Imiquimod, Fluorouracil, or Observation in Treating HIV-Positive Patients With High-Grade Anal Squamous Skin Lesions

Inclusion Criteria:

* HIV-positive; documentation of HIV infection must be based on a federally approved, licensed HIV test performed in conjunction with screening (enzyme linked immunosorbent assay \[ELISA\], western blot, or other test); alternatively, this documentation may include a record that another physician has documented that the patient has HIV based on prior ELISA and western blot; an approved antibody test will be used to confirm diagnosis; if the physician is treating a patient with combination antiretroviral therapy (cART) with a history of HIV positivity based on an approved antibody test then repeat antibody confirmation is not necessary
* Biopsy-proven HSIL (anal intraepithelial neoplasia 2 (AIN2) and/or AIN3) of the anal canal at either the squamocolumnar junction or distal anus, documented within 60 days prior to enrollment, but not less than 1 week prior to enrollment
* HSIL occupies at least 25% of the circumference of the anal canal at either the squamocolumnar junction or distal anus on high-resolution anoscopy (HRA) at screening or entry based on available biopsy results and visual appearance
* Anal HSIL lesions are visible at study entry and no lesions are suspicious for invasive cancer
* Ability to understand and willing to provide informed consent
* Participants must, in the opinion of the Investigator, be capable of complying with the requirements of this protocol including self-administration of study treatment
* Karnofsky performance status of \>= 70%
* Cluster of differentiation (CD)4 count \>= 200 within 120 days prior to enrollment or plasma HIV-1 ribonucleic acid (RNA) \< 200 copies/mL within 120 days prior to enrollment
* For females, cervical cytology (if having a cervix) and gynecologic evaluation within 12 months prior to enrollment
* Absolute neutrophil count (ANC) \> 750 cells/mm\^3 within 90 days prior to enrollment
* Hemoglobin \>= 9.0 g/dL within 90 days prior to enrollment
* Platelet count \>= 75,000/mm\^3 within 90 days prior to enrollment

Exclusion Criteria:

* History of anal cancer
* Prior intra-anal use of topical 5-fluorouracil 5% or imiquimod 2.5%, 3.75% or 5% at any point, or use of perianal imiquimod 2.5%, 3.75% or 5% or topical 5-fluorouracil 5% within 6 months prior to enrollment
* Extensive concurrent perianal or lower vulvar HSIL or condyloma requiring a different treatment modality than the study treatment, or treatment that cannot be deferred in observation arm, per examining provider
* Condyloma occupying more than 50% of the circumference of the anal canal or that obscures a satisfactory exam
* Ongoing use of anticoagulant therapy other than aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)
* Acute treatment for an infection (excluding fungal infection of the skin and sexually transmitted infections) or other serious medical illness within 14 days prior to study entry
* Malignancy requiring systemic therapy; note: Kaposi's sarcoma limited to the skin is not exclusionary unless requiring systemic chemotherapy
* Concurrent systemic corticosteroids, cytokines, and immunomodulatory therapy (e.g. interferons)
* Prior history of HPV vaccination
* Treatment for anal or perianal HSIL, low-grade squamous intraepithelial lesion (LSIL) or condyloma within 4 months of entry; please note that infrared coagulation (IRC) or electrocautery of a biopsy site to stop bleeding does not constitute treatment
* Female participants who are pregnant or breastfeeding; women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to initiating study treatment; all women of childbearing potential must be willing to comply with an acceptable birth control regimen to prevent pregnancy while receiving treatment and for 3 months after treatment is discontinued as determined by the Investigator; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; (note: a woman of childbearing potential is one who is biologically capable of becoming pregnant; this includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives)