HUMAN VACCINES & IMMUNOTHERAPEUTICS

2019, VOL. 15, NOS. 7–8, 1911–1919

https://doi.org/10.1080/21645515.2019.1593083

RESEARCH PAPER

The association between body mass index and anal canal human papillomavirus
prevalence and persistence: the HIM study
Alan G. Nyitraya, Fen Pengb, Rena S. Dayc, Roberto J. Carvalho Da Silvad, Maria Luiza Baggioe, Jorge Salmerónf,g,
Manuel Quiteriog, Martha Abrahamsenh, Eduardo Lazcano-Ponceg, Luisa L. Villai, and Anna R. Giulianoh
a
Clinical Cancer Center and Center for AIDS Intervention Research, Medical College of Wisconsin, Milwaukee, WI, USA; bDepartment of Clinical
Research, Medtronic, Inc, Northridge, CA, USA; cDepartment of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health
Sciences Center School of Public Health at Houston, Houston, TX, USA; dDepartment of STDs, Centro de Referência e Treinamento em DST/AIDS, São
Paulo, Brazil; eCentro de Investigação Translacional em Paulo, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo,
Brazil; fResearch Center on Policies, Population, and Health, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico;
g
Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico; hCenter for Immunization and Infection
Research in Cancer, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; iFaculdade de Medicina, Universidade de São Paulo Department of
Radiology and Oncology, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Brazil

ABSTRACT ARTICLE HISTORY

Background: While receptive anal sex is an established risk factor for anal human papillomavirus (HPV) Received 14 December 2018
infection and squamous cell carcinoma of the anus (SCCA), people with anal HPV infection and SCCA Revised 18 February 2019
commonly report no lifetime receptive anal sex suggesting other factors may also increase risk for anal Accepted 28 February 2019
HPV infection and persistence. Given potential associations between obesity and conditions that may KEYWORDS
cause perianal or anal canal lesions, we hypothesized that body mass index (BMI) was associated with HPV; men; persistence;
HPV infection. epidemiology; BMI;
Methods: Genotyping for 36 HPV types was conducted on anal canal specimens from men, ages 18–70, heterosexual men
from Brazil, Mexico, and the USA. Eligibility included no history of genital warts or HIV. Evaluable
specimens were collected from 328 men having sex with men (MSM) and 1348 men having sex with
women (MSW) who reported no lifetime receptive anal sex. Prevalence of anal HPV infection and six-
month persistence by BMI were estimated in addition to adjusted prevalence ratios for the association
between BMI and HPV infection.
Results: Among MSW, obese men had a higher prevalence of HPV-16 in the anal canal (3.1%), compared
to normal weight men (1.3%) although 95% CI overlapped. Among MSM, prevalence of HPV decreased
with increasing BMI. A similar pattern was observed for persistence. After adjustment for confounders,
obese MSW had 2.4 times higher odds of HPV-16 compared to normal weight men.
Conclusions: BMI may be positively associated with anal HPV (especially HPV-16) among MSW and
negatively associated with anal HPV among MSM which supports continued universal HPV vaccination
programs.

Introduction these types is much higher among men who have sex with
men compared to men who have sex with women.10,11
Squamous cell carcinoma of the anus (SCCA) occurs in men
Persistent HPV infection in the anal canal is a formative
and women who report no receptive anal sex.1 These cases
biological event increasing risk for SCCA. It precedes the devel-
occur within the well-documented increasing incidence of
opment of anal intraepithelial neoplasia 2/3 (AIN 2/3) which is
anal cancer in high-resource countries since the mid-20th
a precursor of SCCA. HPV vaccination, either with Gardasil®
century.2 Much of the increasing incidence of SCCA has
(Merck & Co., Whitehouse Station, NJ USA) which protects
been attributed to the HIV epidemic,3 changing human beha-
against HPV-16, HPV-18, HPV-6, and HPV-11 (4vHPV), or
vior, e.g., an increased number of sexual partners, and
Gardasil 9® (Merck & Co., Whitehouse Station, NJ USA) which
increased cigarette smoking.4–7
protects against the four Gardasil types plus an additional five
SCCA is primarily caused by sexually transmitted human
high-risk HPV types (HPV-31, HPV-33, HPV-45, HPV-52,
papillomavirus (HPV) which is commonly found in the anal
HPV-58) (9vHPV), is known to prevent AIN 2/3. Both
canal of women and men regardless of sexual orientation.8,9
Gardasil and Gardasil 9 are licensed for use in the United States
High-risk HPV genotypes are responsible for the large major-
although Gardasil 9 has supplanted Gardasil.12–14 In addition,
ity of anal cancers. HPV-16, specifically, is responsible for
Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium)
86% of SCCA among HIV-negative persons. Prevalence of

CONTACT Alan G. Nyitray anyitray@mcw.edu Clinical Cancer Center and Center for AIDS Intervention Research, Medical College of Wisconsin, 2071 North
Summit Avenue, Milwaukee, WI 53202, USA
© 2019 Taylor & Francis Group, LLC
1912 A. G. NYITRAY ET AL.
(2vHPV), which protects against HPV-16 and HPV-18, is used in
some countries.15
HPV persistence can occur when the virus enters an epi-
dermal basal cell, a process that requires macro or micro tears
in the epidermis,16 e.g., through receptive anal sex; however,
other sexual behaviors and health conditions may also
increase risk for anal fissures and micro tears including
Crohn’s Disease and low-fiber diets.17–22 In turn, these con-
ditions are also associated with, or an effect of, overweight and
obesity; therefore, we hypothesized overweight and obese
persons were associated with prevalence and persistence of
anal HPV infection due to increased risk of micro and macro
anal epithelial tears.
Results
Among both MSM and MSW, BMI was associated with age
(p < 0.001) with increased BMI among older age groups
(Table 1). Among MSM there were no other characteristics
associated with BMI except duration of relationship with
primary partner and number of male anal sex partners in
the last 3 months. As BMI increased among MSM, they
reported fewer recent sexual partners. For example, among
normal weight MSM, 40.4% of men reported ≥2 male anal sex
partners in the last 3 months while only 18.6% of obese men
reported ≥2 partners. In contrast, among MSW there was no
association between number of female sex partners and BMI.
For example, 24.3% of normal weight MSW reported ≥2
female sex partners in the last 6 months while 19.2% of
obese MSW reported ≥2 female sex partners (p = 0.16).
Among normal weight men, the prevalence of HPV-16 was
much higher among MSM than MSW (11.5%; 95% CI, 7.2%-
17.0% and 1.3%; 95% CI, 0.5%-2.6%, respectively); however,
for obese men, prevalence was more comparable for MSM
and MSW (4.7%; 95% CI, 0.6%-15.8% and 3.1%; 95% CI,
1.3%-5.9%, respectively).
Among MSM, prevalence of anal HPV decreased with
increasing BMI for any HPV type, high-risk types, low-risk
types, and 9vHPV vaccine types although confidence intervals
overlapped (Table 2). Among MSW (Table 3), while over-
weight and obese men had higher prevalence than normal
weight men in 2vHPV, 4vHPV, and 9vHPV vaccine types,
confidence intervals overlapped in all comparisons.
Persistence of an HPV type in the 9vHPV and 4vHPV
vaccine types was substantially higher among MSM compared
with MSW (Figure 1). For 9vHPV and 4vHPV vaccine types,
prevalence estimates for persistence declined among MSM
with increasing BMI (ptrend = 0.01 and 0.07 for 9vHPV and
4vHPV types, respectively) whereas persistence increased with
increasing BMI among MSW BMI (ptrend = 0.17 and 0.04 for
9vHPV and 4vHPV types, respectively).
After controlling for age, city and number of sexual partners
(Table 4), overweight and obese MSW had more than double
the odds of HPV-16 infection compared to normal weight men
(for example, aOR 2.40, 95% CI 0.93–6.15 for overweight MSW
compared to normal weight MSW). In contrast, obese MSM
had approximately one-half the odds of HPV-16 infection
compared to normal weight MSM (for example, aOR 0.52,
95% CI 0.14–2.02 for obese MSM compared to normal weight
MSM). Given the potential for number of sex partners to be in
the causal pathway between BMI and HPV infection, and there-
fore ineligible for inclusion in multivariable analysis, prevalence
ratios were estimated without controlling for sex partners. This
change did not substantially alter prevalence estimates (supple-
mental table).
In mediation analysis among MSW, the number of
female sex partners was not associated with BMI and there-
fore not a potential mediator; however, number of male
anal sex partners was associated with BMI among MSM
(i.e., number of male anal sex partners declined as BMI
increased (Table 1)) indicating that number of sexual part-
ners may be a partial mediator of the association between
BMI and HPV among MSM.
Discussion
We observed a strong positive association between increas-
ing levels of BMI and anal HPV, especially HPV-16, among
MSW and a comparably strong negative association between
increasing levels of BMI and anal among MSM although in
both cases 95% CIs included unity. A similar pattern was
noted for persistence of HPV among both MSM and MSW.
For MSW, as the number of genotypes narrowed from 13
high-risk types, to 9vHPV vaccine types, to 4vHPV vaccine
types and finally HPV-16, the association with overweight
and obese men became stronger.
In this cohort and a second cohort of MSW, we previously
documented a consistent prevalence of HPV infection of
approximately 12% on the mucosal surface of the anal canal
of MSW who report no lifetime sex with men.23,24 Given the
presence of virions, a microtear in the mucosal surface cre-
ated in any manner may provide an opportunity for HPV
infection.25 Hence, the prevalence of anal HPV among men
who acknowledge receptive anal sex is several fold higher
than among men who do not acknowledge receptive anal
sex.9 Indeed, changes in human sexual behavior and the
appearance of HIV likely underpins most, but not all, of the
increased incidence in anal cancer.3,26–28 Nevertheless, men
(and women) who do not acknowledge receptive anal sex
have anal HPV infection and are sometimes diagnosed with
anal squamous cell carcinomas indicating other factors may
also play a role.6,8,29–31
Crohn’s Disease (CD) may facilitate HPV basal cell infection
due to an increased risk of lesions at the perianus or anal
canal.32–34 While earlier efforts did not find an association
between CD and anal cancer,35,36 three recent studies have
found associations between CD and HPV infection and CD
and anal cancer. A cross-sectional study assessed anal canal
HPV infection in 469 gastroenterology female and male patients
including 101 persons with Irritable Bowel Syndrome (IBD). Of
these, 70 patients had CD, 29 had uncreative colitis and 2 per-
sons undetermined colitis. Persons with CD had a higher pre-
valence of high-risk HPV types (30.0%) and HPV-16 (14.0%)
compared to those without CD (p ≤ 0.005). Among CD patients
with perianal involvement (n = 22), one-half had high-risk HPV
types. In contrast, the prevalence of anal HPV among patients
with ulcerative colitis did not differ from those without IBD. In
multivariable analysis, factors associated with anal HPV
 HUMAN VACCINES & IMMUNOTHERAPEUTICS 1913

Table 1. Selected baseline characteristics of men who have sex with men (MSM) and men who have sex with women (MSW) by BMI in the HIM study, No. (%).
MSM (n = 328)a MSW (n = 1348)b
Normal weight
Variable Normal weight (n = 183) Overweight (n = 102) Obese (n = 43) (n = 556) Overweight (n = 531) Obese (n = 261)
Age, y
18–24 51 (27.9) 18 (17.6) 6 (14.0) 217 (39.0) 98 (18.5) 45 (17.2)
25–34 79 (43.2) 32 (31.4) 11 (25.6) 181 (32.6) 164 (30.9) 68 (26.1)
35–44 46 (25.1) 33 (32.4) 20 (46.5) 107 (19.2) 160 (30.1) 85 (32.6)
45–70 7 (3.8) 19 (18.6) 6 (14.0) 51 (9.2) 109 (20.5) 63 (24.1)
Median (range) 29 (18–55) 35 (18–62) 36 (18–61) 28 (18–70) 35 (18–70) 36 (18–70)
City
São Paulo 125 (68.3) 65 (63.7) 29 (67.4) 180 (32.4) 140 (26.4) 56 (21.5)
Cuernavaca 28 (15.3) 22 (21.6) 4 (9.3) 177 (31.8) 231 (43.5) 89 (34.1)
Tampa 30 (16.4) 15 (14.7) 10 (23.3) 199 (35.8) 160 (30.1) 116 (44.4)
Race
White 109 (59.6) 63 (61.8) 25 (58.1) 250 (45.0) 224 (42.2) 110 (42.1)
Black 39 (21.3) 15 (14.7) 10 (23.3) 79 (14.2) 53 (10.0) 46 (17.6)
Other 33 (18.0) 23 (22.5) 8 (18.6) 222 (39.9) 244 (46.0) 105 (40.2)
c
Refuse/Missing 2 (1.1) 1 (1.0) 0 (0.0) 5 (0.9) 10 (1.9) 0 (0.0)
Ethnicity
Hispanic 78 (42.6) 41 (40.2) 11 (25.6) 250 (45.0) 284 (53.5) 113 (43.3)
Non-Hispanic 101 (55.2) 59 (57.8) 32 (74.4) 301 (54.1) 243 (45.8) 145 (55.6)
Refuse/Missing 4 (2.2) 2 (2.0) 0 (0.0) 5 (0.9) 4 (0.8) 3 (1.1)
Duration of relationship with primary sex partner, y
No relationship 87 (47.5) 39 (38.2) 14 (32.6) 125 (22.5) 77 (14.5) 41 (15.7)
<1 39 (21.3) 13 (12.7) 8 (18.6) 126 (22.7) 77 (14.5) 37 (14.2)
1–5 32 (17.5) 21 (20.6) 7 (16.3) 123 (22.1) 120 (22.6) 58 (22.2)
>5 20 (10.9) 26 (25.5) 10 (23.3) 136 (24.5) 213 (40.1) 112 (42.9)
Refuse/Missing 5 (2.7) 3 (2.9) 4 (9.3) 46 (8.3) 44 (8.3) 13 (5.0)
Years of school
<12 31 (16.9) 19 (18.6) 9 (20.9) 105 (18.9) 131 (24.7) 47 (18.0)
12 51 (27.9) 21 (20.6) 13 (30.2) 147 (26.4) 133 (25.0) 53 (20.3)
13–15 47 (25.7) 26 (25.5) 6 (14.0) 156 (28.1) 105 (19.8) 81 (31.0)
≥16 53 (29.0) 36 (35.3) 15 (34.9) 145 (26.1) 162 (30.5) 80 (30.7)
Refuse/Missing 1 (0.5) 0 (0.0) 0 (0.0) 3 (0.5) 0 (0.0) 0 (0.0)
Cigarette smoking status
Never smoker 109 (59.6) 55 (53.9) 25 (58.1) 345 (62.1) 283 (53.3) 133 (51.0)
Former smoker 23 (12.6) 24 (23.5) 10 (23.3) 72 (12.9) 131 (24.7) 78 (29.9)
Current smoker 51 (27.9) 23 (22.5) 8 (18.6) 139 (25.0) 117 (22.0) 50 (19.2)
No. of male anal sex partners in the last 3 mo
0 61 (33.3) 40 (39.2) 21 (48.8) 552 (99.3) 527 (99.2) 256 (98.1)
1 41 (22.4) 27 (26.5) 12 (27.9) 0 (0.0) 0 (0.0) 0 (0.0)
≥2 74 (40.4) 27 (26.5) 8 (18.6) 0 (0.0) 0 (0.0) 0 (0.0)
Refuse/Missing 7 (3.8) 8 (7.8) 2 (4.7) 4 (0.7) 4 (0.8) 5 (1.9)
Median (range) 1 (0–150) 1 (0–150) 0 (0–9) 0 (0–0) 0 (0–0) 0 (0–0)
No. of female sex partners in the last 6 mo
0 115 (62.8) 59 (57.8) 28 (65.1) 158 (28.4) 158 (29.8) 68 (26.1)
1 24 (13.1) 20 (19.6) 6 (14.0) 245 (44.1) 244 (46.0) 139 (53.3)
≥2 36 (19.7) 19 (18.6) 8 (18.6) 135 (24.3) 112 (21.1) 50 (19.2)
Refuse/Missing 8 (4.4) 4 (3.9) 1 (2.3) 18 (3.2) 17 (3.2) 4 (1.5)
Median (range) 0 (0–30) 0 (0–20) 0 (0–4) 1 (0–15) 1 (0–15) 1 (0–7)
a
For MSM, the χ 2 or Fisher’s exact tests P values stratified by BMI were greater than 0.05 for all variables, except for age (P < 0.001), duration of relationship with
primary sex partner (P = 0.02), and number of male anal sex partners in the last 3 months (P = 0.04). Responses that were “Refuse/Missing” were not included in
hypothesis testing.
b
For MSW, the χ 2 or Fisher’s exact tests P values stratified by BMI were less than 0.05 for all variables, except for number of female sex partners in the last 6 month (P
= 0.16).
c
“Other” represents: American Indian, Native Hawaiian, Asian, Mestizo, and more than one race.
d
“Refuse/Missing” were not included in hypothesis testing.

infection included immunosuppressive treatment which may
support the establishment of persistent infection;17 however,
another study of anal dysplasia among persons with IBD
observed no increased dysplasia among immunosuppressed
persons with IBD. In this last study, persons with CD had
increased presence of abnormal anal cytology compared with
non-CD patients with ID.37 Two additional studies observed an
increased risk for SCCA among persons with CD.38,39
As with anal cancer, Crohn’s Disease incidence has
increased in western and developing countries since the
mid-20th century and changes in diets (including the obesity
epidemic) are one environmental factor hypothesized to be
causal for the increase.40,41 Other changes in diets occurring
or accelerating since the mid-20th century, like decreased fiber
consumption and low water intake, may lead to constipation
and the passage of hard stool which, in turn, may also cause
microtears or fissures in the anal canal epithelium;20–22,42
however, we are aware of no data establishing an association
between fiber or water intake and anal HPV infection or
sequelae.
Finally, cigarette smoking, a risk factor for anal cancer, has
also seen dramatically increased use since the early twentieth
century43 and may be an attributable cause of some fraction of
increased anal cancer incidence.
A primary limitation of this study is the lack of other
measures of adiposity. Using only baseline BMI likely mis-
classifies the adiposity of some persons and would not reflect
changes in adiposity over time.44 In addition, although
1914 A. G. NYITRAY ET AL.

Table 2. Prevalence of anal canal HPV infection among men who have sex with men (MSM) by BMI in the HIM study.
No. % (95% CI)
HPV typea Normal weight (n = 183) Overweight (n = 102) Obese (n = 43) Total (n = 328)
Any HPV type 109 59.6 (52.1–66.7) 49 48.0 (38.0–58.2) 17 39.5 (25.0–55.6) 175 53.4 (47.8–58.9)
Any high-risk type 70 38.3 (31.2–45.7) 32 31.4 (22.5–41.3) 10 23.3 (11.8–38.6) 112 34.1 (29.0–39.6)
Any low-risk type 87 47.5 (40.1–55.0) 40 39.2 (29.7–49.4) 12 27.9 (15.3–43.7) 139 42.4 (37.0–47.9)
2vHPV types 32 17.5 (12.3–23.8) 10 9.8 (4.8–17.3) 5 11.6 (3.9–25.1) 47 14.3 (10.7–18.6)
4vHPV types 49 26.8 (20.5–33.8) 19 18.6 (11.6–27.6) 7 16.3 (6.8–30.7) 75 22.9 (18.4–27.8)
9vHPV types 64 35.0 (28.1–42.4) 25 24.5 (16.5–34.0) 8 18.6 (8.4–33.4) 97 29.6 (24.7–34.8)
High-risk types
16 21 11.5 (7.2–17.0) 7 6.9 (2.8–13.6) 2 4.7 (0.6–15.8) 30 9.1 (6.3–12.8)
18 12 6.6 (3.4–11.2) 3 2.9 (0.6–8.4) 3 7.0 (1.5–19.1) 18 5.5 (3.3–8.5)
31 4 2.2 (0.6–5.5) 1 1.0 (0.0–5.3) 0 0.0 (0.0–8.2) 5 1.5 (0.5–3.5)
33 6 3.3 (1.2–7.0) 1 1.0 (0.0–5.3) 0 0.0 (0.0–8.2) 7 2.1 (0.9–4.3)
45 13 7.1 (3.8–11.8) 3 2.9 (0.6–8.4) 0 0.0 (0.0–8.2) 16 4.9 (2.8–7.8)
51 10 5.5 (2.7–9.8) 7 6.9 (2.8–13.6) 3 7.0 (1.5–19.1) 20 6.1 (3.8–9.3)
52 1 0.5 (0.0–3.0) 8 7.8 (3.4–14.9) 1 2.3 (0.1–12.3) 10 3.0 (1.5–5.5)
58 4 2.2 (0.6–5.5) 2 2.0 (0.2–6.9) 1 2.3 (0.1–12.3) 7 2.1 (0.9–4.3)
Low-risk types
6 19 10.4 (6.4–15.7) 7 6.9 (2.8–13.6) 3 7.0 (1.5–19.1) 29 8.8 (6.0–12.5)
11 3 1.6 (0.3–4.7) 3 2.9 (0.6–8.4) 1 2.3 (0.1–12.3) 7 2.1 (0.9–4.3)
53 14 7.7 (4.2–12.5) 10 9.8 (4.8–17.3) 4 9.3 (2.6–22.1) 28 8.5 (5.7–12.1)
61 10 5.5 (2.7–9.8) 6 5.9 (2.2–12.4) 1 2.3 (0.1–12.3) 17 5.2 (3.0–8.2)
62 12 6.6 (3.4–11.2) 3 2.9 (0.6–8.4) 0 0.0 (0.0–8.2) 15 4.6 (2.6–7.4)
70 8 4.4 (1.9–8.4) 1 1.0 (0.0–5.3) 5 11.6 (3.9–25.1) 14 4.3 (2.4–7.1)
73 5 2.7 (0.9–6.3) 8 7.8 (3.4–14.9) 1 2.3 (0.1–12.3) 14 4.3 (2.4–7.1)
81 10 5.5 (2.7–9.8) 5 4.9 (1.6–11.1) 1 2.3 (0.1–12.3) 16 4.9 (2.8–7.8)
82 5 2.7 (0.9–6.3) 0 0.0 (0.0–3.6) 3 7.0 (1.5–19.1) 8 2.4 (1.1–4.7)
84 23 12.6 (8.1–18.3) 7 6.9 (2.8–13.6) 3 7.0 (1.5–19.1) 33 10.1 (7.0–13.8)
89 12 6.6 (3.4–11.2) 5 4.9 (1.6–11.1) 1 2.3 (0.1–12.3) 18 5.5 (3.3–8.5)
a
HPV genotypes shown are those in the 9vHPV vaccine and those with prevalence of  5.0% for any BMI category.

Table 3. Prevalence of anal canal HPV infection among men who have sex with women (MSW) by BMI in the HIM study.
No. % (95% CI)
HPV typea Normal weight (n = 556) Overweight (n = 531) Obese (n = 261) Total (n = 1348)
Any HPV type 66 11.9 (9.3–14.9) 73;13.7 (10.9–17.0) 28 10.7 (7.2–15.1) 167 12.4 (10.7–14.3)
Any high-risk type 38 6.8 (4.9–9.3) 40 7.5 (5.4–10.1) 15 5.7 (3.3–9.3) 93 6.9 (5.6–8.4)
Any low-risk type 39 7.0 (5.0–9.5) 48 9.0 (6.7–11.8) 16 6.1 (3.5–9.8) 103 7.6 (6.3–9.2)
2vHPV types 8 1.4 (0.6–2.8) 15 2.8 (1.6–4.6) 8 3.1 (1.3–5.9) 31 2.3 (1.6–3.2)
4vHPV types 13 2.3 (1.3–4.0) 23 4.3 (2.8–6.4) 13 5.0 (2.7–8.4) 49 3.6 (2.7–4.8)
9vHPV types 22 4.0 (2.5–5.9) 33 6.2 (4.3–8.6) 15 5.7 (3.3–9.3) 70 5.2 (4.1–6.5)
High-risk types
16 7 1.3 (0.5–2.6) 14 2.6 (1.4–4.4) 8 3.1 (1.3–5.9) 29 2.2 (1.4–3.1)
18 1 0.2 (0.0–1.0) 1 0.2 (0.0–1.0) 0 0.0 (0.0–1.4) 2 0.1 (0.0–0.5)
31 0 0.0 (0.0–0.7) 4 0.8 (0.2–1.9) 0 0.0 (0.0–1.4) 4 0.3 (0.1–0.8)
33 2 0.4 (0.0–1.3) 0 0.0 (0.0–0.7) 0 0.0 (0.0–1.4) 2 0.1 (0.0–0.5)
45 3 0.5 (0.1–1.6) 2 0.4 (0.0–1.4) 0 0.0 (0.0–1.4) 5 0.4 (0.1–0.9)
52 3 0.5 (0.1–1.6) 2 0.4 (0.0–1.4) 0 0.0 (0.0–1.4) 5 0.4 (0.1–0.9)
58 2 0.4 (0.0–1.3) 2 0.4 (0.0–1.4) 2 0.8 (0.1–2.7) 6 0.4 (0.2–1.0)
Low-risk types
6 6 1.1 (0.4–2.3) 10 1.9 (0.9–3.4) 4 1.5 (0.4–3.9) 20 1.5 (0.9–2.3)
11 0 0.0 (0.0–0.7) 0 0.0 (0.0–0.7) 1 0.4 (0.0–2.1) 1 0.1 (0.0–0.4)
a
HPV genotypes shown are those in the 9vHPV vaccine and those with prevalence of  5.0% for any BMI category.

clinicians were well trained to collect exfoliated cells from the
anal canal and avoid the perianal region, some collection of
perianal exfoliated cells in possible. It is also possible that
a definition of persistence of six months classifies some infec-
tions as persistent even though they may resolve or become
undetectable in subsequent months.45 It is possible that we
may have misclassified some of the men’s sexual behavior.
Anal sex and same-sex sexual behavior remain highly socially
stigmatized behaviors, and some men avoid acknowledging
them;46 however, we have found the CASI instruments used
in the HIM Study to be highly reliable with men in these 3
cities.47
Among MSM, we observed that as BMI increased the
number of male anal sex partners declined. Similarly, as
BMI increased the prevalence of HPV declined even after
controlling for number of male anal sexual partners. Such
a situation might indicate residual uncontrolled confounding
by number of sex partners among MSM. Number of sexual
partners may also be considered a partial mediator of the
association between BMI and HPV among MSM which sup-
ports its role in a causal network involving the association
between BMI and HPV among MSM but not MSW.
The current study provides limited evidence of increasing
prevalence and persistence of anal canal HPV by BMI among
 HUMAN VACCINES & IMMUNOTHERAPEUTICS 1915

were recruited through a health plan and from factories and the
military. Men in Tampa, Florida were recruited from a university
campus and the general public. MSM were not targeted for
recruitment. All participants consented to the study and received
a nominal incentive for participation. The study was approved by
human subjects committees at each study site.

Figure 1. Prevalence of six-month persistence for 9vHPV and 4vHPV vaccine
types among men who have sex with men (MSM) and men who have sex with
women (MSW) stratified by body mass index (BMI).
persons who report no receptive anal intercourse and no
HIV infection. If obesity increases the risk of HPV persis-
tence at the anal canal, then populations with high rates of
obesity might see increased incidence of anal cancer unless
HPV vaccination programs are broadly implemented and
successful. Given the reach of the global obesity epidemic,
the universal use of HPV vaccination among boys and girls
would be one reasonable preventive strategy.
Materials and methods
Men were recruited in São Paulo, Brazil, Cuernavaca, Mexico,
and Tampa, Florida from June 2005 to September 2009 for the
prospective HPV Infection in Men (HIM) Study, a study of the
natural history of genital HPV. Inclusion criteria included an
age of 18–70 years, no plans to relocate during the 4-year
study, no self-reported history of penile or anal cancer, genital
warts, and no current sexually transmitted infection (STI)
including HIV. Additional details of the study design have
been previously described.48,49
Men were recruited in São Paulo from the general population
through advertisements and from a genitourinary clinic that also
tests for HIV and STIs. Men who went to the clinic because of STI
symptoms or for treatment were excluded. In Cuernavaca, men
Study protocol
A total of 4123 men enrolled in the HIM Study. Follow-up
occurred at 6-month intervals for a total of 4 years. A total of
72 men acknowledged HIV infection after enrollment and
were removed from further analysis (Figure 2). Of the remain-
ing 4051 men, a total of 3661 (90.4%) men returned for at
least the first 6-month follow-up visit. Approximately 93% of
MSM and 81% of MSW consented to the optional collection
of anal canal exfoliated cells at both visits. Those declining
anal canal sampling at either visit were younger (18–30 years
of age), single, never married, MSW, or a Florida resident (all
P < .001) compared to those consenting to sampling. Only
anal canal specimens were included for this analysis.
Men completed an 88-item computer-assisted self-interview
(CASI) at enrollment written in the region’s primary language
(Portuguese, Spanish, or English). The CASI elicited informa-
tion about participant demographics, substance use, and sexual
behaviors. At each follow-up visit, the CASI elicited informa-
tion about a participant’s substance use and sexual behavior
since the prior visit.
At each visit, a study clinician measured the weight (wear-
ing indoor clothing) and height of participants before exam-
ining the men for STI symptoms. For HPV sampling, the
clinician used 3 saline-wetted swabs to collect exfoliated cells
from the penis (coronal sulcus, glans penis, and ventral and
dorsal areas of the shaft) and scrotum. When uncircumcised
men were swabbed for genital HPV, the prepuce was
retracted by the clinician allowing swabbing of the glans
penis and coronal sulcus with subsequent swabbing of the
penile shaft. Then, the clinician used a fourth swab to sample
the anal canal between the anal os and dentate line. Each
swab was placed in its own vial of transport media (STM,
Qiagen, Germany) and stored at – 80°C. First catch urine and
blood were collected to test for Chlamydia trachomatis
(Chlamydia LCx, Abbott Laboratories, Illinois and COBAS

Table 4. Association between BMI and anal HPV prevalence in the human papillomavirus infection in men study adjusted for age, city and number of recent sexual
partners.
Men who have sex with womena
High risk 9vHPV 4vHPV HPV-16
BMI PR aPR 95% CI PR aPR 95% CI PR aPR 95% CI PR aPR 95% CI
Normal 1.0 1.0 – 1.0 1.0 – 1.0 1.0 – 1.0 1.0 –
Overweight 1.10 1.21 0.76–1.93 1.57 1.73 0.98–3.06 1.85 1.97 0.96–4.01 2.09 2.40 0.93–6.15
Obese 0.84 0.95 0.52–1.74 1.45 1.41 0.71–2.79 2.13 1.82 0.82–4.04 2.43 2.23 0.81–6.12
Continuous BMI 1.00 1.01 0.96–1.06 1.03 1.03 0.98–1.08 1.05 1.04 0.98–1.09 1.05 1.03 0.96–1.11
Normal 1.0 1.0 – 1.0 1.0 – 1.0 1.0 – 1.0 1.0 –
Overweight 0.82 0.97 0.69–1.36 0.70 0.82 0.55–1.22 0.70 0.81 0.51–1.29 0.60 0.75 0.33–1.72
Obese 0.61 0.71 0.40–1.26 0.53 0.60 0.31–1.17 0.61 0.69 0.33–1.44 0.41 0.52 0.14–2.02
Continuous BMI 0.96 0.98 0.94–1.01 0.95 0.96 0.92–1.01 0.96 0.97 0.92–1.02 0.91 0.94 0.85–1.04
1916 A. G. NYITRAY ET AL.
Figure 2. Enrollment flow chart.
Amplicor CT/NG Test, Roche Diagnostics, England) and
Herpes simplex virus-2 antibodies (HerpeSelect 2 ELISA
IgG, Focus Diagnostics, California), respectively, at the
enrollment visit and annually thereafter.
HPV analyses
DNA was extracted using the QIAamp Media MDx Kit
(Qiagen, Inc.). The polymerase chain reaction (PCR) consen-
sus primer system (PGMY 09/11) was used to amplify
a fragment of the HPV L1 gene.50 HPV genotyping was
conducted using DNA probes labeled with biotin to detect
36 HPV types (including subtypes).51 Accuracy and potential
contamination were assessed using non-template negative
controls and CaSki DNA positive controls.
In the current analysis, all MSM in the HIM Study who
provided anal canal specimens at the time of consenting and
the six–month visit had anal canal specimens genotyped and
analyzed. Due to funding restrictions, only the first 1626
MSW consenting into the HIM Study who provided anal
canal specimens at both the consenting and the six-month
visits had their specimens genotyped and analyzed. A total of
83% of men had β-globin positive or HPV genotype positive
specimens at both the consenting visit and the six-month visit
and thus were included in analyses.
Statistical analyses
A specimen was considered positive for any anal HPV if it
was positive for ≥1 of 36 genotypes. Specimens were labeled as
high risk if ≥1 of 13 types were detected (16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, and 68)52 regardless of the presence of
other genotypes. Similarly, specimens were labeled as low risk
if any of the remaining 23 types in the Linear Array were
detected regardless of the presence of high-risk types; thus,
prevalence estimates for high-risk and low-risk groups
overlap.
Body mass index (BMI) was calculated from weight and
height measurements at the consenting visit as weight in
kilograms (k)/height (m2). Normal weight was defined as
BMI < 25.0, overweight as 25.0– 29.9 BMI, and obese as
≥30.0 BMI.
Men enrolled in the study were classified as MSM, MSW,
and men having no sex53 solely based upon their answers to
over 20 questions about recent and lifetime penetrative sexual
behavior (vaginal, anal, and oral sex). Recent sexual behavior
was assessed by questions about behavior in the prior 3

months or 6 months, or since the prior study visit. A man was
classified as MSW if he acknowledged sex only with women at
all study visits. A man was classified as MSM if he acknowl-
edged sex with men at any study visit without regard to sex
with women. A total of 1348 MSW and 328 MSM were
available for analysis. Given substantial differences in the
prevalence of HPV infection,9 all analyses were stratified by
MSM and MSW status.
Characteristics of men were assessed at the first consent-
ing visit and stratified by BMI. Fisher exact tests and χ 2
tests were used to assess associations between characteris-
tics and BMI category for both MSM and MSW. To assess
the association between BMI and anal HPV prevalence
among both MSW and MSM we estimated both unadjusted
and adjusted prevalence ratios (and 95% confidence inter-
vals [CI]) for high-risk HPV, 9vHPV types, 4vHPV types,
and HPV-16 infection using Poisson regression with
a robust sandwich estimator of the variance. We conducted
mediation analysis to better understand the role of number
of sexual partners in the association between BMI and
HPV.54
Persistent infection was defined as having the same HPV
genotype at both the consenting visit and the 6-month visit.
Data were analyzed using SAS 9.4 (TS1M5) (SAS Institute
Inc., Cary, North Carolina, USA).
Acknowledgments
Special thanks to the men who provided personal information and
biological specimens for the study. Thanks to the HPV Infection in
Men (HIM) Study Team in São Paulo, Cuernavaca, and Tampa:
Lenice Galan, Elimar Gomes, Elisa Brito, Filomena Cernicchiaro,
Rubens Matsuo, Vera Souza, Ricardo Cintra, Ricardo Cunha, Birgit
Fietzek, Raquel Hessel, Viviane Relvas, Fernanda Silva, Juliana
Antunes, Graças Ribeiro, Roberta Bocalon, Rosária Otero, Rossana
Terreri, Sandra Araujo, Meire Ishibashi, the Centro de Referência
e Treinamento em Doenças Sexualmente Transmissíveis/AIDS nursing
team, Aurelio Cruz, Pilar Hernandez, Griselda Diaz Garcia, Oscar
Rojas Juarez, Rossane del Carmen Gonzales Sosa, Rene de Jesus
Alvear Vazquez, Christine Gage, Kathy Cabrera, Nadia Lambermont,
Kayoko Kennedy, Kim Isaacs-Soriano, Andrea Bobanic, Michael
O’Keefe, Bradley Sirak, and Ray Viscidi (HIM Study Coinvestigator,
Johns Hopkins).
Disclosure of potential conflicts of interest
Dr. Giuliano is a member of several scientific advisory boards of Merck
& Co, Inc, and her institution has received funding to conduct investi-
gator-initiated studies as well as Merck sponsored vaccine clinical trials.
Funding
This Sources of support: National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health (NIH) 5R21AI101417-3
[AGN] and the National Cancer Institute (NCI), NIH RO1 CA098803
01–A1 [ARG]. Publication and report contents are solely the responsi-
bility of the authors and do not necessarily represent the official views of
the NIAID or the NCI.
HUMAN VACCINES & IMMUNOTHERAPEUTICS 1917
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