Surg Clin N Am 82 (2002) 1199–1211

Anal condyloma and HIV-associated

anal disease
Petar Vukasin, MD*
Keck School of Medicine, University of Southern California,
1450 San Pablo Street, Suite 5400, Los Angeles, CA 90033, USA

In the United States, improved understanding and therapy against

the HIV virus since 1996 has been accompanied by a substantial decrease
in those diagnosed with acquired immunodeficiency syndrome (AIDS);
41,113 new cases were diagnosed during the year 2000 [1,2]. A concurrent
decrease in AIDS-related deaths, however, has increased the number of per-
sons living with the disease to an estimated 337,731 in the year 2000 [1].
Although it is more difficult to estimate, more than 900,000 people may
be infected with the HIV virus [3]. Anorectal disorders occur in 5.9% to
34% of the HIV population [4–6] and are often the initial reason to seek
medical attention [7].
Although there are a large variety of anal diagnoses associated with the
HIV population, anal condyloma and anal ulcerations make up the vast
majority (Table 1) [4,5,8,9]. A large percentage of individuals having multi-
ple concurrent pathologies should also be noted [5,8]. Thus, this review will
concentrate on anal condyloma, anal ulceration, HIV, and making note of
other significant issues.

Anal condyloma
Anogenital warts are among the most common sexually transmitted dis-
eases [10] seen in surgical practices, found in up to 1.7% of the population
[5,11]. Even in the pre-HIV era, increased rates were documented in males
with homosexual contact [12]. More recent investigations report that 3%
to 24.9% of HIV positive individuals have anal warts [4,5,13], with Beck
reporting that 18% of military recruits newly diagnosed with HIV had the
anal lesions [13].

* Keck School of Medicine, University of Southern California, 1450 San Pablo Street, Suite
5400, Los Angeles, CA 90033.
E-mail address: vukasin@pacbell.net

0039-6109/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 9 - 6 1 0 9 ( 0 2 ) 0 0 0 8 5 - 3
1200 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211

Table 1
Incidence of anal pathology in HIV infected individuals as a percentage of those treated for
anorectal disorders
Anal condyloma Anal ulcers Multiple pathology
Miles et al 1990 [4] 38% 26% –
Nadal et al 1999 [5] 24.9% 21.8% 17.2%
Orkin et al 1992 [8] 52% 32% 63%
Yuhan et al 1998 [9] 43% 32% 16%

Clinical manifestations of anal warts are variable, with some patients that
are otherwise asymptomatic presenting with only perianal masses, whereas
others may complain of bleeding, itching, or discomfort. Significant pain
is unusual and should prompt a search for other concurrent etiologies, such
as anal ulcers, fissures, malignancy, or abscesses. It is not uncommon for the
initial diagnosis to be made at a routine physical examination. Diagnosis is
usually obvious to the physician by visualization of multiple white, pink, or
gray papillary hyperkeratotic lesions covering variable extents of the ano-
derm. External anal condyloma should always prompt an anoscopic exami-
nation, because up to 78% of such patients will have internal lesions as well
[14]. Because this is an infection of squamous epithelium, warts are unlikely
to be found significantly proximal to the dentate line. A great number of
treatments for anal condyloma have been described (Table 2) [15]. Those
in common usage today are discussed below.

Eradication of condyloma
Podophyllin is a chemical that is cytotoxic to warts and was first
described in clinical use by Kaplan in 1942 [16]. The solution is applied
directly to external anal condyloma. It is often quite irritating to the sur-
rounding normal anoderm, with reported local and systemic toxicity, as well
as having theoretical oncogenic potential [17]. These features limit its use for
internal anal condyloma. Application of petroleum-based gel to the normal
anoderm surrounding the warts before podophyllin application may limit its
local toxicity (R.W. Beart, personal communication, 2000). Success is lim-
ited, with one study showing only 22% of patients free of warts after three
months of use [18]. Another report finds that at 42 weeks, condyloma had
recurred in 68% of those treated with podophyllin, but in only 28% of those
undergoing surgical excision [19].
Imiquimod is a new topical agent, approved for use in 1997, whose appli-
cation locally releases endogenous cytokines such as interferon [20]. This
immunomodulator applied as a 5% cream (Aldara) has been shown to have
activity against genital condyloma [20,21]. Up to 50% of patients had com-
plete eradication of their anogenital warts after three times weekly applica-
tion for 16 weeks, with minimal anodermal irritation and erythema [22].
Bichloroacetic acid causes a chemical burn, destroying the keratin layers
and subsequently exposed tissues underneath. It shares many of the limita-
 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211 1201

