Phase II, randomized, open-label, community-based trial to compare the safety and activity of combination therapy with recombinant interferon-alpha 2b and zidovudine versus zidovudine alone in patients with asymptomatic to mildly symptomatic HIV infection

Objectives: To compare, in a community-based therapeutic setting, the safet y, tolerance, and efficacy of combination therapy with recombinant interfer on-alpha 2b (rIFN-alpha 2b) and zidovudine (ZDV) to ZDV monotherapy. Design: Open-label, two-armed, randomized study. Patients and Methods: Asymptomatic or minimally symptomatic HIV-infected ad ults without an AIDS-defining illness, a CD4 count of 200 to 500 cells/mu l , and less than or equal to 6 months of prior ZDV therapy received ZDV 100 mg orally five times daily. Patients randomized to rIFN-alpha 2b received 3 million IU subcutaneously three Ones weekly for 2 weeks and 5 million IU t hree times weekly thereafter. The groups were compared with respect to adve rse events (AEs), dosing modifications, treatment discontinuation, clinical endpoints and changes in CD4 count. A virology substudy compared the treat ments with respect to HIV viral load and development of ZDV resistance. Results: Between October, 1991 and January, 1993, 139 patients were randomi zed to combination therapy and 117 to ZDV alone. Of AEs reported at any gra de, fatigue, myalgias, and sweating occurred significantly more often with combination therapy (p < .001). Study subjects receiving combination therap y showed modest but significantly greater weight loss (p = .0001), a signif icantly higher frequency of any abnormal laboratory test result (p = .002), neutropenia (p = .002), and leukopenia (p = .02), and also required dosage reduction for hematologic toxicity significantly more often (p < .05) than those in the ZDV monotherapy arm. No statistically significant differences were found between the groups with respect to development of specific AIDS -defining events, overall event rate, time to events, or change in performa nce status or CD4(+) counts, or percentages or development of ZDV resistanc e. Viral burden, reflected by serum p24 antigen and quantitative peripheral blood mononuclear cell (PBMC) microcultures, was greater at baseline in th e combination therapy group. Baseline SI phenotype predicted progression to AIDS (p = .004, chi(2)), whereas intermediate susceptibility to ZDV predic ted development of ZDV resistance (p < .005, chi(2)). The annual rate of de velopment of phenotypic resistance to ZDV was 16.8% and was not affected by administration of rIFN-alpha 2b. Conclusions: At the doses and schedule used in this study, the combination of ZDV with rIFN-alpha 2b was not therapeutically superior to ZDV alone and was less well tolerated. The addition of rIFN-alpha 2b to ZDV did not prev ent or delay the development of ZDV resistance.