Genotypic resistance analyses in nucleoside-pretreated patients failing an indinavir containing regimen: results from a randomized comparative trial: (Novavir ANRS 073).
BACKGROUND
Different studies have shown that most patients failing a first-line treatment containing a protease-inhibitor (PI) had low PI plasma levels and no PI-related resistance mutations. NOVAVIR was a randomized trial comparing stavudine/lamivudine/indinavir (d4T/3TC/IDV) and zidovudine/lamivudine/indinavir (AZT/3TC/IDV) in patients pretreated with AZT, didanosine (ddI) and/or zalcitabine (ddC) but naive for PIs.


OBJECTIVE
To study the mechanisms of virological failure in NOVAVIR trial through analyses of genotypic resistance profiles of reverse transcriptase (RT) and protease (PR), and plasma IDV concentrations at time to failure.


METHODS
Plasma HIV-RNA PR and RT sequences were determined in 27 failing patients (d4T/3TC/IDV n=11; AZT/3TC/IDV n=16) at baseline and at time to failure. IDV plasma measurements were performed in both samples.


RESULTS
At baseline, 20 out of the 27 patients had at least two thymidine analogs associated mutations. At time to failure, mutation M184V in the RT gene was present in 22 out of the 27 failing patients. Thirteen out of the 27 (48%) patients had acquisition of PI mutations compared to baseline sequence. Of the 26 patients with adherence data, 13 (50%) subjects were classified as having difficulty in adherence. The proportion of patients with low adherence was higher in the subgroup of patients failing without acquisition of new PI mutations.


CONCLUSIONS
In patients experienced with NRTIs, failure to PI-containing regimen may occur in spite of appropriate adherence to therapy and is associated with emergence of PI mutations in half of the cases. These results suggest that, although PIs have a high genetic barrier, sub-optimal activity of associated drugs may favor the selection of PI resistance mutations.
Descamps
Diane
D
Laboratoire de Virologie, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France. diane.descamps@bch.ap-hop-paris.fr
Joly
Véronique
V
Flandre
Philippe
P
Peytavin
Gilles
G
Meiffrédy
Vincent
V
Delarue
Séverine
S
Lastère
Stéphane
S
Aboulker
Jean-Pierre
JP
Yeni
Patrick
P
Brun-Vézinet
Françoise
F
D019943:Amino Acid Substitution / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D006678:HIV / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D009154:Mutation; D016896:Treatment Outcome
D017320:HIV Protease Inhibitors; D019469:Indinavir; D054303:HIV Reverse Transcriptase; D016333:HIV Protease