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AIDSZachary Rev. Tyerman 2012;14:3-16 and David M. Aboulafia: Review of Screening Guidelines for Non-AIDS-Defining Malignancies Review of Screening Guidelines for Non-AIDS-Defining Malignancies: Evolving Issues in the Era of Highly Active Antiretroviral Therapy Zachary Tyerman1 and David M. Aboulafia1,2 1Division of Hematology and Oncology, Virginia Mason Medical Center, Seattle, WA, USA; 2Division of Hematology, University of Washington, Seattle, WA, USA Abstract © Permanyer Publications 2012 HIV-associated morbidity and mortality have declined dramatically in the era of HAART. Through direct and indirect benefits of HAART, people with HIV/AIDS are living longer, developing less AIDS-defining cancers and more cancers commonly seen in the seronegative population. Herein, we review cancer screening strategies for people living with HIV and compare and contrast them with those of the general population. The most noticeable differences occur in anal and cervical cancer screening. Although anal cancer is uncommon in the general population, it is more prevalent in men who have sex with of the publisher. men and people at high risk for human papillomavirus infection, especially those infected with HIV. To address this, we recommend that a digital rectal exam and a visual inspection be performed annually. In addition, an anal Pap test should be performed soon after the diagnosis of HIV infection, with follow-up testing every six months until two normal tests. Abnormal cytological results are then investigated with high-resolution anoscopy and biopsy of suspicious lesions. In screening for cervical cancer, a Pap test should be performed during the anogenital exam after initial HIV diagnosis, with a second Pap six months later, then annually if the results are normal. A colposcopy should follow an abnormal result. Human papillomavirus testing as a screening method for cervical cancer in women with HIV can also be efficacious. In lung cancer screening, preliminary data suggest that low-dose computerized tomography may play an important role, but further research is needed. Screening for breast and colon cancer should follow guidelines for the general population. Early screening for prostate cancer based on a diagnosis of HIV lacks clear benefit. (AIDS Rev. 2012;14:3-16) Corresponding author: David M. Aboulafia, [email protected] Key words HIV/AIDS. Non AIDS-defining malignancies. Cancer screening. Highly active antiretroviral therapy era. HAART. propensity of HIV-infected people to develop cancers. ntroduction I AIDS-defining malignancies (ADM) include Kaposi’s sarcoma (KS), intermediate and high-grade non- Among the most dramatic clinical observations dur- Hodgkin’s lymphoma (NHL), primary central nervous ing the early years of the AIDS epidemic was the system lymphoma, and invasive cervical cancer (ICC). Together KS, NHL and ICC made up 16% of AIDS- defining illnesses between 1992 and 19971. These ADM Correspondence to: have been associated with viral infections in addition David M. Aboulafia Section of Hematology/Oncology to HIV, including human herpes virus type 8 (HHV-8) 2 3 Virginia Mason Medical Center in KS , Epstein-Barr virus (EBV) in NHL , and oncogenic 1100 Ninth Avenue types of human papillomavirus (HPV) in cervical cancer4. P.O. Box 900 (H14-HEM) Infections with these viruses are sufficient to promote Seattle, WA 98111-0900, USA neoplasia, but when coinfection with HIV occurs, their No part of this publication may be reproduced or photocopying without the prior written permission E-mail: [email protected] oncogenic potential is enhanced considerably5. 3 AIDS Reviews. 2012;14 While HAART-associated immune reconstitution Coinfection with viruses other than HIV plays a sig- has contributed to a profound decline in AIDS-defining nificant role in promoting malignancy in people infect- opportunistic infections and opportunistic malignan- ed with HIV. In the general population, infection with cies, the reduced morbidity of HIV infection provides oncogenic viruses, including cytomegalovirus, EBV, a longer latency period for development of non-ADM. hepatitis B virus (HBV), hepatitis C virus (HCV), and In the pre-HAART era, non-ADM accounted for 1% of HPV, are important risk factors for malignancy. People the deaths of HIV-infected patients. Currently, 13% with HIV may be more susceptible to successive hits of people with HIV die of non-ADM6-8. The ongoing due to a higher rate of infection with oncogenic viruses HIV/AIDS Cancer Match Study compared the five like HPV, especially HPV-16 and -18. In a representative years from 1991 to 1995 to the five years from 2001 study of HIV-negative women, the baseline HPV preva- to 2005, and found a threefold increase in the preva- lence was 26%22; in contrast, among 634 HIV-infected © Permanyer Publications 2012 lence of non-ADM9. For people living with HIV in the women, the prevalence of HPV was 48%, of whom 94% HAART era, the increasing risk of dying from non-ADM were infected with carcinogenic HPV strains23. can be attributed to evolving comorbidities, exposure Anal HPV is highly prevalent in men who have sex to oncogenic viruses, substance abuse, and older with men (MSM). In one study, anal HPV DNA was age10-13. identified in 93% of HIV-positive MSM and in 61% of Herein, we will briefly discuss the epidemiology and HIV-negative MSM, with HPV-16 being the most of the publisher. risk factors of HIV-associated malignancies of the cer- common type24. vix, anus, breast, prostate, lung, and colon. Though The use of HAART itself continues to be investigated immune reconstitution induced by HAART has helped as a possible risk factor for malignancy. Though there to minimize morbidity and mortality from KS and NHL, have been some reports of association between some its impact on ICC is less certain. Some studies have antiretroviral agents and the occurrence of cancer, a suggested reduced persistence and progression of correlation has not been proven25,26. In an effort to cervical dysplasia14, while others suggest HAART has minimize HAART-related adverse events, a number of no effect15-17. It is clear, however, that women with HIV studies have examined structured treatment inter- remain at substantial risk of ICC even with HAART use18. ruptions. In the SMART study, patients were random- With that in mind, we include it in our discussion of ized to a viral suppression or a drug conservation screening options for non-ADM. group, with treatment interruption occurring at pre- specified CD4+ cell counts27. A higher rate of ADM Risk factors for malignancy and other deleterious clinical events were identified in the drug conservation cohort, while both groups had a The multistage model of cancer etiology was intro- substantial number of non-ADM28. Consequently, patients duced by Armitage and Doll in 195419. It suggests who now begin HAART are encouraged to continue that cancer is caused by discrete changes in a cell’s such treatment without interruptions29,30. genetic information. These “hits” are usually intro- Multiple sexual partners, increased alcohol con- duced by specific environmental factors rather than sumption, illicit drug use, cigarette smoking, and HBV inherited genetic mutations, two common sources be- and HCV coinfection also account for increasing rates ing cigarette smoke and radiation. Infectious agents of non-ADM in HIV-positive patients31-34. In one analysis, can also supply hits by introducing their own genetic 70 of 71 HIV-infected lung cancer patients were active material into the cell19. smokers with a long history of smoking35. Furthermore, The role of immunosuppression in contributing to the Swiss HIV Cohort Study (SHCS) found no lung can- non-ADM risk remains uncertain. In general, the risk of cers in HIV-infected patients who were nonsmokers11. such cancers has not been independently associated Cancer screening strategies should be adjusted with a low CD4+ cell count20, and it is unclear if HIV for the HIV-positive population to meet the increased acts as a direct oncogenic agent. However, HIV may risk they may have of developing certain malignancies. contribute to malignancy by other mechanisms. Im- However, in order to be widely accepted, screening paired immune surveillance, dysregulation of cytokine strategies in this population must comply with guidelines pathways and growth factor production, chronic B-cell such as the World Health Organization’s Principles and stimulation, and balance between cellular proliferation Practice of Screening for Disease36 to show that the and differentiation may contribute to ADM and non- benefits of early diagnosis outweigh its inconveniences No part of this publication may be reproduced or photocopying without the prior written permission ADM to varying degrees21. or deleterious effects. 4 Zachary Tyerman and David M. Aboulafia: Review of Screening Guidelines for Non-AIDS-Defining Malignancies Table 1. Cervical cancer screening guidelines HIV-negative women HIV-positive women Organization AAFP44 ACOG45 ACS46 USPSTF47 CDC48 Pap testing Pap test at least Biennial Pap test Annual Pap test Conventional Pap test Pap test at initial HIV every 3 years for (liquid or 3 years after onset at least every 3 years diagnosis; women who have conventional) after of vaginal for all women within Second test 6 months ever had sex the age of 21, or intercourse; not later 3 years after onset of later 3 years after onset than age 21; sexual activity or by of sexual activity every 2 years with age 21 years (whichever comes liquid-based Pap (whichever comes last)