Table 2
Treatments for condyloma acuminata [15]
Folklore
Charming
Hypnosis
Lime water
Lemon juice
Rubbing with raw potato, then burying this during the full moon
Chemical Methods
Podophyllin
Podpphyllotoxin
Imiquimod
Dinitrochlorobenzene
Fowler’s solution
Phenol
Colchicine
Bichloroacetic acid
Trichloroacetic acid
Dimethyl sulfoxide
5-Fluorouracil
Tetracycline ointment
Bismuth sodium triglycollamate
Thiotepa
Sulfonamide cream
Ammoniated mercury
Idoxuridine
Bleomycin
Cantharidin
Solcoderm
Immunologic methods
Autovaccine
Bacille Calmette-Guerin
Vaccinia
Inerferon
Cryotherapy
Liquid nitrogen
Carbon dioxide snow
Liquid air
Electrocautery
Laser
Surgical excision alone

tions of podophyllin in its local irritation, but is not believed to have sys-
temic effects. 5-Fluorouracil as an antimetabolite chemotherapeutic agent
has been has been used in the treatment of anal warts with some success
[23,24]. Three- to seven-day treatments topically have eradicated anogenital
warts in up to 60% of cases, but as von Krough points out, this treatment
‘‘often causes intolerable discomfort to the patients’’ [24]. He and others rec-
ommend reserving this treatment for warts refractory to other methods.
Cryotherapy, most commonly using liquid nitrogen, has been used to treat
anal condyloma. Direct application of this chemical by either spray or cotton
1202 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211

applicator is relatively easy and inexpensive, and has become a very common
practice, especially by dermatologists, who have the equipment and liquid
nitrogen readily at hand. Although the technique has been reported in the lit-
erature [25,26], there are no strong data as to its efficacy. Clearly, however,
there is significant discomfort to the patient, even though this therapy is
usually reserved for those with limited numbers of condyloma.
Interferon, through its antiproliferative properties toward viruses, has
been shown to be effective treatment for anal condyloma [27,28]. Systemic
use has not been helpful, with studies reporting some decrease in condyloma
burden, but rare eradication [29]. One report found a 36% clearance of con-
dyloma after intralesional injection of up to three warts, three times a week,
for three weeks. Interestingly, 17% of the warts in the same study cleared
with simply placebo injection [27]. Another report showed a similar protocol
achieving condyloma resolution in 62% of patients [28].
The most reliable means of eradicating all condyloma concurrently is by use
of scissor excision and electrocoagulation. These techniques continue to be
avoided in preference to the nonsurgical methods because of the significant
associated pain and the cost of anesthesia. Electrocoagulation is accomplished
by creating first and second degree burns of the condyloma-bearing anoderm
using a diathermy electrode. With both techniques, damage to clinically unin-
volved anoderm should be minimized. Again, little information exists regard-
ing the efficacy of this treatment, but Thomson et al [30] report complete
clearance of condyloma at a single session in 80% of patients, with recurrence,
however, approaching 50% at 3 months. Khawaja [19], on the other hand,
found only 28% recurrence at 10 months after excision, compared with 68%
recurrence after treatment with podophyllin.
The advent of laser surgery has seen its application to condyloma eradi-
cation with success rates similar to those of traditional surgical excision [31].
Two comparative studies [32,33] of laser versus conventional surgical exci-
sion found no differences in postoperative pain, healing time, or scar forma-
tion. Bilingham and Lewis [33] do report a somewhat higher recurrence rate
using laser surgery for excision. Due to the expense of equipment and lack of
clinical advantage, the use of lasers in condyloma surgery has been limited.
In addition, some concern has been raised over the human papilloma virus
(HPV) viral particles known to be aerosolized in the laser plume [34,35], and
at least one case of HPV laryngeal papillomatosis contracted by a laser sur-
geon is reported [36]. Whether similar risks exist for diathermy smoke is
unknown; however, general recommendations include wearing of special-
ized surgical masks and evacuating the surgical ‘‘smoke’’ through a micro-
pore filter.

Condyloma recurrence
The great variability in success of treatment and recurrence of all the
above techniques is likely partly attributable to the extent of disease before
 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211 1203

treatment. At my institution (The Los Angeles County and University of

Southern California Medical Center HIV Clinic in Los Angeles) we prospec-
tively examined 74 HIV positive patients undergoing surgical excision of
warts, and found that those with less than 25% of their anoderm replaced
by condyloma had a recurrence rate of 38% at four months, whereas those
with more than 25% anodermal replacement experienced a 62% recurrence
rate in the same time interval [37].
Although there is great variability of time to recurrence of condyloma,
the majority recur early, usually within months [18,19,24,28,30]. This is most
likely due to residual virus in the anoderm, rather than reinfection. Ferenczy
et al [38] biopsied normal appearing anodermal margins after laser excision
of anal condyloma and found HPV in 45%. Condyloma recurred in 67% of
patients with biopsies showing HPV, but only in 9% of those without resid-
ual virus. The belief that condyloma recurrence is due to persistent anoder-
mal HPV virus after local wart destruction has led to adjuvant HPV
treatment in hopes of reducing this recurrence.
Vance et al [39] found a 38.2% condyloma recurrence after 13 weeks using
laser excision alone. When the sites of excision were injected with interferon,
however, the rate of return of warts fell to 18.5%. In 1994, Fleshner and
Freilich [40] reported similar results after diathermy excision of anal condy-
loma followed by injection of 2 million units of interferon into surrounding
anoderm. They found that at 3.8 months, 12% of those receiving interferon
recurred, versus 39% of those receiving placebo. At our institution, we
recently also found benefit to injecting 4 million units of interferon after sur-
gical resection of extensive anal condyloma in HIV positive patients. The
recurrence rate at four months decreased from 55% to 31% [37]. Other
agents, such as imiquimod, are yet to be studied as adjuncts to eradicative
methods in hopes of preventing recurrence of anal condyloma.

HPV, HIV, and neoplasia

As noted in the beginning of this article, there is an increased incidence of
anal condyloma in the HIV population [4,5,13]. There is also evidence that
condyloma in HIV patients is a more aggressive disease in terms of recur-
rence and dysplasia. Sobhani et al [41] recently showed a higher rate of
recurrence after destruction of anal condyloma in their HIV positive pa-
tients (75%) when compared with those who were HIV negative (6%).
They also demonstrated a higher risk of dysplasia in condyloma from HIV
positive patients. Metcalf and Dean [42] similarly found decreased risk of
dysplasia in warts from heterosexual males (6%) versus homosexual or
bisexual males (28%), although both had an equal risk of squamous cell car-
cinoma at 3%. These authors also found an independently increased risk of
dysplasia with HIV positivity and condyloma located above the dentate line.
These data raise the possibility of more virulent condyloma subtypes pre-
dominating in homosexual and HIV positive populations.
1204 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211

The incidence of anal squamous cell carcinoma among all men in the
United States is 0.7 per 100,000, but the incidence in homosexual men has
been estimated to be between 25 and 37 per 100,000 [43]. Moreover, the inci-
dence in homosexual men with AIDS may be as high as 84 times that of the
general population [44]. An epidemiologic link between anal condyloma and
anal carcinoma was demonstrated by Byars [45], who reported on 275
patients. He found that 12.2% of those with squamous cell carcinoma had
concurrent condyloma, and that 3.5% of those with condyloma had invasive
carcinoma. Of particular interest is an article published by Frisch et al [46] in
1997, in which his group applied infectious disease principles to anal squa-
mous cell carcinoma, effectively demonstrating that this neoplasm fits the
criteria of sexually transmitted diseases (STD). They suggest that practices
to control STDs would reduce the incidence of this anal malignancy.
The infective agent of anal condyloma is the human papilloma virus, a
DNA papovavirus [47], over 100 genotypes of which have been identified,
with more than 30 linked to anogenital warts. However, anal HPV is asso-
ciated with a spectrum of anal pathology including asymptomatic infection,
benign warts, dysplasia, and invasive anal squamous cell carcinoma [48].
Although perfect correlation seems to be lacking, several groups have noted
increased association of subtypes 16 and 18 with anodermal and condyloma
dysplasia, whereas subtypes 6 and 11 correlate with a lack of dysplasia
[49–51]. In one study, 54% of males attending an HIV clinic were found to
have HPV in their anoderm [51].
Further evidence of the association of condyloma and anal squamous cell
carcinoma is given by DNA studies that have identified the HPV genome
within squamous cell carcinomas [46,49,52]. Gal et al [52] reported HPV
genome present in 63% of squamous cell carcinomas from homosexual
patients, whereas those from heterosexual patients were found with HPV
only 33% of the time, again indicating a more aggressive disease in the
homosexual population. Frisch et al [46] identified HPV in 84% of the squ-
amous carcinomas in their mostly HIV negative population. Direct causality
between HPV virus and malignant transformation has not been demon-
strated, however, and the above observations may be due to a cofactor effect
of HPV on other malignancy promoters. This view is supported by Dreau
et al [53], who report that 58% of melanoma biopsies contained HPV DNA,
and those that did contain it acted more aggressively.
Goldstone et al [54] recently reported that 54% of homosexual men who
were referred to them for surgical treatment of other pathology were found
to have high grade dysplasia in the anal canal. Following the precedent set
by female cervical HPV association of dysplasia, routine cytology followed
by colposcopy, biopsy, and eradication of clinically nonevident anal intraepi-
thelial neoplasia (AIN) was reported [13,51]. Palefsky et al [51] found AIN by
cytology in 14% of their HIV positive population. Although the rate of pro-
gression of AIN to invasive squamous cell carcinoma is not known, the above
practice is supported by the observation that anal carcinoma may arise from
 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211 1205

