Sexually Transmitted Diseases:
Determinants of Human Papillomavirus Infection Among Inuit Women of Northern Quebec, Canada
Hamlin-Douglas, Lauren Kay MSc*; Coutlée, François MD, MSc†‡§; Roger, Michel MD, PHD‡¶; Hanley, James PHD*; Franco, Eduardo L. PHD*†; Brassard, Paul MD, MSc*∥
From the Departments of *Epidemiology, Biostatistics and Occupational Health, and †Department of Oncology, McGill University, Montreal, QC; ‡Département de Microbiologie et Immunologie de l'Université de Montréal, Montreal, QC; §Laboratoire de virologie moléculaire, Centre de Recherche du CHUM, Montreal, QC; ¶Laboratoire d'immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC; and ∥Department of Medicine, McGill University, Montreal, QC
The authors thank the Tulattavik Health Centre, the Nunavik Regional Board of Health and Social Services, participating communities, and the many collaborating healthcare professionals and research staff including Serge Déry, Hélène Baribeau, Annie Pelletier, Nathalie Boulanger, Marie-Andrée Robitaille, Brigitte Richer, Solange Piché, Pierre Forest, Hélène Voyer, Simon Gagnon, Diane Gaudreau, and Sarah Vahey, who made this project possible.
Michel Roger, MD, PhD, is recipient of a research scholar award from the Fonds de la recherche en Santé du Québec.
Supported by an operating grant from the Canadian Institutes of Health Research (CIHR) as well as from a Team Grant on HPV Infection and Associated Diseases from the same agency. Supported by CIHR, McGill University Health Centre, and McGill University Department of Medicine (to L.K.H-D.). Supported by a distinguished scientist salary award from the CIHR and the Merck-Frosst Commercial research grant; GSK, Gen-Probe, Roche, Consultant/Advisory board (to E.L.F.). Supported by a CIHR new investigator career award (P.B.).
Correspondence: Paul Brassard, MD, MSc, Division of Clinical Epidemiology, Ross Pavilion, 687 Pine Avenue West, R4.15, Montreal, QC H3A 1A1. E-mail: firstname.lastname@example.org.
Received for publication July 14, 2009, and accepted November 22, 2009.
We investigated risk factors for prevalent high-risk human papillomavirus (HR-HPV) in Inuit women from Quebec. Younger age and having 10 or more lifetime sexual partners were associated with HR-HPV. Findings suggest that for older women, markers of recent sexual activity are more predictive of HR-HPV status than markers of lifetime sexual history.
Cervical cancer is one of the only cancers for which a necessary cause has been identified: human papillomavirus (HPV) infection has been detected in 99.7% of an international collection of cervical cancer specimens,1,2 and the estimated relative risk for HPV infection and cervical neoplasia exceeds 100, which is greater than that for smoking and lung cancer.3 Although HPV is a ubiquitous sexually transmitted infection with an estimated 10% prevalence worldwide,4 some individuals appear to be at higher risk for infection.
Considering the high incidence of cervical cancer amongst Inuit women in Canada and Quebec5–7 and the high mortality amongst Quebec Aboriginal women,6 we examined the determinants of high-risk HPV (HR-HPV) infection in a population of Inuit women in Nunavik, northern Quebec. The unique sociodemographic and cultural makeup of this geographically isolated population warrants an exploration of predictors of HR-HPV infection, which may be different than in other groups. Such knowledge could assist the planning of cervical cancer screening and vaccination programs tailored to this population.
A cohort of women was recruited primarily from clinics in 4 communities in Nunavik when participants presented for a regularly scheduled Papanicolaou (Pap) smear between January 2002 and December 2007. Further details of the study design, questionnaire and sample collection have been reported elsewhere.8 Unconditional logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between risk factor variables and prevalent HR-HPV. Alphapapillomavirus species-specific analyses were also carried out by regrouping types as per the main species in the genus9: α-7 (HPV-18 related types), α-9 (HPV-16 related), and α-3/15 (low-risk types). The reference category for all analyses was no infection with types of the stated group.
