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HIV and Malignancies

HIV and Malignancies. S. De Wit St Pierre Hospital Brussels. HIV and cancer. AIDS- defining malignancies : Kaposi’s sarcoma Non Hodgkin lymphoma 1985 Cervical cancer 1993 Non AIDS-defining malignancies (NADM) is increasing

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HIV and Malignancies

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  1. HIV and Malignancies S. De Wit St Pierre Hospital Brussels

  2. HIV and cancer • AIDS-definingmalignancies: • Kaposi’ssarcoma • Non Hodgkin lymphoma 1985 • Cervical cancer 1993 • Non AIDS-defining malignancies (NADM) is increasing • Linked with virus HPV (Anal), HBV and HCV (Liver), EBV (HL) • Linked with previous immunodeficiency HHV8 EBV HPV

  3. Background • Before introduction of HAART, ADCs common, including Kaposi’s sarcoma, NHL, and invasive cervical carcinoma • Rate of ADCs significantly increased from early to late pre-HAART era and then significantly decreased following introduction of HAART • Rates of nADCs stable during pre-HAART eras and then significantly increased following introduction of HAART Crum-Cianflone N, et al. AIDS. 2009;23:41-50.

  4. SIR = Standardised Incidence Ratio Nb cases of cancer in the HIV population Expected nb of cases in the general population, calculatedwith local cancer registry incidence =

  5. Cancer Incidence in AIDS Patients SIR=Standardized Incidence Ratios Study of cancer risk in AIDS patients from 1980-2006 (N=372,364) Predominantly male (79%), non-hispanic black (42%), MSM (42%) Median age of 36 years at the onset of AIDS Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  6. CancerMortality in AIDS Patients Population attributableriskamongpeoplewith AIDS in the US Cumulative Incidence (%) Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  7. Increased rates of nADCs. Why ? • Increasing survival of patients with HIV might be associated with an increase of traditional cancer • Aging of the HIV population • Life style • Long-term toxicity of ART ?

  8. HIV associated cancers Possible explanations: • Confounding by shared lifestyle cancer risk factors • A direct effect of HIV, likely through an effect of immune deficiency • Importance: • If immune deficiency is responsible, then reversing immune deficiency might decrease cancer risk

  9. Pathogenesis of NADC • Some are virally-induced cancers, but not all • HIV-tat may transactivate cellular genes or proto-oncogenes, inhibit tumor suppressor genes • Microsatellite alterations (MA) due to genetic instability in HIV (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1 • Increase susceptibility to effects of carcinogens (tobacco) • Population differences based on genetics and exposure to carcinogens • Decreased immune surveillance 1Wistuba, AIDS 1999;13:415-26

  10. HIV & Cancers Role of immune deficiency ? Cancer rate should also be increased in other immunosuppressive disorders

  11. Infection-related cancers Grulich et al. Lancet, 2007, 370, 59–

  12. Grulich et al. Lancet, 2007, 370, 59–

  13. Common epithelial cancers Grulich et al. Lancet, 2007, 370, 59–

  14. Cancers in HIV and transplant patients • The range of cancers occurring at increased rates is strikingly similar in the two groups • Mostly those known or suspected to be caused by infective agents • Impact of immunodeficiency on these cancers

  15. CD4 and risk of liver cancer Clifford and Franceschi, Future Oncology 2009

  16. Current CD4 count and death from cancer D:A:D study group AIDS 2008, 22:2143–

  17. Characteristics of cancer immune control • CD4 cell count • CTL function • NK • Immune memory Central/effector memory • Level of immune activation: • PD-1, IL-10, Treg • Immune system on pre-cancerous lesions

  18. Cancer Incidence in AIDS Patients SIR=Standardized Incidence Ratios Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  19. Anogenital Cancers • Invasive cervical carcinoma • Considered an AIDS-defining condition • Anal cancer1 • Not AIDS defining but very common • HPV involvement1-2 • Both derive from premalignant dysplastic lesions due to HPV • Most oncogenic strains: 16, 18, 31, 33, 35, 45 • Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia 1Phelps RM, et al. Int J Cancer. 2001;94:753-757. 2Martin F, et al. Sex Transm Infect. 2001;77:327-331.

  20. HPV-induced cancer • Cervix • Vulva • Vagina • Anal • Oro-pharyngal • Penis 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82

  21. The Natural History of HPV Infection and Cervical Cancer HIV- HIV+ Persistent HPV 5-10% 20-40% Cervical cancer x 3-11 Vulva & vagina cancer x 4-10 Schiffman, M. et al. N Engl J Med 2005;353:2101-2104

  22. Infection withoncogenic HPV in HIV women • Prevalenceishigher :20-40% (vs.5-10%) • Multiplegenotypes: 40 % (vs. 12% ) • New infection? Reactivation of latent infection • Linkedwithyoungerage, lower CD4 and higher HIV VL Paleksky. J Natl Cancer Inst 1999 Strickler. Journal of the National Cancer 2005

  23. D Konopnicki, Y Manigart, C Gilles, de Marchin J*, M Delforge, F Feoli*, P Barlow, S De Wit and N Clumeck. ECCMID 2011 Saint-Pierre Cohort N=592 Prevalence of HR-HPV infection according to both age and CD4 cell strata (count/µL). (p=0.03, logistic regression)

  24. Cancer screening – EACS EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

  25. Screening in developing countries • Screen-and-treat approach • Randomised , n=6555 with 956 HIV-positive women in South Africa, 35-65 years first screen. Excluded macroscopic lesions (6%) • 3 arm • HPV test and cryotherapy • Visual inspection+ acetowhite detection and cryotherapy • Control : delayed at 6 months • Women had colposcopy and biopsy at Month 6 (all), 12, 24 and 36 (subset) HIV pos HIV neg ≥CIN2 at M36 15% 5% p=.0006 Screen HPV RR M36 0.2 (0.06-0.07) 0.3 (0.02-.005) ps for both Screen VIA 0.51 (0.29-0.89) p=ns Kuhn and al. AIDS 2010

  26. Anal Cancer Invasive cancer SIR 6-8 (in USA, St-Pierre Cohort) Piketty AIDS 2008 132 cases of invasive anal cancer among 86322 HIV-patients Median survival 5 years Recent PreEarly Median CD4 188 227 288 Death due to AC 50% 40% 68.8%

  27. Anal Cancer Incidence • Incidence and risk of invasive anal cancer • Higher in HIV-infected vs age- and gender-matched general population (P < .001) • 60/100,000 PYs (95% CI, 40-89) vs 0.52/100,000 PYs (95% CI, 0.27-0.78) • Nonsignificant difference in pre-HAART and post-HAART erafor HIV-positive individuals (P > .05) • 35/100,000 PYs (95% CI, 15-72) vs 92/100,000 PYs (95% CI, 52-149) • Higher relative risk of anal cancer vs general population in post-HAART era • Pre-HAART era, 67 • Post-HAART era, 176 http://clinicaloptions.com/hiv Bower M, et al. J Acquir Immune Defic Syndr. 2004;37:1563-1565.

  28. Anal Cytology Screening for AIN in HIV-positives Screening Pap Normal ASCUS LSIL HSIL Repeat in 12 months Anoscopy with biopsy LSIL HSIL No lesion seen Treat Treat or follow Chin-Hong PV et al. J Infect Dis. 2004;90:2070-2076.

  29. In summary • HPV-induced cancers are not reduced after cART introduction • Screening should be improved for cervical cancer and for anal cancer • Preventive vaccination against HPV should be more extensively studied and applied in HIV patients

  30. Cancer Incidence in AIDS Patients SIR=Standardized Incidence Ratios Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  31. Hodgkin’s Disease • Association with HIV-infection • Hodgkin’s disease: RR: 5 to 30 • Non-Hodgkin’s disease: RR: 24 to 165 • 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% • Early better results with Stanford V and BEACOPP Gerard L, et al. AIDS. 2003;17:81-87.

