INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO.
2, 55
ANOGENITAL WARTS – AN OVERVIEW
Devinder Mohan Thappa*, M Senthilkumar**, Chandrashekar Laxmisha***
ABSTRACT
Anogenital warts refer to the pedunculated, papular
or macular lesions of the anal and / or genital
mucosa and its adjoining area caused by human
papillomavirus (HPV) infection. The true prevalence
of HPV anogenital infection in the community is
unknown. Current evidence suggests that over 50
per cent of sexually active (15–25 years of age) have
been infected with one or more HPV types.
Genotypes 6 and 11 are found in more than 90 per
cent of anogenital warts cases. The diagnosis of
anogenital warts is mainly based on the history of
exposure, clinical appearance, and epidemiological
proof of the warts in the sexual contact. Treatment
options may be categorized into cytodestructive
methods (surgical excision, cryotherapy, laser
therapy, bichloroacetic acid/trichloroacetic acid,
podophyllin and podophyllotoxin), antimetabolic
therapy (5 fluorouracil), antiviral therapy (cidofovir
and interferons [IFNS]) and immunomodulation
(imiquimod). Recently, recommended therapeutic
modalities have been classified into home therapies,
office/hospital therapies and therapies generally not
recommended. The choice of therapy depends on
the morphology and extent of the warts, the
experience of the caregiver and the preference of
the patient.
KEY WORDS
Anogenital Warts, Clinical Features, Diagnosis,
Treatment Options
INTRODUCTION
Although genital warts have been documented since
the time of Hippocrates, they still remain as one of
the most common sexually transmitted disease1.
This is because majority are sub–clinical2 and no
* MD, DHA, MNAMS, Professor & Head,
** MBBS, Junior Resident,
*** MD, Senior Resident
Department of Dermatology & STD
Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry - 605 006, INDIA
Address for Correspondence :
Dr. Devinder Mohan Thappa, MD, DHA, MNAMS, Professor & Head, Department of Dermatology & STD,
JIPMER, PONDICHERRY-605 006, India • e-mail : dmthappa@jipmer.edu
modality of treatment necessarily eradicates warts,
maintains clearance and eliminates the virus3.
DEFINITION
Anogenital warts refer to the pedunculated, papular
or macular lesions of the anal and / or genital
mucosa and its adjoining area caused by human
papillomavirus (HPV) infection.
HISTORICAL BACKGROUND
Genital warts (Condyloma acuminata) have been
known since ancient times. Greek physicians first
described the disorder and coined the term
"Condyloma" (meaning : rounded tumor)4. Roman
physicians discussed the etiology and called it as
"Thymus" (due to its resemblance to the plant
Thymus capitatus) and "Ficus" (due to its similairty
to the surface of the plant Ficus sycomorus).
"Feigwarze" is a German word for condyloma and
there it is still in use4. At the end of 15th Century,
after the arrival of syphilis to Europe, genital warts
were also considered as a manifestation of syphilis.
Hence, some of the specific lesions in secondary
syphilis are still referred to as "Condyloma lata"4. In
1901, Heidingsfeld described the transmission of
this disease through sexual contact. In 1949,
Strauss et al, isloated the agent responsible for
warts, the human papillomavirus. Since then HPV
has become recognized as a significant human
pathogen1.
EPIDEMIOLOGY
The incidence and prevalence of clinical HPV genital
infection have been steadily increasing since the
mid-1960s, But the true prevalence of HPV
anogenital infection in the community is unknown
becuase5 :
(7)
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 56
i. The disease is symptomless and subclinical
infection is common.
ii. Many individuals do not seek medical help.
iii. Most patients consult general practitioners,
who won't notify this infection to public health
authorities.
iv. Even in many STI clinics, from which accurate
data are genernally avialable, the diagnosis
is made only when condyloma are seen.
Current evidence suggests that over 50 per cent of
sexually active adults (15–25 years of age) have
been infected with one or more HPV types6. In
United States, the estimated prevalence among men
and women between 15–49 years of age with genital
warts is 1.4 million and with subclinical infection is
19 million. In Britain and Ireland every year, 80,000
new cases of anogenital warts are reported 6. The
prevalence of anogenital warts in India has been
reported to be 5.1 per cent to 25.25 per cent of STD
partiens 6. Amongst 144 cases of viral warts
attending Dermatology and STD OPD at JIPMER,
Pondicherry between September 2000 and June
2002, genital warts were observed in 15 cases, all
of them were adults and four of them were
seropositive for HIV infection by ELISA7. The mean
age among males was 26 years and among females
24 years with male to female ratio of 2 to 1.
Underlying HIV infection may increase incidence
and prevalence of genital warts6.
The incidence of warts is reported to be between 5
and 27 per cent in HIV infected individuals. In a
prospective study, out of 912 HIV-1 infected patients,
21 per cent had common/plantar warts and 19 per
cent condyloma acuminata 8.
ETIOLOGY
The causative agent, human papillomavirus (HPV)
belongs to the family papillomaviridae, which
includes papillomavirus affecting other species 1.
But HPV has remarkable species specificity.
HPV are non–enveloped and have icosahedral
sysmmetry with 72 capsomeres forming the outer
coat 1. This coat consists of a major capsid protein
and a minor capsid protein. Within this coat, a
circular, supercoiled, double stranded DNA
approximately 8 Kb in length is present. The DNA
has a number of genes or open reading frames and
also a single control region (incorporating promoter
regions and regulator regions). These genes are
divided as early genes (E1 – E7) and late genes
(L1 and L2). Early genes (E1 – E7) are involved
with replication, transcription and also with
oncogenic transformation (E6 and E7). The L1 and
L2 genes encode the major and minor capsid
proteins respectively1.
There are at present more than 100 different
genotypes. Of these forty–five have been found to
infect the genital epithelium 6. Genotypes 6 and 11
are found in more than 90 per cent of anogenital
warts cases 3. Patients with visible warts may be
infected simultaneously with oncogenic "High Risk"
HPVs such as types 16 and 18, which mostly give
rise to subclinical lesions associated with
intraepithelial neoplasia (IN) and anogenital cancer.
The novel HPV types are defind as having less than
90 per cent homology with known types in the L1
open reading frame 1. Several types of HPV can
co-exist in the same wart. These HPV types cannot
be differentiated serologically and cannot be grown
in vitro 6.
PATHOGENESIS
All HPV types target epithelial cells and their
replication depends on the presence of
differentiating squamous epithelium 6. Viral DNA
alone can be deteched in the lower layer of the
epithelium. Capsid (structural) proteins and
infectious viruses are found in the superficial
differentiated cell layers. The infectious virus from
the epithelial cells of infected partner gains entry
through the microabrasions caused by trauma of
sexual act and reaches the basal layer of the
recipient 6. After infection, in the absence of
transformation, HPV follows the normal cycle of
reproduction. Clinical and histopathologic evidence
of HPV infection usually develops 1–8 months after
initial exposure. Untreated, these lesions may
regress spontaneously or persist as benign lesions1.
The persistence can be attributed to the lack of
detectable local immunological response, which may
be due to the following facts 6.
i. The virus producing cells are away from the
basement membrane as far as immune
response is concerned.
ii. Inadequate production of viral particles and
viral antigens.
iii. The infected cells may exhibit insufficient
histocompatibility antigen display on their
surface.
iv. Absence of Langerhan's cells at the site of
warts.
(8)

TRANSMISSION OF THE VIRUS
Genital HPV infections are transmitted primarily
through sexual contact 6. The infectivity of HPV
between sexual partners is estimated to be 60 per
cent. Digital transmission has been reported.
Perinatal transmission can also occur.
IMMUNOLOGY OF WARTS
Inability to propagate HPV in the laboratory has
hampered investigations on the immunology of
warts. 6. Both cell medicated immunity (CMI) and
humoral response have been documented in
patients with genital warts. But CMI appears to be
important.
CELL MEDIATED IMMUNITY
Increase in the CMI has been shown to be effective
in regression, controlling reactivation, preventation
of recurrence and elimination of warts. Evidence for
this has come from followng observations 6.
i. Pateints with deficiency of CMI have an
increased incidence of warts (e.g. HIV
patients, renal transplant receipients receiving
immunosuppressive drugs etc).
ii. Children with warts show reduced tuberculin
reactivity.
iii. Absence of Langerhan's cells and T cells in
the epidermis surrounding the wart.
iv. Marked dermal infiltrate of mononuclear cells
present around spontaneously resolving
warts.
HUMORAL IMMUNITY
Various studies have shown that human sera have
antibodies that react to HPV proteins 6. In patients
with regressing warts, lgM (100 per cent), lgG (97
per cent) and lgA (80 per cent) classes of antibodies
to HPV antigens have been detected. In 83 per cent
of these patients, lgM class of antibodies to virus-
infected cells were also found. The patients with
complement fixing lgG antibodies had higher cure
rate and shorter duration of warts (less than one
year) 6. Whether this increase in antibodies is the
result of the regression of the wart or it is responsible
for the regression of the warts, is still unknown6.
CLINICAL FEATURES
Infection begins with viral entry and then may follow
one of three paths, latent infection in which virus
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 57
remain dormant without producing any gross or
microscopic evidence of disease and, hence,
asymptomatic subclinical infection and clinical
disease, both asymptomatic and symptomatic 1,6.
The lesions appear after an incubation period of 1–
8 months with an average of three months 6. They
may be solitary but generally comprise from 5 to
15 lesions of 1–10 mm diameter. Warts may
coalesce into large plaques which are particularly
common in immunosuppressed individuals and in
diabetics3. In uncircumcised men, the preputial
cavity (frenulum, glans penis, coronal sulcus, inner
aspect of the foreskin) is most commonly affected,
while in circumcised, the shaft of the penis is often
involved. Warts may also occur on the scrotum,
groin, perineum and anal area 3. In females, the
common sites involved are posterior part of the
introitus, labia, perineum and perianal area. Lesions
can also be seen intravaginally or in the cervix, but
these areas are affected commonly in subclinical
infection 6. The urethral meatus is affected in 20–
25 per cent males and 4–8 per cent of females.
Anal warts are seldom found proximal to the dentate
line. Intra –anal warts are most common when
receptive anal intercourse had been practised.
Colour of these warts varies from pinkish raspberry
to salmon red (non-keratinized warts), greyish white
(heavily keratinized lesion) and ashen grey to
brownish black (pigmented lesions). Condylomas
tend to be non-pigmented but, if they are, mostly
seen on pigmented skin (labia majora, penile shaft,
pubis, groin, perineum and anal area )3.
CLINICAL TYPES OF GENITAL WARTS 6
1. Condyloma acuminata (acuminate warts)
These lesions are soft, pink, pedunculated
papilliferous masses (caulifloer like) with
finger like peduncles and irregular surface.
They are usually seen on the moist partially
keratinized epithelium such as preputial
cavity, urinary meatus, labia minora, introitus,
vagina, cervix, anus andanal canal, but may
affect intertriginous areas as well (groin,
perineum and anal area) 4,6.
2. Papular warts
These are protuberant, non-pedunculated,
dome shaped or hemispherical masses, 1–4
mm in diameter and are located on fully
keratinized epithelium 6.
(9)
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 58
3. Verruca vulgaris type or keratotic warts
These are non-pedunculated, firm, papular
lesions with slightly rough, horny surface, size
ranging from few millimeters to few
centimeters in diameter. They are ususally
seen on dry fully keratinized areas like shaft
of the penis, outer aspect of prepuce, labia
majora and perineum 6.
