Human Papillomavirus
Infection and Anal Neoplasia
by Leslie Hanna
Today, powerful antiretroviral treatments and prophylaxis for AIDS-defining
opportunistic infections are bringing welcome changes to people with HIV
infection, such as decreased viral load, and increased CD4 cell counts,
time to AIDS and survival time. Along with improving quality of life for
many people with HIV, recent clinical advances are raising new issues
related to living with HIV infection. As people with HIV live longer,
they may be at increased risk for diseases that develop slowly, such as
cancer.
The mechanisms involved in the development of cancers or malignancies
in people with HIV are complex, multifactorial and incompletely understood.
So far, 3 factors are known to influence the development of malignancy
in people with HIV:
1) the impairment or absence of protective immune surveillance systems
that detect abnormal cell replication;
2) the disruption of the normal balance between cell proliferation (growth)
and differentiation (the specialization of cell function that occurs after
a certain number of cell divisions);
3) the existence of a state of chronic stimulation of the immune system
by antigens (foreign or harmful agents), including viruses such as human
papillomavirus (HPV), the cause of genital warts, and Epstein-Barr virus
(EBV), the cause of mononucleosis.
Anal Neoplasia: Framing the Discussion
Anogenital cancers and their precursor condition, neoplasia, are a major
form of HIV-related malignancy. The other 2 predominant types of cancer
associated with immunocompromise are lymphomas (malignancies that arise
in lymph tissue) and Kaposi’s sarcoma.
This article will focus on anal squamous intraepithelial lesions (ASIL),
a type of anogenital neoplasia that affects HIV positive men and women
alike. ASIL is one of several types of anogenital neoplasia that are of
potential concern to people with HIV. Other forms include cervical, vulvar,
vaginal and penile neoplasia. With the exception of cervical squamous
intraepithelial lesions (CSIL), the other types are less common than ASIL.
HPV infection and HIV-related immunosuppression are risk factors for
all forms of anogenital neoplasia. Physical examination of any person
with HIV should, at minimum, include a thorough inspection of the entire
anogenital region for signs of HPV infection, including the penis or cervix,
vulva and vagina, and the perianal region.
Since anal HPV infection and ASIL are increasingly detected in both women
and men with HIV, all HIV positive persons, particularly those with a
history of anal receptive intercourse, should seek further information
and, possibly, screening.
Perhaps the most familiar and well-understood type of anogenital neoplasia
is CSIL, a precursor to cervical cancer in women. The CSIL disease model
is useful in understanding ASIL. There are more data on the pathogenesis
of CSIL, the biological mechanisms are similar, and the diagnostic tools
and staging criteria are the same as those for ASIL. Thus, many working
hypotheses about how to screen for and treat ASIL are based on current
knowledge of CSIL.
One of the difficulties concerning ASIL for clinicians and patients alike
is the lack of clinical data. Perianal HPV infection and ASIL are believed
to be steps in the pathogenesis of anal cancer, but no large prospective
studies have been conducted to learn about the natural history of the
condition. (Obvious ethical problems prevent withholding treatment from
a person with HIV and ASIL in order to gather data.) Much of contemporary
research is directed at better understanding the molecular biology of
HPV infection (i.e., how HPV infects tissue and causes malignant changes),
as well as treatment for clinically apparent anogenital warts.
Prevalence of Anal HPV and Related Disease in People with HIV
Historically, the incidence rates of ASIL and anal cancer have been low
in the general population. Overall, anal cancer has been more common in
women than in men, except in the subgroup of men with a history of anal
receptive intercourse, among whom rates of anal cancer are reportedly
comparable to rates of cervical cancer in women prior to the institution
of Pap smear screening.
Greater numbers of ASIL and anal cancer cases have been reported over
the past 10 years in both the general and the HIV positive populations.
The increased incidence is partially attributed to the increasing prevalence
of sexually transmitted HPV infection and to the HIV epidemic. In all
likelihood, the increase in reported cases of anal HPV and ASIL reflects
increased awareness of the condition and improved detection (by use of
anal Pap smears and colposcopic examinations), particularly among people
with HIV, and possibly changes in sexual behavior.
