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US
Pharm. 2006;31(9):HS-8-HS-14.
Human
papillomavirus (HPV), the cause of genital warts, is the most common viral
sexually transmitted disease in the United States.1 Because HPV
infection is not reportable to federal or local health officials and because
most people with HPV do not realize they are infected, the exact prevalence
and incidence are unknown. However, it is estimated that at least 20 million
people have an active sexually transmitted HPV infection at any given time,
and about 5.5 million new cases occur each year.2 HPV can lead to
cosmetic complaints or more serious consequences such as cancer of the cervix,
vulva, anus, and rarely, the penis. Several treatment options are available to
manage skin or mucous membrane changes caused by HPV, but no therapy is
curative. The recent FDA approval of the quadrivalent vaccine Gardasil does
offer prevention of some forms of HPV. This article introduces pharmacists to
HPV infection and discusses the nonpharmacologic and pharmacologic management
of HPV sequelae.
Pathophysiology
HPV
is a DNA virus that belongs to the Papovaviridae family.1,3 More
than 100 types of HPV have been identified by genotyping; of these, at least
30 types are sexually transmitted by skin-to-skin contact and are associated
with genital tract lesions.4,5 The other types cause common warts
(verruca vulgaris), plantar warts, and flat warts. Infections with HPV types 6
and 11 are most commonly associated with the development of genital warts.
However, those with visible, external genital warts represent less than 1% of
all patients with genital HPV.6 Infection with other types,
especially 16
and 18, has been linked to the development of cervical dysplasia.
Genital
contact, namely sexual intercourse, is the most common route of genital HPV
transmission, and sexual activity is the most common predictor of genital HPV.7,8
Several risk factors have been identified for contraction of the
infection (Table 1); however, the source of transmission is usually an
asymptomatic carrier of HPV. Rarely, a pregnant mother can transmit HPV to her
baby during delivery.
Clinical Features of HPV
Nongenital
HPV infection typically presents as cutaneous warts located on the hands,
feet, neck, and face. Common and flat warts are usually not painful, while
plantar warts, due to their anatomic location on the soles of the feet or the
palms of the hands, may be painful. Anogenital manifestations of HPV can be
either clinically apparent or subclinical in nature. Those with clinically
apparent disease, or condylomata acuminata, may have single or multiple flesh-
or gray-colored, hyperkeratotic papular lesions. Genital warts may be located
on the penis, vulva, cervix, vagina, perineum, or anal region. Lesions may
vary in size and are asymptomatic in most patients. However, localized
complaints of tenderness, pruritus, burning, and friability are not uncommon.
Immunosuppression (e.g., pregnancy) may cause enlargement of lesions,
resulting in local obstructive symptoms of the pelvic outlet. HPV transmission
to a newborn during vaginal delivery can cause recurrent respiratory
papillomatosis (RRP). RRP is characterized by multiple warts along the
respiratory epithelium and can cause complications such as hoarseness and, in
severe cases, aphonia and respiratory distress.
Several
types of HPV are oncogenic and can cause squamous intraepithelial lesions of
the cervix, vulva, vagina, anus, and penis. HPV infection of the cervix is the
most common cause of cervical malignancy; however, only about 3% to 4% of
known cases of the HPV virus will progress to cancer.9 Immune
response, genetics, and the persistence and type of HPV infection are all
considered factors that influence a woman's risk of cervical cancer. Men are
also susceptible to the aforementioned factors, as the incidence of anal
cancer in HIV-infected homosexual men is increasing.10
Diagnosis
of clinically overt genital HPV typically involves a thorough examination;
however, HPV can be diagnosed cytologically (Pap test) or virologically (DNA
detection) as well.8
Women
with external lesions should have a speculum exam with a Pap test to detect
abnormal cervical cytology. Since most patients with HPV have no obvious
warts, the Pap test is the most frequently used diagnostic test to detect
obscure cytological abnormalities. The Pap test can help identify precancerous
and cancerous changes caused by HPV and can differentiate the severity of
cervical intraepithelial neoplasia (i.e., CIN1, CIN2, and CIN3 [low-,
moderate-, and high-grade dysplasia, respectively]) if it is present. A biopsy
of most typical acuminate lesions is not necessary but is recommended in
atypical cases or when the nature of a lesion is unclear. Dilute solutions of
acetic acid (3% to 5%) can be used during colposcopy to delineate a suspicious
area before biopsy and may be used to help identify male genital tract disease
or a disease that is not readily apparent, such as flat genital warts. HPV DNA
tests are not routinely used but are becoming more widely available. HPV DNA
testing may help health care providers determine whether treatment or further
testing is needed, especially if the Pap test results show atypical squamous
cells of undetermined significance (ASC-US).
