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Delve into the rising instances of AIDS-defining and Non-AIDS-defining cancers in HIV patients, unveiling epidemiological trends, risk factors, and implications for treatment outcomes. Understand the interplay of viral infections, immune dysregulation, and genetic factors in cancer pathogenesis within the HIV population. Explore preventive measures and challenges in managing cancer in HIV-infected individuals.
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Cancers in HIV:A Growing Problem Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)
AIDS Defining Cancers • Kaposi’s sarcoma • B-cell non-Hodgkin’s lymphoma • Primary CNS lymphoma • Cervical cancer
Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005. Cancer Incidences in HIV in USA Shiels M S et al. J Natl Cancer Inst 2011;103:753-762
Categorizing Cancers in PWHA AIDS Defining Cancer (decreasing) KS NHL (BL, CNS, DLCBL) Cervical Cancer ( added in 1993) Non AIDS defining Cancers (increasing) Anal Cancer Lung Cancer Hodgkin Lymphoma Liver Cancer Elevated risk but rare Merkel Carcinoma Leiomyosarcoma Salivary gland LEC Unchanged risk Breast Colorectal Prostate Follicular lymphoma
Cancer is the One of the Most Frequent Causes of Death in HIV-Infected Patients Mortalité 2000 and 2005 studies: Bonnet et al., Cancer 101; 317:2004 and CID 48;633: 2009.
7 Notable Cancers in HIV Refs: Engels AIDS 2006, Biggar JNCI 2007, Engels Int J Cancer 2008, Chaturvedi JNCI 2009, Guiguet Lancet Oncol 2009
Cancers in HIV Disease AIDS-DefiningVirus • Kaposi’s Sarcoma HHV-8 • Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) • Invasive Cervical Carcinoma HPV Non-AIDS Defining • Anal Cancer HPV • Hodgkin’s Disease EBV • Leiomyosarcoma (pediatric) EBV • Squamous Carcinoma (oral) HPV • Merkel cell Carcinoma MCV • Hepatoma HBV, HCV
HIV-Cancers: Overview • Non-AIDS defining malignancies • Anogenital neoplasia • Lymphomas • Kaposi’s Sarcoma • Cancer Prevention
Non AIDS-defining CancersEmerging Epidemiologic Features Engels EA, Int J Cancer. 2008;123:187-194
Factors Contributing to the Increasein Cancer cases in HIV 4-fold increase in HIV/AIDS Population Patients living longer and not dying of OI Rising proportion of HIV pts > 50 yo Cancer incidence increases with age Greater and earlier start to smoking in HIV Increase in some CA incidence rate among HIV Lung (3X), anal (29X), liver (3X), HL (13X) Suggests may be additional risk from HIV
Pathogenesis of Cancer in HIV Many are virally-induced cancers, but not all Immune activation, immune dysregulation, inflammation and decreased immune surveillance HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1 Increase susceptibility to effects of carcinogens Endothelial/epithelial cell abnormalities induced or facilitated by HIV may allow for cancer development Population differences based on genetics and exposure to carcinogens Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26
Outcomes of cancer in HIV With prolonged survival of HIV population and aging, more people will develop cancer, especially NADCs. HIV-infected cancer patients may have worse outcomes in some cancers Late presentation, advanced stage Poor access to care Medical comorbidity, treatment toxicity Unclear if HIV has adverse impact on cancer behavior, immune control, cancer-free survival Limited data for guiding cancer treatment in HIV-infected people Biggar JAIDS 2005, Little J Clin Oncol 2008, Rengan Lancet Oncol 2012, Suneja AIDS 2013
Anogenital Cancers • Invasive cervical carcinoma • Considered an AIDS-defining condition • Leading cause of cancer death in women worldwide • Anal cancer1 • Not AIDS defining but very common and growing incidence • Oral and Head/Neck cancer also HPV related • HPV involvement1-2 • Both derive from precancerous lesions due to HPV • Most cancer causing strains: 16, 18, 31, 33, 35, 45 • Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia • Cancer can be prevented with early diagnosis and vaccines 1Phelps RM, et al. Int J Cancer. 2001;94:753-757. 2Martin F, et al. Sex Transm Infect. 2001;77:327-331.
Spectrum of HPV disease Low-grade disease High-grade disease Morphologic Continuum
Anal anatomy Rectalmucosa Columns ofMorgagni Levator animuscle Dentate(pectinate)line Deep Externalsphincter animuscles Skin Squamousmucosa Subcutaneous Superficial Ryan DP et al. New Engl J Med. 2000;342:792-800.