Anal cancer is increasing among HIV positive men with symptomatic HIV
disease. Anal HPV infection is very common in gay and bisexual men (both
HIV negative and HIV positive), with nearly 100% of gay/bisexual men in
some studies testing HPV positive by polymerase chain reaction (PCR) tests
of anal samples. ASIL is more common among HIV positive men than among
HIV negative men, may be found in one-third of men with symptomatic HIV
disease, and may progress rapidly to high-grade ASIL.
Findings from some studies suggest that anal HPV infection is more common
than cervical HPV infection among both HIV positive and HIV negative women.
Anal cytologic changes are found about as commonly as cervical changes
in HIV positive women.
What is ASIL? Parallels with CSIL
A discussion of the many parallels between CSIL and ASIL with regard
to causation, development and staging is useful in order to understand
ASIL. (See “Cervical Intraepithelial
Neoplasia” on page 31 in the June 1996 issue of BETA.)
A diagnosis of any form of anogenital neoplasia means that new growth
(neoplasia) has been detected in the normal tissue (epithelium) of the
genitalia or anus. Composed of changes that begin on a cellular level,
the new growth may signify a precancerous condition, high-grade SIL. As
high-grade CSIL is a precursor to cervical cancer, high-grade ASIL is
a likely precursor to anal cancer.
Structural parallels between the cervix and the anus lead to a similar
developmental process. CSIL and ASIL both arise most frequently in vulnerable
areas of the vaginal (near the cervix) and anal canals known as transition
zones, where one cell/tissue type (squamous epithelium) yields to another
(columnar epithelium). Squamous epithelial tissue forms the skin and the
linings of the mouth, pharynx (throat), esophagus, lower vagina and anus.
Columnar epithelium lines the digestive tract from the stomach to the
anal canal, and most of the uterus. In the lower portion of the uterus
called the cervix and inside the anal canal, the tissue types meet and
overlap. Although HPV may infect any site in the squamous epithelium,
it most often infects these vulnerable transitional zones and causes lesions.
Most cases of cervical or anal cancer also develop in these regions.
Neoplasia begins when HPV-infected cells in these zones begin to replicate
abnormally. When enough abnormal cells have been produced to effect changes
on the tissue level, the changes can be detected and “graded.”
The Bethesda System, used to stage both cervical and anal disease, provides
a method for classifying cellular changes.
Changes are classified as either low-grade or high-grade squamous intraepithelial
lesion(s). A diagnosis of low-grade SIL can mean detection of either nearly
normal or atypical cells suggestive of HPV infection, condyloma acuminata
(benign genital warts) or mild (stage 1) CSIL or ASIL. The more serious
diagnosis of high-grade SIL indicates CSIL or ASIL stage 2 or 3—moderate
or severe CSIL or ASIL, including cancer. As the severity of CSIL increases,
so too does the risk of developing cervical cancer; this is likely also
the case with ASIL.
ASIL, like CSIL, may be mild and easily treated, moderate, or severe
and difficult to treat. Sometimes (again, this is better known to be the
case with CSIL), lesions associated with ASIL resolve (grow smaller or
disappear) on their own, without treatment; other times, they may persist
and progress to high grade SIL or cancer. Ultimately, if untreated and
unarrested, they may progress to life-threatening invasive (invading surrounding
tissues and organs) anal cancer. As with CSIL, moderate or severe ASIL
is probably more likely to persist or progress, whereas mild ASIL often
regresses without any treatment, possibly overcome by a successful immune
defense.
