HPV and Anal Dysplasia: Current Considerations for Screening and Management

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HPV and Anal Dysplasia:
Current Considerations for
Screening and Management
Edward Cachay, M.D., M.A.S.
UCSD Owen Clinic
10/25/2013

Copyright © Edward Cachay MD, MAS.

1

1. Which of the following is false?
A. Incidence of invasive anal cancer among HIV-infected
patients continues to increase despite HAART.
B. There is sufficient evidence to state that the accuracy of anal
cancer screening procedures (cytology and high-resolution
anoscopy directed biopsy) is comparable to the accuracy of
those used in screening for cervical cancer precursors.
C. There is strong is evidence that the outcome of invasive anal
cancer will improve if we treat anal cancer precursors (HSIL
lesions) after screening rather than at the time the patient
presents with symptoms.

10/25/2013


2

Mr. Carrizales is a 40-yo man who was
referred to our clinic for evaluation of
anal pain in November 2010

10/25/2013


3

Mr. Carrizales
- He had been diagnosed with HIV-infection in 2000
and had no prior opportunistic infections.
- Current CD4: 584 and VL <20 on FTC/TDF + raltegravir
- He reported having anal warts surgically removed in
2005.
- On physical examination, there was rectal discharge
and on digital rectal exam a painful soft lump in the
posterior anal canal was palpable.

10/25/2013


4

CT scan at time of diagnosis

10/25/2013


5

Case continuation
- Intra-operatory findings revealed that the entire right
anal canal was indurated with evidence of a draining
right ischioanal abscess.
- Excisional biopsies confirmed a well-differentiated
keratinizing invasive anal cancer (IAC) with positive
margins. Tumor size was >2cm.
- The patient was treated with chemo radiotherapy
complicated by severe disabling radiation proctitis.

10/25/2013


6

January 2012: CT at the end of treatment

10/25/2013


7

Case continuation:
- Biopsy at the end of treatment showed residual tumor
and the patient underwent an abdominal perineal
resection in March 2012.
- He developed entero-vesical fistulae, recurrent
urinary tract infections, bilateral hydronephrosis and
sepsis.
- At the time of his death (August 2013) his CD4 cell
count was 899 and his HIV viral load remained
undetectable.
10/25/2013


8

US Incidence of cervical cancer:
8 / 100,000 (1)

(1) QAULTERS ET AL, 1992
10/25/2013


9

Incidence of invasive anal cancer (IAC) in the general
population

Chiao et al. J AIDS 2005;40:451-455
10/25/2013


10

Number of Anal Cancers

450

100

P trend (counts) < .001
P trend (rates) < .001

400
350

90
80
70

300

60

250

50

200

40

2005

2004

2003

2002

2001

2000

1999

1998

0
1997

0
1996

10

1995

50

1994

20

1993

100

1992

30

1991

150

Incidence Rate per 100,000 person-years

Burden of invasive anal cancer among people living with AIDS in the United States
during 1991–2005.

Shiels M S et al. J Natl Cancer Inst 2011;103:753-762
.

10/25/2013


11

Incidence of anal carcinoma in men with
history of anal receptive intercourse ≥
35 / 100,000
This value of anal carcinoma incidence
is similar to that of cervical CA prior to
routine PAP screening

10/25/2013


12

IAC incidence on the HAART era

Piketty et al. J Clin Oncol 2012, 30:4360-4366
10/25/2013


13

Anal CA among HIV+ MSM at
least twice the incidence
among HIV– MSM

10/25/2013


14

IAC Outcomes: the importance of early diagnosis

Bentzen et al. Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. e173ee180, 2012
10/25/2013


15

Early detection matters:
• Invasive anal cancer stage at detection has
important prognostic value.
• This provides a rationale to screen for early
stage of invasive anal cancer, in addition to
evolving evidence to support screening for IAC
precursor lesions.

10/25/2013


16

- Anal cancer is similar to cervical cancer in its histology,
location and is associated with oncogenic strains of
Human Papillomavirus (HPV).
- HPV infection is associated with the
development of anal squamous intraepithelial
lesions in the anal canal ‘that are thought to
progress throughout time to development of
anal cancer’.

10/25/2013


17

2. Today, is there any conclusive
evidence of the malignant potential of
anal HSIL?

A. Yes
B. No

10/25/2013


18

Replication cycle of genital HPV
Epithelium

Dead superficial cells laden with virus
L1, L2 genes expressed
Virus amplifies to 1000 genomes copies/cell in
non dividing cells
E6,E7,E 1, E2, E5, E5 genes expressed

Virus and cell replicate together
Very low expression of E6,E7,E 1, E2
Virus infects basal epithelia cells at about 10 virus genomes/cell then amplifies to aprox. 50 genomes/cell
E1, E2?E6, E7 genes expressed
10/25/2013


19

HIV interacts with HPV through different
mechanisms:
1. HIV facilitates HPV entrance into mucosal epithelia
2. HIV-induced immunosuppression decreases cellmediated immune response to HPV, facilitating the
development and perpetuation of HPV infection through
establishment of squamous intraepithelial lesions.
3. HIV may facilitate a different HPV-carcinogenic pathway
as evidenced by a higher frequency of HPV-wide induced
genomic instability rather than the chromosomal instability
observed in HIV-negative patients.
10/25/2013


20

1. HIV-facilitated paracellular penetration of HPV nto
S. Tugizov , 19th International AIDS Conference. 2012 Abstract no. THPDA0104

Tat/gp 120/TNFα/INFγ− mediated
disruption of tight junctions

Intact tight junctions

ZO- 1/2/3

ZO- 1/2

ZO- 1/2
ZO- 1/2

Co-internalization of tight junction proteins
and HPV

mucosal epithelium

Occludin

Claudins

Actin

HSPG
Paracellular passage of HPV
10/25/2013


21

HIV facilitates perpetuation of HPV infection
Antigen processing and presentation by
Langerhans cells
LC taking up and
processing Ag

T
T
^

T
^

Stanley M. Vaccine (2006)
S1/16-S1/22

10/25/2013

LC migrating to
lymph node
T
T

T

T
T

T

T

^

T^
T

T

LC presenting Ag
in lymph node to
naïve T cells

T


22

Molecular biology of invasive squamous anal cell
carcinoma in HIV negative patients
Chromosomal
instability

HPV clearance

5q
HPV
infection

17p
HPVDNA
integration

Normal

AIN 1-2

11q

18q

SCCA

AIN -3

Gervaz. Br J Surg. 2006 May;93(5):531-8
10/25/2013


23

Molecular biology of invasive squamous anal cell
carcinoma in HIV positive patients
Microsatellite
instability ??

HPV
persistence

HPV
infection

HPVDNA
integration

Normal

AIN 1-2

11q

AIN -3

SCCA

Gervaz. Br J Surg. 2006 May;93(5):531-8
10/25/2013


24

Not a hypothesis anymore!

May 2011
10/25/2013

June 2012
Berry JM, 2013 Int J Cancer. Epub ahead of print

25

Guidelines regarding screening for anal cancer: a
work in progress
I. 2007: New York became the only state in USA recommending
universal screening for anal cancer in HIV infected individuals1: DRE
II. 2009: European AIDS Clinical Society guidelines recommend anal
screening by Pap smear for certain HIV populations2, but
implementation of this guidance varies according to national
screening recommendations and local resources.

1. New York State Public Health Department Guidelines Neoplastic Complications Of HIV Infection. 2007
2. Lundgren JD et al. European AIDS Clinical Society Guidelines: Prevention and Management of Non-Infectious CoMorbidities in HIV. 2009.
10/25/2013


26

Anal cytology at baseline and annually in the
following HIV-infected populations:
A. MSM
B. Any patient with a history of anogenital condylomas
C. Women with abnormal cervical and/or vulvar histology

10/25/2013


27

Mr. Tims 33yo HIV+ male with a
PhD in marine oceanography

10/25/2013


28

Mr. Tims
• Dx HIV in 2010 , nadir CD4 180 and currently well controlled on cART
( CD4: 350 and VL UD)
• Never OIs and no other comorbidities, except rectal GC from his
recent return from Thailand.
• He has had annual anal cytology tests as depicted below:

2010: No atypical or malignant cells
2012: No atypical or malignant cells
2013: ASCUS
He will return to Thailand in 3 months to continue working in his
professional project.
10/25/2013


29

3. What would you recommend?
A. Repeat an anal PAP once he return from Thailand
next spring 2014
B. Repeat another anal PAP today and decide next
step with results
C. Refer to a high resolution anoscopy to be
performed before he goes to Thailand

10/25/2013


30

Cumulative proportion of patients
With AIN II and III

Risk factors for anal intraepithelial neoplasia
0.6
0.5

Nadir CD4+ levels
HIV +, CD4+ < 200

0.4

HIV +, CD4+ , 200-500

0.3

HIV +, CD4+ > 500

0.2

HIV -

0.1
0
0

1

2
Year

10/25/2013

3

4

Chin-Hong & Palefky. CID 2002;35:1127-1134


31

Considerations when understanding operational
diagnostic characteristics of anal and cervical cytology

Cervix viewed through speculum
with patient in lithotomy position

10/25/2013


32

The ano-rectal canal is a virtual collapsing space
Squamous columnar junction
Right

Dentate line

Posterior

Anterior
Midcanal wall

Left

Copyrights-Patent:
E. Cachay October 2012

Anal verge
10/25/2013


33

Overall Reproducibility of Cytologic Diagnosis
(n = 642 Patients)

Mathews et al JAIDS 2004;37:1610-5
10/25/2013


34

Cytology performance depends on extent of
disease
Performance of anal cytology compared with area of disease by high-resolution anoscopy
Number of quadrants involved
≥ 1 + positive
HPV effect

≥1

≥2

≥3

4

Sensitivity
95% CI

68% (255/376)
63-73

69% (218/315)
64-74

86% (136/158)
80-91

86% (48/56)
74-94

100% (16/16)
79-100

Specificity
95% CI

71% (147/206)
65-77

64% (171/267)
58-70

58% (246/424)
53-63

49% (260/526)
45-54

47% (268/566)
43-52

PPV
95% CI

81% (255/314)
76-85

69% (218/314)
64-74

43% (136/314)
38-49

15% (48/314)
11-20

5% ( 16/314)
3-8

NPV
95% CI

55% (147/268)
49-61

64% (171/268)
58-70

92% (246/268)
88-95

97% (260/268)
94-99

100% (268/268)
99-100

Nathan et al. AIDS 2010, 24:373–379
10/25/2013


35

Operator Dependence of Screening Performance

Mathews et al. UCSD Owen Clinic data
10/25/2013


Anal cytology is slightly less discriminant than cervical
cytology but not inferior

Cachay et al, PLoS One. 2012;7(7):e38956
10/25/2013


37

Meta-analytically estimated cut-point comparison of the joint
sensitivity and specificity of cervical and anal cytology for biopsy
confirmed high grade dysplasia
Sensitivity (SE)
Cytology Cut-Point

Anal

Specificity (SP)

Cervical

Anal

Cervical

SE

(95% CI)

SE

(95% CI)

SP

(95% CI)

SP

(95% CI)

(HSIL or ASC-H) vs. (LSIL,
ASCUS, Normal)1

0.30

(0.19-0.44)

0.63

(0.56-0.69)

0.93

(0.90-0.95)

0.96

(0.95-0.98)

(HSIL or ASC-H, LSIL) vs.
(ASCUS, Normal)2

0.73

(0.62-0.82)

0.80

(0.75-0.85)

0.55

(0.45-0.65)

0.76

(0.66-0.83)

(HSIL or ASC-H, LSIL,
ASCUS) vs. (Normal)3

0.90

(0.76-0.96)

0.91

(0.88-0.94)

0.33

(0.20-0.49)

0.53

(0.40-0.66)

Cachay et al, PLoS One. 2012;7(7):e38956
10/25/2013


38

Cachay et al AIDS Rev. 2013;15:122-33
10/25/2013


39

Dynamic process and reinfection is a frequent
Pokomandy et al. JID; 2009; 199:965–73
phenomena
The top part of figure presents Kaplan-Meier curves depicting infection clearance
patterns for 3 of the most common HPV types.

12.2 cleared episodes
per 1000 person-months

10.8 new cases

10/25/2013

20.4 cleared episodes

4.4 new cases

26 cleared episodes

4.0 new cases

The lower part of figure shows the cumulative incidence for 3 of the most
common HPV types.
40


Ms. Fox is a 45yo caucasian HIV+
female is transferring care from
Birmingham Women’s hospital in
Boston

10/25/2013


41

Ms. Fox
• Dx in 2007 after her husband was found to be HIV+
• On Atripla( CD4: 621 and VL <20 copies/mm3)
• She works as an elementary teacher and recently got married
again. Her second husband is HIV negative.
• She reported having a cervical pap when she was diagnosed
with HIV that showed low grade HPV and a negative colposcopy
evaluation and biopsy. Her subsequent yearly cervical pap have
been ‘negative’.
• She tells you that she has never had anal sex in her life but her
friends talk about ‘Farrah Fawcett’ at her work.

10/25/2013


42

4. Would you recommend to perform
an anal pap on Ms. Fox?
A. Yes
B. No

10/25/2013


43

Anal cytology and Anal HPV Test results by participant category
for the 621 HIV-infected participants in the SUN study,
2004 -2006
Diagnosis

All participants

MSM

Women

MSW

Anal cytology
Negative

336 (54)

165 (44)

97 (65)

74 (80)

ASC-US

79 (13)

52 (14)

20 (13)

7 (8)

ASC-H

17 (3)

12 (3)

3 (2)

2 (2)

149 (24)

116 (31)

25 (17)

8 (9)

40 (6)

34 (9)

5 (3)

1 (1)

Median Nº of HPV genotypes (IQR)

5 (3-8)

6 (4-8)

5 (2-7)

2 (1-4)

Median Nº of high risk HPV
genotypes (IQR)

3 (2-5)

4 (2-6)

3 (1-4)

1.5 (1-2)

Median Nº of low risk HPV
genotypes (IQR)

2 (1-3)

2 (1-3)

2 (1-3)

1 (0-2)

LSIL
HSIL

Adapted from Conley et al, JID 2010; 202: 1567-1576
10/25/2013


44

Men who have sex with men are not the only ones at risk
Anal sexual behavior in the past 30 days by lifetime history of insertive
heterosexual penile-anal sex (N=1,478)
Yes (n=266)
Variable

No (n=1,212)

n

%

n

%

Anal insertive intercourse

266

18

Inserted finger in partner’s anus

151

53

125

10

Received finger in anus

63

24

35

3

Placed mouth on partner’s anus

63

24

49

4

Received mouth on anus

40

15

23

2

__

McBride et al. Journal of Sex Research, (2010) 47: 2, 123 — 136
10/25/2013


45

High rates of anal dysplasia in HIV-infected men who have sex
with men, women, and heterosexual men
HIV-infected patients screen
with anal cytology (n=2075)

556 (27%) W

218 (10%) HM

233 (43%) W

67 (31%) HM

170 (73%) W

1301 (63%) MSM

40 (60%) HM

Abnormal cytology
(ASCUS or greater)

816 (62%) MSM
Underwent high
resolution anoscopy*

518 (63%) MSM

66 (13%)
MSM

452 (87%)
MSM

Benign

AIN
(any degree)

10/25/2013

162 (31%)
MSM
HSIL or
invasive
carcinoma

55(32%)
W

Benign

115(68%)
W

45(26%)
W

AIN
(any degree)

HSIL or
invasive
carcinoma

16 (40%)
HM
Benign

26(60%)
HM

9 (23%)
HM

AIN
(any degree)

HSIL or
invasive
carcinoma

Gaisa M et al AIDS. 2013 Sep 25. [Epub ahead of print]

46

10/25/2013


47

HPV infection at the cervix, anal canal and oropharynx in
HIV infected women ARV naive from Chennai, India (n=41)
mean age: 33 years , 49% were widowed; 66% < than a high school education;
93% reported monogamy; mean age at sexual debut was 18 years .
60%

cervix
Anal canal

50%

Oropharynx

median CD4 count: 425/mm3

40%
30%
20%

10%
0%
Any HPV genotype

Any Oncogenic HPV

HPV 16

L.J. Menezes, 19th International AIDS Conference. Washington 2012. Abstract no. TUPE140
10/25/2013


48

Anal cancer screening in women with HIV: The
French study- October 19, 2013
• 171 HIV+ women had cervical & anal evaluations:
pap & HPV collections.
• Median age was 47.3 years,
• 98% were on cART. Median CD4+: 650 cells/mm3
• 87% had HIV load was < 50 copies/mL

• No prior history of anal receptive sex
Isabelle Heard et al, Pasteur Institute , Paris , France

14th European AIDS Conference, Brussels, 2013, abstract PS6/4.

10/25/2013


49

Anal cancer screening may be appropriate for all
women with HIV
Heard et al, Pasteur Institute , Paris , France
14th European AIDS Conference, Brussels, abstract PS6/4, 2013

65.4% anal cytology
was normal

50.6

50

Percentage

40
30
20

26.9

12.8

10
1.3
HGAIN

10/25/2013

HGCIN

Anal
high risk HPV


cervical
high risk HPV
50

Ms. Fox anal cytology was LSIL and
she is awaiting HRA next month.

10/25/2013


51

Mr. White is 53yo HIV+ health
provider referred from Irvine for
anal cancer screening evaluation

10/25/2013


52

Mr. White
• Dx HIV in 1993 and always VL UD on cART, last CD4
was 971
• His PCP has collected yearly anal cytologies since
2009 and always showed HSIL.
• Patient has a work-sponsored HMO and is worry
about economical burden of copayments for
potential procedures.

10/25/2013


53

5. What is the probability that Mr. White will developed
invasive anal cancer in the next 5-years according to his
baseline anal HSIL result?
1.
2.
3.
4.

2%
10%
20%
35%

10/25/2013


54

Is this the right model for progression of anal
dysplasia?

LSIL

10/25/2013

HSIL
or
HGAIN


Invasive
anal
cancer

55

Effect of HAART on AIN unclear
Author
Palefsky et
al.

Date

Nº of
subjects

Location

Study design

Outcome

Positive effect attributed to
HAART

2001

98

San Francisco,
California

Cohort

Rates of progression and
regression of anal dysplasia

No

Piketty et al. 2004

45

Paris, France

Cross sectional

Prevalence of anal HPV
infection and dysplasia

No

Wilkin et al.

2004

92

New York

Cross sectional


Yes

Palefsky et
al.

2005

357

San Francisco,
California

Cross sectional


No

Conley et al. 2010

621

Denver, Minneapolis,
Providence & St Louis

Cohort


No

Kojic et al.

120
women

Denver, Minneapolis,
Providence & St Louis

Cohort


No

247

Quebec, Canada

Cohort

infection and high grade
dysplasia

Yes

250

Rotterdam,
Netherlands

Cross sectional


Yes

76

Paris, France

Longitudinal,
prospective

Prevalence and Incidence
anal intraepithelial
neoplasia

No

2011

2011
De
Pokomandy
et al.
2012
Van der
Snoek et al
Piketty et al. 2013

Cachay et al AIDS Rev. 2013;15:122-33
10/25/2013


56

Few studies have addressed the rate of
progression from HGAIN to invasive anal cancer
# patients
HGAIN

# patients progress
HGAIN to IAC

Median time to
develop IAC

Median time of
follow-up

Comments

Scholefield
UK-2005

35

3 ( 8.5%)

60m

63m

No HIV patients
6 patients were
immunosuppressed

Watson New
Zealand 2006

55

8 (14.5%)

42m

60m

7 renal transplant
10 immunosuppressed
5 HIV positive

Devaraj B,
USA- 2006

35

3 (8.5%)

16m

32m

UCSD-Dr. Cosman

10/25/2013


57

Issues with prior published studies
• From inclusion criteria: ‘All patient had gross and histologic
evidence of squamous dysplasia of the anal canal and/or anal
margin’.
• These three studies came from small surgical cohorts with
mostly referred symptomatic patients, thus with considerable
potential for referral bias involving patients selected with
more advance disease.
• Unclear effect of prevalence and spectrum bias

10/25/2013


58

Owen clinic population-based analysis
• 2,804 patients studies between 2001-2012 with
serial anal cytologies
• Patients with diagnosed IAC <180 days excluded
• In addition we investigated the effect of time
dependent covariates such as antiretroviral use, HIV
viremia, and smoking status on progression to IAC.
• 23 patients were diagnosed with IAC during study
period.
Cachay et al submitted for publication Oct 17, 2013
10/25/2013


59

Estimated annual progression probabilities to invasive
anal cancer according to baseline cytology results
Time in

Percent developing IAC from baseline < HSIL

Percent developing IAC from baseline HSIL

years

[percentage, (95% Confidence interval)]

[percentage, (95% Confidence interval)]

1

0.09 (0.02 – 0.36)

0.31 (0.04 – 2.21)

2

0.15 (0.05 – 0.45)

0.69 (0.17 – 2.73)

3

0.33 (0.15 – 0.74)

1.09 (0.35 – 3.35)

4

0.48 (0.24 – 0.96)

1.09 (0.35 – 3.35)

5

0.48 (0.24 – 0.96)

1.77 (0.63 – 4.88)

Cachay et al submitted for publication Oct 17, 2013
10/25/2013


60

Among patients with HSIL at baseline HR point
estimates when analyzed as time-varying covariates:
1. Antiretroviral use: HR 0.24 [95% CI: 0.03-2.21], p=0.09.
2. Suppressed HIV viremia (≤ 400 copies/ml):
HR 0.25 [0.05-1.26], p=0.09.
“suggestive of a protective effect but neither
estimate was significant at conventional levels”.

3. Smoking was not predictive of progression to IAC:
HR=0.95 ( 95% CI: 0.17-5.20), p=0.95.
10/25/2013


61

Not everyone with baseline HSIL cytology is the
same: the importance of performing a staging HRA
With the information provided Mr. White agreed to have a “Staging HRA”

Evident macroscopic
changes consistent with
Anal dysplasia of anal
margin

10/25/2013


62

Severe multifocal disease

Close up SCJ, left posterior quadrant

Coarse punctation on bacground of severe
acetowhitening and thickening

10/25/2013


63

Current management options for anal dysplasia

Expectant monitoring

Intervention

VS.

10/25/2013

-

5% Fluorouracil cream
Imiquimod
Trichloroacetic acid
Photodynamic therapy
Topical lopinavir

Immune
modulation

Ablation

Topical
-

Infrared coagulation
Electrosurgey
CO2 laser


-

Quadrivalent
HPV vaccine
64

Comparative outcomes of published treatments
large enough for results to be of value

Fox PA, Sex Health 2012; 9:587-92
10/25/2013


65

Only one randomized controlled trial thus far
comparing ablation vs. topical treatments
• One randomized controlled trial has been finalized and
published so far. It was performed in the Netherlands.
• Patients with histologically confirmed AIN were randomly
assigned to receive either:
A. 16 weeks of imiquimod (three times a week), or
B. 16 weeks of topical fluorouracil (twice a week), or
C. monthly electrocautery for 4 months.
• The primary endpoint was histological resolution of AIN
measured 4 weeks after treatment and AIN recurrence at
week 24, week 48, and week 72 after treatment.
10/25/2013


66

Characteristics of study participants

Richel et al. Lancet Oncol 2013; 14: 346–53
10/25/2013


67

Ablation therapy is better than imiquimod or
fluorouracil for the treatment of AIN

10/25/2013


68

Response to treatment (per protocol) for peri-anal and
intra-anal lesions separately

10/25/2013


69

No matter what treatment method is used rate
of recurrences is high
Cumulative recurrence rates


10/25/2013


70

Different studies aimed to address some of the unknown
issues regarding therapy and prevention are on their
way…

Forthcoming studies where Owen anal dysplasia clinic will be
participating:

• AMC 072: HPV vaccine for HIV+ MSM ≤ 26yo with ≤LSIL
• AMC 076: Infrared coagulation therapy

10/25/2013


71

Acknowledgements:
•
•
•
•

Christopher Mathews
Bard Cosman
Wollelaw Agmas
Amy Sitapati

10/25/2013


72

Especial tribute to:
Dr. Christopher Mathews-Founder

10/25/2013

Ms. Connie Languido- Heart of the Owen
dysplasia clinic


73

HPV and Anal Dysplasia: Current Considerations for Screening and Management

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HPV and Anal Dysplasia: Current Considerations for Screening and Management