Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus

OBJECTIVES:

Primary

- To evaluate the safety and tolerability of topical cidofovir in HIV-infected patients
with perianal high-grade squamous intraepithelial lesions (HSIL).

- To estimate the regression rate of perianal HSIL in patients treated with this regimen.

Secondary

- To determine the human papilloma virus (HPV) DNA types and HPV strain variants present
in perianal HSIL and normal perianal tissue.

- To determine if clinical regression of perianal HSIL is associated with clearance of HPV
DNA.

- To identify the HPV DNA types present in the anus and cervix and compare them with the
HPV DNA present in the perianus in order to determine if the HPV types associated with
the perianal lesions are the same as those infecting the anus and cervix.

- To determine if there are abnormally methylated genes in perianal HSIL compared with
normal perianal tissue and if these genes are the same or different from those that have
been previously identified in anal and cervical dysplasia.

- To determine whether methylated genes are changed after treatment with cidofovir.

- To characterize differences in gene expression in perianal HSIL compared with normal
perianal tissue.

- To examine changes in gene expression in perianal HSIL after exposure to cidofovir using
RNA microarray analysis and confirm results with real-time polymerase chain reaction.

- To correlate pretreatment CD4 count, viral load, lesion size, methylation pattern,
and/or HPV type and strain with the clinical efficacy of topical cidofovir.

OUTLINE: This is a multicenter study.

Patients apply topical cidofovir to the perianus once daily on days 1-5. Patients undergo
punch biopsy of pretreatment lesional biopsy sites on day 14. Beginning 2-4 weeks after
biopsy, patients receive course 2 of cidofovir therapy. Subsequent treatment repeats every 14
days for up to 6 courses* in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients receive a total of 6 courses of study therapy.

Patients undergo collection of tumor and normal tissue for histopathological and molecular
correlative studies. Punch biopsies are obtained at baseline, after the first course of
therapy, and at 6 weeks after completion of therapy. Tissue samples are examined for
histopathology, human papilloma virus (HPV)DNA typing, DNA methylation, and gene expression
(via RNA microarray analysis and polymerase chain reaction).

After completion of study therapy, patients are followed at 6 weeks.

DISEASE CHARACTERISTICS:

- Histologically confirmed perianal high-grade squamous intraepithelial lesions (HSIL)
within the past 12 weeks

- The perianal skin (i.e., perianus) is defined as extending radially 5 cm from the
anal verge

- Lesions must cover a surface area of ≥ 3 square centimeters

- Lesions extending outside the perianus (e.g., vulvar lesions on the posterior
perineum bordering the perianus) are allowed

- Serologic documentation of HIV infection AND meets 1 of the following criteria:

- Has been on stable highly active anti-retroviral therapy (HAART) for ≥ 12 weeks
prior to study entry

- Has a CD4 count of > 200/mm³ AND is not receiving anti-retroviral therapy OR is
currently receiving a non-HAART* anti-retroviral regimen with no plans to
initiate HAART within the next 12 weeks NOTE: * A non-HAART regimen is considered
to be a therapy that does not include a protease inhibitor or a non-nucleoside
reverse transcriptase inhibitor

- No untreated invasive cancer of the lower genital tract

- No concurrent neoplasia requiring cytotoxic therapy

PATIENT CHARACTERISTICS:

- Karnofsky performance status 70-100%

- Life expectancy ≥ 3 months

- Hemoglobin ≥ 8 g/dL

- ANC ≥ 1,000/mm³

- Platelet count ≥ 75,000/mm³

- Creatinine < 1.5 times upper limit of normal (ULN)

- Total or conjugated (direct) bilirubin ≤ 2.5 times ULN

- AST and ALT ≤ 3 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study therapy

- No acute, opportunistic infection other than oral thrush, yeast vaginitis, or genital
herpes within the past 14 days

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior ablative or surgical treatment of perianal dysplasia

- At least 4 weeks since prior topical treatment for perianal dysplasia

- If any prior treatment caused significant trauma to ther area, healing should
occur prior to starting treatment

- More than 14 days since prior acute treatment for infection (other than for oral
thrush, yeast vaginitis, or genital herpes) or other serious medical illness

- No concurrent corticosteroids other than replacement doses

- No other concurrent investigational drugs except IND-approved anti-retroviral agents

- No concurrent systemic cytotoxic chemotherapy