Brief Summary of the Current Understanding of ASIL in HIV Infection
The paucity of knowledge about HPV and ASIL, particularly in the context
of HIV, places progressive clinicians and proactive patients in a tenuous
position about how best to proceed. However, some risk factors have been
identified and some preliminary, unofficial screening guidelines have
been proffered. Despite significant, outstanding questions, there are
some fundamental certainties:
- HIV positive persons with a history of anal receptive intercourse
or CSIL are at risk for ASIL
- HPV infection is strongly associated with ASIL
- HPV infection is common in gay men (both HIV positive and HIV negative)
and in HIV positive women and, to a lesser extent, in the general adult
population
- the Pap smear is an effective screening tool for detecting the type
of cytologic (cellular) abnormalities associated with intra-anal HPV
infection and ASIL, even in the absence of visible perianal HPV infection
- colposcopic examination of the anal canal is an effective tool for
identifying abnormal cell changes and lesions
- the pattern of HPV infection and the subsequent development of abnormal
cellular changes and neoplasia of the cervix (i.e., CSIL) appear very
similar to those of the anus (i.e., ASIL)
- Pap smears and colposcopic examination of the cervix are associated
with successful early detection and treatment for cervical cellular
abnormalities and CSIL, and reduction in the incidence of cervical cancer
- currently there are no published or official guidelines for screening
of anal disease
- informal, unofficial screening recommendations for ASIL and anal cancer
have been published in AIDS, a peer-reviewed medical journal
- surgical ablation (removal) remains the most common treatment approach
to the lesions that characterize ASIL
Some clinicians are already screening individual patients whose clinical
profiles indicate that they may be at risk for ASIL.
Risk Factors and Cofactors for Anal Intraepithelial Neoplasia
In addition to infection with HPV and HIV-related immunosuppression,
a history of anal receptive intercourse is another major risk factor for
ASIL in people with HIV. The extent of immunosuppression is also a factor;
those at greatest risk are those with fewer than 200 CD4 cells/mm3. With
increasing immunosuppression, neoplasia is likely to be more severe and
progressive. Other risk factors for ASIL are cigarette smoking and, in
women, a history of CSIL.
Other risk factors for CSIL may be relevant to ASIL. Some are surrogate
markers for exposure to HPV, including having multiple sex partners and
having had other sexually transmitted diseases (STD). CSIL researchers
have postulated that other possible cofactors for persistent HPV infection
and HPV-associated neoplasia include nutritional deficiencies such as
depressed levels of certain nutrients (e.g., beta carotene and vitamin
A) or folic acid.
Human Papillomavirus Infection
ASIL is strongly associated with infection with HPV, which may manifest
as warts or may be “invisible.” Of more than 100 types of HPV
that have been identified, approximately one-third may be sexually transmitted.
Types tend to preferentially infect specific regions of the body. For
instance, types 1 and 2 cause warts of the hands and feet, whereas types
6, 11, 16, 18 and 31 are associated with anogenital neoplasia. Those types
that cause anogenital infection and neoplasia are usually acquired through
sexual contact with external or internal lesions. The urethra, semen or
urinary bladder may act as virus reservoirs.
Certain types of HPV also are more virulent, or more capable of causing
disease. The types that are oncogens, or cancer-causing agents, are not
generally associated with visible genital warts and are usually detectable
only by Pap smear screening. However, HPV DNA typing tests of genital
warts in people with HIV have revealed the simultaneous presence of both
benign and virulent types. Types 16, 18 and 31 are most often associated
with invasive cervical cancer and, more recently, with anal cancer. Types
6 and 11 are most often associated with benign genital disease, visible
genital warts, or condyloma acuminata, and sometimes with low-grade dysplasia.
Hybrid Capture, a test for HPV type, is FDA-approved and commercially
available.
HPV infection is often characterized by shifts between clinical, subclinical
and latent disease. Regression of lesions may occur, as well as reactivation
(an increase in lesions as a result of old infection), reinfection and
persistence (no decrease in lesions).
Depending on the size and location of a genital wart, typical treatment
options include trichloracetic acid, 20% podophyllin solution, 5% 5-fluorouracil
cream, electrocautery (burning using electrical current), cryotherapy
(freezing) and laser treatment. Alpha interferon has been tried on persistent
warts, and surgery may be necessary to remove large warts that do not
respond to other treatments.
