CSIRO PUBLISHING
Sexual Health http://dx.doi.org/10.1071/SH15035
Case Study
Human papillomavirus prevalence to age 60 years among Australian women prevaccination Julia M. L. Brotherton A,B,I, John R. Condon C, Peter B. McIntyre D, Sepehr N. Tabrizi E,F,G,H, Michael Malloy A,B, Suzanne M. Garland E,F,G,H and on behalf of the WHINURS study group A
National HPV Vaccination Program Register, PO Box 310, East Melbourne, Vic. 8002, Australia. School of Population and Global Health, Level 4, 207 Bouverie Street, The University of Melbourne, Vic. 3010, Australia. C Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811, Australia. D National Centre for Immunisation Research and Surveillance, University of Sydney and The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E Regional World Health Organisation Human Papillomavirus Laboratory Network, Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Locked Bag 300, Grattan Street and Flemington Road, Parkville, Vic. 3052, Australia. F Department of Obstetrics and Gynaecology, University of Melbourne, The Royal Women’s Hospital, Locked Bag 300, Grattan Street and Flemington Road, Parkville, Vic. 3052, Australia. G Department of Microbiology, Royal Children’s Hospital, 50 Flemington Road, Parkville, Vic. 3052, Australia. H Murdoch Childrens Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, Vic. 3052, Australia. I Corresponding author. Email: [email protected] B
Abstract. Background: The prevalence of human papillomavirus (HPV) at the cervix varies with age, peaking following sexual debut and declining thereafter in most populations. In some populations, a second peak is observed. Here we describe the prevalence of HPV at the cervix among Australian women before the commencement of the HPV vaccination program. Methods: Women aged 15 to 60 years attending health services for cervical screening between 2005 and 2008 were invited to participate. Liquid based cervical specimens were tested for 37 types of HPV using linear array. The percentage and 95% confidence interval of women with any type of HPV, any of 13 high risk HPV types, and with vaccine-preventable HPV types (types 6, 11, 16 and 18) were estimated in 5-year age bands. Results: Among 1929 women aged 15–60 years, HPV prevalence peaked at 64% at age 15–20 years, then declined gradually to 12% at age 41–45 years, whereafter it rose to 19% in women 51–55 years then returned to 14% in 56–60 year olds. Prevalence curves were similar for high-risk HPV types and vaccine-targeted HPV types 6, 11, 16 and 18 and when results were restricted to women with only normal cytology. Conclusions: The shape of the prevalence curve we observed is similar to those from other Western populations. Variation in prevalence curves is likely due to differences in sexual behaviour between populations and over time, reactivation of HPV during perimenopause, and possibly the presence of cervical screening programs. These data are the first such data from the Oceania region. Received 4 March 2015, accepted 15 April 2015, published online 1 June 2015
Background Human papillomavirus (HPV) infection, with one or more of the 40 types which infect mucosal tissue, is the most common sexually transmissible infection with a very high cumulative lifetime incidence (80–90%).1 Most infections are transient and benign. Prophylactic HPV vaccines have been developed which can prevent HPV16 and 18, the two major cancer-causing genotypes, and HPV6 and 11 which cause genital warts.2 Journal compilation Ó CSIRO 2015
These prophylactic vaccines are effective if administered before HPV infection (i.e. before sexual debut).2,3 Large international meta-analyses describe the prevalence of HPV at the cervix.4–6 Prevalence peaks in the period immediately following sexual debut and gradually declines in most populations. However in some populations a second peak is observed in later middle age. It remains unclear whether this second peak is due to: (a) a cohort effect; (b) latent infection with www.publish.csiro.au/journals/sh
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Sexual Health
J. M. L. Brotherton et al.
reactivation of HPV with age or perimenopause; or (c) behavioural changes of women or their partners gaining new sexual partners after middle age.7,8 Recent studies suggest that it is likely that all three factors contribute to the variation in prevalence by age across populations.9–11 To date, no data examining the prevalence of HPV among women spanning the age range have been available from Australia, or the Pacific/Oceania region. Only recently has any Oceania data been available to include in a non-agespecific estimate of HPV prevalence.12 We aimed to describe the age-specific prevalence of HPV at the cervix among Australian women aged 15 to 60 years from a study conducted before Australia’s National HPV Vaccination Program was introduced. Methods Between 2005 and 2008 we recruited women attending health clinics across Australia for cervical screening to provide a sample for HPV testing. In Australia cervical screening is recommended to commence from age 18, or 2 years after first sexual intercourse, (whichever is later) although earlier opportunistic screening does sometimes occur in younger women. The major aim of the source study was to establish whether there were any differences in HPV prevalence between Indigenous and non-Indigenous women aged up to 40 years.
Table 1.
Demographic characteristics and human papillomavirus (HPV) prevalence results for 1929 Australian women from the WHINURS (the Women’s Human papillomavirus Indigenous Non-Indigenous Urban Rural Study) prevaccine prevalence study HR, high risk; NA, not applicable. n
Smoker (%)
Hormonal contraceptive (%)
All women regardless of cytology result 15–20 years 139 41 (29.5) 87 (62.6) 21–25 years 359 106 (29.5) 202 (56.3) 26–30 years 383 86 (22.5) 164 (42.8) 31–35 years 341 76 (22.3) 122 (35.8) 36–40 years 272 59 (21.7) 68 (25.0) 41–45 years 147 18 (12.2) 22 (15.0) 46–50 years 153 20 (13.1) 22 (14.4) 51–55 years 85 6 (7.1) 2 (2.4) 56–60 years 50 9 (18.0) 0 (0) Total 1929 421 (21.8) 689 (35.7) Restricted to women with normal cytology result 15–20 years 106 29 (27.4) 65 (61.3) 21–25 years 287 81 (28.2) 157 (54.7) 26–30 years 340 71 (20.9) 144 (42.4) 31–35 years 313 69 (22.0) 114 (36.4) 36–40 years 250 56 (22.4) 65 (26.0) 41–45 years 143 16 (11.2) 22 (15.4) 46–50 years 145 20 (13.8) 17 (11.7) 51–55 years 82 6 (7.3) 2 (2.4) 56–60 years 45 9 (20.0) 0 (0) Total 1711 357 (20.9) 586 (34.3) A B
Detailed results describing findings for our main objectives have been reported previously.13,14 We additionally extended recruitment to include a sample of non-Indigenous women aged 40 to 60 years to estimate the prevalence of HPV among older Australian women. Thus only non-Indigenous women, in whom we had data available across the age range 15 to 60 years, were included in the present analyses. Detailed recruitment, sample size justification and laboratory methods have been described previously.13 Briefly, women were asked to give informed consent for HPV testing at the time of routine Pap screening. Data collected from participants included postcode, smoking status, hormonal contraception, Indigenous status, pregnancy status and most recent Pap result. Exfoliated cervical cells were collected into Preservcyt (ThinPrep, Hologic, Boxborough, MA, USA) and an aliquot transported for HPV testing at the World Health Organisation Regional HPV Reference Laboratory, Melbourne, Australia. DNA was extracted from samples using MagNA Pure LC (Roche Diagnostics, Mannheim, Germany). Specimens positive for HPV DNA using HPV AMPLICOR (Roche Molecular Systems, Alameda, CA, USA) or, if negative, using an inhouse PGMY09/11-based HPV consensus polymerase chain reaction/ELISA, were genotyped as described previously using LINEAR ARRAY HPV Genotyping Test (Roche Molecular Systems) with modifications. Ethics approval was given by the relevant ethics committees governing the 34 sites
Demographics Pregnant Major city resident (%) (%) 3 5 2 3 0 0 0 0 0 13
(2.2) (1.4) (0.5) (0.9) (0) (0) (0) (0) (0) (0.7)
74 209 246 190 149 89 100 56 34 1147
(53.2) (58.2) (64.2) (55.7) (54.8) (60.5) (65.4) (65.9) (68.0) (59.5)
1 2 2 3 0 0 0 0 0 8
(0.9) (0.7) (0.6) (1.0) (0) (0) (0) (0) (0) (0.5)
58 165 215 174 138 89 95 54 31 1019
(54.7) (57.5) (63.2) (55.6) (55.2) (62.2) (65.5) (65.9) (68.9) (59.6)
Abnormal cytology High-grade Low-grade (%) (%) 5 2 10 2 1 0 0 0 1 21
(3.6) (0.6) (2.6) (0.6) (0.4) (0) (0) (0) (2.0) (1.1)
NA NA NA NA NA NA NA NA NA NA
Detection of any of the 37 types detectable using linear array. The 13 high risk genotypes are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68.
26 65 28 22 15 3 4 1 4 168
(18.7) (18.1) (7.3) (6.5) (5.5) (2.0) (2.6) (1.2) (8.0) (8.7)
NA NA NA NA NA NA NA NA NA NA
Any HPVA (%)
Cervical HPV prevalence HRHPVB HPV 6/11/16/18 (%) (%)
HPV 16/18 (%)
89 194 167 105 60 17 24 16 7 679
(64.0) (54.0) (43.6) (30.8) (22.1) (11.6) (15.7) (18.8) (14.0) (35.2)
74 140 113 69 35 8 11 8 4 462
(53.2) (39.0) (29.5) (20.2) (12.9) (5.4) (7.2) (9.4) (8.0) (24.0)
49 76 59 25 11 1 4 4 1 230
(35.3) (21.2) (15.4) (7.3) (4.0) (0.7) (2.6) (4.7) (2.0) (11.9)
40 67 51 18 9 1 4 4 1 195
(28.8) (18.7) (13.3) (5.3) (3.3) (0.7) (2.6) (4.7) (2.0) (10.1)
57 132 134 86 49 16 22 16 5 517
(53.8) (46.0) (39.4) (27.5) (19.6) (11.2) (15.2) (19.5) (11.1) (30.2)
45 90 86 56 27 7 10 8 2 331
(42.5) (31.4) (25.3) (17.9) (10.8) (4.9) (6.9) (9.8) (4.4) (19.4)
29 51 40 23 8 1 4 4 1 161
(27.4) (17.8) (11.8) (7.4) (3.2) (0.7) (2.8) (4.9) (2.2) (9.4)
22 44 33 16 6 1 4 4 1 131
(20.8) (15.3) (9.7) (5.1) (2.4) (0.7) (2.8) (4.9) (2.2) (7.7)
HPV prevalence in Australian women
Sexual Health
of 16 and/or 18 separately. Descriptive data analysis (point estimates with 95% confidence intervals) was conducted in STATA/SE version 12.1 (StataCorp, College Station, TX, USA).
of recruitment, lead research site ethics approval was received from Royal Women’s Hospital Human Research Ethics Committee, Melbourne. We present our data as prevalence results for all women, regardless of cytology result, and, in order to facilitate comparisons with existing meta-analyses of cervical prevalence by age, we restricted the prevalence estimates by age to women with normal cytology on their current Pap test. For analysis we used 5-year age groups and grouped HPV genotypes into: (a) any of the HPV types detectable (37 types detectable by linear array); (b) high-risk types (13 genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68); and (c) vaccine-targeted types HPV6, 11, 16 and 18. We also examined the prevalence of type 16 and
Results The composition of our sample and HPV prevalence by age are presented in Table 1. Our sample included 1929 women (1711 cytologically normal women), comprising 1494 (1296 normal cytology) aged 15–40 years and 435 (415 normal cytology) aged 41–60 years. Most lived in a major city (1147 (59.5%)), 13 (0.7%) were pregnant, 421 (21.8%) were smokers and 689
(a) 80
64.0 60 54.0 43.6 40 30.8 22.1
20
15.7
18.8 14.0
Prevalence (%)
11.6 0
(b) 80
60 53.8 46.0 40
39.4 27.5
20
19.6
19.5 15.2 11.2
11.1
0
15–20
21–25
26–30
31–35
C
36–40
41–45
46–50
51–55
56–60
Age group Fig. 1. (a) Prevaccination program human papillomavirus prevalence by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program human papillomavirus prevalence by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
D
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J. M. L. Brotherton et al.
(a) 80
60 53.2
40
39.0 29.5 20.2
20
12.9 5.4
7.2
9.4
8.0
Prevalence (%)
0
(b) 80
60
40
42.5 31.4 25.3
20
17.9 10.8 4.9
6.9
9.8 4.4
0
15–20
21–25
26–30
31–35
36–40
41–45
46–50
51–55
56–60
Age group Fig. 2. (a) Prevaccination program high-risk human papillomavirus (genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) prevalence by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program high-risk human papillomavirus (genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) prevalence by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
(35.7%) were using hormonal contraception. Figures 1–3 depict HPV prevalence at the cervix by age. HPV prevalence is very high in late adolescence, peaking at 64% (54% normal cytology) in those 15–20 years of age; it then declines gradually to 12% (11% normal cytology) in the age band of 41–45 years (Fig. 1). After 45 years prevalence rises again to 19% (19.5% normal cytology) in women 51–55 years before dropping back to 14% (11% normal cytology) in 56–60 year olds, although the available precision, as reflected in the confidence intervals, does not exclude the possibility of a flatter curve past age 40. The patterns for high-risk types (Fig. 2) and for vaccine-targeted types, including HPV16 and 18 (Table 1) and HPV16 when examined separately (data not shown), are similar (Fig. 3).
Discussion We found that among Australian women attending for cervical screening either with normal cytology or regardless of cytology result, HPV prevalence peaked in the youngest age group (less than 20 years), before gradually declining to age 40–45, followed by a smaller secondary peak in the early 50s. Patterns were the same for high-risk HPV types and vaccinetargeted HPV types. The high HPV prevalence detected is a consequence of the sensitive methods we used in this sexually active population and are consistent with other studies using similar assays.15,16 While in some populations a U-shaped prevalence curve has been observed (eg. in Central and South America and Western
HPV prevalence in Australian women
Sexual Health
E
(a) 80
60
40 35.3
21.2
20
15.4 7.3
Prevalence (%)
4.0 0.7
0
2.6
4.7
2.0
(b) 80
60
40
27.4
20
17.8 11.8 7.3 3.2
0
15–20
21–25
26–30
31–35
36–40
0.7
41–45
2.8
46–50
4.9
51–55
2.2
56–60
Age group Fig. 3. (a) Prevaccination program vaccine-targeted human papillomavirus prevalence (any of genotype 6, 11, 16, 18) by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program vaccine-targeted human papillomavirus prevalence (any of genotype 6, 11, 16, 18) by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
Africa4), other Western populations have a similar prevalence (e.g. Western Europe, North America)4 although comparison is limited by the maximum age of 60 in our data. The confidence intervals do not exclude the possibility of a flatter prevalence with rising age (rather than a second peak). We also cannot exclude a selection bias if postmenopausal women attending community clinics are more likely to be sexually active or symptomatic. The variation in HPV prevalence curves by country or global region suggests that an interplay of factors determines HPV
prevalence by age. These include sexual behaviours and mixing patterns within populations and changes in these over time (cohort effects). Number of recent and lifetime sexual partners are powerful determinants of the likelihood of HPV infection and related diseases. The sexual revolution of 1965–75, which resulted in a higher average number of sexual partners, may be an important historical factor impacting upon currently observed HPV prevalence curves in Western populations.9 Evidence increasingly supports the existence of a latent state of HPV infection.11 In studies in women of perimenopausal age,
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many newly detected infections cannot be attributed to new partners, suggesting that immunosenescence or hormonal effects may contribute to reactivation.10,17,18 The median age at menopause in Australia is 52 years,19 which coincides with the second HPV peak in our data. It is therefore plausible that HPV rates are rising and may continue to rise among women in their 50s in Australia, if HPV prevalence in older women can indeed be predicted by number of lifetime sexual partners.17,18,20 However there are no historical data from older cohorts for comparison. Any secondary peak in HPV prevalence could potentially be dampened by Australia’s relatively intensive cervical screening program through removal of persistent HPV infections during treatment of screen-detected abnormalities, or a possible immunostimulatory effect of Pap test collection which may relatively protect against HPV infection.8,18,21 In summary, our data provide new information about HPV prevalence in unvaccinated Australian women by age to add to the understanding of the global epidemiology of HPV. Further monitoring of HPV prevalence among Australian women is highly desirable as vaccinated cohorts, and women belonging to cohorts impacted by more liberal attitudes to female sexuality, age. Conflicts of interest JMLB has been an investigator on investigator-designed, unrestricted, epidemiological research grants partially funded through bioCSL/Merck but has received no personal financial benefits. SNT is a chief investigator on a cancer typing study funded by a research grant from bioCSL. SMG has received advisory board fees and grant support from CSL and GlaxoSmithKline, and lecture fees from Merck, GlaxoSmithKline and Sanofi Pasteur. In addition, she has received funding through her institution to conduct HPV vaccine studies for Merck Sharpe Dohme and GlaxoSmithKline. SMG is a member of the Merck Global Advisory Board as well as the Merck Scientific Advisory Committee for HPV. PBM and his affiliation have received in-kind support for research projects from GlaxoSmithKline, Pfizer, CSL Limited and Merck. JC and MM have no competing interests to declare. Funding was received from the Cooperative Research Centre for Aboriginal Health for a pilot study in Alice Springs, Northern Territory. Grants-in-aid from GlaxoSmithKline and CSL Ltd., Melbourne, Australia supported the main study. Funding organisations had no role in the design, analysis, interpretation of data or the decision to submit for publication. Acknowledgements We sincerely thank all of the investigators and collaborators on the WHINURS (the Women’s Human papillomavirus Indigenous NonIndigenous Urban Rural Study) from across Australia.
References 1 Bosch FX, Tsu V, Vorsters A, Van Damme P, Kane MA. Reframing cervical cancer prevention. Expanding the field towards prevention of human papillomavirus infections and related diseases. Vaccine 2012; 30: F1–11. doi:10.1016/j.vaccine.2012.05.090
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2 Schiller JT, Castellsague X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 2012; 30: F123–38. doi:10.1016/j.vaccine.2012.04.108 3 Drolet M, Benard E, Boily M, Ali H, Baandrup L, Bauer H, Beddows S, Brisson J, Brotherton JML, Cummings T, Donovan B, Fairley CK, Flagg EW, Johnson AM, Kahn JA, Kavanagh K, Kjaer SK, Kliewer EV, Lemieux-Melloki P, Markowitz L, Mboup A, Mesher D, Niccolai L. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis 2015. doi:10.1016/S1473-3099(14) 71073-4 4 Bruni L, Diaz M, Castellsague X, Ferrer E, Bosch FX, de Sanjose S. Cervical human papillomavirus prevalence in 5 continents: metaanalysis of 1 million women with normal cytological findings. J Infect Dis 2010; 202: 1789–99. doi:10.1086/657321 5 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. doi:10.1016/j.jadohealth.2008. 07.009 6 de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, Bosch FX. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007; 7: 453–9. doi:10.1016/S1473-3099(07)70158-5 7 Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, Tortolero-Luna G, Kjaer SK, Munoz N. Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine 2008; 26: K1–16. doi:10.1016/j.vaccine.2008.05.064 8 Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce E, Matos E, Molano M, Qiao Y-L, Rajkuma R, Ronco G, de Sanjose S, Shin H-R, Sukvirach S, Thomas JO, Meijer CJLM, Munoz N. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006; 119: 2677–84. doi:10.1002/ijc.22241 9 Gravitt PE, Rositch AF, Silver MI, Marks MA, Chang K, Burke AE, Viscidi RP. A cohort effect of the sexual revolution may be masking an increase in human papillomavirus detection at menopause in the United States. J Infect Dis 2013; 207: 272–80. doi:10.1093/infdis/ jis660 10 Rositch AF, Burke AE, Viscidi RP, Silver MI, Chang K, Gravitt PE. Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women. Cancer Res 2012; 72: 6183–90. doi:10.1158/00085472.CAN-12-2635 11 Gravitt PE. The known unknowns of HPV natural history. J Clin Invest 2011; 121: 4593–9. doi:10.1172/JCI57149 12 Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, Clifford GM. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer 2012; 131: 2349–59. doi:10.1002/ijc.27485 13 Garland SM, Brotherton JM, Condon JR, McIntyre PB, Stevens MP, Smith DW, Tabrizi SN. Human papillomavirus prevalence among indigenous and non-indigenous Australian women prior to a national HPV vaccination program. BMC Med 2011; 9: 104. doi:10.1186/ 1741-7015-9-104 14 Tabrizi SN, Brotherton JML, Stevens MP, Condon JR, McIntyre PB, Smith D, Garland SM, on behalf of the WHINURS group. HPV genotype prevalence in Australian women undergoing routine cervical screening by cytology status prior to implementation of an HPV vaccination program. J Clin Virol 2014; 60: 250–6. doi:10.1016/ j.jcv.2014.04.013 15 Kjaer SK, Breugelmans G, Munk C, Junge J, Watson M, Iftner T. Population-based prevalence, type- and age-specific distribution of
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HPV in women before introduction of an HPV-vaccination program in Denmark. Int J Cancer 2008; 123: 1864–70. doi:10.1002/ijc.23712 16 Kavanagh K, Sinka K, Cuschieri K, Love J, Potts A, Pollock KG, Cubie H, Donaghy M, Robertson C. Estimation of HPV prevalence in young women in Scotland; monitoring of future vaccine impact. BMC Infect Dis 2013; 13: 519. doi:10.1186/1471-2334-13-519 17 Althoff KN, Paul P, Burke AE, Viscidi R, Sangaramoorthy M, Gravitt PE. Correlates of cervicovaginal human papillomavirus detection in perimenopausal women. J Womens Health 2009; 18: 1341–6. doi:10.1089/jwh.2008.1223 18 Brogaard KA, Munk C, Iftner T, Frederiksen K, Kjaer SK. Detection of oncogenic genital human papillomavirus (HPV) among HPV negative older and younger women after 7 years of follow-up. J Med Virol 2014; 86: 975–82. doi:10.1002/jmv.23914
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19 Berecki-Gisolf J, Begum N, Dobson AJ. Symptoms reported by women in midlife: menopausal transition or aging? Menopause 2009; 16: 1021–9. doi:10.1097/gme.0b013e3181a8c49f 20 Gonzalez P, Hildesheim A, Rodriguez AC, Schiffman M, Porras C, Wacholder S, Pineres AG, Pinto LA, Burk RD, Herrero R. Behavioral/lifestyle and immunologic factors associated with HPV infection among women older than 45 years. Cancer Epidemiol Biomarkers Prev 2010; 19: 3044–54. doi:10.1158/1055-9965.EPI10-0645 21 Kjaer SK, Munk C, Junge J, Iftner T. Carcinogenic HPV prevalence and age-specific type distribution in 40,382 women with normal cervical cytology, ASCUS/LSIL, HSIL, or cervical cancer: what is the potential for prevention? Cancer Causes Control 2014; 25: 179–89. doi:10.1007/s10552-013-0320-z
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Sexual Health http://dx.doi.org/10.1071/SH15035
Case Study
Human papillomavirus prevalence to age 60 years among Australian women prevaccination Julia M. L. Brotherton A,B,I, John R. Condon C, Peter B. McIntyre D, Sepehr N. Tabrizi E,F,G,H, Michael Malloy A,B, Suzanne M. Garland E,F,G,H and on behalf of the WHINURS study group A
National HPV Vaccination Program Register, PO Box 310, East Melbourne, Vic. 8002, Australia. School of Population and Global Health, Level 4, 207 Bouverie Street, The University of Melbourne, Vic. 3010, Australia. C Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811, Australia. D National Centre for Immunisation Research and Surveillance, University of Sydney and The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E Regional World Health Organisation Human Papillomavirus Laboratory Network, Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Locked Bag 300, Grattan Street and Flemington Road, Parkville, Vic. 3052, Australia. F Department of Obstetrics and Gynaecology, University of Melbourne, The Royal Women’s Hospital, Locked Bag 300, Grattan Street and Flemington Road, Parkville, Vic. 3052, Australia. G Department of Microbiology, Royal Children’s Hospital, 50 Flemington Road, Parkville, Vic. 3052, Australia. H Murdoch Childrens Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, Vic. 3052, Australia. I Corresponding author. Email: [email protected] B
Abstract. Background: The prevalence of human papillomavirus (HPV) at the cervix varies with age, peaking following sexual debut and declining thereafter in most populations. In some populations, a second peak is observed. Here we describe the prevalence of HPV at the cervix among Australian women before the commencement of the HPV vaccination program. Methods: Women aged 15 to 60 years attending health services for cervical screening between 2005 and 2008 were invited to participate. Liquid based cervical specimens were tested for 37 types of HPV using linear array. The percentage and 95% confidence interval of women with any type of HPV, any of 13 high risk HPV types, and with vaccine-preventable HPV types (types 6, 11, 16 and 18) were estimated in 5-year age bands. Results: Among 1929 women aged 15–60 years, HPV prevalence peaked at 64% at age 15–20 years, then declined gradually to 12% at age 41–45 years, whereafter it rose to 19% in women 51–55 years then returned to 14% in 56–60 year olds. Prevalence curves were similar for high-risk HPV types and vaccine-targeted HPV types 6, 11, 16 and 18 and when results were restricted to women with only normal cytology. Conclusions: The shape of the prevalence curve we observed is similar to those from other Western populations. Variation in prevalence curves is likely due to differences in sexual behaviour between populations and over time, reactivation of HPV during perimenopause, and possibly the presence of cervical screening programs. These data are the first such data from the Oceania region. Received 4 March 2015, accepted 15 April 2015, published online 1 June 2015
Background Human papillomavirus (HPV) infection, with one or more of the 40 types which infect mucosal tissue, is the most common sexually transmissible infection with a very high cumulative lifetime incidence (80–90%).1 Most infections are transient and benign. Prophylactic HPV vaccines have been developed which can prevent HPV16 and 18, the two major cancer-causing genotypes, and HPV6 and 11 which cause genital warts.2 Journal compilation Ó CSIRO 2015
These prophylactic vaccines are effective if administered before HPV infection (i.e. before sexual debut).2,3 Large international meta-analyses describe the prevalence of HPV at the cervix.4–6 Prevalence peaks in the period immediately following sexual debut and gradually declines in most populations. However in some populations a second peak is observed in later middle age. It remains unclear whether this second peak is due to: (a) a cohort effect; (b) latent infection with www.publish.csiro.au/journals/sh
B
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J. M. L. Brotherton et al.
