Hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC), and is also associated with elevated risk for some other types of cancer including pancreatic cancer [1–5] and non-Hodgkin lymphoma (NHL) [6–9]. The mechanisms by which HBV infection increases risk of some extra-hepatic cancers are unclear. However, its protumorigenic effects raise the possibility it could be an oncogenic cofactor [10–15].
HBV infection rates are high among HIV-infected populations and MSM [16–19]. HIV-infected populations have elevated risk for non-AIDS-defining malignancies (NADMs) linked to infections with oncoviruses such as HBV or hepatitis C (HCC) and high-risk human papilloma virus (hrHPV) (genital, anal, and oropharyngeal cancers) [20–31]. Anal squamous cell carcinoma (SCC) is a NADM caused by hrHPV in more than 90% of cases . Anal hrHPV infections are detected in 30–90% of HIV-positive individuals, with the highest rates among MSM [32–37]. However, other factors are required for tumorigenesis . Known risk for anal SCC factors include multiple sexual partners, immunodeficiencies, and smoking [39–42].
Synergistic syndemic interactions between hrHPV and HBV in promoting high-grade squamous intraepithelial lesions (HSIL) were suggested by a previous study . Furthermore, anal hrHPV is more prevalent among individuals with prior HBV  or hepatitis . Here, we evaluated the association between prior HBV infection and anal SCC risk in a prospective cohort of HIV-positive and HIV-negative MSM enrolled in the Multicenter AIDS Cohort Study (MACS).
This is a nested prospective cohort study in the MACS, an ongoing study established in 1984 that has enrolled 7343 HIV-positive and HIV-negative MSM. Clinical and laboratory data were collected at semiannual visits as described [25,39]. Eligible participants were 5298 MSM aged 30–70 years with at least 5 years of follow-up during 1984–2014 and one or more visits with HBV laboratory test data. Baseline was first visit after age 30 years. Institutional Review Boards at each study site approved the research and all participants provided written informed consent.
Data collection, risk factor classification, and cancer outcomes
The MACS public dataset release 25 was used for analyses. Past or current HBV infection was a time-invariant categorical variable defined by two or more positive lab tests for anti-HBV core antigen (ATHBC), HBV surface antigen (HBSAG), HBV e antigen (HBEAG), or HBV DNA (n = 2001), or single positive result for HBSAG (n = 29) or HBEAG (n = 1) any time following enrollment to study endpoint. Incident cancers were classified as described .
Participants were followed from baseline to first instance of incident cancer, last study visit, or age 70. Poisson regression models were restricted to HIV-positive participants. Factors associated with anal SCC in univariate analyses at P less than 0.2 were entered in the multivariate model, with stepwise backward selection used to retain significant features in the model (P < 0.05). Race and HAART use were retained in models as potential confounding factors. Models were sequentially adjusted for additional covariates having known associations with anal SCC risk and/or HBV. Statistical analysis was performed in R version 3.2.4 (R Project for Statistical Computing, Vienna, Austria).
Demographic and behavioral characteristics by HIV and hepatitis B virus infection status
We identified 5298 MSM ages 30–70 enrolled in the MACS during 1984–2010 and contributing 79 334 person-years, with median follow-up of 12 years (Table 1). Thirty-eight percent (n = 2037) had past or current HBV infection at endpoint based on positive tests for ATHBC, HBSAG, HBEAG, and/or HBV DNA, of which 87.7% were positive at enrollment and 21% had one or more positive tests for HBSAG, HBEAG, and/or HBV DNA within follow-up. Age at endpoint, follow-up time, and frequencies of anal SCC and other NADMs were higher among participants with past or current HBV in comparison with HBV-negative participants. By contrast, frequencies of HIV-positive participants with ADMs or death were lower among participants with past or current HBV in comparison with HBV-negative participants. More HIV-negative participants with past or current HBV reported more than two sexual or anal receptive partners/6 months in comparison with HBV-negatives, whereas there was no difference by HBV status among only HIV-positive participants.
Immunological and virological characteristics by HIV and hepatitis B virus infection status
CD4+ cell counts and CD4+ : CD8+ ratios were lower in HIV-positive compared with HIV-negative participants, whereas the relationship of these variables to HBV status varied by HIV status (Table 1). Among HIV-negative participants with past or current HBV, CD4+ cell counts and CD4+ nadirs were lower at 1 year prior to endpoint in comparison with HBV-negative . Among HIV-positive participants with past or current HBV, CD4+ cell counts and CD4+ : CD8+ ratios were higher, fewer participants had CD4+ cell counts less than 350 cells/μl at 1 year prior to endpoint, and HAART or HBV-active medication use was more frequent in comparison with HBV-negative participants (Table 1).
Crude incidence of anal squamous cell carcinoma and other virus-associated cancers
We observed 53 incident cases of anal SCC during follow-up, eight in HIV-negative participants and 45 in HIV-positive participants. Crude incidence rates of anal SCC were higher in participants with past or current HBV regardless of HIV status (Supplemental Digital Content 1, https://links.lww.com/QAD/B386). Past or current HBV was associated with increased risk of anal SCC among HIV-positive participants [crude incidence rate ratio (IRR), 95% confidence interval (CI) 4.92, 2.09–11.63]. Similar IRR was observed among HIV-negative participants (IRR, 95% CI 4.05, 0.82–20.08), but NS due to a low number of cases. Crude incidence rates of liver cancer were higher in participants with vs. without past or current HBV regardless of HIV status. Incidence rates of other NADMs were similar by HBV status (IRRs 1.04–1.27), whereas incidence rates of Kaposi sarcoma and NHL were lower in HIV-positive participants with past or current HBV.
Hepatitis B virus and anal squamous cell carcinoma risk in HIV-positive subjects
In univariate models, past or current HBV was associated with increased risk of anal SCC in HIV-positive participants (IRR, 95% CI 4.92, 2.09–11.63), as was older age and CD4+ cell counts less than 500 or CD4+ : CD8+ ratios less than 0.5 lagged 6 years prior to endpoint (Supplemental Digital Content 2, https://links.lww.com/QAD/B386). The association remained significant in multivariate models adjusted for age, race, HAART use, and CD4+ cell counts or CD4+ : CD8+ ratios (IRRs, 95% CIs 3.07–3.29, 1.24–7.64 to 1.32–8.23; Table 2). In subanalyses of either past or current HBV compared with HBV-negative participants, only past HBV had a significant association with anal SCC risk (IRRs, 95% CIs 3.39–3.71, 1.32–8.75 to 1.42–9.67; Table 2). Further adjustment for HCV infection, number of sexual partners, tobacco use, or poppers use did not attenuate this association (Table 2). CD4+ cell counts less than 500 or CD4+ : CD8+ ratios less than 0.5 at 6 years prior to endpoint were associated with increased anal SCC risk in adjusted models (Table 2). CD4+ cell counts less than 500 or CD4+ : CD8+ ratios less than 0.5 at 1 year prior to endpoint were significant only in adjusted models, whereas nadir values were marginally significant (Supplemental Digital Contents 2 and 3, https://links.lww.com/QAD/B386 and Table 2). A negative association between no HAART use at endpoint and anal SCC risk was significant in unadjusted, but not adjusted models. Older age had a strong association with increased anal SCC risk in adjusted models, tobacco use had a marginally significant association (IRRs 1.60–1.83; P = 0.068–0.159) (Supplemental Digital Content 3, https://links.lww.com/QAD/B386), and race, number of sexual partners, HCV infection, or poppers use had no significant associations (Table 2).
Demographic and clinical characteristics of groups by HIV status and anal squamous cell carcinoma diagnosis
We compared characteristics of the cohort stratified by HIV and anal SCC diagnosis (Supplemental Digital Content 4, https://links.lww.com/QAD/B386). Among HIV-positive participants, lab values indicating past HBV infection were more common among anal SCC cases compared with noncases. Similar trends were observed among HIV-negative participants. Anal SCC cases were older at endpoint, with longer follow-up and lower death rates in comparison with noncases among HIV-positive participants, anal SCC cases had lower CD4+ cell counts and CD4+ : CD8+ ratios lagged 6 years prior to endpoint among HIV-positive participants and lower nadir CD4+ cell counts and nadir CD4+ : CD8+ ratios compared with noncases in HIV-negative participants. HAART and HBV-active medication use were more common among anal SCC cases compared with noncases.
In this prospective study of 5298 MSM enrolled in the MACS from 1984 to 2014, past or current HBV was associated with three-fold increased risk of anal SCC among HIV-positive participants, and remained an independent risk factor in models adjusted for age, HAART use, CD4+ cell counts or CD4+ : CD8+ ratios, and other risk factors. We also confirmed previously reported associations between anal SCC risk and older age, decreased CD4+ cell counts or CD4+ : CD8+ ratios, and smoking. Together with prior studies demonstrating increased HSIL among individuals coinfected with anal hrHPV and HBV , our findings suggest that HBV may be an oncogenic cofactor for development of anal SCC.
The association between HBV infection and anal SCC occurred primarily in HIV-positive participants with resolved HBV . In analyses limited to active or chronic HBV, the association between HBV and anal SCC was NS. Similarly, Hassan et al. found the association between HBV and increased risk of pancreatic cancer was evident in ATHBC-positive, HBSAG-negative individuals. These findings raise the interesting question of how resolved HBV infections might impact cancer risk later in life.
HBV has been associated with elevated risk of several nonhepatic cancers and NHL [1–9]. HBV integrates into host DNA, causing insertional mutagenesis, and encodes the oncogenic hepatitis B X protein, which targets tumor suppressor and DNA damage repair pathways [10,12,13,15]. With regard to indirect roles in promoting risk of anal SCC, HBV induces inflammation and T-cell exhaustion [11,14] and cirrhosis can lead to immune dysregulation and CD4+ lymphopenia [47–49]. However, immunological effects of resolved HBV infections are unknown. We found a significant association between low CD4+ cell counts or CD4+ : CD8+ ratios at 6 years prior to endpoint and anal SCC risk, consistent with . Further studies are warranted to determine if resolved HBV is associated with immunological effects that impact later risk of cancers.
Participants on HAART had greater risk of anal SCC in comparison with those not on HAART, consistent with [39,50]. AIDS-related deaths are a competing risk and HAART prolongs life expectancy, allowing more time during which precursor lesions can progress to anal cancers [39,40,50–52].
We acknowledge limitations of our study. Lack of data related to hrHPV infection precluded modeling its role in anal SCC carcinogenesis. Our study was limited to mostly white MSM in a cohort at high risk of acquiring HIV, HBV, and HPV, with high rates of smoking and substance use, limiting applicability of our findings to the general population. HIV-positive participants with past or current HBV were slightly older, with more HAART and HBV-active medication use, better immunological profiles, and lower death rates. However, a case–control analysis in which each anal SCC case was matched to 10 controls based on recruitment wave, age at enrollment, race, HIV-infection status, smoking, follow-up, and calendar year at endpoint supported all of our main conclusions (data not shown).
In conclusion, this study demonstrates a significant association between prior HBV infection and increased anal SCC risk independent of age, HAART use, and immunological parameters. These results have implications regarding potential benefits of anal SCC screening in HIV-negative and HIV-positive MSM with prior HBV, and suggest that HBV vaccination in at-risk populations has the potential to improve anal cancer prevention.
Data for this article was obtained by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Barbara Crain, Adrian Dobs, Richard Elion, Michelle Estrella, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven Wolinsky (PI), John P. Phair, Sheila Badri, D.G., David Ostrow, Frank J. Palella, Jr., Sudhir Penugonda, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martinez-Maza (Co-PI), Aaron Aronow, Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D'Souza (Co-PI), Alison Abraham, Keri Althoff, Jennifer Deal, Priya Duggal, Sabina Haberlen, Alvaro Munoz, Derek Ng, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. Website located at http://www.statepi.jhsph.edu/macs/macs.html.
Cancer incidence data were provided by the following state agencies: Maryland Cancer Registry, Center for Cancer Prevention and Control, Department of Health and Mental Hygiene, Baltimore, MD 21201; Illinois Department of Public Health, Illinois State Cancer Registry; Bureau of Health Statistics & Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania; Ohio Cancer Incidence Surveillance System (OCISS), Ohio Department of Health (ODH), a cancer registry partially supported in the National Program of Cancer Registries at the Centers for Disease Control and Prevention (CDC) through Cooperative Agreement No. 5U58DP000795-05; and California Department of Public Health pursuant to California Health and Safety Code Section 103885; CDC's National Program of Cancer Registries, under cooperative agreement 5NU58DP003862-04/DP003862; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the CDC for the funds that support the collection and availability of the cancer registry data. The analyses, findings, interpretations, and conclusions of this report are those of the authors. No endorsement by any of the states providing data, the National Cancer Institute, the CDC, or their Contractors and Subcontractors is intended nor should be inferred. The authors acknowledge Steven Wolinsky, Sukrutha Chettimada, Debjani Guha, and Shibani Mukerji for helpful discussions and Elizabeth Carpelan for assistance with article preparation.
J.A. participated in study design, performed data assembly and statistical analysis, drafted the article, and prepared tables and figures. D.R.L. and V.M. participated in data parsing, assembly, and analysis. H.U. participated in study design and statistical analysis. D.G. conceived of the study, supervised its design, coordination, assembly, and analysis, and helped write and edit the article. All authors read, participated in editing the article, and approved the final article.
The work was supported by NIH grants to D.G. (R01 DA030985 and DA046203) and in part by NIH funding to the Northwestern University Clinical Research Unit of the MACS [U01-AI35039, with additional cofunding from National Cancer Institute (NCI) and National Institute on Drug Abuse (NIDA)]. J.A. was supported in part by NIH T32-AI007386-25. The MACS is funded by the National Institute of Allergy and Infectious Diseases (NIAID; U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, and UM1-AI35043), with additional cofunding from the National Cancer Institute (NCI), National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH). MACS data collection is also supported by UL1-TR000424 (JHU CTSA).
Conflicts of interest
There are no conflicts of interest.
1. Hassan MM, Li D, El-Deeb AS, Wolff RA, Bondy ML, Davila M, et al. Association between hepatitis B virus and pancreatic cancer
. J Clin Oncol
2. Hsing AW, Zhang M, Rashid A, McGlynn KA, Wang BS, Niwa S, et al. Hepatitis B and C virus infection and the risk of biliary tract cancer: a population-based study in China
. Int J Cancer
3. Iloeje UH, Yang HI, Jen CL, Su J, Wang LY, You SL, et al. Risk of pancreatic cancer in chronic hepatitis B virus infection: data from the REVEAL-HBV cohort study
. Liver Int
4. Kamiza AB, Su FH, Wang WC, Sung FC, Chang SN, Yeh CC. Chronic hepatitis infection is associated with extrahepatic cancer development: a nationwide population-based study in Taiwan
. BMC Cancer
5. Lee TY, Lee SS, Jung SW, Jeon SH, Yun SC, Oh HC, et al. Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case–control study
. Am J Gastroenterol
6. Li M, Gan Y, Fan C, Yuan H, Zhang X, Shen Y, et al. Hepatitis B virus and risk of non-Hodgkin lymphoma: an updated meta-analysis of 58 studies
. J Viral Hepat
7. Persico E, De Renzo A, La Mura V, Bruno S, Masarone M, Torella R, et al. Occult hepatitis B virus infection in patients with non-Hodgkin lymphoma: the need for early diagnosis in anti-Hbc positive patients
8. Qi Z, Wang H, Gao G. Association of risk of non-Hodgkin's lymphoma with hepatitis B virus infection: a meta-analysis
. Int J Clin Exp Med
9. Wang Q, De Luca A, Smith C, Zangerle R, Sambatakou H, Bonnet F, et al. Chronic hepatitis B and C virus infection and risk for non-Hodgkin lymphoma in HIV-infected patients: a cohort study
. Ann Intern Med
10. Ahn SM, Jang SJ, Shim JH, Kim D, Hong SM, Sung CO, et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification
11. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection
12. Hai H, Tamori A, Kawada N. Role of hepatitis B virus DNA integration in human hepatocarcinogenesis
. World J Gastroenterol
13. Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis
. J Hepatol
14. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer
. Trends Immunol
15. Zhao LH, Liu X, Yan HX, Li WY, Zeng X, Yang Y, et al. Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma
. Nat Commun
16. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection
. J Hepatol
17. Falade-Nwulia O, Seaberg EC, Snider AE, Rinaldo CR, Phair J, Witt MD, et al. Incident hepatitis B virus infection in HIV-infected and HIV-uninfected men who have sex with men from pre-HAART to HAART periods: a cohort study
. Ann Intern Med
18. Thio CL. Hepatitis B and human immunodeficiency virus coinfection
19. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013
20. Crum-Cianflone N, Hullsiek KH, Marconi V, Weintrob A, Ganesan A, Barthel RV, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study
21. Hernández-Ramírez RU, Shiels MS, Dubrow R, Engels EA. Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study
. Lancet HIV
22. Hessol NA, Pipkin S, Schwarcz S, Cress RD, Bacchetti P, Scheer S. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS
. Am J Epidemiol
23. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003
. Ann Intern Med
24. Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection
. J Clin Oncol
25. Seaberg EC, Wiley D, Martinez-Maza O, Chmiel JS, Kingsley L, Tang Y, et al. Cancer incidence in the Multicenter AIDS Cohort Study before and during the HAART era: 1984 to 2007
26. Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, et al. HIV infection and the risk of cancers with and without a known infectious cause
27. Vogel M, Friedrich O, Luchters G, Holleczek B, Wasmuth JC, Anadol E, et al. Cancer risk in HIV-infected individuals on HAART is largely attributed to oncogenic infections and state of immunocompetence
. Eur J Med Res
28. Bedimo R, Chen RY, Accortt NA, Raper JL, Linn C, Allison JJ, et al. Trends in AIDS-defining and non-AIDS-defining malignancies among HIV-infected patients: 1989–2002
. Clin Infect Dis
29. Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, et al. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence
30. Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States
. J Natl Cancer Inst
31. Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America
. Clin Infect Dis
32. Palefsky JM, Holly EA, Ralston ML, Jay N. 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
33. Critchlow CW, Holmes KK, Wood R, Krueger L, Dunphy C, Vernon D, et al. Association of human immunodeficiency virus and anal human papillomavirus infection among homosexual men
. Arch Intern Med
34. Kiviat NB, Critchlow CW, Holmes KK, Kuypers J, Sayer J, Dunphy C, et al. Association of anal dysplasia and human papillomavirus with immunosuppression and HIV infection among homosexual men
35. Breese PL, Judson FN, Penley KA, Douglas JM Jr. Anal human papillomavirus among homosexual and bisexual men: prevalence of type specific infection and association with human immunodeficiency virus
. Sex Transm Dis
36. Critchlow CW, Hawes SE, Kuypers JM, Goldbaum GM, Holmes KK, Surawicz CM, et al. Effect of HIV infection on the natural history of anal human papillomavirus infection
37. 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
38. Castellsague X, Bosch FX, Nubia M. Environmental co-factors in HPV carcinogenesis
. Virus Res
39. D'Souza G, Wiley DJ, Li X, Chmiel JS, Margolick JB, Cranston RD, et al. Incidence and epidemiology of anal cancer in the Multicenter AIDS Cohort Study
. J Acquir Immune Defic Syndr
40. Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, et al. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy
41. Reekie J, Kosa C, Engsig F, Monforte A, Wiercinska-Drapalo A, Domingo P, et al. Relationship between current level of immunodeficiency and nonacquired immunodeficiency syndrome-defining malignancies
42. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis
43. McCloskey JC, Martin Kast W, Flexman JP, McCallum D, French MA, Phillips M. Syndemic synergy of HPV and other sexually transmitted pathogens in the development of high-grade anal squamous intraepithelial lesions
. Papillomavirus Res
44. Nyitray AG, Carvalho da Silva RJ, Baggio ML, Lu B, Smith D, Abrahamsen M, et al. Age-specific prevalence of 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
45. Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, et al. Sexually transmitted infection as a cause of anal cancer
. N Engl J Med
46. Witt MD, Lewis RJ, Rieg G, Seaberg EC, Rinaldo CR, Thio CL. Predictors of the isolated hepatitis B core antibody pattern in HIV-infected and -uninfected men in the Multicenter AIDS Cohort Study
. Clin Infect Dis
47. Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance
. J Hepatol
48. McGovern BH, Golan Y, Lopez M, Pratt D, Lawton A, Moore G, et al. The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients
. Clin Infect Dis
49. Sipeki N, Antal-Szalmas P, Lakatos PL, Papp M. Immune dysfunction in cirrhosis
. World J Gastroenterol
50. Bertisch B, Franceschi S, Lise M, Vernazza P, Keiser O, Schoni-Affolter F, et al. Risk factors for anal cancer in persons infected with HIV: a nested case–control study in the Swiss HIV Cohort Study
. Am J Epidemiol
51. Diamond C, Taylor TH, Aboumrad T, Bringman D, Anton-Culver H. Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy
. Sex Transm Dis
52. Piketty C, Darragh TM, Heard I, Da Costa M, Bruneval P, Kazatchkine MD, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy
. Sex Transm Dis