17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

VIROLOGICAL AND IMMUNOLOGICAL OUTCOMES IN A COHORT OF PATIENTS FAILING INTEGRASE INHIBITORS

Antivir Ther. 2008; 13(Suppl. 3):A12 (abstract no. 10)

H Hatano¹, H Lampiris¹, W Huang², R Hoh¹, S Gupta², S Fransen², JN Martin¹, C Petropoulous² and SG Deeks^1
1University of California, San Francisco, CA, USA; ²Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: Although integrase inhibitors are highly effective in the management of drug-resistant HIV, some patients fail to achieve durable viral suppression. The long-term consequences of integrase inhibitor failure have not been well defined.

METHODS: We identified 13 individuals who exhibited evidence of incomplete viral suppression on a regimen containing an integrase inhibitor. Genotypic and phenotypic resistance testing was performed at Monogram Biosciences.

RESULTS: Baseline CD4+ T-cell count and plasma HIV RNA levels were 66 cells/mm³ and 4.78 log₁₀ copies/ml, respectively. Patients were followed for a median 12.7 months. Despite evidence of integrase inhibitor failure, patients appeared to have a persistent immunological benefit, with a median change in CD4+ T-cell count of +37 and +71 cells/mm³ at month 3 and month 6 of documented failure, respectively. Integrase inhibitor failure was often associated with the emergence of genotypic and phenotypic resistance, although three individuals with partial adherence lacked evidence of resistance. The G140S/Q148H pattern and T97A/Y143R patterns were each associated with high-level phenotypic resistance (>400-fold change in IC₅₀). One individual harbouring a virus with an isolated N155H mutation (41-fold change in IC₅₀) discontinued raltegravir while remaining on a stable background regimen. Plasma HIV RNA levels remained stable in the absence of raltegravir (suggesting limited residual antiviral activity), but subsequently increased 10fold as genotypic/phenotypic evidence for raltegravir resistance waned (suggesting a significant fitness defect).

CONCLUSIONS: Although experience from clinical trials suggests that the majority of patients receiving the newer antiretroviral agents do well, there remains a subset of individuals for whom these drugs will not work because of preexisting resistance or non-adherence. There may, however, be a residual clinical benefit despite lack of viral suppression. This benefit may be due in part to alterations in viral fitness, as suggested by changes after removal of raltegravir in a single individual. Notably, this latter observation is consistent with observations from the SIV-infected macaque model, where removal of integrase inhibitors in animals harbouring the N155H mutation was associated with initial stable viraemia followed by rapid increase in viraemia as the mutations waned.

2008-06-10
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