External Genital Warts: Diagnosis, Treatment, and Prevention

SUPPLEMENT ARTICLE
External Genital Warts: Diagnosis, Treatment,

and Prevention
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D. J. Wiley,1 John Douglas,6 Karl Beutner,3,5 Tom Cox,4 Kenneth Fife,7 Anna-Barbara Moscicki,2 and Lynne Fukumoto1
1
Division of Primary Care, School of Nursing, University of California, Los Angeles; 2Division of Adolescent Medicine, Department of Pediatrics,
and 3Department of Dermatology, University of California, San Francisco; 4Colposcopy Quality Control, University of California, Santa Barbara;
5
Solano Clinical Research, Division of Dow Pharmaceutical Sciences, Vallejo, California; 6Department of Public Health, Denver, Colorado;
and 7Indiana University, School of Medicine, Indianapolis
External genital warts (EGWs) are visible warts that occur in the perigenital and perianal regions. They are
due primarily to non-oncogenic human papillomavirus (HPV) types, usually types 6 and 11. Physical exam-
ination assisted by bright light and magnification is the recommended approach for primary diagnosis. Biopsy
is indicated when EGWs are fixed to underlying structures or discolored or when standard therapies are not
effective. Recurrences are common, and there is no single treatment that is superior to others. Among women
with atypical squamous cells, molecular HPV testing may be useful in determining who should be referred
for colposcopy. Condoms may provide some protection against HPV-related diseases and thus are recommended
in new sexual relationships and when partnerships are not mutually monogamous. Because the efficacy of
cesarean section in preventing vertical transmission of HPV infection from women with EGWs to their progeny
has not been proved, it is not recommended.
Genital human papillomavirus (HPV) infection is onstrate that HPV types 6 and 11 are most often as-
probably the most common of infections that can be sociated with external genital warts (EGWs) [7–25].
sexually transmitted and is an important public health Clinical warts are the most common recognized clin-
problem because of its clear association with cervical ical manifestation of genital HPV infection. Although
cancer in women and its potential association with HPVs infect the squamous epithelium at a variety of
other anogenital malignancies [1, 2]. HPV specifically anatomical locations, the present review focuses on
infects and replicates in the lower levels of stratified EGWs; these are visible warts that occur on the peri-
epithelium; these infections manifest clinically as warty genital and perianal region: the penis, scrotum, and
growths and dysplastic areas of cellular proliferation [3, vulva; pubic, perineal, and perianal areas; and crural
4]. HPVs are classified and referred to as “types” on folds. We focus primarily on the available treatments,
the basis of their genetic similarities; the terms “sero- including studies published since our prior review [26],
type” and “strain” are not appropriate characteriza- and factors that influence treatment decisions. In ad-
tions. Currently, 180 different HPV types have been dition, we briefly review diagnostic criteria and issues
sequenced and officially classified, ∼30 of which have pertinent to prevention, including approaches relevant
been found to infect genital epithelium [5, 6]. Seminal to EGW-affected patients and their partners and the
work has shown and clinical trial data continue to dem- prevention of transmission, both sexual and perinatal.
BACKGROUND
Reprints or correspondence: Dr. D. J. Wiley, School of Nursing, University of
California at Los Angeles, Los Angeles, CA 90095-6919 (dwiley@ucla.edu). Papillomaviruses infect virtually all vertebrates. Al-
Clinical Infectious Diseases 2002; 35(Suppl 2):S210–24
2002 by the Infectious Diseases Society of America. All rights reserved.
though there may be as many as 230 different HPV
1058-4838/2002/3508S2-0010$15.00 types according to data from partially sequenced virus
S210 • CID 2002:35 (Suppl 2) • Wiley et al.

fragments, 180 HPV types have been officially sequenced and Clinical manifestations of HPV infection include asymptom-
typed [5, 6]. HPV classification is based on genetic similarities atic infection and dysplastic cellular changes that range from
in the virus capsid peptide L1; different types share !90% ho- minor histological perturbations, such as koiliocytosis, to pre-
mology [6]. HPVs are nonenveloped, double-stranded DNA cancerous and malignant cellular changes. Studies of cervical
viruses that are tropic for epithelium; although the virus initially HPV infection have suggested that infections are largely tran-
infects the basal cell layer, the virus life cycle is inextricably sient; most women clear the virus within 9 months–1 year of
linked to the progressive differentiation of epithelial cells. Re- when it is first detected [48, 56, 57]. Two published studies
cent work has identified a6 integrin as a potential HPV binding have reported clearance rates for low-risk (HPV) type infec-
site [27, 28]. The a6b4 complex is expressed on the basal cell tions: Moscicki et al. [58] reported that 60% of women with
layer of epithelium and, for one, is involved in anchoring these low-risk HPV type cervicovaginal infection cleared infection
cells to their basement membrane [27, 29]. In vitro studies have within 10 months, and Franco et al. [50] reported that 12%

