Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Lesions

Inclusion Criteria:

* HIV positive. Documentation of HIV-1 infection by means of any one of the following: 1) Documentation of HIV diagnosis in the medical record by a licensed health care provider; 2) Documentation of receipt of ART by a licensed health care provider (receipt of at least two agents is required); 3) HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating \>1000 RNA copies/mL; or, 4) Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay.
* Biopsy-proven HSIL at baseline
* At least one focus of HSIL must be identified that is not within a condyloma that may be treated after enrollment into the study
* For females, documentation that the participant is being followed for cervical cytology (if having a cervix) and/or HPV testing per current ASCCP guidelines, and visual examination of the vulva, vagina, and cervix to rule out cancer/suspicion for cancer within 12 months prior to enrollment
* Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 (Karnofsky \>= 70%)
* Life expectancy of greater than 5 years
* Absolute neutrophil count: \>= 750/mm\^3
* Platelets: \>= 75,000/mm\^3
* Hemoglobin \>= 9.0 g/dL
* Women of childbearing potential must have a negative urine pregnancy test within 7 days of initiating study treatment if they have been randomized to the treatment arm; all women of childbearing potential must agree to use a reliable birth control method (oral contraceptive pills, intrauterine device, Nexplanon, DepoProvera, or permanent sterilization, etc., or another acceptable method as determined by the investigator) during the entire period of the trial (5 years or more), and must not intend to become pregnant during study participation and for 3 months after treatment is discontinued; all participants must be willing to comply with an acceptable birth control regimen as determined by the Investigator
* Men randomized to the treatment arm should not father a baby while receiving topical treatment during this study. Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse if receiving topical treatment during the study, and for 2 weeks after stopping topical treatment.
* Ability to understand and the willingness to sign a written informed consent document
* Participant is willing to be randomized and able to comply with the protocol
* Clinician is comfortable with either following patient for up to 5 years without therapy or treating patient for up to 5 years

Exclusion Criteria:

* Inability to provide informed consent
* Patients who are receiving any other immunomodulatory investigational agents (replacement doses of steroids for adrenal insufficiency or treatment with prednisone ≤5 mg/day is permitted) within the 4 weeks before randomization enrollment, other than investigational antiretroviral agents for HIV, or investigational or approved agents for Hepatitis C.
* History of anal cancer, penile, vulvar, vaginal or cervical cancer, or signs of these cancers at baseline.
* Treatment or removal of HSIL less than 6 months prior to randomization.
* Participant has symptoms related to HSIL and would benefit more from immediate treatment than from entry into the study and potential for randomization to active monitoring arm
* Current systemic chemotherapy or radiation therapy that potentially causes bone marrow suppression that would preclude safe treatment of HSIL
* Participants who only have a single HSIL lesion that is likely to be removed entirely with the initial screening biopsy
* Warts so extensive that they preclude the clinician from determining the extent and location of HSIL
* Participant plans to relocate away from the study site to a location without an ANCHOR study site during study participation