Trends in Malignancies Among HIV-Infected Patients. Roger Bedimo, MD, MS VA North Texas Health Care System UT Southwestern Medical Center

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1 Trends in Malignancies Among HIV-Infected Patients Roger Bedimo, MD, MS VA North Texas Health Care System UT Southwestern Medical Center Denver, April 2011

2 Learning Objectives At the conclusion of this presentation, participants should be better able to: 1. Distinguish changes in the spectrum of cancers among HIV-infected patients in the Highly Active Anti-Retroviral Therapy era 2. Identify risk factors of selected cancers in HIVinfected patients in your practice. 3. Appraise the role of immunodeficiency in the incidence of non-aids-defining cancers. 4. Utilize the management and prognosis of selected non-aids-defining cancers to plan care for affected HIV-infected patients in their practice

3 Which statement is true? 1. The risk of non-aids-defining cancers has substantially decreased in the HAART era. 2. Among patients with AIDS, mortality from non-aids-defining cancers increased in the HAART era. 3. The risk of Hodgkin s lymphoma is higher among patients with lower CD4+ count (<200). 4. Anal Papanicolaou testing can be used to screen for anal dysplasia and anal cancer.

4 All the following are thought to be contributors for the higher incidence of non-aids-defining cancers among HIV-infected patients, except: 1. Increased survival and aging resulting in decrease in fatal opportunistic infections 2. High prevalence of traditional cancer risk factors (i.e. smoking or excessive alcohol) 3. Higher prevalence of viral co-infections (such as HCV and HPV) 4. HIV-induced immunosuppression 5. High viral load 6. The HAART era

5 Outline Role of Malignancies in the Mortality of HIV-Infected Patients Changing Spectrum of Malignancies Among HIV-Infected Patients Trends of AIDS-Defining vs. Non-AIDS- Defining Malignancies Seven Key Facts in non-aids-defining Malignancies Prevention, Management and Prognosis

6 Trends in Morbidity and Mortality: The Changing Face of HIV Disease Increased survival and aging of HIV-infected patients Trends in causes of death among persons with HIV/AIDS in the HAART era

7 Changing Face of HIV/AIDS Epidemic Palella et al., JAIDS Volume 43(1) September 2006 pp 27-34

8 Age Distribution of HIV Infected Veterans In Care Year Number in Care Age <30 Age Age Age Age Age Age >79 Mean Age , % 18.1% 43.3% 28.1% 6.3% 2.1% , % 14.4% 40.7% 33.9% 7.1% 2.6% , % 10.1% 34.3% 39.8% 11.4% 2.6% 0.3% , % 9.0% 32.1% 41.1% 13.2% 2.9% 0.3% , % 8.0% 29.8% 41.3% 16.1% 3.2% 0.4% , % 7.3% 27.6% 40.8% 19.1% 3.3% 0.4% 52.6 Data from: National VA HIV Registry Reports; 2008 and Center for Quality Management Historic Reports 2000, 2002, ; accessed 02/22/10

9 Changing Face of HIV/AIDS Epidemic Median CD4 cont Underlying cause of death in HIV-infected adults: Overall distribution in 2000 (n = 964) and 2005 (n = 1042), and most recent CD4 cell count by cause; Mortalite 2000 and 2005 surveys, France. Lewden; J Acquir Immune Defic Syndr Aug 15;48(5):590-8

10 Simard. Clin Infect Dis Oct 15;51(8):957-62

11 Key Fact #1 While the risk of ADM has declined, the risk of non-adm among HIV-infected patients is increasing in the HAART era.

12 Cancer incidence among people with AIDS in the US ( ) Engels et al., AIDS. Aug ;20(12):

13 Incidence and Types of Cancers in HIV Patients Patel et al., Ann Intern Med. 2008, May 20;148(10):146

14 Incidence and Types of Cancers in HIV Patients Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7; P=0.0004). During the late HAART era, 71% of cancers were NADCs. NADCs were predicted by increasing age and white race (due to skin cancers). Crum-Cianflone et al., AIDS Jan 2;23(1):41-50

15 Key Fact # 2 The risk of non-adm among HIVinfected patients is much higher than that of HIV-uninfected population, even after adjusting for age, gender, and race.

