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Human Papillomavirus Prevalence at the USA-Mexico Border Among Women 40 Years of Age and Older

Posted on: Friday, 8 April 2005, 03:00 CDT

Summary: The incidence of cervical cancer increases with age among USA Hispanics and women living in Latin America starting in the fourth decade of life. We conducted a study of women ≥40 living at the USA-Mexico border to determine the prevalence and risk factors for human papillomavirus (HPV) infection detected by polymerase chain reaction. In all, 9.2% of participants tested HPV positive. Compared with women aged 50-59, odds ratios of 8.82 and 6.67 were observed for women ≥60 and 40-49, respectively. Among women aged 40-49, both oncogenic and non-oncogenic HPV infections were detected; however, women ≥60 were positive for predominantly oncogenic genotypes. HPV risk significantly increased with ≥2 lifetime sexual partners in adjusted models. These data suggest that the prevalence of HPV infection may have a second peak among post-menopausal Hispanic women.

Keywords: human papillomavirus, USA-Mexico border, Hispanic women

Introduction

Cancers of the anogenital tract and their precursor lesions have been strongly linked to infection with the sexually transmitted human papillomavirus (HPV) among men and women.1 One of the most commonly occurring cancers caused by HPV is invasive cervical cancer, estimated to account for 12% of all cancers worldwide.2 Latin America has one of the highest cervical cancer incidence rates in the world, with an age-adjusted annual incidence of 44.4/ 100,000, far above the 9.5/100,000 for North America. Cervical cancer is also a major concern among Hispanics in the USA, whose incidence (17.1/100,000) is significantly elevated in comparison to the rate for non-Hispanic whites (7.5/

100,00O).3

In the USA, rates of invasive cervical cancer are highest among women in their fourth and fifth decades of life. Among Hispanics in the USA, the age pattern of cervical cancer incidence differs such that rates continue to increase past the fifth decade of life, peaking among women 60-69 years of age.3 This is similar to what has been observed for the Central America region, which includes Mexico, where the rate of invasive cervical cancer increases with age and peaks among women over 65 years of age.2 HPV prevalence studies conducted in the USA have indicated that the prevalence of HPV declines linearly with age.4' However, recent population-based studies conducted in Costa Rica6 and Mexico7 suggest that the prevalence of HPV is bimodal, decreasing with age and then increasing in the fifth decade of life. In previous research, we did not observe a bimodal HPV prevalence distribution among a clinic- based population at the USA-Mexico border.4 However, this may have been a biased sample as only women self-referring for care were included in the study. To further examine the prevalence of HPV among older Mexican and Mexican-American women, we conducted a study of women 40 years of age and older residing at the USA-Mexico border.

Methods

A cross- sectional survey was conducted from August 1999 to September 2000 in the contiguous border communities of Agua Prieta, Sonora, Mexico and Douglas, AZ, USA. Full description of these methods has previously been published.8

Bilingual interviewers in Arizona and interviewers in Sonora recruited women for the study at their home. If the woman met the following eligibility criteria, (a) 40 years of age or older, (b) resident of the household, and (c) not pregnant or at least two months postpartum, she was invited to complete an interviewer- administered questionnaire. Overall, there was a 45% participation rate. The predominant reason for refusal among USA women was that they were overwhelmed with issues of safety as illegal migration to the USA was high at this portion of the border between 1999 and 2000. There was 100% participation among women recruited in the Mexican community. The final study sample consisted of 456 completed face-to-face interviews.

All participants completed an informed consent form that had been approved by the Institutional Review Boards of both the University of Arizona and the Colegio de Sonora.

After completing the in-home interview, women were invited to attend a 'no-cost' clinical visit during which a Papanicolaou (Pap) smear was collected, followed by a sample of exfoliated cervical cells to determine HPV status. Of the 456 women completing an in- home interview, 318 (69.7%) attended a clinical visit, and 304 of these (95.6%) had valuable DNA for HPV testing. The 304 women with HPV results did not significantly differ from those without HPV results (n = 152) on lifetime number of sexual partners, age at first intercourse, smoking history, having a pap smear in the past three years, condom use, hormone replacement therapy (HRT) use, and history of STDs. A significantly higher proportion of women with HPV results were younger, married, less educated, and residents of Mexico compared with women without HPV results.

Laboratory testing

The methodology for collection and detection of HPV samples has been published elsewhere.4 Cervical cells were collected for HPV analysis from the ectocervix and endocervix using the Cone Brush Cytosoft(TM) and immediately suspended in 0.6 mL Digene Diagnostics Sample Transport Medium (Digene Corporation, Gaithersburg, MD, USA).

HPV DNA analyses were conducted using polymerase chain reaction (PCR). Genomic DNA was extracted following standard techniques. Specimens were tested for the presence of HPV using the PGMY09/11 Ll consensus primer system and AmpliTaq Gold polymerase (Perkin-Elmer, Foster City, CA, USA). Each amplification contained 10 PCR Buffer II, 25mmol/L MgCl^sub 2^, 200 L (each) dCTP, dGTP, and dATP, 600 L dUTP, 5 U of AmpliTaq Gold polymerase, 50 mol/l of PGMY09, 50 mol/L PGMYIl, 50 mol/L of B_PC04 and 50 mol/L of B_GH20 globin primers, and 5 mol/L of the template. To determine specimen adequacy, the GH20/PC04 human β-globin target was co-amplified with the HPV consensus primers. The following amplification profile was used: 95C hot start for 9min, 95C denaturation for 1 min, 55C annealing for 1 min, and 72 C extension for 1 min for 40 cycles, followed by a 5 min terminal extension at 72 C, and a hold step at 4 C using Perkin- Elmer GeneAmp PCR System 9700. HPV genotyping was conducted using the reverse line blot method4 on samples positive by PCR. This detection method utilizes the HPV Ll consensus PCR products labelled with biotin to detect 27 HPV types. All reagents were provided by Roche Molecular Systems Inc (Alameda, CA, USA). Strip interpretation was performed with a labelled overlay, with lines indicating the position of each probe relative to the reference mark. Oncogenic HPV types detected were 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, and nononcogenic HPV types detected were 6,11,2b, 40, 42, 53, 54, 55, 57, 66, 73, 82, 83, and 84.5

Statistical analysis

Due to limited numbers of women with non-oncogenic HPV types, we evaluated associations with any HPV type. To investigate the relationship between predictor variables and HPV positivity, we examined the magnitude of the association by calculating the age- adjusted odds ratios (ORs) for each variable. To evaluate which of these variables were potential confounders and factors independently associated with HPV, we estimated maximum-likelihood logistic models. Multivariate regression analyses determined the best model and yielded the final adjusted ORs and corresponding 95% confidence intervals (CI). No statistical interactions were found among these variables. All analyses were conducted using Intercooled Stata SE (StataCorp. Stata Statistical Software: Release 7.0. College Station, TX: Stata Corporation, 2001).

Results

The mean age of study participants was 51.2 8.7 years. The majority of participants were married or cohabiting (71.4%), and had one male sexual partner in their lifetime (65.6%). A complete description of the study population has been previously published."

Overall, HPV DNA was detected in 28 women (9.2%). Of these, 18 (64.3%,) tested positive for any oncogenic HPV type and 10 (35.7%) were infected with only non-oncogenic HPV types. Multiple infections were detected in seven (25.0%) of the 28 women positive for HPV and five (17.9%) women were infected with both oncogenic and non- oncogenic HPV types. Among the 301 women with cervical cytology results, 258 (85.7%) had normal cytology (data not shown). Twenty- one women (7.0%) had ASCUS/AGUS, 11 (3.7%) had LSIL/HSIL, and Π (3.7%) had results that were inconclusive (unsatisfactory Pap cytology). HPV positivity was significantly associated with cytology outcome (data not shown).

Among study participants, the most commonly detected oncogenic HPV infections were HPV 16 (2.0%), 58 (1.3%), and 52 (1.0%). HPV 84 (1.6%) and HPV 55 (1.0%) were the most commonly detected non- oncogenic infections (data not shown). In women 40-19 years of age, numerous HPV types, both oncogenic and non-oncogenic, were detected. In contrast, women aged ≥60 years were positive for predominantly oncogenic HPV genotypes. No significant associations were detected between age and cytology outcome.

The frequency distribution of selected risk factors and their association with HPV (any type) is shown in Table 1. Risk for HPV positivity was lowest among women aged 50-59 years(referent). Compared with this group, risk was higher among women aged 60-82 years (OR = 8.82, CI 1.72-15.22) and 40-49 years (OR = 6.67, CI 1.50- 29.64). Age, marital status, and lifetime number of sexual partners were significantly associated with HPV prevalence in age-adjusted analyses. In multivariate analyses only age and lifetime number of partners remained significantly associated with HPV infection.

Figure 1 shows the prevalence of any HPV type, oncogenic types, and non-oncogenic types by age group. Detection of non-oncogenic HPVs decreased from a high of 4.5% among women aged 40-19 years to 2.0% among women aged 50 years and older. In contrast, the distribution of oncogenic HPV types was U-shaped. Oncogenic types were detected in 7.7% of women aged 40-19 years, not detected among women aged 50-59 years, and detected among 11.8% of women 60 years and older.

Discussion

This study, conducted among Mexican and Mexican-American women at the USA-Mexico border, adds to the growing body of literature suggesting that the prevalence of HPV may have a second peak in older women.6'7 In addition to age, ≥1 lifetime sexual partners was significantly associated with HPV detection among women ≥40 years. We observed an overall HPV prevalence of 9.2%, of which 64% were oncogenic HPV types and HPV 16 was the most commonly detected (21%).

In a previous study at the USA-Mexico border, we observed a HPV prevalence of 10% among women 40 years and older, with a significant linear decrease with age for both oncogenic and nononcogenic HPV types.9 At the time this work was published, the only reports of a second HPV prevalence peak with older age were from population- based studies.6'7 We therefore postulated that the lack of a second peak in our study might have been due to selection bias, as women were recruited from those self-referring for care. In the past three years, four clinic-based studies of HPV prevalence have been published.10'13 There is no consistency in the age-specific prevalence of HPV or in the age at which a second peak occurs in these studies. Among women living in the Netherlands, a linear decrease in HPV prevalence with age was observed.10 In Hong Kong, a second HPV prevalence peak corresponding to unclassified HPV types was observed among women aged 51-55 years.11 In Canada, a second HPV peak for oncogenic infections was observed among women aged 60 years and older.12 Finally, in a study in West Africa, HPV infection generally increased with age, peaking in the age group 55 and older.13

In population-based studies of HPV prevalence conducted in Latin America, a second peak in HPV infection was noted in all three populations examined.6'7'14 In addition, there is a suggestion of a second HPV infection peak among women aged 55 years and older in the population-based study in Ho Chi Minh City.15 While all these studies demonstrated non-linear associations with age, the type of HPV infection that was elevated varied across populations. In our study, only oncogenic HPV types were elevated, with the second peak observed starting at approximately age 60 years. This is similar to the published literature where the second peak appears to begin at approximately 55 years of age, with Mexico representing the exception, demonstrating a second peak at a younger age.7

There are several possible explanations for the U-shaped distribution of HPV prevalence with age. Jacobs et al.w have suggested that the second peak could be a function of study design, as most population-based studies have not included women with cervical abnormalities. However, in our study and the study in Vietnam,'? women with cervical abnormalities were enrolled and a second HPV peak was observed. Alternative explanations proposed are changes in immune function with aging,14 hormonal changes due to menopause,7 or a cohort effect whereby older women were part of a generation more heavily exposed to HPV.6 It is plausible that age- related immune dysfunction varies across populations contributing to differences in observed age-related HPV prevalence. However, in this study, we did not observe an association between age and cervical abnormalities, a finding that would be expected if declining immune function was contributing to increasing HPV prevalence. Given that in most cases the second HPV peak begins years past the mean age of menopause, hormonal changes influencing HPV prevalence appear unlikely. Finally, depending on the population and the societal norms, the second peak of infection may be due to new infections introduced by the male partner.

As with all epidemiological studies, the limitations of this study need to be considered when interpreting the study findings. We attempted to recruit a population-based representative sample of women residing at the USA-Mexico border. However, during the study period, drug trafficking and violence were escalating the USA- Mexico border, resulting in study participation reluctance on the USA side. This lower rate of participation may have resulted in a biased sample. However, on the Mexican side of the international border, we had complete participation. The lower numbers of women recruited to study limited the statistical power to evaluate the association between age, HPV prevalence, and abnormal cervical cytology, and differences in the samples enrolled form the two sides of the international border. A study with larger numbers of participants and LSIL and HSIL cases is needed to evaluate this further.

Table 1 Distribution of selected variables and association with human papillomavirus

Figure 1 Prevalence of human papillomavirus by oncogenicity and age group

The finding of a second peak of oncogenic HPV types suggests that post-reproductive age women are at significantly elevated risk for cervical cancer, and can benefit from programmes that reduce HPV infection persistence and increase detection and treatment of pre- cancerous lesions. More research is needed to describe the natural history of oncogenic HPV infections in older women.

Acknowledgements: This work was presented in part at the 20th International Papillomavirus Conference, Paris, France, October 2002 (abstract P368). Informed consent was obtained from all participants in the study, in accordance with guidelines of the University of Arizona Human Subjects Committee and the Colegio de Sonora. This project was financially supported in part by the Centers for Disease Control and Prevention (Contract No. 0009963027).

References

1 Palefsky JM. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer lust Monogr 1998;23:15-20

2 Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. hit J Cancer 1999;80:827-41

3 National Cancer Institute. Surveillance, Epidemiology, and End Results (seeR) Program [www.seer.cancer.gov] seeR*Stat Database: Incidence-seeR 9 Regs Public-Use, Nov 2002 Sub (1973-2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003, based on the November 2002 submission

4 Giuliano AR, Papenfuss M, Abrahamsen M, et al. Human papillomavirus infection at the United StatesMexico border: implications for cervical cancer prevention and control. Cancer Epidemiol Biomarkers Prev 2001 ;10: 1129-36

5 Bauer H, Hildesheim A, Schiffman M, et al. Determinants of genital human papillomavirus infection in low risk women in Portland, OR. Sex Transm Dis 1993;20:274-8

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8 Hunter JB, Guernsey de Zapien J, Denman CA, et al. Healthcare access and utilization among women 40 and older at the US-Mexico border: predictors of a routine check-up. J Community Health 2003;28:317-33

9 Giuliano AR, Papenfuss M, Abrahamsen M, Inserra P. Differences in factors associated with oncogenic and nononcogenic human papillomavirus infection at the United States-Mexico border. Cancer Epidemiol Biomarkers Prev 2002;11:9304

10 Jacobs MV, Walboomers JMM, Snuders PJF, et al. Distribution of 37 mucosotropic HPV types in women with cytologically normal cervical smears: the age-related patterns for high-risk and low- risk types. Int J Cancer 2000;87:221-7

11 Chan PKS, Chang AR, Cheung JLK, et al. Determinants of cervical human papillomavirus infection: differences between high- and low-oncogenic risk types. J Infect Dis 2002;185:28-35

12 Sellors JW, Karwalajtys TL, Kaczorowski JA, et al. Prevalence of infection with carcinogenic human papilloma-virus among older women. CMA] 2002;167:871-3

13 Xi LF, Toure P, Critchlow CW, et al. Prevalence of specific types of human papillomavirus and cervical squamous intraepithelial lesions in consecutive, previously unscreened, West-African women over 35 years of age. lut J Cancer 2003;103:803-9

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;87:324-33

15 Anh PTH, Hieu NT, Herrero R, et al. Human papillomavirus infection among women in South and North Vietnam. lut J Cancer 2003;104:213-20

(Accepted 7 January 2004)

A R Giuliano PhD1, M R Papenfuss MS1, C A Denman PhD3, J Guernsey de Zapien BA2, M Abrahamsen MPH1 and J B Hunter MPH2

1 The Moffitt Cancer Center and Research Institute, Tampa, Florida; 2 Mel and EnId Zuckerman Arizona College of Public Health, University of Arizona, Tucson, AZ, USA; 3 EI Colegio de Sonora, Hermosillo, Sonora, Mexico

Correspondence to: Dr Anna Giuliano,

Email: agiuliano@azcc.arizona.edu

Copyright Royal Society of Medicine Press Ltd. Mar 2005

Source: International Journal of STD & AIDS

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