A U-shaped prevalence curve was observed for HPV across all risk categories8 and age was expressed as a categorical variable with 5 age strata. The following variables were selected for inclusion into a multivariable model for HR-HPV infection based on a priori evidence of association in different populations: age, markers of sexual activity (single marital status, lifetime number of sexual partners), smoking, and number of lifetime deliveries. Educational attainment was also included as a measure of socioeconomic status. Additional variables were considered for inclusion in the age-stratified multivariate models if they were significantly associated with the outcome in univariate analysis.
Multiple imputation, a technique that is considered a valid method for handling missing data,10–12 was used to assign values for missing data. Data management was performed using SAS statistical software version 9.1 and all statistical analyses were carried out in R statistical software version 2.4.1.
Overall HPV-deoxyribonucleic acid prevalence was 28.9% for this population; HR-HPV was detected in 20.4% of subjects. A U-shaped curve was observed in HR-HPV, with the highest prevalence amongst 15- to 19-year-olds (47.0%), a decrease amongst middle-aged women, and a resurgence amongst 50- to 69-year-olds (9.1%) (Table 1). When cytology results were examined by age category (Table 1), the highest proportion of overall abnormality (low-grade squamous intraepithelial lesions/high-grade squamous intraepithelial lesions) was observed amongst 15- to 19-year-olds. The proportion of low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions decreased and increased with age, respectively. There were no cytologic abnormalities detected in the group of women aged 40 years and older.
We examined determinants of HR-HPV infection (Table 2) in univariate and multivariate analysis. In a multivariable model for HR-HPV, younger age and having 10 or more lifetime sexual partners (odds ratio: 2.58; 95% confidence interval: 1.58–4.22) were associated with prevalent HR-HPV.
Although high-risk and low-risk classifications are commonly used to categorize HPV types, species represent more natural groupings, as HPV types within species tend to share similar biologic characteristics. We analyzed predictors of HPV types in the α-7, α-9, and α-3/15 HPV species separately (Table 3) and found that age was significantly associated with all species groupings, with older age being protective. This finding is in contrast to previous work that found older age to be associated with α-3/15 infections and found α-9 types more commonly in younger women which suggested an effect of the age-dependent composition of cells sampled from the cervix on the detection of specific HPV types.13 Of particular interest in our study was that the lifetime number of sexual partners was associated with α-7 and α-9 species, which cause high-grade lesions, but not with α-3/15 types, which are associated with benign lesions or with asymptomatic, subclinical infections.
An age-stratified analysis was performed in order to explore effect modification of risk factors for HR-HPV. This analysis showed differences in the importance of markers of sexual activity between the younger (under 40 years) and the older (40 years and older) age strata. Amongst the older women (Table 4), having 10 or more lifetime sexual partners or having 2 or more sexual partners in either the past month or the past year was associated with a higher risk of HR-HPV (only model with the latter shown), whereas in the younger group (Table 5), having 10 or more lifetime sexual partners and having initiated sexual intercourse at a younger age (in univariate only) were associated with the outcome. Being of single marital status was only associated with HR-HPV in the younger age stratum. These findings may suggest that for older women, markers of recent sexual activity are more predictive of current HR-HPV status than markers of lifetime sexual history.
In a study of Columbian women, Molano et al14 reported some age-specific patterns in HPV infection. In particular, having 2 or more regular sexual partners was a more important risk factor in women less than 25-years-old, less important in women aged 25 to 35 years, and was not associated in women 35 years and older. Interestingly, an opposite effect was observed in our stratified analysis, in which having had 2 or more sexual partners in the past month was associated with HR-HPV infection in women aged 40 years and older, but not amongst women under 40 years of age.
