Impact of drug resistance mutations on virologic response to salvage therapy. Swiss HIV Cohort Study.
OBJECTIVE
To assess the prognostic significance of drug-associated mutations in the protease and reverse transcriptase (RT) genes on virological response to salvage therapy.


METHODS
All patients from four centres of the Swiss HIV Cohort Study who were switched, between February and October 1997, to nelfinavir plus other antiretroviral drugs following failure of highly active antiretroviral therapy (HIV-1 RNA >1000 copies/ml after > 3 months).


METHODS
Direct sequencing of RT and protease genes derived from plasma RNA was performed in 62 patients before salvage therapy. Baseline predictors (drug-resistance mutations, drug exposure, clinical and biological parameters) of virological response after 4-12 weeks of therapy were assessed by linear regression analyses.


RESULTS
Patients had been treated with RT inhibitors and protease inhibitors for a median duration of 35.6 and 12.2 months, respectively. Baseline median CD4 cell count was 113 x 10(6)/l and HIV-1 RNA 5.16 log10 copies/ml. The median decrease of HIV-1 RNA was 0.38 log10; 32% of the patients showed > 1 log10 decrease. At baseline, 90% of the patients had RT inhibitor-resistance mutations with a median number per patient of four (range, 0-7). Primary and secondary protease inhibitor-resistance mutations were detected in 69% and 89% of the patients, respectively. The median number of total protease inhibitor-resistance mutations per patient was four (range, 0-9). In univariate analysis, virological response to salvage therapy was associated with number of RT inhibitors, primary and secondary protease inhibitor-resistance mutations, history of protease inhibitor use (duration and number), but not with clinical stage, HIV-1 RNA level or CD4 cell count. After adjustment for all variables, the number of RT inhibitor plus protease inhibitor-resistance mutations was the only independent predictor.


CONCLUSIONS
In patients with advanced HIV infection, the virological response to salvage therapy containing nelfinavir is best predicted by the number of baseline RT inhibitor plus protease inhibitor-resistance mutations.
Lorenzi
P
P
AIDS Centre, Geneva University Hospital, Switzerland.
Opravil
M
M
Hirschel
B
B
Chave
J P
JP
Furrer
H J
HJ
Sax
H
H
Perneger
T V
TV
Perrin
L
L
Kaiser
L
L
Yerly
S
S
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D011237:Predictive Value of Tests; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016879:Salvage Therapy / Q000379:methods
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease