Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V.
BACKGROUND
Virological failure of first-line antiretroviral therapy based on lopinavir boosted with ritonavir (lopinavir/r) has rarely been associated with resistance in protease. We identified a new genotypic resistance pathway in 3 patients who experienced failure of first-line lopinavir/r treatment.


METHODS
Viral protease and the C-term part of Gag were sequenced. The observed mutations were introduced in a reference strain to investigate impact on protease inhibitor susceptibility and replication capacity.


RESULTS
A detailed longitudinal analysis demonstrated the selection of the M46I+L76V protease mutations in all 3 patients. The L76V conferred a solitary 3.5-fold increase in one-half the maximal inhibitory concentration to lopinavir but severely hampered viral replication. Addition of M46I, which did not confer any lopinavir resistance on its own, had a dual effect. It partly compensated for the loss in replication capacity and increased the one-half maximal inhibitory concentration to above the lower clinical cutoff (11-fold). Analysis of a large clinical database (>180,000 human immunodeficiency virus [HIV] sequences) demonstrated a significant association (Spearman rho, 0.93) between the increased presence of L76V in clinical samples (0.5% in 2000 to 3.4% in 2006) and lopinavir prescription over time.


CONCLUSIONS
The HIV protease substitution L76V, in combination with M46I, confers clinically relevant levels of lopinavir resistance and represents a novel resistance pathway to first-line lopinavir/r therapy.
Nijhuis
Monique
M
Department of Medical Microbiology, Division of General Medicine, Infectious Diseases and Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands. m.nijhuis@umcutrecht.nl
Wensing
Annemarie M J
AM
Bierman
Wouter F W
WF
de Jong
Dorien
D
Kagan
Ron
R
Fun
Axel
A
Jaspers
Christian A J J
CA
Schurink
Karin A M
KA
van Agtmael
Michael A
MA
Boucher
Charles A B
CA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D061466:Lopinavir; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D017211:Treatment Failure; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D019380:Anti-HIV Agents; D011744:Pyrimidinones; D054301:gag Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir