Affiliations of authors: Departments of Medicine (PVC-H, SB, GC, MDC, JMP), Epidemiology and Biostatistics (EV, SB), and Pathology (TD), University of CaliforniaSan Francisco, San Francisco, CA; Department of Medicine, University of CaliforniaLos Angeles, Los Angeles, CA (RDC); Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA (LB); Department of Public Health, San Francisco, CA (SB, GC,); Abt Associates, Inc., Cambridge, MA (DJB); Department of Public Health, Denver, CO (FJ); New York Blood Center, New York, NY (BK); Fenway Community Health Center, Boston, MA (KHM)
Correspondence to: Peter V. Chin-Hong, MD, Box 0654, 521 Parnassus Ave., Rm. C-443, University of CaliforniaSan Francisco, San Francisco, CA 941430654 (e-mail: pvch{at}itsa.ucsf.edu).
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ABSTRACT |
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INTRODUCTION |
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Several studies have shown that the detection of cervical cytologic abnormalities (i.e., LSILs and HSILs) is strongly associated with age. Using population-based sampling, Herrero et al. (9,10) demonstrated that the prevalence of LSILs in the cervix peaked at 5.2% among women younger than 25 years, decreased sharply to 2.7% by ages 2534 years, and then continued to decrease to 0.4% among women older than 65 years. The prevalence of HSILs in the cervix peaked later, at ages 2534 years, and was followed by a less pronounced decline at ages 3544 years and a smaller increase in prevalence among women older than 65 years old compared with the increase that was observed at ages 2534 years. It has been estimated that cervical HSILs, if undetected, can progress to invasive cervical cancer in 910 years (11).
Knowledge of the age-related prevalence and natural history of CSILs has guided the development of screening strategies for cervical cancer, in which women older than 30 years who have had no previously detected lesion may undergo cytology screening at longer than annual intervals because they have a relatively low likelihood of developing a cervical lesion de novo (12,13). Although several studies have examined the age-associated distribution of CSILs in women (9,14), and one study has investigated the age-associated prevalence of anal HPV infection in MSM (15), no studies have reported the age-associated prevalence of ASILs in MSM or in other populations at high risk for anal cancer. Two studies of ASILs in MSM reported the prevalence, incidence, and risk factors for ASILs for a narrow age spectrum of men living in Seattle (16) or San Francisco (17) only. As is the case for CSILs, understanding how age affects the prevalence of ASILs may have implications for anal cytology screening recommendations.
The objectives of this study were to describe the age-related prevalence and risk factors for ASILs in MSM. We also compared the prevalence of ASILs among MSM in four U.S. cities. We report results of the first study to describe ASILs in a geographically diverse population of HIV-negative MSM spanning a wide age range.
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SUBJECTS AND METHODS |
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We enrolled men who were concurrently enrolled in four of six EXPLORE trial study cities (Boston, Denver, New York, and San Francisco). The EXPLORE trial is a randomized clinical trial of the efficacy of a behavioral intervention to reduce the risk of HIV acquisition among sexually active HIV-negative MSM (1820). Men were eligible for the EXPLORE trial if, at baseline, they were HIV-negative, were 16 years of age or older, and reported having had receptive or insertive anal sex with one or more men during the previous year. Men who had been involved in seroconcordant, monogamous relationships with a male partner for 2 or more years were excluded from the EXPLORE trial. Recruitment strategies for the EXPLORE trial varied slightly among study sites and included advertising and outreach at clubs, bars, bathhouses, sex clubs, health clubs, and video arcades. EXPLORE baseline visits occurred from January 28, 1999, to February 7, 2001, and subsequent visits were made at 6-month intervals. Enrollment in the HPV substudy was offered to EXPLORE participants in four of six cities after the month 12 EXPLORE study visit. From January 2, 2001 to October 23, 2002, 1409 men were enrolled in the HPV substudy. At enrollment, each participant provided written informed consent. This study was conducted with the approval of the institutional review boards of each participating center (the University of California at San Francisco; the Department of Public Health at San Francisco, CA and Denver, CO; the New York Blood Center; and the Fenway Community Health Center).
Data Collection
The EXPLORE trial collected information on participants' reported drug use and sexual behaviors with the use of Audio Computer-Assisted Self-Interview (ACASI) technology (21) that enabled study participants to either hear or read the questions and enter their answers on a keyboard. Both English and Spanish versions of the study questionnaire were available. Compared with interviewer-administered questionnaires, ACASI has been shown to increase the likelihood that sensitive behaviors, such as unprotected anal intercourse, are accurately reported (21). We obtained additional data on sexual history and smoking for the HPV substudy by having each participant complete a questionnaire which they then sealed in an envelope after completion for collection. Questionnaires were batched and returned to us by study coordinators.
Anal sample collection and cytology. Trained personnel at each study site collected anal specimens from each study participant by rotating a water-moistened Dacron swab in the anal canal without direct visualization. The swab was then agitated vigorously in a methanol-based fixative (PreservCyt solution; Cytyc Corporation, Boxborough, MA). The resulting solution was then stored at room temperature and later used for the preparation of thin-layer slides for cytology as well as for the detection of HPV DNA by the polymerase chain reaction (PCR). Anal cytology was evaluated by a single pathologist (T. Darragh) who had no knowledge of the clinical status of the participants, their questionnaire or ACASI responses, or other test results. Anal cytology specimens were classified as normal, atypical squamous cells (ASCs) comprising ASCs of undetermined significance and ASCs that cannot exclude HSILs), LSILs, or HSIL, using the 2001 Bethesda System criteria that are used to evaluate cervical cytology (22).
HPV DNA testing. To prepare DNA from the anal specimens, we gently swirled the PreservCyt solutions containing the anal sample to suspend the cells, removed 1.5 mL of the solution to labeled microfuge tubes, and centrifuged the tubes at 16g for 15 minutes. The supernatants were decanted, and pelleted material was dried overnight at room temperature or for 1 hour at 65 °C. The pellets were resuspended in 100 µL Sample Transport Medium (Digene, Silver Spring, MD) and 200 µg/mL proteinase K (Boehringer Mannheim, Indianapolis, IN), mixed by vortexing, incubated for 1 hour at 56 °C in a water bath, heated for 10 minutes at 95 °C for to inactivate the proteinase K, and frozen at 20 °C.
We used 5 µL of each sample to detect the presence of one or more HPV types by PCR amplification using a standard 40-cycle protocol, as previously described (23). PCR products from positive samples were typed by dot-blot hybridization with 39 type-specific probes. We classified HPV types as high risk (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, or 73) or low risk (HPV types 6, 11, 53, 54, 55, 66, Pap 155, or Pap 291) based on the strength of the association of specific HPV types to invasive anogenital cancer (24,25).
Statistical Analysis
We used sample proportions to estimate the age-specific prevalence of LSILs and HSILs. Independent determinants of ASILs were identified using logistic regression methods. Factors that were statistically significantly associated with ASILs at P<.15 in univariate analyses, as well as those that were identified as being important in previous studies, were retained in the final multivariable models. We used a polytomous logistic regression model to estimate and compare associations with risk factors that distinguished between participants with normal cytology (the referent group) and participants with LSILs and HSILs. The analysis was carried out using Stata software (version 8.0; Stata Corporation, College Station, TX). All statistical tests were two-sided.
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RESULTS |
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Of 1409 participants recruited for this study, samples from 1262 men were sufficient for cytologic analysis at baseline. Participants had a median age of 37 years (interquartile range [IQR] = 3143 years) (Table 1). The median age of participants at first receptive anal intercourse was 20 years (IQR = 1724 years). Study participants reported having a median of eight sex partners (IQR = 420) and three receptive anal sex partners (IQR = 011) during the previous 6 months. Men younger than 35 years reported a median of eight sex partners (IQR = 416 partners), men at least 35 years old but younger than 50 years also reported a median of eight sex partners (IQR = 420 partners), and men 50 years of age or older reported a median of 10 partners (IQR = 324 partners) during the previous 6 months. Condoms were always used by 38% of the study participants during the previous 6 months. Participants in San Francisco, New York, Boston, and Denver were similar with respect to median age, other sociodemographic factors, and the median number of receptive anal sex partners they reported having in the previous 6 months (data not shown). There was no statistically significant difference between HPV substudy participants and all enrollees in the EXPLORE trial or between HPV substudy participants with sufficient cytologic samples and those with insufficient samples with respect to age, race, income, sexual behavior, or illicit drug use (data not shown).
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The overall prevalence of any abnormal cytology (ASCs, LSILs, or HSILs) in this population was 32% and was similar for all age groups (i.e., a test of trend was not statistically significant). The overall prevalence of ASILs (either LSILs or HSILs) was 20%, and the prevalences of LSILs and HSILs were 15% and 5%, respectively. The prevalences of LSILs and HSILs were similar for all age groups (Figure 1).
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Variables that were statistically significantly associated with the risk of ASILs in unadjusted analyses included higher number of male receptive anal sex partners in the previous 6 months (P<.001 for linear trend), any use of poppers (alkyl nitrites) compared with no use in the previous 6 months (OR = 1.6, 95% CI = 1.2 to 2.1, P = .002), use of injection drugs two or more times per month compared with no use in the previous 6 months (OR = 6.7, 95% CI = 1.7 to 27, P = .007), anal HPV infection (OR = 7.5, 95% CI = 4.9 to 11, P<.001), and anal HPV infection with increasing numbers of HPV types (P<.001 for linear trend) (Table 2). In unadjusted analyses, the risk of ASILs was also statistically significantly associated with infection with high-risk HPV types only (OR = 5.1, 95% CI = 3.1 to 8.4, P<.001), infection with low-risk HPV types only (OR = 9.6, 95% CI = 6.0 to 15, P<.001), and infection with both high-risk and low-risk HPV types (OR = 21, 95% CI = 12 to 35, P<.001) compared with men who were not infected with HPV. However, age, age at first receptive anal intercourse, and smoking status were not associated with ASILs (P>.10).
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Risk Factors for LSILs Compared With Risk Factors for HSILs
Factors that were associated with the risk of LSILs in unadjusted analyses were having more than five male receptive anal sex partners during the previous 6 months compared with having fewer than two receptive anal sex partners (OR = 2.7, 95% CI = 1.8 to 4.0, P = .001), older age at first receptive anal intercourse (OR = 1.3 per 10-year increase in age, 95% CI = 1.02 to 1.5, P = .035), use of poppers during the previous 6 months compared with no use (OR = 1.9, 95% CI = 1.4 to 2.6, P<.001), cocaine use during the previous 6 months compared with no use (OR = 1.3, 95% CI = 1.1 to 2.4, P = .013), use of injection drugs two or more times per month during the previous 6 months compared with no use (OR = 7.5, 95% CI = 1.8 to 31, P = .006), anal HPV infection (OR = 7.6, 95% CI = 4.7 to 12, P<.001), and anal HPV infection with increasing numbers of HPV types (P<.001 for linear trend) (Table 3). The risk of LSILs was also associated with infection with high-risk HPV types only (OR = 4.6, 95% CI = 2.6 to 8.3, P<.001), with infection with low-risk HPV types only (OR = 11, 95% CI = 6.5 to 18, P<.001), and with infection with both high-risk and low-risk HPV types (OR = 20, 95% CI = 11 to 36, P<.001) compared with men who were not infected with HPV. Factors that showed independent, statistically significant associations with LSILs in a multivariable model were having more than five male receptive anal sex partners during the previous 6 months compared with having fewer than two receptive anal sex partners (OR = 1.9, 95% CI = 1.1 to 3.2, P = .028), older age at first receptive anal intercourse (OR = 1.6 per 10-year age increase, 95% CI = 1.2 to 2.1, P = .004), injection drug use two or more times per month during the previous 6 months (OR = 19, 95% CI =1.3 to 277, P = .03), use of poppers during the previous 6 months (OR = 1.6, 95% CI = 1.1 to 2.5, P = .03), and anal HPV infection with increasing numbers of HPV types (P<.001 for linear trend) (Table 3). There was suggestive evidence that anal HPV infection, as detected by PCR, may be associated with the risk of LSILs (OR = 2.2, 95% CI = 0.98 to 5.1, P = .056). There was no statistically significant association between age or geographic location and the risk of LSILs in the adjusted model.
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DISCUSSION |
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Several studies have demonstrated that, among women, the prevalence of cervical HPV infection and subsequent CSILs are strongly associated with age (9,14). Women may acquire HPV infection at the onset of sexual activity, typically during late adolescence or during their early 20s. Most of these HPV infections are thought to resolve spontaneously. However, a small proportion of women have a persistent HPV infection that leads to CSILs, the incidence of which typically peaks 23 years after the initiation of sexual activity and then drops substantially among older women. An age-related decline in the prevalence of cervical HPV infection has been observed even among high-risk populations, such as female sex workers in Spain (27) and Mexico City (28), as well as among sexually active inner-city women in New York (29). By contrast, in the cohort of urban HIV-negative MSM that were recruited for this study, we previously demonstrated that anal HPV infection was not related to age, that anal HPV infection was found in 57% of participants, and that there was no age-related decrease in the prevalence of anal HPV infection (15). Consistent with this finding is the lack of any age-related decrease in the prevalence of anal cytologic abnormalities, in sharp contrast with what has been observed for CSILs in women.
A number of factors could contribute to differences between the age associations of epidemiology of CSILs in women and that of ASILs in MSM. Although the cervix and the anus are histologically similar, they exist in different hormonal milieus, and the hormonal milieu of the cervix varies with age and menopausal status. However, a more likely explanation for the differences in age associations between the epidemiology of CSILs in women and that of ASILs in MSM is differences in the levels of sexual activity among women in the previous studies and the MSM in our study. The MSM in our study reported having a median of eight male sexual partners during the previous 6 months, a number that remained relatively constant for all age groups, but is substantially greater than the number of new sexual partners reported by most women older than 30 years. For example, behavioral data reported in previous cervical HPV epidemiologic studies show that sexual activity ranged from greater than 50% of subjects having one lifetime sexual partner in a population-based study of cervical dysplasia in Costa Rica (9) to means of 2.2 sexual partners during the previous year among women 30 to 39 years old and 1.4 sexual partners during the previous year among women older than 40 years in a study of cervical HPV infection among a group of inner-city women in New York (29). Studies of cervical HPV in sex workers in Mexico and Spain reported high numbers of sexual partners (27,28) but did not report the age-associated prevalence of cervical cytologic abnormalities and thus cannot be directly compared with our study.
Most of the men in our study had never been screened for ASILs before study entry. It was therefore interesting that the prevalence of LSILs and HSILs did not increase substantially with age because in the absence of screening and subsequent treatment of disease, we would expect an increasing proportion of men to develop ASILs in the older age groups. The fact that we did not observe a cumulative increase in the proportion of MSM with anal cytologic changes with increasing age suggests that many of the lesions that develop after HPV infection are transient. Consistent with this interpretation, we previously reported that the prevalence of anal HPV infection was consistent across all age groups (15) and was not cumulative. Our observation that older age at first receptive anal sex was associated with the risk of LSILs also suggests that many HPV lesions are transient in nature. If HPV lesions were transient, men who were younger at the time of their first sexual experience were probably exposed to HPV and then developed LSILs that regressed over time. Another, less likely, explanation for this finding would be a cohort effect: Older MSM could have been more sexually active and more intensely exposed to HPV than younger MSM in this prevalence study. The 20% prevalence of ASILs in the older men could therefore reflect a true age-related decrease in the prevalence of ASILs if that particular cohort of men had a substantially higher prevalence of ASILs during their 20s and 30s.
