Malignancies and infection due to the human immunodeficiency virus. Are these emerging diseases?

+Model

ARTICLE IN PRESS

Rev Clin Esp. 2017;xxx(xx):xxx---xxx

Revista Clínica Española www.elsevier.es/rce

REVIEW

Malignancies and infection due to the human immunodeficiency virus. Are these emerging diseases?夽 M.E. Valencia Ortega Servicio de Medicina Interna-Unidad de VIH, Hospital Universitario La Paz, Madrid, Spain Received 21 May 2017; accepted 30 July 2017

KEYWORDS Undiagnosed AIDS tumors; Malignancies and HIV; Mortality

PALABRAS CLAVE Tumores no diagnósticos de sida; Neoplasias y VIH; Mortalidad

Abstract Since the start of the human immunodeficiency virus (HIV) epidemic, tumor disease among patients has been significant. The collection of malignancies can be divided primarily into 2 groups: those associated with HIV (all of which are related to viral diseases) and those not associated with HIV (only some of which are associated with viral diseases). The origin of these malignancies is multifactorial, and the main causes that have led to an increase in tumor disease are immunosuppression, coinfection with oncogenic viruses and life prolongation secondary to the use of antiretroviral therapy. Establishing the general characteristics of the undiagnosed AIDS tumors is difficult, mainly because they are a highly heterogeneous group formed by malignancies of a diverse nature. The treatments do not differ from those used in the general population, although the management can be more difficult due to the late diagnosis, drug interactions and associated comorbidities. © 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.

Neoplasias e infección por el virus de la inmunodeficiencia humana: ¿enfermedades emergentes? Resumen Desde los inicios de la epidemia del virus de la inmunodeficiencia humana (VIH), la patología tumoral ha sido muy importante. El conjunto de las neoplasias se puede dividir básicamente en 2 grupos: las asociadas al VIH, todas ellas relacionadas con enfermedades virales, y las no asociadas al VIH, entre las que algunas están asociadas a enfermedades virales y otras no.

夽 Please cite this article as: Valencia Ortega ME. Neoplasias e infección por el virus de la inmunodeficiencia humana: ¿enfermedades emergentes?. Rev Clin Esp. 2017. https://doi.org/10.1016/j.rce.2017.07.011 E-mail address: [email protected]

2254-8874/© 2017 Elsevier Espa˜ na, S.L.U. and Sociedad Espa˜ nola de Medicina Interna (SEMI). All rights reserved.

RCENG-1426; No. of Pages 7

+Model

ARTICLE IN PRESS

2

M.E. Valencia Ortega El origen es multifactorial y las principales causas que han llevado a que se produzca un aumento de la patología tumoral son la inmunodepresión, la coinfección con virus oncogénicos y la prolongación de la vida secundaria al uso de tratamiento antirretroviral. Establecer las características generales de los tumores no diagnósticos de sida es difícil fundamentalmente porque son un grupo muy heterogéneo formado por neoplasias de diversa índole. Los tratamientos no difieren de los empleados en la población general, aunque el manejo puede ser más difícil por el diagnóstico tardío, las interacciones medicamentosas y las comorbilidades asociadas. © 2017 Elsevier Espa˜ na, S.L.U. y Sociedad Espa˜ nola de Medicina Interna (SEMI). Todos los derechos reservados.

Background In recent years, non-AIDS related diseases (NARDs) have increased progressively and are one of the main causes of morbidity and mortality in patients infected by the human immunodeficiency virus (HIV). These processes include cardiovascular and kidney diseases, osteoporosis, neurocognitive impairment and cancer, especially non-AIDS-defining cancers (NADCs).1---6 A recent publication showed how AIDSrelated mortality has declined over time while NARD-related mortality has increased, with NADCs constituting the main cause of death.7 The set of malignancies presented by patients with HIV is divided into 2 groups: HIV-related and non-HIV-related (some of which are related to other viral diseases) (Fig. 1).8---16 The HIV-related malignancies include 1) Kaposi’s sarcoma, related to the human herpesvirus type 8 virus (HHV-8); 2) non-Hodgkin’s lymphomas, related to the Epstein Barr virus (EBV); and 3) cervical carcinoma, related to the human papilloma virus (HPV). The tumor diseases independent of HIV infection and related to viral diseases include Hodgkin’s lymphoma (HL), related to EBV; anal canal carcinoma, related to HPV; and hepatocarcinoma, associated with the hepatitis C (HCV) and B (HBV) viruses.17 Shepherd et al.18 proposed that the classification of malignancies be based on their relationship (or lack thereof) with viral infections. Tumor diseases without viral involvement are represented mainly by lung carcinoma (Fig. 1). We recently reviewed the tumor diseases in 4994 patients with HIV treated at our center from 1986 to 2016. At least 1 tumor was diagnosed in 416 patients (8.3%).19,20 In our experience, as the use of antiretroviral treatment (ART) has spread, the incidence of AIDS-defining cancers (ADCs) has decreased, while the incidence of NADCs has increased.19,20