  32. Risk of Hodgkin lymphoma by CD4 count Clifford and Franceschi, 2009

  33. Cancer Incidence in AIDS Patients SIR=Standardized Incidence Ratios Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  34. LUNG CANCER

  35. Frish 302,834 R yes 4 no Parker 26,181 R yes 6.5 no Grulich 31,616 R yes 3.8 no Dal Maso 60,421 R yes 2.4 no Herida 77,025 P yes 1 yes 2 Bower 8640 R yes 1 yes 8.93 Excess of risk of lung cancer in HIV • Pre-HAART epidemiological studies Author n HIV Study Pre-HAART SIR* Post-HAART SIR* Reviewed in Lavolé, Lung Cancer 2005. *SIR isdefined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age

  36. Excess of risk of lung cancer in HIV • Bias due to difference of smoking habits in HIV ? • risk factors for cardiovascular disease • age 35 to 44 years old • HIV patients, n=274 (APROCO cohort) • non HIV-persons, n=1038 (WHO-MONICA project) % of smokers 57 HIV Non HIV 33 Savès, CID 2003

  37. SIR = 2.5 Excess of risk of lung cancer in HIV • Bias due to difference of smoking habits in HIV • expectednumber of LC in the general population if 100 % of the personsweresmokers 40 40 SIR = 6.5 30 30 LC observed in HIV Number of LC Number of LC 20 20 LC expected in HIV 10 10 0 0 unknown % of smokers 100 % of smokers Parker, Chest 1998

  38. Excess of risk of lung cancer in HIV • Hypothesies for causal factors… • increased frequency of smoking in HIV population, but intensity and duration not different • HIV status seems probable, but the mechanisms remain unknown : • degree of immune deficiency • duration of immune deficiency • oncogenic role of HIV per se • other oncogenic virus • role of HAART Cadranel, Respiration 1999; Bower, AIDS 2004

  39. Normal Hyperplasia Metaplasia Dysplasia Carcinoma Excess of risk, which mechanisms Smoking + HIV + ID + HAART… 3p LOH, microsatellite alterations 9p21 LOH telomeraseupregulation, MYC over expression 8p21-23 LOH neoangiogenesis, loss of FHIT, P53 mutations, aneuploidy, methylation 5q21 APC-MCC LOH, K-ras 12 mutation Increase of genomic instability ? Wistuba, JAMA 1997

  40. Lung Cancer • Most frequent NADC in HAART era • Incidence 2-4 fold higher than general population • SIRS between 2 and 3 and stable over time • Diagnosed at younger age with advanced disease and primarily in smokers • Adenocarcinoma is most frequent sub-type • No clear screening strategy • No argument to treat differently than non-HIV infected patients

  41. Cancer Incidence in AIDS Patients SIR=Standardized Incidence Ratios Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  42. Hepatocellular Carcinoma • Linked to coinfection by hepatitis B and C viruses • No clear difference between HAART users and non-users • Estimated to be 7 times more frequent than in general population • Optimal treatment similar to general population

  43. Breast cancer • No higher incidence in HIV-positive women • There mightevenbe a lower incidence: • Significantdecreasewasrecorded in Tanzaniafollowing HIV epidemics. Amir. J Natl Med Assoc2000 • Significantdecrease in relative risk (observed cases/expected cases based incidence in general population ). Frisch. JAMA 2001

  44. Whybreast cancer couldbelessfrequent in HIV women? • Reduced incidence is also found in other immunosuppressed patients Steward. Lancet 1995 • Suggesting that physiological immune response is a facilitating factor in breast carcinogenesis

  45. Why breast cancer could be less frequent in HIV women? • Hormone production is reduced in HIV: oestradiol or testosterone • Body composition change with HAART (waist gain)…and the USA obesity epidemics

  46. Why breast cancer could be less frequent in HIV women? • CXCR4-tropic HIV is protective against breast cancer because • In vitro: this receptor is highly expressed by tumor cells and CXCR4 HIV induces tumor cells apoptosis Endo M. Curr HIV Res 2008 • In vivo : decreased incidence of breast cancer when compared to CCR5 HIV-infected patients Hessol N . PloS ONE Dec 2010. vol 5;12:e14349. • Ritonavir has been studied in preclinical trials for its activity against breast cancer growth

  47. Cancer screening – EACS EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

  48. Other Malignancies • Non-melanomatous skin cancer • Conjunctival cancer • Sarcoma • Melanoma • Germ cell tumors • Other hematopoietic neoplasms including myeloma and leukemia • Many present with advanced disease at diagnosis

  49. HAART and chemotherapy • Many patients will receive HAART and chemotherapy concurrently with high likelihood of drug interactions • Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of cytochrome P450 system (CYP) • Many anti-neoplastic drugs also metabolized by CYP system leading to either drug accumulation and possible toxicity or decreased efficacy • Paclitaxel and docetaxel • Vinca alkaloids

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