There was no difference in the overall prevalence of ASILs by geographic location. However, there was some evidence that location was a risk factor for HSILs, but not for LSILs. San Francisco had the highest prevalence of HSILs, at 8%, whereas the other sites each had an HSIL prevalence of approximately 4%. The reasons for this difference in prevalence, if it is a true difference, are not immediately apparent but may reflect differences in behaviors that were not captured by our questionnaire. This possible regional difference in the prevalence of HSILs should be explored in future population-based studies.
As has been seen previously (30,31), anal HPV infection and the number of HPV types were important risk factors for anal lesions in our study. The strong association between anal HPV infection and ASILs that we found is consistent with the established role of HPV infection in the development of anal cancer (4,25). Infection with multiple HPV types may be a marker of persistent disease and of the progression of LSILs to HSILs (7). At present, there is little evidence that direct molecular interactions among different HPV types potentiate disease pathogenesis, but having multiple HPV types may represent an unmeasured factor(s) that is important in ASIL pathogenesis, such as attenuated HPV-specific immunity. Infection with a greater number of HPV types may also result from having a larger number of sexual encounters, which could potentially increase exposure to other unmeasured risk factors associated with anal intercourse, such as inflammation. Finally, infection with a greater number of HPV types may also reflect a greater number of lesions, which would increase the probability that an abnormality would be detected by anal cytology.
Previous studies have demonstrated that HPV type (i.e., high-risk versus low-risk) is associated with the type of lesions that later develop (24,25). Compared with men in whom no HPV DNA was detected, men infected with low-risk HPV types only as well as men infected with high-risk HPV types only had an increased risk of LSILs. Similarly, men who were infected with low-risk HPV types only or with high-risk HPV types only had an increased risk of HSILs compared with men with no HPV infection. Given that earlier studies reported that only high-risk HPV types are closely linked with the development of invasive cervical and anal cancers [reviewed in (25)], it is interesting to note that low-risk HPV types were also associated with the risk of HSILs in our study population. However, we found that infection with both high-risk and low-risk HPV types was more strongly associated with either LSILs or HSILs than infection with either high-risk or low-risk HPV types only, consistent with our observation that an increasing number of HPV types is an important risk factor for ASILs. Longitudinal studies that examine the temporal association between type-specific HPV infection and progression of ASILs are needed to clarify the relationship between infection with specific HPV types and the risk of incident and persistent HSILs.
Behavioral determinants that were strongly associated with the risk of ASILs included the number of male sex partners during the previous 6 months and the number of receptive anal sex partners during the previous 6 months. These behavioral risk factors for ASILs are not surprising, given the strong evidence for the role of sexual transmission of HPV as a necessary step for development of anal cancer precursor lesions (4). We also found evidence for the independent association of injection drug use and use of poppers with the risk of ASILs. A high prevalence of ASILs and anal HPV infection was previously reported among HIV-infected injection drug users who denied having anal intercourse (32). The roles of injection drug use and the use of poppers in the pathogenesis of ASILs is unclear; however, the use of such substances may be a proxy for partner selection or for risk behaviors that were not captured in our structured questionnaire.
Strengths of our study include the large number, geographic diversity, and wide age spectrum of the participants. One limitation of our study is that study participants of all ages remained sexually active, with multiple partners. Thus, it is possible that our results are not generalizable to all HIV-negative MSM. However, data collected by the probability-based Urban Men's Health Study (33) on the sexual behavior of predominantly HIV-negative MSM in four cities (San Francisco, Los Angeles, New York, and Chicago) suggest that the men in our study are highly representative of urban MSM with respect to age at first anal intercourse, any history of anal sex, and history of anal sex during the previous year. Multiple recent cross-sectional surveys of mostly HIV-uninfected MSM in San Francisco (34), London (35), and Amsterdam (36) also report sexual behavior similar to that of the men in our study. Thus, although participants in our study are likely to be representative of many urban HIV-negative MSM, future studies that use probability-based sampling are needed before these findings can be generalized to all MSM, particularly to those who have fewer sexual partners than reported by participants in this study. Another possible limitation of our study is the fact that only one pathologist reviewed all of the cytology. Moreover, any potential under- or overdiagnosis of ASILs would probably affect only our prevalence estimates, not the estimates of associations with potential risk factors. However, the pathologist who interpreted the slides for this study participated in a study of interobserver variability in anal cytology, which showed moderately good interobserver agreement ( = 0.550.88) for anal cytology between experienced pathologists (T. Darragh, personal communication).
Our data indicate that a high proportion of sexually active HIV-negative MSM in all age groups have ASILs, including HSILs. The high prevalence of ASILs may have direct implications for anal cancer screening. Given the similarities between cervical cancer and anal cancer and given the success of cervical cancer screening in reducing mortality, Palefsky et al. (26) have proposed an anal cytology screening protocol to identify women and men who may have anal cancer precursor lesions. Results of cost-effectiveness analyses indicate that a reasonable screening interval is 23 years for HIV-negative MSM (37). It has been further suggested that patients who have an abnormal anal cytology (i.e., Pap) test should undergo high-resolution anoscopy, which uses magnification and characteristic changes in appearance of diseased tissue after the application of acetic acid to identify lesions that should undergo biopsy and staging. Various treatment options that are based on the grade, size, and location of these lesions have been described (38). Given that anal cancer occurs only rarely in HIV-negative men aged younger than 40 years, one approach would be to initiate screening only among men older than 40 years. In addition, although the role of anal HPV testing to identify MSM who are at risk for anal cancer has not been fully explored, its primary use may rest in its negative predictive value.
Our study illustrates that the epidemiology of anal cancer precursor lesions in sexually active HIV-negative MSM is different from that of cervical cancer precursor lesions in sexually active women. The high prevalence of HPV-related anal disease at all age groups reflects a population that continues to have a large number of new sexual exposures over many decades of life. In contrast, the prevalence of HPV-related cervical disease in women is lower and declines with age. Extrapolations from the cervical cancer prevention literature to anal cancer screening cannot be made blindly. Specific knowledge of anal HPV and ASIL epidemiology is even more relevant today as advances continue to be made in the therapy of ASILs (39), as well as in HPV-specific therapeutic (40) and prophylactic (41) vaccines.
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NOTES |
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Support was provided by the University of California University AIDS Research Program [UARP-R97-SF-1030 (JMP)], and by K23 AI054157 (PCH), R01 CA54053 (JMP), R01 CA/AI 88739 (JMP), the General Clinical Research Center, UCSF with funds provided by the Division of Research Resources 5 M01-RR-00079 (JMP), and by Cytyc Corporation. This work was also supported by the HIV Network for Prevention Trials sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS), through contract N01 AI35176 with Abt Associates, Inc.; contract N01 AI45200 with the Fred Hutchinson Cancer Research Center; and subcontracts with the Denver Department of Health and Hospitals, the Fenway Community Health Center, the New York Blood Center and the Public Health Foundation Inc. Support was also given by the HIV Prevention Trials Network, sponsored by NIAID, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research of the NIH and DHHS, through a cooperative agreement with Family Health International (cooperative agreement 5 U01 AI46749) with a subsequent subcontract to Abt Associates, Inc. and subcontracts to the Denver Department of Health and Hospitals; cooperative agreement U01 AI48040 to the Fenway Community Health Center; cooperative agreement U01 AI48016 to Columbia University (including a subagreement with the New York Blood Center); and cooperative agreement U01 AI47995 to the University of California, San Francisco.
The authors thank Joseph Catania and Lance Pollack of the Urban Men's Health Study, Tom Coates, the HPV EXPLORE site coordinators (Louise Austin, Anthony Buckman, Ken Miller, Arnel Montenegro, David Pantalone, and Dave Ward) and counselors, Linda Ta and Jess Thompson from the University of California San Francisco HPV laboratory, Terry O'Donnell for administrative support, Maria Madison at Abt, Eileen Hess from the SCHARP statistical center at the Fred Hutchinson Cancer Research Center, and the study participants.
Presented in part at Human Papillomavirus 21st International Conference, Mexico City, February 2026, 2004 (abstract 538).
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REFERENCES |
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(1) Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:526.
(2) Goedert JJ, Cote TR, Virgo P, Scoppa SM, Kingma DW, Gail MH, et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998;351:18339.[CrossRef][ISI][Medline]
(3) Cress RD, Holly EA. Incidence of anal cancer in California: increased incidence among men in San Francisco, 19731999. Prev Med 2003;36:55560.[CrossRef][ISI][Medline]
(4) Shah KV. Human papillomaviruses and anogenital cancers. N Engl J Med 1997;337:13868.
(5) Surawicz CM, Kirby P, Critchlow C, Sayer J, Dunphy C, Kiviat N. Anal dysplasia in homosexual men: role of anoscopy and biopsy. Gastroenterology 1993;105:65866.[ISI][Medline]
(6) Frisch M, Olsen J, Bautz A, Melbye M. Benign anal lesions and the risk of anal cancer. N Engl J Med 1994;331:3002.
(7) Palefsky JM, Holly E, Ralston MR, Jay N, Berry JM, Darragh TM. High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 1998;12:495503.[CrossRef][ISI][Medline]
(8) Palefsky JM, Holly EA. Molecular virology and epidemiology of human papillomavirus and cervical cancer. Cancer Epidemiol Biomarkers Prev 1995;4:41528.[ISI][Medline]
(9) Herrero R, Hildesheim A, Bratti C, Sherman ME, Hutchinson M, Morales J, et al. Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst 2000;92:46474.
(10) Herrero R, Schiffman MH, Bratti C, Hildesheim A, Balmaceda I, Sherman ME, et al. Design and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project. Rev Panam Salud Publica 1997;1:36275.[Medline]
(11) Ponten J, Adami HO, Bergstrom R, Dillner J, Friberg LG, Gustafsson L, et al. Strategies for global control of cervical cancer. Int J Cancer 1995;60:126.[ISI][Medline]
(12) Sherman ME, Schiffman M, Cox JT. Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 2002;94:1027.
(13) Melkert PW, Hopman E, van den Brule AJ, Risse EK, van Diest PJ, Bleker OP, et al. Prevalence of HPV in cytomorphologically normal cervical smears, as determined by the polymerase chain reaction, is age-dependent. Int J Cancer 1993;53:91923.[ISI][Medline]
(14) Schiffman MH. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst 1992;84:3948.[ISI][Medline]
(15) Chin-Hong PV, Vittinghoff E, Cranston RD, Buchbinder S, Cohen D, Colfax G, et al. Age-specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. J Infect Dis 2004;190:20706.[CrossRef][ISI][Medline]
(16) Kiviat NB, Critchlow CW, Holmes KK, Kuypers J, Sayer J, Dunphy C, et al. Association of anal dysplasia and human papillomavirus with immunosuppression and HIV infection among homosexual men. AIDS 1993;7:439.[ISI][Medline]
(17) Palefsky JM, Holly E, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17:3149.[ISI][Medline]
(18) Koblin B, Chesney M, Coates T. Effects of a behavioural intervention to reduce acquisition of HIV infection among men who have sex with men: the EXPLORE randomised controlled study. Lancet 2004;364:4150.[CrossRef][ISI][Medline]
(19) Chesney MA, Koblin BA, Barresi PJ, Husnik MJ, Celum CL, Colfax G, et al. An individually tailored intervention for HIV prevention: baseline data from the EXPLORE Study. Am J Public Health 2003;93:9338.
(20) Koblin BA, Chesney MA, Husnik MJ, Bozeman S, Celum CL, Buchbinder S, et al. High-risk behaviors among men who have sex with men in 6 US cities: baseline data from the EXPLORE Study. Am J Public Health 2003;93:92632.
