G190A SUBSTITUTION IS ASSOCIATED WITH DELAVIRDINE (DLV) HYPERSUSCEPTIBILITY IN VITRO AND CLINICAL RESPONSE WITH DLV INTENSIFICATION
Introduction: Although much interest exists regarding NNRTI hypersusceptibility (HS), there are limited data describing the clinical impact of DLV HS. In particular, the G190A RT mutation (which emerges during NVP therapy and confers >40 fold change (FC) to NPV and >4 FC to EFV) confers HS (FC (0.4) to DLV. Furthermore, in the presence of other NNRTI mutations (K101E or K103N) the G190A confers further FC increases to NPV or EFV but a decrease in FC to DLV.
Purpose: We describe a unique patient whose HIV possessed the G190A in a background of high-level NRTI/PI resistance and whose plasma viral load (PVL) was successfully and durably suppressed by DLV intensification of a failing megaHAART salvage regimen.
Description: The patient was HAART experienced with CD4<5 cells/mm3 and PVL>100,000 c/mL on therapy for >12 months. He underwent a nine-month treatment interruption (TI) during which he developed CMV retinitis/colitis. Post-TI his PVL = 417,336 c/mL and CD4=0 cells/mm3. Genotype pre and post-TI showed RT: 35V, 39A, 40F, 41L, 43E, 54I, 67N, 75M, 88C, 190A, 211K, 214F, 215Y, 219Q, 223Q; Protease- 10I, 20R, 35D, 36I, 41K, 54V, 62V, 63P, 71I, 77I, 82A, 90M, 93L. The patient began a salvage regimen with ZDV, 3TC, ABC, ddI, LPV/RTV, and APV resulting in a gradual suppression of PVL<50 c/mL after 12 months. However, he experienced a rebound with PVL sustained >1,000c/mL. Rebound genotype demonstrated mutations in addition to baseline: RT 68G, Protease: 33F, 46L, 84T. Rebound phenotype (Phenosense, ViroLogic) showed FC ZDV-1096, 3TC-13, ddI-3.2, ABC-12, RTV>160, LPV-48, APV-15, NVP-54, EFV-2.5 and DLV 0.1. Salvage regimen was intensified with DLV single agent and resulted in PVL suppression to <50 c/ml within 6 weeks. PVL has remained < 50c/mL at last follow-up to 72 weeks with CD4 gain from 3 to 426 cells/mm3.
Conclusion: The G190A substitution is a unique RT mutation emerging during NVP therapy. While this mutation confers resistance to NVP and EFV it may produce HS to DLV. The successful DLV intensification of a failing deep salvage regimen in this case uniquely highlights the clinical impact of G190A and DLV HS on DLV activity. These data also suggest that sequential use of specific NNRTIs (NVP(DLV) may be possible in the setting of specific NNRTI resistance profiles.
The 2nd IAS Conference on HIV Pathogenesis and Treatment
" N. Bellosillo , et al.
G190A SUBSTITUTION IS ASSOCIATED WITH DELAVIRDINE (DLV) HYPERSUSCEPTIBILITY IN VITRO AND CLINICAL RESPONSE WITH DLV INTENSIFICATION.
The 2nd IAS Conference on HIV Pathogenesis and Treatment: