Human Papillomavirus-Associated Diseases in HIV-Infected Men Who Have Sex with Men Alexander Kreutera and Ulrike Wielandb

Home , Penile cancer

Human papillomavirus-associated diseases in HIV-infected men who have sex with men Alexander Kreutera and Ulrike Wielandb

aDepartment of Dermatology, Ruhr University Bochum, Purpose of review Bochum and bInstitute of Virology, University of Ko¨ln, Cologne, Germany Persistent human papillomavirus (HPV) infection is very frequent in HIV-positive men who have sex with men. This review summarizes recent data on papillomavirus-induced Correspondence to Alexander Kreuter, MD, Department of Dermatology, Ruhr University Bochum, anal intraepithelial neoplasia and anal cancer in these patients. Moreover, data are Gudrunstr. 56, 44791 Bochum, Germany provided on penile and oral HPV-associated diseases, for which only limited information Tel: +49 234 509 3439; e-mail: [email protected] is available in the literature. Current Opinion in Infectious Diseases 2009, Recent ﬁndings 22:109–114 The incidence of anal intraepithelial neoplasia rises in HIV-positive men who have sex with men despite the introduction of highly active antiretroviral therapy. Increasing evidence indicates that high-grade lesions can progress to anal cancer over time. Anal cytology has been recommended as the primary screening tool for anal dysplasia in the at-risk population. Individuals with abnormal cytology should undergo high-resolution anoscopy to appropriately identify and treat dysplastic lesions. Anal cancer has become one of the most common non-AIDS-deﬁning tumors in HIV-infected individuals. In the era of highly active antiretroviral therapy, the outcome of combined chemoradiotherapy in HIV-positive individuals with anal cancer is similar to that in HIV-negative persons. Penile and oral HPV-associated diseases seem to be more frequent in HIV-positive men than reported for HIV-negative heterosexual men. Summary Diagnostic and therapeutic guidelines should be implemented for at-risk populations for anal dysplasia/anal cancer, such as HIV-positive men who have sex with men. More study is required to get better insights into the natural history of penile and oral HPV-associated benign and malignant lesions.

Keywords anal, anal cancer, HIV, human papillomavirus infection, men who have sex with men, oral intraepithelial neoplasia, penile

Curr Opin Infect Dis 22:109–114 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0951-7375

lial neoplasia (AIN) [3]. Within the last decade, sufﬁcient Introduction data were published to conclude that AIN and anal cancer Human papillomavirus (HPV) infections belong to the continuously increase in HIV-positive MSM despite most common sexually transmitted infections worldwide. the use of highly active antiretroviral therapy (HAART). High HPV prevalence has been reported especially in the In contrast, only limited data are currently available young and sexually active population. In a recent study on HPV-associated diseases at other body sites of on immunocompetent heterosexual men, overall anogen- HIV-positive MSM, for example, penis or oral cavity. ital HPV infections have been observed in 65.4% and anal HPV infection was present in 24.8% of these patients [1,2]. The vast majority of HPV infections in immuno- Anal human papillomavirus infection and competent individuals is transient, and the amount of associated diseases in HIV-positive men who persistent infections is rather low. This is in contrast to have sex with men immunosuppressed individuals, for example, transplant AIN is a potential precursor lesion of squamous cell recipients or patients with HIV infection, exhibiting high carcinoma of the anus. Its pathophysiology is similar to rates of persistent HPV infection. Consequently, these other intraepithelial neoplasias induced by HPV such as individuals have a high risk for HPV-associated malig- cervical intraepithelial neoplasia (CIN), penile intrae- nant disease. Among HIV-positive patients, men who pithelial neoplasia (PIN), oral intraepithelial neoplasia have sex with men (MSM) are at highest risk for anal (OIN), and vulvar intraepithelial neoplasia. Among HIV- cancer and its potential precursor lesion, anal intraepithe- positive individuals, MSM are particularly prone to AIN,

0951-7375 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/QCO.0b013e3283229fc8

and a 60-fold increase in relative risk for AIN compared to HIV-positive patients showed that those with abnormal the general population has been reported [4]. There is anal cytology had a significantly higher occurrence of anal reasonable evidence that AIN is causally linked to infec- disease on perianal visual inspection [11]. Obtaining tions with certain high-risk HPV types such as HPV16 or samples for anal cytology is easy. Therefore, pilot studies HPV18. Several studies published since the early 1990s on self-collected versus clinician-collected anal cytology have shown that anal HPV infection is almost always were conducted some years ago, but several limitations present in HIV-positive MSM, and infections with and conflicting results do not allow us to draw general multiple HPV types are common. In a large prospective conclusions. A recent study demonstrated that the sen- study from San Francisco County, 95% of 357 HIV- sitivity of anal cytology to detect AIN is higher in positive MSM had anal HPV infection. Moreover, 88% clinician-collected versus self-collected smears [12]. of them had more than one specific HPV type and 42% of In clinical practice, the rates of anal cancer screening patients had six or more detectable anal HPV types, and intention to screen among MSM seem to be rather respectively [5]. To analyze AIN prevalence, a composite low, and primary care physicians should be prepared to diagnosis based on cytology and histology was used in this discuss anal cancer screening with their patients [13]. study. Eighty-one per cent of all patients had AIN of any grade and 52% had high-grade AIN (AIN 2 or 3). Ninety- eight per cent of patients with high-grade AIN were HPV High-resolution anoscopy positive. Importantly, the use of HAART was associated Anal cytology should only be performed in settings where with an increased estimated risk for AIN compared to abnormal findings are subjected to further diagnostic and men not taking antiretroviral medications, confirming therapeutic steps. High-resolution anoscopy (HRA) is an previous data that HAART has no or only little impact excellent tool to identify and treat anal dysplasia. HRA is on AIN development. A recent study from France con- similar to conventional colposcopy and uses the same firmed that the use of HAART is not associated with equipment. After application of 5% acetic acid, an ano- regression of anal dysplasia [6]. scope is inserted into the anal canal. Thereafter, the entire circumference of the distal rectum, transformation zone, anal canal, and perianal skin is inspected at 30-fold Cytology in anal intraepithelial neoplasia magnification. Lugol’s solution helps in visualizing screening intraanal lesions (dysplastic lesions appear yellow or Cytology is the primary screening test for CIN and unstained, whereas normal mucosa turns dark brown). cervical cancer. Facing the biological similarities of Intraanal dysplasia might present as flat or elevated CIN and AIN, anal cytology in at-risk populations has leukoplakic lesions with signs of HPV infection such been recommended by several research groups according as punctuation and mosaicism. Terminal capillaries are to the principles of cervical screening. In practice, a swab typical of condyloma, whereas neovascularization, vessel is inserted blindly into the anal canal until resistance is interruption, and caliber variation are suspicious for felt at the distal rectum wall, rotated in a circular motion, malignant disease. As mentioned before, all patients with and then rolled on a glass slide and sprayed with a abnormal anal cytology should undergo HRA. A recent cytology fixative. Anal cytology testing every 1–2 years study, however, demonstrated that the probability of AIN has been projected to be a cost-effective procedure to in a patient with normal cytology is not low enough to not prevent the development of anal cancer [7]. A systematic recommend HRA in patients with normal cytology done review summarized studies that calculated the sensitivity as a one-time test [12]. Therefore, ideally, all high-risk and specificity of anal cytology by comparing the results patients should undergo HRA. As HRA is currently of Pap smears and histology of anal biopsies. Sensitivity available only in a few specialized centers, there is a and specificity ranged from 69 to 93% and from 32 to 59%, clear lack of trained providers in this area. respectively [8]. These findings are similar to those of studies comparing cervical cytology and cervical biopsy results. In a recent study from Los Angeles (USA), 67% of Treatment of anal intraepithelial neoplasia 235 HIV-positive MSM had abnormal anal cytology, and Treatment guidelines for AIN and recommendations for the positive predictive value of anal cytological abnorm- adequate posttreatment follow-up intervals are still miss- ality to predict any degree of anal dysplasia was 95.7% ing. Although there is a lack of controlled studies on AIN [9]. Thus, abnormal anal cytology seems highly predic- treatment, several smaller studies have been published tive of anal dysplasia on biopsy. Both sensitivity and within the last years. As high-grade AIN has been shown specificity of anal cytology are higher for internal disease to progress to anal cancer, experts agree that (at least) all (lesions within the anal canal and distal rectum) as high-grade lesions should be treated [14]. In general, compared to external disease (perianal region). This is treatment methods can be divided into ablative [e.g. most likely related to low cellularity due to dry and surgery, electrocautery, laser therapy, infrared coagu- keratinized surfaces [10]. Interestingly, a study on 276 lation (IRC)] and topical (e.g. podophyllotoxine, liquid

nitrogen, trichloroacetic acid, imiquimod) approaches. incidence rates in non-AIDS-defining malignancies were Surgical treatment of high-grade AIN was reported some observed for anal cancer, continuously increasing in three years ago, but is associated with high recurrence rates and periods from 1992 to 2003. Similar trends towards a steady high posttreatment morbidity. A recent 10-year retro- increase of anal cancer in the HAART era were shown in spective study on HRA-targeted surgical destruction of an analysis of the ‘French Hospital Database on HIV’ AIN showed more promising results, with 18.7% persist- including 86 322 patients [26]. As in transplant recipi- ence rate of posttreatment AIN. However, the recurrence ents, long-term immune deficiency together with the rate (57%) again was very high [15]. In the past, IRC has significantly improved survival rate under HAART seems been demonstrated to be a highly effective ablative to be primarily responsible for the increases in infection- approach for noncircumferential AIN lesions treatable related cancers [27]. In line with this, a study on in an office-based setting. In a retrospective study on 68 incidence and risk factors for anal cancer in HIV-positive HIV-positive MSM, posttreatment clearance rate after people showed that anal cancer incidence was exten- IRC was 64% [16]. Similarly, another study on 18 HIV- sively higher in the HAART era than in the pre-HAART positive patients showed a 62.5% clearance rate after era (incidence rate ¼ 137 vs. 30 per person-years) [28]. A IRC, with 37.5% of recurrent/persistent AIN. There significantly higher risk for anal cancer was observed in was no change in HPV viral loads after treatment [17]. HIV-positive men with low CD4 cell count nadirs, in Laser therapy is another treatment option for AIN. In a cigarette smokers, and in men with a high number of study on 141 patients with AIN, 63% were disease free at unprotected receptive anal intercourse partners. More- 12 months after diode laser therapy, but HIV-positive over, older men above 50 years taking HAART seem to patients had a significantly worse outcome [18]. A remis- have an increased risk for anal cancer. sion rate of 83% after CO2 laser therapy was reported in a study on 106 patients with condylomatous or neoplastic Before the advent of HAART, several observational anogenital lesions (25.5% of them had high-grade AIN), studies have shown a poorer outcome of combined che- and there was no difference in outcome between immu- moradiotherapy (CRT) in HIV-positive individuals with nocompetent and immunosuppressed patients [19]. In anal cancer. In contrast, a recent retrospective cohort two pilot studies, imiquimod, a topical immune response study in 1184 patients with anal cancer revealed similar modifier, has been shown to be effective in patients with 2-year survival rates for HIV-positive persons on HAART AIN at mostly perianal locations [20,21]. In a recent long- and HIV-negative persons (77 vs. 75%) [29]. A multi- term follow-up study of our group of AIN patients that centric Swiss cohort comparison between HIV-positive completely cleared their disease with imiquimod, 74% and HIV-negative individuals with anal cancer showed remained free of AIN during a mean follow-up period of that those with HIV infection were younger (mean age 48 30 months [22]. High-risk HPV viral loads remained vs. 62 years), predominantly men (93 vs. 25%), and had significantly lower than before imiquimod treatment, and large cell histopathology (90 vs. 67%) [30]. There were persisted at low levels. However, new dysplatic lesions no statistically significant differences in complete with previously undetected HPV types frequently response after CRT or radiotherapy alone (92% in occurred at other locations. A first study testing a thera- HIV-positive and 96% in HIV-negative patients) and peutic vaccine for high-grade AIN in HIV-positive in the 5-year overall survival (61% in HIV-positive and patients revealed preliminary evidence for clinical 65% in HIV-negative patients). However, HIV-positive activity, although regression rates of AIN were low [23]. patients had a higher relapse rate, lower long-term local disease control, and lower long-term sphincter preser- vation. Moreover, a high proportion of patients seem to Anal cancer experience acute adverse events (mostly acute skin Anal cancer is a rare malignancy in the general popu- toxicity) and require interruption of radiotherapy [31]. lation, accounting for approximately 1% of all gastroin- Taken together, the outcome of CRT in the HAART era testinal tumors. In a large study from the year 2000, anal is comparable to the outcome in HIV-negative individ- cancer incidence in HIV-positive MSM has been uals and therefore CRT should not be deintensified reported to be 37-fold higher than in men in the general or withheld. population [4]. A recent analysis of the San Francisco AIDS surveillance registry on 14 210 patients with AIDS during the period 1990–2000 showed that anal cancer was Anal condyloma the second most common non-AIDS-defining malig- In contrast to AIN and anal cancer, only few data on nancy [24]. Another study analyzed the incidence of benign HPV-related disease such as condyloma have various cancer types in 54 780 HIV-positive persons from been published within the last years. Condyloma are two large prospective cohorts in the United States: the frequently observed in HIV-positive people referred ‘Adult and Adolescent Spectrum of HIV Disease Project’ for AIN screening. A French study recently showed and the ‘HIV Outpatient Study’ [25]. The highest that 23% of 473 HIV-positive patients undergoing

proctoscopy presented with macroscopic HPV-related [38]. Interestingly, almost all of them also had AIN lesions [6]. Forty-seven per cent of them only had within the observation period. Invasive penile cancer lesions within the anal canal, and the majority of these was so far not observed in our patient cohort. In a patients were MSM. As HRA was not performed in this meta-analysis on cancer in HIV-infected patients, stan- study, it is tempting to speculate that initial/microscopic dardized incidence ratios of 4.42 for penile cancer and lesions could have been missed. In our own cohort 28.75 for anal cancer were calculated [27]. This differ- of more than 450 MSM, 53% presented with anal ence might suggest a lower susceptibility of the penile condyloma while undergoing HRA, and more than epithelium for HPV infection and a lower risk of dyspla- three-quarters of cases of anal condyloma were asympto- sia/cancer development of penile HPV infections com- matic and located in the anal canal (unpublished own pared to the anal transformation zone. There is general data). Relapse rates after ablative or topical treatment in consensus that all penile condyloma and PIN lesions condyloma of HIV-positive patients are very high, especi- should be treated. Treatment of PIN includes all differ- ally at intraanal locations. Interestingly, 78% of 27 HIV- ent topical and ablative modalities reported for AIN and positive MSM who had undergone removal of anal warts should be initiated after biopsies have excluded penile showed signs of dysplasia (52% high-grade AIN) within cancer. In general, PIN treatment is easier to perform their condyloma [32]. Thus, all genital warts in HIV- than AIN treatment for anatomical reasons. As HIV- positive patients should be histologically examined in positive MSM seem to have an increased risk for PIN/ order to avoid missing focal dysplasia. penile cancer and since explosive courses of penile cancer have been reported in AIDS patients, PIN screening in addition to AIN screening should be performed in all Penile human papillomavirus infection and HIV-positive MSM. More studies are mandatory to get associated diseases in HIV-positive men better insights into the natural history of penile HPV who have sex with men infection and PIN in HIV-positive MSM. Several recent studies demonstrated that HPV infection is present in a high proportion of HIV-negative heterosexual men, with rates of overall genital HPV infection Oral human papillomavirus infection and (glans penis, penile shaft, and scrotum) ranging from 52 to associated diseases in HIV-positive men who 72% [1,33,34]. Most of these HPV infections are tran- have sex with men sient and HPV-clearance occurs fast in immunocompe- Estimates of the prevalence of oral HPV infection in tent persons [33]. Comparable investigations in HIV- individuals without oral cancer are highly variable. positive MSM have so far not been performed. In two Little is known about oral HPV infection and OIN in small studies including HIV-positive MSM, significant HIV-positive MSM. A comparative study in HIV- lower rates of penile HPV infection (23.5% in a Dutch positive and HIV-negative adults showed that HIV- study and 38% in a Spanish study) were detected, which positive individuals were more likely to have an oral might be explained by the lower number of smears and HPV infection (25.3 vs. 7.6%), to be infected with a less effective sampling techniques [35,36]. In contrast to high-risk HPV type (13.7 vs. 4.5%), and to be infected sampling a moist surface (e.g. anal canal or cervix), smears with multiple HPV types (5.8 vs. 1.5%). Oral mucosa from a keratinized surface such as prepuce or glans penis abnormalities such as leukoplakia, erythroplakia, and are more difficult to obtain. In order to increase the papillomas were also more frequent in HIV-positive cellular input of penile smears, pretreatment with sand- persons [39]. In multiple logistic regression, the odds paper or emery paper has been suggested by several of oral HPV infection in HIV-infected patients investigators. Although cytology and HRA have been increased with low CD4 cell counts (<200 cells/ml), shown to be reliable tools for AIN screening, no standar- herpes simplex virus-2 seropositivity, mucosa abnorm- dized methods exist to detect PIN. Five per cent acetic alities,andmorethanoneoralsexpartnerwithinthelast acid is helpful in detecting subclinical penile lesions. year [39]. HPV infection is associated with a subset of However, unspecific acetowhitening might occur in trau- oral squamous cell carcinoma (OSCC), especially those matic abrasions, superficial erosions, and chronic balani- arising from the base of the tongue and tonsils. Although tis. The term PIN encompasses three clinical entities the incidence of HPV-unrelated OSCCs associated with with different epidemiological associations and prognos- tobacco and alcohol use has been shown to decline over tic implications: erythroplasia of Queyrat, Bowen’s dis- the last decades, OSCCs related to HPV significantly ease, and bowenoid papulosis. Concerning PIN in HIV- increased, particularly among white men and at younger positive MSM, only few reports exist. HIV-positive men ages [40]. This seems to be a result of changes in seem to have high-grade PIN more frequently than HIV- sexual behaviors. Given the standardized incidence negative men [37]. In a recent prospective study of our ratios of 2.32 for OSCCs in HIV-infected persons, group, 4.2% of 263 HIV-positive MSM presented with attention should be paid to this particular type of oral PIN, and the majority of them had high-grade lesions cancer, especially in HIV-positive MSM [27].

11 Scott H, Khoury J, Moore BA, Weissman S. Routine anal cytology screening Conclusion for anal squamous intraepithelial lesions in an urban HIV clinic. Sex Transm Dis Progression of HIV infection to AIDS and death has 2008; 35:197–202. 12 Chin-Hong PV, Berry JM, Cheng SC, et al. Comparison of patient- and notably decelerated in the HAART era, and longer survival clinician-collected anal cytology samples to screen for human papilloma- rates have led to a steady increase of diseases with a long virus-associated anal intraepithelial neoplasia in men who have sex with men. Ann Intern Med 2008; 149:300–306. latency period such as HPV-related cancers. Anal cancer This study demonstrated that the sensitivity of cytology to detect AIN is higher for has become one of the most common non-AIDS-defining clinician-collected than for self-collected specimens. The probability of AIN in a patient with a negative cytology result may not be low enough for clinicians to be malignancies, especially in HIV-positive MSM. Because comfortable recommending no anoscopy for those with a negative cytology result. anal cancer might be preventable by early treatment of its All high-risk patients for AIN should undergo HRA. precursor lesions, cytological AIN screenings should be 13 D’Souza G, Cook RL, Ostrow D, et al. Anal cancer screening behaviors and intentions in men who have sex with men. J Gen Intern Med 2008; 23:1452– implemented in high-risk populations, including HRA in 1457. cases with abnormal findings. There is need for treatment This cross-sectional study shows low rates of anal cancer screening and intention to screen among MSM. guidelines in AIN, preferably based on the results of 14 Scholefield JH, Castle MT, Watson NF. Malignant transformation of controlled studies that have not yet been performed. high-grade anal intraepithelial neoplasia. Br J Surg 2005; 92:1133– Recent observations indicate that the risk for PIN and 1136. OIN might also be increased in HIV-infected individuals. 15 Pineda CE, Berry JM, Jay N, et al. High-resolution anoscopy targeted surgical destruction of anal high-grade squamous intraepithelial lesions: a ten-year More research is required to realize better insight into the experience. Dis Colon Rectum 2008; 51:829–835. natural history of penile and oral HPV infection. This is a large retrospective study showing that high-resolution anoscopy-targeted surgical destruction is effective in controlling anal dysplasia. However, recurrence rates are high. 16 Cranston RD, Hirschowitz SL, Cortina G, Moe AA. A retrospective clinical Acknowledgement study of the treatment of high-grade anal dysplasia by infrared coagulation in a There are no conflicts of interest. population of HIV-positive men who have sex with men. Int J STD AIDS 2008; 19:118–120. 17 Stier EA, Goldstone SE, Berry JM, et al. Infrared coagulator treatment of References and recommended reading high-grade anal dysplasia in HIV-infected individuals: an AIDS malignancy Papers of particular interest, published within the annual period of review, have consortium pilot study. J Acquir Immune Defic Syndr 2008; 47:56–61. been highlighted as: 18 Nathan M, Hickey N, Mayuranathan L, et al. Treatment of anal human of special interest papillomavirus-associated disease: a long term outcome study. Int J STD of outstanding interest AIDS 2008; 19:445–449. Additional references related to this topic can also be found in the Current 19 Aynaud O, Buffet M, Roman P, et al. Study of persistence and recurrence World Literature section in this issue (p. 202). rates in 106 patients with condyloma and intraepithelial neoplasia after CO2 laser treatment. Eur J Dermatol 2008; 18:153–158. 1 Nielson CM, Harris RB, Dunne EF, et al. Risk factors for anogenital human papillomavirus infection in men. J Infect Dis 2007; 196:1137–1145. 20 Wieland U, Brockmeyer NH, Weissenborn SJ, et al. Imiquimod treatment of anal intraepithelial neoplasia in HIV-positive men. Arch Dermatol 2006; 2 et al. Nyitray A, Nielson CM, Harris RB, Prevalence of and risk factors for anal 142:1438–1444. human papillomavirus infection in heterosexual men. J Infect Dis 2008; 197:1676–1684. 21 Sanclemente G, Herrera S, Tyring SK, et al. Human papillomavirus (HPV) viral load and HPV type in the clinical outcome of HIV-positive patients treated with 3 Palefsky J. Human papillomavirus-related tumors in HIV. Curr Opin Oncol imiquimod for anogenital warts and anal intraepithelial neoplasia. J Eur Acad 2006; 18:463–468. Dermatol Venereol 2007; 21:1054–1060. 4 Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in 22 Kreuter A, Potthoff A, Brockmeyer NH, et al. Imiquimod leads to a decrease of patients with human immunodeficiency virus infection and acquired immu- human papillomavirus DNA and to a sustained clearance of anal intraepithelial nodeficiency syndrome. J Natl Cancer Inst 2000; 92:1500–1510. neoplasia in HIV-infected men. J Invest Dermatol 2008; 128:2078–2083. 5 Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the This study shows a high rate of long-term clearance of AIN after imiquimod highly active antiretroviral therapy era among HIV-positive men who have sex treatment. with men. AIDS 2005; 19:1407–1414. 23 Palefsky JM, Berry JM, Jay N, et al. A trial of SGN-00101 (HspE7) to treat high- 6 Abramowitz L, Benabderrahmane D, Ravaud P, et al. Anal squamous intrae- grade anal intraepithelial neoplasia in HIV-positive individuals. AIDS 2006; pithelial lesions and condyloma in HIV-infected heterosexual men, homosexual 20:1151–1155. men and women: prevalence and associated factors. AIDS 2007; 21:1457– 24 Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active anti- 1465. retroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am This study from France shows high rates of histological condyloma and anal J Epidemiol 2007; 165:1143–1153. dysplasia not only in HIV-positive men but also in HIV-positive heterosexual men This is a large study of the San Francisco AIDS surveillance registry evaluating the and HIV-positive women. A previous history of condyloma was shown to be a impact of HAART on non-AIDS-defining malignancies. strong predictor of anal dysplasia. 25 Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among 7 Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and HIV-infected persons compared with the general population in the United cost-effectiveness of screening for anal squamous intraepithelial lesions in States, 1992–2003. Ann Intern Med 2008; 148:728–736. homosexual and bisexual HIV-positive men. JAMA 1999; 281:1822–1829. This is a study on cancer incidences of two large prospective cohorts of 8 Chiao EY, Giordano TP, Palefsky JM, et al. Screening HIV-infected individuals HIV-positive patients showing the highest incidence rates for anal cancer among for anal cancer precursor lesions: a systematic review. Clin Infect Dis 2006; non-AIDS-defining malignancies. 43:223–233. 26 Piketty C, Selinger-Leneman H, Grabar S, et al. Marked increase in the 9 Cranston RD, Hart SD, Gornbein JA, et al. The prevalence, and predictive incidence of invasive anal cancer among HIV-infected patients despite treat- value, of abnormal anal cytology to diagnose anal dysplasia in a population of ment with combination antiretroviral therapy. AIDS 2008; 22:1203–1211. HIV-positive men who have sex with men. Int J STD AIDS 2007; 18:77–80. This is a study on a large cohort of HIV-positive persons from France confirming the This study showed that abnormal anal cytology is highly predictive of anal dysplasia continuous increase of anal cancer in the HAART era. on biopsy. 27 Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in 10 Garcia FU, Haber MM, Butcher J, et al. Increased sensitivity of anal cytology in people with HIV/AIDS compared with immunosuppressed transplant recipi- evaluation of internal compared with external lesions. Acta Cytol 2007; ents: a meta-analysis. Lancet 2007; 370:59–67. 51:893–899. This is a meta-analysis on cancer incidences in people with HIV/AIDS compared This study showed that sensitivity and specificity of anal cytology are higher for with immunosuppressed transplant recipients. Increased incidences of all HPV- internal than in external lesions. related cancers were found in both groups.

28 D’Souza G, Wiley DJ, Li X, et al. Incidence and epidemiology of anal cancer in 34 Giuliano AR, Lazcano-Ponce E, Villa LL, et al. The human papillomavirus the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2008; infection in men study: human papillomavirus prevalence and type distribution 48:491–499. among men residing in Brazil, Mexico, and the United States. Cancer This study describes incidence rates and risk factor for anal cancer in HIV-positive Epidemiol Biomarkers Prev 2008; 17:2036–2043. people. 35 van der Snoek EM, Niesters HG, Mulder PG, et al. Human papillomavirus 29 Chiao EY, Giordano TP, Richardson P, El-Serag HB. Human immunodefi- infection in men who have sex with men participating in a Dutch gay-cohort ciency virus-associated squamous cell cancer of the anus: epidemiology and study. Sex Transm Dis 2003; 30:639–644. outcomes in the highly active antiretroviral therapy era. J Clin Oncol 2008; 26:474–479. 36 Sirera G, Videla S, Pinõl M, et al. High prevalence of human papillomavirus This study shows that HIV-associated anal cancer is a disease of mainly young infection in the anus, penis and mouth in HIV-positive men. AIDS 2006; men, and that survival rates after therapy are similar between HIV-positive and HIV- 20:1201–1204. negative individuals. 37 Gomousa-Michael M, Gialama E, Gomousas N, Gialama G. Genital human 30 Oehler-Ja¨nne C, Huguet F, Provencher S, et al. HIV-specific differences in papillomavirus infection and associated penile intraepithelial neoplasia in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort males infected with the human immunodeficiency virus. Acta Cytol 2000; study of HIV-positive patients receiving highly active antiretroviral therapy. 44:305–309. J Clin Oncol 2008; 26:2550–2557. This retrospective study showed that CR and OS are similar in HIV-positive and HIV- 38 Kreuter A, Brockmeyer NH, Weissenborn SJ, et al. Penile intraepithelial negative individuals following combined chemoradiotherapy for anal cancer. There is, neoplasia is frequent in HIV-positive men with anal dysplasia. J Invest Dermatol however, a higher rate of relapse and acute skin toxicity in HIV-positive patients. 2008; 128:2316–2324. This is one of the few studies on PIN in HIV-positive men showing a surprisingly 31 Wexler A, Berson AM, Goldstone SE, et al. Invasive anal squamous-cell high incidence of PIN in patients with AIN. carcinoma in the HIV-positive patient: outcome in the era of highly active antiretroviral therapy. Dis Colon Rectum 2008; 51:73–81. 39 Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in 32 McCloskey JC, Metcalf C, French MA, et al. The frequency of high-grade adults is associated with sexual behavior and HIV serostatus. J Infect Dis intraepithelial neoplasia in anal/perianal warts is higher than previously 2004; 189:686–698. recognized. Int J STD AIDS 2007; 18:538–542. 40 Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for 33 Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and human papillomavirus-related and -unrelated oral squamous cell carcinomas duration of human papillomavirus infections in a cohort of 290 US men. J Infect in the United States. J Clin Oncol 2008; 26:612–619. Dis 2008; 198:827–835. This is a large study on nine cancer registries showing increases in HPV- This study demonstrated high HPV prevalence in HIV-negative men, with relatively associated oral squamous cell carcinomas, perhaps as a result of changing sexual rapid rates of acquisition and clearance. behaviors.