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J Infect Dis. Author manuscript; available in PMC May 1, 2011.
Published in final edited form as:
PMCID: PMC2851490
NIHMSID: NIHMS176282

Sequential Acquisition of Human Papillomavirus Infection of the Anus and Cervix: The Hawaii HPV Cohort Study

Abstract

Background

Relatively little is known about the epidemiology of anal HPV infection among healthy women and its relation to cervical HPV infection.

Methods

The association of an incident cervical (or anal) HPV infection with the subsequent risk of a genotype-concordant incident anal (or cervical) HPV infection was examined through a longitudinal cohort study of 751sexually-active women. Age-adjusted hazard ratios, obtained using Cox regression, served as measures of relative risk (RR).

Results

The RR of acquiring an anal HPV infection after a cervical HPV infection with the same genotype was 20.5 (95% CI: 16.3-25.7); and the RR of acquiring a cervical HPV infection following an anal HPV infection with the same genotype was 8.8 (95% CI: 6.4-12.2) compared to women without a preceding anal/cervical HPV infection with a concordant genotype. RRs varied by phylogenetic species, with α3/α15 and α1/α8/α10 types having a greater likelihood than other types of infecting the anus among women with a preceding same-type infection at the cervix.

Conclusions

It appears common for anal and cervical HPV infections to occur consecutively. The high degree of genotype-specific concordance suggests that the cervix (vagina) and anus may serve as reservoirs for HPV infection at the other anatomic site.

Keywords: human papillomavirus, natural history, cohort, anus, cervix, acquisition, risk factors

INTRODUCTION

Anal cancer is an uncommon malignancy with an incidence of ~1 per 100,000, but rates have been increasing among women and men in the United States for more than three decades. Although the cause of this increase is uncertain, it is notable that the incidence of anal cancer among women in the United States is higher than among men [1]. Human papillomavirus, predominantly oncogenic types 16 (HPV-16) and 18 (HPV-18), have been detected in approximately 80% of squamous cell anal cancers which account for the majority of anal cancers in the US and Europe [2].

The histology of the anus shares important parallels with the cervix, including a transition zone from the squamous epithelium of the anus to the columnar epithelium of the rectum where most malignancies are identified [3]. The natural histories of HPV-related malignancies of the anus and cervix begin with viral infection and progress to a dysplastic precursor lesion, ‘intraepithelial neoplasia’, followed by cancer [4]. Women with cervical dysplasia and cervical cancer are at increased risk for anal cancer [5-8], presumably because of a shared exposure to oncogenic HPV types. The prevalence of anal HPV infection is reported to be higher than cervical HPV infection among HIV-infected women [4]. Indeed, the positive association between lifetime number of sexual partners and the incidence of high-risk (HR) anal HPV infection supports the notion that sexual intercourse is the primary route of anal infection [9]. However, we [9] and others [4,10,11] have found that a history of anal intercourse is not a significant risk factor for incident anal HR-HPV infection or anal cancer, suggesting alternative routes of transmission. Aside from potential under-reporting of anal sex, other sexual and nonsexual routes of transmission are possible, including non-penetrative sex or inoculation through fomites, fingers, or vaginal discharge [12,13].

In a previous analysis of the Hawaii HPV Cohort Study, we observed a high degree of genotype-specific concordance among concurrent anal and cervical HPV infections, indicating a common source of infection [14]. The objective of the present analysis was to extend this observation through a longitudinal evaluation of anal and cervical HPV infection concordance. Specifically, we wished to determine whether cervical HPV infection was a risk factor for anal HPV infection with the same viral genotype; and, conversely, whether anal HPV infection predicted future genotype-specific cervical HPV infection.

MATERIALS AND METHODS

Subject recruitment and data collection

Between 1998 and 2008, sexually-active women, 18-85 years of age, were recruited from five clinics on Oahu, Hawaii, to participate in a longitudinal cohort study of cervical and anal HPV infection [14,15]. Women scheduled for gynecology appointments who were not pregnant or postpartum within the past six months, had no treatment for cervical disease or abnormal cytology within the past 18 months, and had no plans to relocate in the next year were approached for participation in the cohort. Informed consent was obtained from all study participants using a protocol and forms approved by the University of Hawaii Institutional Review Board.

At each visit, trained clinicians obtained exfoliated cervical cell samples for cytology and HPV DNA detection. A Dacron swab and cytology brush were used consecutively to sample the entire ectocervix and endocervix, including the entire transformation zone. The swab and brush were then each placed in separate vials of 1.0 mL buffered medium (Digene). The two cervical samples were later combined in the laboratory for HPV DNA testing. The collection of anal specimens was optional for study subjects. Following the cervical specimen collection, an exfoliated anal cell specimen was obtained using a Dacron swab moistened with sterile water. The swab was inserted ~1.5 to 2.0 cm into the anus and rotated 360° clockwise (5 times) and counter-clockwise (5 times). The swab was placed in 1.0 mL medium. Upon completion of the examination, a study questionnaire was interviewer-administered covering demographics, reproductive history, sexual activity and history of sexually transmitted infections, hormone use, medical history, and tobacco and alcohol use.

Selection and follow-up of cohort

The results of the baseline cervical smear and HPV-DNA testing were necessary to establish the women’s final eligibility for participation in the study. Women whose specimens were inadequate (i.e., were negative for the human β-globin gene) at baseline were excluded; women who were enrolled in the study were asked to return to the clinic every 4 months for examination and testing. Women who were treated for a cervical abnormality were excluded from the study. A more detailed interview was conducted during the second and subsequent follow-up visits. A total of 751 women were recruited, tested for anal and cervical HPV DNA by PCR with β-globin-positive specimens, and completed at least two visits.

Detection and genotyping of HPV

HPV DNA was extracted from exfoliated cervical cell and anal cell specimens using commercial reagents (Qiagen). Specimens were analyzed for the presence or absence of HPV DNA by PCR using a modified version of the PGMY09/PGMY11 primer system [16]. HPV DNA-positive specimens were genotyped using a reverse line blot detection method for 36 different HPV types [17], including high-risk (HR) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68; possible high-risk types 26, 34, 53, 66, 70, 73, 82; low-risk (LR) types 6, 11, 40, 42, 44, 54, 61, 72, 81, and 89; and undetermined-risk types 62, 67, 71, 83, and 84 [18,19]. We defined the risk (oncogenic potential) associated with various HPV types using the definition of Castle [19]. HPV-positive specimens that subsequently had negative results of the genotyping assay were considered unclassified HPV-positive specimens. All specimens were also tested for the human β-globin gene as an internal control for sample sufficiency.

Statistical analysis

We analyzed sequential concordance of cervical and anal HPV infections, where an infection at one site (cervix or anus) was followed at a subsequent visit by an HPV infection of the same type at the other anatomic site (anus or cervix). Anal and cervical HPV infections were classified by phylogenetic species and by oncogenic risk (all infections, high-risk (HR), and possible-, low- or undetermined-risk (LR) genotypes), and by species (α1/α8/α10: HPV 6, 11, 32, 40, 42, 44, 74; α3/α15: 61, 62, 71, 72, 81, 83, 84; α5/α6: 26, 51, 53, 56, 66, 69, 82; α7: 18, 39, 45, 59, 68, 70; α9/α11: 16, 31, 33-35, 52, 58, 67, 73). Because we were interested in sequential acquisition, we only considered incident, not prevalent, infections at the subsequent (second, target) anatomic site, i.e. infections initially detected at the second or subsequent clinic visit. Prevalent infections detected at the first clinic visit, as well as incident infections, were both considered in determining HPV status at the initial (presumptive source) site. Infections acquired concurrently in the cervix and the anus were not included in the analyses. Our approach was conservative, because including such infections would likely result in stronger associations.

For a number of participant visits we only had a valid cervical sample, but not an anal sample, because anal sample collection was optional and the proportion of beta-globin negative samples was higher among anal samples (27%) than among cervical samples (0.6%). All such visits were excluded from the analyses. Because inadequate anal samples were not significantly associated with participants’ cervical HPV status or important baseline characteristics, this exclusion is unlikely to have biased the analysis results.

The risk of HPV acquisition at the second site (cervix or anus) after a same-type infection at the first site (anus or cervix) was modeled through Cox regression using days since infection acquisition at the first site as the time metric, after adjustment for age at study entry. Infections with unclassified HPV types were excluded from the analysis. If a study participant tested positive for the same HPV genotype after clearance, only the first acquisition of that genotype was considered. A woman could experience a subsequent incident infection with the same HPV type during follow-up and could be infected with more than one HPV type at one time. We assigned a separate infection path to every HPV genotype detected. For every HPV group or genotype, the risk of a subsequent infection at the second site among ‘exposed’ participants with a same-type infection at the first site was compared to that among ‘unexposed’ participants with no prior same-type infection at the first site, as well as to the risk among the participants exposed to other HPV groups or genotypes. Because each subject was allowed to experience more than one event throughout the course of the study, we used a robust sandwich variance estimate [20], aggregated over subjects, to prevent artificially deflated standard errors and confidence interval estimates.

Because nearly 10% of study participants did not provide the number of their lifetime sexual partners, this factor was not included as an adjustment variable. Other adjustment factors were considered, but their inclusion in the models did not result in at least a 10% change in the parameter estimates [21], nor in a significantly better fit according to the likelihood ratio test. The proportional hazards assumption for Cox models was verified by plotting scaled Schoenfeld residuals against time to HPV acquisition at the second site [22]. Hazard ratios (RRs) and 95% confidence intervals (CIs) were used as measures of association. All analyses were conducted using SAS version 9.2 (SAS Institute, Inc., Cary NC). All p-values were two-sided, and p < 0.05 was defined as significant.

RESULTS

Characteristics of the cohort

During the follow-up period, the 751 cohort participants experienced 382 incident cervical infections and 383 incident anal infections, defined as HPV genotypes not identified on a previous visit. Baseline and follow-up analyses included 3990 visits in which cervical specimens were collected (mean, 5.3 visits / woman); and 2348 visits in which anal specimens were collected (mean, 3.1 visits / woman) (Table1). The mean age of the multiethnic cohort was 34 years. Only 14% of the women were current tobacco smokers, and 55% were current alcohol drinkers at baseline. Anal sex was practiced by 8% of the women at enrollment.

Table 1
Study Sample Characteristics.

Sequential acquisition of an anal HPV infection following a cervical HPV infection with a concordant genotype

The risk of an incident anal HPV infection was increased significantly (RR: 20.5; 95% CI: 16.3-25.7) among women with a preceding concordant cervical HPV infection compared to women without a preceding cervical HPV infection with a concordant genotype (Table 2). In general, the risk was lower (RR: 0.58; 95% CI: 0.39-0.86) for acquiring a HR-HPV infection than a LR-HPV infection in the anus with the same HPV genotype as identified previously in the cervix than among women without a previous concordant cervical HPV genotype. Risk varied by phylogenetic species, with α3/α15 and α1/α8/α10 types having a greater likelihood than other types of infecting the anus among women with a preceding same-type infection at the cervix. Among single types, the risk of acquiring an anal HPV-18 infection given a previous infection of the cervix with HPV-18 was 34.8 (95% CI: 9.7-124) compared to women without a preceding cervical HPV-18 infection.

Table 2
Risk of sequential acquisition of cervical and anal HPV infection.

Sequential acquisition of a cervical HPV infection following an anal HPV infection with a concordant genotype

The risk of a cervical HPV infection following an anal HPV infection with a concordant genotype was 8.8 (95% CI: 6.4-12.2), somewhat lower than the risk of an anal HPV infection following a concordant cervical HPV infection. Unlike the results for cervical HPV infection followed by anal HPV infection, the risk was similar for acquiring a LR-HPV than a HR-HPV in the cervix following an anal HPV infection with a concordant genotype. Although the number of events was small, α9/α11 species had a slightly higher probability than other HPV types of infecting the cervix following a concordant anal HPV infection.

Baseline factors associated with an incident anal / cervical HPV infection following a concordant cervical / anal HPV infection

The risk of an incident anal / cervical HPV infection following a concordant incident cervical / anal HPV infection decreased significantly with age (Table 3). The risk of an incident cervical HPV infection following a concordant incident anal HPV infection increased significantly with a history of anal sex. None of the other baseline factors were significantly associated with the sequential acquisition of an incident cervical or anal HPV following a concordant HPV infection at the other anatomic site.

Table 3
Baseline risk factors for sequential acquisition of cervical and anal HPV infection.

DISCUSSION

A high degree of genotypic concordance was observed in the sequential incidence of cervical and anal HPV infections. Women were significantly more likely to have an incident anal or cervical HPV infection with the same genotype observed previously in the adjacent anatomic site (i.e., cervix or anus) than with a discordant HPV type or no previous HPV infection. Although this result might be expected considering the sexual nature of genital HPV transmission, the degree of HPV concordance in the sequential acquisition of HPV was high, especially for the risk of an anal HPV infection following a cervical infection with the same HPV type.

In previous analyses of the Hawaii HPV Cohort study [9], we found that acquisition of anal HPV infections was a relatively common event: 70% of women in the cohort had at least one anal HPV infection during the follow-up period of average duration 1.3 years. We also observed that 87% of anal HPV infections cleared within 1 year, perhaps explaining why the incidence of anal cancer is much lower than that of cervical cancer in spite of a similar rate of HR-HPV infection at both anatomic sites. The present analysis extends these findings, suggesting that women with a cervical HPV infection are at greater risk of an anal HPV infection. These results are consistent with the observation that women with cervical intraepithelial neoplasia or cervical cancer are at increased risk of anal intraepithelial neoplasia or cancer [5-8].

Several studies suggest that low- or undetermined-risk HPV types display tropism for the squamous epithelium of the vagina compared with the squamocolumnar epithelium of the cervix [23-26]. Although we were unable to examine this possibility in our data, both the HPV α3/α15 and α1/α8/α10 phylogenetic species appear to preferentially infect or persist in vaginal epithelium rather than in cervical epithelium [24-26]. It is plausible that vaginal / vulvar infections may later migrate to both the anus and cervix via intercourse or sexual foreplay, shedding of vaginal cells, or autoinoculation through fingers and other means. This migration is particularly important in the instance of HPV-16 and HPV-18 which are implicated in anal cancer [2]. Our data suggest that the risk of acquiring an anal HPV-18 infection given a previous cervical HPV-18 infection was quite high. Alternatively, vaginal squamous epithelium and anal epithelium may be more similar than cervical and anal epithelium, explaining the tropism of low-risk HPV types for these tissues.

The risk of an incident cervical HPV infection following a concordant anal HPV infection increased significantly with a history of anal sex. However, in the present analysis we found that 48% of incident cervical HPV following anal HPV and 63% of incident anal HPV following cervical HPV infection occurred in the absence of a self-reported history of anal sex. Although it is possible that cohort participants were embarrassed by our questions regarding anal sex and provided false-negative responses, the 29% prevalence of ever practicing anal sex in our population was similar to the 23% prevalence of anal intercourse reported in another study of sexually-active university students [27] and the 22% prevalence of anal intercourse reported among sexually-active women in a population-based study in Northern California [28]. Furthermore, a population-based Danish case-control found that the majority of men and women with anal cancer did not engage in anal sex [29]. Piketty et al. [11] reported that anal HPV infection was acquired in the absence of anal intercourse in HIV-infected men. Other modes of transmission should be considered.

