E D I T O R I A L C O M M E N TA R Y
Duration of Anal Human Papillomavirus Infection
among Immunocompetent Women: Clues to Anal Cancer
Epidemiology and Possible Prevention Strategies
Elizabeth Y. Chiao
Department of Medicine, Baylor College of Medicine, and Houston Center for Quality of Care and Utilization Studies, Health Services Research and Development
Service, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
(See the article by Shvetsov et al. on pages 536–46)
Squamous cell cancer of the anus (SCCA)
is a rare malignancy in the general US
population; however, the incidence of
SCCA has increased significantly in the
past decade among both men and women,
especially among individuals aged 35–54
years [1]. SCCA, like invasive squamous
cell cancer of the cervix, has been etiolog-
ically linked to human papillomavirus
(HPV) infection; thus, the increased in-
cidence of anal cancer likely reflects the
changing epidemiology of HPV infection
[2].
Although the increased incidence of
SCCA among the growing population of
immunosuppressed individuals in the
United States accounts for some of the
overall increased incidence [3], immu-
nocompetent women with cervical disease
[4, 5] and men who have sex with men
[6] are also at an elevated risk for SCCA.
Although several studies have evaluated
Received 27 November 2008; accepted 3 December 2008;
electronically published 27 January 2009.
The views expressed in this article are those of the author
and do not necessarily represent the views of the Department
of Veterans Affairs.
Reprints or correspondence: Dr. Elizabeth Y. Chiao,
Veterans Affairs Medical Center (152), 2002 Holcombe Blvd.,
Houston, TX 77030 (echiao@bcm.edu).
Clinical Infectious Diseases 2009; 48:547–9
 2009 by the Infectious Diseases Society of America. All
rights reserved.
1058-4838/2009/4805-0003$15.00
DOI: 10.1086/596759
anal cancer precursors and HPV infection
among HIV-infected cohorts [7, 8], there
have been fewer studies evaluating im-
munocompetent populations. The Hawaii
HPV cohort study is one of the largest
cohort studies that has evaluated the ep-
idemiology of HPV disease in healthy,
immunocompetent women and has pro-
vided valuable epidemiological informa-
tion regarding the incidence, prevalence,
and duration of cervical and anal HPV
infection among these women. In this is-
sue of Clinical Infectious Diseases, Shvetsov
et al. [9] used the Hawaii HPV cohort
study to determine the patterns of dura-
tion and clearance of anal HPV infection
among women. Their findings add im-
portant insights into risk factors for per-
sistent anal HPV infection and into the
improvement of strategies for SCCA
screening.
In previous studies, the investigators of
the Hawaii HPV cohort study evaluated
the prevalence [10] and incidence [11] of
anal HPV infections. In the first study of
the cohort, Hernandez et al. [10] found a
prevalence of anal HPV infection of 27%
among 1363 immunocompetent women.
They found that women with cervical in-
fection had a 13-fold increased risk for
anal HPV infection and that although the
prevalence of concurrent cervical and anal
EDITORIAL COMMENTARY • CID 2009:48 (1 March) • 547
HPV infection decreased with increasing
age, the prevalence of anal HPV infection
only (without concurrent cervical infec-
tion) remained constant among the
women. They hypothesized that these
findings may be related to initiation of
anal sex practices at an older age among
women in their cohort or to the fact that
anal HPV infection is a more persistent
infection in the anus, compared with the
cervix. However, they acknowledge that
their findings may have been biased be-
cause women who agreed to provide anal
samples were significantly more likely to
have engaged in anal intercourse and were
more likely to be older than were women
who did not provide specimens.
Goodman et al. [11] found that new
HPV infection was a relatively common
event and that 70% of a cohort of 431
women had ⭓1 HPV infection during the
follow-up period of average duration 1.3
years. They reported that the incidence of
new HPV infection was almost 50 cases
per 1000 woman-months and that the in-
cidence of high-risk (HR) HPV infections
was 19.5 cases per 1000 woman-months,
which was comparable to that reported in
previous studies that evaluated cervical
HR HPV infections. The most common
incident anal HR HPV types were HPV-
53, HPV-52, and HPV-16. Baseline cer-
vical and anal HR HPV infection signifi-
cantly increased the risk of an incident
anal infection. In addition, they found that
younger age, white ethnicity, lower socio-
economic status, greater lifetime number
of sexual partners, past estrogen use, and
condom use but not anal sex were asso-
ciated with increased risk of acquiring anal
HR HPV infection.
The present study conducted by Shvet-
sov et al. [9] focuses on the duration and
clearance of anal HPV infection among
the same cohort of 431 women studied by
Goodman et al. [11], who evaluated the
incidence of HPV infection. The cohort
of healthy women who attended 5 clinics
in Oahu, Hawaii, from 1998 through 2003
underwent follow-up visits every 4
months. Shvetsov et al. [9] found that in-
cident HPV infection was relatively com-
mon, with 50% of the cohort experiencing
⭓1 incident anal HPV infection. In ad-
dition, they found that anal HPV infec-
tions had relatively short duration; 87%
of anal HPV infections cleared within 1
year. They also found that the median du-
ration of anal HR HPV infection was 5
months, which was shorter than the me-
dian duration of 8 months for cervical HR
HPV infection in the same cohort. In con-
trast to most studies of cervical HPV in-
fection, their study found that low-risk
(LR) HPV infections had higher clearance
rates than did HR HPV infections. The
authors also conducted a relatively novel
analysis by evaluating the effect of multiple
HPV genotypes on the clearance of anal
HPV. In a previous article about the same
cohort, Goodman et al. [12] found that
clearance times for cervical HPV were fas-
ter among older women and women with
multiple HPV genotypes. In contrast, this
study found that the rate of clearance of
anal HR and LR HPV infections was not
significantly increased in the presence of
⭓1 other HPV genotype. Also, coinfection
with specific HPV genotypes did not ap-
pear to have a significant effect on the
clearance of HR HPV infection, although
Shvetsov et al. may have had only enough
power to detect large changes, because of
548 • CID 2009:48 (1 March) • EDITORIAL COMMENTARY
the sample size. Finally, they also reported
nonviral factors associated with clearance
of anal HPV. They found that age did not
significantly affect clearance of HR HPV
infection but that long-term tobacco
smoking, douching, and the current prac-
tice of anal sex reduced clearance rates of
anal HPV.