4. Sessile warts
These warts resembling plane warts on the
non-genital skin, are multiple, non-coalescent,
tiny lesions with no horny surface, tend to be
seen on the shaft of the penis, but they are
not seen on vulva 6.
5. Flat warts
Although not being very protuberant, flat warts
are also slightly raised or macular which may
exhibit undulating wavy surface, sometimes
with micro spikes. They may be located
anywhere on the genital epithelium, are
probably more common than acuminate warts
and are often overlooked 4,6. On the vulvar
vestibule, velvety, granular or cobblestone like
surface has been named as "vulvar
papillomatosis"9. On colposcopic examination
these lesions have been colorfully described
as "Arizona cactus-like projections", "camel
hump – like projections" and "stony colonial
pavement – like projections"
6. Intraepithelial neoplaisa – Bowenoid
Papulosis & Bowen's Disease
Boweniod papulosis (BP) and Bowen's
disease (BD) are visible lesions associated
with oncogenic HPV types, most commonly
HPV 16 that exhibits full thickness intraepithelial
neoplasia (IN-III) 3. These conditions are
distinguished based on clinical grounds patients
age being most important, BP appears at 25–
35 years and BD at 40 – 50 years or over. BP
presents as multiple, small, verucous or velvety,
often pigmented papules that involve the
anogenital region of young adults3.
7. "Giant condyloma" (Buschke-Lowenstein
tumor)
This is a very rare variant of HPV 6 and 11
assoicated disease, characterized by
aggressive down growth into underlying
dermal structures3. A complex histological
pattern may exist with areas of benign
condyloma intermixed with foci of atypical epithelial
cells or well differentiated squamous cell carcinoma.
Diagnosis of Buschke-Lowenstein tumor often
requires multiple surgical biopsies, computed
tomography or magnetic resonance imaging 3.
SUB–CLINICAL INFECTION
Sub–clinical HPV infections together with latent
infection are probably the most likely outcome after
exposure to HPV 2. They are associated with
symptoms such as itching, burning, fissuring and
dyspareunia. In general, the mucosal surface is
normal looking until acetic acid is applied, after
which well–demarcated, roundish white lesions may
appear. In men, entity called papillomavirus
associated balanoposthitis has been proposed, this
condition is characterized by recurrent, painful
fissuring of the frenulum, the coronal sulcus or the
prepuce, causing dyspareunia. In women the lesions
are often found on vulva, perineal and perianal area
but seldom around urethral meatus. Treatment
should be offered to only those patients who are
sypmptomatic. But, predominantly sub–clincial
infections are asymptomatic 2.
ATYPICAL LESIONS
These are considered to be brownish red or
hyperkeratotic macules clinicially identifiable by the
naked eye without acetic acid application 2. If
biopsied, these lesions are generally found to contain
neoplastic lesions and HPV of the high – risk type.
Like sub–clinical infection, atypical lesions are also
found in the vicinity of clinically apparent lession 2.
PHYSICAL AND PSYCHOSEXUAL IMPLICATIONS
Physical symptoms may include inflammation,
fissuring, itching, bleeding or dyspareunia 3 .
Clinically apparent lesions are disfiguring and can
impact sexual lifestyle. They cause feelings of guilt,
anger, anxiety and loss of self esteem and create
concerns about future fertility and of cancer risk 3.
CLINICAL EVALUATION AND INVESTIGATIONS
The diagnosis of anogenital warts is mainly based
on the history of exposure, clinicial appearance, and
epidemiological proof of the warts in the sexual
contact 6. In both sexes, a careful inspection of the
outer geinitalia is performed with a clear and
powerful light. Use of a lens is highly recommended
for small lesions. In women with anogenital warts,
25 per cent also have acuminate and / or vaginal
warts and up to 50 per cent have flat lesions or
(10)

cervical intraepithelial neoplasia (CIN) lesions,
majority being low grade. Hence, all women with
anogenital warts should have a speculum
examination to identify the presence of co-existing
vaginal and / or cervical warts. For flat lesions,
colposcopy and / or cytology recommended. It is
essential to look for concurrent STDs and tests
for them should be offered. Before therapy,
recording the distribution of solitary, multiple or
plaque lesions at various sites allows for
subsequent evaluation of clearing of original
lesions and the identification of any new lesions
that develop 3.
THE ACETIC ACID TEST
Following application of 3 – 5 per cent acetic acid,
HPV lesions turn greyish white 2,3,4. Examination
of the vulva and penis should be done after 2 or
3 minutes, but on cervix uteri, the reaction
generally appears within one minute. This whitish
appearance is attributed to an over expression of
cytokeratin 10 in the HPV infected suprabasal
cells. These cells are undifferentiated and have
high protein content and the whitening might be
caused by de caused by denaturation. This test
has poor spcificity and its false positivity is
commonly due to inflammatory conditions and
give rise to ragged irregular acetowhite borders.
Also low sensitivity, since this test reveals areas
with undifferentiated epithelium that might or
might not be HPV associated. Hence, it is not
recommended for screening purposes but can be
used for visualizing sub – clinical genital HPV
associated lesions, identifying lesions for targeted
biopsy and for demarcating lesions during surgical
therapy.
COLPOSCOPY
It has a higher sensitivity espcially for low grade
CIN 3 . It also helps in taking biopsies of
representative areas and delineation of the afilicted
areas during therapy.
MEATOSCOPY
The meatal lips can be everted using cotton wool
swab but a fuller inspection of the fossa navicularis
in men is perfomed by "meatoscopy" using a small
speculum (spreader) or an otoscope, about 5 per
cent of cases require urological investigations for
adequate delieations of the proximal border 3. As a
rule, the posterior urethra of male patients is not
involved without previous or simultaneous growth
of meatal warts.
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 59
PROCTOSCOPY
Concurrent perineal and perianal warts exist in one
third of patients, hence, anoscopy is indicated 3.
SOUTHERN BLOT HYBRIDIZATION
This technique is the "Gold standard" among HPV
DNA detection methods with a sensitivity range
between 0.1 and 0.01 viral copies per cell, but is
too time consuming and labour intensive for routine
diagnosis 4.
IN SITU HYBRIDIZATION
It helps in determining the localization of HPV DNA
within the specimen4. Here biotinlyated probes are
used, since they are more stable than the readiactive
probes and do not expose the staff to radioactivity.
POLYMERASE CHAIN REACTION
This is the most sensitive method for detection of
HPV DNA, being able to detect one viral genome in
100,000 cells 4. This technique is able to detect latent
infection but has little benefit in routine diagnosis
and management and is primarily used as a
research tool 6.
HISTOPATHOLOGICAL EXAMINATION
The histological characteristics of the "classical
protuberant growth type of condyloma acuminatum
in the anogenital region are 6,9,10.
1. Parakeratotic hyperkeratosis of varying
degree.
2. Moderate granulomatosis.
3. Pronounced acanthosis with thickening and
elongation of the rate ridges and
papillomatosis.
4. Mitotic figures may be present in the epidermis
5. The most characteristic feature important for
diagnosis is the "Koilocytes", which are mature
squamous cells with a large, clear perinuclear
zone and smudgy nuclei, scattered throughout
the outer cell layers.
The nuclei of koilocytes may be enlarged and
hyperchromatic and double nuclei are often seen6.
Ultrastructural studies show virus in some of the
cell nuclei. Although koilocytes are thought to
represent a specific cytopathic effect of HPV,
koilocytic features are often subtle and other cellular
changes may mimic koilcytic change. Thus detection
of koilocytes is not a sensitive or reliable predictor
(11)
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 60
of cervical HPV infection. Viral antigen can be
demonstrated in the nuclei of cells in the stratum
granulosum by peroxidase–antiperoxidase test,
indirect immunofluorescence and indirect immuno-
alkaline phosphatase reaction 6. Genital warts are
differentiated from plane warts by the presence of
basket weave orthokeratosis, instead of
hyperkeratosis in plane warts 6. Usually, invasive
squamous cell carcinoma can be ruled out becuase
the epithelial cells show an orderly arrangement and
the border between the epithelial proliferations and
the dermis is sharp 10.
Biopsy is unnecessary for newly occuring, multiple,
acuminate warts in patients younger than 35 years
but is recommended in atypical cases for differential
diagnositc purpose or in any case where the benign
nature of a papular or macular lesion is unclear such
as in conspicuous Bowenoid papulosis, Bowen's
disease and giant condlylomas. HPV typing of
anogenital warts does not add information of clinical
use 3.
DIFFERENTIAL DIAGNOSIS
Morphologically, various conditions, which need to
be differentiated from verrucous lesions of genital
warts, are condyloma lata of syphilis, non-venereal
treponematosis, hypertrophic verrucous type of
granuloma inguinale, tuberculosis verrucosa cutis,
skin tags, and malignancy2,3,6 . For small genital
warts, various differential diagnoses need to be
considered are pearly penile papules, vestibular
papillomatosis, molluscum contagiosum,
seborrhoeic kertosis, Fordyce's spots, urethral
caruncle, lichen planus and foreign body
granuloma2,3,6 . For sub–clinical infection (seldom
appears reddish), candidial infection of the vulva
and repeated topical application of antifungals need
to be ruled out. Others benign tumors like
neurofibroma, lipoma, fibroepitheliomata, and
normal physiological glands like Tyson's glands also
need to be considered before appropriate diagnosis
is made. Around the anus, prolapse and sentinel
piles, and anal tags may be confused with anogenital
warts. In unhygienic persons, dry smegma may
appear like warts and, hence, cleaning the sub-
preputial region is emphasized before the
examination of warts in male genitalia. For the
pathological specimen of genital warts, various
diferential diagnoses considered are seborrhoeic
keratosis, mollusucm contagisum, psoriasis, lichen,
planus, condylomata lata, Bowen's disease and
squamous cell carcinoma 2.
TREATMENT
Realistic expectations of treatment should be
set in the context of a disease that currently
has a high treatment failure and recurrence rate
11
. Hence, the three main therapeutic goals, are
(1) induction of wart – free periods to alleviate
anxiety and to reduce the risk of transmission
of HPV.
(2) therapy that is no worse than the disease and
(3) minimization of morbidity and mortality for
cervical cancer.
Treatment options may be categorized into
cytodestructive methods (surgical excision,
cryotherapy, laser therapy, bichloroacetic acid /
trichloroacetic acid, podophyllin and
podophyllotoxin), antimetabolic therapy (5
fluorouracil), antiviral therapy (cidofovir and
interferons [IFNs]) and immunomodulation
(imiquimod)1. Recently, recommended therapeutic
modalities have been classified as follow 3.
Home therapy
l Podophyllotoxin (0.5 per cent solution or 0.15
per cent cream).
l Imiquimod
Office/Hospital therapy
l Electro surgery / laser / curettage / scissors
excision
l Cryotherapy
l Tricholoracetic Acid.
THERAPIES NOT GENERALLY RECOMMENDED
(Used only in speical situations) 3
They include Interferons, 5-Fluorouracil or
podophyllin.
The choice of therapy depends on the duration,
morphology and extent of the warts, the experience
of the caregiver and the preference of the patient 3.
First line treatment will achieve clearance in most
patients within 1–6 months, although disease
persists in up to one third of patients 3. In general,
home therapy can be proposed in most cases as
first line therapy for a first attack of acuminate warts
(Acuminate warts respond in up to 90 per cent) but
papular and macular lesions in only 50 per cent of
cases) and for patient with limited disease (1–5
warts) may benefit from simple office therapy.
Lesions occuring at new sites during treatment or
(12)

after clearance do not necessitate a change of the
treatment modality. Peristence or reappearance of the
treated lesion is usually an indication to switch to
another treatment modality 6 . Also treatment modality
is changed if a patient has not improved substantially
after three provider administered treatments or if the
warts have not cleared after six treatments.
Recurrence rates, including new lesions at
previously treated or new, remote sites are often
20-30 per cent3 . All therapies are associated with
local skin reactions including itching, burning,
erosions and pain. Hence, patients should be
informed that periods of coital rest throughout the
course of therapy might reduce therapy related
symptoms.
HOME THERAPY
Podophyllotoxin 0.5 per cent solution & 0.15 per
cent cream of Podofilox
This a purified extract of the Podophyllum plant,
binds to cellular microtubules, inhibits mitotic division
at metaphase and induces necrosis of condylomas
that is maximal 3–5 days after admininstration 3.
Erosion occuring as the warts necrotize following
therapy are shallow and heal within a few days.
The solution or cream is applied with cotton swab
or finger respectively, over the condylomas (also
on normal appearing skin between the lesions)
twice daily for three days followed by four days of
no therapy 6 . Podofilox has a stable half–life, does
not need to be washed off after application. Such
treatment is given for a total of 3 cycles. The total
area of treatment should not exceed 10 cm2 and
total volume should not exceed 0.5 ml. The initial
application is by health provider to demonstrate
proper application and subsequently by patients
themselves 3. Use of 0.5 per cent podofilox soulition
is convenient for penile warts. However, vulvar and
anal warts are more feasibly and efficiently treated
with 0.15 per cent podofilox cream. Efficacy is better
in uncircumcised males than in females and
circumcised males. Urinary meatus warts and warts
on keratinized skin are often refractor3. Its efficacy
has been recorded in 42–88 per cent of the cases11.
Up to 50-65 per cent of patients using
podophyllotoxin, experience transient and
acceptable burning, tenderness, erythema and / or
erosions for a few days when the warts necrotize3.
They are less likely to cause systemic toxicity. Side
effects are usually only associated with first course
of therapy.
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 61
IMIQUIMOD CREAM (5 PER CENT)
Imiquimod (imidazoquinolinamine) is a nucleoside–
like compound that by topical application to warts
acts as an immune response modifier inducing local
production of cytokines including interferon gamma,
tumor necrosis factor alpha, etc., by peripheral
monouclear cells and recruitment of immune cells
including CD4+T cells 3,6 . This process may be
followed by an immune induced wart regression,
which is accompanied by a reduction in HPV DNA.
There is no direct antiviral activity.
Imiquimod cream, supplied in single use sachets,
is applied to the warts with fingers three times per
week (Every other night) and the area washed with
mild soap and water the next morning 3,6 . Treatment
continued until wart clearance, or for a maximum of 16
weeks. Local reaction at the treatment site may occur
and a rest period of several days may be taken if required
5
. Erythema develops in the majority of indiviuduals treated
with imiquimod, but excoriation and erosion are found in
just fewer than 50 per cent of patients.
Although imiquimod is expensive in comparison to
other wart treatments, it may be cost-effective5.
However, it is not suitable for the treatment of long
standing, fibrotic warts 3. In a pivotal clinical study,
it has been found that female and circumcised men
had better clearance rates than uncircumcised
men12. One study suggests that maximum potential
is seen only after removal of warts to prevent their
recurrence. Hence, it can be used in combination
with surgical excision, cryotherapy or ofter non-
surgical interventions 12.
CONTRAINDICATIONS & PROBLEMS
ASSOCIATED WITH HOME THERAPY
Both imiquimod and podofilox have not approved
for treatment of perianal, rectal, urethral, vaginal or
cervical warts 3,6 . Safety in pregnancy has not been
established for both the agents, Hence, woman of
childbearing age must use contraception or abstain
from penetrative sexual acitvity during therapy.
Skin reactions to podophyllotoxin generally develop
on day 3 of therapy and to imiquimod, after 3-4
weeks 3,6 . Wart resolve spontaneously within a drug
free period of a few days.
A rare but important complication is difficulty in
retracting the foresin becuase of painful erosions or
edema when treating multiple warts in the preputial
cavity 6 . For this, medical supervision is required.
Daily symptomatic office therapy include using saline
rinses and a topical corticosteroid cream applied
liberally under the foreskin until improvement.
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INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 62
OFFICE / HOSPITAL THERAPY
1. Surgical Treatment
It is not possible to give clear directions for
the surgical method of choice, as this is a
matter of wart distribution, local tradition and
the clinical skills and experience of the
physician 3. More excessive destruction may
lead to fibrosis and scarring. When performed
carefully, simple surgical procedures leave
highly cosmetic results, with the exception of
some depigmentation, which is
disadvantageous on very pigmented skin.
All lesions treated properly by surgery
virtually disappear. However, regardless of
the technique, 20–30 per cent of patients
will develop new lesions at the borders of
the treated tissue and or at remote sites.
a. Scissors Excision
Superficial scissors excision is useful, if
only a few lesions are present and may be
assisted by diathermy to control bleeding
and to destroy any conspicuous wart tissue
remaining after the excision 3,9. Hence, it
is best used for a limited number of warts
and for those with a narrow base. However,
circumcision for extensive prepucial warts
find no place in the list of treatments for
genital warts in men, which was tried
successfully in a case in India13.
b. Electrosurgery
Modern electrosurgical units utilize
monopolar systems, where the electric
current flows from the active electrode, the
ball or the loop, through the patient's body
to the retun pad of the electrode 3. Heat is
produced in the tissue at the point of entry
of high frequency currents 5 . Several
methods like electrofulguration,
electrodessication and cutting may be
useful in the treatment of genital warts.
