AIDS CLINICAL ROUNDS
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinic...
HPV and Anal Dysplasia:
Current Considerations for
Screening and Management
Edward Cachay, M.D., M.A.S.
UCSD Owen Clinic
1...
1. Which of the following is false?
A. Incidence of invasive anal cancer among HIV-infected
patients continues to increase...
Mr. Carrizales is a 40-yo man who was
referred to our clinic for evaluation of
anal pain in November 2010

10/25/2013

Cop...
Mr. Carrizales
- He had been diagnosed with HIV-infection in 2000
and had no prior opportunistic infections.
- Current CD4...
CT scan at time of diagnosis

10/25/2013

Copyright © Edward Cachay MD, MAS.

5
Case continuation
- Intra-operatory findings revealed that the entire right
anal canal was indurated with evidence of a dr...
January 2012: CT at the end of treatment

10/25/2013

Copyright © Edward Cachay MD, MAS.

7
Case continuation:
- Biopsy at the end of treatment showed residual tumor
and the patient underwent an abdominal perineal
...
US Incidence of cervical cancer:
8 / 100,000 (1)

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

Copyright © Edward Cachay MD, MAS.
...
Incidence of invasive anal cancer (IAC) in the general
population

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

Copyrig...
Number of Anal Cancers

450

100

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

400
350

90
80
70

300

60

250

50

200...
Incidence of anal carcinoma in men with
history of anal receptive intercourse ≥
35 / 100,000
This value of anal carcinoma ...
IAC incidence on the HAART era

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

Copyright © Edward Cachay MD, M...
Anal CA among HIV+ MSM at
least twice the incidence
among HIV– MSM

10/25/2013

Copyright © Edward Cachay MD, MAS.

14
IAC Outcomes: the importance of early diagnosis

Bentzen et al. Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. e173e...
Early detection matters:
• Invasive anal cancer stage at detection has
important prognostic value.
• This provides a ratio...
- Anal cancer is similar to cervical cancer in its histology,
location and is associated with oncogenic strains of
Human P...
2. Today, is there any conclusive
evidence of the malignant potential of
anal HSIL?

A. Yes
B. No

10/25/2013

Copyright ©...
Replication cycle of genital HPV
Epithelium

Dead superficial cells laden with virus
L1, L2 genes expressed
Virus amplifie...
HIV interacts with HPV through different
mechanisms:
1. HIV facilitates HPV entrance into mucosal epithelia
2. HIV-induced...
1. HIV-facilitated paracellular penetration of HPV nto
S. Tugizov , 19th International AIDS Conference. 2012 Abstract no. ...
HIV facilitates perpetuation of HPV infection
Antigen processing and presentation by
Langerhans cells
LC taking up and
pro...
Molecular biology of invasive squamous anal cell
carcinoma in HIV negative patients
Chromosomal
instability

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

HPV
per...
Not a hypothesis anymore!

May 2011
10/25/2013

June 2012
Berry JM, 2013 Int J Cancer. Epub ahead of print
Copyright © Edw...
Guidelines regarding screening for anal cancer: a
work in progress
I. 2007: New York became the only state in USA recommen...
Anal cytology at baseline and annually in the
following HIV-infected populations:
A. MSM
B. Any patient with a history of ...
Mr. Tims 33yo HIV+ male with a
PhD in marine oceanography

10/25/2013

Copyright © Edward Cachay MD, MAS.

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 o...
3. What would you recommend?
A. Repeat an anal PAP once he return from Thailand
next spring 2014
B. Repeat another anal PA...
Cumulative proportion of patients
With AIN II and III

Risk factors for anal intraepithelial neoplasia
0.6
0.5

Nadir CD4+...
Considerations when understanding operational
diagnostic characteristics of anal and cervical cytology

Cervix viewed thro...
The ano-rectal canal is a virtual collapsing space
Squamous columnar junction
Right

Dentate line

Posterior

Anterior
Mid...
Overall Reproducibility of Cytologic Diagnosis
(n = 642 Patients)

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

Copyrigh...
Cytology performance depends on extent of
disease
Performance of anal cytology compared with area of disease by high-resol...
Operator Dependence of Screening Performance

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

Copyright © Edward Cachay M...
Anal cytology is slightly less discriminant than cervical
cytology but not inferior

Cachay et al, PLoS One. 2012;7(7):e38...
Meta-analytically estimated cut-point comparison of the joint
sensitivity and specificity of cervical and anal cytology fo...
Cachay et al AIDS Rev. 2013;15:122-33
10/25/2013

Copyright © Edward Cachay MD, MAS.

39
Dynamic process and reinfection is a frequent
Pokomandy et al. JID; 2009; 199:965–73
phenomena
The top part of figure pres...
Ms. Fox is a 45yo caucasian HIV+
female is transferring care from
Birmingham Women’s hospital in
Boston

10/25/2013

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

10/25/2013

Copyright © Edward Cachay MD, MAS.

43
Anal cytology and Anal HPV Test results by participant category
for the 621 HIV-infected participants in the SUN study,
20...
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 in...
High rates of anal dysplasia in HIV-infected men who have sex
with men, women, and heterosexual men
HIV-infected patients ...
10/25/2013

Copyright © Edward Cachay MD, MAS.

47
HPV infection at the cervix, anal canal and oropharynx in
HIV infected women ARV naive from Chennai, India (n=41)
mean age...
Anal cancer screening in women with HIV: The
French study- October 19, 2013
• 171 HIV+ women had cervical & anal evaluatio...
Anal cancer screening may be appropriate for all
women with HIV
Heard et al, Pasteur Institute , Paris , France
14th Europ...
Ms. Fox anal cytology was LSIL and
she is awaiting HRA next month.

10/25/2013

Copyright © Edward Cachay MD, MAS.

51
Mr. White is 53yo HIV+ health
provider referred from Irvine for
anal cancer screening evaluation

10/25/2013

Copyright © ...
Mr. White
• Dx HIV in 1993 and always VL UD on cART, last CD4
was 971
• His PCP has collected yearly anal cytologies since...
5. What is the probability that Mr. White will developed
invasive anal cancer in the next 5-years according to his
baselin...
Is this the right model for progression of anal
dysplasia?

LSIL

10/25/2013

HSIL
or
HGAIN

Copyright © Edward Cachay MD,...
Effect of HAART on AIN unclear
Author
Palefsky et
al.

Date

Nº of
subjects

Location

Study design

Outcome

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

# patients progres...
Issues with prior published studies
• From inclusion criteria: ‘All patient had gross and histologic
evidence of squamous ...
Owen clinic population-based analysis
• 2,804 patients studies between 2001-2012 with
serial anal cytologies
• Patients wi...
Estimated annual progression probabilities to invasive
anal cancer according to baseline cytology results
Time in

Percent...
Among patients with HSIL at baseline HR point
estimates when analyzed as time-varying covariates:
1. Antiretroviral use: H...
Not everyone with baseline HSIL cytology is the
same: the importance of performing a staging HRA
With the information prov...
Severe multifocal disease

Close up SCJ, left posterior quadrant

Coarse punctation on bacground of severe
acetowhitening ...
Current management options for anal dysplasia

Expectant monitoring

Intervention

VS.

10/25/2013

-

5% Fluorouracil cre...
Comparative outcomes of published treatments
large enough for results to be of value

Fox PA, Sex Health 2012; 9:587-92
10...
Only one randomized controlled trial thus far
comparing ablation vs. topical treatments
• One randomized controlled trial ...
Characteristics of study participants

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

Copyright © Edward Cachay M...
Ablation therapy is better than imiquimod or
fluorouracil for the treatment of AIN

Richel et al. Lancet Oncol 2013; 14: 3...
Response to treatment (per protocol) for peri-anal and
intra-anal lesions separately

Richel et al. Lancet Oncol 2013; 14:...
No matter what treatment method is used rate
of recurrences is high
Cumulative recurrence rates

Richel et al. Lancet Onco...
Different studies aimed to address some of the unknown
issues regarding therapy and prevention are on their
way…

Forthcom...
Acknowledgements:
•
•
•
•

Christopher Mathews
Bard Cosman
Wollelaw Agmas
Amy Sitapati

10/25/2013

Copyright © Edward Cac...
Especial tribute to:
Dr. Christopher Mathews-Founder

10/25/2013

Ms. Connie Languido- Heart of the Owen
dysplasia clinic
...
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HPV and Anal Dysplasia: Current Considerations for Screening and Management

  1. 1. AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
  2. 2. 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
  3. 3. 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 Copyright © Edward Cachay MD, MAS. 2
  4. 4. Mr. Carrizales is a 40-yo man who was referred to our clinic for evaluation of anal pain in November 2010 10/25/2013 Copyright © Edward Cachay MD, MAS. 3
  5. 5. 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 Copyright © Edward Cachay MD, MAS. 4
  6. 6. CT scan at time of diagnosis 10/25/2013 Copyright © Edward Cachay MD, MAS. 5
  7. 7. 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 Copyright © Edward Cachay MD, MAS. 6
  8. 8. January 2012: CT at the end of treatment 10/25/2013 Copyright © Edward Cachay MD, MAS. 7
  9. 9. 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 Copyright © Edward Cachay MD, MAS. 8
  10. 10. US Incidence of cervical cancer: 8 / 100,000 (1) (1) QAULTERS ET AL, 1992 10/25/2013 Copyright © Edward Cachay MD, MAS. 9
  11. 11. Incidence of invasive anal cancer (IAC) in the general population Chiao et al. J AIDS 2005;40:451-455 10/25/2013 Copyright © Edward Cachay MD, MAS. 10
  12. 12. 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 Copyright © Edward Cachay MD, MAS. 11
  13. 13. 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 Copyright © Edward Cachay MD, MAS. 12
  14. 14. IAC incidence on the HAART era Piketty et al. J Clin Oncol 2012, 30:4360-4366 10/25/2013 Copyright © Edward Cachay MD, MAS. 13
  15. 15. Anal CA among HIV+ MSM at least twice the incidence among HIV– MSM 10/25/2013 Copyright © Edward Cachay MD, MAS. 14
  16. 16. 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 Copyright © Edward Cachay MD, MAS. 15
  17. 17. 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 Copyright © Edward Cachay MD, MAS. 16
  18. 18. - 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 Copyright © Edward Cachay MD, MAS. 17
  19. 19. 2. Today, is there any conclusive evidence of the malignant potential of anal HSIL? A. Yes B. No 10/25/2013 Copyright © Edward Cachay MD, MAS. 18
  20. 20. 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 Copyright © Edward Cachay MD, MAS. 19
  21. 21. 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 Copyright © Edward Cachay MD, MAS. 20
  22. 22. 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 Copyright © Edward Cachay MD, MAS. 21
  23. 23. 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 Copyright © Edward Cachay MD, MAS. 22
  24. 24. 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 Copyright © Edward Cachay MD, MAS. 23
  25. 25. 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 Copyright © Edward Cachay MD, MAS. 24
  26. 26. Not a hypothesis anymore! May 2011 10/25/2013 June 2012 Berry JM, 2013 Int J Cancer. Epub ahead of print Copyright © Edward Cachay MD, MAS. 25
  27. 27. 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 Copyright © Edward Cachay MD, MAS. 26
  28. 28. 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 Copyright © Edward Cachay MD, MAS. 27
  29. 29. Mr. Tims 33yo HIV+ male with a PhD in marine oceanography 10/25/2013 Copyright © Edward Cachay MD, MAS. 28
  30. 30. 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 Copyright © Edward Cachay MD, MAS. 29
  31. 31. 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 Copyright © Edward Cachay MD, MAS. 30
  32. 32. 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 Copyright © Edward Cachay MD, MAS. 31
  33. 33. Considerations when understanding operational diagnostic characteristics of anal and cervical cytology Cervix viewed through speculum with patient in lithotomy position 10/25/2013 Copyright © Edward Cachay MD, MAS. 32
  34. 34. 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 Copyright © Edward Cachay MD, MAS. 33
  35. 35. Overall Reproducibility of Cytologic Diagnosis (n = 642 Patients) Mathews et al JAIDS 2004;37:1610-5 10/25/2013 Copyright © Edward Cachay MD, MAS. 34
  36. 36. 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 Copyright © Edward Cachay MD, MAS. 35
  37. 37. Operator Dependence of Screening Performance Mathews et al. UCSD Owen Clinic data 10/25/2013 Copyright © Edward Cachay MD, MAS.
  38. 38. Anal cytology is slightly less discriminant than cervical cytology but not inferior Cachay et al, PLoS One. 2012;7(7):e38956 10/25/2013 Copyright © Edward Cachay MD, MAS. 37
  39. 39. 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 Copyright © Edward Cachay MD, MAS. 38
  40. 40. Cachay et al AIDS Rev. 2013;15:122-33 10/25/2013 Copyright © Edward Cachay MD, MAS. 39
  41. 41. 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 per 1000 person-months 10/25/2013 20.4 cleared episodes per 1000 person-months 4.4 new cases per 1000 person-months 26 cleared episodes per 1000 person-months 4.0 new cases per 1000 person-months The lower part of figure shows the cumulative incidence for 3 of the most common HPV types. 40 Copyright © Edward Cachay MD, MAS.
