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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

M MOODLEY

Gynaecology Oncology

Nelson R Mandela School of Medicine, Durban, South Africa


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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


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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?


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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


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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.


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Relationship between HPV & HIV

  • 3 major studies:

    • New York cervical Disease study (NYCDS)

    • Women’s Interagency HIV study (WIHS)

    • HIV Epidemiology Research Study (HERS)


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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)


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Relationship between HPV & HIV

  • WIHS & HERS:

    • showed similar pattern


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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


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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


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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%


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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


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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


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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


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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


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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”


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Mechanisms HIV induced HPV related diseases

  • Biology of HPV in HPV Adv Dent Res 2006:99-105 Palefsky J


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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)


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What is the prevalence HIV amongst ICC?

  • Gichangi 2002: 31%

  • Lomalisa 2000: 7.2%

  • Moodley 2001: 21%


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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)


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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


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Repeat study 2003

  • Moodley et al 2003 IJGC


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ICC:HIV (+) KwaZuluNatal South Africa 2003




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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”.


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Management Cancer cervix

  • Bloods – FBC, UE, CD4

  • Radiological – CXR, US abdomen

  • Staging

  • Rx depends on:

    • General medical health

    • Stage

    • CD4


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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


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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)


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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


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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


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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)


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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


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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


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Surgery early stage

  • Moodley M IJGC 2007

    Radical hysterectomy LND early stage cervical

    cancer


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CONCLUSION

  • Well defined relationship HIV / HPV / SIL

  • No definite relationship HIV and ICC

  • Challenges

    • HIV epidemic

    • ICC epidemic

    • Appropriate Mx ICC in HIV (+)