Intensive coagulation can result in slow wound
healing, secondary haemorrhage, infection and
scarring. Wart clearance can be achieved in 94
per cent of the cases.
c. Laser excision
The carbondioxide laser is the most widely
used laser for the treatment of anogenital
warts 5. Carbondioxide laser emission are in
the infrared range 3 . The energy emitted is
focussed to a specific spot by a system of
mirrors and lenses, and is strongly absorbed
by all types of tissue. Since total absorption
of the carbondioxide enery occurs in about
0.1 mm of the skin, very high power densities
can be attained in small tissue volumes. This
is recommended for bulky lesions and at
specific sites such as the urethral meatus, in
the vagina, on the cervix and in the anal
canal3. Although initital clearance rates are
good (27–89 per cent) relapses are high,
though this may be improved with
postoperative treatment with interferons and
5 fluorouracil. Both electrosurgery and laser
surgery should be performed with the use of
surgical masks by the treatment team, and
smoke evacuator is requred 3.
2. Cryotherapy
Cryotherapy destroys warts by cytolysis,
directly as the result of the formation of
intracelluar ice crystals and their later thawing,
and from injury to the microcirculation. As a
result of vasoconstriction and damage to the
endothelium, thrombosis develops in the
arterioles and venules of the tissue 5 .
Treatment is usually performed at weekly
interals, a freeze-thaw–freeze technique used
at each session 3. Open application of liquid
nitrogen can be performed either by spray
device or by direct swab application, freezing
the lesion and a margin of healthy skin 1 to 2
mm beyond the periphery of the lesion for
about 20 seconds. Closed cryoprobe systems
utilize ciruclation of carbondioxide, nitrous
oxide, or nitrogen, the probe gently pressed
to the surface, moistened with saline or
lubricating jelly and freezing performed until
a freezing "halo" occurs a few millimeteres
around the lesions.
Cryotherapy has the advantage of being
simple, inexpensive and rarely causes
scarring or depigmentation. Clinical studies
report an efficacy range of 63–88 per cent 11.
These treatments are suitable for warts at all
automic sites but becasue of discomfort,
should not be used on large areas.
Cryotherapy is a safe treatment in pregancy5.
Cryotherapy can be very successful in
clearing warts that failed to respond to
podophyllin.
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 INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 63
3. Trichloroacetic acid (TCA) 80–90 per cent
soultion
TCA is a caustic agent that causes skin
destruction by coagulation of cellular proteins.
It is applied directly to the wart surface with a
cotton tip applicator 3,11. It is most suitable for
small acuminate or papular warts but less
efficacious for keratinizd or large lesion.
Reported clearance rate of lesions is similar
to that of cryotherapy and podophyllin. Multiple
applications at 1-2 weekly intervals may be
required but repeated therapy is not well
tolerated because intense burning may be
experienced for up to 10 minutes after
applications. TCA is extremely corrosive and
overzealous use may caused excessive pain,
deep ulcerations into the dermis and scarring.
Care should be taken to avoid contact with
the surrounding normal skin and the solution
be allowed to dry before the patient sits or
stands 5. If pain is intense, dusting with sodium
bicarbonate can neutralize the acid. A
5.
neutralizing agent (for example, sodium
bicarbonate, talc, liquid soap) should be
readily available in case of excess application
or spills 3,11. When used optimally, a shallow
ulcer forms that heals without scarring. TCA
can be used safely during pregnancy.
Therapies not generally recommended
Becuase of several shortcomings including low
efficacy and toxicity problems, routine use of
interferons, 5- fluorouracil cidofovir, retinoids
or podophyllin is not recommended
generally 1,3. In the specialist setting, 5-
fluorouracil is sometimes used against urethral
warts and interferons alpha and beta, as
adjuvant to surgery in problem cases.
Interferons
Interferons (IFNs) are naturally occuring
antiproliferative and antiviral compounds1.
Three IFNs have been identified. IFN alpha,
IFN beta, and IFN gamma. Their therapeutic
actions in HPV infection seem to be secondary
to induction of antiviral protein synthesis and
stimulation of cell mediated immunity.
Interferons may be administered topically,
systemically or intralesionally. Side effects of
topical therapy are mild. Systemic therapy may
be given intramuscularly or subcutaneously.
Given systemically, IFN may be more
efficacious than placebo. Intralesional IFN
injections seem to have the greatest efficacy
in the treatment of HPV interferon therapy for
warts. It is extremely expensive and systemic
side effects (with intralesional as well as
subcutaneous or intramuscular delivery)
frequently occur including headaches and flu
like syndrome of fever, myalgias and malaise
as well as transient leukopenia 1,9.
Interferon therapy is contraindicated in
individuals with known hypersenstivity cardiac
disease, severe renal, hepatic or myeloid
dysfunction, severe depression and poorly
controlled epilepsy 5. The safety of interferons
in pregnancy has not been established.
Overall, there has been failure to show a clear
advantage of interferon treatments over
conventional therapy with respect to efficacy.
In HIV infected patients, interferons are not
effecitve in eradicating the lesions 14. This
finding suggests that some component of the
host immune system must be intact for
successful treatment with interferon.
Fluorouracil (5-FU)
The antimetabolite (5-FU is a pyrimidine
analog that is incorporated into RNA in
preference to the natural substrate uracil. It
inhibits thymidylate synthetase, thereby
inhibiting DNA and RNA sythesis, and
disrupting cell division 5 . This medication may
be applied topcially (5 per cent cream) or
injected directly into warts. The cream is
applied once or twice per day to the warts until
they regress or until pain or ulceration
necessitates cessation of treatment. It has
also been observed that the application of 5-
FU on two consecutive nights per week for 10
weeks is as effective as continuous therapy,
but there are fewer side effects. Side effects
of topical 5-FU include local inflamation and
irritation, but ulceration may be a troublesome
complication5. Side effects of intralesional 5-
FU treatment include pain, erythema, skin
discoloration, ulcerations and erosions. 5-FU
is a known mutagen and teratogen, and its
use should be avoided in pregnant and
lactating women 1.