shown that the binding of viruslike particles to these complexes per month of women similarly infected cleared infection. How-
induces cell proliferation through Ras-MAP kinase pathways ever, no studies have specifically determined whether infection
[29]. Additionally, Joyce et al. [30] have demonstrated a hep- duration for affected external genital tissues is comparable to
arin-binding region located within the carboxy-terminus of L1 those of cervicovaginal epithelium. Also, placebo-controlled tri-
that interacts with heparin and with human keratinocyte cell- als have suggested that for some patients, EGWs may spon-
surface glycosaminoglycans that resemble heparin in vitro; these taneously clear without treatment, probably because of acquired
regions may be important to virus binding in vivo. cellular immune responses [26, 59–63]. Although some trials
More than 30 of the sequenced HPV types infect genital showed no regressions among placebo-treated patients, many
epithelium, and ∼20 have been classified as “oncogenic” or trials have reported that as many as 40% of placebo-treated
“high risk” because of their association with cervical cancers patients show spontaneous clearance [26, 62, 63]. Finally, the
(e.g., HPV-16 and -18) [1, 2, 11, 12, 31–37]. The oncogenic rapid emergence of HPV-related lesions among immunocom-
HPVs also appear to be commonly associated with other ano- promised patient populations, specifically among organ trans-
genital cancers [38]. The other HPV types are considered to plant patients and HIV-infected men and women, suggests that
be “low-risk” or “non-oncogenic” because they are rarely, if HPV may be harbored in a latent form, in vivo [64–72]. How-
ever, associated with anogenital cancers [7, 12]. EGWs are gen- ever, to date, latent infection has not been shown conclusively.
erally due to low-risk HPV types, particularly HPV types 6 and Recurrent respiratory papillomatosis (RRP) is associated with
11; however, high-risk types have been found in a small pro- low-risk HPV types. RRP can occur in adults but principally
presents in children; among children, it is thought to be due
portion of patients, especially those with immunodeficiency
to birth-associated exposure to HPV [73–79]. RRP is rare, is
[7–12, 39–45].
not malignant, and recurs often [77–79]. RRP can be life-threat-
The prevalence of HPV infection varies, but experts generally
ening if papillomas grow to a size that obstructs the airway.
agree that ∼1% of the adult population have symptomatic
EGWs, that most genital HPV infections occur during the first
few years after the onset of sexual activity and are transient,
DIAGNOSTIC CONSIDERATIONS
and that more than half of the middle-aged adult population
bear some evidence of historical infection (e.g., serum anti- Accurate diagnosis is an essential first step in treatment of
bodies) [46–49]. Because epidemiological research has focused EGWs. They can be flat, dome-shaped, keratotic, pedunculated,
largely on cervical infection in women, we know more about and cauliflower-shaped; they may occur singularly, in clusters,
HPV infection among women than among men and about or as plaques [80–82]. Understanding the morphological pre-
cervical infection and its clinical correlates than about any other sentation of these lesions is essential to accurate diagnosis of
manifestation. For example, data from 8 studies that evaluated EGWs and their differentiation from other lesions that mimic
4843 female and 135 male heterosexuals showed that infection them. As was previously mentioned, warts are not exclusive to
is relatively common and that infection with low-risk HPV external genital tissues. Sexual exposure can be associated with
types is less common than infection with high-risk types [48, warts in the urethra and at the meatus, cervix, vagina, anus,
50–55]. Population-based data have suggested that the inci- and oral cavity. Cervical warts, however, require clinicians to
dence of genital HPV infections, including infections with low- rule out high-grade dysplasia using Papanicolaou (Pap) tests
risk types, decreases with age [48, 50]. Thus, detection of HPV prior to treatment.
infection among older women is more likely to reflect persistent EGWs can be diagnosed through direct visual inspection with
infection, whereas detection among younger women more often bright light and magnification [63]. The male urinary meatus
represents recently acquired and probably transient infection and the fossa navicularis can be fully inspected with an otoscope
[48, 50]. and small spreader [83]. Biopsy is not recommended routinely.
External Genital Warts • CID 2002:35 (Suppl 2) • S211

However, when EGWs are not responsive to therapy or when of uncertainty over the effect of treatment on future trans-
neoplasia is suspected because of blue or black discoloration, mission and the possibility of spontaneous resolution, an ac-
sudden recent growth or increased pigmentation, or fixation ceptable alternative for some patients is not to undergo therapy
to underlying structures, biopsy and histological evaluation unless their lesions persist or enlarge.
should be performed [26, 63]. Patients should be referred to A wide variety of therapies are available to treat EGWs. Some
a specially trained clinician whenever neoplasia is suspected or treatments are based on long-standing use and are supported
when EGWs are recalcitrant [26, 63]. Specialized tests, includ- by historical practice, smaller trials, and case-series data,
ing acetowhite testing and virus-typing assays, are not rec- whereas recently developed treatment modalities are supported
ommended routinely for accurate diagnosis [26, 63, 84]. There by more rigorous research. Not all EGW therapies have been
are no data to suggest that molecular testing for nucleic acids well studied, and not all are available in every treatment setting.
(e.g., hybrid capture assays) are effective, and they are not Thus, effective treatment is dependent on an understanding of

recommended in the routine diagnosis or management of the underlying disease process and available treatment options.
EGWs [26, 63]. Although there have been no clinical trials or observational
The differential diagnosis for EGWs includes a number of studies that specifically addressed the factors that influence se-
skin conditions: condyloma latum, seborrheic keratoses, dys- lection and treatment by patients with EGWs, 2 studies have
plastic and benign nevi, molluscum contagiosum, pearly penile examined the effectiveness of treatment guidelines. Clinical al-
papules, and neoplasms. Condyloma latum is due to secondary gorithms that follow formal treatment guidelines appear to
syphilis, an infection caused by Treponema pallidum, and can improve wart clearance rates [102, 103]. Treatment guidelines
be diagnosed with dark-field microscopy and standard sero- offer structure to clinicians who are less experienced as well as
logical tests for syphilis [85]. Seborrheic keratoses are common, support to experienced clinicians who treat particular outcomes
localized hyperpigmented lesions that are rarely associated with infrequently. Clinical algorithms also provide a framework on
malignancy [86]. Molluscum contagiosum is caused by a pox- which to base systematic evaluation of patient care outcomes.
virus, highly infectious, and common in immunodeficiency; When EGWs remain after therapy, referral to a specialist con-
lesions are usually umbilicated [87]. Pearly penile papules are tinues to be advised [63]. However, EGWs recur frequently,
angiofibromas that occur at the penile corona and are normal and it is often unclear whether recurrences are due to recru-
variants that require no treatment except reassurance [88]. descence, reinfection, or other factors—for example, individual
High-grade intraepithelial lesions and cancers that may immune responses or inadequate treatment.
mimic EGWs include Bowen’s disease, Bowenoid papulosis, Once treatment has been decided on, complete clearance of
squamous cell carcinomas, Buschke-Lowenstein’s tumors, vul- visible EGWs is the patient care goal. No currently recom-
var intraepithelial neoplasias (VINs), and dysplastic nevi.
mended therapies treat HPV infection directly; however, IFN,
Bowen’s disease, an in situ squamous cell carcinoma, is con-
a cytokine, and imiquimod, an immune response modifier, seek
fined to the epidermis and becomes invasive infrequently [9,
to treat infection by stimulating immune responses. In addition,
89, 90]. Associations between Bowen’s disease and both low-
cidofovir, an acyclic nucleoside phosphonate approved for
and high-risk HPV types have been reported [91, 92]. Bow-
treatment of cytomegalovirus infection, directly affects viral
enoid’s papulosis often presents as EGWs, but histological ex-
replication and is being tested currently for treatment of EGWs
amination favors squamous cell carcinoma in situ and, for
and other HPV-related outcomes [104–106].
women, VIN [93–98]. Both low- and high-risk HPV types have
Sex-specific differences in clearance and recurrence have
been isolated from Bowenoid’s papulosis [97]. Also, Buschke-
been reported; it is likely that EGWs on smooth moist tissues,
Lowenstein tumors, a rare and highly differentiated genital car-
including the urinary meatus, respond better to treatment than
cinoma, are associated with particular subtypes of low-risk HPV
those located on dry, cornified tissues [107–110]. However, only
types [99–101]. Dysplastic nevi can be differentiated from be-
the most recent clinical trials have possessed enough statistical
nign nevi and EGWs; the former shows nonuniformity of color
power to answer sex-specific questions about treatment out-
and irregular borders, is often accompanied by a reported his-
come; the absence of these data in early studies is most often
tory of recent growth in size or shape or increased pigmen-
due to inadequate sample size.
tation, and may be 16 mm in diameter [89].
Meatal EGWs are infrequently evaluated separately in clinical
trial analyses, but where they have been reported, clearance
TREATMENT rates appear to be similar to clearance rates reported for women
in other studies [107–112]. If these data are representative, it
There are no data to indicate whether treatment for EGWs seems likely that higher clearance rates may be related to the
eliminates infectivity; thus, the primary goal of treatment is to tissue type affected.
ameliorate symptoms and remove symptomatic warts. Because Treatments are often classified as either surgical or non-

surgical in nature or, more recently, are divided into provider- Recurrences have been reported for 4%–38% of patients fol-
and patient-applied therapy groups. The clinical trial literature lowed in clinical trials [115, 120, 124]. Safety during pregnancy
for these therapies has been reviewed extensively elsewhere [26, has not been evaluated; effective contraception for women of
62, 63, 113]. Surgical treatments include electrosurgery, surgical childbearing age is advised.
excision, cryotherapy, and laser surgery; these are classed to- Imiquimod/imidazoquinolinamine (Aldara). Aldara is an
gether with other provider-applied treatments. Nonsurgical imidazoquinolinamine derivative (1-[2-methylpropyl]-1H-im-
provider-prescribed and -applied therapies include podophyllin idazo[4,5-c]quinolin-4-amine) that has no in vitro antiviral
resin, IFN, and bi- and tri-chloroacetic acid (BCA/TCA). Pa- activity but does induce macrophages to secrete cytokines (e.g.,
tient-applied nonsurgical treatments include podophyllotoxin IL-2 and IFN-a). In vivo studies have shown enhanced cytolytic
(podofilox), imiquimod (Aldara), and 5-fluorouracil (5-FU) and lymphoproliferative responses after administration [163,
cream. As with any pharmacological agent, the use of a non- 164, 167, 168]. It has been tested in animals and humans [126,

