of Cutaneous Human
RIVERA MD (1)
STEPHEN K. TYRING MD, PhD, MBA (2)
Houston, TX, USA
August 29, 2005
(1) Department of Dermatology, Baylor College
of Medicine, Houston, Texas, USA
(2) Professor of Dermatology, University of Texas Health Science
Center, Houston, Texas, USA
Human Papillomaviruses (HPV) are double-stranded DNA viruses,
which result in a variety of clinical manifestations according to
type. The most common cutaneous lesions include warts located on
the skin and genitalia. Because there is currently no cure for HPV
infection, treatment focuses on the alleviation of signs and symptoms.
Unfortunately, therapy has not been proved to affect transmissibility.
Traditional treatment modalities have focused on the destruction
of infected tissue through a variety of techniques. These include
podophyllin resin, podophyllotoxin, salicylic acid, trichloroacetic
acid, bichloroacetic acid, cryotherapy, laser, and surgical techniques.
None of these modalities have been proved to be superior. More recently,
immunomodulatory compounds with antiviral properties have demonstrated
superior efficacy with clearance rates up to 77% and low recurrence
rates. Most importantly, clinical trials of vaccines to prevent
acquisition of oncogenic HPV are demonstrating marked safety and
Keywords: human Papillomavirus, therapy,
Human Papillomaviruses (HPV) are common pathogens associated with
a variety of benign and malignant epithelial lesions. The most common
sites of involvement are the skin and genitals. Other locations
include the mouth, esophagus, conjunctiva, and respiratory tract.
Clinical lesions vary and are primarily determined by the infecting
HPV type. The most frequent cutaneous manifestations in the general
population are common
warts, plantar warts, and flat warts. Common warts represent 70%
of cutaneous HPV and occur primarily
in children, whereas plantar and flat warts occur in a slightly
older population. Mucosal HPV infection most often presents as condyloma
acuminatum (genital warts). It is the most prevalent sexually transmitted
disease and affects 1% of sexually active adults. Some HPV types
also play a role in the malignant transformation of
anogenital and cervical squamous cell carcinoma (1,2). Skin and
anogenital warts are extremely common
reasons for office visits. Because cure is not yet possible, treatment
focuses on symptomatic relief of discomfort and psychological distress.
It is not yet known whether treatment reduces transmissibility (3).
Lesions are notoriously difficult to treat and sometimes resolve
on their own with time. Traditional treatment modalities have been
primarily destructive in nature. These include podophyllin, cryotherapy,
and surgery. More recently, immunomodulators with antiviral properties
have been investigated for their role in HPV therapy. Treatment
choice should be determined by characteristics of the lesions such
as distribution, size, and number as well as the patient’s
age, prior treatments, comorbid conditions, cost, patient preference,
provider experience, and potential adverse reactions. If lesions
do not improve within three months of therapy, a new modality should
be considered (4,5).
The use of nonantiviral, nonimmunomodulatory therapies to treat
HPV infection is common. These modalities are often employed as
first line therapy for common warts as well as many anogenital lesions.
The rapid resolution achieved with these destructive methods is
unfortunately shortlived. Recurrence rates are usually greater than
25% (see Tables 1, 2). No evidence of significantly superior efficacy
has been established for any modality.
Podophyllin resin was once commonly used to treat anogenital
warts. The plant resin arrests mitosis and consequently causes tissue
necrosis. The resin is administered in a 10–25% solution,
which is not standardized and thus varies in composition by batch.
The solution is sparingly applied
to lesions by a physician one time each week and allowed to air
dry. After one to four hours, lesions
should be washed with soap and water. Standard treatment durations
are four to six weeks. Although
efficacy varies according to batch, clearance rates of 30–60%
have been reported. Recurrence rates are high and range from 30–70%
(6–8). Local adverse reactions consist of mild to moderate
irritation and occur in less than 15% of patients. Irritant potential
varies with batch strength. Because of a high percutaneous absorption,
systemic toxicity is an issue. Potential reactions include hypokalemia,
immunosuppression, and coma. To reduce the risk of systemic adverse
reactions, application should be limited to 0.5 mL of podophyllin
or an area of < 10 cm (2) of warts per session. As a result of
teratogenic potential, this drug is contraindicated in pregnancy.
