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Mutations in the protease gene associated with virological failure to lopinavir-containing regimens in clinical samples

Purpose of the study

Lopinavir/ritonavir (LPV/r) is increasingly being introduced in resource-limited settings as second-line therapy. Data on selection of resistance mutations (RAMs) in treatment-experienced populations failing LPV/r could provide insight into future ramifications of this strategy. We investigated the RAMs in patients with prior or current LPV/r failure.

Methods

We identified 195 samples from multi-treated patients submitted for routine resistance testing. Seventy-one (36%) never received LPV/r, 75 (38.5%) had previously failed LPV/r, and 49 (25%) were currently on LPV/r. Medians, interquartile ranges or percentages, Kruskal-Wallis, χ2 or Fisher test were used whenever appropriate.

Summary of results

Median CD4 282 cells/μl (IQR:252), HIV-1 VL 4.17 log10 (IQR 1.35), and duration of HIV infection 13 years. Number of NRTI, NNRTI and PI RAMs: 5 (IQR:4), 1 (IQR:1), and 6 (IQR:4), respectively. Patients exposed to LPV/r had received more HAART regimens (p < 0.001), PIs (p < 0.001), and NRTIs (p < 0.001). RAMs significantly associated with prior or current LPV/r exposure were: L10I/F (p = 0.02, p = 0.001), K20R (p = 0.023), L24I (p = 0.01), L33F (p < 0.001), M36I (p = 0.029), M46I/L (p = 0.023, p = 0.003), I47V (p = 0.022), G48V (p = 0.08), F53L (p = 0.017), I54V (p < 0.001), A71V (p < 0.001), G73S (p = 0.008), V82A (p < 0.001), I84V (p < 0.001), and L90M (p = 0.037). Two NRTI mutations were also associated with LPV/r failure: E44D (p = 0.002) and V118I (p = 0.048). L76V was found in only one sample. RAMs associated only with current (and not previous) LPV/r failure were: L33F, M36I, M46I, I47V, G48V, A71V, G73S, I84V, L90M. These RAMs are all included in the IAS-USA LPV/r list, except M36I and G48V, found to be associated with prior saquinavir use (p = 0.02 and p < 0.001, respectively). Mutations included in the IAS-USA list for LPV but not found to be associated with LPV/r previous or current failure: L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, L63P, A71T, I76V, and V82F/T/S.

Conclusion

In multi-treated patients, L33F, M36I, M46I, I47V, G48V, A71V, G73S, I84V, L90M, but not L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, L63P, A71T, I76V, and V82F/T/S may be over-represented in LPV/r failure. Enrichment of these mutations should be expected in populations receiving widespread salvage with LPV/r. This may assist in considering future options, together with previous use of other PI and subtype prevalence.

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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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Santos, J., Llibre, J., Pérez-Álvarez, N. et al. Mutations in the protease gene associated with virological failure to lopinavir-containing regimens in clinical samples. JIAS 11, P191 (2008). https://doi.org/10.1186/1758-2652-11-S1-P191

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  • DOI: https://doi.org/10.1186/1758-2652-11-S1-P191

Keywords

  • Interquartile Range
  • Clinical Sample
  • Resistance Mutation
  • Saquinavir
  • Resistance Testing