surgical treatment is contraindicated when there is any history 163–165, 167]. Imiquimod has been studied extensively and is
of hypersensitivity to any product constituent. Data suggest that a new therapy relative to other EGW treatments.
there is no single treatment modality that is vastly superior to Imiquimod is applied topically, and both 1% and 5% prep-
other therapies [26, 62, 63, 113]. However, the randomized arations have been studied; 5% cream is more efficacious and
clinical trials data do suggest that podofilox, imiquimod, cryo- has been approved for EGW treatment by the US Food and
therapy, podophyllin resin, BCA/TCA, and topically applied Drug Administration [109, 126, 165]. In 3 randomized placebo-
and intralesionally injected IFN are more effective than placebo controlled trials of 5% cream, 37%–54% of treated patients
and that, compared with one another, surgical treatments are showed clearance within 16 weeks (table 1) [102, 126, 165].
largely equivalent [113]. Unlike many early EGW clinical trials, these studies were de-
signed with enough power to detect differential effects among
subgroups. For example, Edwards et al. [126] reported that
PATIENT-APPLIED THERAPIES women were nearly twice as likely to show complete clearance
compared with men; however, these relationships have not been
Podophyllotoxin/podofilox (Condylox). Podofilox is an an- replicated by others [102].
timitotic agent that destroys warts by inducing tissue necrosis Imiquimod is dispensed as an individual dose and is applied
locally [26]. Podofilox is supplied in 0.5% gels, solutions, and directly to the affected area at bedtime, 3 times/week for up to
creams; preparations ranging from 0.15% to 8% have been 16 weeks [83]. Patients are advised to wash the affected area
evaluated, as have a variety of treatment frequencies and du- with mild soap and water on awakening, to remove residual
ration, in randomized studies [23, 25, 114–119]. However, gen- drug [83].
erally, podofilox is applied twice daily for 3 consecutive days Mild to severe erythema has been associated with EGW treat-
and repeated for 2–4 cycles [24, 83, 120]. ment that uses 5% imiquimod cream [126]. In addition, lo-
Unlike its parent agent, podophyllin resin, both podofilox calized erosion, itching, and burning sensations are often as-
gel and solution are devoid of the mutagenic flavenoids quer- sociated with imiquimod; irritation, induration, scabbing,
cetin and kaempherol [26, 121]. Podofilox solutions and gels tenderness, and pain have been reported less frequently [113,
for the treatment of EGWs have been well evaluated historically 126]. Recurrences have been reported in 13%–19% of clinical
and reviewed elsewhere. Prior placebo-controlled trials have trial subjects who were treated with 5% imiquimod cream. As
shown that 45%–77% of patients attained clearance within 4–6 with other EGW treatments, safety during pregnancy has not
weeks of treatment [24, 26, 62, 63, 113, 120, 122]. Since our been tested; effective contraception is advisable for women of
last report, one new study of podofilox gel has shown results childbearing age.
that are not (statistically) significantly different from prior in-
vestigations; 37% of 167 patients treated with podofilox 0.5%
gel showed EGW clearance, compared with placebo (table 1) PROVIDER-APPLIED THERAPIES
[123].
Untoward outcomes have been reviewed extensively else- Podophyllin resin. Podophyllin resin is an antimitotic agent
where; in brief, commonly reported side effects due to podo- that, like podofilox, destroys warts by inducing tissue necrosis
filox include local inflammation or irritation, most often ero- locally. Podophyllin resin is one of the oldest nonsurgical EGW
sion, burning, pain, and itching [26, 63, 113]. Symptoms treatments available. It is compounded as a 10%–25% suspen-
uncommonly associated with podofilox include balanoposthitis sion in tincture of benzoin; to avoid the risk of systemic ab-
(inflammation of the foreskin and glans in uncircumcised sorption and possible toxicity, podophyllin should not be used
males), dyspareunia, bleeding, scarring, and insomnia; one case for areas 110 mm2 [26, 63].
of preputial tightening has been reported [26, 63, 113, 124]. Podophyllin resin has been evaluated extensively, relative to

Table 1. Summary of randomized controlled trials for and select uncontrolled studies of external genital wart therapies: percentage of patients showing wart clearance, recurrence
by end of study, guideline-based recommended use, and safety during pregnancy.
Wart clearance, Recurrence, Safety during pregnancy

Treatment % [reference] % [reference] [reference] Note [reference]
Recommended
Patient-applied
Podophyllotoxin/podofilox 45–88 [24, 119, 120, 4–38 [115, 120, 124] Unknown, no flavenoid Compared with placebo and podophyllin resin
122–125] mutagens in
preparation
Podophyllotoxin gel 37 [123] Data from randomized clinical trials suggest that 0.5% podofilox gel is more effective than
placebo (RR, 16.0; 95% CI, 4.0–63.7; at conclusion of therapy, 37% of subjects on gel
showed clearance vs. 2% of placebo-treated subjects [123]
Imiquimod 5% 27–54 [102, 109, 126, 13–19 [109, 126] Unknown Comparisons to placebo [109, 126]; effectiveness data suggest that, in clinic settings, effective-
127] ness is comparable to reported efficacy [102]
Provider-applied
Cryotherapy 27–88 [13, 107, 111, 21 [107] Yes [130, 131] Compared with podophyllin resin, TCA, and electrosurgery; comparisons have been made with
128, 129] and without IFN as an adjunct therapy
Podophyllin resin (20%–25%) 23–72 [110, 124, 23–65 [110, 124, No, contains flavenoid Compared with podophyllotoxin, cryotherapy, electrosurgery, TCA, and surgical excision;
132–135] 132–135] mutagenic flavenoids, comparisons have been made with and without IFN as an adjunct therapy
quercetin and kaem-
pherol [121]
BCA/TCA 63–70 [128] Yes
Electrosurgery 61–94 [107, 136, 137] 22 [107] Yes Compared with IFN, cryotherapy, and podophyllin resin
Surgical excision 35–72 [138–140] 19–29 [138, 139] Yes Compared with CO2 laser and podophyllin resin.
Laser surgery 23–52 [20, 140–142] 60–77 [20, 140, 141] Yes Comparison of laser vs. laser plus IFN alone and laser surgery vs. conventional surgery
Not recommended
IFN
Topical 33–90 [143, 144] No
Topical IFN: 1.0 ⫻ 106 IU/g and 0.15 Not applicable [145] IFN gel, 54–62; pla- No Topical IFN-b was somewhat more effective in preventing recurrences compared with placebo
⫻ 106 IU/g gel vs. placebo as cebo, 75 [145] (for 1 million IU/g concentration RR, 0.82; 95% CI, 0.60–1.14; for 0.15 million IU/g concentra-
adjuvant therapy to prevent tion RR, 0.72; 95% CI, 0.51–1.04) [145]
recurrences
Intralesional 17–63 [146–154] No
Systemic 17–67 [13–20, 136, 141, 9–69 [13, 15, 19, 159] No Compared with placebo, no difference [14, 15, 18, 19, 160, 161]; podophyllin or diathermo-
142, 155–159] coagulation as adjunct therapy
Topical 5 fluorouracil 10–50 [162–164] 50 [162] No Case series, vulvar application [165], compared solution and cream preparations [166]
Cidofovir (S-1-(3-hydroxy-2-phosphonyl- 33 [105] Not reported Unknown HIV-infected patients; genital ulcers related to treatment reported for 8/10 treated patients [105]
methoxypropyl) cytosine
NOTE. Newly published and reviewed studies are [102, 105, 123, 144]. BCA, bichloroacetic acid; CI, confidence interval; RR, relative risk; TCA, trichloroacetic acid.

