chemoprevention of anal neoplasia arising secondary to anogenital human papillomavirus infection in persons with hiv infection.

Conditions: HIV Infections; Anus Neoplasms

Summary: primary: in phase i, to define a broadly tolerable dose of isotretinoin that can be used in combination with interferon alfa-2a (ifn alfa-2a). in phase ii, to determine trends in efficacy of isotretinoin alone or in combination with ifn alfa-2a as chemoprevention (preventing progression or recurrence) of anal intraepithelial neoplasia ( ain ) / squamous intraepithelial lesions ( sil ) in patients with hiv infection. secondary: to evaluate the effects of isotretinoin alone or in combination with ifn alfa-2a on immune function markers, human papillomavirus (hpv) type, and hpv dna levels. patients with hiv infection have a significant risk of recurrence following local ablation of intraepithelial neoplasia; thus, anogenital epithelial may become an increasingly important cause of morbidity, and possibly mortality, as the hiv epidemic matures. clinical studies of non-hiv-infected subjects have established that synthetic retinoids inhibit the progression of epithelial preneoplastic conditions and some neoplastic states.

patients with hiv infection have a significant risk of recurrence following local ablation of intraepithelial neoplasia; thus, anogenital epithelial may become an increasingly important cause of morbidity, and possibly mortality, as the hiv epidemic matures. clinical studies of non-hiv-infected subjects have established that synthetic retinoids inhibit the progression of epithelial preneoplastic conditions and some neoplastic states. in the phase i portion of the study, 20 patients per site each receive isotretinoin in escalating doses. if a patient experiences grade 2 or worse toxicity (or grade 3 or worse hypertriglyceridemia), dose is reduced to the previously tolerated dose for the remainder of the 6 week period. patients are then reassessed for anal neoplasia; those with no progression and no grade 2 or worse toxicity receive an additional 6 weeks of isotretinoin in combination with interferon alfa-2a. for phase ii of the study, a separate group of patients who have undergone ablative therapy are randomized to one of three arms (26 patients/arm): isotretinoin alone at the dose tolerated by at least 60 percent of patients in phase i; isotretinoin plus interferon alfa-2a; or observation only. treatment continues for 48 weeks.

Eligibility criteria:
inclusion criteria concurrent medication: allowed: * pcp prophylaxis (required for patients with cd4 count \< 200 cells/mm3). * chemoprophylaxis for candidiasis and herpes simplex. * metronidazole for up to 14 days. * erythropoietin. patients must have: * hiv seropositivity. * no active opportunistic infection requiring treatment with prohibited drugs. * phase i - current grade 1 ain (i.e., low grade sil) or treated or untreated grade 2 or 3 ain (i.e., high grade sil). phase ii - prior histologically confirmed grade 2 or 3 ain / high grade sil, with ablative therapy within the past 30-90 days. * capability of complying with study protocol. note: * the terms condyloma, grade 1 ain, and low grade sil are interchangeable. grade 2 or 3 ain is interchangeable with high grade sil. exclusion criteria co-existing condition: patients with the following symptoms or conditions are excluded: * active medical problems for which the patient is undergoing evaluations or for which prohibited therapy is required. * other active malignancies requiring systemic therapy. * significant symptomatic cardiac disease. note: * patients with malignancies being managed with local therapy (e.g., kaposi's sarcoma, basal cell carcinoma) may enroll at the discretion of the site investigator. concurrent medication: excluded: * g-csf (filgrastim). * myelosuppressive antibiotics (except co-trimoxazole for pcp prophylaxis). * corticosteroids. * biologic response modifiers. * cytotoxic chemotherapy. concurrent treatment: excluded: * radiation therapy. patients with the following prior conditions are excluded: history of ventricular arrhythmias or myocardial infarction. prior medication: excluded within 20 days prior to study entry: * g-csf (filgrastim). * myelosuppressive antibiotics (except co-trimoxazole for pcp prophylaxis). * corticosteroids. * biologic response modifiers. * cytotoxic chemotherapy. prior treatment: excluded within 20 days prior to study entry: * radiation therapy. excluded within 14 days prior to study entry: * transfusion. active substance abuse or illegal drug use (alcohol consumption is strongly discouraged).

Keywords: interferon alfa-2a acquired immunodeficiency syndrome aids-related complex anus neoplasms papillomavirus, human papovaviridae infections tumor virus infections isotretinoin