reactivation of HPV with age or perimenopause; or (c) behavioural changes of women or their partners gaining new sexual partners after middle age.7,8 Recent studies suggest that it is likely that all three factors contribute to the variation in prevalence by age across populations.9–11 To date, no data examining the prevalence of HPV among women spanning the age range have been available from Australia, or the Pacific/Oceania region. Only recently has any Oceania data been available to include in a non-agespecific estimate of HPV prevalence.12 We aimed to describe the age-specific prevalence of HPV at the cervix among Australian women aged 15 to 60 years from a study conducted before Australia’s National HPV Vaccination Program was introduced. Methods Between 2005 and 2008 we recruited women attending health clinics across Australia for cervical screening to provide a sample for HPV testing. In Australia cervical screening is recommended to commence from age 18, or 2 years after first sexual intercourse, (whichever is later) although earlier opportunistic screening does sometimes occur in younger women. The major aim of the source study was to establish whether there were any differences in HPV prevalence between Indigenous and non-Indigenous women aged up to 40 years.
Table 1.
Demographic characteristics and human papillomavirus (HPV) prevalence results for 1929 Australian women from the WHINURS (the Women’s Human papillomavirus Indigenous Non-Indigenous Urban Rural Study) prevaccine prevalence study HR, high risk; NA, not applicable. n
Smoker (%)
Hormonal contraceptive (%)
All women regardless of cytology result 15–20 years 139 41 (29.5) 87 (62.6) 21–25 years 359 106 (29.5) 202 (56.3) 26–30 years 383 86 (22.5) 164 (42.8) 31–35 years 341 76 (22.3) 122 (35.8) 36–40 years 272 59 (21.7) 68 (25.0) 41–45 years 147 18 (12.2) 22 (15.0) 46–50 years 153 20 (13.1) 22 (14.4) 51–55 years 85 6 (7.1) 2 (2.4) 56–60 years 50 9 (18.0) 0 (0) Total 1929 421 (21.8) 689 (35.7) Restricted to women with normal cytology result 15–20 years 106 29 (27.4) 65 (61.3) 21–25 years 287 81 (28.2) 157 (54.7) 26–30 years 340 71 (20.9) 144 (42.4) 31–35 years 313 69 (22.0) 114 (36.4) 36–40 years 250 56 (22.4) 65 (26.0) 41–45 years 143 16 (11.2) 22 (15.4) 46–50 years 145 20 (13.8) 17 (11.7) 51–55 years 82 6 (7.3) 2 (2.4) 56–60 years 45 9 (20.0) 0 (0) Total 1711 357 (20.9) 586 (34.3) A B
Detailed results describing findings for our main objectives have been reported previously.13,14 We additionally extended recruitment to include a sample of non-Indigenous women aged 40 to 60 years to estimate the prevalence of HPV among older Australian women. Thus only non-Indigenous women, in whom we had data available across the age range 15 to 60 years, were included in the present analyses. Detailed recruitment, sample size justification and laboratory methods have been described previously.13 Briefly, women were asked to give informed consent for HPV testing at the time of routine Pap screening. Data collected from participants included postcode, smoking status, hormonal contraception, Indigenous status, pregnancy status and most recent Pap result. Exfoliated cervical cells were collected into Preservcyt (ThinPrep, Hologic, Boxborough, MA, USA) and an aliquot transported for HPV testing at the World Health Organisation Regional HPV Reference Laboratory, Melbourne, Australia. DNA was extracted from samples using MagNA Pure LC (Roche Diagnostics, Mannheim, Germany). Specimens positive for HPV DNA using HPV AMPLICOR (Roche Molecular Systems, Alameda, CA, USA) or, if negative, using an inhouse PGMY09/11-based HPV consensus polymerase chain reaction/ELISA, were genotyped as described previously using LINEAR ARRAY HPV Genotyping Test (Roche Molecular Systems) with modifications. Ethics approval was given by the relevant ethics committees governing the 34 sites
Demographics Pregnant Major city resident (%) (%) 3 5 2 3 0 0 0 0 0 13
(2.2) (1.4) (0.5) (0.9) (0) (0) (0) (0) (0) (0.7)
74 209 246 190 149 89 100 56 34 1147
(53.2) (58.2) (64.2) (55.7) (54.8) (60.5) (65.4) (65.9) (68.0) (59.5)
1 2 2 3 0 0 0 0 0 8
(0.9) (0.7) (0.6) (1.0) (0) (0) (0) (0) (0) (0.5)
58 165 215 174 138 89 95 54 31 1019
(54.7) (57.5) (63.2) (55.6) (55.2) (62.2) (65.5) (65.9) (68.9) (59.6)
Abnormal cytology High-grade Low-grade (%) (%) 5 2 10 2 1 0 0 0 1 21
(3.6) (0.6) (2.6) (0.6) (0.4) (0) (0) (0) (2.0) (1.1)
NA NA NA NA NA NA NA NA NA NA
Detection of any of the 37 types detectable using linear array. The 13 high risk genotypes are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68.
26 65 28 22 15 3 4 1 4 168
(18.7) (18.1) (7.3) (6.5) (5.5) (2.0) (2.6) (1.2) (8.0) (8.7)
NA NA NA NA NA NA NA NA NA NA
Any HPVA (%)
Cervical HPV prevalence HRHPVB HPV 6/11/16/18 (%) (%)
HPV 16/18 (%)
89 194 167 105 60 17 24 16 7 679
(64.0) (54.0) (43.6) (30.8) (22.1) (11.6) (15.7) (18.8) (14.0) (35.2)
74 140 113 69 35 8 11 8 4 462
(53.2) (39.0) (29.5) (20.2) (12.9) (5.4) (7.2) (9.4) (8.0) (24.0)
49 76 59 25 11 1 4 4 1 230
(35.3) (21.2) (15.4) (7.3) (4.0) (0.7) (2.6) (4.7) (2.0) (11.9)
40 67 51 18 9 1 4 4 1 195
(28.8) (18.7) (13.3) (5.3) (3.3) (0.7) (2.6) (4.7) (2.0) (10.1)
57 132 134 86 49 16 22 16 5 517
(53.8) (46.0) (39.4) (27.5) (19.6) (11.2) (15.2) (19.5) (11.1) (30.2)
45 90 86 56 27 7 10 8 2 331
(42.5) (31.4) (25.3) (17.9) (10.8) (4.9) (6.9) (9.8) (4.4) (19.4)
29 51 40 23 8 1 4 4 1 161
(27.4) (17.8) (11.8) (7.4) (3.2) (0.7) (2.8) (4.9) (2.2) (9.4)
22 44 33 16 6 1 4 4 1 131
(20.8) (15.3) (9.7) (5.1) (2.4) (0.7) (2.8) (4.9) (2.2) (7.7)
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of 16 and/or 18 separately. Descriptive data analysis (point estimates with 95% confidence intervals) was conducted in STATA/SE version 12.1 (StataCorp, College Station, TX, USA).
of recruitment, lead research site ethics approval was received from Royal Women’s Hospital Human Research Ethics Committee, Melbourne. We present our data as prevalence results for all women, regardless of cytology result, and, in order to facilitate comparisons with existing meta-analyses of cervical prevalence by age, we restricted the prevalence estimates by age to women with normal cytology on their current Pap test. For analysis we used 5-year age groups and grouped HPV genotypes into: (a) any of the HPV types detectable (37 types detectable by linear array); (b) high-risk types (13 genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68); and (c) vaccine-targeted types HPV6, 11, 16 and 18. We also examined the prevalence of type 16 and
Results The composition of our sample and HPV prevalence by age are presented in Table 1. Our sample included 1929 women (1711 cytologically normal women), comprising 1494 (1296 normal cytology) aged 15–40 years and 435 (415 normal cytology) aged 41–60 years. Most lived in a major city (1147 (59.5%)), 13 (0.7%) were pregnant, 421 (21.8%) were smokers and 689
(a) 80
64.0 60 54.0 43.6 40 30.8 22.1
20
15.7
18.8 14.0
Prevalence (%)
11.6 0
(b) 80
60 53.8 46.0 40
39.4 27.5
20
19.6
19.5 15.2 11.2
11.1
0
15–20
21–25
26–30
31–35
C
36–40
41–45
46–50
51–55
56–60
Age group Fig. 1. (a) Prevaccination program human papillomavirus prevalence by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program human papillomavirus prevalence by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
D
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(a) 80
60 53.2
40
39.0 29.5 20.2
20
12.9 5.4
7.2
9.4
8.0
Prevalence (%)
0
(b) 80
60
40
42.5 31.4 25.3
20
17.9 10.8 4.9
6.9
9.8 4.4
0
15–20
21–25
26–30
31–35
36–40
41–45
46–50
51–55
56–60
Age group Fig. 2. (a) Prevaccination program high-risk human papillomavirus (genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) prevalence by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program high-risk human papillomavirus (genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) prevalence by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
(35.7%) were using hormonal contraception. Figures 1–3 depict HPV prevalence at the cervix by age. HPV prevalence is very high in late adolescence, peaking at 64% (54% normal cytology) in those 15–20 years of age; it then declines gradually to 12% (11% normal cytology) in the age band of 41–45 years (Fig. 1). After 45 years prevalence rises again to 19% (19.5% normal cytology) in women 51–55 years before dropping back to 14% (11% normal cytology) in 56–60 year olds, although the available precision, as reflected in the confidence intervals, does not exclude the possibility of a flatter curve past age 40. The patterns for high-risk types (Fig. 2) and for vaccine-targeted types, including HPV16 and 18 (Table 1) and HPV16 when examined separately (data not shown), are similar (Fig. 3).
Discussion We found that among Australian women attending for cervical screening either with normal cytology or regardless of cytology result, HPV prevalence peaked in the youngest age group (less than 20 years), before gradually declining to age 40–45, followed by a smaller secondary peak in the early 50s. Patterns were the same for high-risk HPV types and vaccinetargeted HPV types. The high HPV prevalence detected is a consequence of the sensitive methods we used in this sexually active population and are consistent with other studies using similar assays.15,16 While in some populations a U-shaped prevalence curve has been observed (eg. in Central and South America and Western
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E
(a) 80
60
40 35.3
21.2
20
15.4 7.3
Prevalence (%)
4.0 0.7
0
2.6
4.7
2.0
(b) 80
60
40
27.4
20
17.8 11.8 7.3 3.2
0
15–20
21–25
26–30
31–35
36–40
0.7
41–45
2.8
46–50
4.9
51–55
2.2
56–60
Age group Fig. 3. (a) Prevaccination program vaccine-targeted human papillomavirus prevalence (any of genotype 6, 11, 16, 18) by age group in 1929 Australian women with any cervical cytology result. (b) Prevaccination program vaccine-targeted human papillomavirus prevalence (any of genotype 6, 11, 16, 18) by age group in 1711 Australian women with normal cervical cytology. The vertical lines indicate the 95% confidence interval.
Africa4), other Western populations have a similar prevalence (e.g. Western Europe, North America)4 although comparison is limited by the maximum age of 60 in our data. The confidence intervals do not exclude the possibility of a flatter prevalence with rising age (rather than a second peak). We also cannot exclude a selection bias if postmenopausal women attending community clinics are more likely to be sexually active or symptomatic. The variation in HPV prevalence curves by country or global region suggests that an interplay of factors determines HPV
prevalence by age. These include sexual behaviours and mixing patterns within populations and changes in these over time (cohort effects). Number of recent and lifetime sexual partners are powerful determinants of the likelihood of HPV infection and related diseases. The sexual revolution of 1965–75, which resulted in a higher average number of sexual partners, may be an important historical factor impacting upon currently observed HPV prevalence curves in Western populations.9 Evidence increasingly supports the existence of a latent state of HPV infection.11 In studies in women of perimenopausal age,
F
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many newly detected infections cannot be attributed to new partners, suggesting that immunosenescence or hormonal effects may contribute to reactivation.10,17,18 The median age at menopause in Australia is 52 years,19 which coincides with the second HPV peak in our data. It is therefore plausible that HPV rates are rising and may continue to rise among women in their 50s in Australia, if HPV prevalence in older women can indeed be predicted by number of lifetime sexual partners.17,18,20 However there are no historical data from older cohorts for comparison. Any secondary peak in HPV prevalence could potentially be dampened by Australia’s relatively intensive cervical screening program through removal of persistent HPV infections during treatment of screen-detected abnormalities, or a possible immunostimulatory effect of Pap test collection which may relatively protect against HPV infection.8,18,21 In summary, our data provide new information about HPV prevalence in unvaccinated Australian women by age to add to the understanding of the global epidemiology of HPV. Further monitoring of HPV prevalence among Australian women is highly desirable as vaccinated cohorts, and women belonging to cohorts impacted by more liberal attitudes to female sexuality, age. Conflicts of interest JMLB has been an investigator on investigator-designed, unrestricted, epidemiological research grants partially funded through bioCSL/Merck but has received no personal financial benefits. SNT is a chief investigator on a cancer typing study funded by a research grant from bioCSL. SMG has received advisory board fees and grant support from CSL and GlaxoSmithKline, and lecture fees from Merck, GlaxoSmithKline and Sanofi Pasteur. In addition, she has received funding through her institution to conduct HPV vaccine studies for Merck Sharpe Dohme and GlaxoSmithKline. SMG is a member of the Merck Global Advisory Board as well as the Merck Scientific Advisory Committee for HPV. PBM and his affiliation have received in-kind support for research projects from GlaxoSmithKline, Pfizer, CSL Limited and Merck. JC and MM have no competing interests to declare. Funding was received from the Cooperative Research Centre for Aboriginal Health for a pilot study in Alice Springs, Northern Territory. Grants-in-aid from GlaxoSmithKline and CSL Ltd., Melbourne, Australia supported the main study. Funding organisations had no role in the design, analysis, interpretation of data or the decision to submit for publication. Acknowledgements We sincerely thank all of the investigators and collaborators on the WHINURS (the Women’s Human papillomavirus Indigenous NonIndigenous Urban Rural Study) from across Australia.
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