Although the HPV types that cause visible genital warts are not usually
the same as those associated with invasive cancer (again, people with
HIV may have genital warts that are composed of multiple types), the sexual
contact that led to genital warts may have also led to infection with
more virulent and oncogenic HPV types. Therefore, persons with genital
warts should receive not only treatment for the warts but also close examination
for anogenital HPV and dysplasia.
Screening and Prevention
There are guidelines for screening and preventing CSIL in women with
HIV. Although the guidelines are the subject of much debate among experts,
they at least provide a blueprint. While the risks for ASIL and anal cancer
are known to be increased among gay men and HIV positive women, the official
word, according to the U.S. Public Health Service (U.S. PHS), is that
“the role of anal cytological screening [i.e., Pap smear] and treatment
of ASIL in preventing anal cancer” is not well defined. The U.S.
PHS refrains from making any recommendations whatsoever regarding periodic
anal screening for detecting and treating ASIL.
ASIL experts and researchers such as Joel Palefsky, MD, who has studied
a cohort of 608 gay male San Francisco residents, have accumulated important
data that have led to the formation of some thoughtful suggestions. According
to Palefsky, defining target groups for screening is difficult in the
absence of cost-benefit analyses that would compare the costs of anal
Pap smears, colposcopies, treatment and follow-up. One reason such cost-benefit
analyses have not been conducted is that the data needed to do so do not
exist, creating a catch-22.
Palefsky suggests 3 groups of HIV positive persons who should consider
anal screening:
1. All HIV positive men, regardless of CD4 cell count
2. HIV positive women with fewer than 500 CD4 cells/mm3
3. HIV positive women with high-grade CSIL.
Such persons, particularly those with a history of anal receptive intercourse,
should be screened once annually. Pap smears are inexpensive and widely
available.
Screening Methodology
Screening and diagnostic procedures for ASIL have been borrowed from
CSIL. Currently, there is less certainty about the best methods for screening
and treatment of ASIL.
Detecting ASIL and assessing the stage of disease development may be
done by examination and sometimes biopsy (removal of a small piece of
tissue for examination under a microscope) of the affected tissues in
and around the anus, anal canal and lower rectum. This involves having
an anal Pap smear or anal swab and a colposcopic examination. The examination
is simple and relatively painless (although some people find it uncomfortable),
and can be performed during a regular outpatient visit to a doctor. In
a traditional Pap smear, cell samples collected by swabbing are smeared
onto a slide and examined under a microscope. Today, an innovative screening
technique may make screening easier for less experienced clinicians. The
Cytyc system involves immersing collected cell samples into a solution.
A special machine then makes monolayered slides to be read by a pathologist.
Pap smears using this technology are considered more uniform and more
easily interpretable.
Colposcopy involves the shallow insertion of an instrument that allows
closer visual examination of the tissue of the vagina and cervix or of
the anal canal and lower rectum. A vinegar solution is applied directly
to the tissue to highlight any lesions or suspicious-looking areas. ASIL
diagnoses are largely made on the basis of colposcopic examination, and
biopsy and analysis of lesions thereby detected (the diagnostic “gold
standard”).
Treatment for ASIL
Optimal treatment for ASIL has not yet been established. There are no
official guidelines for treating anal disease in men or women. The overarching
treatment goal is to arrest if not cure ASIL, in order to prevent the
subsequent development of anal cancer. The options are few and simple.
Generally, only high-grade ASIL is treated.
Low-grade ASIL is primarily managed through regular, periodic monitoring.
Ideally, the body’s immune response will contain or eradicate any
low-grade tissue abnormalities. This approach derives from data gathered
in natural history studies of CSIL, in which low-grade lesions often regressed
spontaneously. Those that progressed were detected well before the development
of cancer. Monitoring examinations are usually scheduled every 6 months,
and may involve repeat Pap smears, and biopsies as needed.
