hr)HPV test algorithms, which are current “gold

standards” for epidemiologic and for clinical purposes,

i.e., the SPF10 LiPA25 (version 1) (Figure 5) and the

GP5+/6+ EIA (Figure 6), respectively.

This thesis is divided into three main parts: 1) the

assessment of analytical accuracy of several recently

developed assays for HPV genotyping (Chapters 2Chapters 2Chapters 2Chapters 2----5555), 2)

the application of (novel) techniques for HPV

characterization in several avenues of research

(Chapters Chapters Chapters Chapters 6666----9999), and 3) the utility of novel

methodologies for hrHPV detection and self-sample

collection within a clinical setting (Chapters 10Chapters 10Chapters 10Chapters 10----11111111).

The findings of this thesis are discussed in the context

of other studies in the general discussion (Chapter 12Chapter 12Chapter 12Chapter 12).

Part1: Chapters 2 to 5 are technical chapters. These focus

on evaluating the analytical accuracy of novel HPV

genotyping assays.

Recently, three novel tests for HPV genotyping have

been introduced, i.e., INNO-LiPA HPV Genotyping

Extra (INNO-LiPA), the GP5+/6+ strip (previously

marketed as digene HPV Genotyping RH Test) and the

GP5+/6+ LMNX (previously marketed as digene HPV

Genotyping LQ Test). Each test was evaluated against

an established genotyping assay that is relevant for its

intended use (‘gold standard’), i.e., analytical or clinical.

The INNO-LiPA was compared to the original SPF10

LiPA25 strip (version 1), the analytically sensitive gold

standard assay for epidemiologic studies and vaccine

trials (Chapter 2Chapter 2Chapter 2Chapter 2). Both assays were evaluated on a

selected panel of cervical swabs and biopsies, the two

types of specimens mostly used in epidemiologic HPV

research.

In contrast, the GP5+/6+ strip and GP5+/6+

LMNX were evaluated against the Reverse Line Blot

assay, an established in-house method for reflex

genotyping following the clinically validated GP5+/6+

PCR, in Chapter 3Chapter 3Chapter 3Chapter 3 and Chapter 4Chapter 4Chapter 4Chapter 4, respectively.

Accurate identification of individual hrHPVs by these

assays might be valuable for further risk stratification of

women that tested hr HPV positive in a clinical setting.

In Chapter 5Chapter 5Chapter 5Chapter 5, we investigated if the GP5+/6+ strip and

GP5+/6+ LMNX can be used for direct genotyping of

PCR products generated by another hrHPV test, i.e.,

Amplicor, in addition to the GP5+/6+ amplicons.

Part 2: Chapters 6 to 9 describe the applications of

genotyping assays in a research setting, e.g., surveillance

of prevalence, epidemiology (disease association), and

natural history of HPV infections

The SPF10 LiPA25 algorithm was used to determine the

prevalence of and determinants for hrHPV genotypes in

Paramaribo, Suriname, providing baseline data prior to

implementation of an HPV vaccination program in

2013 (Chapter 6Chapter 6Chapter 6Chapter 6). Pre- and post-vaccination

surveillance of HPV prevalence is important for short-

term evaluation of the effects of a local HPV

vaccination program.

Chapter 7Chapter 7Chapter 7Chapter 7 describes the HPV genotype

distribution established by the SPF10 LiPA25 algorithm

in a worldwide collection of 10,575 cases of invasive

cervical carcinoma (ICC). The estimated attribution of

individual HPVs to ICC can provide insight into which

types should be given priority for assessment of cross-

protective effects of current vaccines and for

development of second-generation polyvalent vaccines.

In the same collection of ICC, we investigated the

presence of HPV types rarely targeted by current HPV

genotyping tests, using a novel sequence methodology

(Chapter 8Chapter 8Chapter 8Chapter 8). The contribution of rare HPVs classified

as possibly high-risk (Class 2B) due to their

phylogenetic relation with established hrHPVs (Class

1/2A), is of particular interest. Class 2B HPVs are

30

Chapter 1


currently not targets of hrHPV tests intended for

cervical cancer screening, but their occurrence as single

infections in ICC could strengthen the circumstantial

evidence of a carcinogenic role.

