ZIDOVUDINE RESISTANCE AND HIV-1 DISEASE PROGRESSION DURING ANTIRETROVIRAL THERAPY

Objective: To evaluate the association between resistance of human imm unodeficiency virus type 1 (HIV-1) to zidovudine and clinical progress ion. Design: Retrospective analysis of specimens from patients in the AIDS Clinical Trials Group (ACTG) protocol 116B/117, a randomized comp arison of didanosine with continued zidovudine therapy in patients wit h 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: Z idovudine susceptibility testing and assays for syncytium-inducing phe notype were done on baseline HIV-1 isolates. Relative hazards for clin ical progression or death associated with baseline clinical, virologic , and immunologic factors were determined from Cox proportional hazard s regression models. Results: Compared with other patients, 15% (26 of 170) with isolates showing high-level zidovudine resistance (50% inhi bitory 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 d eath (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.2 1 to 6.39) in analyses that controlled for baseline CD4(+) T-lymphocyt e count, syncytium-inducing HIV-1 phenotype, disease stage, and random ized treatment assignment. The clinical benefit of didanosine was not limited to patients with highly zidovudine-resistant baseline HIV-1 is olates. Conclusions: High-level resistance of HIV-1 to zidovudine pred icted more rapid clinical progression and death when adjusted for othe r factors. However, patients with advanced HIV-1 disease may benefit f rom a change in monotherapy from zidovudine to didanosine whether high -level HIV-1 resistance to zidovudine is present or absent, and labora tory assessment of zidovudine resistance is not necessary for deciding when to switch monotherapy from zidovudine to didanosine.