High-grade ASIL requires treatment, which may be given on an outpatient
basis and usually involves removing lesions (surgical ablation). Surgical
removal can be performed by cold scalpel, thermal excision or electrocautery
through a sigmoidoscope (a flexible tube that allows viewing of the distal
sigmoid colon). Local cell destruction therapies (e.g., TCA, cryotherapy)
may be applied to small internal lesions. Physicians later must confirm
that lesions have been eradicated and do not recur. Although there are
not many data on recurrence rates, it appears that recurrence is likely
and that ASIL may require multiple treatments.
Overall, treatment remains controversial because there is no proof that
treatment for ASIL will prevent anal cancer, and the assumption that it
will is based on knowledge of CSIL.
Recent Research Findings on Anal HPV Infection and Neoplasia
In studies of men and women with HIV, researchers continue to find and
report elevated incidences of anal HPV infection and ASIL, relative to
rates in men and women without HIV.
Researchers in Great Britain prospectively followed 26 HIV positive gay
men, noting the prevalence of ASIL and its progression over a 15-month
period. The sensitivity of cell studies of these men was secondarily evaluated.
Every 4 months, anal swab tests (Pap smears) were given and analyzed by
PCR for HPV type. Results of cell studies were graded. At the end of the
study period, 22 men received colposcopy and biopsies. At enrollment,
10 participants (38.5%) were diagnosed with ASIL (9 low-grade and 1 high-grade)
and 16 (61.5%) had normal results. During the study, 19 of the 26, or
73%, progressed—16 to high-grade ASIL and 3 to low-grade ASIL.
No associations were found between high-grade ASIL and low CD4 cell count
(fewer than 200 CD4 cells/mm3) or behavioral factors. A past
history of genital warts was significantly associated with absence of
high-grade ASIL. All participants had HPV; 25 of the 26 had at least one
type known to be oncogenic (16, 18, 31 or 33). Nineteen of the 22 who
had biopsies had confirmed ASIL. None of those who had negative smears
had ASIL on biopsy. Researchers concluded that ASIL progresses rapidly
in gay HIV positive men, and that Pap smears and biopsy are sensitive
screening tools for ASIL.
A recent study spearheaded by the U.S. Centers for Disease Control and
Prevention (CDC) evaluated the prevalence of anal HPV infection in women
with HIV and the incidence of related anal cellular abnormalities. Participants
included 102 HIV positive and 96 HIV negative, demographically similar
women as controls. All participants received Pap smears of the cervix
and of the anus. Anal swabs were tested for HPV DNA. HIV positive women
were more likely than HIV negative women to have a history of current
or previous genital warts (16% vs 3%) or a history of CSIL or cervical
cancer (19% vs 1%).
Results indicated that 27% of 99 smears taken from HIV positive women
had cellular abnormalities. Of these, 22 were classified as mild cytologic
atypia (mild cellular changes), while 5 were classified as low-grade ASIL.
Only 6 smears (6%) from HIV negative women had any cellular abnormality;
5 were classified as mild cytologic atypia, and 1 was low-grade ASIL.
No cases of moderate or high-grade ASIL or anal cancer were found.
A high prevalence of anal HPV infection was found in HIV positive women
in this study—in 29% of HIV positive women compared to 2% of HIV
negative women. The difference was statistically significant. Researchers
did not perform colposcopy, which might have detected more cases of ASIL.
Anal HPV infection was shown to be associated with some risk factors already
known for HPV infection of the cervix—history of prostitution, CSIL
and cigarette smoking—but not for others, such as age and number
of lifetime sexual partners. The most significant risk factor for both
anal HPV infection and for anal cellular abnormalities was HIV infection.
A team of researchers from New York studied HIV positive and negative
women to investigate the relationship of HIV to persistent anogenital
HPV infection. The participants are being followed longitudinally as part
of a different study of HIV disease. Women were evaluated every 6 months
for 1 year. At study entry, 16.6% of HIV negative women and 35.3% of HIV
positive women were positive by PCR for oncogenic types of HPV. HIV positive
women were more likely to be persistently positive for HPV. Among sexually
active HIV positive women, acquisition of an oncogenic type of HPV was
associated independently with sex during menstruation, low CD4 cell count
and current cigarette smoking.
Future Directions
Of the few experimental treatment drugs in the research pipeline, most
are for anogenital warts. The one furthest along in the development process
is a gel formulation of cidofovir (Forvade), manufactured by Gilead Sciences.
(Intravenous cidofovir is used for treating cytomegalovirus disease, a
common viral infection in AIDS.) This nucleotide-based antiviral gel with
a broad spectrum of action is applied topically to lesions once daily
for either 5 or 10 days. Preclinical data have shown that cidofovir is
active against HPV. Results of a Phase I/II clinical trial of open-label
cidofovir topical gel, also applied to lesions once daily for 5 or 10
days, showed that 68% of 67 HIV positive participants with genital warts
refractory to standard treatment had complete or partial (greater than
50%) responses. The only side effect noted was transient, reversible local
irritation (in 52%), rash, itch, ulcer and/or pain.
A currently enrolling Phase II/III study of the efficacy of cidofovir
gel for genital warts has enrolled approximately 70 people. Recently Gilead
filed an application with FDA for 1% cidofovir gel, the formulation being
studied for HPV, for use by people with AIDS and acyclovir-resistant herpes
simplex virus. Unfortunately, the gel is used only for HPV-related warts
or lesions on the external genitalia, because researchers suspect that
the drug may cause irritation to vaginal and anal mucosa. Future plans
may include evaluating other antivirals such as adefovir dipovoxil, an
oral drug that is also a nucleotide-based antiviral with a broad range
of action.
Other new, forthcoming therapies at different stages in the development
process—but to date, not widely available—include imiquimod,
an injectable formulation of 5-fluorouracil, and antisense therapies for
HPV. The National Cancer Institute, in recognition of the strong association
between HPV and anogenital cancer, plans to develop a vaccine against
genital HPV. Still other potential research areas include the relationship
between HPV viral load measurements and risk of ASIL and anal cancer,
and more widespread use of HPV DNA typing tests to identify, monitor and
treat those with oncogenic strains of HPV.
Conclusion
Researchers continue to collect data that will enable a better understanding
of the pathogenesis of ASIL and anal cancer as well as better prevention
and treatment strategies.
Since one of the risk factors for HIV-related cancers is immunosuppression
over time, and since survival time for people with HIV is increasing,
screening and early treatment for malignancies are becoming greater priorities.
Data have shown that widespread use of Pap smear testing of the cervix
for screening purposes has resulted in a marked reduction in cervical
cancer rates in developed countries. Other data suggest that Pap smear
screening and cell studies, coupled with colposcopy and biopsy, effectively
detect ASIL. It is likely that early detection and treatment of moderate
to severe ASIL may reduce the future development of anal cancer associated
wtih HPV.
ASIL treatment options are limited for the time being. There are currently
no official guidelines for screening or treatment of anal disease. As
the results of further studies and guidelines are pending, it is important
to know now that Pap smear screening is already available and effective.
Extrapolating from what is known about CSIL and HIV, it may be prudent
for clinicians and patients (particularly those at greatest risk) to consider
screening for anal HPV infection and ASIL.
Leslie Hanna is Associate Editor of BETA.
References
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Hanna L. Cervical inraepithelial neoplasia. Bulletin
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Hillemanns P and others. Prevalence of anal human papillomavirus
infection and anal cytologic abnormalities in HIV-seropositive women.
AIDS 10(14):1641-1647. December 1996.
Palefsky J. Anal human papillomavirus infection and anal
cancer in HIV-positive individuals: an emerging problem. AIDS
8(3): 283-295. 1994.
Palefsky J. Personal communication. April 14, 1997.
Palefsky J and Holly EA. Molecular virology and epidemiology
of human papillomavirus and cervical cancer. Cancer Epidemiology
4: 415-428. June 1995.
Schneider A. Human papillomavirus infections of the lower
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Page last updated 1 October 1997
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