1. Anal Human Papillomavirus Infection in HIV-Infected Men Who Have Sex With Men (MSM) and Men Who Have Sex with Women (MSW) in the SUN Study
John T. Brooks1, Pragna Patel1, Erna Milu Kojic2,
Lois Conley1, Tim Bush1, Elizabeth Unger1,
Teresa Darragh3, Keith Henry4, John Hammer5,
Turner Overton6, Joel Palefsky3, Susan Cu-Uvin1
1. CDC, Atlanta GA
2. The Miriam Hospital, Providence RI
3. UCSF School of Medicine, San Francisco CA
4. Hennepin County Medical Center, Minneapolis MN
5. Rose Medical Center, Denver CO
6. Washington University School of Medicine, St. Louis MO

2. Background Anal cancer incidence increased among HIV-infected men
Anal human papillomavirus (HPV) infection
Immunosuppression
Need for effective anal cancer screening algorithms
Considerable interest in “anal Pap smear” evaluation
Existing data inadequate to inform guidelines
No randomized controlled clinical trials

3. Objectives
1) Describe prevalence of anal HPV within a contemporary cohort of HIV-infected men
Men who have sex with men (MSM)
Men who have sex with women (MSW)
2) Describe the utility of anal HPV testing to detect the presence of anal cytopathology in these men
HPV screening 
anal cytology  high resolution anoscopy

4. Methods – Study Population
The “SUN” Study*:
- Closed prospective observational cohort study 700 adults
- Natural history of HIV disease in the contemporary era
Minneapolis
Providence
Denver
St. Louis
* Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy

5. Methods – Study Population
Inclusion
either ARV-naïve with CD4 cell count cells/µL
or HAART-experienced with CD4 cell count >100 cells/µL
Enrolled 2004 – 2006
Sexuality (i.e., MSM vs. MSW) defined based on self report on an audio-computer assisted self-interview

6. Methods – Baseline Examination
Clinicians collected two Dacron® anal swabs at enrollment:
HPV screening
Roche Linear Assay  37 types – CDC (E. Unger)
Categorized as high-risk and low-risk types
Cytopathological examination
Bethesda system – UCSF (T. Darragh)

7. Results - Characteristics at Time of Specimen Collection
MSM (N = 410)
MSW (N = 97)
Median age, years (IQR*)
42 ( )
42 ( )
Race/Ethnicity
- White, non-Hispanic (%)
- Black, non-Hispanic (%)
- Hispanic (%)
- Other or Unknown (%)
308 (75)
61 (15)
36 ( 9)
5 ( 1)
33 (34)
46 (47)
14 (14)
4 ( 4)
Proportion prescribed HAART
87%
91%
Undetectable HIV RNA viral load (%)
305 (75)
73 (76)
Median enrolment CD4 cell count†, cells/µL (IQR)
483 ( )
435 ( )
Median nadir CD4 cell count†, cells/µL (IQR)
216 ( )
138 ( )
* IQR = interquartile range (25th to 75th percentile), † n = 503, ‡ n = 497

8. Median number of types (IQR)
Prevalence of Anal HPV by Type among
507 Enrolled Males
MSM (N = 410)
MSW (N = 97) 6
(3-8) 2
(2-4) 3
(2-5) 1
(1-2)
(1-3)
(0-2)
Median number of types (IQR)

9. Association of Anal HPV with Cytopathological Abnormalities, MSM (N = 375)
 HPV detected
Abnormal*
(n = 212)
Normal
(n = 163)
RR**
95% CI†
p-value
Any HPV
210 (99%)
149 (91%)
1.08
1.03 – 1.14
< 0.001
Any high-risk type
200 (94%)
132 (81%)
1.16
1.07 – 1.26
Any type 16 or 18
127 (60%)
64 (39%)
1.53
1.22 – 1.90
> 5 types any HPV
128 (60%)
57 (35%)
1.73
1.36 – 2.19
No HPV
2 ( 1%)
14 ( 9%)
0.92
0.88 – 0.97
* Atypical cells of undetermined significance (ASCUS)
Low-grade squamous intraepithelial lesion (LSIL)
High-grade squamous intraepithelial lesion (HSIL)
**RR = unadjusted relative risk, † 95% CI = 95% confidence interval

10. Association of Anal HPV with Cytopathological Abnormalities, MSW (N = 89)
 HPV detected
Abnormal*
(n = 17)
Normal
(n = 72)
RR**
95% CI†
p-value
Any HPV
17 (100%)
36 (50%)
2.00
1.59 – 2.52
< 0.001
Any high-risk type
15 (88%)
32 (44%)
1.98
1.45 – 2.71
0.001
Any type 16 or 18
9 (53%)
6 ( 8%)
6.35
2.62 – 15.4
> 5 types any HPV
16 (94%)
23 (32%)
9.88
2.85 – 34.4
No HPV
0 ( 0%)
0.50
0.40 – 0.63
* ASCUS, LSIL or HSIL, **RR = unadjusted relative risk, † 95% CI = 95% confidence interval

11. Test Characteristics of Anal HPV Detection
For Any Abnormal Anal Cytology (N = 464)
MSM (N = 375)
MSW (N = 89)
Any abnormal cytology
Any abnormal cytology + - + -
42%
falsely
positive
68%
falsely
positive
210
149 17 36 + +
Any
HPV
Any
HPV
52%
abnormal
19%
abnormal 4%
no further
work-up
40%
no further
work-up 2* 14 36 - -
* both ASCUS
Sensitivity 99
Specificity 9
Positive predictive value 58
Negative predictive value 88
Sensitivity
100
Specificity 50
Positive predictive value 32
Negative predictive value

12. Limitations We did not include severely immunosuppressed patients
We did not conduct simultaneous anoscopy and biopsies to assess correlation of cytology and histology
We did not examine negative predictive value of anal HPV testing for absence of abnormal anal histology

13. Conclusions
Anal HPV was highly prevalent among men in this contemporary cohort of HIV-infected patients
Anal HPV prevalence was significantly greater among MSM than among MSW
The absence of HPV (“negative test”) was highly predictive of the absence of anal cytopathology

14. Recommendations
As anal cancer screening algorithms are developed, the high negative predictive value of HPV testing for the absence of cytopathology we observed deserves further consideration as an initial screening step to exclude men from the need for high resolution anoscopy, especially among groups of men with low to moderate prevalence of anal HPV infection
Need randomized controlled study to examine utility of anal cytological screening for detecting abnormal histology and reducing anal cancer morbidity and mortality

15. SUN Study Sites and STI Laboratories
CDC/ Division of HIV/AIDS Prevention
John T. Brooks, Pragna Patel,
Lois Conley, Tim Bush
Cerner Corporation
Kathleen Wood, Rose Baker,
Cheryl Akridge
Hennepin County Medical Center (Minneapolis)
Keith Henry , Jason Baker, Eddie Gunderson,
Miki Olson, John Hall
Abbott-Northwestern Hospital (Minneapolis)
Frank Rhame, Mark Olson, Eve Austad
Park-Nicollet Institute (Minneapolis)
Hal Martin, Meaghan Morton, Cheri Murch
Emory University
Angie Caliendo
Miriam Hospital (Providence)
Charles Carpenter, Susan Cu-Uvin, Kenneth Mayer,
Milu Kojic, Jennifer Florczyk, Sara Metzler,
Patricia D’Aiello
Washington University School of Medicine (St. Louis)
E. Turner Overton, Lisa Kessels, Mariea Snell,
Dorothea Dedeaux-Turner, Sara Hubert,
Kenneth Griffie
Denver Infectious Disease Consultants (Denver)
John Hammer, Barbara Widick, Tara Kennedy,
Billy Thomas
University of Colorado Health Science Center ( Denver)
Kenneth Lichtenstein, Cheryl Stewart
CDC/ Division of STD Prevention
John Papp, Carol Farshy  

16. Comparison of Testing Characteristics
HPV Testing
Sensitivity
Specificity
Positive predictive value
Negative predictive value
MSM, anal – any* 99 9 58 88
MSW, anal – any*
100 50 40
Women, cervix – HSIL† 82 78 18
Women, cervix – LSIL† 66 91 26 98
* From the present study
† U.S. Preventive Services Task Force. Screening for Cervical Cancer: Recommendations and Rationale.
AHRQ Publication No A. January Agency for Healthcare Research and Quality,
Rockville, MD.

17. MSM, high-risk types
MSM, low-risk types
Non-MSM, high-risk types
Non-MSM, low-risk types

18. Prevalence of Anal HPV by Type among
507 Enrolled Males,
Characteristic
MSM (n = 410)
MSW (n = 97)
p-value
Any HPV types 16 or 18 (%)
209 (51)
17 (18)
<0.001
49%
no HPV 16 or 18
83%
no HPV 16 or 18

19. Prevalence of Anal HPV by CD4 Cell Count among 507 Enrolled Males
MSM (N = 407)
MSW (N = 96)
(n = 24) (n = 195) (n = 198)
CD4 cell count (cells/µL)
(n =11) (n = 51) (n = 34)
P-value for trend: 0.189
P-value for trend: 0.448

20. Table 1. Characteristics of the 507 Enrolled Male Participants, the SUN Study, 2004-2006 (N = 507)
MSM (N = 410)
MSW (N = 97)
Median age, years (IQR*)
42 ( )
42 ( )
Race/Ethnicity
- White, non-Hispanic (%)
- Black, non-Hispanic (%)
- Hispanic (%)
- Other or Unknown (%)
308 (75)
61 (15)
36 ( 9)
5 ( 1)
33 (34)
46 (47)
14 (14)
4 ( 4)
Proportion prescribed HAART
87%
91%
Ever smoked (%)
274 (67)
66 (68)
Current smoker (%)
164 (43)
43 (44)
History of any receptive anal sex (%)
360 (93)
10 (11)
* IQR = interquartile range (25th to 75th percentile), † n = 503, ‡ n = 497

21. Table 2. Prevalence of Anal Human Papillomavirus Infection among Male Participants, the SUN Study, (N = 507)
Characteristic
MSM (n = 410)
MSW (n = 97)
p-value
Any HPV (%)
391 (95)
58 (60)
<0.001
Any high-risk HPV types (%)
362 (88)
52 (54)
Any low-risk HPV types (%)
346 (84)
40 (41)
Any HPV types 16 or 18 (%)
209 (51)
17 (18)
Any high-risk types other than HPV 16 or 18 (%)
349 (85)
49 (51)
Any HPV types 6 or 11
166 (40)
15 (15)
Any low-risk types other than HPV 6 or 11 (%)
312 (76)
32 (33)
Median number of types (IQR)
5.5 (3 - 8)
2 (2 - 4)
Median number of high-risk types (IQR)
3 (2 - 5)
1 (1 - 2)
Median number of low-risk types (IQR)
2 (1 - 3)
1 (0 - 2)

22. Methods - Statistical Univariate associations
Chi-square or Fisher’s exact test  categorical variables
Wilcoxon rank sum test  continuous variables