This study demonstrates the importance of HPV infection among sexually active Inuit women living in northern Quebec. Age and previous exposure measured by number of lifetime sexual partners were strong predictors of HR-HPV infection. These analyses have to be interpreted taking into account the limitations of our study. Although participants were not selected randomly, they represented 58% of women in the target age group living in the 4 primary study communities and we believe that our conclusions are generalizable to the female Inuit population of Nunavik. In addition, selection bias was assessed by comparing participants to the general female population of Nunavik, which showed comparable educational attainment, participation in the workforce, marital status, and smoking habits.15,16 The most striking difference was a lower frequency of Pap screening amongst study subjects than in the general population, except amongst participants aged 45 years and older, who were screened slightly more often.16 This suggests that the study population may in fact exhibit less health-seeking behavior than the general population and thus may be at higher risk for HPV infection and cofactors that influence its natural history.
The overall prevalence of HPV (28.9%) and HR-HPV (20.4%) in this Quebec Inuit population compares to other “high-risk” Canadian populations including Montreal University students and attendees of a Winnipeg inner-city clinic.17,18 Age-specific prevalence followed a U-shaped curve, with increasing overall HPV and HR-HPV prevalence in women aged 50 years and older, a pattern which has been reported elsewhere.14,19 Determinants of HR-HPV infection in this population of Quebec Inuit women are consistent with the literature which, across many studies, identifies age and markers of sexual activity as the most consistent risk factors for overall and HR-HPV infection.14,18,20–25 In general, less is known about predictors of infection with the α-3 and α-15 species, which represent low-risk HPV types. In our study, past exposure to HPV as measured by the lifetime number of sexual partners was not predictive of α-3/15 infection, in contrast with α-7 and α-9 species. This may reflect a high level of transmission and prevalence of α-3/15 species in this population or may be related to the collection of cervical rather than vulvar or vaginal specimens.26,27 Alpha-3/15 may more frequently infect vulvar or vaginal rather than cervical epithelium; therefore, self-obtained samples may be more appropriate to study determinants of α-3/15 infection.
The burden of HPV infection in this female Inuit population did not differ markedly from other “high-risk” populations studied in Canada17,18; yet, cervical cancer rates are clearly elevated amongst Inuit women. Although genetic host susceptibility factors28–32 represent a plausible explanation for these differences, this hypothesis is yet to be verified. Thus, this population may benefit most from improved case detection through Pap screening or HPV testing-augmented programs that specifically target peri- and postmenopausal women. In addition, although HPV vaccination is taking place in Quebec, screening will continue to play an important role in cervical cancer prevention amongst all age groups of this high-risk population.
1. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004; 111:278–285.
2. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12–19.
3. Franco EL, Duarte-Franco E, Ferenczy A. Cervical cancer: Epidemiology, prevention and the role of human papillomavirus infection. CMAJ 2001; 164:1017–1025.
4. de Sanjose S, Diaz M, Castellsague X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: A meta-analysis. Lancet Infect Dis 2007; 7:453–459.
5. Nielsen NH, Storm HH, Gaudette LA, et al. Cancer in circumpolar Inuit 1969–1988. A summary. Acta Oncol 1996; 35:621–628.
6. Louchini R, Beaupré M. Cancer Chez les Autochtones du Québec Vivant dans les Réserves et les Villages Nordiques, de 1984 à 2004–Incidence et Mortalité. Quebec, QC: Institut National de Santé Publique, 2008.
7. Healey SM, Aronson KJ, Mao Y, et al. Oncogenic human papillomavirus infection and cervical lesions in aboriginal women of Nunavut, Canada. Sex Transm Dis 2001; 28:694–700.
8. Hamlin-Douglas LK, Coutlée F, Roger M, et al. Prevalence and age distribution of human papillomavirus infection in a population of Inuit women in Nunavik, Quebec. Cancer Epidemiol Biomarkers Prev 2008; 17:3141–3149.
9. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004; 324:17–27.