In Chapter 9Chapter 9Chapter 9Chapter 9, we performed a longitudinal study

towards the natural history of infections with different

variant lineages of HPV16, the most carcinogenic HPV

type. European, African, Asian, North American and

Asian-American HPV16 variants were studied in

cervical swabs, whole-tissue sections and laser-capture

micro-dissected regions from biopsies, using a recently

developed HPV16 variant reverse hybridization assay.

We aimed to determine the prevalence of the different

variant lineages, and the dynamics of these infections

over time.

Part 3: Chapters 10 and 11 describe the applications of

genotyping assays in a clinical setting, e.g., for primary

cervical cancer screening and combined with a self-

sampling device.

Chapter 10 Chapter 10 Chapter 10 Chapter 10 describes a clinical evaluation of the

GP5+/6+ LMNX using the GP5+/6+ EIA as a clinically

validated comparator hrHPV test. The utilized sample

panel was collected from a cervical cancer screening

setting by an international consortium (VALGENT)

and provides a cross-sectional clinical equivalence

comparison. A non-inferiority analysis of sensitivity

and specificity for detecting women with CIN2+ and

CIN3+ allows clinical validation of the GP5+/6+ LMNX

for screening purposes.

HrHPV analysis performed on cervicovaginal self-

collected specimens seems a suitable alternative for

liquid-based cervical specimens collected by a physician,

particularly for non-responders in cervical cancer

screening and in low-resource settings. The FTA solid-

state carrier cartridge is a novel self-sampling device

and was compared to physician-collected specimens

using two different HPV assays, i.e., GP5+/6+ LMNX

and the SPF10 LiPA25 algorithm, in CCCChapter 11hapter 11hapter 11hapter 11.

31



Figure 5: Figure 5: Figure 5: Figure 5: Schematic overview of the SPF10 LiPA25 (version 1) test algorithm that is currently used as the gold standard

for HPV detection and genotyping in a research setting. Additional or alternative technologies for HPV

characterization that have been recently developed are also shown. The different technologies were evaluated and/or

applied in the indicated chapters of this thesis.

Processed clinical specimen

SPF10 PCR (version 1)

DEIA (version 1)

LiPA25 (version 1)

HPV16 variant RHA

Novel sequence methodology

HPV positive

HPV16 positive

HPV not typed

INNOSPF10 PCR

INNO-LiPA

Chapter 2: Alternative SPF10-based HPV

genotyping algorithm

Chapter 6: Pre-vaccination surveillance

of HPVs in Suriname

Chapter 7: Global attribution of HPVs to

cervical cancer

Chapter 8: Detection of rare, possibly hrHPVs in

cervical cancers

CChhaapptteerr 99:: NNaattuurraall hhiissttoorryy ooff HHPPVV1166 vvaarriiaanntt

iinnffeeccttiioonnss

32

Chapter 1


Figure 6: Figure 6: Figure 6: Figure 6: Schematic overview of the GP5+/6+ EIA test algorithm that is currently regarded as one of the clinically

validated reference assays for hrHPV detection in a clinical setting. Alternative technologies for hrHPV detection and

genotyping as well as a novel method for sample collection are also shown. These novel technologies were evaluated in

the indicated chapters of this thesis.

Chapter 11: Alternative self-sampling method

using FTA solid carrier

Chapter 3: Alternative GP5+/6+-based hrHPV genotyping read-out

Chapter 4: Alternative GP5+/6+-based hrHPV genotyping read-out

Processed clinical specimen

GP5+/6+ PCR

EIA

Reverse Line Blot

hrHPV positive

Chapter 10: Alternative GP5+/6+-based hrHPV

detection read-out

LMNX (LQ Test)

Strip (RH Test)

LMNX (LQ Test)

Amplicor PCR

Amplicor

hrHPV positive

Chapter 5: Direct Amplicor-based hrHPV

genotyping read-out

33



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Documents

CHAPTER 1 1.pdf · Chapter 1. 209130-L-bw-Geraets 1.11.1.111.1 BACKGROUNDBACKGROUND 1.1.11.1.1.1.111.1.1 Short introduction Infection of cervical epithelium with a human papillomavirus