Subtle decreases in stavudine phenotypic susceptibility predict poor virologic response to stavudine monotherapy in zidovudine-experienced patients.
To identify the level of phenotypic susceptibility for stavudine (d4T) that is associated with a diminished virologic response to d4T therapy, phenotyping was performed on archived baseline HIV isolates from 26 subjects who received d4T monotherapy in AIDS Clinical Trials Group (ACTG) 302 who had received >3 years of prior zidovudine (ZDV) monotherapy. Seven of 26 subjects achieved a virologic response of >0.3-log10 copies/mL reduction in plasma HIV RNA after 8 weeks of d4T. Responders had lower fold changes in susceptibility to d4T (1.0 vs. 1.6, p=.003), lower baseline viral loads (4.26 vs. 4.74 log10 copies/mL, p=.004), and fewer thymidine analog mutations (TAMS) (1 vs. 2, p=.059). Lower baseline d4T fold change in susceptibility predicted greater reductions in HIV RNA from baseline to week 8 after adjusting for baseline HIV RNA, ZDV fold change in susceptibility, and number of TAMS. Using the same phenotypic assay, drug susceptibility among 240 antiretroviral-naive patients found all HIV isolates to have d4T susceptibility <or=1.4-fold change. Using <or=1.4 as the d4T cutoff, the positive predictive value for a virologic response in this study was 44%, and the negative predictive value was 100%. d4T susceptibility greater than 1.4-fold change was associated with failure to achieve significant viral load reduction after 8 weeks of d4T monotherapy.
Shulman
Nancy S
NS
Stanford University School of Medicine, California 94305, USA. nshulman@stanford.edu
Hughes
Michael D
MD
Winters
Mark A
MA
Shafer
Robert W
RW
Zolopa
Andrew R
AR
Hellmann
Nicholas S
NS
Bates
Michael
M
Whitcomb
Jeannette M
JM
Katzenstein
David A
DA
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018119:Stavudine / Q000494:pharmacology / Q000627:therapeutic use*; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D013936:Thymidine