In considering the generalizability of the results of this study, the collection of anal specimens was optional so only 66% of women agreed to participate in both cervical and anal specimen collection. Although there is no reason to think that this may have biased our findings, it is possible that women who participated in anal specimen collection considered themselves at greater risk for sexually transmitted infection. A further weakness of our methodology was the inability to determine whether HPVs of the same genotype present in the cervix and anus were part of a transmission event. Analysis of sequence variants would permit distinction between the same or different infection with the same genotype and may be included in future investigations. Similarly, some incident infections may have represented reactivations from latency or previously missed infections due to sampling error or viral levels below the limit if detection. Exfoliation of cells from the perianal region may have contaminated our anal specimens, although we had no means of examining this possibility. Swabs from participants’ back as well as from the examination table were routinely taken as clinical and environmental controls to monitor possible HPV contamination during the collection process. HPV DNA was not detected in any clinical or environmental control specimens. Some potential visits (25%) were excluded from the analysis because women refused anal sampling or the levels of β-globin were insufficient for HPV genotyping. Women excluded from the analysis did not significantly differ from women included in the analysis by demographics or sexual behaviors, such as anal receptive intercourse, that may have influenced the results. Finally, we note that few incident high-risk HPV events were observed, particularly for a cervical HPV infection following a high-risk anal HPV infection. It is possible that anal HPV infections are cleared too quickly for transmission to the cervix to occur.

The results of this study suggest that it is common for anal and cervical HPV infections to occur consecutively. The high degree of genotype-specific concordance indicates a common source of infection, such as vaginal and anal intercourse with the same infected partner(s), although alternate routes of transmission, including non-penetrative sexual contact and autoinoculation, need to be explored. The clinical consequences of our observations include higher rates of genital warts, and anal and cervical cancers among HPV-infected women through the spread of infection within the anogenital area, although cytological information was not included in this analysis. These results provide at least a partial basis for the finding that women with cervical intraepithelial neoplasia or cancer are at higher risk of anal cancer. Although anal cytology screening is cost-effective in HIV-infected men who have sex with men [30], studies of the efficacy of this approach in other high-risk groups have not been conducted.

ACKNOWLEDGMENT

We thank the following individuals and organizations for their assistance with this study: Clara Richards, April Hallback, Arlene McCafferty, and the staff of the University of Hawaii Cancer Research Center of Hawaii; Dora Irvine, Christian Sunoo and the staff of the Kaiser Permanente Hawaii Medical Systems; Marge Bernice, Cathy Cramer Bertram, Mark Hiraoka, Bruce Kessel, Mark Wakabayashi, and the staff of the Queen’s Medical Center; Momi Breault, David Easa, Emily Fritz, Louise Medina, and the staff of the University of Hawaii Clinical Research Center; Jamie Boyd and the staff of the University of Hawaii Leeward Community College Health Center; Gwen Barros, Sue Myhre, and the staff of the University of Hawaii University Health Services; and Janet Kornegay (Roche Molecular Systems). Reagents for the HPV PGMY-LB assay were kindly supplied by Roche Molecular Systems.

Financial Support: US Public Health Service grant R01-CA-077318 from the National Cancer Institute, NIH, Department of Health and Human Services.

Abbreviations

HPV
human papillomavirus
HR
high-risk
LR
low-risk
CI
confidence interval
OCP
oral contraceptive pill
PCR
polymerase chain reaction
SIL
squamous intraepithelial lesion

Footnotes

Conflict of Interests: Authors declare no conflicts.