Anal and Cervical Cancer Incidence Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000 Cervical cancer currently: 8-10/100,000 Anal cancer among HIV+ MSM in USA: up to 137/100,000 American Cancer Society. Cervical cancer facts. 2006.Daling JR et al. N Engl J Med. 1987;317:973-977. Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.
Prevalence of anal HPV detection among MSMPopulation-based data Prevalence, % All participants HIV-negativeparticipants HIV-seropositiveparticipants Chin-Hong et al. Ann Int Med. 2008;149;300-6. 19
Pathology of AIDS-RelatedNon-Hodgkin’s Lymphoma • Small noncleaved-cell lymphoma • Burkitt’s lymphoma and Burkitt-like lymphoma • Immunoblastic lymphoma (primary CNS) • Diffuse large-cell lymphoma (90% CD20+) • Large noncleaved-cell lymphoma • CD30+ anaplastic large B-cell lymphoma • Plasmablastic lymphoma • Advanced stage (>75% III or IV) • Extranodal involvement • Central nervous system, liver, bone marrow, gastrointestinal Tirelli U, et al. AIDS. 2000;14:1675-1688.
EBV-positive tumors Burkitt’s lymphoma Nasopharyngeal carcinoma
AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General Population Besson et al. Blood. 2001; 98: 2339-2344 Little et al Blood. 2003; 101: 4653-4659
Hodgkin’s Disease • Association with HIV-infection • Hodgkin’s disease: RR: 5 to 30 • Non-Hodgkin’s disease: RR: 24 to 165 • Incidence increasing rapidly in post HAART era • >95% are EBV+ • Patients with HIV present with: • B symptoms (70% to 96%), worse histology, higher-stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia • Good response to MOPP/ABV • Complete response: 74.5% • 2-year disease-free survival: 62% but more relapses in HIV • Early good results with Stanford V, BEACOPP and brentuximab vendotin Gerard L, et al. AIDS. 2003;17:81-87.
Kaposi’s Sarcoma • One of the first recognized AIDS-defining illnesses • Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sites • Human herpesvirus-8 (HHV8) or KSHV • HHV8 • DNA virus found in both HIV+ and HIV- KS. • Tropism for B cells and endothelial cells, high titers in saliva • Also associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIV • Genome codes for viral homologs of human proteins involved in cell cycle regulation and signaling • HIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growth
AIDS-associated Kaposi’s Sarcoma • Transmission • Mostly MSM in US • IVDU and Heterosexual as well • Resource limited setting – Africa and S. America • KS still most common cancer in HIV • Prevalence • 1300 cases/100,000 persons/yr 1992 • 170 cases/100,000 persons/yr 2006 • Decline of 10% / year • Cause of considerable morbidity and mortality in Africa and Latin America
Clinical Manifestations • Mucocutaneous, macular or nodular, dark color • Lymphadenopathy • Visceral • Often asymptomatic • Mouth, esophagus, stomach, bowel, liver, spleen • Pulmonary KS • Rapidly fatal • Dyspnea without fever, hemoptysis • Diffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusions • Edema, can be extensive and symptomatic
Radiation therapy Photodynamic (laser) therapy Cryotherapy Alitretinoin gel – 9-cis retinoic acid (topical) Antiretroviral therapy Liposomal anthracyclines Paclitaxel Bleomycin Vinca alkaloids Gemcitabine Alpha Interferon Treatments for Kaposi’s Sarcoma Local1 Systemic1,2 1Levine AM, et al. Eur J Cancer. 2001;37:1288-1295. 2Mitsuyasu RT, et al. Cancer Management. 2008:609-632.
Cancer Prevention • Smoking Cessation – Highest priority • Hepatitis and HPV vaccination • Yearly cervical and anal Pap tests – Gyn and HRA • Maintain high index of suspicion for cancer • Yearly breast, prostate (incl. PSA) exam • Advise sun screen and avoid overexposure • Complete family history for malignancies • If Hepatitis B or C positive, follow LFTs and perhaps AFP periodically (?)
Summary • As patients live longer with HIV, morbidity and mortality from cancers are increasing • The types of cancers in HIV may vary in different populations around the world • Treatment of malignancies in HIV should be vigorous and appropriate to the situation • Side effects of therapy should be treated/prevented • Prevention strategies for virally-associated malignancies in HIV need to be investigated • Through prospective clinical trials research can treatment and prevention strategies be effectively evaluated
Thank You For information on AMC clinical trials see:http://www.aidscancer.org For information on NCI programs in HIV cancer see: http://www.cancer.gov/cancertopics/types/AIDS To refer for AMC clinical trials in LA, call UCLA CARE Center 310-557-1891 ask for Maricela Gonzalez or page/email Dr. Mitsuyasu, rmitsuya@mednet.ucla.edu