Additionally, podophyllin contains two mutagens, quercetin and kaempherol,
which have been implicated in carcinogenesis. Long-term application
has also been associated with transitory dysplastic changes (1,8).
Despite being inexpensive with a tolerable side effect profile,
podophyllin’s negative qualities have made it unpopular, except
where other options are not available.
Podophyllotoxin (Podofilox®) is a standardized compound
containing the active ingredient of podophyllin without any mutagens.
It is effective in much lower concentrations than podophyllin
and is available in 0.5% solution and 0.05% gel preparations. Podophyllotoxin
is one of two FDAapproved
(Food and Drug Administration) treatments that patients can self-apply
at home. Patients must be compliant and must be able to visualize
and reach their warts. The recommended regimen is application to
lesions twice daily for three consecutive days alternating with
four days without therapy. Rinsing of hands after treatment is recommended,
but rinsing of lesions is not necessary. Application can continue
for up to four to six weeks if necessary. Correct application technique,
as well as identification of treatable lesions, should be demonstrated
by the physician (5). Clearance rates with the solution range from
45–75% with recurrence rates of 30–70% (7,9). Gel formulations
yield clearance rates of 26% and 38% after four weeks. The most
commonly reported adverse event is mild to moderate irritation.
Other reactions include pain, burning, pruritus, erosions, and bleeding.
Severe burning and pain have also been reported in up to 11% of
patients (6,7,9,10). Compared to podophyllin, this compound has
a higher clearance rate, a more rapid healing time,
and lower potential for systemic toxicity. However, podophyllotoxin
is also limited by recommendations
that the treatment area be limited to less than 10 cm (2) and that
no more than 0.5 mL should be used per day. It is also not indicated
for use in pregnant women or for perianal, vaginal, or urethral
warts. Additionally, the high cost makes it less optimal (5,8).
Salicylic acid (Compound W) is a commonly used over-the-counter
treatment for nongenital warts in adults and children. It causes
desquamation of the infected tissue without affecting viable epidermis.
This patient-directed therapy is available in solution, gel, or
discs soaked with solution. The skin is often soaked in water for
five minutes and dried prior to application. For best results, the
wart should be filed down. The solution and gel are applied two
to three times daily and allowed to dry, whereas discs are applied
and covered for
48 hours before removal. Treatment can continue for up to 12 weeks.
Clearance rates of up to 75% have been reported. Adverse reactions
consist of local irritation, flaking, and desquamation. Safety in
pregnancy has not been determined.
See Table 1 and 2
Trichloroacetic acid/bichloroacetic acid
Trichloroacetic acid (TCA) and bichloroacetic acid (BCA)
induce 80–90% chemical coagulation of proteins resulting in
wart destruction. The solutions are used for warts in any location.
TCA and BCA must be applied sparingly to individual lesions with
careful avoidance of normal skin or mucous membranes. For this reason,
it should be administered by a physician or nurse. Once-weekly application
can continue for several weeks. Despite its widespread use, TCA
and BCA have not been thoroughly studied. Limited studies reveal
clearance rates of up to 81% with recurrence rates of 36% (11).
Adverse reactions include irritation and
occasional ulceration. TCA and BCA are safe for use in children
and pregnant women. Best results
occur with small, moist warts.
5-Fluorouracil (5-FU) is a chemotherapeutic agent, which
interferes with DNA and RNA synthesis.
Although not recommended by the Center for Disease Control (CDC)
nor FDA-approved, both topical and intralesional compounds have
been used to treat genital warts (12). The cream is applied in a
thin layer one to three times each week. It should be washed off
with soap and water after 3–10 hours, depending on the location.
Treatment can continue for several weeks. Two studies report clearing
in 41–68% of women with recurrence rates of up to 10% (13,14).
