| Title: |
Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V |
| Authors: |
Nijhuis, Monique; Wensing, Annemarie M J; Bierman, Wouter F W; de Jong, Dorien; Kagan, Ron; Fun, Axel; Jaspers, Christian A J J; Schurink, Karin A M; van Agtmael, Michael A; Boucher, Charles A B |
| Source: |
Nijhuis, M, Wensing, A M J, Bierman, W F W, de Jong, D, Kagan, R, Fun, A, Jaspers, C A J J, Schurink, K A M, van Agtmael, M A & Boucher, C A B 2009, 'Failure of treatment with first-line lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V', Journal of Infectious Diseases, vol. 200, no. 5, pp. 698-709. https://doi.org/10.1086/605329 |
| Publication Year: |
2009 |
| Subject Terms: |
/dk/atira/pure/keywords/researchprograms/AFL001000/EMCMM042701; name=EMC MM-04-27-01; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0022-1899; 1537-6613 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/19627247; info:eu-repo/semantics/altIdentifier/pissn/0022-1899; info:eu-repo/semantics/altIdentifier/eissn/1537-6613 |
| DOI: |
10.1086/605329 |
| Availability: |
https://pure.eur.nl/en/publications/3b3a4b7a-8089-4bf2-91b1-3b2e5dbacafe; https://doi.org/10.1086/605329; https://pure.eur.nl/ws/files/46822207/200812030010110.pdf; https://hdl.handle.net/1765/17581 |
| Rights: |
info:eu-repo/semantics/openAccess ; https://www.eur.nl/en/library/media/2024-12-researchoutputsundertaverne-backgroundandtermsofusev2 |
| Accession Number: |
edsbas.C44A0B8A |
| Database: |
BASE |