high grade dysplasia in visually normal anoderm in homosexual men [55]. In

2002, however, Chang et al [56] reported that after surgical eradication of all
high grade AIN lesions in 29 HIV positive patients, 23 had recurrent high
grade AIN lesions by 12 months. Lack of data concerning incidence of pro-
gression of AIN to invasive carcinoma, coupled with poor options for treat-
ment of this lesion, have kept the screening for and treatment of clinically
nonevident anal dysplasia in HIV positive patients controversial.

HIV-associated anal ulcer disease

In 1981, Siegal and coworkers [57] were the first to appreciate an associ-
ation of anal ulcerative disease with HIV when they reported four immuno-
deficient homosexuals with large perianal ulcers due to herpes simplex virus
(HSV) infection. Their writing that this association was ‘‘part of a nation-
wide epidemic of immunodeficiency among male homosexuals’’ now seems
prophetic. Ulcerations remain as one of the two most common anal pathol-
ogies in HIV patients [4,5,8,9]. Possible ulcer etiologies are listed in Table 3
[58,59]; however, in many cases a specific cause can not be found and the
ulcer is termed idiopathic [57,59,60]. In any case, these ulcers can become
chronic and quite debilitating [6,58], with the most common presenting
symptoms being pain, purulent discharge, and bleeding [61].

Nonsurgical management
Aggressive work-up to identify the etiology of ulcers is usually unsuccess-
ful, with the exception of biopsy in cases clinically suspicious for neoplasm
[60]. Goldberg [61] reported cytomegalovirus isolated by culture from 8% of
his anal ulcer patients, but it is not clear whether this was a concomitant
infection or causative, as subsequent antiviral treatment was not particularly

Table 3
Causes of ulcerations in HIV (+) patients [58,59]
Benign
Anal fissure
Trauma
Infectious
Herpes simplex virus
Cytomegalovirus
Chancroid
Tuberculosis
Cryptococcosis
Actinomycosis
Neoplastic
Lymphoma
Anal carcinoma
KS
Idiopathic HIV anal ulcers
1206 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211

successful. Fifty per cent of anoderm adjacent to ulcerations is found to con-

tain HPV infection [62], but the association was not thought to be causal.
Nonoperative management with antibacterial and antiviral agents showed
variable results, but generally poor success [63,64]. Newer strategies include
anecdotal reports of intralesional steroid injections of nonhealing ulcers
[6,65], and use of thalidomide [66]. Broader experience is needed before
assessing the true efficacy of these agents.
Idiopathic HIV-associated anal ulcers can be reliably clinically differenti-
ated from anal fissures and other ulcerative diseases by a set of characteristic
features described by Viamonte et al [58]. These include noting the lesion’s
location, associated sphincter tone, sphincter or postanal space invasion,
associated skin tags and mucosal bridging, and the width of the ulcer base
(Table 4). Additional experience at our institution shows that HSV ulcers
tend to be multiple, more superficial, and quite a bit more tender to palpa-
tion than idiopathic ulcers.

