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

HIV-1 GAG POLYMORPHISMS DETERMINE TREATMENT RESPONSE TO BEVIRIMAT (PA-457)

Antivir Ther. 2008; 13(Suppl. 3):A10 (abstract no. 8)

S McCallister¹, J Lalezari², G Richmond³, M Thompson⁴, R Harrigan⁵, D Martin⁶, K Salzwedel⁶ and G Allaway^6
1Panacos Pharmaceuticals, Watertown, MA, USA; ²Quest Clinical Research, San Francisco, CA, USA; ³Fort Lauderdale, FL, USA; ⁴AIDS Research Consortium of Atlanta, Atlanta, GA, USA; ⁵BC Centre for Excellence in HIV/AIDS, Vancouver, Canada; ⁶Panacos Pharmaceuticals, Gaithersburg, MD, USA

BACKGROUND: Bevirimat is a novel HIV-1 maturation inhibitor in Phase II development that targets the capsid SP-1 cleavage site of Gag. Despite optimal plasma concentrations, not all patients given bevirimat have a robust viral load reduction (VLR). The determinants of treatment response were unknown.

METHODS: In a study to assess the bevirimat trough level associated with an optimal treatment response, 44 heavily treatment-experienced patients were given bevirimat for 14 days as functional monotherapy in escalating dose groups. Baseline clinical and virological variables were assessed to establish the determinants of bevirimat response. Response was also correlated with a standard Gag amino acid sequence.

RESULTS: Nineteen of the 20 responder patients (≥0.5 log₁₀ VLR) and 19/24 non-responder patients (<0.5 log₁₀ VLR) had optimal bevirimat trough levels of at least 20 µg/ml. In this bimodal bevirimat treatment response distribution, the mean VLR was -1.26 or -0.05 log₁₀ copies/ml for responder or non-responder patients, respectively. Non-responder patients had more frequent baseline Gag polymorphisms near the capsid SP-1 cleavage site than responders (7.3; 5.9; P=not significant); Q369H, V370A and T371A/T371 deletion were more frequent in non-responders. Patients with any amino acid change at positions 369, 370 and 371 had mean VLR of -0.16, -0.24 and -0.32 log₁₀, respectively. Patients with consensus amino acid at 369, 370 and 371 had mean VLR of -0.69, -0.79 and -0.73 log₁₀, respectively. Patients without any change at 369, 370 or 371 had mean VLR of -1.08 log₁₀. Twelve (92%) of the 13 patients with bevirimat trough >20 µg/ml and with consensus amino acid at 369, 370 or 371 had VLR >0.5 log₁₀. Lower baseline CD4+ T-cell count was the only clinical variable significantly (P=0.01) associated with non-response. Analysis of Gag genotype in a separate database of 567 treatment-naïve HIV positive patients showed that 60.2% had the clade B consensus amino acid at positions 369, 370 or 371.

CONCLUSIONS: Using a genotype assay, treatment response to bevirimat is associated with baseline amino acid polymorphisms at Gag positions 369, 370 or 371 on SP-1; lower baseline CD4+ T-cell count may be a surrogate for these Gag changes. The Gag data were confirmed by phenotypic assay and a new prospective clinical study to verify these findings is underway.

2008-06-10
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