The results of the findings by Shvetsov
et al. [9] need to be interpreted in light of
several important caveats: (1) the collec-
tion of anal specimens was optional for
patients, and the 66% of the cohort who
did provide anal samples were significantly
older and were more likely to have en-
gaged in anal sex, compared with the rest
of the Hawaii HPV cohort; (2) the authors
defined clearance by a single visit with
negative findings after a positive finding
(other investigators have recommended a
definition that includes 2 visits with neg-
ative findings); and (3) the authors as-
sumed that the same genotype detected at
consecutive visits represented the same
persistent infection, not repeat infection,
and thus clearance rates may have been
underestimated.
Despite the limitations of the present
study, the published findings from mul-
tiple studies of anal HPV infection pro-
duced from the Hawaii HPV cohort sug-
gest that incident anal HPV infection is
relatively common but that anal HPV in-
fection is cleared quickly, with a short du-
ration of infection. This may explain in
part why, despite a similar incidence of
HR HPV infection at cervical and anal
sites, the incidence of anal cancer is much
lower than that of cervical cancer. The
findings also may explain why the prev-
alence of anal HPV infection and, con-
sequently, the incidence of anal dysplasia
and SCCA are higher among immuno-
suppressed individuals. For example, Pal-
efsky et al. [8] evaluated anal HPV infec-
tion and results of anal Papanicolaou
(pap) smear tests for 223 HIV-infected
women and 57 HIV-uninfected women.
Of the HIV-infected women, 76% had
anal HPV detected, compared with 42%
of HIV-uninfected women. In addition,
26% of the HIV-infected women had
abnormal anal pap smear test results, com-
pared with 8% of the HIV-uninfected
women. Although there have been no studies
directly comparing the HPV clearance rate
between HIV-infected and HIV-uninfected
women, the results from the Hawaii HPV
cohort study suggest that, because anal HPV
infection is common among presumed HIV-
uninfected women, the higher prevalence of
anal HPV infection among HIV-infected
women, compared with among HIV-unin-
fected women, may be because immuno-
compromised women have slower anal HPV
clearance rates.
The present study is significant because
the findings highlight the specific impor-
tance not only of evaluating the incidence
and prevalence of anal HPV infection but
also of carefully studying anal HPV clear-
ance. The findings provide evidence that
anal HPV clearance might differ from cer-
vical HPV clearance and that factors that
decrease anal HPV clearance rates may be
important for development of neoplasia
and may partially explain the differences
in epidemiology between squamous cell
cancer of the cervix and SCCA. For ex-
ample, it is interesting to note that, in this
study, the nonviral factors associated with
anal HPV clearance (long-term tobacco
smoking and anal intercourse) are factors
that have been associated with SCCA. In
contrast, these factors are different from
the factors associated with cervical HPV
clearance identified by Goodman et al.
[12]. In addition, they are different from
the factors that Goodman et al. [11] iden-
tified as related to the incidence of anal
HPV infection (younger age, lower socio-
economic status, greater lifetime number
of sexual partners, past use of hormones,
and condom use), which are not as closely
linked to SCCA risk factors. Thus, al-
though the present study did not evaluate
the correlation between HPV clearance
and anal histology, it appears that anal
HPV clearance may be an important fac-
tor in determining the risk for anal
dysplasia.
In the past decade, stronger links be-
tween HPV infection and noncervical
squamous cancers, including anal, vaginal,
vulvar, and oropharyngeal cancers, have
been established as a result of improved
techniques for HPV detection. This and
the increasing incidences of these cancers
(and the coincident US Food and Drug
Administration approvals of HPV vac-
cines) have led to an increased interest in
HPV epidemiology and the initiation of
screening protocols for HPV-related can-
cers. Shvetsov et al. [9] have provided im-
portant epidemiological information re-
garding anal HPV infection, and although
they provide a reasonable argument
against the use of detection of anal HR
HPV infection as a screening tool for
SCCA in women, several questions remain
unanswered. For instance, it will be im-
portant to determine whether delayed
HPV clearance is associated with devel-
opment of high-grade anal dysplasia. In
addition, evaluation of the effect of cer-
vical HR HPV infection and dysplasia on
anal HPV clearance will help to determine
the efficacy of screening for anal dysplasia
among these women. Finally, SCCA
screening programs using anal pap smear
tests have been shown to be cost-effective
for HIV-infected men who have sex with
men [13]. Even if women who are at
higher risk for SCCA can be identified, the
cost-effectiveness and clinical efficacy of
such screening programs will need to be
evaluated.
Acknowledgments
Financial support. E.Y.C. receives salary sup-
port from National Institutes of Health grant
K23CA124318. This work was supported in part
by the Houston VA HSR&D Center of Excellence
(HFP90-020).
Potential conflicts of interest. E.Y.C.: no
conflicts.
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