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Advances in the Diagnosis, Management and Epidemiology of Cancers Associated with HIV Infection

Advances in the Diagnosis, Management and Epidemiology of Cancers Associated with HIV Infection. Corey Casper, MD, MPH Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Division of Infectious Disease, University of Washington . Outline.

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Advances in the Diagnosis, Management and Epidemiology of Cancers Associated with HIV Infection

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  1. Advances in the Diagnosis, Management and Epidemiology of Cancers Associated with HIV Infection Corey Casper, MD, MPH Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center Division of Infectious Disease, University of Washington

  2. Outline • History of Cancer in the HIV Epidemic • Epidemiology of Cancer in Persons with HIV • Resource-rich regions • Resource-poor regions • Factors associated with increased risk of cancer in persons with HIV • Diagnostic and Therapeutic Strategies for cancer prevention and treatment in persons with HIV

  3. The History of Cancer and HIV in the United States In 1981, the description of 8 young men in New York City with a previously rare cancer, Kaposi Sarcoma (KS), heralded the beginning of the HIV epidemic Hymes KB, et. al. Lancet 1981; 2:598-600. By 1983, one of every 3 persons with HIV in the United States had KS Within one year of widespread availability of HAART in US, incidence dropped 10-fold Eltom MA, J Natl Cancer Inst 2002;94:1204-10. Today, KS is the most common cancer in the entire population of Uganda, and the most common cancer among persons with HIV worldwide IARC SciPubl 2002;155:1-781 Eltom MA, J Natl Cancer Inst 2002;94:1204-10

  4. The History of Cancer and HIV in Resource-Poor Settings Now that persons in resource-poor settings are living longer with HIV, second epidemics of cancer are now being realized KS is now the most common cancer in the entire population of many countries in Sub-Saharan Africa Epidemics of lymphoma are being described in India and South America

  5. Original AIDS-Defining Malignancies

  6. Original AIDS-Defining Malignancies

  7. Viral Oncogens

  8. Risk of AIDS-Defining Cancers in HIV Patients vs. General Population • Meta-analysis of over 444,000 persons with HIV in resource-rich regions consistently found standardized incidence ratio (SIR) of AIDS-defining cancers up to 3600 times that of the general population • KS: 3640 (95% CI 3226-3975) • Cervical Cancer: 5.3 (3.58-7.57) • NHL: 22.60 (20.77-24.55) Grulich A, Lancet 2007

  9. Risk of “Non AIDS-Defining Cancers” in US / European HIV Patients Grulich A, Lancet 2007

  10. Risk of AIDS-Defining Cancers in Persons with HIV Compared to General US Population Patel P, Ann Int Med 2008

  11. Risk of Non-AIDS-Defining Cancers in Persons with HIV Compared to General US Population Patel P, Ann Int Med 2008

  12. Risk of Cancer Among US Military HIV Cohort Crum –Cianflone N, AIDS 2009

  13. Predictors of Cancer with HIV:Military Cohort Crum –Cianflone N, AIDS 2009

  14. Cancer Incidence In US Veterans: Impact of HIV Infection Bedimo RJ, J Acquir Immune Defic Syndr 2009

  15. Cancer Diagnoses Increasingly Account for Deaths Among Persons with HIV • In 2000, nearly 1/3rd of deaths among French patients with HIV were attributable to cancer • 15% due to “AIDS-malignancies” • 13% due to “non-AIDS malignancies” • Bonnet F, et. al. Cancer. 2004; Jul 15;101(2):317-24

  16. Incidence of AIDS-Associated Cancers in Africa • Case-control study of cancer in 3 major tertiary care centers in South Africa reviewed odds of HIV infection in 8,487 cancers since 1999 (Stein, et. al. Intl. J Cancer 2008)

  17. HIV-Associated Cancers in Africa: Meta-Analysis

  18. Incidence of Cancer In Persons with HIV - India Dihr Cancer Causes Control 2008

  19. Epidemiology of Cancer in Persons with HIV: Conclusions • Data from a wide variety of clinical cohorts in more than 5 continents confirms that persons with HIV are at increased risk of both “AIDS-defining” and “non-AIDS defining” malignancies • Common Non-AIDS Defining Cancers • Head / Neck Cancers • Anal Cancer • Lung Cancer • Hodgkin’s Lymphoma • Liver Cancer

  20. Factors Which May Impact Risk of Cancer in Setting of HIV • Immunosuppression • HIV Replication • Antiretroviral Therapy • Environmental / Demographic Factors

  21. Immunosuppression and Oncogenesis • Long appreciated that immune surveillance plays a role in cancer prevention • Higher incidence of cancer in organ transplant recipients • Immunotherapy for melanoma • Reduction of immunosuppresion leads to regression of cancers after transplant • KS after kidney transplant • Recurrent leukemia / lymphoma after HSCT

  22. HIV-Related Immunosuppression and Cancer Risk Biggar R, JNCI 2007

  23. Not All Immunosuppression is the Same… Grulich A, Lancet 2007

  24. Both CD4 and HIV RNA Contribute to Cancer Risk Bruyand M, CID 2009

  25. The Effect of HAART on Cancer Incidence • The reduced incidence of KS is one of the most dramatic effects of HAART • Not attributable to decreased HHV-8 prevalence Osmond DH, et al. Jama 2002; 287:221-5. SEER Cancer Registry and JNCI 2000; 92:1827

  26. No Change in KS Incidence with ART Rollout in Uganda Nguyen HQ, Casper C. The Epidemiology of Kaposi Sarcoma. In: Pantanowitz L, Stebbing J, Dezube BJ, eds. Kaposi Sarcoma: A Model of Oncogenesis. Kerala, India: Research Signpost; 2010:197-232.