Management of Genital Warts
If
left untreated, most cases of genital HPV lesions spontaneously regress, along
with most cases of CIN1. Treatment of genital warts is usually reserved for
those with clinical manifestations of the disease and aims at removing or
destroying symptomatic lesions. Unfortunately, the recurrence of lesions is
common: Success rates are only about 20% to 75%, regardless of therapy type.6
Selection
of therapy for genital warts is dependent on a variety of factors, including
patient preference, available resources, and the expertise of the health care
provider. Additional factors that may influence choice of treatment modality
include wart size, morphology, anatomic location, the cost of treatment, and
convenience. Candidates for self-application of therapy may include those who
are able to successfully identify where to apply medication and who are
physically able to reach the warts that require treatment, as well as those
who understand how to use their medication properly.8
Nonpharmacologic
Management:
Cryotherapy, laser therapy, electrocautery, and surgical excision are all
nonpharmacologic techniques used to manage genital warts. Of these methods,
cryotherapy with liquid nitrogen is considered first-line therapy and is most
effective for minimally extensive disease. During cryotherapy, freezing of the
wart occurs, causing cytolysis that results in sloughing of the wart and other
affected tissues.8 Several weekly treatments are usually required.
Cryotherapy of external lesions is a safe option for pregnant women and is
generally well tolerated. For women who have CIN2 or CIN3, cryotherapy may be
applied to destroy abnormal tissue. Loop electrosurgical excision procedure
(LEEP)using a hot wire loop can also be used to remove affected tissue. CIN1
lesions are usually not treated, since most low-grade cell changes are
transient and will often resolve on their own.
Carbon
dioxide laser therapy can be used to destroy anogenital warts but may require
local, regional, or general anesthesia, depending on the location and extent
of the lesions. Lesions can also be destroyed by electrocautery or may be
removed by tangential excision with a pair of fine scissors or a scalpel, or
by curettage. Both laser surgery and electrocautery can be used for more
extensive disease, but the possibility of scarring is a concern. Surgical
excision of anogenital warts is often reserved for warts that are refractory
to other treatment modalities. While these methods are useful for those with
contraindications to pharmacologic treatment and provide the advantage of
eliminating many warts at a single appointment, they often require additional
equipment, substantial office training, and a longer office visit.10
Pharmacologic
Management: Pharmacologic
management of genital warts can be achieved through either patient-applied
treatments, which can be administered at home, or office-based therapies,
which are applied under the direction of a physician.10
Home-based
chemical destruction of external genital warts involves the use of podofilox
(Condylox)--the active component of podophyllin resin. Podofilox is a
keratolytic agent that arrests mitosis. Patient-applied podofilox is available
as a 0.5% solution that is indicated for genital warts only; podofilox 0.5%
gel is indicated for anogenital warts. The solution or gel should be applied
to the wart(s) with a cotton-tipped swab every 12 hours for three days,
followed by four days of no therapy. The seven-day cycle can be repeated as
necessary for a total of four cycles until there is no visible wart tissue.
Localized irritation is the most common adverse effect of podofilox. Safety
beyond four treatment cycles is not well established, and treatment during
pregnancy is not recommended.
Imiquimod
(Aldara) 5% cream is another option for patient-applied therapy. Imiquimod is
an immune modulator that induces local production of cytokines, including
interferon-alpha, and enhances T-cell-mediated cytolytic activity against
viral targets. Treatment with imiquimod cream should be applied topically at
bedtime three times per week. The cream should be left on the skin for at
least six to 10 hours and then washed off with soap and water. Treatment
should continue until no warts are present (up to a maximum of 16 weeks) and
should be limited to a treatment area of no more than 20 cm2 .
Adverse reactions consist of erythema, itching, burning, flaking, and erosions
of the skin and are more likely to occur in moist, hairless areas (e.g.,
vulvar region in women, glans penis in men). Daily application does not
improve clearance rates and is not recommended. Due to the time necessary for
wart clearance (median duration, 10 to 12 weeks), reduced recurrence rate, and
convenience, imiquimod cream may be the preferred treatment, compared to other
therapies.
5-Fluorouracil
(5-FU) applied as a 5% topical cream (Efudex) has been shown to be effective
for genital warts when applied daily for five to seven days. When combined
with epinephrine, 5-FU may be injected intralesionally by a practitioner, but
it often produces pain and ulceration and is not widely used. Topical 5-FU is
associated with localized dermatologic side effects, and those who are
immunosuppressed or pregnant should avoid its use.
Office-based
therapy is another option for managing genital warts. Podophyllin 10% or 25%
resin in a compound tincture of benzoin can be applied in small amounts to
each wart and allowed to air dry. Treatment can be repeated weekly if
necessary. Local irritation is common, and some specialists recommend
thoroughly washing the area of application one to four hours following
administration. Neurologic, hematologic, and febrile complications and
allergic sensitization are rare complications of systemic absorption of large
podophyllin levels. When podophyllin is compared to its counterpart podofilox,
patient-applied therapy of podofilox may be preferred because it has a longer
shelf-life, does not need to be washed off, and has less systemic toxicity.11
Trichloroacetic
acid (TCA) or bichloroacetic acid (BCA) 80% to 90% are caustic agents that can
be applied to warts and allowed to air dry, causing a white "frosting" to
develop. Application of either TCA or BCA results in wart destruction via
coagulation of proteins. A neutralizing agent, such as talc, sodium
bicarbonate (e.g., baking soda), or liquid soap preparations, should be
available to remove unreacted residual acid following application. If needed,
treatment can be administered weekly (usually up to four weeks of therapy) and
may be best suited for small lesions. Because these solutions have low
viscosity, caution should be used in avoiding overapplication to ensure that
the product does not contact adjacent normal tissue.8
Alternatively,
interferon-alpha has been studied as a treatment for genital warts, due to its
immunomodulating, antiproliferative, and antiviral effects. Interferon-alpha
has been shown to be effective when 1 million units are injected
intralesionally every other day for eight to 12 weeks. Systemic side effects
can occur, and the route and frequency of administration prohibit interferon
therapy as a first-line agent. Immunosuppressed patients should avoid the use
of interferon-alpha to treat genital warts, since an optimal immune response
is required for maximum effect.
Recent
reviews have examined the nucleoside analog cidofovir for the treatment of
HPV. In addition, topically applied viable bacille Calmette-Guerin has also
been used, but few studies on these agents are available to support their use,
compared to more conventional therapies.
Although
most genital warts respond within three months of therapy, patient response
and side effects should be evaluated throughout treatment, and the treatment
modality should be changed if substantial improvement is not seen or if side
effects are troublesome.10 Generally, the use of expensive or more
toxic therapies are not recommended as first-line therapy. Referral to a
specialist is advised for refractory disease.5
Prevention of HPV
Avoiding
sexual contact is the most effective way to minimize the risk of HPV. In
people who are sexually active, a long-term, mutually monogamous relationship
with an uninfected partner will help reduce the risk, but previous sexual
contact cannot exclude a current infection with HPV. Latex condom use has been
associated with a decreased risk of cervical cancer. However, both male and
female genital areas that are covered or protected can be infected with HPV
during foreplay, nonvaginal sex, and contact between the scrotum and vulva.
Vaccines:
A major focus of genital HPV research has been the development of a polyvalent
vaccine that would offer protection against several common types of HPV and
those types associated with cervical cancer. Gardasil, a quadrivalent HPV
recombinant vaccine manufactured by Merck, is the first vaccine to be approved
by the FDA and released for the prevention of HPV types 6, 11, 16, and 18.
Gardasil targets the major types of HPV, which cause 90% of genital wart
cases, 70% of cervical cancer cases, and a large percentage of cervical and
vulvar intraepithelial neoplasias.12
Efficacy
and safety studies on Gardasil have found that when compared to placebo, fully
vaccinated women who remained negative for infection throughout the study
period were 100% protected from CIN2+ associated with HPV 16 or 18, and
external genital warts associated with HPV 6 or 11. When efficacy was
evaluated starting one month after the first immunization, protection against
CIN2+ and external genital warts was greater than 90%. Currently, studies on
the stability of antibody titers after Gardasil vaccination suggest protection
lasts beyond 3.5 years.13
Gardasil
is administered as a series of three intramuscular injections of 0.5 mL each.
The first dose should be administered at an elected date, followed by
subsequent doses at two and six months after the first dose. For ease of
administration, Gardasil comes in a prefilled syringe, as well as a
single-dose vial. Vaccine-related adverse effects of Gardasil were
similar to those of placebo and included injection site reactions, such as
pain, erythema, and swelling. The most common systemic side effect is a
postdose low-grade fever. Although the manufacturer labels Gardasil as
pregnancy category B, administration during pregnancy is not currently
recommended.12
Another
HPV vaccine, Cervarix, manufactured by GlaxoSmithKline, is not yet available
on the market but is expected to be submitted for FDA approval in late 2006.
In a long-term follow-up study of Cervarix, antibodies to HPV types 16 and 18
were pres
ent up to four years after vaccination. Partial protection against HPV types
45 and 31, two strains linked to cervical cancer, was also seen in many women.
The
federal Advisory Committee on Immunization Practices (ACIP)14 has
set forth recommendations for vaccination against HPV. Females ages 11 to 12
years should be given the vaccine, and in some instances, health care
providers may advocate vaccinating girls as young as age 9. ACIP also
recommends that women ages 13 to 26 who have not been vaccinated receive
"catch up" doses of the vaccine. In order for the vaccine to be most
effective, it should be given before a person becomes sexually active, and all
doses should be administered within one year. Studies are under way to
determine the HPV vaccine's efficacy in preventing genital warts and
anogenital cancers in young men.
Screenings:
Although
a vaccine is available to help prevent HPV, routine Pap testing is still
recommended, and patients can still develop cervical cancer from other HPV
strains. The American Cancer Society recommends that women begin receiving
cervical cancer screenings three years after engaging in first vaginal
intercourse but no later than age 21 years (Table 2). Testing should
then be done each year with a conventional Pap test or every two years using
the ThinPrep or AutoCyte PREP methods--two liquid-based preparations with
improved accuracy in detecting abnormal cytology, compared to conventional Pap
testing. Beginning at age 30, women may opt to have screenings every two to
three years if they have had three previous normal Pap tests. Another option
for these women is to have a Pap test every three years, in addition to HPV
DNA testing. Women who have certain risk factors, such as a history of
cervical cancer or diethylstilbestrol exposure before birth, and those who
have immunocompromised conditions should continue to be tested annually.16
The Pharmacist's Role
While
few treatment options exist for managing genital warts, those that are
available require careful utilization. Adequate education is needed for
patient-applied therapies, such as imiquimod and podofilox, to ensure that
patients understand how to use their therapy appropriately for optimum
efficacy and safety. Pharmacists may also recommend patient-specific
prevention and treatment strategies for HPV and genital warts. Understanding
that genital HPV infection is common among sexually active adults and that
most patients will never experience symptoms, as well as informing patients
that the types of HPV that cause genital warts and cervical or anogenital
cancer are different, is essential. Taking steps to reduce the risk of
HPV-associated diseases and recommending regular screening should also be
encouraged.
REFERENCES
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