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. 2015 Jan;70(1):243-8.
doi: 10.1093/jac/dku365. Epub 2014 Sep 16.

HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir

K A Sutherland  1 , J Ghosn  2 , J Gregson  3 , J L Mbisa  4 , M L Chaix  5 , I Cohen Codar  6 , J F Delfraissy  7 , C Delaugerre  8 , R K Gupta  9
Affiliations

HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir

K A Sutherland et al. J Antimicrob Chemother. 2015 Jan.

Abstract

Objective: PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy.

Methods: Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response ('successes'). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain.

Results: Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001).

Conclusions: We report an association between reduced PI susceptibility (using full-length Gag-protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure.

Keywords: antiretroviral therapy; gag; protease inhibitor; resistance.

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Figures

Figure 1.
Figure 1.
Box plots of phenotypic assay FC in EC50 of lopinavir (LPV) by treatment outcome.
Figure 2.
Figure 2.
Box plots of phenotypic assay FC in EC50 of lopinavir (LPV) by subtype.
Figure 3.
Figure 3.
Scatter plot of FC in EC50 of lopinavir (LPV) versus (a) replicative capacity and (b) baseline viral load.
See this image and copyright information in PMC

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