  42. 42. Ms. Fox is a 45yo caucasian HIV+ female is transferring care from Birmingham Women’s hospital in Boston 10/25/2013 Copyright © Edward Cachay MD, MAS. 41
  43. 43. 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 Copyright © Edward Cachay MD, MAS. 42
  44. 44. 4. Would you recommend to perform an anal pap on Ms. Fox? A. Yes B. No 10/25/2013 Copyright © Edward Cachay MD, MAS. 43
  45. 45. 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 Copyright © Edward Cachay MD, MAS. 44
  46. 46. 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 Copyright © Edward Cachay MD, MAS. 45
  47. 47. 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] Copyright © Edward Cachay MD, MAS. 46
  48. 48. 10/25/2013 Copyright © Edward Cachay MD, MAS. 47
  49. 49. 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 Copyright © Edward Cachay MD, MAS. 48
  50. 50. 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 Copyright © Edward Cachay MD, MAS. 49
  51. 51. 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 Copyright © Edward Cachay MD, MAS. cervical high risk HPV 50
  52. 52. Ms. Fox anal cytology was LSIL and she is awaiting HRA next month. 10/25/2013 Copyright © Edward Cachay MD, MAS. 51
  53. 53. Mr. White is 53yo HIV+ health provider referred from Irvine for anal cancer screening evaluation 10/25/2013 Copyright © Edward Cachay MD, MAS. 52
  54. 54. 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 Copyright © Edward Cachay MD, MAS. 53
  55. 55. 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 Copyright © Edward Cachay MD, MAS. 54
  56. 56. Is this the right model for progression of anal dysplasia? LSIL 10/25/2013 HSIL or HGAIN Copyright © Edward Cachay MD, MAS. Invasive anal cancer 55
  57. 57. 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 Prevalence of anal HPV infection and dysplasia Yes Palefsky et al. 2005 357 San Francisco, California Cross sectional Prevalence of anal HPV infection and dysplasia No Conley et al. 2010 621 Denver, Minneapolis, Providence & St Louis Cohort Prevalence of anal HPV infection and dysplasia No Kojic et al. 120 women Denver, Minneapolis, Providence & St Louis Cohort Prevalence of anal HPV infection and dysplasia No 247 Quebec, Canada Cohort Prevalence of anal HPV infection and high grade dysplasia Yes 250 Rotterdam, Netherlands Cross sectional Prevalence of anal HPV infection and dysplasia 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 Copyright © Edward Cachay MD, MAS. 56
  58. 58. 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 Copyright © Edward Cachay MD, MAS. 57
  59. 59. 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 Copyright © Edward Cachay MD, MAS. 58
  60. 60. 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 Copyright © Edward Cachay MD, MAS. 59
  61. 61. 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 Copyright © Edward Cachay MD, MAS. 60
  62. 62. 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 Copyright © Edward Cachay MD, MAS. 61
  63. 63. 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 Copyright © Edward Cachay MD, MAS. 62
  64. 64. Severe multifocal disease Close up SCJ, left posterior quadrant Coarse punctation on bacground of severe acetowhitening and thickening 10/25/2013 Copyright © Edward Cachay MD, MAS. 63
  65. 65. 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 Copyright © Edward Cachay MD, MAS. - Quadrivalent HPV vaccine 64
  66. 66. Comparative outcomes of published treatments large enough for results to be of value Fox PA, Sex Health 2012; 9:587-92 10/25/2013 Copyright © Edward Cachay MD, MAS. 65
  67. 67. 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 Copyright © Edward Cachay MD, MAS. 66
  68. 68. Characteristics of study participants Richel et al. Lancet Oncol 2013; 14: 346–53 10/25/2013 Copyright © Edward Cachay MD, MAS. 67
  69. 69. Ablation therapy is better than imiquimod or fluorouracil for the treatment of AIN Richel et al. Lancet Oncol 2013; 14: 346–53 10/25/2013 Copyright © Edward Cachay MD, MAS. 68
  70. 70. Response to treatment (per protocol) for peri-anal and intra-anal lesions separately Richel et al. Lancet Oncol 2013; 14: 346–53 10/25/2013 Copyright © Edward Cachay MD, MAS. 69
  71. 71. No matter what treatment method is used rate of recurrences is high Cumulative recurrence rates Richel et al. Lancet Oncol 2013; 14: 346–53 10/25/2013 Copyright © Edward Cachay MD, MAS. 70
  72. 72. 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 Copyright © Edward Cachay MD, MAS. 71
  73. 73. Acknowledgements: • • • • Christopher Mathews Bard Cosman Wollelaw Agmas Amy Sitapati 10/25/2013 Copyright © Edward Cachay MD, MAS. 72
  74. 74. Especial tribute to: Dr. Christopher Mathews-Founder 10/25/2013 Ms. Connie Languido- Heart of the Owen dysplasia clinic Copyright © Edward Cachay MD, MAS. 73

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