Treatment of anal intraepithelial neoplasia in HIV-positive patients, a triple-arm randomized clinical trial

Due to effective antiretroviral treatment (HAART), overall HIV/AIDS related
mortality has decreased. However, as a result of the increased life span new
causes of morbidity and mortality have become important. Several malignancies,
in particular anal carcinoma, are observed in excess in HAART-treated HIV
patients: the relative risk of anal carcinoma in HAART-treated HIV+ homosexual
men (MSM) is 352 as compared to HIV-negative men. Like in cervical cancer, the
development of anal carcinoma appears to require infection with oncogenic HPV
types. Precancerous anal lesions (Anal Intraepithelial Neoplasia, graded AIN I
to AIN III), are present in a large proportion (over 50%) of HIV+ MSM and
women, and sensitive and specific screening methods are available.
As the annual incidence of invasive anal carcinoma in this group exceeds by far
(224 vs. 10 per 100.000 persons at risk) the incidence of cervical cancer in
HIV-negative women, for whom regular cervical screening is standard-of-care,
this suggests that HIV+ MSM and women should be screened regularly and their
preneoplastic lesions be treated.
However, at this stage the optimal treatment of precancerous lesions is
insufficiently known. Electro-coagulation is standard-of-care, but local
imiquimod treatment was better tolerated and showed a 77% clinical and
histological clearance and a low recurrence rate. Also treatment with
fluorouracil crème shows promising results. However, these treatment modalities
have not been evaluated in a head-to-head comparison.

To establish the preferred treatment of AIN to prevent the development of
severe anal neoplasia (persistent AIN III or anal carcinoma) in HIV+ MSM and
HIV+ woman.

In this study, we will screen 300 HIV+ MSM and women treated at the HIV
outpatient clinics of the AMC, at two consecutive years, by performing high
resolution anoscopy (HRA) using a colposcope. Besides anal swabs for
HPV-typing, biopsies will be taken in if suspicious lesions are seen,. In this
case also biopsies of healthy tissue are taken for studies regarding local
immunity.
In case of AIN I-III in anal biopsies patients will be randomized (1:1:1)
between three treatment regimens: local treatment of lesions with fluorouracil,
imiquimod or with electro-coagulation. Treatment duration is 16 weeks.
Imiquimod is applied three times a week, fluorouracil twice a week. Coagulation
is repeated every 4 weeks when lesions persist.
Four weeks after treament early efficacy is evaluated by HRA and biopsies.
Follow up is at 24, 48 and 72 weeks after treatment.

Treatment-arm 1: electro-coagulation during high resolution anoscopy, repeated
every 4 weeks if necessary
Treatment-arm 2: imiquimod (Aldara-creme), 3 times a week, applied by the
patient
Treatment-arm 3: fluorouracil (Efudix-creme), twice a week, applied by the
patient

Patiënts will have to come to the outpatient clinic at least twice, maximum 11
times. The visits will take aproximately thirty minutes. At part of these
visits high-resolution anoscopy (HRA) will be performed, which is inconvenient
for the patient. A bloodsample will be taken, which can cause discomofort, like
bruising.
A very rare complication of taking biopsies and coagulation is perforation.
Coagulation can sometimes be painful and can cause scaring which can lead to
narrowing of the anus. Adverse effects of imiquimod and fluorouracil are minor.
Both cause normally redness of the skin where applied. A burning feeling can
occur. Sometimes little erosions are seen with bleeding. In rare cases
fluorouracil can cause narrowing of the anus. Eightteen percent of patients
treated with imiquimod report flu-like symptoms during the first two weeks of
treatment. Patients are instructed to refrain from anal intercourse for eight
hours after application of fluorouracil (twice a week) and imiquimod (three
times a week).