Baseline antiretroviral drug susceptibility influences treatment response in patients receiving saquinavir-enhancing therapy.
OBJECTIVE
To relate baseline plasma HIV genotypic and virtual phenotypic antiretroviral drug susceptibility to subsequent virological response in patients receiving saquinavir (SQV)-enhancing therapy. Individuals were randomized to receive stavudine (d4T), SQV, and one of ritonavir, nelfinavir, or delavirdine to enhance SQV blood levels.


METHODS
The protease and reverse transcriptase baseline sequences of 31 treatment-experienced patients were analyzed by genotype and virtual phenotype and were related to viral load at weeks 12 and 24. Genotypic resistance to SQV was defined by the presence of G48V and/or L90M mutations in the protease gene. Potential cross-resistance to d4T in zidovudine (ZDV)-experienced individuals was defined by the presence of thymidine-associated mutations in the reverse transcriptase gene.


RESULTS
ZDV-associated mutations did not affect the virological response at 24 weeks. Individuals who were sensitive to SQV at baseline as determined by either genotyping or virtual phenotyping showed a greater decrease in viral load at week 24 than those resistant to SQV, irrespective of treatment arm. By genotyping, SQV-sensitive individuals had a median log decrease of 1.12 compared to 0.32 for those individuals who were SQV resistant. By virtual phenotyping, SQV-sensitive individuals had a median log decrease of 1.0 compared to a rise of 0.08 in resistant individuals.


CONCLUSIONS
Thymidine analogue-associated mutations at baseline did not influence the response to subsequent therapy involving d4T. Individuals who were sensitive or resistant to SQV by genotyping or virtual phenotyping responded to SQV-enhancing regimens, but the virological response was greater in those who were sensitive.
Middleton
T
T
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia. tracey.middleton@mh.org.au
Smith
D
D
Larder
B
B
Law
M
M
Birch
C
C
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019258:Saquinavir / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; D019258:Saquinavir