16 Incidence and Types of Cancers in HIV Patients Compared to General Population Patel et al., Ann Intern Med. 2008, May 20;148(10):146

17 Non-AIDS-Defining Malignancies: VA Aging Cohort Study A total of 33,420 HIV+ and 66,840 HIVveterans were followed for a median of 5.1 and 6.4 years respectively. Incidence rates of non-adm per 100,000 person-years were 1260 and 841 among HIV+ and HIV- patients respectively. Compared to HIV-, the incidence rate ratio (IRR) of non-adm in HIV+ was 1.6 (95% CI: ). Bedimo et al., J Acquir Immune Defic Syndr 2009;52:

18 Non-ADM Rates in HIV Patients Compared to Matched Controls Cancer Type Frequency Incidence Rate 1 HIV+ to HIV- IRR 3 (95% CI) HIV+ HIV- HIV+ HIVanal ( ) lung ( ) melanoma ( ) prostate ( ) Hodgkin s ( ) liver ( ) All non-adm ( ) 1 per 100,000 person-years 2 includes all cancers except KS, lymphoma, cervical, skin, and ill-defined 3 Incidence Rate Ratios (IRR) and 95% CI adjusted for age, race, and gender using Poisson models Bedimo et al., J Acquir Immune Defic Syndr 2009;52:

19 Key Fact #3 Many non-adms have not been found to be associated with low CD4 counts

20 AIDS-Defining Malignancies and Degree of Immunosuppression All data was pre-1996 (pre-haart) Linked records from AIDS and cancer registries in 11 US regions ( ) Standardized incidence ratios of Kaposi s sarcoma (258) and Non-Hodgkin s lymphoma (78) increased with level of immunosuppression RR for each fall of 100 CD4 cells = 1.36 & 1.48 resp. Risk of other cancers, including cervical cancer were unrelated to CD4 counts Mbulaiteye et al. JAIDS 2003 Apr 15;32(5):

21 CD4 Count and Risk of AIDS- Defining Malignancies Clifford et al., J Natl Cancer Inst Mar 16;97(6):425-32

22 CD4 Count and Risk of Non- AIDS-Defining Malignancies Clifford et al., J Natl Cancer Inst Mar 16;97(6):425-32

23 Non-ADM Rates in HIV Patients: Impact of Immunosuppression Cancer Type Frequency Incidence Rate 1 HIV+ to HIV- IRR 3 (95% CI) Median CD4 of HIV+ Cancer HIV+ HIV- HIV+ HIV- Yes No P-value anal ( ) <0.001 lung ( ) melanoma ( ) prostate ( ) <.001 Hodgkin s ( ) liver ( ) All non-adm ( ) per 100,000 person-years 2includes all cancers except KS, lymphoma, cervical, skin, and ill-defined 3Incidence Rate Ratios (IRR) and 95% CI adjusted for age, race, and gender using Poisson models Bedimo et al., J Acquir Immune Defic Syndr 2009;52:

24 Incidence of Non-ADM; Impact of HAART & Immunosuppression Reference Comparing HIV+ to HIV- Cancer risk in HIV+ vs. HIV- SIR 1 (95% CI; p) Among HIV Patients Cancer risk in HAART vs. pre-haart SIR 1 (95% CI; p) Cancer risk association with low CD4 Count Int. Coll[5] N/A 3 Unchanged SIR: 0.96 ( ) 2 N/A Clifford [6] Increased SIR: 2.8 ( ) Unchanged No association with CD4 count Mbulaiteye [7] Increased SIR: 2.1 ( ) N/A All data in pre-haart era None RR 4 per drop of 100 CD4 cells 0.92 ( ; p=0.19) Herida [8] Increased SIR: 1.91 ( ) 5 No change SIR: 0.96 for men N/A Frisch [9] Increased SIR: 2.7 ( ) N/A Decreased rate in patients with AIDS diagnosis Bedimo. Curr. HIV/AIDS Rep Aug;5(3):140-9

25 Incidence of Non-ADM; Impact of HAART & Immunosuppression Reference Bedimo [14] Engels [16] Hessol [19] Serraino [22] Bedimo [23] Comparing HIV+ to HIV- Cancer risk in HIV+ vs. HIV- SIR 1 (95% CI; p) N/A Among HIV Patients Cancer risk in HAART vs. pre-haart SIR 1 (95% CI; p) Increased SIR: 3.32 ( ; P<0.0002). Cancer risk association with low CD4 Count Non-ADM had lower nadir CD4 count 72 vs. 126 Increased SIR: 2.0 ( ) 6 Unchanged N/A Increased SIR: 2.3 Increased SIR: 1.9 ( ) Increased SIR: 1.6 ( ) Trend towards increase SIR: 1.43 ( ; p= 0.06) N/A Most data pre-haart N/A N/A N/A Associated with lower median CD4 count 249 vs. 270; p=0.02 Bedimo. Curr. HIV/AIDS Rep Aug;5(3):140-9