other treatment modes (table 1) [26, 63, 113]. When compared, control are priorities with all surgical treatments. The resulting
individually, with podofilox, cryotherapy, and electrosurgery or surgical wound for most EGW excisions, if performed properly,
when used with intralesional IFN as an adjunct therapy, these should extend only into the upper regions of the dermis. Ad-
treatments were statistically equivalent to podophyllin alone equate local anesthesia and postprocedural prescription of mild
[113]. However, a variety of adverse effects including bone analgesics should control discomfort during the procedure and
marrow suppression, hepatocellular dysfunction, neurological during wound healing, respectively. Local anesthesia can be
compromise, hallucinations, psychosis, nausea, vomiting, di- achieved rapidly by standard preparations (e.g., lidocaine);
arrhea, and acute abdominal pain have been reported over the preparations that contain epinephrine both prolong the anes-
past 20 years [83, 166, 169–178]. These untoward effects oc- thetic effect and provide hemostasis [181].
curred in situations where the treatment area was extensive or When reviewing clinical trial data, it is important to remem-
on skin surfaces that favored systemic absorption. Together with ber that the duration of follow-up significantly affects efficacy

the large number of alternative therapies now available, these estimates; the immediacy of results related to surgical treat-
reports of side effects have led some European experts to rec- ments almost always favors these treatments. Nonsurgical ther-
ommend against use of podophyllin in primary-care settings apies, no matter who applies them, almost always require time
[83]. for the agent to act; thus, when compared with surgical pro-
Recurrences have been reported for 23%–65% of clinical trial cedures, their short-term efficacy is generally less favorable. No
participants [110, 124, 132–135]. Podophyllin contains mu- randomized clinical trials that have compared the efficacy of
tagenic flavenoids, quercetin, and kaempherol [121] and thus scalpel and scissors excision against sham or no treatment have
is not safe during pregnancy. Effective contraception for women been reported. Generally, untoward effects of surgical treat-
of childbearing age is essential [26, 63, 113]. ments for EGWs include pain and the risk of infection. All
BCA/TCA. BCA/TCA is corrosive to the skin and mucous surgical treatments can be used during pregnancy.
membranes; the acid denatures and precipitates proteins and Surgical excision. Surgical excision that uses scalpel, cu-
kills EGW-affected tissues [179]. BCA/TCA is not readily ab- rettage, or scissors directly removes wart-affected tissues. No
sorbed through the skin [179], and, although BCA/TCA has new studies have been reported since the last guidelines were
rarely been studied, it is widely used in practice. Treatment issued (table 1). Older clinical studies that compared these
concentrations are not standardized, but early studies reported procedures against other forms of therapy suggested that
the use of 85% and 95% concentrations [26, 128, 180]. 35%–72% of patients show clearance of visible warts imme-
Effectiveness in randomized clinical trials ranges from 63% diately and, ∼1 year after excision, 19%–29% of patients
to 70%, and no new studies have been reported during the past showed recurrences [138, 139]. Podophyllin resin appears to
2 years. BCA/TCA has been compared with cryotherapy and be less effective than surgical excision; however, when compared
laser therapy in case series and randomized trials reviewed else-
with laser therapy, surgical excision is about equally effective
where [26, 62, 63, 113], and acid ablation is no more effective
[138–140].
than cryotherapy (table 1) [113]. The rates of recurrences for
Electrosurgery. Electrosurgery uses electrical energy, in the
patients treated with BCA/TCA remain unclear.
form of thermal coagulation or electrocautery, to destroy EGW-
BCA/TCA may run onto adjacent, healthy skin if overap-
affected tissues. Since our last review, we have found no new
plied. Applying carefully and allowing drying time afterward
studies of electrosurgical methods for EGW removal (table 1)
will prevent the spreading of acid onto unaffected areas [26].
[26, 62, 113]. Our prior evaluation showed that electrosurgery
Local pain, ulceration, and scabbing have been reported [113].
was evaluated by use of case series reports; 3 comparisons,
BCA/TCA has been administered adjunctively with laser ther-
which used randomization of subjects, compared electrosurgery
apy during pregnancy; although 97% of treated women showed
against IFN, cryotherapy, and podophyllin resin [26, 62, 63,
clearance, significant side effects attributable to this treatment
107, 113, 136, 137]. Overall, 61%–94% of electrosurgery-treated
combination included suprapubic catheterization in 7 of 32
patients showed clearance in 3 comparative trials 3–6 weeks of
treated women, premature labor in 2 women, premature rup-
treatment [26, 62, 107, 113, 136, 137]. In these trials, electro-
ture of membranes in 1 woman, and prolonged rupture of
surgery was found to be ∼3 times more effective than intra-
membranes in 2 others [180].
muscular IFN and ∼6 times more effective than subcutaneously
injected IFN [113, 136]. Compared with podophyllin resin,
SURGICAL TREATMENTS electrotherapy is about twice as effective initially but equally
effective 3 months after therapy [107]. Similarly, 2 randomized
Surgical treatments directly ablate or excise wart-affected tis- trials showed slightly greater efficacy for electrotherapy com-
sues, using curettage or tangential excision, electrocautery, or pared with cryotherapy; however, the differences in treatment
electrotherapy. Generally, anesthesia, analgesia, and infection arms did not persist after 3 months of follow-up [107, 137].

The loop electrosurgical excision procedure (LEEP) has been trials and reviewed elsewhere [26, 63, 113]. Both preparations
compared with laser treatment for EGWs; Schoenfeld et al. are associated with a systemic flulike syndrome, including head-
[182] reported that 24 (86%) of 28 lesions treated with LEEP ache, fever, myalgia, fatigue, nausea, and/or vomiting. Since the
and 21 (75%) of 28 lesions treated with a laser showed no HPV CDC sexually transmitted disease (STD) treatment guidelines
DNA within a 20-mm circumference of the treated lesion. In were issued, one new clinical trial has evaluated topical IFN-b
clinical studies, 14%–22% of patients have shown recurrences as an adjunct therapy to CO2 laser, electrotherapy, or liquid
[107, 182]. nitrogen treatment to prevent recurrence [144]. IFN is asso-
Cryotherapy. Cryotherapy uses liquid nitrogen to freeze ciated with a number of systemic untoward effects.
and kill EGW-affected tissues; after several days, the tissues Intralesional IFN is injected directly into the base of each
from the treated area slough, and inflammation ensues, then EGW. For this reason, the procedure is painful, and local an-
subsides as healing is evident. No new studies have been re- esthesia is recommended to minimize discomfort. Intralesional

ported since our last review; prior studies compared cryother- IFN has been found to be more effective than placebo in one
apy against TCA and evaluated its efficacy when used in com- trial [147] but was not of statistically greater benefit in a second
bination with IFN, variable freeze-thaw–cycle patterns, and [154]. As an adjunct therapy to podophyllin resin, intralesional
placebo (table 1) [26, 62, 63, 113]. Handley et al. [129] and IFN showed no greater added benefit than placebo after 11
Eron et al. [13] each reported data for comparison groups who weeks of follow-up [110].
received cryotherapy plus placebo; wart clearance was 40% at Systemic IFN has not been shown to be effective as a primary
3 months and 27% at 6 months, respectively, for these groups. or adjunct therapy for EGWs [113]. Bone marrow suppression
Data have suggested that recurrence rates may be 38%–73% has been reported in as many as one-quarter of treated patients.
by 6 months after treatment [13, 129]. Anaphylactic reaction, bronchospasm, and depression have
Laser therapy. Laser therapy uses focused, infrared light been reported in a few subjects. Because IFNs have no advan-
energy to vaporize EGW-affected tissues. Laser treatment is tage over other standard therapies in treating EGWs and be-
more complex and costly than other surgical treatments such cause there are significant constitutional side effects associated
as cryotherapy and electrosurgery and requires specialized with their use, these preparations are not recommended forms
equipment and additional clinical training to perform properly of therapy.
[26, 63]. Although some specialists offer laser treatment as an Topical IFN as a primary treatment has shown inconsistent
in-office procedure, there are circumstances in which in-hos- and widely varying clearance rates in the few trials that have
pital treatment and general anesthesia are indicated. For ex- been reported [143, 183, 184]. New data have suggested that
ample, if EGWs are extensive and the treatment field is large, 54%–62% of those treated with IFN gel as an adjunct to CO2
in-office laser treatment may not be feasible [26, 63]. Children
laser, electrocautery, and cryosurgery developed recurrences,
and young adolescents may also require general anesthesia for
whereas 75% of placebo-treated participants showed recur-
treatment [26, 63].
rences (i.e., for 0.15 ⫻ 10 6 IU/g, relative risk [RR], 0.72; 95%
No new clinical trials have been reported that have compared
confidence interval [CI], 0.51–1.04; for 1 ⫻ 10 6 IU/g, RR, 0.82,
laser treatment for EGWs with other treatments or with groups
and 95% CI, 0.60–1.14) (table 1) [144]. Topical IFN is asso-
that received sham or no treatment (table 1) [26, 62, 63, 113].
ciated with local burning and itching and sometimes with flu-
Clinical studies of laser treatment are problematic because of
like syndrome, including fever, headache, and pruritis [113].
their small sample sizes and poor study design that cannot
5-FU cream. 5-FU cream as a treatment for EGWs has
control adequately for the effects of confounders. Three-quar-
not been evaluated adequately; no randomized controlled trials
ters of the randomized trials we reviewed previously evaluated
have been performed [113]. Case-series data showed wart clear-
adjunct therapies in combination with laser therapy [26, 62,
ance in 10%–50% of treated patients within 3 months of treat-
63, 113]. In those studies, the efficacy of laser treatment ranged
ment onset [158, 159, 162]. However, little is known about
from 23% to 52% for studies where follow-up ranged from 3
recurrences when 5-FU cream is used; in one study, EGWs
to 18 months [20, 140–142]. Recurrence rates for patients en-
recurred in 50% of the few patients that were followed beyond
rolled in studies that used a randomized controlled design
the initial study period [158]. 5-FU is a mutagen and teratogen
ranged from 60% to 77% [20, 140, 141].
and is contraindicated during pregnancy; thus, women of child-
bearing age should use effective contraception if 5-FU cream
THERAPIES NOT CURRENTLY RECOMMENDED is prescribed [185, 186]. To date, no untoward outcomes have
been reported when inadvertent exposure during pregnancy
IFNs. IFNs are proinflammatory cytokines that have broad occurred [186, 187]. Experts have suggested that 5-FU not be
antiviral effects. Intralesional and systemically administered used in the primary care setting [26, 83].
IFNs have been evaluated extensively in randomized clinical Cidofovir. Cidofovir is a nucleoside analog of deoxycyti-

dine monophosphate used systemically to treat cytomegalovirus In general, patients should be educated about HPV infection
and herpes virus infections [188]. It is being tested against HPV and its manifestations, including EGWs. When EGWs are di-
with use of intralesionally injected and topical preparations. agnosed, clinicians should discuss their origin, treatment, and
Cidofovir directly treats viral infection, and in vitro data suggest outcomes that are associated with them. It is critical to dispel
that viral polymerases are more sensitive to cidofovir than cel- misunderstanding about this diagnosis—for example, the HPV
lular polymerases [188]. Thus, interruption of cellular poly- types that are associated with EGWs rarely, if ever, cause
merases in transcribing human proteins is less likely. To date, cancers.
one study has shown EGW clearance in 4 of 12 HIV-infected When one sex partner is symptomatic for HPV infection,
patients treated with topical drug, and case reports have also questions about the source of infection and about fidelity often
suggested clearance may be achieved with topical administra- arise. Patients often express concern about disclosure and
tion (table 1) [104–106]. Ulcerations at the treatment site have whether partners should be examined. Questions about mo-

been reported [104–106]. Larger, more extensive studies of this lecular HPV testing often occur when one partner is asymp-
investigational preparation are needed. tomatic. Symptomatic patients often want to know whether
their partners should be examined, whether condoms will pro-
tect their partners, whether they will be persistently infectious,
COMFORT AND CARE ASSOCIATED WITH
and whether infection can be transmitted to others through
TREATMENT
casual contact.
Almost all successful EGW treatments result in some disruption Examination of sex partners is not necessary for the man-
of skin integrity; for that reason, there are general patient ed- agement of EGWs, because there are no data indicating that
ucation and comfort measures that may improve outcomes. reinfection from untreated partners plays a role in recurrences.
Infection control is a priority whenever skin integrity is dis- However, partners of EGW-affected patients may benefit from
rupted; surgical wounds and disruptions association with des- examination to assess the presence of EGW, from STD and Pap
iccation can provide additional portals of entry for infection. smear screening, and from counseling about the implications
Before the patient leaves the office, providers should assure of having a partner with EGW and their own future trans-
themselves that patients are able to see their EGWs; for perianal, mission potential [63]. It is important to convey that even if
perineal, and vulvar warts, examination with a hand-held mir- one partner has visible warts, the other may not, although both
ror should be possible. This is especially important for patients have likely been exposed in an ongoing sexual relationship [55].
who elect to use patient-applied therapies. Patients should ex- HPV molecular testing for patients with EGWs or their partners
amine the areas being treated daily to detect any symptoms of has no real utility in the clinical setting at this time; one study
infection, including increased redness, swelling, or discharge has suggested that even if virus testing were performed, it is
(green, yellow, brown, or frothy). Malodorous discharge or any likely that only one partner would test positive for HPV DNA
other signs of infection, including fevers, should be reported [55].
to the clinician immediately. Educational resources are helpful to patients and providers;
Sitz baths, the use of warm water, and other traditional forms these include telephone resources sponsored by the CDC (STD,
of pericare may aid in healing and minimize secondary irri- 800-227-8922 and 800-342-2427; Spanish, 800-344-7432). Also,
tation. After cleansing, heat sources (e.g., heat lamps and warm the American Social Health Association sponsors a telephone
air from hair dryers) can be useful to aid in healing and alleviate hotline for HPV infection and cervical cancer prevention (919-
discomfort. If heat lamps are used, they should be placed no 361-4848), as well as a number of online resources through
closer than 18 inches from the perigenital region; low-wattage their Web site (http://www.ashastd.org or, more specifically,
bulbs (e.g., 45–60-watt bulbs) and fewer than 10–15 min of http://www.ashastd.org/hpvccrc/index.html).
use several times daily are advisable. If patients use hair dryers Cervical cancer screening and EGWs. As for all sexually
to dry the affected area, the dryer should be held ⭓18 inches active women, it continues to be recommended that women
from the affected area, and heat should be adjusted to the lowest with EGWs and the female sex partners of patients with EGWs
possible heat setting. Prophylactic antibiotics are not indicated. be screened regularly for cervical cancer with the Pap test [26,
63]. This recommendation is made irrespective of the sex of a
woman’s partners [189, 190].
PREVENTION ISSUES
Although molecular HPV typing is not recommended for
Education and counseling. Education and counseling mes- the diagnosis or treatment of EGWs, it has been shown to be
sages should seek to improve individuals’ understanding of effective in the triage of women with cervical Pap test findings
their infection and should include key concepts that will enable that show atypical squamous cells of undetermined significance
them to better manage self-care after diagnosis and treatment. (ASCUS). ASCUS bears a limited but significant risk of occult