Adverse reactions include moderate to severe irritation. Several
patients discontinued therapy as a result of irritation. Vaginal
ulceration and an isolated case of vaginal adenosis with clear cell
carcinoma have also been reported (15). Because of teratogenic potential,
5-FU is contraindicated during pregnancy (5). For intralesional
treatment, 5-FU 30 mg/mLhas been compounded with epinephrine 0.1
mg/ mL and bovine collagen in a gel. Individual anogenital lesions
are injected by the physician once weekly for up to six weeks. Reported
clearance rates range from 55–77%. However, published recurrence
rates are 58% at three months posttreatment and 70% at six months
post-treatment. Adverse reactions include pain with injection, local
skin irritation and ulceration. As with topical
application, intralesional 5-FU is contraindicated during pregnancy
Bleomycin is a chemotherapeutic drug, which interferes with DNA
synthesis and results in lesion necrosis. It has traditionally been
administered by subdermal injection. However, multiple alternative
techniques have been studied in order to reduce the associated pain.
These include combination with anesthetic, lateral injection, topical
application with tape, and pricking with a bifurcated needle. Variable
clearance rates have been achieved ranging from 33–92%. In
particular, the multipuncture method has achieved excellent
clearance rates of 92% in two trials. For this technique, bleomycin
1 mg/mL in saline is dropped on the wart and “pricked”
into the wart by multiple rapid stabs. It usually requires one to
four treatments. Adverse reactions associated with intralesional
bleomycin include pain, Raynaud’s phenomenon, nail dystrophy,
and nail loss. Some sources report clearing of untreated lesions
whereas others did not observe this phenomenon (18–20).
Cryotherapy destroys warts by thermal cytolysis. It can be used
to treat warts in any location. An experienced physician applies
liquid nitrogen with a cotton applicator, cryospray, or cryoprobe.
Individual lesions and 2–5 mm of surrounding normal skin are
frozen for 30 seconds. Some recommend
that initial freezing should be followed by thawing and repeat freezing.
Blistering usually occurs within 24 hours followed by ulceration
and healing within 10–14 days. Several treatments repeated
at two- to four-week intervals are often necessary for clearance
(4). As a result of pain associated with this technique, anesthetic
is often employed prior to therapy. Options include local anesthetic
and topical lidocaine/prilocaine (EMLA®) cream. A combination
in which EMLA cream is applied for 15 minutes prior to 1% lidocaine
injection has been reported to be superior to either modality alone.
The EMLA cream reduces pain associated with injection and both agents
synergistically reduce the discomfort associated with cryotherapy
(21). Published clearance rates range from 50–70%, and recurrence
rates extend from 20–30%. In sixmonth
follow-up studies, high recurrence rates of up to 70% have been
reported. Adverse effects include pain and scarring (1,8). Cryotherapy
is optimally used for patients with limited disease in any location.
Surgical excision allows the rapid removal of warts.
It is most useful for those with large condylomas
and resistant lesions. Techniques include scissor excision, shave
excision, curettage, and electrocautery. Anesthesia is required.
Clearance usually requires one to two treatments. Although patients
are satisfied with the immediate clearing of the lesion, the recurrence
rate is high with published rates of 5–30% (8). Additionally,
local adverse reactions such as pain, scarring, bleeding, and secondary
infection can occur. Bleeding is less likely with electrocautery,
but recurrence remains high. Concern has also developed regarding
the potential for aerosolized transmission of HPV DNA with electrocautery.
Laser surgery is recommended as an alternative therapy by the CDC
(4). It is indicated primarily for large or recalcitrant warts in
adults and children. Laser treatment is superior to cryotherapy
in these applications (8). Carbon dioxide lasers are employed to
treat superficial lesions whereas NdYag (Neodymium-doped Yttrium-aluminumgarnet)
lasers have a role in treating deeper and larger warts. Treatment
protocols vary and require experienced operators, especially when
using the NdYag laser. Lesions heal within three to four
weeks, often without scarring. Patients usually require two to three
treatments. Local or general anesthesia is required. Local anesthetic
usually suffices in adults unless the lesion is large, but children
often require general anesthesia. During treatment, a fume evacuator
should be used to prevent potential inhalation of aerosolized HPV
DNA in laser plumes. Aerosolized transmission of HPV has not been
proved or refuted (22–25). Clearance rates of up to 100% have
been reported with few associated adverse events. Recurrence rates
are similar to other surgical techniques. Despite the superior efficacy,
the high recurrence rates along with the hefty price tag, anesthesia
requirement, and need for a skilled NdYag operator makes this treatment
modality far from ideal. It is useful for only a select group of
patients with large or refractory warts. Lasers are safe in both
children and pregnant women (5,8,26–28).