Surgical management
Three of four of Siegel et al’s original patients died with their anal ulcer-
ations [57]. Wexner and colleagues then reported their early experience in
1986 of surgical management of AIDS-associated anorectal disorders [67],
noting a 16% major complication rate, a 43% death rate at six months, and
only a 12% healing rate at 30 days after surgical treatment of anal ulcers.
These initial reports set a foreboding environment for surgical approaches
to HIV-associated anorectal diseases, but subsequent reports became more
positive. In 1991, Miles et al [63] reported 11 of 12 HIV positive patients
healing within 10 weeks after excision of perianal ulcerations. In the same
year, Burke et al [68] reported a 94% healing rate after anorectal surgery
in a similar population. Also in 1991, Savavi’s group [6] showed significant
improvement or resolution in symptoms of 87% of postoperative patients,
despite a wound healing rate of only 53%. Similarly, Nadal in 1999 [59]
reported relief of symptoms in all 33 HIV positive patients undergoing ulcer
excision, but with variable healing.

Table 4
Characteristic features of HIV-associated anal ulcers [58]
Benign anal fissure Idiopathic anal ulcer
Location Low High
Sphincter Normal to hypertonic Lax
Invasion ÿ +
Sentinel tag + ÿ
Mucosal bridging ÿ +
Width Narrow Broad-based
AIDS +/ÿ (50%) + (100%)
 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211 1207

Several authors have reported relief of HIV anal ulceration associated

symptoms after surgical excision, despite poor healing and persistent
wounds [6,59,69,70]. The etiology of this phenomenon is not known, nor
is the healing rate for each individual patient reliably predictable. However,
Safavi et al [6] reported healing after anorectal surgery in 69% of those who
were HIV positive, but in only 26% of those with AIDS. Nadal’s group [69]
reported fistulotomy in their patients followed by healing in an average of
44.8 days for HIV negative patients, versus 60.8 days in those who were HIV
positive. 22% of their patients with advanced AIDS did not heal. Another
study found that poor anal ulcer healing was associated with low T4-cell
counts [70]. It seems prudent to advise patients with AIDS who are about
to undergo surgery for anal ulcerations and other anorectal disorders that
there is the possibility of poor wound healing, but that symptomatic relief
is nonetheless highly likely.

Treatment algorithm
Based on available data at the time, in 1993 our institution established an
algorithm for the treatment of HIV-associated perianal ulcerations [71]. Ini-
tially, cultures for HSV were positive in about 50% of our patients. These
were treated with oral acyclovir at 800 mg three times daily for 14 days.
Those who returned HSV culture negative were treated with metronidazole
at 500 mg. three times daily for 14 days. This antibiotic choice was based on
its known benefits in Crohn’s anal ulcerations [72,73] and analgesic effects
after hemorrhoidectomy [74], both of which were thought to have clinical
similarities to HIV-associated anal ulcers. Treatment success was defined
as relief of anal symptoms, which was often seen before healing of the ulcer-
ations, as has been reported by others after surgical ulcer excision [6,
59,69,70]. Antimicrobial failures then underwent additional intervention,
such as change of antiviral therapy, intralesional steroid injection, or surgical

Fig. 1. Algorithm for management of HIV-associated anal ulcers.

1208 P. Vukasin / Surg Clin N Am 82 (2002) 1199–1211

excision. Under this algorithm, 85% of cases resolved after antimicrobial

treatment, and only 9% required surgical intervention, all of whom healed.
The algorithm was simplified in 1997 to that seen in Fig. 1. and was used
for all HIV related ulcerations not associated with mass suspicious for
malignancy or prior history of anal malignancy in that patient. Antimicro-
bial therapy for all patients consisted of concurrent treatment with acyclovir
and metronidazole at the same doses and time period as above. 76% of
patients responded to initial treatment, and 21% subsequently went on to
surgical excision, all of whom attained symptomatic relief and complete
wound healing within 5.3  4.6 weeks. 21 ulcerations recurred at a mean
of 17.1  13.1 weeks. These were treated again with antimicrobials, achiev-
ing an 82% success rate, and the 18% of these that persisted responded to
surgical excision.
We feel that the success of this treatment protocol has been very helpful
in the management of our HIV infected population.

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