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Cervical Cancer and
AIDS -related malignancies
Dr Masangu Mulongo
IAS Conference, Durban 2016
AIDS-related malignancies
People living with HIV/AIDS have a higher risk of developing the
following cancers:
AIDS-defining malignancies:
• Cervical Cancer(HPV)
• Kaposi’s Sarcoma (Human Herpes Virus 8)
• Non-Hodgkin’s Lymphoma( EBV)(Burkitt’s Lymphoma)
Other less common cancers in HIV/AIDS:
• Hodgkin’s Lymphoma
• Anal & Penile Cancer
• Liver Cancer
• Lung cancer
• Testicular cancer
World Incidence of Common Cancers
•
•
•
Globally, Breast Cancer is the leading female cancer….
BUT in the developing world Cervical Cancer is the No. 1 cancer killer in women
High co-morbidity of cervical cancer with HIV
Estimated cervical cancer incidence
worldwide (2012)
GLOBOCAN, 2012
Global Primary Prevention:
HPV Vaccination
Global Secondary Prevention:
Coverage of cervical cancer screening in 57
countries (Gakidou, 2008)
Anatomy of the Cervix
Cause: Human Papillomavirus (HPV)
• Double stranded DNA virus
• Grouped into low and high risk
depending on malignant potential
• Over 130 different genotypes / 40 types
infect genital tract
• Infects both men and women
• Transmitted sexually (in most cases)
• Worldwide types 16/18 most common in
ICC, Southern Africa 16/18 only 40%
• 80% eliminated by immune system within
± 18 months in most cases; 20% persist
Risk Factors for HPV infection
•
•
•
•
•
•
•
Age of first intercourse/early sexual debut
Number of lifetime partners
Current use of oral birth control
Educational level/Poverty/Diet
Smoking
Family history
HIV OVERRIDES ALL OF THESE TRADITIONAL
RISK FACTORS
Natural history of HPV infection
I
N
F
E
C
T
I
O
N
First
Lesion
Incubation
(1–8 months)
Immune
Response
Active Growth
(3–6 months)
About
9 months
Sustained
clinical
remission
Late
Stage
Host
Containment
(3–6 months)
Persistent or
recurrent
disease
Natural history of cervical cancer in HIV
negative patients
~40%
60%
HPV
Infection
20%
Lowgrade
CIN
(CIN 1)
20-30%
Highgrade
CIN
(CIN 2/3)
Invasive
Cancer
Natural history of cervical cancer
10–15 years?
Basement Membrane
CIN 1
CIN 2
CIN 3
Cancer
CERVICAL CANCER : CLINICAL PROGRESSION
Normal
HSIL
(CIN2/3)
ICC
IMMUNOCOMPETENT THIS PROCESS CAN TAKE 15 YEARS
HIV FASTER
Cervical cancer in HIV + women
• The risk of HPV infection – including infection with multiple
hrHPV types – is substantially higher in HIV+ women
• HIV+ women are at 2-5x higher risk of cervical pre-cancer and
cancer
• Prolonged life-expectancy on ART means they now live long
enough to develop and die from cancer than OIs.
• HIV+ women present with cervical cancer at much younger
ages
• Treatment of cervical cancer is also more complicated in HIV+
women, making cure more difficult to achieve
HIV / AIDS and Cervical Dysplasia Prevalence rates –
higher
• USA -16.2% Dysplasia (LSIL 14.1%, HSIL 2.1%)
• 4% Dysplasia in HIV negative Massad et al AIDS 2004 18: 109-113
• Europe-26.5% Dysplasia ( LSIL 19%, HSIL 7.5%) 7.5% in HIV
negative Six etal AIDS 1998 12;(1047-1756)
• Brazil 26.7% Dysplasia (LSIL 21% HSIL 5.7%) personal communication Professor Breatriz
Grinsztejn
• Zambia 76% Dysplasia (HSIL 33% 43% LSIL)Parham et al Gynecol Oncol 103 (101710220
• South Africa 51% Dysplasia (HSIL 18% and 23.5% LSIL) Firnhaber et
al Cancer Causes Control epub 1 Dec 2009 HIV unknown status 26% Dysplasia Conje Int J
Gynaecol Obstet 84:101-108
South Africa --rural areas (unpublished confirmed reports
of 60% HSIL)
HIV positive women have higher rates
of HPV and significant diversity
• Our clinic in Jo’burg (191 women screened)
Over 80% our women screened have an HR type of HPV
Two women had 8 different oncogenic types
Different types also 40% 16 then 56, 66
ZAMBIA- 85% had HR HPV types 52, 58
BRAZIL - 38.6% HR HPV
THAILAND- 51% HR HPV
Types 16 and 18 seen but also 33,35,52,53 and 81
Prevalence of HPV types by cervical disease among 191
HIV-HPV infected women
100%
80%
60%
40%
20%
0%
HPV 16
HPV 18
Normal N=90
HPV 33
HPV 56
HPV 59
HPV 66
AGUS/ASCUS N=14
HSIL N=36
Any HPV Oncogenic Multiple
LSIL N=51
Prevalence of HPV types by CD4 category
100%
80%
60%
40%
20%
0%
HPV 16
HPV 18
HPV 33
<200
HPV 56
HPV 59
HPV 66
200-500
Any HPV Oncogenic Multiple
oncogenic
>500
Progression Rates higher
• Italian group found cervical dysplasia progression
rates in HIV positive women higher OR 3.506 95% CI
(0.816-15.0)
• HPV clearance was seen in 69% HIV negative vs.
22.8% in HIV + women OR 0.33 95% CI (0.163-0.670)
Branca et rnational J STD & Aids 2003 14 (417-425)
• USA group found progression in 20% HIV positive
women vs. 5% HIV negative women in 30 months of
follow up (incidence of 8.3 and 1.8 cases per 100
years P< .001)
Ellerbrook Jama 2000 1031-1037
Regression rates lower
• Same Italian group found dysplasia regressed more
frequently in HIV negative women, more frequently
than HIV positive women: 13.5% vs. 7.9% OR 0.584
95% CI 0.2-1.5)
• Another European group found that 69% of LSIL
regressed in HIV negative women (and HIV positive
women CD>500) vs. 20% regression of LSIL lesions in
HIV positive with CD4 <500
Six etal AIDS 1998 12;(1047-1756)
Condoms
• A study in HIV negative women showed a decrease in the
rate of genital HPV infection from 89.3 per 100 patient-years
at risk, in women reporting inconsistent partner condom use
to 37.8 patient-years at risk, in women reporting 100%
partner condom use
• Consistent use of condoms increases the clearance of HPV
and increases the rate of regression.
Winer N Engl J Med.2006;354:2642-2654.
• Our study in HIV + women who used condoms had a lower
risk of HSILPR=0.7 CI (0.5-0.9) no effect on risk LSIL
Firnhaber et al Cancer
Causes Control epub 1 Dec 2009
Primary Prevention of Cervical Cancer:
HPV Vaccination
Vaccine protects against 70% of CC
Dosage: 0,1ml given at 0, 1 and 6 months
Efficacy of 2 doses: study by Dobson et al ( JAMA) showed
Immunogenicity of 2 doses given to girls 9-13yrs at 0 and 6
Months was as effective against types 16 & 18 as 3 doses
TYPES: - Bivalent (GSK) : 16, 18 HR HPV types (Cervarix)
- Quadrivalent (Merck) : 6, 11, 16, 18 (Gardasil)
- Nanovalent (6, 11,16,18, 31, 33, 45, 52, 58) (Gardasil 9)
ISSUES -Cost (in RLCs)
- Bivalent : R 500-800/ dose x 3doses
- Quadrivalent : R 900+ /dose x 3 doses
- Safety in HIV & Pregnancy
- Safe in HIV : not live attenuated vaccine
- Safe in pregnancy, but not recommended
ELIGIBILITY: - Girls & Boys, 9-26yrs,
Secondary Prevention of Cervical Cancer:
Screening Modalities:
1. The Papanicolaou test ( Pap smear or Pap test)
• is a routine test used to screen for cervical cancer.
• The test looks for abnormal changes in the cells of the cervix that
could indicate a precancerous condition or
cervical cancer.
2. Liquid-based cytology (LBC)
3. VIA/VILI (Visual inspection with acetic acid/ Lugol’s iodine)
• “See & Treat” screening involving the application of vinegar/ dye to
the cervix and identifying an abnormality
4
HPV Testing
• Molecular testing for DNA of HPV
Secondary prevention: Pap smear screening
Visual Inspection of the Cervix- VIA
See and Treat
Place 5% acetic acid or Iodine on the cervix
White areas consider abnormal
Freeze with cryotherapy using N2O or CO2
Guidelines for managing pap smears in HIV (SA HIV
2010)
PAP SMEAR RESULTS
REFERRAL CRITERIA
Normal
Repeat smear in 3 years (S.A.NDoH annual smears)*
LSIL
Repeat smear in 1 year
HSIL
Refer for colposcopy
ASCUS
Manage as LSIL
ASCUS-H
Refer for Colposcopy
Glandular
Refer for endometrial investigations
VIA studies
• VIA has been shown to be at least or even more
sensitive than the Pap smear but not as specific in
several studies in multiple countries ( non HIV)
• A study in India reports an 88% sensitivity and a 78%
specificity for VIA compared with the gold standard of
colposcopy with biopsy.
• One study performed in Nicaragua shows that VIA
detected up to twice as many invasive cancers but
that for every diagnosis, eight false positives were
identified at the referral center.
Comparison of Cervical Cancer screening tests
85%
Screening modality
Sensitivit Specificit
y
y
Visits for
screening and
treatment
• Visual
VIA screening
79%
85%
≥1
VILI screening
91%
85%
≥1
57%
93%
≥3
62%
94%
≥2
85%
• Cytological
Pap screening
• Molecular
HC2 HPV
screening
Definitive Diagnosis of Cervical Cancer:
Colposcopy &Biopsy
• One of the techniques to locate abnormal appearing epithelium
place acetic acid on the cervix
• Direct biopsies to suspicious areas
• Biopsy necessary to establish origin of acetowhite area or
abnormal vessels (mosaic, punctuation)
Treatment
Of pre-cancerous lesions:
Removal abnormal Transformation Zone:
1. Excisional treatment:
• LEEP / LLETZ: Loop electrical excision procedure/ Lagre Loop Electrical
Excision of the TZ
– under colposcopic guidance, outpatient, specific criteria
• Cold knife cone biopsy
2. Ablative treatment:
– Cryotherapy: cryo-necrosis with N2O, specific criteria
Of cancerous lesions:
•
•
•
Hysterectomy
Chemo-radiation
Palliative care
LEEP/LLETZ
Utensils
LEEP /LLETZ
Machine
LEEP/LLETZ PROCEDURE:
LEEP/LLETZ OUTCOME:
Let us prevent another epidemic—
SCREEN/TREAT!
•
•
•
•
Cervical Cancer screening/treatment imperative!
HIV seropositive women are living longer now RLC
Preventable cancer
Beginning to see cancer in women under 40 years of
age
• HIV positive women need screening don’t wait till 30
“Every woman
has the right to
live a life free
from cervical
cancer”
Thank You