From the *Lluita Contra La SIDA Foundation, Barcelona, Spain; †Retrovirology Laboratory IrsiCaixa Foundation, Barcelona, Spain; ‡Department of Sanitat i Anatomia Animal, Universitat Autònoma de Barcelona, Catalonia, Spain; §Labco.General-Lab, Barcelona, Spain; Departments of ¶Surgery and ∥Medicine, HIV Clinical Unit, University Hospital Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Catalonia, Spain.
The authors thank Dr Christian Brander and Dr Roger Paredes (HIVACAT, Barcelona, Spain) for the critical revision and Mr Eric Goode for the English correction of this manuscript. Special thanks also go to the male patients of the HIV Unit.
HIV-HPV Study Group: University Hospital Germans Trias i Pujol, Badalona (Barcelona), Autonomous University of Barcelona. Department of Proctology: Ms I. Fernández; Department of Pathology: Dra E. Castella and Dra M Llatjós; • HIV Clinical Unit and Internal Medicine Department: Dra A. Bonjoch, Dra P. Echevarría, Dr M. Jabaloyas, Dr A. Jou, Dr J.M. Llibre, Dr J. Moltó, Dra E. Negredo, Ms N. Pérez-Alvarez, Dr C. Rey-Joly, Dr J. Romeu, Dr JR. Santos, and Dra C. Tural; Nurses of HIV Clinical Unit: Ms C. Alcalde, Ms R. Guerola, and Ms A. Salas; Lluita contra la SIDA Foundation: S.Gel; Labco.General-Lab, Department of Molecular Biology: Ms I. Castilla, Dr V. Cirigliano, Dr M. Ejarque, Ms E. López, Ms E. Ordóñez, and Ms L. Rueda.
Supported by grants from Red de Investigación en SIDA (RIS), ART AIDS Foundation, Gilead Sciences, Obra Social Caixa Sabadell, and Gala contra la SIDA-Barcelona 2011.
S. Videla and L. Darwich contributed equally to this study. B. Clotet and G. Sirera contributed equally to the design and direction of this work.
S.V. has received honoraria for collaborating with Laboratorios Dr Esteve for work unrelated to human papillomavirus/HIV. B.C. has received honoraria for speaking and participating in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer, Merck, Janssen-Tibotec, and Siemens. The remaining authors have no conflict of interest.
S. Videla, G. Sirera, and B. Clotet designed and wrote the study protocol; G. Sirera and J. Coll visited and interviewed the patients; M.P. Cañadas and L. Darwich performed human papillomavirus detection and genotyping with multiplex polymerase chain reaction; F. García-Cuyás, M. Piñol, and P. Cobarsi collected anal, penile, and oral specimens; S. Videla, L. Darwich, M.P. Cañadas, J. Coll, and B. Clotet wrote the manuscript; data management was performed by R. Molina, L. Darwich, and S. Videla; and statistical analysis was performed by R. Molina. All authors have read and approved the final manuscript.
Correspondence: Laila Darwich, DVM, PhD, Veterinary Faculty, Department of Sanitat i Anatomia Animal, Universitat Autònoma de Barcelona, 08193, Spain. E-mail: Laila.firstname.lastname@example.org.
Received for publication February 21, 2012, and accepted August 28, 2012.
High-risk (H-R) oncogenic human papillomavirus (HPV) types are the etiologic agent for several specific squamous cancers such as cervical,1 anal,2 and some penile3,4 and oropharyngeal5,6 cancers. Some of these HPV-associated malignancies occur at higher rates in persons with HIV/AIDS.7 Likewise, the incidence of anal cancer among HIV-positive men who have sex with men (MSM) has been estimated to be twice that seen in HIV-negative MSM.8,9
It is widely accepted that the persistence of HPV infection is a prerequisite for abnormal anogenital cytology. In HIV-negative people, most HPV infections are self-limiting and do not progress to histologic lesions.10 It is currently unknown whether this also happens in HIV-positive patients. Furthermore, although HIV-1 and HPV are both sexually transmitted diseases, the risk of HPV infection is increased in certain sexual behaviors.11 Among the HIV-infected population, MSM are particularly susceptible to HPV infection in the anal canal.12–14 The incidence and clearance rates can differ among HPV types, and a lower clearance rate for anal infection with HPV-16 in MSM has been reported.14 In this line, Silva et al.,15 also found that HIV infection was a risk factor for the clearance and persistence of HPV in the penis.
Data on the spread of HPV infection of different body sites involved in sexual practices in both MSM and heterosexual men are limited. A prospective cohort study of HIV-positive men (MSM and heterosexual) was conducted to obtain a better understanding of the natural history of HPV infection in the anus, penis, and mouth.
PATIENTS AND METHODS
The Can Ruti HIV+ Men cohort was a single-center, prospective cohort study, annually assessing HPV infection at anal, penile, and oral sites of HIV-positive men attending the Outpatient HIV Clinic of the Hospital Germans Trias i Pujol (Badalona, Spain). The study was approved by the hospital’s independent ethics committee.
HIV-positive men were eligible for participation if they were older than 18 years and reported no previous diagnosis of HPV-related pathology at anal, penile, and oral sites. Consecutive patients’ recruitment, based on outpatients who attended their AIDS routine clinic visit, was carried out by 1 staff care provider from 2005 to 2007, and it has been done by 2 staff care providers since 2008. The patients were informed of the study and invited to be seen in the Clinical Proctology HIV Unit–created ad hoc (2 afternoons per week). If they accepted to participate, written informed consent was obtained.
The following data were collected: date of birth, date of HIV-positive diagnosis, baseline CD4 cell counts (the closest value determined during participants’ usual clinical follow-up visits before the sample collection), CD4 nadir counts (the lowest CD4 value abstracted from medical records), plasma HIV load (the closest value determined before the sample collection), highly active antiretroviral therapy (HAART) previous to inclusion and time on HAART, other previous treatments, and history of sexually transmitted infections (STIs). Cellular counts were determined by flow cytometry (HIV viral load by Nuclisens; bioMerieux, Inc, Durham, NC).
The schedule of visits was as follows: all participants completed a detailed self-administered baseline questionnaire and then a clinical examination (visual inspection) of the 3 body sites studied (anal canal, penile, and oral sites), and a digital rectal examination was performed at the baseline visit. Samples from the 3 areas were collected to detect HPV infection (multiplex polymerase chain reaction [PCR]). The sample from the anal canal was also used to carry out the cytologic analysis (Papanicolaou test; data not shown). After baseline visit, all patients had to be evaluated and monitored annually. Patients who were diagnosed as having HPV-related pathology at the anal canal (anal warts or anal intraepithelial neoplasia grades II–III), penile, or oral sites at baseline visit or during follow-up visits completed their participation in this study.
Behavioral data were collected at the enrollment visit through a questionnaire administered by a health professional who was not the participants’ primary caregivers. The information collected was as follows: sociodemographic characteristics (including sexual history and sexual practices), history of STI, circumcision, history of drug consumption (tobacco, alcohol, intravenous drug), and HIV history (including HIV treatment). In the follow-up visits, the questionnaire contained a reduced set of questions and also elicited responses aimed at verifying the consistency of the information given at baseline.
Anal samples were obtained introducing a cytobrush (Eurogine SL, Spain) 3 cm into the anal canal and gently rotating it for 30 to 45 seconds. The cytobrush was introduced into and shaken in a 20 mL of PreservCyt/ThinPrep Papanicolaou test solution (Cytyc Iberia SL, Spain) for 30 seconds.
Two different dacron swabs were used for the penis. Trained clinicians collected the first 2 cm of the urethral epithelium with a dacron urethral swab. A second saline prewetted dacron swab was used to obtain cells from the 4 quadrants of penile shaft, glans penis, and coronal sulcus. The glans penis was first scratched with sandpaper to increase the cellular yield. Both penile samples were pooled in the same tube and suspended in 1 mL of 0.1 M phosphate-buffered saline.
Oral samples were obtained by brushing both sides of the oral cavity with a cytobrush and by vigorously swishing and gargling 5 mL of phosphate-buffered saline for 30 seconds and spitting it into a collection recipient. Both oral samples were combined into one sample. Oral and penile samples were stored at −20°C until analysis.
DNA extraction was performed by the Qiamp Viral DNA kit (QIAGEN, Hilden, Germany). Human papillomavirus detection and typing were performed using the commercial IVD-CE F-HPV typing (Molgentix SL, Barcelona, Spain). The assay permits the detection of 13 H-R genotypes, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, and 2 low-risk (L-R) genotypes, including 6 and11. A human short tandem repeat sequence included in the same multiplex was amplified as the internal control to check for DNA integrity and the absence of PCR inhibitors.
If the baseline anal sample was not satisfactory because of the lack of PCR internal control amplification, the sampling was repeated up to 3 times over the first 6 months. However, only 1 sample from the penile and oral sites at baseline was obtained. In the follow-up controls, only 1 sample from the anal canal, penile, and oral sites was collected per visit.
A sample size representative of our HIV-positive male patients was calculated, assuming that the prevalence of anal HPV infection in our HIV-positive men was 75%.12 In addition, we assumed a 10% cumulative incidence of anal HPV infection per year. Moreover, we assumed that a 30% of the patients would have anal warts at baseline or would be lost during the follow-up. We attempted to conserve an MSM/heterosexual ratio of 3:1, taking into account the characteristics of the overall population attended to in our clinical unit.
The MSM or heterosexual status was obtained through the questionnaire and then verified by checking the medical record. The existence of a current HPV infection was considered when 1 or more HPV types were detected in a sample. Prevalent HPV infection was defined as detectable HPV infection at baseline. Clearance, assessed using the prevalent HPV infection, was defined as detection of HPV infection at baseline and the absence of detection in follow-up samples. Incidence was defined as the absence of any HPV infection at baseline and positive detection in the next sampling. No HPV infection was defined as nondetectable HPV infection at any sampling time point.
Prevalence and 95% confidence intervals (95% CIs) were calculated. Differences were evaluated by the χ2 test for qualitative variables, and their 95% CIs were calculated. Clearance and incidence of HPV infection were analyzed using the Kaplan-Meier method, and differences were assessed using the Mantel-Haenzel log-rank test. Clearance and incidence rates were also calculated based on person-time denominator (1000 person-years). Bivariate and multivariate logistic analyses and Cox proportional hazard regression models were performed, when appropriate, to determine potential factors associated with the prevalence, clearance, and incidence of HPV infection. Multivariate regression models were adjusted to different covariates (sexual behavior; age; HIV infection (years); time on HAART; presence of HAART; nadir, basal CD4 counts; history of STI; tobacco, alcohol, intravenous drug users; sexual partners (number); practice of receptive anal intercourse (RAI); oral sex practices; presence of circumcision; treatment with interferon). The association between potential explanatory variables and HPV infection was tested in 3 steps. First, a bivariate regression model was performed to obtain an indication of the relevance of the explanatory variables in the risk of HPV infection. Second, factors showing a P value less than 0.25 were further scrutinized for associations using the Pearson correlation coefficient (r) so as to avoid colinearity problems. The third step involved a multiple regression model using a stepwise selection of variables. Confounding was considered to be clinically relevant if changes in the association measure from the crude analyses were more than 10%. Odds ratios (ORs) for prevalence and hazard ratios (HRs) for clearance and incidence were estimated as well as their corresponding 95% CI. A P value of 0.05 or less was considered statistically significant. Data analysis was carried out using SPSS version 15.0 statistical software (Chicago, IL, USA).
Subject Recruitment and Follow-Up
A total of 911 HIV-positive men were approached for participation in the study, of which 764 (84%) signed the informed consent form. Thirty-one patients never attended the baseline visit, leaving 733 men included in the cohort.
The inclusion period comprised the period between January 2005 and May 2009. The database was closed when the last patient included had had at least 1 year of follow-up. Seventeen percent (127/733) of the patients were lost from this study for different reasons. No differences based on sexual behavior (17% [90/538] MSM and 19% [37/195] heterosexual, P = 0.4789) were found. In 127 patients, information from their baseline visit was only used: 22 patients (3% [17/538] MSM, 3% [5/195] heterosexual) were dropouts (10 decided to end their collaboration and 12 changed their hometown residence) and 105 patients (14% [73/538] MSM, 16% [32/195] heterosexual) were withdrawn (93 had been treated in the past for anal warts and 12 died for different reasons unrelated to HPV infection). A total of 606 (83%) patients were included to assess the evolution of HPV infection. The median (interquartile range) follow-up time was 24 (12–36) months: 38 individuals (6%) completed 5 years of follow-up (6 visits); 21% (126/606), 4 years (5 visits); 22% (132/606), 3 years (4 visits); 29% (176/606), 2 years (3 visits); and 22% (134/606), 1 year (2 visits).
The patients included in the cohort were stratified by sexual behavior into 2 groups: MSM (n = 538) and heterosexual (n = 195). The MSM population had a shorter time from HIV diagnosis to enrolment, a lower percentage of AIDS diagnosis, and higher nadir CD4 counts in comparison with the heterosexual population (P < 0.001). Moreover, heterosexual patients had a higher percentage of past intravenous drug use and smoking. Furthermore, a larger number of those patients had been treated with interferon, mainly due to hepatitis C. As expected, MSM had RAI practices and a higher number of lifetime sexual partners compared with the heterosexual men (Table 1). No patient had a history of or presented with HPV-related cancer during this study.
HPV Infection at Anal Canal Site
Prevalence could be estimated including all patients (538 MSM, 195 heterosexual); clearance, including 387 MSM and 66 heterosexual with prevalent HPV infection at baseline; and incidence, including 70 MSM and 83 heterosexual with nondetectable HPV infection at baseline. The overall baseline prevalence, cumulative clearance, and incidence of anal HPV infection were 73% (534/733), 30% (136/453), and 36% (55/153), respectively.
The MSM group presented a higher prevalence (84% vs. 42%; OR, 7.3; 95% CI, 5.1–10.6) and a lower cumulative probability of clearance of anal HPV infection (28% vs. 42%; HR, 0.5; 95% CI, 0.3–0.9) than the heterosexual group (Table 2). The cumulative probability of an incidence of anal HPV infection was also higher in the MSM group (Table 2). Most of the anal infections in MSM were caused by multiple HPV types (Table 3). It is worth mentioning that the prevalence of anal HPV infection in the heterosexual group was also high (42%) and principally involved a single HPV type (Table 3).
The most commonly detected H-R HPV types at the baseline were HPV-16 (32%), HPV-33 (22%), HPV-51 (18%), and HPV-58 (18%) in the MSM group and HPV-16 (11%), HPV-39 (7%), and HPV-33 (5%) in the heterosexual group. Among the 2 L-R HPV types analyzed, HPV-6 was the most frequent type in both groups (23% in MSM and 13% in heterosexuals, respectively).
HPV Infection at Penile Site
The prevalence could be estimated including 457 MSM and 191 heterosexual. Clearance was estimated including 86 MSM and 42 heterosexuals, and incidence could be estimated including 301 MSM and 104 heterosexuals. The overall baseline prevalence, the cumulative probability of clearance, and the incidence of HPV infection in the penis were 26% (166/648), 56% (72/128), and 17% (70/405), respectively.
Men who have sex with men presented a higher cumulative incidence of penile HPV infection than the heterosexual group (HR, 2.3; 95% CI, 1.2–4.8) (Table 2), but this difference was not statistically relevant in the multivariate model (Table 4). The HPV prevalence (Table 3) and clearance at the penile site were similar between groups. The most prevalent HPV types were HPV-6 (8%), HPV-16 (5%), and HPV-39 (4%) in MSM and HPV-6 (9%), HPV-16 (7%), HPV-51 (4%), and HPV-58 (4%) in heterosexual men. The prevalence of HPV-18 was 1% in MSM and 2% in heterosexual HIV-positive men, and HPV-11 was 2% in both groups. Similar clearance and incidence rates of HPV-16 were observed between groups.
HPV Infection at Oral Site
Oral prevalence could be estimated including 458 MSM and 192 heterosexual. Clearance was estimated including 60 MSM and 29 heterosexuals, and the incidence was estimated, including 333 MSM and 118 heterosexuals. The overall prevalence at baseline, the cumulative probability of clearance, and the incidence of oral HPV infection were 16% (107/650), 44% (39/89), and 11% (49/451), respectively.
Slightly higher prevalence and lower clearance of oral HPV infection were observed in the heterosexual group with respect to MSM group, although differences did not reach statistical significance (Tables 2 and 3). A similar incidence of oral HPV infection was observed in both HIV-infected groups.
The most prevalent HPV types in MSM were HPV-16 (4%), HPV-33 (3%), and HPV-6 (3%), whereas they were HPV-16 (8%) and HPV-39 (4%) in heterosexual men. Only 1 MSM presented with a detectable HPV-18 infection in the mouth, and 2 patients showed the presence of HPV-11 (1 MSM, 1 heterosexual).
Concurrent HPV Infection in the Anus, Penis, and Mouth
The overall baseline prevalence of concurrent HPV infection in 3 different body sites was 7% (43/648), with a prevalence of 6% (29/457) in MSM and 7% (14/191) in heterosexual men. Concurrent infection with HPV-16 at the 3 body sites studied was only found in 2 (1%; 2/191) heterosexual patients.
The prevalence of concurrent HPV infection at anal and penile sites was 21% (135/648), with a prevalence of 23% (104/457) in MSM and 16% (31/191) in heterosexual men; concurrent infections of 14% were observed at anal and oral sites (89/650), with a prevalence of 14% (65/458) in MSM and 13% (24/192) in heterosexual men. The prevalence of concurrent infections at penile and oral sites at baseline was 7% (47/648), with a prevalence of 7% (30/457) in MSM and 9% (17/191) in heterosexual men. A history of anal warts was the unique factor associated with a higher prevalence of HPV infection at the 3 sites (Table 4).
Risk factors associated with prevalence, clearance, and incidence of HPV infection at the 3 anatomical sites are represented in Table 4. Sexual behavior (MSM) was only a risk factor for prevalence and incidence of the anal HPV infection, and RAI was only a risk factor for the anal canal clearance of this infection. The history of anal warts was a common risk factor for the prevalence at the 3 body sites studied. In contrast, it was a protective factor for clearance of the oral HPV infection. It is noteworthy that to be on HAART at baseline was a risk factor for the oral HPV infection prevalence. On the other hand, to be on HAART was a protective factor for the anal prevalence. It was the same for the period on HAART in terms of anal and penile prevalence.
Few studies have systematically assessed the presence of HPV infection at different body sites involved in sexual practices in HIV-positive MSM and heterosexual men in parallel and with up to 5 years of follow-up. Our results corroborate the high prevalence and incidence of anal HPV infection in MSM HIV-positive population in comparison with the heterosexual HIV-infected subjects.14 However, it is worth mentioning the high prevalence of anal HPV infection in the heterosexual HIV-positive men in comparison with the expected in healthy men and the similar prevalence and clearance of HPV infection at penile and oral sites compared with the MSM of this cohort.
The anal canal site was the site with the highest presence of detectable HPV, especially among MSM, and was higher than the cervical prevalence of HPV infection in our cohort of HIV-positive women.16 Only limited data (based mainly on cross-sectional studies) regarding the epidemiology of anal HPV infection in heterosexual HIV-positive population are available.17,18 Our results show a high prevalence (42%) of anal HPV infection in heterosexual HIV-infected men, which was considerably higher than that reported for heterosexual HIV-negative men (12%).19 The aforementioned suggests that anal HPV infection may also be acquired by HIV-infected men independently of the sexual behavior and even in the absence of RAI, in agreement with other reports.20 Thus, the immunosuppressant effects of HIV coinfection might favor the colonization of the anal canal by HPV. Another important result obtained was the role of a history of anal warts as the only risk factor associated with a higher HPV prevalence at the 3 body sites examined.
The total and HPV type–specific prevalence and clearance rates found at the anal canal site of our MSM group were similar to those reported in an MSM HIV-positive cohort,14 with HPV-16 being the most frequently detected genotype found at the 3 body sites. In addition, HPV-33, HPV-51, HPV-52, and HPV-58 were the codominant genotypes at the anal canal site, and all have been associated with invasive cervical cancer,21 This suggests that other genotypes, aside from HPV-16 or HPV-18, may be involved in anal carcinogenesis. Multiple HPV infections at the anal canal site were considerably more prevalent in the MSM population.9,14 It is possibly due to the frequency of anal sexual practices.
Despite the introduction of HAART, anal cancer among the HIV-positive is increasing.18,22–24 This fact might imply that improvements of HIV-related immunosuppression due to HAART are insufficient to reduce the incidence of anal cancer. In our study, a longer period on HAART was associated with a lower prevalence of anal HPV infection, but this effect was weak, given the high prevalence observed. Owing to the well-established association between HPV infection and squamous cell cancers and the elevated risk of anal cancer among HIV-positive men,24–26 periodic assessments of HPV infection in anal canal should be considered in both MSM and heterosexual HIV-infected men.
One of the objectives of this study was to gather insights into the natural history of HPV infection at the penile site in HIV-positive men. The only difference found between sexual behavior groups was the elevated incidence of penile HPV infection in the MSM group. According to the adjusted regression model results, this finding should not be attributed to the sexual condition. Other factors such as a shorter period of HIV infection or time under antiretroviral treatment may be related to this outcome. In this line, no differences in persistence and clearance of HPV infection at the penile site were found between HIV-positive and HIV-negative men.15 Nevertheless, it is noteworthy that the prevalence found in our HIV-infected men was considerably lower than that reported for HIV-negative men27; this difference may be due to the sampling method used.
The overall prevalence (16%) of oral HPV infection in our HIV-infected men was notably higher than the described prevalence in a small population of healthy men (4%).28 Conversely, HPV infection at the oral site was less prevalent than HPV infection at the anal and penile sites in our cohort. It is reasonable to suppose that the oral site may be less susceptible to HPV infection than the anogenital sites or that oral sex and autoinoculation may be less likely to result in oral infection.
There are several limitations in this study. The defined clearance terms may be overestimated for patients with only one sample in the follow-up. Similarly, a 1-year sampling interval may be too long to determine incidence rates because many incident infections could have already been cleared by the time of the next study visit, leading us to underestimate the true incidence rates. However, shorter intervals, which were not possible to set in the protocol because of economic and logistic constraints, may result in lower patient compliance in the follow-up. Another drawback may be the detection method, which only allowed for the detection of 13 H-R HPV and 2 L-R HPV types. However, these H-R types are the ones most commonly associated with malignant lesions at anogenital sites, and L-R types are the ones most involved in condylomatous lesions and targeted by the current HPV vaccine. Likewise, another limitation has to be considered; this study only involves one center.
In conclusion, the present study provides important information about the natural history of HPV infection at the different body sites involved in sexual practices in HIV-infected men. Although MSM presented the highest risk of anal HPV infection, heterosexual men also showed a clinically remarkable prevalence of anal HPV infection and a comparable risk of penile and oral HPV infection than MSM. Taking into account all these results, the careful inspection of the anal canal (including at least a digital rectal examination and a cytologic examination once per year), penile and oral sites should at least be routine in each clinic visit of HIV-infected men independently of their sexual behavior. Furthermore, whenever possible, carrying out the screening for type-specific HPV infection, at least at the anal canal site, should be recommended. Ongoing surveillance of this cohort will help to better understand the natural history of HPV infection.
1. Bosch FX, de San José S. Chapter 1: Human papillomavirus and cervical cancer—burden and assessment of causality. J Natl Cancer Inst Monogr 2003; 31: 3–13.
2. Welton ML, Sharkey FE, Kahlenberg MS. The etiology and epidemiology of anal cancer. Surg Oncol Clin N Am 2004; 13: 263–275.
3. Dillner J, von Krogh G, Horenblas S, et al.. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol 2000; 205: 189–193.
4. Aboulafia DM, Gibbons R. Penile cancer and human papillomavirus (HPV) in a human immunodeficiency virus (HIV)–infected patient. Cancer Invest 2001; 19: 266–272.
5. Mork J, Lie AK, Glattre E, et al.. Human papillomavirus infection as a risk factor for squamous cell carcinoma of the head and neck. N Engl J Med 2001; 344: 1125–1131.
6. Herrero R, Castellsagué X, Pawlita M, et al.. IARC Multicenter Oral Cancer Study Group. Human papillomavirus and oral cancer: The International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003; 95: 1772–1783.
7. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000; 92: 1500–1510.
8. Goedert JJ, Coté TR, Virgo P, et al.. Spectrum of AIDS-associated malignant disorders. Lancet 1998; 351: 1833–1839.
9. Palefsky JM, Holly EA, Efirdc JT, et al.. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005; 19: 1407–1414.
10. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol 1993; 12: 186–192.
11. Epstein RJ. Primary prevention of human papillomavirus dependent neoplasia: No condom, no sex. Eur J Cancer 2005; 41: 2595–2600.
12. Sirera G, Videla S, Piñol M, et al.. High prevalence of human papillomavirus infection in the anus, penis and mouth in HIV-positive men. AIDS 2006; 20: 1201–1204.
13. Critchlow CW, Hawes SE, Kuypers JM, et al.. Effect of HIV infection on the natural history of anal human papillomavirus infection. AIDS 1998; 12: 1177–1184.
14. de Pokomandy A, Rouleau D, Ghattas G, et al.. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: The HIPVIRG cohort study. J Infect Dis 2009; 199: 965–967.
15. Silva RJ, Casseb J, Andreoli MA, et al.. Persistence and clearance of HPV from the penis of men infected and non-infected with HIV. J Med Virol 2011; 83: 127–131.
16. Videla S, Darwich L, Cañadas MP, et al.. Epidemiological data of different human papillomavirus genotypes in cervical specimens of HIV-1–infected women without history of cervical pathology. J Acquir Immune Defic Syndr 2009; 50: 168–175.
17. 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: 453–459.
18. Wilkin TJ, Palmer S, Brudney KF, et al.. Anal intraepithelial neoplasia in heterosexual and homosexual HIV-positive men with access to antiretroviral therapy. J Infect Dis 2004; 190: 1685–1691.
19. Nyitray AG, Carvalho da Silva RJ, Baggio ML, et al.. Age-specific prevalence and risk factors for anal human papillomavirus (HPV) among men who have sex with women and men who have sex with men: The HPV in men (HIM) study. J Infect Dis 2011; 203: 49–57.
20. Ogunbiyi OA, Scholefield JH, Raftery AT, et al.. Prevalence of anal human papillomavirus infection and intraepithelial neoplasia in renal allograft recipients. Br J Surg 1994; 81: 365–367.
21. de Sanjose S, Quint WG, Alemany L, et al.. Human papillomavirus genotype attribution in invasive cervical cancer: A retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11: 1048–1056.
22. Hessol NA, Pipkin S, Schwarcz S, et al.. The impact of highly active antiretroviral therapy on non–AIDS-defining cancers among adults with AIDS. Am J Epidemiol 2007; 165: 1143–1153.
23. Bower M, Palmieri C, Dhillon T. AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis 2006; 19: 14–19.
24. D’Souza G, Wiley DJ, Li X, et al.. Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2008; 48: 491–499.
25. Piketty C, Selinger-Leneman H, Grabar S, et al.. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 2008; 22: 1203–1211.
26. Chaturvedi AK, Madeleine MM, Biggar RJ, et al.. Risk of human papillomavirus–associated cancers among persons with AIDS. J Natl Cancer Inst 2009; 101: 1120–1130.
27. Giuliano AR, Lee JH, Fulp W, et al.. Incidence and clearance of genital human papillomavirus infection in men (HIM): A cohort study. Lancet 2011; 377: 932–940.
28. Kreimer AR, Villa A, Nyitray AG, et al.. The epidemiology of oral HPV infection among a multinational sample of healthy men. Cancer Epidemiol Biomarkers Prevent 2011; 20: 172–182.