Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer

Inclusion Criteria

• •HIGH-RISK STRATUM: Participant is able to understand and willing to sign a written informed consent document
• •HIGH-RISK STRATUM: HIV-positive. Documentation of HIV-1 infection by means of any one of the following:
• •* Documentation of HIV diagnosis in the medical record by a licensed health care provider. If the record contains information that the patient is taking Food and Drug Administration (FDA)-approved combination therapy for HIV infection, then this can be part of the record substantiating the HIV positive diagnosis
• •* HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating \> 1000 RNA copies/mL
• •* 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.
• •* NOTE: The term "licensed" refers to a kit that has been certified or licensed by an oversight body within the participating country and validated internally (e.g., United States \[U.S.\] FDA)
• •* WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test must be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load
• •HIGH-RISK STRATUM: Age \>= 18 years
• •* Because no dosing or adverse event data are currently available on the use of nivolumab in participants \< 18 years of age, children are excluded from this study
• •HIGH-RISK STRATUM: Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 50%)
• •HIGH-RISK STRATUM: Life expectancy of greater than 6 months
• •HIGH-RISK STRATUM: Hemoglobin \> 10 g/dL (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Absolute neutrophil count: \>= 1,500/mm\^3 (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Platelets: \>= 100,000/mm\^3 (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Total bilirubin: \< 2 X upper limit of normal (ULN) (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]): =\< 2.5 X institutional ULN (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Albumin \>= 3.0 g/dL (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Creatinine levels =\< 1.5 X normal institutional limits; or calculated creatinine clearance must be \> 50 ml/min (within 2 weeks before enrollment)
• •HIGH-RISK STRATUM: Females of childbearing potential (FOCBP) must agree to follow contraception requirements:
• •* The effects of nivolumab on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, FOCBP must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation and 5 months after completion of nivolumab administration. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
• •* NOTE: A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• •HIGH-RISK STRATUM: Participant must have a CD4 count of \>= 100 cells/uL at least 2 weeks prior to enrollment OR \>= 100 cells/uL before receiving prior CRT, as CD4 may be low due to the effects of CRT
• •HIGH-RISK STRATUM: Participant must be on a stable antiretroviral therapy (ART) regimen for at least 2 weeks prior to enrollment with no intention to change the regimen within 12 weeks after enrollment
• •HIGH-RISK STRATUM: Participant must have an HIV RNA viral load of \< 200 copies/mL
• •HIGH-RISK STRATUM: Participant must have received at least 54 Gy of radiation to the PTVp (primary) and 45 Gy to PTVn (elective nodal region) for the treatment of the anal cancer within 9 weeks before enrollment
• •HIGH-RISK STRATUM: Participant must have =\< grade 2 diarrhea
• •* Participants with grade 1 or grade 2 diarrhea are eligible provided stool for ova/parasites and stool cryptosporidium studies are negative
• •HIGH-RISK STRATUM: Purified protein derivative (PPD) negative. Alternatively, the QuantiFERON-tuberculosis (TB) Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used. An individual is considered positive for M. tuberculosis infection if the interferon (IFN)-gamma response to TB antigens is above the test cut-off (after subtracting the background IFN-gamma response in the negative control). The result must be obtained within 20 weeks prior to enrollment. PPD positive (or QuantiFERON assay positive) participants are permitted if prophylaxis has been completed prior to enrollment
• •HIGH-RISK STRATUM: Participants with impaired decision-making capacity (IDMC) may be eligible for the study provided all other eligibility criteria are satisfied:
• •* The participant's legally authorized representative (LAR) is able and willing to sign consent in addition to the study candidate
• •* Both participant and LAR agree to follow study parameters per protocol
• •HIGH-RISK STRATUM: The participant, in the opinion of the treating investigator, is able to receive IV contrast injections:
• •* All participants in the High-risk Stratum must have an oral contrast (rectal contrast optional) and IV iodine contrast abdomen and pelvis contrast CT (A/P C+CT) and chest C+CT at baseline and for all clinical follow up time points. Imaging centers should follow their local routine guidelines for determination of patient eligibility for IV contrast injection and appropriate post contrast follow up renal function determinations
• •SCREENING ELIGIBILITY LOW-RISK STRATUM: Participant is able to understand and willing to sign a written informed consent document
• •SCREENING ELIGIBILITY LOW-RISK STRATUM: Age \>= 18 years
• •* Because no dosing or adverse event data are currently available on the use of low-dose radiation concurrent with mitomycin-C/fluorouracil (5-FU) or mitomycin-C/capecitabine in participants \< 18 years of age, children are excluded from this study
• •HIGH-RISK STRATUM: Pregnant or breastfeeding.
• •* Pregnant women are excluded from this study because nivolumab is an anti-PD-1MAb agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, breastfeeding should be discontinued if the mother is treated with nivolumab
• •* All FOCBP must have a blood test or urine study within 2 weeks prior to enrollment to rule out pregnancy
• •HIGH-RISK STRATUM: Participant has not recovered from adverse events due to CRT (i.e., have residual toxicity \> grade 1), excluding alopecia
• •HIGH-RISK STRATUM: Participant has had prior potentially curative surgery (i.e., abdominal-perineal resection) for carcinoma of the anus
• •HIGH-RISK STRATUM: Participant is receiving other standard anti-cancer therapy or experimental agent concurrently with the study drugs
• •HIGH-RISK STRATUM: Participant has a known autoimmune disease
• •* Participants with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to participants with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and participants with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Participants with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Participants with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and participants with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• •HIGH-RISK STRATUM: Participant requires steroid treatment or other immunosuppressive treatment
• •* Participants will be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration. Topical corticosteroid or occasional inhaled corticosteroids are allowed
• •HIGH-RISK STRATUM: Any surgery must have been completed \>= 4 weeks before treatment initiation
• •LOW-RISK STRATUM: Has undergone prior potentially curative surgery (i.e., abdominal-perineal resection) for carcinoma of the anus
• •LOW-RISK STRATUM: Receiving any other standard anti-cancer therapy or investigational agents concurrently with study therapy
• •LOW-RISK STRATUM: Significant cardiovascular disease including myocardial infarction, unstable angina, stroke, transient ischemic attack, symptomatic coronary artery disease, symptomatic congestive heart failure, or uncontrolled cardiac arrhythmia within 6 months of enrollment
• •LOW-RISK STRATUM: History of prior chemotherapy for this malignancy
• •LOW-RISK STRATUM: Pregnant and/or breast-feeding women
• •* Pregnant and/or breast-feeding women are excluded from this study because the study treatment administered