10. Kmetic A, Joseph L, Berger C, et al. Multiple imputation to account for missing data in a survey: Estimating the prevalence of osteoporosis. Epidemiology 2002; 13:437–444.
11. Arnold AM, Kronmal RA. Multiple imputation of baseline data in the cardiovascular health study. Am J Epidemiol 2003; 157:74–84.
12. Barzi F, Woodward M. Imputations of missing values in practice: Results from imputations of serum cholesterol in 28 cohort studies. Am J Epidemiol 2004; 160:34–45.
13. Castle PE, Jeronimo J, Schiffman M, et al. Age-related changes of the cervix influence human papillomavirus type distribution. Cancer Res 2006; 66:1218–1224.
14. Molano M, Posso H, Weiderpass E, et al. Prevalence and determinants of HPV infection among Colombian women with normal cytology. Br J Cancer 2002; 87:324–333.
15. Statistics Canada. 2001 Census: Community Highlights for Région du Nunavik. Quebec, QC: Statistics Canada, 2003.
16. Santé Québec. A Health Profile of the Inuit: Report of the Santé Québec Health Survey Among the Inuit of Nunavik, 1992. Montreal, QC: Ministère de la Santé et des Services Sociaux, Gouvernement du Québec, 1994.
17. Richardson H, Kelsall G, Tellier P, et al. The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev 2003; 12:485–490.
18. 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. Sex Transm Dis 1997; 24:293–298.
19. Herrero R, Hildesheim A, Bratti C, et al. Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst 2000; 92:464–474.
20. Giuliano AR, Papenfuss M, Schneider A, et al. Risk factors for high-risk type human papillomavirus infection among Mexican-American women. Cancer Epidemiol Biomarkers Prev 1999; 8:615–620.
21. Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005; 191:1796–1807.
22. Rousseau MC, Abrahamowicz M, Villa LL, et al. Predictors of cervical coinfection with multiple human papillomavirus types. Cancer Epidemiol Biomarkers Prev 2003; 12:1029–1037.
23. Ferreccio C, Prado RB, Luzoro AV, et al. Population-based prevalence and age distribution of human papillomavirus among women in Santiago, Chile. Cancer Epidemiol Biomarkers Prev 2004; 13:2271–2276.
24. Sellors JW, Mahony JB, Kaczorowski J, et al. Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. Survey of HPV in Ontario Women (SHOW) group. CMAJ 2000; 163:503–508.
25. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297:813–819.
26. Petignat P, Faltin DL, Bruchim I, et al. Are self-collected samples comparable to physician-collected cervical specimens for human papillomavirus DNA testing? A systematic review and meta-analysis. Gynecol Oncol 2007; 105:530–535.
27. Petignat P, Hankins C, Walmsley S, et al. Self-sampling is associated with increased detection of human papillomavirus DNA in the genital tract of HIV-seropositive women. Clin Infect Dis 2005; 41:527–534.
28. Odunsi KO, Ganesan TS. The roles of the human major histocompatibility complex and human papillomavirus infection in cervical intraepithelial neoplasia and cervical cancer. Clin Oncol (R Coll Radiol) 1997; 9:4–13.
29. Breitburd F, Ramoz N, Salmon J, et al. HLA control in the progression of human papillomavirus infections. Semin Cancer Biol 1996; 7:359–371.
30. Apple RJ, Becker TM, Wheeler CM, et al. Comparison of human leukocyte antigen DR-DQ disease associations found with cervical dysplasia and invasive cervical carcinoma. J Natl Cancer Inst 1995; 87:427–436.
31. Apple RJ, Erlich HA, Klitz W, et al. HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nat Genet 1994; 6:157–162.
32. Sanjeevi CB, Hjelmstrom P, Hallmans G, et al. Different HLA-DR-DQ haplotypes are associated with cervical intraepithelial neoplasia among human papillomavirus type-16 seropositive and seronegative Swedish women. Int J Cancer 1996; 68:409–414.
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HPV; epidemiology; determinants; Aboriginal; Inuit
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