  27. Change in Kaposi Sarcoma Incidence with Increasing ART Coverage, South Africa and Uganda Casper C, in press Ann Rev Med.

  28. HIV-Associated Malignancies:Change in Incidence Over Epidemic “Eras” • Pre-HAART: <1996 • Early HART: 1996-2001 • Established HAART: 2002-2007 Powles, et. al. JCO 2009

  29. Factors Associated With Development of Cancer in HIV+ Patients: Conclusions • Immunosuppresion clearly contributes to risk of many HIV-associated malignancies • Depth or Duration of low CD4 Count? • What is different about the exceptions (NHL, Cervical Ca, KS?) • HIV replication may lead to permissive environment for tumorigenesis • Increased viral oncogen replication • “Inflammatory / Angiogenic Milieu” • Not all HAART regimens may be the same in terms of prevention of cancer in those at high risk

  30. Public Health Ramifications of Relationship between HIV and Cancer • When to start HAART • Adhere to WHO guidelines in areas with high incidence of HIV-associated cancers? • Heed call for starting HAART at higher CD4 counts to avoid cancer risk? • What HAART to start • Given ease of Atripla and cost of Triomune, are there exceptions to when they should be used as first-line therapy • How to screen for HIV-associated cancers?

  31. From Primary Infection to Malignancy Vaccine eliciting neutralizing antibodies Primary Infection Chronic Infection Agents to Promote Viral Latency Antiviral Agents Viral Replication • Angiogenesis Inhibitors • Cell cycle agents • Cytokines • Antibody Therapy Transformation to Malignancy Chemotherapy

  32. Vaccines for Prevention of Viral Associated Malignancies: HPV

  33. Vaccines to Prevent Viral Associated Malignancies: EBV • Antibodies to a glycoprotein on the surface of EBV, gp350, neutralize infection and transformation of lymphoid cells • Cross-sectional studies have shown that all persons asymptomatically infected with EBV possess neutralizing antibodies. • Neutralizing antibody levels are reduced in persons with EBV-associated malignancies • 1/3rd of patients with nasopharyngeal carcinoma (NPC) and 1/5th of those with Hodgkin’s disease lacked EBV neutralizing antibodies • The geometric mean titer of EBV neutralizing antibodies was over 3-fold higher in asymptomatically infected • Antibodies raised to gp350 through vaccination were protective against EBV-induced malignant lymphoma in monkeys

  34. Vaccines to Prevent Viral Associated Malignancies: HHV-8 • Neutralizing antibodies may be protective against HHV-8 • Kimball, et. al. JID 2004

  35. Antimicrobial Therapy as the New Chemotherapy?

  36. Antivirals in the Prevention and Treatment of EBV-Associated Lymphomas • High-dose aciclovir was ineffective in the prevention of lymphoma among HIV-infected persons • OR 0.83, insufficient power due to small number of cases • Ioannidis JP, et al. J Infect Dis. 1998 Aug;178(2):349-59 • Ganciclovir use is associated with the regression of EBV-associated lymphoma in combination with chemotherapy and antiretroviral therapy • Raez L, et al. AIDS Res Hum Retroviruses. 1999 May 20;15(8):713-9. • Brockmeyer NH, et al. Eur J Med Res. 1997 Mar 24;2(3):133-5. • Aboulafia DM. Clin Infect Dis. 2002 Jun 15;34(12):1660-2.

  37. Antiviral Medications Against HHV-8 • In a randomized, placebo-controlled, crossover study of valganciclovir’s effect on HHV-8 oropharyngeal replication, 46% reduction in detection of HHV-8 in oropharynx during valganciclovir administration (p=0.02)

  38. Why Prevention is Important:KS is Difficult to Treat, Regardless of Resources

  39. NHL in Uganda: Impact of ART Survival Data courtesy of Dr. Moses Bateganya

  40. Access to Chemotherapy is Vital in Resource-Limited Settings

  41. Screening for HPV / Anal Cancer • Serologic HPV testing is unreliable • 93% of HIV-infected men and 76% of women may have HPV DNA detected in the anal mucosa (poor positive predictive value), usually type 16 • Matthews WC. Top HIV Med. 2003 Mar-Apr;11(2):45-9 • Anal Pap tests have poor reproducibility, but any abnormal cytology on Pap smear is suggestive of high grade lesions on biopsy • Panther LR, et. al. Clin Infect Dis. 2004 May 15;38(10):1490-2 • No good evidence that treating high grade lesions prevents anal cancer, and recurrences are common

  42. Algorithm for Anal Cancer Screening? Chin-Hong PV, CID 2002

  43. Preventing Malignancies in HIV-Infected Patients

  44. Conclusions • The increasing survival of HIV-infected patients may predispose to an epidemic of malignancies among long-term survivors • AIDS-Defining: KS, Cervical Cancer, Lymphoma • Non-AIDS-Defining: Anal, lung, prostate, and hepatocellular cancer • HAART use may be associated with declines in some, but not all, malignancies in persons with HIV • In addition to AIDS-defining malignancies, may reduce cervical and anal cancer • Effective screening and prevention measures have yet to be defined for the non-AIDS-defining malignancies in HIV-infected persons, but may be inferred from those in HIV-negative high risk persons • Vaccines and antiviral therapy may come to play an increasing role in the prevention and treatment of virally-mediated cancers

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