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HIV & CERVICAL CANCER

HIV & CERVICAL CANCER. M MOODLEY Gynaecology Oncology Nelson R Mandela School of Medicine, Durban, South Africa. Introduction. Estimated > 40 million adults/children HIV/AIDS 70% sub-Saharan Africa Majority cervical cancer sub-Saharan Africa Cervical cancer screening deficient/inadequate

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HIV & CERVICAL CANCER

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  1. HIV & CERVICAL CANCER M MOODLEY Gynaecology Oncology Nelson R Mandela School of Medicine, Durban, South Africa

  2. Introduction • Estimated > 40 million adults/children HIV/AIDS • 70% sub-Saharan Africa • Majority cervical cancer sub-Saharan Africa • Cervical cancer screening deficient/inadequate • Mortality 50% • 1993 CDC cervical cancer commonest cancer (1.3%) in 16 784 cases AIDS (AIDS-defining) • 2 epidemics

  3. Questions • Are cervical precancerous lesions more common? • Is cervical cancer more common? • Is cervical cancer AIDS-defining? • What is appropriate management cervical cancer in HIV-infected women?

  4. Human Papillomavirus (HPV) • Well established causal link • “Necessary” cause • STI-cancer • HPV essentially all pre/cancers (99%) • 5-40% of all women/men HPV carriers • Majority infections asymptomatic/subclinical

  5. Cervical Cancer Is Essentially Caused by Oncogenic HPV • Infection with oncogenic HPV types is the most significant risk factor in cervical cancer etiology.1 • HPV is a main cause of cervical cancer.2 • Analysis of 932 specimens from women in 22 countries indicated prevalence of HPV DNA in cervical cancers worldwide = 99.7%.2 • Tissue samples were analyzed for HPV DNA by 3 different polymerase chain reaction (PCR)–based assays, and the presence of malignant cells was confirmed in adjacent tissue sections.2 1. Muñoz N, Bosch FX, de Sanjosé, et al. N Engl J Med. 2003;348:518–527. 2. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19.

  6. Relationship between HPV & HIV • 3 major studies: • New York cervical Disease study (NYCDS) • Women’s Interagency HIV study (WIHS) • HIV Epidemiology Research Study (HERS)

  7. Relationship between HPV & HIV • NYCDS: (Sun et al, 1995) • HIV-infected vs control of HIV non-infected women • FFg-up at 6 monthly intervals for 5 yrs • HPV DNA, smear and colposcopy • Enrolment: 60% HPV vs 36% • HPV 16 commonest (18% vs 15%) • HIV: Multiple HPV types • 2yr ffg-up: HPV 16 types detection 45% vs 30% for HPV 18 types (18 & 45)

  8. Relationship between HPV & HIV • WIHS & HERS: • showed similar pattern

  9. Relationship between immunosuppression and HPV DNA detection • General pattern: HPV detection increases with increasing degree of immunosuppression • HERS: • 54% HIV-infected had HPV CD4 >500 vs 75% with CD4 <200 • 31% VL <200 were HPV (+) vs 79% VL >30 000

  10. Natural history HPV in HIV-infected women • NYCDS: Persistent HPV infection 24% vs 4% • HR HPV greater risk persistence • New HPV types in older women: reactivation of HPV types acquired sometime in the past

  11. Relationship between HIV & CIN lesions • General pattern: increasing prevalence of CIN amongst HIV-infected women • Provencher et al, 1988: • 63% CIN vs 5% • Subsequent studies confirmed this trend • Ellerbrock et al,(2000) 36% CIN lesions <200 vs 13% >500 • HERS: 18% vs 5% • NYCDS: • CIN 1: 13% vs 4% • CIN 2/3: 7% vs 1%

  12. Impact HAART on HPV & CIN • What is expected? • Discordant results • Lillo et al, (2002): • no improvement in HPV or CIN lesions with HAART • Heard et al, 1998 • CIN decreased 69% to 53% • subsequent study: rate regression twice as high in HAART • HERS: 0.68 times less likely to have cytological progression and 1.5 times more likely to show progression

  13. Is cervical cancer more common?Developed countries • 1993 CDC: AIDS-defining condition & first year 1.3% AIDS had cervical cancer • 1998 CDC: 10 cases/1000 vs 6/1000 • Fransceschi et al, 1998: RR15.5 (HIV/AIDS) • Dal Maso et al, 2001: • WHO European region • cervical cancer detected in 2.3% of women with AIDS

  14. Is cervical cancer more common? • Dorrucci et al, 2001: • After 1996 with HAART still higher incidence Ca Cx, unlike other cancers • HERS: 871 HIV-infected women 1993 and 2000 5 cases (0 cases HIV non-infected) (p=0.17) • WIHS: 1 case cervical cancer • Regular cytological screening invasive cervical cancer is uncommon

  15. Is cervical cancer more common? • Clear relationship between KS NHL and HIV • HIV cervical cancer conflicting reports • Sentinel hospital surveillance system: • Modest increase 10.4 cases/1000 cf 6.2/1000 • de Sanjose (2007) Spanish women SIR 41.8 • Reports rapidly progressive SIL to ICC

  16. Is cervical cancer more common?Developing countries • Developing countries: Limited data • Gichangi et al, 2002: no increase in cervical cancer despite 3-fold increase in HIV infections • Similar patterns from Zambia and Uganda • Wright et al, 2007: “Unlikely that the average African woman would live long enough to present with symptomatic cancer”

  17. Mechanisms HIV induced HPV related diseases • Biology of HPV in HPV Adv Dent Res 2006:99-105 Palefsky J

  18. Mechanisms • HIV induced immunosuppression • > susceptibility to HPV • Effects of HIV and HPV on mucosal immune response Molecular interactions between HPV & HIV > % of immature Langerhan’s cells (Eur J Gynecol Reprod Biol 2004;11421 – 227)

  19. What is the prevalence HIV amongst ICC? • Gichangi 2002: 31% • Lomalisa 2000: 7.2% • Moodley 2001: 21%

  20. Invasive Cancer: HIV South AfricaKwa ZuluNatal • Prevalence antenatal population • 1990 – HIV 1.6% • 1990 – HIV + cancer cervix: 5% • 1999 – HIV 32.5% vs 21% HIV+ cervical cancer (Moodley IJGC 2001)

  21. ICC:HIV KwaZuluNatal South Africa 1999 • Moodley M IJGC 2001 • 672 cervical cancer cases • Mean ages 55.2 yrs vs 39.8 • 50% HIV (+) between 30 – 40 yr age group • Majority late stage disease • Majority HIV (+) poorly diff.tumors • Majority HIV (-) mod. diff. tumors

  22. Repeat study 2003 • Moodley et al 2003 IJGC

  23. ICC:HIV (+) KwaZuluNatal South Africa 2003

  24. ICC:HIV KwaZulu Natal South Africa

  25. ICC: HIV KwaZuluNatal, South Africa 1999 2003 No 672 271

  26. Cervical Cancer: HIV • “In Africa, no increase in ICC amongst HIV positive women where both HIV and cancer cervix are epidemic ? short lifespan of HIV-positive women in comparison to the 10 years needed to progress from CIN to invasive disease”.

  27. Management Cancer cervix • Bloods – FBC, UE, CD4 • Radiological – CXR, US abdomen • Staging • Rx depends on: • General medical health • Stage • CD4

  28. Management ICC with HIV • Early stage: I - IIa surgery treatment of choice • Late stage IIb - IIIb radical concurrent chemoradiation • Stage IV – Individualise – Palliative XRT or symptomatic Rx depending on performance status • Meticulous follow-up

  29. Does ICC behave differently? • Reports more rapidly progressive disease (Mitchel 1998) • Younger age at presentation: • Moodley et al 2001, Lomalisa et al, 2000, Sekerime 2000 • More advanced stage wrt CD4 counts • Lomalisa et al: CD4 <200 more advanced disease (77% vs 55.8%) • Recurrence rates : up to 88% (Maiman 1997)

  30. Does ICC behave differently? • Shrivastava et al (2005): (outcome XRT) • Compliance poor 24% discontinue Rx • 17% given palliative XRT • 22/42 women completed XRT of which 50% had complete response • Grade III-IV GIT toxicity: 14% • Grade III skin toxicity: 27% Rx delays

  31. HIV & XRT • Gichangi et al, 2006 (Kenya) • 218 patients EBRT • 54% grade III-IV acute toxicity • 7X higher risk multisystem toxicity (skin, GIT, GUT) • HIV infection to be independent risk factor for Rx interruptions • 19% residual tumour 7/12 post EBRT • HIV adverse prognostic factor for Rx outcomes

  32. HIV & XRT • Kigula-Mugambe, 2006 Uganda • Small study: 7 HIV (+) & 29 HIV (-) • Both brachy / teletherapy • Mean CD4 289 • HIV (-): 89%, 62% & 51% • HIV(+): 67%, 40% & 27% • By year 4: survival 0 & 46% (p=0.0001)

  33. Does ICC behave differently? • Maiman JNCI 1998 • Mean time to death: 10 months vs 23 months • Mean CD4 360 • Close monitoring for therapeutic efficacy and toxicity • Surgery early stage- no excess morbidity • Chemo-XRT for late stages • Transient lymphopenia

  34. Management ICC with HIV • Early stage: I - IIa surgery treatment of choice • Late stage IIb - IIIb radical concurrent chemoradiation • Stage IV – Individualise – Palliative XRT or symptomatic Rx depending on performance status • Meticulous follow-up

  35. Surgery early stage • Moodley M IJGC 2007 Radical hysterectomy LND early stage cervical cancer

  36. CONCLUSION • Well defined relationship HIV / HPV / SIL • No definite relationship HIV and ICC • Challenges • HIV epidemic • ICC epidemic • Appropriate Mx ICC in HIV (+)

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