Althought topical 5-FU is not quite as effecitve
as other treament modalities, such as laser, it
has the advantage of easy home application
by the patient 14. 5-FU is also useful in
decreasing the size of very extensive lesions,
making them more amenable to more
definitive therapies.
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INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 64
CIDOFOVIR
Cidofovir, an antiviral nucleotide analogue initially
approved for treatment of cytomegalovirus
infections, also has shown promise in treating HPV1.
It has been succefully used topically in refractory
warts and in HIV infected patients with genital warts.
Side effects of topical cidofovir include erythema,
local irritation, ulcerations,and post treatment
hyperpigmentation1.
RETINOIDS
Retinoids are another theroritically promising
modality for the treatment of HPV disease 9. They
have been demonstrated to enhance both humoral
and cell-mediated immunity. These compounds are
also well known regulators of cellular differentation.
Several reports have documented beneficial results
with systemic retinoids used for immunosuppressed
patients with HPV disease.
PODOPHYLLIN
Although podophyllin has only moderate efficacy
and more side effects than podophyllotoxin, this drug
still deserves full consideration as first line therapy
in developing countries like India because of its
cheaper rate, widespread clinical use and
nonavailablity of podophyllotoxin and imiquimod, and
its often–spectacular initial effects 6.
Podophyllin was introduced in the treatment of warts
in 1942 5. It is an ethanol extract prepared from the
dried rhizome and roots of the plant Podophyllum
spp. (Greek podos-a foot, phyllon- a leaf), so
named as the leaf has a fancied resemblance to a
webbed foot 6. It is a complex resinous material
containig podophyllotoxin, alpha peltatum and beta
peltatum, obtained from American plant,
Podophyllum peltatum and P. emodi, an Indian plant,
growing in the Himalayas (May apple or Mandrake).
Podophyllin inhibits mitosis at metaphase and
causes swelling and necrosis of cells. It is used as
a dry powder or by making solutions with mineral
oil, rectified spirit, liquid paraffin, propylene glycol;
and tincture of benzoin, 10–25 per cent is the usual
form used worldwide. Podophyllin is applied to the
warts by clinicians using cotton tipped swab once
or twice a week for up to six weeks. Applications
are limited to less than 0.5 ml or 10cm 2 per
treatment session. The surrounding skin is protected
with vaseline/petrolatum, powder or both. One to 4
hours after application, it is completely washed off.
After 6 sittings if the warts persist, other treatment
modalities need to be considered 6. Wart clearance
rate at the end of the treatment has been 32–79 per
cent11.
Podophyllin is contraindicated in pregnancy 6. It
leads to fetal death and abortions. Systemic
absorption of podophyllin can rarely result in renal
toxicity, cardiovasuclar crisis, neuropathy, coma,
hepatotoxicity, granulocytopenia, and
thrombocytopenia. Prolonged use of podophyllin is
not advocated for the fear of its oncogenic potential
due to its two chemical mutagens (quercetin and
kaempherol)11.
As per a recent report, it has been pointed out that
podophyllin, which has low efficacy, high toxicity, and
a serious mutagenicity profile does not comply with
the WHO guidelines for plant-derived treatments 15.
It has been suggested that this product should be
reomoved from clinical treatment protocols.
MANAGEMENT ISSUES IN LATENT &
SUBCLINICAL HPV INFECTION
Subclinical HPV infection is one that is not clinically
visible with the unaided eye, requiring colposcopy
with or without aceto-whitening or histopathology
to confirm the diagnosis 14. Latent HPV infection is
an infection in which the presence of HPV can be
confirmed only by the detection of the HPV DNA. It
seems reasonable that totally asymptomatic patients
probably should be left alone, because, there is no
completely successful treatment available to
eliminate HPV from infected cells and potential
morbidity from over treatment can be significant. The
cases where subclinical disease is identified by
ancillary means, they can be treated by a variety of
methods, including cryotherapy or laser.
COURSE & PROGNOSIS
The natural couse of genital warts spans the entire
spectrum of behaviour, from limited, easily treatable
disease to extensive progressive disease resulting
in intraepithelial neoplasia or invasive squamous cell
carcinoma 14. Although malignant transformation is
believed to be rare occurrence, genital warts can
be found immediately adjacent to vulvar carcinomas
about 15 per cent of the times.
ANOGENITAL WARTS & PREGNANCY
Warts flourish in pregnancy and there is increase in
both size and number 6. This may be due to the
influence of increased hormone level, vascularity
and immune deficiency, which are seen in
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pregnancy. Large warts may cause dystocia. Even
without treatment, warts may reslove after delivery.
The newborn may pick up infection during labour.
Cryotherapy and TCA are ideal for warts in pregnant
women. Large warts can be surgically excised.
Podophyllin, podofilox, imiquimod, and 5-
Fluorouracil are not advocated in pregnancy. Some
clinicians prefer elective caesarian section to prevant
transmission of the infection to the neonate 6.
ANOGENITAL WARTS IN CHILDREN
Genital warts in children may result from several
modes of transmission acquistion at birth by HPV
transmission from the material genital tract,
autoinoculation from finger warts, and non–sexual
transmission from family members/carers 3 .
However, the potential of sexual abuse must always
be borne in mind, in one large series, child abuse
was documented in 43 per cent of the cases of
genital warts. A multidisciplinary team that includes
a pediatrician should, therefore, manage children
with anogenital warts. Genital warts present at
delivery are associated with a risk of 1 in 400 of the
infant developing juvenile laryngeal papillomatosis.
