Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy

Objective: To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression. Design: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comparison of didanosine with continued zidovudine therapy in patients with advanced HIV-1 disease who had received 16 weeks or more of previous zidovudine therapy. Setting: Participating ACTG virology laboratories. Patients: 187 patients with baseline HIV-1 isolates. Measurements: Zidovudine susceptibility testing and assays for syncytium-inducing phenotype were done on baseline HIV-1 isolates. Relative hazards for clinical progression or death associated with baseline clinical, virologic, and immunologic factors were determined from Cox proportional hazards regression models. Results: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhibitory zidovudine concentration [greater than or equal to] 1.0 [mu]M) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% Cl, 1.00 to 3.03) and 2.78 times the risk for death (Cl, 1.21 to 6.39) in analyses that controlled for baseline [CD4.sup.+] T-lymphocyte count, syncytium-inducing HIV-1 phenotype, disease stage, and randomized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 isolates. Conclusions: High-level resistance of HIV-1 to zidovudine predicted more rapid clinical progression and death when adjusted for other factors. However, patients with advanced HIV-1 disease may benefit from a change in monotherapy from zidovudine to didanosine whether high-level HIV-1 resistance to zidovudine is present or absent, and laboratory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.
Patients with advanced HIV-1 disease that is highly resistant to zidovudine antiretroviral therapy may be at greater risk of disease progression and death. A study of 187 patients enrolled in a study comparing zidovudine with didanosine found that patients whose viral strain had become resistant to zidovudine had almost three times the risk of death than other HIV patients. They were almost twice as likely to develop an AIDS-related complication. Those with a viral strain that causes cells to clump together also had a higher risk of disease progression. Didanosine may slow the progression of HIV infection in those whose viral strains have become resistant to zidovudine.