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Slide 1 - HIV & CERVICAL CANCER M MOODLEY Gynaecology Oncology Nelson R Mandela School of Medicine, Durban, South Africa
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Slide 3 - 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
Slide 4 - 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?
Slide 5 - 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
Slide 6 - 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.
Slide 7 - Relationship between HPV & HIV 3 major studies: New York cervical Disease study (NYCDS) Women’s Interagency HIV study (WIHS) HIV Epidemiology Research Study (HERS)
Slide 8 - 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)
Slide 9 - Relationship between HPV & HIV WIHS & HERS: showed similar pattern
Slide 10 - 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
Slide 11 - 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
Slide 12 - 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%
Slide 13 - 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
Slide 14 - 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
Slide 15 - 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
Slide 16 - 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
Slide 17 - 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”
Slide 18 - Mechanisms HIV induced HPV related diseases Biology of HPV in HPV Adv Dent Res 2006:99-105 Palefsky J
Slide 19 - 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)
Slide 20 - What is the prevalence HIV amongst ICC? Gichangi 2002: 31% Lomalisa 2000: 7.2% Moodley 2001: 21%
Slide 21 - 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)
Slide 22 - 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
Slide 23 - Repeat study 2003 Moodley et al 2003 IJGC
Slide 24 - ICC:HIV (+) KwaZuluNatal South Africa 2003
Slide 25 - ICC:HIV KwaZulu Natal South Africa
Slide 26 - ICC: HIV KwaZuluNatal, South Africa 1999 2003 No 672 271
Slide 27 - 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”.
Slide 28 - Management Cancer cervix Bloods – FBC, UE, CD4 Radiological – CXR, US abdomen Staging Rx depends on: General medical health Stage CD4
Slide 29 - 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
Slide 30 - 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)
Slide 31 - 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
Slide 32 - 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
Slide 33 - 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)
Slide 34 - 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
Slide 35 - 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
Slide 36 - Surgery early stage Moodley M IJGC 2007 Radical hysterectomy LND early stage cervical cancer
Slide 37 - 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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