(21) Metzger DS, Koblin B, Turner C, Navaline H, Valenti F, Holte S, et al. Randomized controlled trial of audio computer-assisted self- interviewing: utility and acceptability in longitudinal studies. HIVNET Vaccine Preparedness Study Protocol Team. Am J Epidemiol 2000;152:99106.
(22) Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:21149.
(23) Palefsky J, Holly E, Ralston M, Da Costa M, Greenblatt R. Prevalence and risk factors for anal human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis 2001;183:38391.[CrossRef][ISI][Medline]
(24) Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:51827.
(25) Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000;342:792800.
(26) Palefsky J, Holly E, Hogeboom CJ, Berry JM, Jay N, Darragh TM. Anal cytology as a screening tool for anal squamous intraepithelial lesions. J Acquir Immune Defic Syndr 1997;14:415422.
(27) Canadas MP, Bosch FX, Junquera ML, Ejarque M, Font R, Ordonez E, et al. Concordance of prevalence of human papillomavirus DNA in anogenital and oral infections in a high-risk population. J Clin Microbiol 2004;42:13302.
(28) Juarez-Figueroa LA, Wheeler CM, Uribe-Salas FJ, Conde-Glez CJ, Zampilpa-Mejia LG, Garcia-Cisneros S, et al. Human papillomavirus: a highly prevalent sexually transmitted disease agent among female sex workers from Mexico City. Sex Transm Dis 2001;28:12530.[CrossRef][ISI][Medline]
(29) Burk RD, Kelly P, Feldman J, Bromberg J, Vermund SH, DeHovitz JA, et al. Declining prevalence of cervicovaginal human papillomavirus infection with age is independent of other risk factors. Sex Transm Dis 1996;23:33341.[ISI][Medline]
(30) Palefsky JM. Anal squamous intraepithelial lesions in human immunodeficiency virus-positive men and women. Semin Oncol 2000;27:4719.[ISI][Medline]
(31) Palefsky JM, Holly E, Ralston MR, Arthur SP, Jay N, Berry JM, et al. Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17:3206.[ISI][Medline]
(32) Piketty C, Darragh TM, Costa MD, Bruneval P, Heard I, Kazatchkine MD, 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;138:4539.
(33) Catania JA, Osmond D, Stall RD, Pollack L, Paul JP, Blower S, et al. The continuing HIV epidemic among men who have sex with men. Am J Public Health 2001;91:90714.[Abstract]
(34) Chen SY, Gibson S, Katz MH, Klausner JD, Dilley JW, Schwarcz SK, et al. Continuing increases in sexual risk behavior and sexually transmitted diseases among men who have sex with men: San Francisco, Calif, 19992001, USA. Am J Public Health 2002;92:13878.
(35) Elford J, Bolding G, Sherr L. High-risk sexual behaviour increases among London gay men between 1998 and 2001: what is the role of HIV optimism? AIDS 2002;16:153744.[CrossRef][ISI][Medline]
(36) Stolte G, Dukers NH, de Wit JB, Fennema H, Coutinho RA. A summary report from Amsterdam: increase in sexually transmitted diseases and risky sexual behaviour among homosexual men in relation to the introduction of new anti-HIV drugs. Euro Surveill 2002;7:1922.
(37) Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Palefsky JM. Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men. Am J Med 2000;108:63441.[CrossRef][ISI][Medline]
(38) Chin-Hong PV, Palefsky JM. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect Dis 2002;35:112734.[CrossRef][ISI][Medline]
(39) Chang GJ, Berry JM, Jay N, Palefsky JM, Welton ML. Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum 2002;45:4538.[CrossRef][ISI][Medline]
(40) Galloway DA. Papillomavirus vaccines in clinical trials. Lancet Infect Dis 2003;3:46975.[CrossRef][ISI][Medline]
(41) Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:164551.
Manuscript received September 28, 2004; revised April 11, 2005; accepted April 27, 2005.
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