Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. AIDS Clinical Trials Group Protocol 116B/117 Team and the Virology Committee Resistance Working Group.
OBJECTIVE
To evaluate the association between resistance of human immunodeficiency virus type 1 (HIV-1) to zidovudine and clinical progression.


METHODS
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.


METHODS
Participating ACTG virology laboratories.


METHODS
187 patients with baseline HIV-1 isolates.


METHODS
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 > or = 1.0 microM) had 1.74 times the risk for progressing to a new AIDS-defining event or death (95% CI, 1.00 to 3.03) and 2.78 times the risk for death (CI, 1.21 to 6.39) in analyses that controlled for baseline CD4+ 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.
D'Aquila
R T
RT
Massachusetts General Hospital, Beth Israel Hospital, Harvard Medical School, Boston.
Johnson
V A
VA
Welles
S L
SL
Japour
A J
AJ
Kuritzkes
D R
DR
DeGruttola
V
V
Reichelderfer
P S
PS
Coombs
R W
RW
Crumpacker
C S
CS
Kahn
J O
JO
Richman
D D
DD
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000328:Adult; D018791:CD4 Lymphocyte Count; D016049:Didanosine / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D015215:Zidovudine / Q000627:therapeutic use*
D015215:Zidovudine; D016049:Didanosine