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Re-evaluation of resistance algorithms for lopinavir/ritonavir in the TITAN trial

Background

Genotypic algorithms used to predict the clinical efficacy of lopinavir/ritonavir (LPV/r) have included a range of mutation lists and efficacy end-points. HIV clinical trials are normally powered to detect a difference between treatment arms of 10–12% for the end-point of HIV-1 RNA suppression <50 copies/mL. The TITAN trial (TMC114-C214) evaluated LPV/r vs. darunavir/ritonavir in treatment-experienced patients with HIV-1 RNA >1000 copies/mL. Baseline genotypic resistance to darunavir was rare in the TITAN trial.

Methods

Baseline genotype data were classified using seven genotypic resistance algorithms: IAS-USA LPV mutations (cut-off = 6), Abbott 2007 (King) mutation list (cut-off = 3), ANRS mutations (cut-off = 6), FDA mutations (cut-off = 3), Stanford, REGA and IAS-USA major PI mutations. Efficacy in the TITAN trial (HIV-1 RNA <50 at week 48) was correlated with the number of mutations from each list, to show the "efficacy advantage cut-off level": the number of mutations from each list associated with a difference in efficacy between treatment arms of at least 12%. The linearity of the correlation between mutation count and efficacy of LPV/r was analysed in TITAN, with sensitivity analysis for the French LPV ATU, BMS-045 and RESIST trials.

Summary of results

In TITAN, the concordance between baseline lopinavir resistance, defined by the mutation scores, ranged from 79–95%. Multivariate analysis identified lower than previously reported genotypic cut-off levels where there was at least 12% lower efficacy for LPV/r versus darunavir/ritonavir. These "efficacy advantage cut-off levels" were: IAS-USA LPV mutations, cut-off = 3; Abbott 2007, cut-off = 2; ANRS LPV cut-off = 3; FDA LPV mutations, cut-off = 2 and major IAS-USA PI mutations, cut-off = 1, Stanford algorithm, cut-off = low level LPV resistance; REGA algorithm, cut-off = Intermediate level LPV resistance. There were linear falls in HIV-1 RNA suppression rates with rising mutation counts in the TITAN, French LPV ATU, BMS-045 and RESIST trials.

Conclusion

The analysis identified more sensitive cut-off levels for several lopinavir genotypic algorithms, below those currently used, at which there is significant efficacy advantage for treatment with darunavir/ritonavir versus lopinavir/ritonavir in the TITAN trial. These new cut-off levels also detect a higher percentage of patients with virological failure than previous cut-off levels.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Calvez, V., Hill, A. & Marcelin, A. Re-evaluation of resistance algorithms for lopinavir/ritonavir in the TITAN trial. JIAS 11, P178 (2008). https://doi.org/10.1186/1758-2652-11-S1-P178

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  • DOI: https://doi.org/10.1186/1758-2652-11-S1-P178

Keywords

  • Virological Failure
  • Lopinavir
  • Darunavir
  • Mutation Score
  • Titan Trial