Low genetic barrier to large increases in HIV-1 cross-resistance to protease inhibitors during salvage therapy.
HIV-1 resistance to protease inhibitors (PIs) is characterized by extensive cross-resistance within this drug class. Some PIs, however, appear less affected by cross-resistance and are often prescribed in salvage therapy regimens for patients who have failed previous PI treatment. To examine the capacity of HIV-1 to adapt to these treatment changes, we have followed the evolution of HIV-1 protease genotypes and phenotypes in 21 protease-inhibitor-experienced patients in whom 26 weeks of an aggressive salvage regimen associating lopinavir, amprenavir and ritonavir failed to suppress viral replication. Baseline genotypes exhibited a median of seven resistance mutations in the protease. After 26 weeks of treatment, changes in protease genotypes were seen in 13/21 patients. The evolution of these protease genotypes was rapid, with more than one-third of the changes occurring during the first 6 weeks. Although the mean number of additional mutations was small (2.15 new mutations at week 26) these mutations were sufficient to promote remarkable changes in resistance phenotype. In several patients, some of the new mutations were found to exist before salvage treatment as part of minority quasi-species. Thus, in the face of the strong pharmacological pressure exerted by combinations of PIs to which it has never been exposed, and in spite of limited cross-resistance to these drugs before salvage therapy, HIV-1 can rapidly adapt its resistance genotype and phenotype at a minimal evolutionary cost.
Morand-Joubert
Laurence
L
AP-HP, Centre Hospitalo-Universitaire Saint-Antoine, Paris, France.
Charpentier
Charlotte
C
Poizat
Gwendoline
G
Chêne
Geneviève
G
Dam
Elisabeth
E
Raguin
Gilles
G
Taburet
Anne-Marie
AM
Girard
Pierre-Marie
PM
Hance
Allan J
AJ
Clavel
François
F
D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral; D019143:Evolution, Molecular; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D016879:Salvage Therapy
D017320:HIV Protease Inhibitors; D016333:HIV Protease