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24 September, 2009 HIV-Associated Malignancies in the Antiretroviral Era Corey Casper, MD, MPH

24 September, 2009 HIV-Associated Malignancies in the Antiretroviral Era Corey Casper, MD, MPH. HIV-Associated Malignancies in the Antiretroviral Era. Corey Casper, MD, MPH Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center Division of Infectious Disease,

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24 September, 2009 HIV-Associated Malignancies in the Antiretroviral Era Corey Casper, MD, MPH

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  1. 24 September, 2009 HIV-Associated Malignancies in the Antiretroviral Era Corey Casper, MD, MPH

  2. HIV-Associated Malignancies in the Antiretroviral Era Corey Casper, MD, MPH Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center Division of Infectious Disease, University of Washington

  3. Outline • The history of cancer in the HIV epidemic • Definition of AIDS-defining and non-AIDS defining cancers • The epidemiology of cancers in persons with HIV • Specific AIDS-associated malignancies • Cervical Cancer • Anal Cancer • Hepatocellular Carcinoma • Lung Cancer • Kaposi Sarcoma • Lymphoma • Prevention and Treatment Strategies

  4. Case 1 54 year old man presents with several painless, raised, purple lesions on the chest, back and in the groin

  5. Case 1: Additional History • History of Hairy Cell Leukemia, in remission for 5 years after treatment with cladaribine and an experimental agent at the National Cancer Institute • In steady relationship with male partner for 3 years • Tested HIV-negative one week after starting present relationship

  6. Case 1: KS • HIV test: positive EIA, confirmed by Western Blot • CD4 count: 96 • HIV viral load: >500,000 copies • Follow-up: • Improving after starting tenofovir, emtricitabine and Kaletra

  7. KS in the HAART Era • 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. • May be due to immune reconstitution, or direct antiviral effect of ART on HHV-8 SEER Cancer Registry and JNCI 2000; 92:1827

  8. Decline in KS Incidence with HAART May Not Be Seen in Endemic Areas No change in KS incidence in Uganda despite over 100,000 persons started on HAART

  9. Current Treatment for KS in Resource-Rich Settings is Inadequate Nguyen HQ, et. al. AIDS 2008

  10. Current Treatment of KS in Resource-Poor Settings is Inadequate • 177 patients with HIV-associated KS seen at the Infectious Disease Institute followed for 2 years • Over 1 year, 70% improved with ART and/or chemotherapy, but only 8% resolved • Associated with improvement: male sex, HAART, and chemotherapy • Less likely to improve: low BMI and lesions located on the lower extremities • Among patients on HAART, those receiving efavirenz- and protease inhibitor-containing HAART were 6.9 (95% CI: 1.7-27, p=0.006) and 15 times (95% CI: 1.3-183, p=0.03) more likely to experience resolution compared to those receiving Triomune (stavudine-lamivudine-nevirapine).

  11. The History of an Epidemic… • 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 • In 1994, KS attributed to infection with human herpesvirus 8 • Chang Y, et. al. Science 1994; 266:1865-9. • 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.

  12. Original AIDS-Defining Malignancies

  13. Original AIDS-Defining Malignancies

  14. Viral Oncogens

  15. 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

  16. Winning the Battle Against HIV… • Mortality has dropped dramatically among persons with HIV in the highly active antiretroviral era • Persons living with HIV have a nearly normal risk of death when compared with HIV-negative persons… Mocroft A, et al. Lancet 2003;362:22-9 Mocroft A, et. al. Lancet 2003

  17. …But Losing the War to Cancer?Resource-Rich Regions • 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

  18. …Losing the War to Cancer?Africa UNAIDS 2006

  19. Burden of Cancer in Africa

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

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

  22. HIV-Associated Malignancies:Change in Incidence Over Epidemic “Eras” Powles, et. al. JCO 2009

  23. Not All Immunosuppression is the Same…

  24. Incidence of AIDS-Associated Cancers in Resource-Poor Settings • 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)

  25. Cancer Incidence Trends in Uganda, 1992-2005

  26. Case 2 • 45 year old Kenyan woman with B3 HIV (CD4 375, HIV RNA 51,000, not on ART) presents for routine annual PAP • Found to have high-grade squamous epithelial lesion (HSIL) • Referred for colposcopy, where biopsy reveals CIN III • Treated with surgical ablation, topical flurouricil, and intiation of HAART

  27. Cervical Cancer in the HAART Era • In the Women’s Interagency HIV Study (WIHS), both increasing HIV plasma RNA levels and decreasing CD4 counts were associated with an increased risk of abnormal cervical cytology • Massad LS, et al. J Acquir Immune Defic Syndr. 1999 May 1;21(1):33-41 • The use of HAART was associated with an increased rate of “regression” over six months (two normal Pap smears) • Ahdieh-Grant L, et al J Natl Cancer Inst. 2004 Jul 21;96(14):1070-6

  28. Cervical Cancer Screening in HIV-Positive Patients • Cervical cancer screening twice in the first year after diagnosis of HIV infection and then annually, provided the test results are normal. • HPV testing? • Increased frequency of testing (q6 months?) if positive for high-risk strain • Some recommend a screening colposcopy at initial evaluation

  29. Case 3 • 51 year old Caucasian male with history of C3 HIV (current CD4 405, HIV RNA undetectable) presents with rectal bleeding • Presented with AIDS-dementia with CD4 count of 7 in 2000, treated successfully with AZT / lamivudine / Kaletra • On rectal exam, large verrucous lesion originating from the posterior half of the anus or from 9 o'clock to 3 o'clock position, originating from multiple narrow pedicles.

  30. Anal Cancer in the HAART Era • Risk of anal cancer among HIV-positive men who have sex with men is 60-fold higher than the general population Frisch M, et al. J Natl Cancer Inst. 2000; 92:1500-10 • Grade of squamous intraepithelial lesions may be correlated with degree of immunosuppression in both men and women Mathews WC. Top HIV Med. 2003 Mar-Apr;11(2):45-9 • Effective HAART use may not be associated with a decline in anal dysplasia / cancer Piketty C, et. al. Sex Transm Dis. 2004 Feb;31(2):96-9

  31. 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

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

  33. Case 4 • 41 year old man with B2 HIV (last CD4 311, HIV RNA undetectable on Atripla) presents with 20 pound weight loss over the last 3 months • History of untreated hepatitis C virus infection and cirrhosis on liver biopsy • Non-compliant with annual ultrasound and alpha-fetoprotein screening

  34. HCC in the HAART Era • Co-infection with HIV and viral hepatitis (B and C) could result in an epidemic of hepatocellular carcinoma in long term survivors of HIV • Suppression of HBV or HCV replication is associated with reduced risk of cancer • Patients with HIV may be between 2-8 times more likely to develop hepatocellular carcinoma when compared with the general population Chiao E, et al. Curr Opin Oncol 2003:15; 389

  35. Case 5 • 43 year old Cambodian man with A3 HIV (last CD4 621, HIV RNA undetectable on Atripla) presents with fevers of 3 weeks duration but no other symptoms • Solitary pulmonary nodule detected on chest x-ray and confirmed on CT scan

  36. Case 5: CT Scan

  37. Lung Cancer in the HAART Era • HIV-infected patients may be at 1.5-4.5 times increased risk of lung cancer compared with the general population • May be attributable to: • High rates of tobacco use? • Two studies have found risk to be independent of tobacco use • Permissive cytokine milieu by HIV (Tat, etc.) • Differences in DNA methylation patterns Chiao E, et al. Curr Opin Oncol 2003:15; 389

  38. Prostate Cancer in the HAART Era • Large series have found conflicting evidence for an increased rate of prostate cancer among persons with HIV • Chiao E, et al. Curr Opin Oncol 2003:15; 389 • One study found a relationship between duration of HIV infection and prostate cancer, suggesting that prostate cancer may become an issue among long-term survivors of HIV • Crum NF, et. al. Cancer 2004: 101; 294-9

  39. Case 6 • 31 year old Ethiopian woman with C3 HIV (AIDS-defining illness = KS, current CD4 981 HIV RNA undetectable on Atripla) presents with fevers of 6 months duration, weight loss of 15 kg, fatigue • Exam reveals diffuse lymphadenopathy, hepatosplenomegaly • Complete blood count reveals pancytopenia

  40. Case 6 – CT Scan of Abdomen Showing Massive Splenomegaly and Lymphadenopathy

  41. Reduction in all types of NHL is not uniform Those associated with EBV show the greatest decline NHL in the HAART Era JNCI 2000; 92:1827 and Eltom MA, et al. JNCI 2002; 94:1204-10

  42. NHL in Uganda: Predictors of Survival • Retrospective study of 228 patients with NHL at UCI from 2004-2007 • Sought to determine the correlates of successful treatment of NHL in Uganda Bateganya M, IAS 2009

  43. NHL in Uganda: Impact of ART Survival Bateganya M, IAS 2009

  44. NHL in Uganda:Impact of Chemotherapy on Survival Bateganya M, IAS 2009

  45. Conclusions about NHL in Uganda • Profound increase in the incidence of NHL since 1992 • Large proportion of NHL patients are HIV-infected, and treatment of HIV is associated with successful treatment of NHL • Majority of patients with NHL present with late-stage disease • Chemotherapy and ART afford a reasonable odds of survival for those who can access optimal treatment courses

  46. Preventing Malignancies in HIV-Infected Patients

  47. 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

  48. Vaccines for Prevention of Viral Associated Malignancies: HPV

  49. 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

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