Retinoids, contact sensitizers, glutaraldehyde, formaldehyde, cantharidin,
monochloroacetic acid, and adhesive tape have also been used with
variable success. Combining various methods has been recommended
by some. However, other sources claim that combination therapy may
increase risk of adverse reactions without affecting efficacy.
Immunomodulators are involved in the regulation of the immune system.
Interferon was the first FDA-approved immunomodulator for HPV and
has more recently been joined by imiquimod. Through various interactions,
these drugs stimulate the host immune system to react against HPV.
Immunomodulators have been met with higher success rates and lower
recurrence rates than destructive techniques (see Tables 1, 2).
Interferons (IFN) are immunologically active proteins, which function
as the body’s first line of defense against viruses. Three
distinct types exist: IFNa, IFN ß, and IFNõ . All three
have been evaluated for their role in treating HPV infections. Various
modes of administration have been studied including topical, intralesional,
systemic, and combination with ablative techniques. Topical formulations
were initially promising but have had variable results. The lack
of a standardized, proved topical formulation has limited clinical
use. Systemically administered IFN has also yielded highly variable
clearance rates. Response rates range from less than 15% with IFN
õ, 18–71% with IFN á, and 51– 81% with
IFN ß. Intralesional injection of IFN has met the most success.
Approximately 1 million international units (MIU) of IFN a is injected
into each lesion with a 30-gauge needle two to three times weekly
for up to eight weeks. Clearance rates of 36–63%
have been achieved. Low recurrence rates ranging from 0–32%
are promising (10,29–36). The most
common adverse reaction is a flu-like syndrome characterized by
fever, chills, myalgia, headache,
and fatigue. Symptoms begin six hours after injection and last for
six hours. Tolerance typically develops after three or more injections.
Nonsteroidal anti-inflammatory agents or acetaminophen can be used
before or after treatment to ameliorate symptoms. Laboratory changes
occur infrequently and include elevated liver enzymes, leukopenia,
and thrombocytopenia. All adverse reactions are dose-related, and
at the recommended dose of 1 MIU, they are uncommon. At doses greater
than 5 MIU, nausea, vomiting, diarrhea, rash, peripheral neuropathies,
hypotension, and cytopenias can occur. Limiting treatment to only
five warts per session decreases risk of systemic reactions. Relative
contraindications include pregnancy, autoimmune diseases, renal
disease,peripheral neuropathy, cardiovascular disease, and use of
other myelosuppressive medications (2). Combination therapy with
interferon and other treatment modalities has also been investigated.
Dual therapy with cryotherapy, electrocautery, surgery, laser surgery,
and podophyllin have all been investigated. Surgical removal of
warts followed by IFNa has yielded synergistic benefits, in
terms of 100% complete clearance associated with reduced recurrence
Imiquimod (Aldara®) is a heterocyclic imidazoquinoline amide
with immunomodulator properties (37). Although its mechanism is
not fully understood, it is known to potently induce cytokines by
stimulating Toll-like receptor 7 on peripheral immune cells, Langerhans
cells, and keratinocytes (38). Released cytokines augment both innate
and acquired cellular immunity (39). Imiquimod also enhances the
immune system within the skin by the production of intracellular
IFN a , IL-6, IL-8, and TNF a mRNA (40). Imiquimod 5% cream is FDA-approved
for treatment of anogenital warts (as well as actinic keratoses).
Along with podophyllotoxin, it is one of two options for patientdirected
therapy at home. Patient selection is similar to that with podophyllotoxin
and should be limited to responsible, compliant patients who can
easily visualize and apply cream to lesions. The cream is approved
for application to lesions three times weekly for up to 16 weeks.
