HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed.
BACKGROUND
Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed.


OBJECTIVE
To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation.


METHODS
Retrospective clinical cohort study.


METHODS
University-based HIV clinic.


METHODS
54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months.


METHODS
HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL.


RESULTS
In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included.


CONCLUSIONS
In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.
Zolopa
A R
AR
Division of Infectious Diseases and Geographical Medicine, Stanford University School of Medicine, CA 94305, USA. azolopa@stanford.edu
Shafer
R W
RW
Warford
A
A
Montoya
J G
JG
Hsu
P
P
Katzenstein
D
D
Merigan
T C
TC
Efron
B
B
D000328:Adult; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D010450:Endopeptidases / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D011237:Predictive Value of Tests; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000627:therapeutic use*; D019258:Saquinavir / Q000627:therapeutic use*
D017320:HIV Protease Inhibitors; D012194:RNA-Directed DNA Polymerase; D010450:Endopeptidases; D019258:Saquinavir; D019438:Ritonavir