REFERENCES

1. Joseph DA, Miller JW, Wu X, Chen VW, Morris CR, Goodman MT, Villalon-Gomez JM, Williams MA, Cress RD. Understanding the burden of human papillomavirus-associated anal cancers in the US. Cancer. 2008;113(10 Suppl):2892–900. [PMC free article] [PubMed]
2. Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer. 2009;124:2375–83. [PubMed]
3. Palefsky JM. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer Inst Monogr. 1998;23:15–20. [PubMed]
4. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis. 2001;183:383–91. [PubMed]
5. Scholefield JH, Sonnex C, Talbot IC, Palmer JG, Whatrup C, Mindel A, Northover JM. Anal and cervical intraepithelial neoplasia: possible parallel. Lancet. 1989;2:765–9. [PubMed]
6. Rabkin CS, Biggar RJ, Melbye M, Curtis RE. Second primary cancers following anal a and cervical carcinoma: evidence of shared etiologic factors. Am J Epidemiol. 1992;136:54–8. [PubMed]
7. Frisch M, Olsen JH, Melbye M. Malignancies that occur before and after anal cancer: clues to their etiology. Am J Epidemiol. 1994;140:12–9. [PubMed]
8. Edgren G, Sparén P. Risk of anogenital cancer after diagnosis of cervical intraepithelial neoplasia: a prospective population-based study. Lancet Oncol. 2007;8:311–6. [PubMed]
9. Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Ning L, Killeen J, Kamemoto L, Hernandez BY. Acquisition of anal human papillomavirus (HPV) infection in women: the Hawaii HPV Cohort study. J Infect Dis. 2008;197:957–66. [PubMed]
10. Williams AB, Darragh TM, Vranizan K, Ochia C, Moss AR, Palefsky JM. Anal and cervical human papillomavirus infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstet Gynecol. 1994;83:205–11. [PubMed]
11. Piketty C, Darragh TM, Da Costa M, et al. High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med. 2003;138:453–9. [PubMed]
12. Palefsky J. Biology of HPV in HIV infection. Adv Dent Res. 2006;19:99–105. [PubMed]
13. Moscicki AB, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev. 1999;8:173–8. [PubMed]
14. Hernandez BY, McDuffie K, Zhu X, et al. Anal human papillomavirus infection in women and its relationship with cervical infection. Cancer Epidemiol Biomarkers Prev. 2005;14:2550–6. [PMC free article] [PubMed]
15. Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Thompson PJ, Ning L, Killeen J, Kamemoto L, Hernandez BY. Prevalence, acquisition, and clearance of cervical human papillomavirus infection among women with normal cytology: Hawaii Human Papillomavirus Cohort Study. Cancer Res. 2008;68:8813–24. [PMC free article] [PubMed]
16. Gravitt PE, Peyton CL, Alessi TQ, et al. Improved a amplification of genital human papillomaviruses. J Clin Microbiol. 2000;38:357–61. [PMC free article] [PubMed]
17. Gravitt PE, Peyton CL, Apple RJ, Wheeler CM. Genotyping of 27 human papillomavirus types by using L1 consensus PCR products by a single-hybridization, reverse line blot detection method. J Clin Microbiol. 1998;36:3020–7. [PMC free article] [PubMed]
18. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology. 2004;324:17–27. [PubMed]
19. Castle PE. The evolving definition of carcinogenic human papillomavirus. Infect Agent Cancer. 2009;4:7. [PMC free article] [PubMed]
20. Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model. J Am Stat Assoc. 1989;84:1074–8.
21. Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation. Am J Epidemiol. 1989;129:125–37. [PubMed]
22. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.
23. Castle PE, Schiffman M, Bratti MC, et al. A population-based study of vaginal human papillomavirus infection in hysterectomized women. J Infect Dis. 2004;190:458–67. [PubMed]
24. Castle PE, Rodriguez AC, Porras C, et al. A comparison of cervical and vaginal human papillomavirus. Sex Transm Dis. 2007;34:849–55. [PMC free article] [PubMed]
25. Castle PE, Jeronimo J, Schiffman M, et al. Age-related changes of the cervix influence human papillomavirus type distribution. Cancer Res. 2006;66:1218–24. [PubMed]
26. Winer RL, Hughes JP, Feng Q, O’Reilly S, Kiviat NB, Koutsky LA. Comparison of incident cervical and vulvar/vaginal human papillomavirus infections in newly sexually active young women. J Infect Dis. 2009;199:815–8. [PubMed]
27. Baldwin JI, Baldwin JD. Heterosexual anal intercourse: an understudied, high-risk sexual behavior. Arch Sex Behav. 2000;29:357–73. [PubMed]
28. Misegades L, Page-Shafer K, Halperin D, McFarland W, YWS Study Investigators Group Young Women’s Survey. Anal intercourse among young low-income women in California: an overlooked risk factor for HIV? AIDS. 2001;15:534–5. [PubMed]
29. Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med. 1997;337:1350–8. [PubMed]
30. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA. 1999;281:1822–9. [PubMed]
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