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.
Massachusetts General Hospital, Beth Israel Hospital, Harvard Medical School, Boston.
R T
RT
D'Aquila
V A
VA
Johnson
S L
SL
Welles
A J
AJ
Japour
D R
DR
Kuritzkes
V
V
DeGruttola
P S
PS
Reichelderfer
R W
RW
Coombs
C S
CS
Crumpacker
J O
JO
Kahn
D D
DD
Richman
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