Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions.
BACKGROUND
A new HIV-1 treatment strategy based on repeated structured treatment interruptions (STI) is currently being evaluated in clinical trials to determine whether immune cell-mediated control of viral replication can be stimulated by intermittent periods of viral replication. The potential for selection of drug-resistant quasi-species remains a major concern of such a treatment strategy.


METHODS
Plasma and peripheral blood lymphocyte (PBL) samples from 12 patients who had three consecutive STIs were studied. Genotypic analysis was based on population and clonal sequencing. Drug susceptibility and their corresponding replication capacities were evaluated by a single-cycle growth assay.


RESULTS
Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents.


CONCLUSIONS
Drug-resistant virus can rise to high frequencies in chronically HIV-1 infected individuals during consecutive STIs. Evolution of resistance is likely to be more important in patients with prior suboptimal therapies, particularly when few mutations are required for resistance. Maximum care should be taken in designing STI protocols that minimize development of drug-resistant mutations that may lead to treatment failure. Thus, drug-resistance testing may be useful before restarting treatment during STI studies.
Martinez-Picado
Javier
J
IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain. javiermp@ns.hugtip.scs.es
Morales-Lopetegi
Kristina
K
Wrin
Terri
T
Prado
Julia G
JG
Frost
Simon D W
SD
Petropoulos
Christos J
CJ
Clotet
Bonaventura
B
Ruiz
Lidia
L
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
D019380:Anti-HIV Agents; D012367:RNA, Viral