Neoplasms

Associated with HIV

Not associated with HIV

Kaposi’s sarcomaassociated herpesvirus 8

EBV Hodgkin's

EBV non-Hodgkin's

HCV-HBV

lymphomas

hepatocarcinoma

Lymphoma

HPV Cervical

HPV carcinoma

carcinoma

of the anal canal

Lung carcinoma

Etiopathogenesis

Figure 1 Classification of the main malignancies presented by patients with human immunodeficiency virus infection. Malignancies related to viral infections can be seen in the inset. Abbreviations: EBV, Epstein Barr virus; HCV, hepatitis C virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus; HPV, human papilloma virus.

The origin of tumor diseases in patients with HIV infection is multifactorial. The most important factors are the HIV itself, immunosuppression, co-infection with oncogenic viruses and increased survival due to the use of ART.21---24 HIV is a necessary but not sufficient condition, because it is not an oncogenic virus. However, the presence of HIV creates a

condition of chronic immunosuppression, which is related to ADCs.21,25 Immune impairment and uncontrolled HIV viremia increase the risk of developing malignancies, such that an undetectable viral load and CD4+ lymphocyte counts

+Model

ARTICLE IN PRESS

Malignancies and infection due to HIV: Are these emerging diseases? greater than 500/mm3 are factors that protect against the development of some tumors, mainly ADCs. However, coinciding with the introduction of highly active ART regimens, there has been an increase in NADCs because although the immunologic situation improves, it is not completely restored.26---29 The influence of ART on the onset of tumors is independent of the drug employed. There are no differences between patients treated with regimens based on non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.19,20,27---32 Moreover, treatment interruptions, which have been performed in the past, increase the incidence of NADCs. This outcome was established in the SMART study, where all NARDs, including NADCs, were significantly more common in patients who had treatment interruptions than in those who continued the therapy uninterrupted.33 Another important factor for the development of malignancies in patients with HIV infection is co-infection with other viruses, particularly HPV, which is related to cervical carcinoma, anal canal carcinoma and otorhinolaryngological carcinoma. Other oncogenic viruses include the previously mentioned hepatotropic viruses, EBV and HHV-8.18,34,35 Ultimately, the increase in survival is one of the factors that has most affected the increase in neoplastic diseases in this population.36,37

Non-AIDS-defining cancers This group of malignancies is highly heterogeneous and varies by geographical area. They generally appear in young patients and have an atypical presentation, with large tumor masses that can quickly progress despite treatment.38---42 The treatments do not differ from those used in the general population, although their administration can be more complex due to drug interactions and associated comorbidities.43 These characteristics mean that mortality is always higher in the population with HIV infection.44,45 Currently, the overall prognosis of NADCs is poorer than that of ADCs. An Italian multicenter study that analyzed the mortality rate of patients with HIV infection who were diagnosed with a malignancy observed that only 45% of those who had an NADC lived to 10 years versus 60% of those who had an ADC.46 The most common virus-related NADCs are those of the anal canal, HL and hepatocarcinoma. Lung carcinoma is one of the most common smoking-related NADCs. Other common tumors in the general population, such as breast, prostate and colon carcinoma, do not have a higher incidence rate among patients with HIV, and their evolutionary behavior is similar.25,47 Nevertheless, breast carcinoma is also less frequent among women with HIV but is usually more aggressive.48,49

Hodgkin’s lymphoma HL is one of the most common NADCs and has an incidence rate between 15 and 30 times higher than that of the general population. Patients with HL do not present significant immunosuppression. In a number of series, the incidence of LH was higher the greater the CD4+ lymphocyte count.50,51 To explain this finding, it has been speculated that

3

there is a possible relationship between Reed---Sternberg cells and the CD4+ lymphocytes that surround them. In this respect, Reed---Sternberg cells, which produce cytokines, attract nearby CD4+ and other inflammatory cells. As a result, these CD4+ cells are activated and send the necessary signals for the proliferation and survival of malignant cells, which would be more pronounced in patients with higher CD4+ lymphocyte counts.52 In most cases, HL in patients with HIV presents in stage IVB, and the treatment does not differ from that used in HIV-negative patients. As with any other type of tumor, the use of ART and the prophylaxis of opportunistic infections are an essential part of the treatment.3,43,53 In patients with HIV infection, HL survival is determined by the tumor-associated prognostic factors; however, ART has primary importance. In a Spanish multicenter study,54 the overall survival of these patients at 10 years was 60%.

Hepatocarcinoma The incidence rate of hepatocarcinoma in the population with HIV infection is 8 times higher than that of the general population, although its etiopathogenesis and evolutionary behavior do not differ significantly between the 2 populations.55---57 The factors involved in the development of hepatocarcinoma are chronic viral hepatitis (especially hepatitis C in our community), cirrhosis of any etiology and alcohol consumption. The main and possibly only prevention measure is HCV treatment; however, risk reduction in patients with sustained response to antiviral treatment is not absolute. We therefore need to continue using screening strategies even when the HCV infection has been cured.58

Carcinoma of the anal canal Carcinoma of the anal canal is closely related to the oncogenic genotypes of HPV, which is detected in more than 90% of cases. While the incidence rate of this carcinoma in the population with HIV infection is 55---144/100,000 patients/year, the rate in the general population is only 1---1.5/100,000 patients/year.59 Homosexual men are at greatest risk for this disease, but it has been diagnosed in women who have anal sex and in patients with genital warts.59 The main recommended preventive measures are the use of condoms (although they do not provide protection in all cases) and vaccination, whose efficacy in preventing cervical carcinoma has already been proven.60,61 According to the recommendations of the AIDS workgroup (GESIDA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, anal cytology should be performed for the early diagnosis of at-risk patients, regardless of the presence or absence of HPV (Fig. 2).43

Lung carcinoma Lung carcinoma is the most common tumor, both in the population with HIV infection and the general population, and has a close relationship with tobacco use. However, in patients

+Model

ARTICLE IN PRESS

4

M.E. Valencia Ortega

Anal cytology autotoma

Proper sample

Nonrepresen tative material

Cytology in dermatology consultation

ASCUS, SIL Normal

carcinoma

Annual review

Anuscopy and biopsy

Normal

Annual review

ASCUS,SIL carcinoma

Anuscopy and biopsy

Figure 2 Algorithm for the early diagnosis of carcinoma of the anal canal. ASCUS, atypical squamous cells of undetermined significance; IL, intraepithelial lesion. Source: Adaptation of Santos, Valencia and the Expert Panel of GeSIDA.43

with HIV infection, regardless of their smoking habit, lung carcinoma has been observed to be 2---4 times more common, occurring at younger ages, with a more aggressive behavior and a poorer prognosis.62---65 Lung cancer is one of the main causes of death. Until recently, however, there has been no screening method that enabled an early diagnosis. Based on the published data of the National Lung Screening Trial in 2013,66 the current proposal is to use low-radiation computed tomography for the at-risk population without HIV, because it has been shown to be useful in the early diagnosis of this tumor, although its cost-effectiveness is still being evaluated. In the population with HIV infection, this aspect has been scarcely studied. GESIDA has therefore conducted a multicenter study to assess the efficacy of this measure (GESIDA 8815).67

Treatment of non-AIDS-defining cancers Treatment of NADCs, as with ADCs, is based on 3 fundamental pillars44,68---70 : 1. Antineoplastic treatment should be the same as that used for HIV− patients. If this premise is not considered, the mortality can increase because inappropriate therapies will be performed.71 2. Treatment of the HIV infection with an effective and safe (without drug interactions) ART should be started early.72---74 3. Prophylaxis and treatment of opportunistic infections is an essential measure and should be performed for infections directly related to the immunosuppression and for those infections (such as tuberculosis) that have a high incidence rate in the community. After employing chemotherapy or radiation therapy, the total CD4+

lymphocyte count will be reduced by 30---50% compared with baseline. Regaining pretreatment levels will take more than 6---12 months.75 Always performing prophylaxis with cotrimoxazole is therefore recommended, even if at the start of treatment the CD4+ lymphocyte counts are greater than 200/mm3 .

Early diagnosis and prevention With regard to the measures aimed at the early diagnosis of malignancies, none of the ART guidelines (except those of the European AIDS Clinical Society76 ) expressly mention this point. In Spain, GESIDA has prepared a document (drafted independently from the ART guidelines) on managing NADCs, covering both prevention and early diagnosis, which basically does not differ from the recommendations for the general population (Table 1).43 According to the recommendations, the most important preventive measures with proven efficacy are developing healthy life habits (reducing alcohol and tobacco consumption), HCV treatment and the use of vaccines against HPV and, to a lesser extent, HBV.43,57,58,60,61,77---79

Conclusions 1. Most malignancies (ADCs and NADCs) that appear in patients with HIV infection are related to viral infections. NADCs have a higher frequency and greater severity than ADCs. 2. An undetectable viral load (HIV) and CD4+ lymphocyte counts higher than 500/mm3 are factors that protect against the development of some tumors, mainly ADCs. 3. Treatment for malignancies in patients with HIV resembles that used in the general population.

+Model

ARTICLE IN PRESS

Malignancies and infection due to HIV: Are these emerging diseases?

5

Table 1 Measures aimed at the prevention and early diagnosis of various malignancies diagnosed in patients with human immunodeficiency virus infection. Type of malignancy

Susceptible population

Early diagnosis

Prophylaxis

Carcinoma of the anal canal

MSM, women who engage in anal sex, patients with genital warts Sexually active women Patients with cirrhosis

Annual anal cytology

HPV vaccination

Annual cervical cytology Abdominal ultrasonography every 6 months Low-radiation contrastless chest CT Annual fecal occult blood ± colonoscopy every 5 years Rectal examination ± PSA Mammography

HPV vaccination HBV vaccination Treatment of hepatitis by HCV and HBV Smoking cessation

Cervical carcinoma Hepatocarcinoma

Lung cancer Colon cancera

Prostate cancera Breast cancera

Smokers older than 45 years People between 50 and 75 years of age. Family history of colon cancer Men older than 50 years Women between 50 and 70 years

a

In these 3 tumors, the recommended measures for early diagnosis do not differ from those used in the general population. Abbreviations: MSM, men who have sex with men; PSA, prostate-specific antigen; CT, computed tomography; HBV, hepatitis B virus; HCV, hepatitis C virus; HPV, human papilloma virus.

4. Prophylaxis of opportunistic infections should be employed while administering chemotherapy, even when CD4 counts are higher than 200/mm3 .

Conflict of interest The authors declare that they have no conflicts of interest.

References 1. Garriga C, García de Olalla P, Miró JM, Oca˜ na I, Knobel H, Barberá MJ, et al. Mortality, causes of death and associated factors relate to a large HIV population-based cohort. PLOS ONE. 2015;10:e0145701. 2. Berenguer J. Mortalidad en personas infectadas por el virus de la inmunodeficiencia humana. Enferm Infec Microbiol Clin. 2016;34:217---8. 3. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384:241---8. 4. Trickey A, May MT, Vehreschild J, Obel N, Gill MJ, Crane H, et al. Cause-specific mortality in HIV-positive patients who survived ten years after starting antiretroviral therapy. PLOS ONE. 2016;11:e0160460, doi:10.1371/journal.pone.0160460. 5. Marcus JL, Chao Ch, Leyden WA, Xu L, Yu J, Horberg MA, et al. Survival among HIV-infected and HIV-uninfected individuals with common non-AIDS-defining cancers. Cancer Epidemiol Biomarkers Prev. 2015;24:1167---73. 6. Meijide H, Mena A, Pernas B, Castro A, López S, Vázquez P, et al. Malignancies in HIV-infected patients: descriptive study of 129 cases between 1993 and 2010. Rev Chilena Infectol. 2013;30:156---61. 7. López C, Masiá M, Padilla S, Aquilino A, Bas C, Gutiérrez F. Muertes por enfermedades no asociadas directamente con el sida en pacientes con infección por el VIH: un estudio de 14 a˜ nos (1998---2011). Enferm Infecc Microbiol Clin. 2016;34:222---7.

8. Antman K, Ghang Y. Kaposi’s sarcoma. N Engl J Med. 2000;342:1027---38. 9. Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis. 2008;47:1209---15. 10. Centers for Disease Control (CDC). Classification system for human T lymphotropic virus type III/lymphadenophatyassociated virus infections. MMWR Morb Mortal Wkly Rep. 1986;35:334---9. 11. Ribera J, Navarro J. HIV-related non-Hodgkin’s lymphomas. Haematologica. 2008;93:1129---32. 12. Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, et al., HIV/AIDS Cancer Match Study. Trends in cancer risk among people with AIDS in the United States 1980---2002. AIDS. 2006;20:1645---54. 13. CDC 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41:1---19. 14. 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. AIDS. 2009;23:2337---45. 15. Silverberg M, Leyden W, Chao C, Xu L, Tang B, Horberg M, et al. Infection related non-AIDS-defining risk in HIV-infected and uninfected persons. In: 16th conference on retrovirus and opportunistic infections. 2009 [abstract 30]. 16. Suárez-García I, Jarrín I, Iribarren JA, López-Cortés LF, LacruzRodrigo J, Masiá M, et al. Incidence and risk factors of AIDSdefining cancers in a cohort of HIV-positive adults: importance of the definition of incident cases. Enferm Infecc Microbiol Clin. 2013;31:304---12. 17. Riedel DJ, Tang LS, Rositch AF. The role of viral co-infection in HIV-associated non-AIDS-related cancers. Curr HIV/AIDS Rep. 2015;12:362---72. 18. Shepherd L, Borges Á, Ledergerber B, Domingo P, Castagna A, Rockstroh J, et al., EuroSIDA in EuroCOORD. Infection-related and -unrelated malignancies. HIV and the aging population. HIV Med. 2016;17:590---600.

+Model

ARTICLE IN PRESS

6 19. Montejano R, Arribas J, Bernardino J, Martin-Carbonero L, Montes M, Moreno V, et al. A descriptive study of cancer incidence in a cohort of HIV-infected patients followed since 1986. In: HIV drug therapy. 2016. p. 198. 20. Montejano R, Arribas J, Bernardino J, Martin-Carbonero L, Montes M, Moreno V, et al. Análisis retrospectivo de las neoplasias diagnosticadas en una cohorte de pacientes con infección por VIH en seguimiento desde 1986. Donostia-San Sebastián: Congreso Nacional de GESIDA; 2016. p. 231. 21. Silverberg MJ, Lau B, Achenbach CJ, Jing Y, Althoff KN, D’Souza G, et al. Cumulative incidence of cancer among persons with HIV in North America: a cohort study. Ann Intern Med. 2015;163:507---18. 22. Brickman C, Palefsky JM. Cancer in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep. 2015;12:388---96. 23. 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. Lancet. 2007;370:59---67. 24. Mitsuyasu RT. Non-AIDS-defining cancers. Top Antivir Med. 2014;22:660---5. 25. Serrano-Villar S, Gutiérrez F, Miralles C, Berenguer J, Rivero A, Martínez E, et al. Human immunodeficiency virus as a chronic disease: evaluation and management of nonacquired immune deficiency syndrome-defining conditions. Open Forum Infect Dis. 2016;3:1---15. 26. Monforte A, Abrams D, Prader C, Weber R, Reiss P, Bonnet F, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008;22:2143---53. 27. Silverberg MJ, Abrams DI. Do antiretrovirals reduce the risk of non-AIDS defining malignancies? Curr Opin HIV AIDS. 2009;4:42---51. 28. Kesselring A, Gras L, Smit C, van Twillert G, Verbon A, Reiss P, et al. Immunodeficiency as a risk factor for non-AIDS defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2011;52:1458---65. 29. Reekie J, Gatell J, Yust I, Bakowska E, Rakhmanova A, Losso M, et al. Fatal and non-fatal AIDS and non-AIDS events in HIV-1 positive individuals with high CD4 counts according to viral load strata. AIDS. 2011;25:2259---68. 30. Brugnaro P, Morelli E, Cattelan F, Petrucci A, Panese S, Eseme F, et al. Non-AIDS definings malignancies among human immunodeficiency virus-positive subjects: epidemiology and outcome after two decades of HAART era. World J Virol. 2015;4: 209---18. 31. Crum-Cianfione N, Huppler K, 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. AIDS. 2009;23:41---50. 32. Yanik EL, Napravnik S, Cole SR, Achenbach CJ, Gopal S, Dittmer DP, et al. Relationship of immunologic response to antiretroviral therapy with non-AIDS-defining cancer incidence. AIDS. 2014;28:979---87. 33. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al., Strategies for management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283---96. 34. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirusassociated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. 2000;92:1500---10. 35. Engels EA, Frisch M, Lubin JH, Gail MH, Biggar RJ, Goedert JJ. Prevalence of hepatitis C virus infection and risk for hepatocellular carcinoma and non-Hodgkin lymphoma in AIDS. J Acquir Immune Defic Syndr. 2002;31:536---41.

M.E. Valencia Ortega 36. Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007;448:767---74. 37. Hasse B, Ledergerber B, Furrer H, Battegay M, Hirschel B, Cavassini M, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV cohort study. Clin Infect Dis. 2011;53:1130---9. 38. Ramírez-Olivencia G, Valencia-Ortega ME, Martín-Carbonero L, Moreno-Celda V, González-Lahoz J. Tumores en pacientes con infección por el virus de la inmunodeficiencia humana: estudio de 139 casos. Med Clin (Barc). 2009;133:729---35. 39. 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. 2008;148:728---36. 40. Chisi SK, Kollmann MK, Karimurio J. Conjunctival squamous cell carcinoma in patients with human immunodeficiency virus infection seen at two hospitals in Kenya. East Afr Med J. 2006;83:267---70. 41. Galceran J, Marcos-Gragera R, Soler M, Romaguera A, Ameijide A, Izquierdo A, et al. Cancer incidence in AIDS patients in Catalonia, Spain. Eur J Cancer. 2007;43:1085---91. 42. Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Ann Intern Med. 2010;153:452---60. 43. Santos J, Valencia E, Panel de expertos de GeSIDA. Guía de práctica clínica sobre los tumores no definitorios de sida e infección por el virus de la inmunodeficiencia humana. Enferm Infecc Microbiol Clin. 2014;32:515---22. 44. Raffetti E, Albini L, Gotti D, Segala D, Maggiolo F, di Filippo E, et al. Cancer incidence and mortality for all causes in HIVinfected patients over a quarter century: a multicentre cohort study. BMC Public Health. 2015;15:235. 45. Coghill AE, Shiels MS, Suneja G, Engels EA. Elevated cancerspecific mortality among HIV-infected patients in the United States. J Clin Oncol. 2015;33:2376---83. 46. Gotti D, Raffetti E, Albini L, Sighinolfi L, Maggiolo F, di Filippo E, et al. Survival in HIV-infected patients after a cancer diagnosis in the cART Era: results of an Italian multicenter study. PLOS ONE. 2014;9:e94768. 47. Bower M, Collins S, Cottrill C, Cwynarski K, Montoto S, Nelson M, et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med. 2008;9:336---88. 48. Hessol NA, Napolitano LA, Smith D, Lie Y, Levine A, Young M, et al. HIV tropism and decreased risk of breast cancer. PLOS ONE. 2010;12:e14349. 49. Cubasch H, Joffe M, Hanisch R, Schuz J, Neugut AI, Karstaedt A, et al. Breast cancer characteristics and HIV among 1092 women in Soweto, South Africa. Breast Cancer Res Treat. 2013;140:177---86. 50. Corti M, Villafane MF, Trione N, Narbaitz M. Linfoma de Hodgkin asociado al virus de la inmunodeficiencia humana tipo 1: hallazgos epidemiológicos, clínicos e histopatológicos de 18 pacientes. Med Clin (Barc). 2005;124:116---7. 51. Carbone A, Spina M, Gloghini A, Tirelli U. Classical Hodgkin’s lymphoma arising in different host’s conditions: pathobiology parameters, therapeutic options, and outcome. Am J Hematol. 2011;86:170---9. 52. Spina M, Carbone A, Gloghini A, Serraino D, Berretta M, Tirelli U. Hodgkin’s disease in patients with HIV infection. Advanc Haematol. 2011;2011, doi:10.1155/2011/402682. Article ID 402682. 53. Berenguer J, Miralles P, Ribera JM, Rubio R, Valencia E, Mahillo B, et al. Characteristics and outcome of AIDS-related Hodgkin lymphoma before and after the introduction of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;47:422---8. 54. Xicoy B, Ribera JM, Miralles P, Berenguer J, Rubio R, Mahillo B, et al. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral

+Model

ARTICLE IN PRESS

Malignancies and infection due to HIV: Are these emerging diseases?

55.

56. 57.

58.

59.

60.

61.

62. 63.

64.

65. 66.

67.

therapy in advanced stage, human immunodeficiency virusrelated Hodgkin’s lymphoma. Haematologica. 2007;92:191---8. Sahasrabuddhe VV, Shiels MS, McGlynn KA, Engels EA. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2012;118:6226---33. El-Serag HB, Hepatocellular carcinoma. N Engl J Med. 2011;365:1118---27. Montes Ramírez ML, Miró JM, Quereda C, Jou A, von Wichmann MÁ, Berenguer J, et al. Incidence of hepatocellular carcinoma in HIV-infected patients with cirrhosis: a prospective study. J Acquir Immune Defic Syndr. 2014;65:82---6. Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, de Santo JL, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52:833---44. 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. 2008;148:728---36. Bailey HH, Chuang L, du Pont NC, Eng C, Foxhall LE, Merrill JK, et al. American Society of Clinical Oncology statement: human papillomavirus vaccination for cancer prevention. J Clin Oncol. 2016;34:1803---12. Bruni L, Serrano B, Bosch X, Castellsagué X. Vacuna frente al virus del papiloma humano. Eficacia y seguridad. Enferm Infecc Microbiol Clin. 2015;33:342---54. Mena Á, Meijide H, Marcos PJ. Lung cancer in HIV-infected patients. AIDS Rev. 2016;18:138---44. Bedimo RJ, McGinnis A, Dunlap M, Rodriguez-Barradas MC, Justice AC. Incidence of non-AIDS-defining malignancies in HIV-infected versus non-infected patients in the HAART era: impact of immunosuppression. J Acquir Immune Defic Syndr. 2009;52:203---8. Shiels MS, Cole SR, Kirk GD, Poole Ch. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52:611---22. Sigel K, Pitts R, Crothers K. Lung malignancies in HIV infection. Semin Respir Crit Care Med. 2016;37:267---76. Aberle DR, DeMello S, Berg CD, Black WC, Brewer B, Church TR. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369:920---31. Estudio prospectivo para la detección precoz de carcinoma pulmonar en pacientes con infección por VIH. Promotor: Fundación SEIMC-GESIDA. Código GESIDA 8815.

7

68. Deeken JF, Tjen-A-Looi A, Rudek MA, Okuliar C, Young M, Little RF, et al. The rising challenge of non-AIDS-defining cancer in HIV-infected patients. Clin Infect Dis. 2012;55: 1228---35. 69. Suneja G, Shiels MS, Angulo R, Coppeland GE, Gonsalves L, Hakenewerth AM, et al. Cancer treatment disparities in HIV-infected individuals in the United States. J Clin Oncol. 2014;32:2344---50. 70. Malfitano A, Barbaro G, Perretti A, Barbarini G. Human immunodeficiency virus-associated malignancies: a therapeutic update. Curr HIV Res. 2012;10:123---32. 71. Vaccher E, Serraino D, Carbone A, Paoli P. The evolving scenario of non-AIDS-defining cancers: challenges and opportunities of care. Oncologist. 2014;19:860---7. 72. Borges AH, Dubrow R, Silverberg MJ. Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier cART will alter this risk. Curr Opin HIV AIDS. 2014;9:34---40. 73. Rudeck MA, Flexner C, Ambrinder RF. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol. 2011;12:905---12. 74. Spano JP, Poizot-Martin I, Costagliola D, Boué F, Rosmorduc O, Lavolé A, et al., CANCERVIH Working Group. Non-AIDSrelated malignancies: expert consensus review and practical applications from the multidisciplinary. Ann Oncol. 2016;27: 397---408. 75. Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley Dk, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:794---810. 76. European Guidelines for treatment of HIV-positive adults in Europe. Versión 8.2; January 2017. Available from: http://www.eacsociety.org/guidelines/eacs-guidelines/eacsguidelines.html 77. Catherine FX, Piroth L, Hepatitis B. Virus vaccination in HIV-infected people: a review. Hum Vaccin Immunother. 2017;16:1---10. 78. Villanti AC, Jiang Y, Abrams DB, Pyenson BS. A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLOS ONE. 2013;8:e71379. 79. Snee M, Hatton MQ. Longstanding challenges in lung cancer: are we meeting them? Clin Oncol. 2016;28:669---71.