Once-daily treatment regimens have also been reported, but with
more local inflammation. Patients should be instructed to apply
a thin layer to the affected area and then thoroughly massage it
into the skin
until absorbed. The skin should be washed with soap and water 6–10
hours after application. As with podophyllotoxin, the correct technique
should be demonstrated by the physician and the lesions to be treated
should be indicated. Patients should also be warned to avoid sexual
contact as the cream is on the skin and imiquimod may weaken condoms
and vaginal diaphragms (4,41). Overall clearance rates range from
more than 50% in patients who have failed other therapies. Interestingly,
women have consistently higher response rates of up to 77%. Rest
periods of one to seven days do not affect efficacy. Only 13–19%
of patients experienced wart recurrence. Adverse events occur most
often during Weeks two to five of treatment and include mild to
moderate local inflammatory reactions. Erythema is the most frequent
side effect and has been considered by some to be a sign of efficacious
treatment. Other less frequently reported reactions are pruritus,
burning, edema and erosions. However, only 1–2% of patients
discontinue therapy as a result of local reactions. No laboratory
or systemic abnormalities have been reported (2,41–46). Several
small studies have indicated that imiquimod is safe and is somewhat
efficacious in HIV seropositive patients and other immunocompromised
persons. In such patients, imiquimod may be best used in combination
with surgical or cytodestructive therapy. Safety in pregnant patients
has not been established (47,48).
Cidofovir is a nucleotide analog, which inhibits viral DNA polymerase
and induces apoptosis (49). Although the exact mechanism against
HPV is not completely understood, cidofovir may disrupt chain elongation
by its incorporation into HPV DNA. The compound is only currently
available for intravenous administration to HIV patients for treatment
of cytomegalovirus. However, a topical gel has been evaluated for
use in the treatment of HPV infections in two trials. HIV seropositive
patients (median CD4 of 257) with refractory anogenital warts participated
in the phase I/II study. The gel (0.3%, 1%, or 3%) was applied once
for 5 or 10 days followed by two weeks of observation. The regimens
cumulatively yielded a 15% complete clearance rate with 50% of patients
experiencing partial clearance of warts. This type of response in
an immunosuppressed population is encouraging. Adverse reactions
were limited to mild application site reactions (50). A phase II
trial revealed a 47% complete clearance rate with minimal adverse
reactions (51). Furthermore, two children were reported to have
complete clearing of refractory common warts with topical 3% gel
(52). Success has also been demonstrated in the treatment of high-grade
dysplastic lesions of the
cervix with 1% gel three times daily every other day for one month;
47% ( n = 15) of women had complete responses, whereas 33% demonstrated
partial responses with reduced grades of dysplasia (53). Although
there are limited data available at this time, cidofovir appears
to be a promising drug for the treatment of HPV infection. Unfortunately,
the topical compound is very expensive.
Prophylactic and therapeutic vaccines for HPV are at various stages
of development. Unfortunately, there are several obstacles which
must be overcome. First, a greater understanding of the immune response
to HPV is needed. Also, the large number of HPV serotypes causing
infection presents a problem. If a common epitope cannot be found,
a multivalent vaccine will be necessary. Third, there is no reliable
serological test for HPV. Despite these challenges, work on vaccines
is proceeding. Most vaccines currently in clinical trials are prophylactic
in nature and focus on oncogenic anogenital serotypes, especially
HPV 16. A phase III study of an HPV 16 vaccine composed of “virus-like
particles” was both markedly safe and efficacious in reducing
the incidence of HPV 16 infection and HPV 16-related cervical intraepithelial
neoplasia (54). Therapeutic vaccines remain in early development
and have not yet reached trials (1,55).
The high prevalence and malignant potential of cutaneous and anogenital
HPV infections make them a public health issue. Treatment is extremely
heterogeneous, with no single treatment or group of treatments as
a standard. Quite frequently, home treatments are followed by unsuccessful
cryotherapy. Often dissatisfied with recurrence, patients proceed
to a number of alternative therapies and are often met with failure.
Despite the wide array of available treatment options, only imiquimod
has achieved satisfactory clearance and recurrence rates. Further
investigation will be needed to reduce the incidence and prevalence
of HPV infections, especially oncogenic HPV with the use of prophylactic
|Comments from Faculty and Members
Fadi Hajjah MD, Abu Dhabi, UAE on Aug
Michael Bigby, MD, Associate Professor of Dermatology,
Beth Israel Deaconess Medical Centre, Harvard Medical School,
Boston, MA, USA on Aug 29, 2005
The paper lacks an assessment of the quality of the evidence
supporting the treatment recommendations.
Joel Bamford MD, Duluth, MN, USA on Nov
Articles are sometimes read months after they first appear.
Don't erase them just yet! To have an expert confirm OTC sal
acid as a reasonable treatment, for competent patient, is