Canadian oncogenic human papillomavirus cervical infection prevalence: Systematic review and meta-analysis

  • Andrea C Tricco1Email author,

    Affiliated with

    • Carmen H Ng2,

      Affiliated with

      • Vladimir Gilca3,

        Affiliated with

        • Andrea Anonychuk4,

          Affiliated with

          • Ba’ Pham5, 6 and

            Affiliated with

            • Shirra Berliner7

              Affiliated with

              BMC Infectious Diseases201111:235

              DOI: 10.1186/1471-2334-11-235

              Received: 1 May 2011

              Accepted: 5 September 2011

              Published: 5 September 2011

              Abstract

              Background

              Oncogenic human papillomavirus (HPV) infection prevalence is required to determine optimal vaccination strategies. We systematically reviewed the prevalence of oncogenic cervical HPV infection among Canadian females prior to immunization.

              Methods

              We included studies reporting DNA-confirmed oncogenic HPV prevalence estimates among Canadian females identified through searching electronic databases (e.g., MEDLINE) and public health websites. Two independent reviewers screened literature results, abstracted data and appraised study quality. Prevalence estimates were meta-analyzed among routine screening populations, HPV-positive, and by cytology/histology results.

              Results

              Thirty studies plus 21 companion reports were included after screening 837 citations and 120 full-text articles. Many of the studies did not address non-response bias (74%) or use a representative sampling strategy (53%).

              Age-specific prevalence was highest among females aged < 20 years and slowly declined with increasing age. Across all populations, the highest prevalence estimates from the meta-analyses were observed for HPV types 16 (routine screening populations, 8 studies: 8.6% [95% confidence interval 6.5-10.7%]; HPV-infected, 9 studies: 43.5% [28.7-58.2%]; confirmed cervical cancer, 3 studies: 48.8% [34.0-63.6%]) and 18 (routine screening populations, 8 studies: 3.3% [1.5-5.1%]; HPV-infected, 9 studies: 13.6% [6.1-21.1%], confirmed cervical cancer, 4 studies: 17.1% [6.4-27.9%].

              Conclusion

              Our results support vaccinating females < 20 years of age, along with targeted vaccination of some groups (e.g., under-screened populations). The highest prevalence occurred among HPV types 16 and 18, contributing a combined cervical cancer prevalence of 65.9%. Further cancer protection is expected from cross-protection of non-vaccine HPV types. Poor study quality and heterogeneity suggests that high-quality studies are needed.

              Keywords

              human papillomavirus systematic review meta-analysis Bethesda system cervical cancer

              Background

              Human Papillomavirus (HPV) is one of the most prevalent sexually transmitted infections in the world [1]. Over 100 virus genotypes have been identified and at least 13 are classified as oncogenic or "high-risk" (HR) because they are known to cause cervical cancer or other genital cancers [2, 3]. The association between HR HPV infection and cervical cancer has been well established in the literature with HR HPV DNA detected in nearly 100% of all cervical cancers [46].

              For nearly half a century, cervical cancer prevention programs consisted mainly of cervical cancer screening for early detection of pre-cancerous lesions [7]. Although screening programs are effective, [8] cervical cancer remains a problem due to a large portion of women who remain unscreened or under-screened, [914] as well as false negative results on the Papanicolau test [15, 16]. In 2009, an estimated 1,300 Canadian women developed cancer of the cervix and 390 died as a result of this disease [8]. The recent introduction of two prophylactic vaccines [17, 18] offer further reduction of HPV, yet the most optimal primary and secondary prevention strategies remain unclear [19, 20].

              Baseline prevalence data is necessary to inform optimal prevention programs and evaluate current and future prevention strategies [21, 22]. Since HPV is not a reportable disease in Canada, data on HPV prevalence are widely scattered in the literature and mainly reported among specific populations. We aimed to consolidate the prevalence of DNA-confirmed cervical HPV infection among Canadian females prior to immunization programs through a systematic review and meta-analysis.

              Methods

              A systematic review protocol was compiled based on guidelines from The Cochrane Collaboration [23] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [24]. The protocol is available upon request.

              Eligibility criteria and study selection

              Studies reporting DNA-confirmed (i.e., through hybrid capture I or hybrid capture II (HCI or HCII) or polymerase chain reaction (PCR)) HPV prevalence estimates among Canadian females who were not previously vaccinated against HPV were included. Authors of studies not reporting the sample size were contacted and the study was excluded if the sample size could not be obtained. Inclusion was not limited by study design, publication status, year of dissemination or language of dissemination.

              In order to ensure reliability, a training exercise was conducted prior to commencing the screening process. Two independent reviewers screened the search results for inclusion using a pre-defined relevance criteria form, obtained the full-text of potentially relevant articles and screened them to determine inclusion. Discrepancies were resolved by discussion or the involvement of a third reviewer.

              Information sources and search

              Medical Subject Headings and text words related to the prevalence of HPV cervical infection among Canadian females were used to search MEDLINE (OVID interface, 1950 to October week 5, 2009), EMBASE (OVID interface, 1980 to 2009 week 44), The Cochrane Library (Wiley interface), and POPLINE (Knowledge for health interface 1970 to Nov 2, 2009). The electronic database search was supplemented by conducting a targeted search of Canadian public health websites (e.g., Public Health Agency of Canada, Health Canada, Institut National de Sante Publique du Quebec), websites of organizations that produce guidelines (e.g., Canadian Agency for Technologies in Health, Society of Obstetrics and Gynecologists of Canada), and vaccine manufacturer websites (e.g., GlaxoSmithKline, Merck). Furthermore, general Internet searches were conducted in Google and the first 60 unique hits were scanned. In addition, the reference lists of included studies were scanned, the authors' personal files were searched, and HPV experts in public health and industry were emailed to ensure that all potentially relevant data was obtained.

              An experienced information specialist conducted all of the literature searches. The search strategy for the main (MEDLINE) search is presented in Additional File 1. It was peer reviewed by another information scientist using Peer Review of Electronic Search Strategies (PRESS) [25]. The main search was modified for the other databases, as necessary (full search strategies for the other databases available upon request).

              Data collection process and data items

              A draft data abstraction form was developed, piloted, and modified as necessary. Two reviewers abstracted all of the data using the standardized data abstraction form, independently. Discrepancies were resolved by discussion or the involvement of a third reviewer.

              The data abstracted included study characteristics, (e.g., study design, period of data collection, sample size, setting, province or territory and city of study conduct), participant characteristics (e.g., population, mean age and standard deviation), HPV detection method (e.g., HC-I or HC-II, PCR), PCR primers (e.g., MY09, MY11), number of HPV positive, as well as the overall HPV prevalence. As done in previous reviews of HPV prevalence, [2628] we focused on HR HPV types commonly recognized to be associated with cervical cancer. These included the following HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 [3]. Specimens that were excluded from study analysis due to inadequate specimen integrity (e.g., negative for β-globin) were not included in the sample size.

              Four of the included studies directly compared prevalence results for different tests (e.g., PCR versus HC-II) or methods (e.g., wood versus plastic spatula; cotton swab versus cytobrush) [2932]. For these studies, prevalence results for the test or method found to be the most sensitive were abstracted. These included HC-II, [31, 32] plastic spatula, [29] and cytobrush [30]. In some instances, multiple study publications reported data from the same population (i.e., companion reports). When this occurred, the report with the largest sample size was included and the other report(s) was used for supplementary data.

              A commonly used and validated quality tool for observational studies does not exist [33]. As such, a generic methodological quality tool was developed and applied to all of the included studies, regardless of study design using a similar format that was used in a previous systematic review [34]. One item was added from The Cochrane Collaboration's Risk of Bias Tool on outcome reporting bias, which ensures that all outcomes that were assessed are reported in the study report [23]. The final tool consisted of the sampling strategy, sensitivity of sampling, timing of sampling, non-response bias, outcome reporting bias, and conflict of interest (Additional File 2).

              Age-specific prevalence synthesis

              Studies reporting the age-specific prevalence of HR HPV infection were plotted and variation due to timing of data collection, HPV detection methods, and study location was noted. In order to ensure consistency across studies, only studies that collected samples in routine screening (i.e., routine Papanicolau test) were included in the plot. These results were described narratively and not combined via meta-analysis to view the wide heterogeneity observed across studies.

              Prevalence meta-analyses

              HPV prevalence among routine screening populations was defined as the proportion of individuals who were positive for HR HPV infection divided by the total population tested for HPV infection. HPV type-specific prevalence among routine screening populations was defined as the proportion of females testing positive for the specific HR HPV type among all of those testing for HPV infection. These analyses only included studies of females engaged in routine screening.

              HR HPV prevalence and HR HPV type-specific prevalence was also calculated for those testing positive for HPV infection. These analyses included studies of females engaged in routine screening, as well as those returning after a previous abnormal cytological test [35].

              HPV type-specific prevalence by cytology or histology was defined as the proportion of individuals testing positive for the specific HR HPV type broken down by the cytological and/or histological category according to the 2001 Bethesda System (Additional File 3) [36]. Studies using routine screening, those returning after a previous abnormal cytological test, as well as those receiving a biopsy were included in this analysis. Individuals diagnosed with squamous cell carcinoma of the cervix and/or aden/adenosquamous carcinoma of the cervix were included in the confirmed cancer category.

              Pooled estimates of type-specific prevalence of HR HPV infection were derived using a random-effects model [37]. The 95% CIs were derived based on a normal distribution. In order to produce conservative prevalence estimates and corresponding 95% CIs, studies reporting zero for the number of positives were imputed as being 0.5. Each HR HPV type was considered individually; hence prevalence estimates might include concomitant infection with other HPV types. All analyses were conducted in SAS 9.1 software (SAS Institute Inc., Cary, NC, USA).

              Results

              Literature search

              The literature search resulted in a total of 837 citations (i.e., titles and abstracts). Thirty study reports [2932, 35, 3862] plus 21 companion reports [27, 28, 6381] fulfilled the inclusion criteria and were included after screening 120 full-text articles (Figure 1).
              http://static-content.springer.com/image/art%3A10.1186%2F1471-2334-11-235/MediaObjects/12879_2011_1581_Fig1_HTML.jpg
              Figure 1

              Study flow.

              Study characteristics

              Data were collected from 1960 [42] to 2007 [48] (Table 1). Sample sizes varied from 46 [38] to 9,620 females [54]. Most of the included studies reported the actual number of HPV positive, except for one study, which reported weighted estimates [39]. Twenty-eight of the included studies were published in journals and two were theses [48, 55]. Six studies reported infection with multiple HPV types (i.e., multiple infection), which was an average of 17.1% (median 4.4%) and ranged from 1.2% to 62.0% [31, 39, 40, 49, 58, 62].
              Table 1

              Study characteristics

              Reference

              Study population; year of data collection; province(s)

              Sample size

              Mean age (SD) or age range

              Method of detection

              #

              cases‡

              HPV types detected

              Overall HPV prevalence

              (any type)†

              HR HPV prevalence

              Methodological quality components

              Peng

              1988 [30]

              Patients with abnormal pap smears

              Dates NR

              Ontario

              200

              NR

              In-situ hybridization

              28 (HR16, 18)

              Specific HPV types probed§

              NA

              14%

              (HR16, 18)

              1.N, 2.Y, 3.U, 4.N, 5.Y, 6.N, 7.Y

              Caussy

              1990 [42]

              Cases with cervical cancer, controls with CIN without cervical cancer

              1960-1986

              British Columbia

              141

              35.6 (24)

              In-situ hybridization

              31

              HR-16, 18

              22%

              17.0%

              1.N, 2.Y, 3.U, 4.Y, 5.N, 6.N, 7.Y

              Duggan

              1990 [29]

              Patients referred to colposcopy clinic

              Dates NR

              Alberta

              119

              NR

              Dot blot hybridization

              28 (HPV 16/18/33)

              HR-16, 18, 33

              LR-6, 11

              NA

              23.5%

              (HPV 16/18/33)

              1.N, 2.Y, 3.U, 4.N, 5.Y, 6.N, 7.U

              Rohan

              1991 [60]

              University Students: Routine Screening

              1990

              Ontario

              105

              23 (median age)

              PCR (E7/E6)

              19

              HR-16, 18, 33

              LR-6, 11

              12.3%

              10.5%

              1.Y, 2.Y, 3.Y, 4.N, 5.Y, 6.Y, 7.Y

              Guijon

              1993 [47]

              Patients referred to colposcopy clinic

              1985-1990

              Manitoba

              409

              25.7 (NR)

              In-situ hybridization

              280

              HR-16, 18, 33

              LR-6, 11

              NA

              68.5%

              (HPV 16/18)

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.N, 7.Y

              Brisson

              1994 [41]

              Patients referred to colposcopy clinic

              1988-1989

              Quebec

              1140

               

              Southern Blot

              28.2 (6.6)

              HR-16, 18

              LR-6, 11

              NA

              24.3% (HPV-16)

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.N, 7.Y

              Bosch

              1995 [38]

              Tumor biopsies of invasive cervical cancer

              1989-1992

              Province NR

              46

              NR

              PCR (MY09/

              MY11)

              43

              HR-16

              93.5%

              91.3%

              1.NA, 2.Y, 3.NA, 4.N, 5.N, 6.Y, 7.Y

              Duggan 1995 [43]*

              [27, 68]

              Cervical cancer tumour biopsies

              1970-1990

              Alberta

              76

              47.3 (16.7)

              Dot blot supplemented by PCR

              53

              All

              70.0%

              65.8%

              1.NA, 2.Y, 3.NA 4.Y, 5.N, 6.Y, 7.Y

              Franco

              1996 [46]

              Cervical cancer tumour biopsies

              1983-1990

              Quebec

              69

              NR

              PCR (GP5+/GP6+)

              59

              HR-16, 18, 31, 33, 35

              LR-6, 11

              85.5%

              40.6%

              (HPV 16/18)

              1.NA, 2.Y, 3.NA, 4.N, 5.N, 6.Y, 7.Y

              Young

              1997 [62]

              General Public (Low-income, inner-city area): Routine Screening

              1992-1995

              Manitoba

              1263

              73% less than 30 years

              PCR (MY09/

              MY11)

              411

              HR-16, 18, 31

              LR-6, 11

              32.5%

              18.0%

              (HPV 16/18)

              1.N, 2.Y, 3.U, 4.N, 5.Y, 6.Y, 7.Y

              Duggan 1997 [44]*

              [67, 69, 70]

              Cervical biopsies

              NR

              Alberta

              525

              28.0

              PCR

              249

              HR-16, 18, 31, 33, 35

              LR-6, 11

              47.4%

              28.0%

              (HPV 16/18)

              1.N, 2.Y, 3.U, 4.Y, 5.Y, 6.Y, 7. U

              Michael

              1999 [55]

              University Students: Routine Screening

              NR

              Ontario

              99

              NR

              PCR (MY09/

              MY11)

              40

              HR-16, 18, 31, 33, 35

              LR-6, 11

              40.4%

              10.1%

              (HPV 16/18)

              1.N, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Hankins 1999 [49]* [63, 64, 66, 71]

              HIV positive

              1993-2000

              Multiple provinces

              375

              32.5

              PCR (MY09/

              MY11)

              252

              HR-16, 18

              67.2%

              49.1%

              1.N, 2.Y, 3.U, 4.Y, 5.Y, 6.Y, 7.Y

              Richardson 2000 [58]

              University Students: Routine Screening

              1992-1993

              Quebec

              375

              18-24

              PCR (MY09/

              MY11)

              85

              HR- [11]

              LR-6,11,53

              22.7%

              11.8%

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.Y, 7.U

              Sellors 2000a [31]*

              [65, 74, 79]

              General Public: Routine Screening

              1998-1999

              Ontario

              955 (HC-II);

              824 (PCR)

              15-49

              PCR (MY09/

              MY11;

              HC-II

              110

              HR- [11]

              LR- [16]

              13.3%

              12.7%

              (HC-II)

              1.Y, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Sellors 2000b [35]

              Patients recalled after an Abnormal Pap on Routine Screening

              1996-1997

              Ontario

              200

              31.5 (9.4)

              HC-II/PCR (L1)

              125

              HR- [13]

              LR-6,11,42,53

              62.5%

              90.3% HSIL

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.Y, 7.Y

              Ratnam 2000 [57]

              General Public: Routine Screening

              1996-1998

              Newfoundland

              2098

              30 (NR)

              HC-I/HC-II

              227 (HR13)

              HR- [13]

              LR-6,11,42,53

              NA

              10.8%

              1.Y, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Feoli-Fonseca 2001 [45]*

              [77]

              Biopsies suspected of HPV

              Dates NR

              Quebec

              691

              26.1

              PCR (MY09/

              MY11/GP5+/GP6+)

              484

              HR- [13]

              70.0%

              92.0% (CIN III)

              100% (carcinoma in situ)

              1.NA, 2.Y, 3.NA, 4.Y, 5.N, 6.Y, 7.Y

              Healey

              2001 [50]*

              [72, 73]

              General Public (Inuit): Routine Screening

              1999

              Nunavut

              1290

              13-79

              HC-II

              333

              HR- [13]

               

              25.8%

              1.Y, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Tran-Thanh

              2002 [61]*

              [80]

              Cases with SIL or invasive cancer and controls with normal cytology and no history of cervical disease

              1998-2000

              Quebec

              320

              16-73

              PCR (MY09/

              MY11)

              206

              HR- [13]

              64.4%

               

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.Y, 7.Y

              Sellors 2002 [32]

              General Public: Routine Screening

              1999-2000

              Ontario

              156

              50 and over

              HCII/PCR

              13

              HR- [13]

              LR- [14]

              NA

              8.3%

              (HC-II)

              1.N, 2.Y, 3.N, 4.N, 5.Y, 6.Y, 7.U

              Richardson

              2003 [59]*

              [81]

              University Students: Routine Screening

              1996-1998

              Quebec

              621

              83% under age 27 years; mean age 23 (NR)

              PCR (MY09/

              MY11)

              180

              HR- [13]

              29%

              21.8%

              1.N, 2.Y, 3.U, 4.N, 5.Y, 6.Y, 7.Y

              Lytwyn

              2003 [75]*

              [53]

              Patients recalled after an Abnormal Pap: ASCUS or LSIL only

              1995-1998

              Ontario

              105

              30.3 (8.1)

              HC-II

              57 (HR13)

              HR- [13]

              LR- [14]

              NA

              54.3%

              1.Y, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Koushik

              2005 [52]*

              [76, 78]

              General Public: Cases with CIN from colposcopy clinics, controls with normal pap from screening.

              2001-2003

              Quebec

              357 cases,

              760 controls

              32.0 (9.1) Cases,

              31.7 (10.0) Controls

              PCR (MY09/

              MY11)

              579

              HR- [13]

              51.8%

              41.8%

              1.N, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Mayrand

              2006 [54]

              General Public: Routine Screening

              2002-2004

              Quebec, Newfoundland

              9620

              NR

              HCII

              591

              HR- [13]

              LR- [24]

              NA

              6.1%

              1.N, 2.Y, 3.Y, 4.Y, 5.Y, 6.Y, 7.Y

              Ogilvie

              2007 [56]

              Sex trade workers or women with a history of alcohol or drug abuse

              2004-2005

              British Columbia

              151

              39.0

              HC-II

              43 (HC13)

              HR- [13]

              NA

              28.5%

              1.N, 2.Y, 3.Y, 4.N, 5.Y, 6.Y, 7.Y

              Kapala 2007 [51]

              General Public: Routine Screening

              Date NR

              Ontario

              320

              73% age 30 or greater

              HC-II

              92 (HR13)

              HR- [13]

              NA

              28.8%

              1.NA, 2.Y, 3.NA, 4.N, 5.Y, 6.Y, 7.U

              Antionishyn 2008 [40]

              Cervical biopsies

              1995-1998

              Saskatchewan

              1355

              NR

              PCR (GP5+/GP6+)

              753

              HR- [13]

              55.6%

              56.8% CIN III (16 and 18)

              1.NA, 2.Y, 3.NA, 4.N, 5.Y, 6.Y, 7.Y

              Hamlin-Douglas 2008 [48]

              General Public (Inuit): Routine Screening

              2002-2007

              Quebec

              554

              35.5 (14.4)

              PCR (MY09/

              MY11)

              160

              All

              28.9%

              20.4%

              1.Y, 2.Y, 3.N, 4.Y, 5.Y, 6.Y, 7.Y

              Moore

              2009 [39]

              Population-based estimates weighted by cytology

              2004

              British Columbia

              4821

              13-86

              PCR (GP5+/GP6+)

              810

              All

              16.8%

              13.9%

              1.NA, 2.Y, 3.NA, 4.Y, 5.Y, 6.Y, 7.N

              Notes: * major publication and other references are companion reports, number of women positive for human papillomavirus, † calculated by using the "number of cases" value as the numerator and the "sample size" as the denominator, expressed as a percent. Abbreviations: SD standard deviation, NR not reported, HC hybrid capture, PCR polymerase chain reaction.

              Overall, 74% (17/23) did not address non-response bias, 53% (16/30) did not use a representative sampling strategy (i.e., they included individuals with risk factors for HPV and their results cannot be generalized to the general population), 17% (5/30) did not use adequate timing of sampling (e.g., retrospective instead of prospective), and 17% (5/30) did not use sensitive sampling techniques (e.g. hybridization). Seven studies out of 30 were not relevant to the non-response bias and response rate methodological quality items because they included data from cancer biopsies (Additional File 4) [3840, 43, 45, 46, 51]. Excluding these studies, some of the others (35%, 8/23) did not report the response rate or used an inappropriate approach to calculate the response rate (9%, 2/23). Individual methodological quality components for each study are reported in Table 1.

              Age-specific HPV prevalence

              The age-specific prevalence was generally highest among females less than 20 years of age and slowly declined as age increased, despite widespread heterogeneity across studies (Figure 2). HPV prevalence among females less than 20 years of age [31, 48, 50, 58] ranged from 14.1% among university students [58] to 46.9% among Inuit females from Nunavut [48]. For women aged 20-25 years, HPV prevalence ranged from 13.0% among university students [58] to 24.0% among the general population of Ontario [31]. The prevalence among Nunavut women aged 21-30 years was 31.3% [50] and the prevalence of Inuit women from Quebec aged 20-29 years was 24.5% [48]. Ontario women aged 25-29 years had a prevalence of 16.4% [31] and Newfoundland women aged 25-34 years had a prevalence of 11.8% [57].
              http://static-content.springer.com/image/art%3A10.1186%2F1471-2334-11-235/MediaObjects/12879_2011_1581_Fig2_HTML.jpg
              Figure 2

              Age-specific HPV prevalence. Abbreviations: Coll collection, NUN Nunavit, HC hybrid capture, n total sample size, ON Ontario, QC Quebec, PCR polymerase chain reaction, NFLD Newfoundland.

              HPV prevalence among women aged 30-39 years [31, 48, 50, 54, 57] ranged from 7.0% in Newfoundland [54] to 17.2% among Inuit women from Quebec [48]. For women aged 40-49 years, [31, 48, 54] the prevalence ranged from 4.0% in Newfoundland [54] to 8.3% in Ontario [31]. Prevalence among women aged 50-59 years [32, 48, 54] ranged from 2.5% in Newfoundland [54] to 8.9% among women aged 50-54 years in Ontario [32]. For women aged 60-69 years, [48, 54] the prevalence ranged from 1.2% in Newfoundland [54] to 12.5% among Inuit women from Quebec [48]. Finally, the prevalence among Ontario women aged greater than 60 was 11.3% [32]. Overall, age-specific HPV prevalence estimates were higher for other populations (i.e., those testing positive for HPV and HPV prevalence by histology/cytology) compared to the routinely screened populations (data not shown).

              Meta-analysis results

              The meta-analysis results of HPV prevalence among routine screening populations are presented in Figure 3 and the three HPV types with the highest prevalence (HPV-16, -18, and -52) are highlighted here. The studies included in these analyses were conducted between 1990 and 2007, included an average of 1,019 individuals, and varied in their study location (British Columbia (BC), Manitoba (MB), ON, QC) [31, 39, 48, 49, 55, 5860, 62]. For HPV-16, the pooled prevalence was 8.6% (95% CI: 6.5-10.7%); the lowest prevalence estimate was reported among university students (4.8%); [58] while the highest prevalence estimate was among participants from a low-income, inner city population (12.6%) [62]. The pooled prevalence for HPV-18 was 3.3% (95% CI: 1.5-5.1%) [31, 39, 48, 49, 55, 5860, 62]. The lowest prevalence estimate was 0% among university students, [60] while the highest prevalence was 11.8% among a low-income, inner city population [62]. Four studies reported HPV prevalence for HPV-52 and their pooled prevalence was 2.8% (95% CI: 1.2-4.4%) [39, 48, 49, 58]. The lowest prevalence estimate was 0% among a sample of university students, [58] while the highest prevalence estimate was 10.8% among women presenting to an sexually transmitted disease clinic [49].
              http://static-content.springer.com/image/art%3A10.1186%2F1471-2334-11-235/MediaObjects/12879_2011_1581_Fig3_HTML.jpg
              Figure 3

              HPV prevalence meta-analyses among all participants. Note: Each point estimate and 95% confidence interval is a separate meta-analysis. Abbreviations: HR high risk, HPV human papillomavirus, CI confidence interval.

              The meta-analysis results for HPV prevalence among HPV-positive are presented in Figure 4 and the three HPV types with the highest prevalence (HPV-16, -18, and -31) are highlighted here. The studies included in these analyses were conducted between 1990 and 2007, included an average of 985 individuals, and varied in their study location (e.g., BC, MB, ON, QC) [31, 35, 39, 48, 55, 5860, 62]. For HPV-16, the pooled prevalence from these nine studies was 43.5% (95% CI: 28.7-58.2%). The lowest prevalence was among Inuit women (19.4%) [48] and the highest prevalence was among participants with an abnormal Pap test (76.0%) [35]. For HPV-18, the pooled prevalence from these nine studies was 13.6% (95% CI: 6.1-21.1%). The lowest prevalence was among university students (0%), [60] while the highest prevalence was from a general population sample from a low-income, inner-city area (36.3%) [62]. For HPV-31, the pooled prevalence was 10.1% (95% CI: 4.8-15.3%), [35, 39, 49, 5860, 62] and ranged from 2.3% among the general population [39] to 24.8% among participants with an abnormal Pap test [35].
              http://static-content.springer.com/image/art%3A10.1186%2F1471-2334-11-235/MediaObjects/12879_2011_1581_Fig4_HTML.jpg
              Figure 4

              HPV prevalence meta-analyses among HPV-infected participants. Notes: Each point estimate and 95% confidence interval is a separate meta-analysis. One study (Aho 2003) included in the HPV prevalence among all participants was not included here because only one HPV type was examined (HPV-52). Abbreviations: HPV human papillomavirus, CI confidence interval.

              The meta-analysis results according to the Bethesda classification system are presented in Table 2. The prevalence generally increased as the type of cervical lesion approached cervical cancer. The observed prevalence of combined HR HPV types for those with negative cytology or histology was 40.5% (95% CI: 26.4%-54.6%); 15.7% (95% CI: 9.3%-22.0%) for benign lesions; 40.5% (95% CI: 26.4%-54.6%) for ASC-US; 73.6% (95% CI: 55.3%-91.8%) for LSIL; and 89.9% (95% CI: 84.8%-95.1%) for HSIL.
              Table 2

              Prevalence of HPV by Bethesda classification system

              HPV Type

              Bethesda classification

              # studies

              Reference(s)

              # cases

              Total sample size

              % Prevalence (95% CI) from meta-analysis

              HR

              Negative†

              9

              [31, 35, 39, 48, 49, 51, 52, 54, 57]

              1451

              15102

              40.5% (26.4%-54.6%)

               

              Benign

              2

              [51]

              42

              275

              15.7% (9.3%-22.0%)

               

              ASC-US

              5

              [31, 39, 48, 51, 53, 54]

              136

              350

              40.5% (26.4%-54.6%)

               

              LSIL

              10

              [31, 35, 39, 45, 48, 49, 51, 52, 54, 57]

              928

              1563

              73.6% (55.3%-91.8%)

               

              HSIL

              8

              [31, 35, 39, 45, 51, 54, 57, 78]

              559

              628

              89.9% (84.8%-95.1%)

               

              Cervical Cancer

              2

              [51, 54]

              2

              3

              *

              16

              Negative

              6

              [35, 3941, 48, 52]

              473

              6017

              7.9% (4.9%-11.0%)

               

              Benign

              1

              [39]

              2

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              7

              [35, 3941, 45, 48, 52]

              506

              1925

              28.3% (15.1%-41.5%)

               

              HSIL

              7

              [35, 3941, 45, 48, 61]

              516

              1068

              54.0% (45.6%-62.4%)

               

              Cervical Cancer

              3

              [38, 43, 61]

              81

              172

              48.8% (34.0%-63.6%)

              18

              Negative

              5

              [35, 39, 40, 42, 48]

              156

              4891

              3.6% (1.6%-5.6%)

               

              Benign

              1

              [39]

              14

              250

              *

               

              ASC-US

              1

              [48]

              2

              17

              *

               

              LSIL

              6

              [35, 39, 40, 42, 48, 52]

              81

              1312

              5.8% (3.6%-7.9%)

               

              HSIL

              5

              [35, 39, 40, 42, 48]

              47

              662

              7.9% (3.8%-12.0%)

               

              Cervical Cancer

              4

              [38, 42, 43, 80]

              42

              219

              17.1% (6.4%-27.9%)

              31

              Negative

              4

              [35, 39, 40, 48]

              33

              4849

              2.1% (0.1%-4.1%)

               

              Benign

              1

              [39]

              2

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              5

              [35, 39, 40, 48, 52]

              76

              1241

              7.3% (2.7%-11.8%)

               

              HSIL

              4

              [35, 39, 40, 48]

              64

              432

              14.2% (4.0%-24.5%)

               

              Cervical Cancer

              3

              [38, 43, 61]

              3

              172

              1.2% (0.0%-2.73%)

              33

              Negative

              4

              [35, 39, 40, 48]

              38

              4849

              0.6% (0.0%-1.3%)

               

              Benign

              1

              [39]

              1

              250

              *

               

              ASC-US

              1

              [48]

              2

              17

              *

               

              LSIL

              4

              [35, 39, 40, 48]

              35

              884

              3.6% (1.2%-6.0%)

               

              HSIL

              4

              [35, 39, 40, 48]

              24

              432

              5.6% (3.5%-7.8%)

               

              Cervical Cancer

              3

              [38, 43, 61]

              4

              172

              2.1% (0.0%-4.2%)

              35

              Negative

              4

              [35, 39, 40, 48]

              28

              4849

              0.5% (0.3%-0.8%)

               

              Benign

              1

              [39]

              1

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              4

              [35, 39, 40, 48]

              31

              884

              3.1% (0.3%-6.0%)

               

              HSIL

              4

              [35, 39, 40, 48]

              8

              432

              1.8% (0.5%-3.0%)

               

              Cervical Cancer

              3

              [38, 43, 61]

              0

              172

              *

              39

              Negative

              3

              [39, 40, 48]

              11

              4770

              0.8% (0.0%-2.0%)

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              1

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              6

              860

              0.6% (0.0%-1.5%)

               

              HSIL

              3

              [39, 40, 48]

              2

              374

              *

               

              Cervical Cancer

              2

              [38, 61]

              1

              96

              *

              45

              Negative

              3

              [39, 40, 48]

              31

              4770

              0.6% (0.4%-0.9%)

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              9

              860

              1.1% (0.4%-1.7%)

               

              HSIL

              3

              [39, 40, 48]

              6

              374

              *

               

              Cervical Cancer

              2

              [38, 61]

              8

              96

              7.7% (2.4%-13.0%)

              51

              Negative

              3

              [39]

              7

              4470

              *

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              1

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              2

              860

              *

               

              HSIL

              3

              [39, 40, 48]

              3

              374

              *

               

              Cervical Cancer

              2

              [38, 61]

              0

              96

              *

              52

              Negative

              4

              [39, 40, 48, 52]

              41

              5530

              1.4% (0.1%-2.7%)

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              1

              17

              *

               

              LSIL

              4

              [39, 40, 48, 52]

              50

              1217

              2.9% (0.8%-5.1%)

               

              HSIL

              3

              [39, 40, 48]

              9

              374

              2.4% (0.9%-4.0%)

               

              Cervical Cancer

              2

              [38, 61]

              3

              96

              2.6% (0.0%-7.1%)

              56

              Negative

              3

              [39, 40, 48]

              74

              4770

              1.4% (0.8%-2.0%)

               

              Benign

              1

              [39]

              5

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              52

              860

              5.8% (3.2%-8.3%)

               

              HSIL

              3

              [39, 40, 48]

              4

              374

              *

               

              Cervical Cancer

              2

              [38, 61]

              2

              96

              1.6% (0.0%-4.1%)

              58

              Negative

              4

              [35, 39, 40, 48]

              37

              4849

              1.0% (0.3%-1.6%)

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              4

              [35, 39, 40, 48]

              22

              884

              2.3% (1.3%-3.3%)

               

              HSIL

              4

              [35, 39, 40, 48]

              11

              432

              2.0% (0.0%-4.3%)

               

              Cervical Cancer

              2

              [38, 61]

              0

              96

              *

              59

              Negative

              3

              [39, 40, 48]

              25

              4770

              0.5% (0.0%-1.1%)

               

              Benign

              1

              [39]

              2

              250

              *

               

              ASC-US

              1

              [48]

              1

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              9

              860

              0.9% (0.3%-1.6%)

               

              HSIL

              3

              [39, 40, 48]

              9

              374

              2.1% (0.7%-3.6%)

               

              Cervical Cancer

              2

              [38, 61]

              0

              96

              *

              68

              Negative

              3

              [39, 40, 48]

              5

              4470

              *

               

              Benign

              1

              [39]

              0

              250

              *

               

              ASC-US

              1

              [48]

              0

              17

              *

               

              LSIL

              3

              [39, 40, 48]

              1

              860

              *

               

              HSIL

              3

              [39, 40, 48]

              2

              374

              *

               

              Cervical Cancer

              2

              [38, 61]

              1

              96

              *

              Notes: *meta-analysis not feasible due to small numbers, †negative for intraepithelial lesion or malignancy, ‡ includes analyses of all HR types combined (i.e., multiple-infection). Abbreviations: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), HSIL high-grade squamous intraepithelial lesions (HSIL).

              The most prevalent HPV type among those classified as negative for intraepithelial lesion or malignancy was HPV-16 (7.9%) and the prevalence for each of the other HR types was less than 5%. Among those classified with LSIL, the three most prevalent types were HPV-16 (28.3%), HPV-31 (7.3%), and HPV-18 (5.8%). Among those classified with HSIL, the three most prevalent types were HPV-16 (54.0%), HPV-31 (14.2%), and HPV-18 (7.9%). Among those with confirmed cervical cancer, the highest prevalence was observed for HPV-16 (48.8% [95% CI: 34.0-63.6%]) [38, 43, 61], followed by HPV-18 (17.1% (95% CI: 6.4-27.9%) [38, 42, 43, 61], and HPV-45 (7.7%, [95% CI: 2.4-13.0%]) [38, 61].

              Sensitivity analysis

              We conducted a post hoc sensitivity analysis of the meta-analysis results for key study characteristics including study location, study design, HPV detection method, sample size, and methodological quality. Differences in prevalence estimates across the included studies were not identified (data not shown).

              Discussion

              To our knowledge, this is the most comprehensive systematic review for a single country. Other HPV prevalence reviews included worldwide data and grouped all countries in North America together [27, 28, 65]. The past reviews included few Canadian studies, while data from 30 Canadian studies along with 21 companion reports were included here. Previous reviews focused on HPV prevalence among cervical cancer [27, 28, 65], HIV [82] or healthy individuals [83]. Our review includes data on the full spectrum of HR HPV infection, providing a more comprehensive understanding of the role of HPV genotypes in different manifestations of infection.

              HPV prevalence data are required to provide information related to baseline HPV burden of disease when implementing vaccination programs. All of the included studies were either conducted prior to HPV vaccination or did not include vaccinated individuals. These data can be used to evaluate current HPV vaccination program in the future, including vaccine impact on HR genotype prevalence. The data are also useful for health economic evaluations and epidemiological modeling research. HPV is not a reportable disease so baseline prevalence data could only be obtained by synthesizing highly heterogeneous individual studies. A limited number of studies provide population-based estimates of HPV prevalence and only one provincial based study [39] was available for our meta-analyses.

              The results can inform optimal vaccination program scheduling. Our findings indicate that HPV prevalence was highest among females aged less than 20 years. Some countries (such as Canada) have publicly funded vaccination programs targeting pre-adolescent and adolescent girls and our results support this approach. High age-specific HR HPV prevalence up to the age of 30 years stresses the need of evaluating the impact of catch-up vaccination programs in these older age groups.

              Our results indicate that the prevalence of HR HPV varies among different subgroups of the population with indications of higher prevalence in those at greater risk of being under-screened. In our review, socially disadvantaged individuals (i.e., living in low-income, inner-city areas or Aboriginal communities) had the greatest HPV prevalence. Although declines in incidence and mortality due to routine screening have occurred, [84] false-negative Pap test results continue to raise important questions regarding optimal screening policies [15, 16]. Our review identified a positive HPV test (e.g., 7.9% HPV-16 and 3.6% HPV-18) among females with a negative Pap test. Both tests have associated sensitivities and specificities, and while there is continuing research in identifying the best screening policies with these tests, vaccination remains an effective method to prevent infection with the major HR HPV types [85]. In addition to errors due to diagnostic sensitivity and specificity, 12% of Canadians never go for a Pap test [9]. Individuals less likely to obtain the Pap test include those of lower education, [10, 12, 13] lower income, [10, 12, 13] recent immigrants, [14, 86] ethnic minorities, [11] living in rural areas, [11] and those who are obese [87]. These groups of individuals merit special attention when implementing and evaluating HPV vaccination programs.

              The HPV vaccines protect against oncogenic strains HPV-16 and -18. These two HPV types contributed a combined prevalence of 12% for HR HPV infection and 66% of cervical cancer, which potentially can be prevented by the vaccines assuming 100% efficacy and long-lasting immunity. These estimates are slightly lower than previous reviews that reported this estimate as being approximately 70%, [26] indicating that our results might be conservative. Emerging data showing cross-protection against several non-vaccine HR HPV types is encouraging. According to the bivalent vaccine product monograph, protection against HPV-31 (according to protocol cohort) and -45 (total vaccinated cohort) was also observed [17]. These two HR HPV types contributed an estimated combined prevalence of 8.9% (1.2% for HPV-31 and 7.7% for HPV-45) for cervical cancer, indicating that additional cancer protection is a possibility. According to the quadrivalent vaccine product monograph, there was some cross-protection against HPV-31, but not against -45 [18]. Ongoing follow-up of clinical trials and national registries can help understand the potential impact of cross-protection on HPV-related cancer reduction.

              Our results are similar to previous reviews of HPV prevalence. The overall HR HPV prevalence observed in our systematic review was 27.1% among screening populations, which is lower than the prevalence for any HPV infection in HIV positive women (36.3%) reported in a previous review, as expected [82]. In addition, another previous review found that HPV prevalence peaked in younger women (≤ 25 years of age) and decreased with age, which is consistent with our results [83]. Similar to another review, [65] we found that there was an inconsistent relationship between HPV prevalence in HSIL versus cervical cancer cases across different HPV types. For example, we found a higher HPV prevalence in HSIL versus cervical cancer (including squamous cell carcinoma of the cervix and/or aden/adenosquamous carcinoma of the cervix) for HPV 16 (54.0% HSIL versus 48.8% cervical cancer), 31 (14.2% HSIL versus 1.2% cervical cancer), and 33 (5.6% HSIL versus 2.1% cervical cancer), whereas the reverse was true for HPV 18 (7.9% HSIL versus 17.1% cervical cancer) and 52 (2.4% HSIL versus 2.6% cervical cancer). The relationship between HSIL and cervical cancer could not be explored for the other HPV types, due to insufficient data. Furthermore, many of the cervical cancer estimates were based on a small number of studies, making these results difficult to interpret.

              We found that multiple infections occurred in 17.1% of the included prevalence estimates. Multiple infections occurred in 11.2% of the prevalence estimates in a review of invasive cervical cancer [26] and 11.9% in a review limited to women infected with HIV [82]. Factors that can explain the difference in multiple infections across reviews include different duration of specific types of infection (i.e., natural clearance of one or several types but persistence of the main one); and/or potentially different number of new sexual partners during the last months in females with LSIL, HSIL and those with cervical cancer or HIV.

              Compared to different regions throughout the world, HPV prevalence in Canada is moderate. One review found that the highest prevalence of HPV among middle-aged women (35-50 years) was observed for Africa, Central and South America, and the United States (approximately 20%), while a lower prevalence was observed in Asia, Australia, Europe, Middle East, and Canada (approximately 15%) [83]. Furthermore, the proportion of cancer cases associated with HPV 16 and 18 was found to be the highest in Africa (94.2%), moderate in North America (89.2%), and the lowest in Asia (68%) [26].

              Limitations of this systematic review include that the meta-analyses were based on each HPV type individually so may include concomitant infection. Data were also pooled across studies using different tests to measure the presence of HPV (e.g., hybridization, PCR, HC) and these tests vary in their sensitivity and specificity. For example, HC-II has been found to be a more sensitive test versus HC-I [88]. The methodological quality of the included studies was variable; less than half used a representative sampling strategy and many had small sample sizes.

              Population-based, high-quality, HPV prevalence studies are warranted. These studies should report age-specific prevalence, overlap between single and multiple infection, and HPV type-specific infection. A recently published prevalence study from the United Kingdom is an excellent example of such a study [89]. These data can lead to a better understanding of HPV prevalence, as well as the impact of new prevention programs at the national and international levels.

              Conclusions

              Prevalence data of cervical human papillomavirus infection is necessary to inform optimal prevention programs and evaluate current prevention strategies. Previous HPV prevalence reviews included worldwide studies and focused on HPV prevalence among cervical cancer, HIV or healthy individuals. To our knowledge, this is the most comprehensive systematic review for a single country and the data can be used in health economic evaluations and epidemiological modeling research to help inform public health policy. Our results show that the highest prevalence occurred among females < 20 years of age, yet prevalence remained high among women up to 30 years of age.

              Declarations

              Acknowledgements and Funding

              We thank Maraki Fikre Merid for her assistance with drafting the introduction on a previous version of this manuscript, Dr Minh Do for his assistance with the data abstraction and screening on a previous version of this review, Natasha Nanwa for her administrative assistance, Maggie Hong Chen for assisting with the statistical analysis, and Dr Jessie McGowan for the literature searches. Funding for this systematic review was received from GlaxoSmithKline, Canada.

              Authors’ Affiliations

              (1)
              Li Ka Shing Knowledge Institute, St Michael’s Hospital
              (2)
              School of Population and Public Health, University of British Columbia
              (3)
              Centre de Recherche du CHUL (CHUQ), l’Université Laval
              (4)
              GlaxoSmithKline Biologicals
              (5)
              Health Policy Management and Evaluation, University of Toronto
              (6)
              Toronto Health Economics and Technology Assessment, University of Toronto
              (7)
              Department of Epidemiology, University of Western Ontario

              References

              1. Schiffman M, Kjaer SK: Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr 2003, 14–19.
              2. Munoz N, Bosch FX, de SS, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ: Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003, 348:518–527.PubMedView Article
              3. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El GF, brahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V: A review of human carcinogens--Part B: biological agents. Lancet Oncol 2009, 10:321–322.PubMedView Article
              4. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999, 189:12–19.PubMedView Article
              5. Bernard HU, Calleja-Macias IE, Dunn ST: Genome variation of human papillomavirus types: phylogenetic and medical implications. Int J Cancer 2006, 118:1071–1076.PubMedView Article
              6. Aubin F, Pretet JL, Jacquard AC, Saunier M, Carcopino X, Jaroud F, Pradat P, Soubeyrand B, Leocmach Y, Mougin C, Riethmuller D: Human papillomavirus genotype distribution in external acuminata condylomata: a Large French National Study (EDiTH IV). Clin Infect Dis 2008, 47:610–615.PubMedView Article
              7. Shepherd LJ, Bryson SC: Human papillomavirus--lessons from history and challenges for the future. J Obstet Gynaecol Can 2008, 30:1025–1033.PubMed
              8. Canadian Cancer Society's Steering Committee: Canadian cancer statistics 2009. Toronto. 2009.
              9. Health Canada: Cervical cancer screening in Canada: 1998 Surveillance report. Ottawa. 2002.
              10. Gupta S, Roos LL, Walld R, Traverse D, Dahl M: Delivering equitable care: comparing preventive services in Manitoba. Am J Public Health 2003, 93:2086–2092.PubMedView Article
              11. Johnston GM, Boyd CJ, MacIsaac MA: Community-based cultural predictors of Pap smear screening in Nova Scotia. Can J Public Health 2004, 95:95–98.PubMed
              12. Katz SJ, Hofer TP: Socioeconomic disparities in preventive care persist despite universal coverage. Breast and cervical cancer screening in Ontario and the United States. JAMA 1994, 272:530–534.PubMedView Article
              13. Lofters A, Glazier RH, Agha MM, Creatore MI, Moineddin R: Inadequacy of cervical cancer screening among urban recent immigrants: a population-based study of physician and laboratory claims in Toronto, Canada. Prev Med 2007, 44:536–542.PubMedView Article
              14. McDonald JT, Kennedy S: Cervical cancer screening by immigrant and minority women in Canada. J Immigr Minor Health 2007, 9:323–334.PubMedView Article
              15. Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, Szarewski A, Birembaut P, Kulasingam S, Sasieni P, Iftner T: Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006, 119:1095–1101.PubMedView Article
              16. Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, Matchar DB: Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000, 132:810–819.PubMed
              17. Cervarix™ Product Monograph, August 2010
              18. Gardasil™ Product Monograph, May 2011
              19. Franco EL, Ferenczy A: Cervical cancer screening following the implementation of prophylactic human papillomavirus vaccination. Future Oncol 2007, 3:319–327.PubMedView Article
              20. Franco EL, Cuzick J, Hildesheim A, de SS: Chapter 20: Issues in planning cervical cancer screening in the era of HPV vaccination. Vaccine 2006,24(Suppl 3):S3171-S3/177.
              21. Erickson LJ, De WP, Farand L: An analytical framework for immunization programs in Canada. Vaccine 2005, 23:2470–2476.PubMedView Article
              22. Howlett RI, Miller AB, Pasut G, Mai V: Defining a strategy to evaluate cervical cancer prevention and early detection in the era of HPV vaccination. Prev Med 2009, 48:432–437.PubMedView Article
              23. Higgins JPT, Green S, editors: [http://​www.​cochrane-handbook.​org] Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration; 2009. Version 5.0.2 [updated September 2009].
              24. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009, 339:b2535.PubMedView Article
              25. Sampson M, McGowan J, Lefebvre C, Moher D, Grimshaw J: PRESS: Peer Review of Electronic Search Strategies. Ottawa. 2008.
              26. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM: Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer 2010.
              27. Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S: Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003, 88:63–73.PubMedView Article
              28. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, Clifford GM: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007, 121:621–632.PubMedView Article
              29. Duggan MA, Inoue M, McGregor SE, Nation JG: A comparison of cervical scrapes for HPV typing by dot-blot hybridization obtained by wood and plastic spatulas. Journal of Virological Methods 1990, 29:267–277.PubMedView Article
              30. Peng HQ, Roth P, Caussy D, Rawls W: Comparison of the Cytobrush and cotton swabs in sampling cervical cells for filter in situ hybridization detection of human papillomavirus types 16 and 18 DNA. Acta cytologica 1988, 32:311–313.PubMed
              31. Sellors JW, Mahony JB, Kaczorowski J, Lytwyn A, Bangura H, Chong S, Lorincz A, Dalby DM, Janjusevic V, Keller JL: Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. Survey of HPV in Ontario Women (SHOW) Group.[see comment]. CMAJ Canadian Medical Association Journal 2000, 163:503–508.
              32. Sellors JW, Karwalajtys TL, Kaczorowski JA, Mahony JB, Lytwyn A, Chong S, Sparrow J, Lorincz A, Survey of HPV in Older Ontario Women (SHOOW) Group: Prevalence of infection with carcinogenic human papillomavirus among older women. CMAJ Canadian Medical Association Journal 2002, 167:871–873.
              33. Sanderson S, Tatt ID, Higgins JP: Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007, 36:666–676.PubMedView Article
              34. Bishop FL, Prescott P, Chan YK, Saville J, von EE, Lewith GT: Prevalence of complementary medicine use in pediatric cancer: a systematic review. Pediatrics 2010, 125:768–776.PubMedView Article
              35. Sellors JW, Lorincz AT, Mahony JB, Mielzynska I, Lytwyn A, Roth P, Howard M, Chong S, Daya D, Chapman W, Chernesky M: Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. CMAJ Canadian Medical Association Journal 2000, 163:513–518.
              36. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T Jr, Young N: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002, 287:2114–2119.PubMedView Article
              37. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986, 7:177–188.PubMedView Article
              38. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV: Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995, 87:796–802.PubMedView Article
              39. Moore RA, Ogilvie G, Fornika D, Moravan V, Brisson M, mirabbasi-Beik M, Kollar A, Burgess T, Hsu R, Towers L, Lo J, Matisic J, Brooks-Wilson A: Prevalence and type distribution of human papillomavirus in 5,000 British Columbia women--implications for vaccination. Cancer Causes Control 2009, 20:1387–1396.PubMedView Article
              40. Antonishyn NA, Horsman GB, Kelln RA, Saggar J, Severini A: The impact of the distribution of human papillomavirus types and associated high-risk lesions in a colposcopy population for monitoring vaccine efficacy. Arch Pathol Lab Med 2008, 132:54–60.PubMed
              41. Brisson J, Morin C, Fortier M, Roy M, Bouchard C, Leclerc J, Christen A, Guimont C, Penault F, Meisels A: Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. American Journal of Epidemiology 1994, 140:700–710.PubMed
              42. Caussy D, Marrett LD, Worth AJ, McBride M, Rawls WE: Human papillomavirus and cervical intraepithelial neoplasia in women who subsequently had invasive cancer. CMAJ Canadian Medical Association Journal 1990, 142:311–317.
              43. Duggan MA, McGregor SE, Benoit JL, Inoue M, Nation JG, Stuart GC: The human papillomavirus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis. Hum Pathol 1995, 26:319–325.PubMedView Article
              44. Duggan MA, McGregor SE, Stuart GC, Morris S, Chang-Poon V, Schepansky A, Honore L: The HPV determinants of CIN I. European Journal of Gynaecological Oncology 1997, 18:117–123.PubMed
              45. Feoli-Fonseca JC, Oligny LL, Brochu P, Simard P, Falconi S, Yotov WV: Human papillomavirus (HPV) study of 691 pathological specimens from Quebec by PCR-direct sequencing approach. Journal of Medical Virology 2001, 63:284–292.PubMedView Article
              46. Franco E, Bergeron J, Villa L, Arella M, Richardson L, Arseneau J, Stanimir G: Human papillomavirus DNA in invasive cervical carcinomas and its association with patient survival: a nested case-control study. Cancer Epidemiology, Biomarkers & Prevention 1996, 5:271–275.
              47. Guijon F, Paraskevas M, McNicol P: Human papillomavirus infection and the size and grade of cervical intraepithelial neoplastic lesions associated with failure of therapy. International Journal of Gynaecology & Obstetrics 1993, 42:137–142.View Article
              48. Hamlin-Douglas L: Prevalence and determinants of human papillomavirus (HPV) infection in Inuit women of Nunavik, Quebec. In PhD Thesis. McGill University; 2008.
              49. Hankins C, Coutlee F, Lapointe N, Simard P, Tran T, Samson J, Hum L: Prevalence of risk factors associated with human papillomavirus infection in women living with HIV. Canadian Women's HIV Study Group. CMAJ Canadian Medical Association Journal 1999, 160:185–191.
              50. Healey SM, Aronson KJ, Mao Y, Schlecht NF, Mery LS, Ferenczy A, Franco EL: Oncogenic human papillomavirus infection and cervical lesions in aboriginal women of Nunavut, Canada. Sexually Transmitted Diseases 2001, 28:694–700.PubMedView Article
              51. Kapala J, Jang D, Patel J, Biers K, Smieja M, Chernesky M: Pap cytopathology and the presence of high-risk human papillomavirus in SurePath liquid preservative and Digene cervical sampler specimens. Journal of Virological Methods 2007, 142:223–225.PubMedView Article
              52. Koushik A, Ghosh A, Duarte-Franco E, Forest P, Voyer H, Matlashewski G, Coutlee F, Franco EL, Biomarkers of Cervical Cancer Risk (BCCR) Study Team: The p53 codon 72 polymorphism and risk of high-grade cervical intraepithelial neoplasia. Cancer Detection & Prevention 2005, 29:307–316.View Article
              53. Lytwyn A, Sellors JW, Mahony JB, Daya D, Chapman W, Ellis N, Roth P, Lorincz AT, Gafni A: Comparison of human papillomavirus DNA testing and repeat Papanicolaou test in women with low-grade cervical cytologic abnormalities: a randomized trial. HPV Effectiveness in Lowgrade Paps (HELP) Study No. 1 Group. CMAJ Canadian Medical Association Journal 2000, 163:701–707.
              54. Mayrand MH, Duarte FE, Coutlée F, Rodrigues I, Walter SD, Ratnam S, Franco EL, CCCaST-Study-Group: Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: design, methods and preliminary accrual results of the Canadian cervical cancer screening trial (CCCaST). International journal of cancer Journal international du cancer 2006, 119:615–623.PubMedView Article
              55. Michael P: PCR screening for human papillomavirus infections, and evaluation of the estimated infection prevalence for a population of females. In PhD Thesis. Laurentian University; 1999.
              56. Ogilvie G, Krajden M, Maginley J, Isaac-Renton J, Hislop G, Elwood-Martin R, Sherlock C, Taylor D, Rekart M: Feasibility of self-collection of specimens for human papillomavirus testing in hard-to-reach women. CMAJ Canadian Medical Association Journal 2007, 177:480–483.View Article
              57. Ratnam S, Hogan K, Hankins C: Prevalence of HIV infection among pregnant women in Newfoundland. CMAJ: Canadian Medical Association Journal 1996, 154:1027–1032.PubMed
              58. Richardson H, Franco E, Pintos J, Bergeron J, Arella M, Tellier P: Determinants of low-risk and high-risk cervical human papillomavirus infections in Montreal University students. Sexually Transmitted Diseases 2000, 27:79–86.PubMedView Article
              59. Richardson H, Kelsall G, Tellier P, Voyer H, Abrahamowicz M, Ferenczy A, Coutlee F, Franco EL: The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiology, Biomarkers & Prevention 2003, 12:485–490.
              60. Rohan T, Mann V, McLaughlin J, Harnish DG, Yu H, Smith D, Davis R, Shier RM, Rawls W: PCR-detected genital papillomavirus infection: prevalence and association with risk factors for cervical cancer. Int J Cancer 1991, 49:856–860.PubMedView Article
              61. Tran-Thanh D, Koushik A, Provencher D, Drouin P, Dubuc-Lissoir J, Gauthier P, Allaire G, Kornegay J, Franco E, Coutlee F: Detection of human herpes virus type 6 DNA in precancerous lesions of the uterine cervix. J Med Virol 2002, 68:606–610.PubMedView Article
              62. Young TK, McNicol P, Beauvais J: Factors associated with human papillomavirus infection detected by polymerase chain reaction among urban Canadian aboriginal and non-aboriginal women.[see comment]. Sexually Transmitted Diseases 1997, 24:293–298.PubMedView Article
              63. Aho J, Hankins C, Tremblay C, Lang F, Forest P, Pourreaux K, Rouah F, Coutlee F: Molecular analysis of human papillomavirus type 52 isolates detected in the genital tract of human immunodeficiency virus-seropositive and -seronegative women. J Infect Dis 2003, 188:1517–1527.PubMedView Article
              64. Aho J, Hankins C, Tremblay C, Forest P, Pourreaux K, Rouah F, Coutlee F: Genomic polymorphism of human papillomavirus type 52 predisposes toward persistent infection in sexually active women. J Infect Dis 2004, 190:46–52.PubMedView Article
              65. Clifford GM, Smith JS, Aguado T, Franceschi S: Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer 2003, 89:101–105.PubMedView Article
              66. Coutlee F, Hankins C, Lapointe N: Comparison between vaginal tampon and cervicovaginal lavage specimen collection for detection of human papillomavirus DNA by the polymerase chain reaction. The Canadian Women's HIV Study Group. Journal of Medical Virology 1997, 51:42–47.PubMedView Article
              67. Duggan MA, Inoue M, McGregor SE, Stuart GC, Morris S, Chang-Poon V, Schepansky A, Honore L: A paired comparison of dot blot hybridization and PCR amplification for HPV testing of cervical scrapes interpreted as CIN 1. European Journal of Gynaecological Oncology 1994, 15:178–187.PubMed
              68. Duggan MA, Benoit JL, McGregor SE, Nation JG, Inoue M, Stuart GC: The human papillomavirus status of 114 endocervical adenocarcinoma cases by dot blot hybridization. Hum Pathol 1993, 24:121–125.PubMedView Article
              69. Duggan MA, McGregor SE, Stuart GC, Morris S, Chang-Poon V, Schepansky A, Honore L: The natural history of CIN I lesions. European Journal of Gynaecological Oncology 1998, 19:338–344.PubMed
              70. Duggan MA, McGregor SE, Stuart GC, Morris S, Chang-Poon V, Schepansky A, Honore L: Predictors of co-incidental CIN II/III amongst a cohort of women with CIN I detected by a screening Pap test. European Journal of Gynaecological Oncology 1998, 19:209–214.PubMed
              71. Gagnon S, Hankins C, Tremblay C, Pourreaux K, Forest P, Rouah F, Coutlee F, The Canadian Women's HIV Study Group: Polymorphism of human papillomavirus type 31 isolates infecting the genital tract of HIV-seropositive and HIV-seronegative women at risk for HIV infection. Journal of Medical Virology 2005, 75:213–221.PubMedView Article
              72. Healey SM: Human papillomavirus infection and cervical dysplasia in Nunavut. In PhD Thesis. Queen's University; 2000.
              73. Healey SM, Aronson K, Mao Y, Franco EL: Human papillomavirus and cervical dysplasia in Nunavut: prelude to a screening strategy. International Journal of Circumpolar Health 2004,63(Suppl):201.
              74. Karwalajtys T, Howard M, Sellors JW, Kaczorowski J: Vaginal self sampling versus physician cervical sampling for HPV among younger and older women. Sexually Transmitted Infections 2006, 82:337–339.PubMedView Article
              75. Lytwyn A, Sellors JW, Mahony JB, Daya D, Chapman W, Howard M, Roth P, Lorincz AT, Gafni A, Walter SD: Adjunctive human papillomavirus testing in the 2-year follow-up of women with low-grade cervical cytologic abnormalities: a randomized trial and economic evaluation. Archives of pathology & laboratory medicine 2003, 127:1169–1175.
              76. Mahmud SM, Koushik A, Duarte-Franco E, Costa J, Fontes G, Bicho M, Coutlee F, Franco EL, Biomarkers of Cervical Cancer Risk Study Team: Haptoglobin phenotype and risk of cervical neoplasia: a case-control study. Clinica Chimica Acta 2007, 385:67–72.View Article
              77. Oligny LL, Feoli-Fonseca JC, Brochu P, Simard P, Falconi S, Yotov WV: Human papillomavirus PCR direct sequencing study of cervical precancerous lesions in Quebec children. Sexually Transmitted Infections 2001, 77:391.PubMedView Article
              78. Schaffer A, Koushik A, Trottier H, Duarte-Franco E, Mansour N, Arseneau J, Provencher D, Gilbert L, Gotlieb W, Ferenczy A, Coutlee F, Pollak MN, Franco EL: Insulin-like growth factor-I and risk of high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 2007, 16:716–722.PubMedView Article
              79. Sellors JW, Karwalajtys TL, Kaczorowski J, Mahony JB, Lytwyn A, Chong S, Sparrow J, Lorincz A, Survey of HPV in Ontario Women Group: Incidence, clearance and predictors of human papillomavirus infection in women.[see comment][comment]. CMAJ Canadian Medical Association Journal 2003, 168:421–425.
              80. Tran-Thanh D, Provencher D, Koushik A, Duarte-Franco E, Kessous A, Drouin P, Wheeler CM, Dubuc-Lissoir J, Gauthier P, Allaire G, Vauclair R, Dipaolo JA, Gravitt P, Franco E, Coutlee F: Herpes simplex virus type II is not a cofactor to human papillomavirus in cancer of the uterine cervix. Am J Obstet Gynecol 2003, 188:129–134.PubMedView Article
              81. Richardson H, Abrahamowicz M, Tellier PP, Kelsall G, du BR, Ferenczy A, Coutlee F, Franco EL: Modifiable risk factors associated with clearance of type-specific cervical human papillomavirus infections in a cohort of university students. Cancer Epidemiology, Biomarkers & Prevention 2005, 14:1149–1156.View Article
              82. Clifford GM, Goncalves MA, Franceschi S: Human papillomavirus types among women infected with HIV: a meta-analysis. AIDS 2006, 20:2337–2344.PubMedView Article
              83. Smith JS, Melendy A, Rana RK, Pimenta JM: Age-specific prevalence of infection with human papillomavirus in females: a global review. J Adolesc Health 2008, 43:S5–25, S25.PubMedView Article
              84. Marrett LD, Innes M, Howlett R, Cotterchio M: Insight on Cancer: News and information on cervical cancer. Toronto. 2005.
              85. National Advisory Committee on Immunization (NACI): National Advisory Committee on Immunization (NACI) statement on human papillomavirus vaccine. 2007.
              86. Woltman KJ, Newbold KB: Immigrant women and cervical cancer screening uptake: a multilevel analysis. Can J Public Health 2007, 98:470–475.PubMed
              87. Maruthur NM, Bolen SD, Brancati FL, Clark JM: The association of obesity and cervical cancer screening: a systematic review and meta-analysis. Obesity (Silver Spring) 2009, 17:375–381.
              88. Kuhn L, Denny L, Pollack A, Lorincz A, Richart RM, Wright TC: Human papillomavirus DNA testing for cervical cancer screening in low-resource settings. J Natl Cancer Inst 2000, 92:818–825.PubMedView Article
              89. Howell-Jones R, Bailey A, Beddows S, Sargent A, de SN, Wilson G, Anton J, Nichols T, Soldan K, Kitchener H: Multi-site study of HPV type-specific prevalence in women with cervical cancer, intraepithelial neoplasia and normal cytology, in England. Br J Cancer 2010, 103:209–216.PubMedView Article
              90. Pre-publication history

                1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2334/​11/​235/​prepub

              Copyright

              © Tricco et al; licensee BioMed Central Ltd. 2011

              This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.