There is no proof treatment of pregnant women
diminishes this risk. Although reduction of viral
burden would seem possible.
ANOGENITAL WARTS AND IMMUNOSUPPRESSION
Immunosuppression, as consequence of HIV
infection, and iatrogenically, as a result of transplant
grafting, is linked to a significant increase in
multicentric and refractory condylomas, and of
intraepithelial neoplasia 3. Hence, annual cytological
screening of HIV positive and allografted women is
advised. In the management of anogenital wart in
HIV–infected patients, imiquimod has been found
useful 5. Although, there is no complete clearance
of warts, a reduction more than 50 per cent in the
area of the warts was noted.
VACCINES
Since treatment is often unsatisfactory and is not
directed at elimination of the virus, some progress
has been made in the development of the
vaccines 16.
PROPHYLACTIC VACCINE
All these preparations are based on virus like
particles (VLP), which are recombinant versions of
the major capsid protein (L1) of the relevant HPV
INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 65
types 6,16. These are under trials and the aim of these
trials is to develp a vaccine against oncogenic HPV
types.
THERAPEUTIC VACCINES
These preparations are also under trial, and here
DNA based vaccines and the VLP that have protein
other than the L1 proteins are used 3,16. Their aim is
to produce a vaccine, which promote neutralizing
antibodies, and also a cellular immune response,
which may eleminate an established intracellular
viral infection.
PATIENT COUNSELING
Information and counseling are fundamental to
proper management and need to be non-
judgmental, supportive and focus on the nature of
the disease, therapy expectations, and a balanced
perspective on sexual issues 3. Patients should
receive clear information as to the cause, treatment
outcomes and possible complication of anogenital
warts. Advise female patients about regular
participation in cervical cytology screening
programmes. Encourage patients to use barrier
protection with new sexual contacts until successful
treatment has been completed. The use of condoms
within a stable relationship may not be needed, as
the partner will already have been exposed to the
infection by the time of consultation. Current partner
and if advisable, other partners within the past 6
months, should be assessed for the presence of
lesions and for education and couseling about STDs
and their prevention.
REFERENCES
1. Brentjens MH, Yeung-Yue KA, Lee PC, Tyring SK.
Human papillomavirus; a review. Dermatol Clin 2002;
20:315-331.
2. Strand A, Rylander E. Human Papillomavirus-
subclinical and atypical manifestations. Dermatol
Clin 1998; 16:817-822.
3. Von Krogh G, Lacey CJN, Gross G, Barrasso R,
Schneider A. European course on HPV associated
pathology; guidelines for primary care physician for
the diagnosis and manangement of anogenital warts.
Sex Trans Infect 2000; 76:162-168.
4. Wikstrom A. Clinical and serological manifestations
of genital human papillomavirus infection. Acta Derm
Venereal Suppl (Stockh) 1995; 193:1-85.
5. McMillan A, Ogilvie MM. Human papillomavirus
infection In: McMillan A, Young H, Ogilvie MM, Scott
GR, Eds. Clinical Practice in Sexually Transmissible
infections London. Elsevier Science Limited,
2002:71-105.
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INDIAN J SEX TRANSM DIS 2004; VOL. 25 NO. 2, 66

6. Usman N, Anogenital warts, In: Sharma VK, ed.
Sexually Transmitted Diseases and AIDS. New Delhi,
Viva books private limited, 2003:273-282.
7. Laxmisha C, Thappa DM, Jaisankar TJ. Viral warts
A clinico epidemiological study. Indian J Dermatol
2003; 48:142-145.
8. Sterling JC, Kurtz JB. Viral infections. In : Champion
RH, Burton, JL, Burns DA, Breathnach SM, eds.
Rook/Wilkinson/Ebling Textbook of Dermatology, Vol
2, 6th edn., Oxford : Blackwell Science Ltd.,
1998:995-1095.
9. Cobb MW. Human Papillomavirus infection J Am
Acad Dermatol 1990; 22:547-566.
10. Penneys N. Disease caused by virus. In : Elder D,
Elenitsas R, Jaworsky C, Johnson, Jr B, eds.
Histopathology of the sin, 8th edn. New York ;
Lippincort-Raven publishers, 1997: 569-589.
11. MawRD. Treatment of anogenital warts. Dermatol
Clin 1998; 16:829-834.
12. Carrasco D, Straten MV, Tyring SK. Treatment of
anogenital warts with imiquimod 5 per cent cream
followed by surgical excision of residual lesions. J
Am Acad Dermatol 2002; 47:S212-S216.
13. Dogra S, Kumar B. Circumcision in genital warts-let
us not forget! (Letter). Sex Transm Infect 2003;
79:265.
14. Sawchuk WS. Vulvar manifestations of human
papillomavirus infection. Dermatol Clin 1992; 10:405-
414.
15. von Krogh G, Longstaff E. Podophyllin office therapy
against condyloma should be abandoned. Sex
Transm Infect, 2001; 77:409-412.
16. Rowen, D, Lacey C. Towards a human papillomavirus
vaccine. Dermatol Clin 1998; 16:835-838.

In
Onychomycosis,

Onylac Ciclopirox Topical Solution 8 % w/w

The Brush - on treatment for Healthy Nails

l Onylac is a chemically and physically stable soultion.
l Viscosity of the lacquer allows it to flow freely into all the edges and grooves of the nail, for
ease of application.
l On application, Onylac dries quickly (3-5 mins) and forms an even film on the nail plate.
l Lacqure film adhereas well to the nail plate and does not come foo during daily activites.
l Onlyac can be removed with cleaning pads.
l Ciclopirox is slowly released from the film and penetrates in to the nail.
l Onlyac is colourless and non-glossy and hence will be acceptable to male patients.
vvvvvvvvvvvvvv

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