high-grade cervical intraepithelial neoplasia; 5%–20% of AS- orrhea) and their likely protective benefit for some manifes-
CUS Pap tests are due to high-grade disease [49, 191–196]. tations of HPV infection, condoms are always recommended
The commercially available Hybrid Capture-II HPV DNA de- in new sexual relationships and when partnerships are not mu-
tection test, which uses a battery of probes to detect any of a tually monogamous [217].
group of 13 high-risk types, has been reported in several studies Disclosure. Disclosure of newly diagnosed EGWs to cur-
to have high sensitivity and acceptable specificity for detection rent sex partners may be important, as noted above. However,
of high-grade squamous intraepithelial lesion. Although its cost once warts have resolved, it is not clear that productive infection
effectiveness has not yet been determined, this strategy provides persists or that partners are infectious. Although one clinical
clinicians with a triage tool to decide who might best benefit study has suggested that virions are cleared from symptomatic
from colposcopic evaluation [191, 193]. tissues when EGWs are removed [182], others have found virus
Anal cancer screening and EGWs. Anal cancer is a rare after clearance [219]. Thus, because genital HPV infection is

malignancy whose incidence has been increasing among some so common among persons who have been sexually active and
US populations, most especially among those at risk for HIV because the duration of infectivity is unknown, the value of
infection [66, 67, 69, 72, 197–209]. There is an increasing body disclosing a previous diagnosis of EGW to future partners is
of data documenting its association with high-risk types of unclear.
genital HPV infection [69]. On the basis of analogies with the Preventing perinatal transmission. Patients are often con-
success of Pap smear screening for the prevention of cervical cerned about the effect that HPV infection might have on re-
cancer and concerns over the increase of anal cancer among production. HPV infection does not induce infertility. Although
persons with HIV infection, there has been interest in the use there is clear evidence that HPV DNA can be recovered from
of anal Pap smear screening in selected high-risk populations the lower genital tracts of pregnant women [220–232], the re-
[210–212]. This interest is supported both by evaluations that lationship between HPV exposure among newborns and pro-
have suggested that anal Pap smears have sensitivity similar to ductive infection remains unclear [220–232]. Juvenile-onset
that of cervical smears [209, 213]. Anal Pap testing shows sen- RRP (JORRP) is a rare condition that is associated with high
sitivity and specificity similar to cervical screening that uses Pap morbidity and is thought to be due to low-risk HPV types. The
tests to detect malignant cell phenotypes [202, 204, 205, risk for conveying RRP to progeny is low; prevalence estimates
214–216]. To date, there has been no standard of care for treat- range from 1 in 400 births [76, 233] and 0.36 (95% CI,
ment and follow-up for low- and high-grade anal dysplasias. 0.12–1.13) and 1.1 (95% CI, 0.58–2.13) per 100,000 resident
However, because of limited information about key issues such children aged !18 years [78, 79]. To avoid exposure to the
as the natural history of high-grade anal squamous intraepi- virus, delivery by cesarean section has been proposed by some
[160], however, only a very limited cost-benefit analysis has
thelial lesion and the efficacy and untoward effects of treatment
been performed, and the true effectiveness of this procedure is
for lesions detected prior to invasive cancer, anal cancer screen-
unknown [161]. In addition, the morbidity associated with
ing is not routinely recommended at this time, pending further
cesarean section is significant and, when conservative estimates
studies.
are used, the risks associated with cesarean section are greater
Preventing sexual transmission. Abstinence is the only
than the risk of rearing a child with JORRP [78, 79, 234]. Thus,
known method of preventing HPV infection completely. A re-
cesarean section is not recommended for prevention of JORRP.
cent report that reviewed the efficacy of condoms for specific
sexually transmitted infections concluded that condoms appear
to be effective in preventing HIV infection for men and women OTHER RECOMMENDATIONS: PREGNANCY
and gonorrhea in men but that existing data were inadequate
to answer the question for most STDs [217]. Although con- Several factors may promote growth of HPV-induced lesions
doms have not shown protection against HPV infection, per in pregnancy, including promoting effects of pregnancy hor-
se, Adams et al. [217] concluded that condoms may afford mones and diminished immunoresponsiveness. There are few
some protection against EGWs for men and cervical neoplasia treatments that have been tested and recommended in preg-
for women. Our review of the literature supports this conclu- nancy. Only BCA/TCA, cryotherapy, electrocautery, and sur-
sion; some studies show protection and others do not [48, 218]. gical excision, including laser treatment, are recommended
Well-designed randomized, controlled studies to test condom currently.
efficacy in relation to sexual transmission of HPV infection are
unethical; thus, it is unlikely that we can definitively quantify
Acknowledgment
condom efficacy beyond what can be achieved by well-per-
formed observational studies. However, given the evidence of We thank Jill Donofrio for her assistance in preparing this
condom efficacy for at least some STDs (e.g., HIV and gon- manuscript.

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