In the recent years, dramatic increases in HIV transmission among men who have sex with men (MSM) have been observed in China. Human papillomavirus (HPV) infection related anal cancer is more common among HIV-infected MSM as compared to the general population. However, HPV infection and anal cytology has been rarely studied in HIV-infected MSM in China.
HIV-infected MSM in Beijing, China were invited to participate in this study between January and April 2011. Anal swabs were collected for examining cytology and HPV genotypes.
Ninety-five eligible participants with complete questionnaire and laboratory data were included in the analyses. Thirty six of them (37.9%) showed abnormal anal cytology as follows: atypical squamous cells of undetermined significance (ASC-US) in 19 (20.0%), atypical squamous cells but cannot exclude HSIL (ASC-H) in 1 (1.1%), low-grade squamous intraepithelial lesion (LSIL) in 15 (15.8%), and high-grade squamous intraepithelial lesion (HSIL) in 1 (1.1%). HPV6 (20.0%), HPV16 (10.9%), HPV56 (10.9%), HPV52 (9.1%) and HPV39 (9.1%) were observed most frequently among those with normal anal cytology, while different distribution was found in the ones with abnormal anal cytology as HPV6 (19.4%), HPV16 (19.4%), HPV45 (16.7%), HPV52 (16.7%) and HPV18 (11.1%). In addition, HPV16, HPV45, HPV52 and HPV18 were the most frequent high-risk types in patients with abnormal anal cytology. HPV multiplicity was found to be significantly related to the prevalence of abnormal anal cytology (p for trend = 0.04).
Citation: Yang Y, Li X, Zhang Z, Qian H-Z, Ruan Y, Zhou F, et al. (2012) Association of Human Papillomavirus Infection and Abnormal Anal Cytology among HIV-Infected MSM in Beijing, China. PLoS ONE 7(4): e35983. https://doi.org/10.1371/journal.pone.0035983
Editor: D. William Cameron, University of Ottawa, Canada
Received: January 5, 2012; Accepted: March 26, 2012; Published: April 25, 2012
Copyright: © 2012 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work was partly supported by National Natural Sciences Foundation of China (Grant No: 81001272) and Vanderbilt University Clinical & Translational Research Scholar (VCTRS) Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
While anal carcinoma is rare in the general population , it is more common among men who have sex with men (MSM) ,  and individuals with human immunodeficiency virus (HIV) infection , . In the past decades, the incidence of anal cancer has been increasing in both general MSM and HIV-infected MSM , . Screening of anal precancerous lesions in HIV-infected MSM has been suggested to be important for cancer prevention . In China, dramatic increases in HIV transmission among MSM have been observed in recent years. MSM accounted for nearly one-third of new HIV infections in 2009 . Anal screening should be attached importance to this high-risk population. Unfortunately, high-resolution anoscopy is still a resource that is both costly and difficultly to access for HIV-infected MSM in China at present. Anal cytology, despite of its high sensitivity and low specificity characteristics, should be much helpful to this target population for monitoring the development of anal precancerous lesions , .
Human papillomavirus (HPV) infection, especially high-risk HPV (HR-HPV) viral types such as HPV 16 and HPV 18, is a significant risk factor for development of anal intraepithelial neoplasia (AIN) and anal cancer , . Two recent meta-analyses have shown that 73.4% and 65.6% of all anal cancer are caused by HPV 16 , . HPV has not only been linked to the transformation from innocent cervical epithelium into dysplastic precancerous states known as cervical interstitial neoplasia (CIN), but has also been associated with the development of anal squamous intraepithelial lesions (ASIL) . Other risk factors include: receptive anal intercourse, history of sexually transmitted disease, number of lifetime sexual partners, HIV status, lower CD4 cell count, immunosuppression after solid-organ transplantation, and current cigarette smoking , . Recent studies have demonstrated that more than 90% of HIV positive MSM were also infected with HPV –. This particular group has a very high risk of developing ASIL and anal cancer . HPV genotyping and anal cytology are important to assess the risks of HPV-related anal diseases in high-risk populations. To our knowledge, this topic has not yet been studied in China. The objective of this pilot cross-sectional study was to investigate the prevalence and distribution of HPV genotypes in HIV-infected MSM with abnormal anal cytology in Beijing, China.
Subject recruitment and characteristics
A total of 98 eligible participants gave consent to be included into the study. Three of them were exclude in the final data analysis because of unsatisfactory cytological evaluation. Of the remaining participants, about three quarters (75.1%) were aged 20–39 years (Table 1). The majority was of Han ethnic (94.7%), and over half had been educated over 12 years (56.8%). Around 72.6% described themselves as homosexuals, and 85.3% of these had their first homosexual intercourse at 18 years old or later. More than half (53.7%) reported a history of sexually transmitted diseases (STD) other than HIV, and 54.7% were within the first 2 years of their HIV diagnosis. Over sixty (65.3%) of participants had a recent CD4 cell count between 200 to 500 cells/µL of blood, and 30.5% participants ever had highly active antiretroviral therapy (HAART) (Table 1). Forty-nine participants (51.6%) got positive results in syphilis test. Only three subjects showed abnormal physical signs related to STD and two of them were newly diagnosed with anal warts (2.1%).
Association between sociodemographic/sexual factors and abnormal anal cytology
As shown in Table 2, of the study participants, 37.9% (36/95) had abnormal anal cytology, 20.0% (19/95) had atypical squamous cells of undetermined significance (ASC-US), 1.1% (1/95) with atypical squamous cells but cannot exclude HSIL (ASC-H), 15.8% (15/95) with low-grade squamous intraepithelial lesion (LSIL), and 1.1% (1/95) with high-grade squamous intraepithelial lesion (HSIL). Half of the participants who had been educated equal to or less than nine years showed abnormal anal cytology. As the CD4 count (cells/µL of blood) increases, study participants appear more likely to have normal anal cytology (<200: 42.9%; 200–500: 54.8%; >500: 78.6%). Among participants with CD4 count <200, 57.1% had abnormal anal cytology and 42.9% had ASIL/ASC-H. Among participants who had ever received HAART, 48.3% had abnormal anal cytology while only 17.2% had ASIL/ASC-H. Among participants who had been diagnosed as HIV positive for less than 2 years, 40.4% had abnormal anal cytology and 23.1% had ASIL/ASC-H. On the other hand, among participants who had been diagnosed as HIV positive for more than 3 years, 31.3% had abnormal anal cytology and no one had ASIL/ASC-H. A higher prevalence of abnormal anal cytology was observed among those taking receptive anal sex as a regular homosexual behavior (Table 3 and Table 4). In addition, a positive history of STD was found to be related with an increased risk of ASIL/ASC-H (12/19 vs. 4/16, p = 0.01) among those with abnormal anal cytology.
HPV genotypes and abnormal anal cytology
Table 5 shows the distribution of HPV genotypes of the study participants. Among those with abnormal anal cytology (n = 36), 77.8% were positive for at least one of the 26 targeted HPV types, and 44.4% were infected with multiple HPV type while this prevalence was only 20% in those with normal anal cytology. Among 17 participants with ASIL/ASC-H, 87.5% were infected with at least one type of HPV. The most common types among those with normal anal cytology were HPV6 (20.0%), HPV16 (10.9%), HPV56 (10.9%), HPV52 (9.1%) and HPV39 (9.1%). For those with abnormal anal cytology, the most prevalent types were HPV6 (19.4%), HPV16 (19.4%), HPV45 (16.7%), HPV52 (16.7%) and HPV18 (11.1%) were observed most frequently.
The association between anal HR-HPV infection and anal cytology result
As shown in Table 6, having a high-risk HPV type infection was at an increased risk of ASIL/ASC-H with an adjusted odds ratio (OR) of 2.48 (95% confidence interval (95% CI): 0.68–9.00). Having a high-risk HPV type infection is associated with a 63% increased risk of ASC-US (adjusted OR: 1.63; 95% CI: 0.49–5.43). There was a significant association between HPV multiplicity and the prevalence of abnormal anal cytology. Increased risks were observed for subjects carrying more HPV types (p for trend = 0.04). Individuals positive for three or more HPV types were at a significantly increased risk of abnormal anal cytology with an adjusted OR of 4.71 (95% CI: 1.02–21.76) compared to those HPV anal infection negative, these individuals were also at a high risk of ASIL/ASC-H with an adjusted OR of 7.49 (1.07–52.21).
To our knowledge, this pilot study was the first investigation into the prevalence of HPV genotypes in HIV-infected MSM with abnormal anal cytology in China. Based on a cross-sectional study design, a total of 95 HIV-infected MSM were included in the study, 36 of them (37.9%) showed abnormal anal cytology including 17 with ASIL/ASC-H (17.9%). Different HPV genotype distributions were found between patients with normal and abnormal anal cytology. Infection of multiple HPV types and high-risk types were found to be associated with an increased risk of abnormal anal cytology.
Invasive anal cancer has well-documented precursors, known as HSIL (cytology) or AIN2/3 (histology) . LSIL and AIN 1 are not considered to be direct precursors of invasive anal cancer, but may precede the later development of HSIL or AIN2/3. Therefore, ASIL, which include LSIL and HSIL, was considered as AIN to predict the presence of anal dysplasia. Palefsky JM and colleagues reported the prevalence of AIN2/3 as 52% in 81 HIV-positive MSM participants from US in 2005 . In 2010, Salit IE and colleges assessed the prevalence of abnormal anal cytology based on a cross-sectional study of 401 HIV-positive MSM from Canada. They found cytology was abnormal in 67% of patients: HSIL, 12%; LSIL, 43% and ASC-US, 12% . In addition, when de Pokomandy A and colleagues performed anal cytology and high-resolution anoscopy (HRA) in the baseline screening of a cohort study with 247 HIV- seropositive MSM, the anal abnormal cytology results were ASCUS, 33%; LSIL, 26%; HSIL, 6%, while HRA findings were AIN1, 50%; AIN2, 17% AIN3, 13% . In Asians, Li AH and colleagues reported the prevalence of anal abnormal cytology among HIV positive MSM in in Thailand: 16.1% had ASC-US, 14.4% had LSIL and 3.4% had HSIL . In our present study, the prevalence of abnormal anal cytology was 37.9%: ASC-US, 20.0%; LSIL, 15.8%; HSIL, 1.1%. Our results were very close to the data from Thailand but not the data from US and Canada especially with respect to the prevalence of HSIL. While it is difficult to directly compare the results from different studies due to the various characteristics of the study participants including age, stage of disease, status of immune system, and history of HAART. As reported, current CD4 cell count, CD4 cell count at beginning of HAART and duration of HAART might influence risks of AIN2/3 among HIV-infected MSM . Consistently, our results also observed increased prevalence of normal anal cytology among those with higher current CD4 cell count (p for trend = 0.04). Despite of the heterogeneity between studies, it is consistent that abnormal anal cytology is common in MSM with HIV infection. Considering anal cancer risk in this population is present and increasing, anal screening could prove to be important . Although anal cytology testing is currently imperfect with low specificity, it is still a useful tool in identifying high-risk patients with HIV infection in regions with limited clinical resources. In addition, it also provides an important support for the study addressing the impact of specific HPV types during the development of anal cancer.
In the past decade, multiple studies have reported that anal HPV infection is common among MSM especially in HIV-infected MSM , –. In our previous study, the prevalence of HPV infection was reported as 96% in newly diagnosed HIV-infected Chinese MSM . In the present study the prevalence of HPV infection was 70.3%. Considering 30.5% of study participants were receiving HAART and only 7.4% of them with low CD4 cell counts less than 200 cells/µL of blood, the negative correlation between anal HPV infection and CD4 cell count might be a possible explanation to the observed lower HPV prevalence . In addition, although it has been consistently reported that HAART had little effect on ASIL and anal cancer in HIV-infected MSM , , the role of HAART on the natural history of anal HPV infection including clearance and acquisition is still not clear , . Studies with larger sample sizes are needed to address this important issue and to explore ways of controlling HPV infection and related disease in patients with HIV infection. Consistent with previous reports, multiple HPV type infection was common in our study participants, HPV multiplicity and high-risk HPV types were associated with increased risks of ASIL. Among those with abnormal anal cytology, the most common high-risk types were found to be HPV16 (19.4%), HPV45 (16.7%), HPV52 (16.7%) and HPV18 (11.1%) . In a recently published article from Germany, it was reported that the most common high-risk HPV types were HPV16 (72.5%), HPV18 (25%) and HPV68 (12.5%) in HIV-infected MSM with HSIL . The different prevalence and distribution of HPV subtypes in different study populations should be given exclusive attention, because it might reflect various geographic distribution of the genotypes or heterogeneous host susceptibility to the pathogens. This important issue is also crucial for the development of specific prevention strategies including vaccine. In addition, the different prevalence of HPV types might contribute to, at least in part, the lower prevalence of HSIL (1.1%) observed in our study as well. Further studies with large sample size are needed to verify these important postulations.
Some limitations of this study should be considered. First, HRA needs more advanced medical recourses especially for HIV-infected patients , to our knowledge, no hospital provides HRA for HIV infections in China currently. As recently reported , in HIV-infected MSM, the direct use of HRA is the most cost-effective strategy for detecting AIN 2/3. However, the higher cost per use for HRA was offset by the high sensitivity and low specificity of HPV and cytology testing. Therefore, the major aim of this pilot study focused on the investigation of the association between HPV prevalence and abnormal anal cytology. At the present time, we are trying to set up HRA for HIV-infected MSM under cooperation with infectious diseases hospital which would be much helpful for anal cancer screening among HIV-infected MSM. Second, with respect to the observed extremely lower prevalence of HSIL (1.1%) as compare to the previous reports (6%–12%) , , the potential misclassification of anal cytology in our study could not be completely excluded. The techniques of cervical cytology has been mature in China, however, training for anal cytologist still should be strengthened in China. Third, socio-demographic data and risk behaviors were based on an interview using a standardized questionnaire which is open to recall and information bias. Forth, the small sample size of this pilot study limited further analysis, and potential selection bias cause by the used sampling method should be kept in mind as well when interpreting the prevalence data.
In conclusion, the high prevalence of HPV infection and abnormal anal cytology was observed among HIV-infected MSM in China. Infection of multiple HPV types and high-risk types were found to be associated with an increased risk of abnormal anal cytology. Considering the high prevalence of HIV infection in this high-risk population in China, more studies addressing anal HPV infection and related diseases in HIV-infected MSM are needed.
Materials and Methods
The study was approved by the Ethics Committee of the Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College. Written informed consent was obtained from each study participant before the interview, sample collection and testing.
Study participants were outpatients of the Capital City Dermatology Hospital and were recruited through local MSM nongovernment organization (Beijing Rainbow Volunteers Workstation) between January and April 2011. To maximize outreach of study information to HIV-infected MSM community, multiple methods were used for recruitment including MSM website advertisement, distributing flyers with study-related information at MSM-frequented venues (e.g., MSM clubs, bars, parks and bathhouses), and participants were also encouraged to refer their friends and acquaintances to attend the study. Those eligible to participate were males, 18 years or older, HIV positive, ever had homosexual behaviors, willing to take tests for anal HPV infection and anal cytology, and provision of written informed consent. The presence or absence of any symptoms, including anal symptoms, did not influence eligibility. Study participants who were positive for suspicious symptoms related to STD (purulent secretion, rash, ulcer, pain, abnormal outgrowth and pruritus on the penis or crissum) and abnormal cytology were informed by study personnel in private and referred to the Capital City Dermatology Hospital or the Beijing Cancer Hospital for further diagnosis and treatment.
Sociodemographic and sexual behavior data were collected using one-to-one interviews in a separate room and a standardized questionnaire. The content of the questionnaire includes self-reported sociodemographic characteristics (e.g., age, income, ethnicity, education, employment, and marriage status), regular homosexual behavior, sexual behaviors in the past 6 months, status of HIV infection and treatment, knowledge on STD, history of STD, and lifestyle factors (i.e. current drinking status, history of drug abuse and injection drug use). As explained to the participants, regular homosexual behavior was defined as at least 50% of sexual activities occurring with males. Each study participant was assigned a unique code that was used to link the questionnaire and specimens. Personal contact information, which was blinded to researchers, was kept by the Beijing Rainbow Volunteers Workstation for test results feedback and data validation.
Cytological analysis and HPV DNA typing
Trained personnel collected anal samples for cytological analysis and HPV typing by rotating a saline water moistened nylon flocked swab in the anal canal for about 2 minutes. The cytological specimens were then placed on a glass slide and stained with a Papanicolaou's stain. The cytology slides were read by a cytologist from Hospital of Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College (Dr. Zhihui Zhang). Using the Bethesda system criteria for evaluation of cervical cytological results , the anal cytological results were classified as normal and abnormal. Abnormal results were further classified as ASC-US, ASC-H, LSIL and HSIL . Smears were classified as unsatisfactory if no epithelial cells were present. After cytological samples have been collected, the swab was then kept in a 3 mL sample transport medium of the Tellgenplex™ HPV DNA Test (Tellgen Life Science, Shanghai, China). Tellgenplex™ HPV DNA Test is based on suspension bead array method to identify HPV types. Suspension bead array is a technical based on PCR, beads coated hybridization, flow cytometry, lasers and digital signal processing. Target HPV DNA-specific probes can be coated on the surface of spectrally addressable polystyrene beads. As the beads are internally labeled with a ratio of two spectrally distinct fluorophores, the bead lots are assignable to class-specific HPV subtypes. Mixtures of different bead suspensions can be used in the same well of a 96-well plate format allowing for multiplex analysis. Tellgenplex™ HPV DNA Test provides identification of 19 recommended high-risk subtypes (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 55, 56, 58, 59, 66, 68, 82, and 83) which are associated with cervical cancer. Besides that, the kit also provides detection of 7 low-risk subtypes (6, 11, 40, 42, 44, 61, and 73). The tests were performed by Xiangwei Li and Yu Yang in the laboratory located in the institute of Pathogen Biology as described in elsewhere .
Double entered questionnaires and laboratory results were analyzed using Statistical Analysis System (SAS 9.2 for Windows; SAS Institute Inc., NC, USA). The study population was described by age, ethnicity, education, marriage status, age at the first homosexual act, number of homosexual partners ever had, status of syphilis, ever had STD other than HIV, had receipted HAART, latest CD4 cell count (tested in the recent three months), time since HIV diagnosis, regular sex behavior (anal sex, receptive anal sex, insertive anal sex, oral sex, anilinction), number of partners in the past six months and condom use during these activities. Differences between groups were assessed using Pearson chi-square or Fisher exact test.
The associations of potential risk factors with HPV infection and anal cytological results were estimated by means of OR and 95% confidence intervals (CI) using logistic regression analysis. Covariates with a significant association in the univariate analyses were included the following multivariate analysis using a significance level of 0.05. In order to investigate the combined effect of HPV types, the risk of anal cytological results was then assessed with respect to the HPV subgroups according to carcinogenicity and the number of HPV types in each sample. Tests for trend by were performed by treating categories of the number as continuous variable in the logistic regression analysis.
We thank volunteers from Beijing Rainbow Volunteers Workstation and for their great effort on the enrollment of study participants. We also thank Dr. Theresa Redaniel, at University of Bristol, for her kind assistance and comments on the English in the manuscript, which led to important improvements.
Conceived and designed the experiments: LG QJ. Performed the experiments: YY XWL FZ CG MFL. Analyzed the data: LG YY XWL. Contributed reagents/materials/analysis tools: YHR HZQ FZ CG MFL. Wrote the paper: YY LG QJ HZQ. Performed cytology and results classification: YY ZHZ.
- 1. Abbas A, Yang G, Fakih M (2010) Management of anal cancer in 2010. Part 1: Overview, screening, and diagnosis. Oncology (Williston Park) 24: 364–369.A. AbbasG. YangM. Fakih2010Management of anal cancer in 2010. Part 1: Overview, screening, and diagnosis.Oncology (Williston Park)24364369
- 2. Cress RD, Holly EA (2003) Incidence of anal cancer in California: increased incidence among men in San Francisco, 1973–1999. Prev Med 36: 555–560.RD CressEA Holly2003Incidence of anal cancer in California: increased incidence among men in San Francisco, 1973–1999.Prev Med36555560
- 3. Frisch M, Smith E, Grulich A, Johansen C (2003) Cancer in a population-based cohort of men and women in registered homosexual partnerships. Am J Epidemiol 157: 966–972.M. FrischE. SmithA. GrulichC. Johansen2003Cancer in a population-based cohort of men and women in registered homosexual partnerships.Am J Epidemiol157966972
- 4. Chaturvedi AK, Madeleine MM, Biggar RJ, Engels EA (2009) Risk of human papillomavirus-associated cancers among persons with AIDS. J Natl Cancer Inst 101: 1120–1130.AK ChaturvediMM MadeleineRJ BiggarEA Engels2009Risk of human papillomavirus-associated cancers among persons with AIDS.J Natl Cancer Inst10111201130
- 5. Diamond C, Taylor TH, Aboumrad T, Bringman D, Anton-Culver H (2005) Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy. Sex Transm Dis 32: 314–320.C. DiamondTH TaylorT. AboumradD. BringmanH. Anton-Culver2005Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy.Sex Transm Dis32314320
- 6. Chin-Hong PV, Vittinghoff E, Cranston RD, Buchbinder S, Cohen D, et al. (2004) 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 190: 2070–2076.PV Chin-HongE. VittinghoffRD CranstonS. BuchbinderD. Cohen2004Age-Specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study.J Infect Dis19020702076
- 7. Palefsky JM, Rubin M (2009) The epidemiology of anal human papillomavirus and related neoplasia. Obstet Gynecol Clin North Am 36: 187–200.JM PalefskyM. Rubin2009The epidemiology of anal human papillomavirus and related neoplasia.Obstet Gynecol Clin North Am36187200
- 8. Lam JM, Hoch JS, Tinmouth J, Sano M, Raboud J, et al. (2011) Cost-effectiveness of screening for anal precancers in HIV-positive men. AIDS 25: 635–642.JM LamJS HochJ. TinmouthM. SanoJ. Raboud2011Cost-effectiveness of screening for anal precancers in HIV-positive men.AIDS25635642
- 9. Wang N, Wang L, Wu Z, Guo W, Sun X, et al. (2010) Estimating the number of people living with HIV/AIDS in China: 2003–09. Int J Epidemiol 39: Suppl 2ii21–28.N. WangL. WangZ. WuW. GuoX. Sun2010Estimating the number of people living with HIV/AIDS in China: 2003–09.Int J Epidemiol39Suppl 2ii2128
- 10. Goedert JJ, Cote TR, Virgo P, Scoppa SM, Kingma DW, et al. (1998) Spectrum of AIDS-associated malignant disorders. Lancet 351: 1833–1839.JJ GoedertTR CoteP. VirgoSM ScoppaDW Kingma1998Spectrum of AIDS-associated malignant disorders.Lancet35118331839
- 11. Fox P (2009) Anal cancer screening in men who have sex with men. Curr Opin HIV AIDS 4: 64–67.P. Fox2009Anal cancer screening in men who have sex with men.Curr Opin HIV AIDS46467
- 12. Palefsky JM, Holly EA, Gonzales J, Berline J, Ahn DK, et al. (1991) Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51: 1014–1019.JM PalefskyEA HollyJ. GonzalesJ. BerlineDK Ahn1991Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer.Cancer Res5110141019
- 13. Shah KV (1997) Human papillomaviruses and anogenital cancers. N Engl J Med 337: 1386–1388.KV Shah1997Human papillomaviruses and anogenital cancers.N Engl J Med33713861388
- 14. Hoots BE, Palefsky JM, Pimenta JM, Smith JS (2009) Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer 124: 2375–2383.BE HootsJM PalefskyJM PimentaJS Smith2009Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions.Int J Cancer12423752383
- 15. De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S (2009) Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 124: 1626–1636.H. De VuystGM CliffordMC NascimentoMM MadeleineS. Franceschi2009Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis.Int J Cancer12416261636
- 16. Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, et al. (1997) Colposcopic appearance of anal squamous intraepithelial lesions. Diseases of the colon & rectum 40: 919–928.N. JayJM BerryCJ HogeboomEA HollyTM Darragh1997Colposcopic appearance of anal squamous intraepithelial lesions.Diseases of the colon & rectum40919928
- 17. Palefsky JM, Shiboski S, Moss A (1994) Risk factors for anal human papillomavirus infection and anal cytologic abnormalities in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr 7: 599–606.JM PalefskyS. ShiboskiA. Moss1994Risk factors for anal human papillomavirus infection and anal cytologic abnormalities in HIV-positive and HIV-negative homosexual men.J Acquir Immune Defic Syndr7599606
- 18. Palefsky JM, Holly EA, Ralston ML, Jay N (1998) Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis 177: 361–367.JM PalefskyEA HollyML RalstonN. Jay1998Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men.J Infect Dis177361367
- 19. Gao L, Zhou F, Li X, Yang Y, Ruan Y, et al. (2010) Anal HPV infection in HIV-positive men who have sex with men from China. PLoS One 5: e15256.L. GaoF. ZhouX. LiY. YangY. Ruan2010Anal HPV infection in HIV-positive men who have sex with men from China.PLoS One5e15256
- 20. de Pokomandy A, Rouleau D, Ghattas G, Vezina S, Cote P, et al. (2009) Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis 199: 965–973.A. de PokomandyD. RouleauG. GhattasS. VezinaP. Cote2009Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study.J Infect Dis199965973
- 21. Kreuter A, Wieland U (2009) Human papillomavirus-associated diseases in HIV-infected men who have sex with men. Curr Opin Infect Dis 22: 109–114.A. KreuterU. Wieland2009Human papillomavirus-associated diseases in HIV-infected men who have sex with men.Curr Opin Infect Dis22109114
- 22. Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, et al. (1998) High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 12: 495–503.JM PalefskyEA HollyML RalstonN. JayJM Berry1998High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men.AIDS12495503
- 23. Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, et al. (2005) Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 19: 1407–1414.JM PalefskyEA HollyJT EfirdcM. Da CostaN. Jay2005Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men.AIDS1914071414
- 24. Salit IE, Lytwyn A, Raboud J, Sano M, Chong S, et al. (2010) The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening. AIDS 24: 1307–1313.IE SalitA. LytwynJ. RaboudM. SanoS. Chong2010The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening.AIDS2413071313
- 25. de Pokomandy A, Rouleau D, Ghattas G, Trottier H, Vezina S, et al. (2011) HAART and progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV. Clin Infect Dis 52: 1174–1181.A. de PokomandyD. RouleauG. GhattasH. TrottierS. Vezina2011HAART and progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV.Clin Infect Dis5211741181
- 26. Li AH, Phanuphak N, Sahasrabuddhe VV, Chaithongwongwatthana S, Vermund SH, et al. (2009) Anal squamous intraepithelial lesions among HIV positive and HIV negative men who have sex with men in Thailand. Sex Transm Infect 85: 503–507.AH LiN. PhanuphakVV SahasrabuddheS. ChaithongwongwatthanaSH Vermund2009Anal squamous intraepithelial lesions among HIV positive and HIV negative men who have sex with men in Thailand.Sex Transm Infect85503507
- 27. Ho KS, Cranston RD (2010) Anal cytology screening in HIV-positive men who have sex with men: what's new and what's now? Curr Opin Infect Dis 23: 21–25.KS HoRD Cranston2010Anal cytology screening in HIV-positive men who have sex with men: what's new and what's now?Curr Opin Infect Dis232125
- 28. Panther LA, Wagner K, Proper J, Fugelso DK, Chatis PA, et al. (2004) High resolution anoscopy findings for men who have sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus. Clin Infect Dis 38: 1490–1492.LA PantherK. WagnerJ. ProperDK FugelsoPA Chatis2004High resolution anoscopy findings for men who have sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus.Clin Infect Dis3814901492
- 29. van der Snoek EM, Niesters HG, Mulder PG, van Doornum GJ, Osterhaus AD, et al. (2003) Human papillomavirus infection in men who have sex with men participating in a Dutch gay-cohort study. Sex Transm Dis 30: 639–644.EM van der SnoekHG NiestersPG MulderGJ van DoornumAD Osterhaus2003Human papillomavirus infection in men who have sex with men participating in a Dutch gay-cohort study.Sex Transm Dis30639644
- 30. Vajdic CM, van Leeuwen MT, Jin F, Prestage G, Medley G, et al. (2009) Anal human papillomavirus genotype diversity and co-infection in a community-based sample of homosexual men. Sex Transm Infect 85: 330–335.CM VajdicMT van LeeuwenF. JinG. PrestageG. Medley2009Anal human papillomavirus genotype diversity and co-infection in a community-based sample of homosexual men.Sex Transm Infect85330335
- 31. Parisi SG, Cruciani M, Scaggiante R, Boldrin C, Andreis S, et al. (2011) Anal and oral human papillomavirus (HPV) infection in HIV-infected subjects in northern Italy: a longitudinal cohort study among men who have sex with men. BMC Infect Dis 11: 150.SG ParisiM. CrucianiR. ScaggianteC. BoldrinS. Andreis2011Anal and oral human papillomavirus (HPV) infection in HIV-infected subjects in northern Italy: a longitudinal cohort study among men who have sex with men.BMC Infect Dis11150
- 32. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Bonner H, et al. (2001) Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr 28: 422–428.JM PalefskyEA HollyML RalstonM. Da CostaH. Bonner2001Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection.J Acquir Immune Defic Syndr28422428
- 33. Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, et al. (2008) Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 22: 1203–1211.C. PikettyH. Selinger-LenemanS. GrabarC. DuvivierM. Bonmarchand2008Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy.AIDS2212031211
- 34. Silling S, Kreuter A, Hellmich M, Swoboda J, Pfister H, et al. (2012) Human papillomavirus oncogene mRNA testing for the detection of anal dysplasia in HIV-positive men who have sex with men. J Clin Virol. S. SillingA. KreuterM. HellmichJ. SwobodaH. Pfister2012Human papillomavirus oncogene mRNA testing for the detection of anal dysplasia in HIV-positive men who have sex with men.J Clin Virol
- 35. Lam JM, Hoch JS, Tinmouth J, Sano M, Raboud J, et al. (2011) Cost-effectiveness of screening for anal precancers in HIV-positive men. AIDS 25: 635–642.JM LamJS HochJ. TinmouthM. SanoJ. Raboud2011Cost-effectiveness of screening for anal precancers in HIV-positive men.AIDS25635642
- 36. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, et al. (2002) The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 287: 2114–2119.D. SolomonD. DaveyR. KurmanA. MoriartyD. O'Connor2002The 2001 Bethesda System: terminology for reporting results of cervical cytology.JAMA28721142119
- 37. Park IU, Palefsky JM (2010) Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men. Curr Infect Dis Rep 12: 126–133.IU ParkJM Palefsky2010Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men.Curr Infect Dis Rep12126133