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

1. Advances in the Diagnosis, Management and Epidemiology of Cancers Associated with HIV Infection Corey Casper, MD, MPH Vaccine and Infectious Disease, Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Cancer Research Center Departments of Medicine, Epidemiology and Global Health, 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 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 • Hymes KB, et. al. Lancet 1981 ; EltomMA, J Natl Cancer Inst 2002; IARC SciPubl2002

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. 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)

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

14. 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

15. Achenbach AIDS 2011

16. 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

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

18. 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

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

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

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

22. The Effect of HAART on Cancer Incidence: The Hope • 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

23. The Effect of HAART on Cancer Incidence: The Reality (US)? • More than 50,000 people living with HIV in the US have been diagnosed with cancer since widespread use of HAART • ADCs have plateaued while NADCs continue to increase Shiels JNCI 2011

24. The Effect of HAART on Cancer Incidence: The Reality (Africa)? Incidence of AIDS-Defining Cancers vs. ART Coverage, Kampala Mutyaba I, et. al. Lancet 2010

25. Protease Inhibitors May Have Direct Effect on Oncogenic Virus Replication:Data from Clinical Cohorts Casper C, CROI 2004

26. Protease Inhibitors May Have Direct Effect on Oncogenic Virus Replication

27. Clinical Data in Support of Protease Inhibitors for HIVAM: Kaposi Sarcoma in Uganda Ngyuen HQ, ICMAOI 2009

28. 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

29. 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 Infection to Cancer:Novel Opportunities for Cancer Prevention and Treatment Vaccine against HBV nearly eradicated the most common cancer in Taiwanese Children • Treatment of HBV / HCV prevents development of HCC • Treatment of HHV-8 prevents development of lymphoma • Vaccine against EBV may prevent cancer in Chinese adults Primary Infection Chronic Infection • Predictive and Treatment-Selective Biomarkers • EBV DNA quantity in blood predicts development of NPC in China Replication Progression to Cancer Antibiotics cure some forms of stomach cancer associated with H. pylori

32. Antimicrobial Therapy as the New Chemotherapy?

33. 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.

34. Chemotherapy for KS in Seattle: Some Hope, Some Challenges Ngyuen HQ, AIDS 2008

35. Chemotherapy for KS in Uganda: Some Hope, Some Challenges Ngyuen HQ, ICMAOI 2008

36. NHL in Uganda: Impact of ART Survival

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

38. 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

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

40. Preventing Malignancies in HIV-Infected Patients

41. 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

42. Funding generously provided by the Doris Duke Charitable Foundation, NIH (NIAID, NCI), Centers for AIDS Research, USAID and the Fred Hutchinson Cancer Research Center