26 Non-AIDS-defining Cancers in HIV+ and HIV- Patients 18,890 adult HIV patients, matched with 189,804 HIV negative Kaiser members. Follow-up: 01/96 cancer diagnosis or 12/06 RR compared b/w HIV+ and HIV-; Changes in RRs over time were evaluated for the periods , , and Infection-related cancers: anal cancer, head and neck cancer (often linked to HPV, but also to noninfectious causes such as smoking), liver cancer (HBV & HCV), and Hodgkin's lymphoma (EBV). M. Silverberg. CROI 2009; Abstract 30

27 Key Fact #4 The spectrum of non-adm among HIV-infected patients is somewhat similar to the spectrum of malignancies among recipients of solid-organ transplantation

28 Cancers in HIV Patients vs. Transplant Patients Grulich et al., Lancet 2007;370:59

29 Immune Deficiency Linked to Non-AIDSdefining Cancers with Infectious Causes Infection-related non-aids cancers in HIV+: 220 (29.7 per 10,000 PY); HIV-: 398 (4.4 per 10,000 PY); RR: 6.8. Anal cancer (RR 81.4; P <0.001), Hodgkin's (RR 17.4; P <0.001), and head and neck cancers (RR 2.1; P <0.001). Infection-unrelated rates: HIV+: 36.4; HIV-:30.6 ; RR 1.2 (P = 0.002). HIV positive patients had a lower rate of prostate cancer (RR 0.7; P = 0.007). M. Silverberg. CROI 2009; Abstract 30

30 Key Fact #5 The increased risk of non-adm is not entirely accounted for by higher prevalence of traditional malignancy risk factors among HIV-infected patients

31 Potential Causes of High Rates of Non-AIDS-Defining Malignancies Differences in lifestyle and rates of traditional cancer risk factors among HIV patients (eg. Smoking) HIV, Immune deficiency and Immune activation Chronic B-cell stimulation, Cytokine dysregulation CD4 count almost certainly doesn t explain all effects of HIv on immunological surveillance Oncogenic potential of viral co-infections or HAART? Blattner. Proc Assoc Am Phys 1999;111:563; Ott. Science 1997;275:1481

32 Traditional Cancer Risk Factors in Individuals with HIV/AIDS Higher incidence of smoking among HIV patients lung, head and neck, renal and colon cancers Synergy with HPV for cervical cancer Higher prevalence of virus co-infections: HPV, HBV, HCV, HSV and EBV Cervical, anal, head and neck, liver, Hodgkin s, nasopharyngeal carcinoma Direct and indirect adjustments for some of these risk factors show HIV independently associated with higher risk of non-aidsdefining cancers Chaturvedi. AIDS 2007; 21:207; Engels J Clin Oncol 2006; 24:1383.

33 HIV infection is associated with an increased risk for lung cancer. After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (RR, 3.6; 95% CI, ). Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. Kirk et al., Clin Infect Dis Jul 1;45(1):

34 Lung Cancer Increase Independent of Smoking Kirk et al., Clin Infect Dis Jul 1;45(1):

35 Impact of HAART on Non-AIDS- Defining Malignancies Comparing incidence in pre-haart vs. HAART period Incidence unchanged in most earlier studies Higher incidence in the HAART era reported for Hodgkin s disease, skin, lung, anal and for all Non- ADMs combined Accounting for individual patients HAART use Trend towards higher incidence in users 1 Trend for an increased risk in the ART era, but a lower risk of NADMs for ART users 2 1 Clifford et al., J Natl Cancer Inst Mar 16;97(6): Hessol et al.,j Epidemiol 2007; 165:1143

36 Key Fact #6 The clinical presentation and prognosis of non-adm among HIV-infected patients might be different from that of HIVuninfected patients; some non- ADM show improved prognosis in the HAART era

37 Prognosis of non-adm before and after HAART Historically, non-adm have had poorer outcome in HIV patients (even after immune recovery on antiretrovirals) than in general population Non-ADM prognosis appears to have significantly improved in the HAART era. Best outcomes with HAART + Chemo Non-Small Cell Lung Cancer: Prognosis was worse in HIV than non-hiv patients before HAART Now, similar: Median survival: 4 months Hodgkin s disease: HIV patients have more aggressive disease mixed cellularity or lymphocytic depletion subtype); Also, more associated with EBV Improved prognosis in HAART era, especially with concomitant use of HAART and chemotherapy.

38 Cervical Cancer in HIV Patients Most common HIV-associated cancer among women in some US centers Occurs at younger age; higher rate of recurrence and high mortality Incidence of cervical intra-epithelial neoplasia 4-5 times higher than in non-hiv women with highrisk sexual behavior Degree of immunosuppression predicts occurrence and severity of disease in some series HPV infection prevalence, HPV persistence & more oncogenic HPV types, Palefsky. J Natl Cancer Inst 1999; 91:226.; Denny. Obstet Gynecol 2008; 111:1380

39 Anal Cancer in HIV Patients Incidence much higher in HIV-infected MSM than in heterosexual men or HIV-infected women; Much higher in African-Americans than in Whites (OR: 3.0; CI: ; P.001). Median age: 49 y vs. 63 y in HIV-negative in VA cohort (P.001). In MSM, abnormal anal cytology highly predicative of any anal dysplasia on biopsy ( %, and high-grade anal dysplasia was %). Survival was similar to HIV-negative patients (2- year survival: 77% vs. 75%) Chiao et al., J Clin Oncol 2008; 3: ; Cranston; Int J STD AIDS. 2007;18:77-80.

40 Key Fact #7 There is as yet no solid evidence for HIV-specific cancer prevention guidelines for most non-adms.

41 Reducing the Cancer Risk in HIV Infection Diagnose and treat HIV infection before advanced stage (relationship between cancer risk and CD4 cell count) Customary prevention message re: smoking, alcohol Vaccinate appropriately (HBV, HPV) Screen as recommended, especially with lower CD4 cell count Early referral to oncologist knowledgeable regarding HIV infection

42 Cancer Screening: USPSFT Guidelines Problem Patients 1 Procedure Evidence of benefit Breast cancer Women 40 y Mammography breast cancer mortality Screening interval Additional comments 1-2 years High rate of false + b/w 40 & 50 y; Individualize if >70 y. Cervical cancer Sexually active women Anal cancer Homosexua l men, women Colorectal cancer Prostate cancer Persons yrs Men >50 yrs Papanicolau test Digital rectal exam ± Papanicolau test FOBT, C-scope, Flex Sig, DCBE Digital rectal exam ± PSA cervical cancer mortality Unknown - advocated by some experts colorectal cancer diag. & q 6 mo. If CD4>200 & normal cytology, q 1y. If Pap test abnormal, colposcopy 1-3 years Benefit is marginal; Highres. anuscopy (HRA) if abnormal cytology FOBT q1 Flex q5, C- scope q10 Except if high risk group 2 Pros: early diagnosis Cons: Overtreatment, no cancer-related mortality Controversial 1-3 years No recomm. By USPSTF, but by AUA 1 If CD4<350, discuss screening in context of prognosis, preferences and health goals 2 High risk: 1 st & 2 nd degree relatives (earlier), IBD & Hx of colon Ca (earlier & more freq.)

43 Cervical Dysplasia and Management of Abnormal Pap Smear Results Screening Pap Insufficient data to recommend HPV DNA testing for oncogenic HPV types Normal ASCUS ASC-H LSIL HSIL Repeat in 12 months (if CD4>200), 6 months if CD4<200 Colpscopy with biopsy No lesion seen LSIL HSIL Optimal ablative therapy, role of postablative treatment with topical agents, and timing and method of follow-up, are still largely unknown; American Society for Colposcopy and Cervical Pathology (ASCCP) recommends management similar to non-hiv patients. ; Wright et al., Am J Obstet Gynecol Oct;197(4):

44 Anal Cytology Screening for AIN in HIV-Positives Screening Pap Normal ASCUS LSIL HSIL Repeat in 12 months Anoscopy with biopsy No lesion seen LSIL HSIL Treat or follow Treat Chin-Hong PV et al. J Infect Dis. 2004;90:

45 Conclusions 1. Incidence of non-adm increased in the HAART era 2. Incidence of non-adm higher than in non- HIV pts a. Much higher for infection-related non-adm 3. Spectrum of non-adm similar to transplant recipients 4. Risk of many non-adm not associated with degree of immunosuppression

46 Conclusions 4. Increased risk of non-adm among HIV patients not entirely explained by increased prevalence of risk factors a. Unclear role of long survival, immune activation, HAART, HIV itself 5. Clinical presentation and prognosis of non- ADM different from those among HIVnegative patients 6. No HIV-specific prevention guidelines for most non-adms