Session 66Poster Presentations New Antiretrovirals Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
561 Viral Resistance and Pharmacologic Analyses of Phase I/II Study Patients Treated with the HIV-1 Entry Inhibitor PRO 542 W. Olson*1, R. Israel1, J. Jacobson2, L. Vassilatos1, D. Tran1, N. Stambler1, M. Barish1, B. O'Hara1, T. Ketas1, B. Sullivan1, J. Moore3, C. Petropoulos4, P. Maddon1 1Progenics Pharm, Inc, Tarrytown, NY; 2Beth Israel Med Ctr, New York, NY; 3Weill Med Coll of Cornell Univ, New York, NY; and 4ViroLogic, San Francisco, CA
Background: HIV-1 entry into target cells proceeds via a cascade of events involving viral attachment, coreceptor interactions, and membrane fusion. Each step of this process has been validated as a target for therapy, and HIV-1 entry inhibitors represent an emerging mode of antiretroviral therapy. PRO 542 (CD4-IgG2) is a novel HIV-1 attachment inhibitor that broadly and potently neutralizes primary viruses. PRO 542 has shown favorable tolerability, pharmacology, and antiviral activity in Phase I/II trials. In this analysis, antiviral effects were examined in relation to PRO 542 exposure and to the PRO 542 sensitivity of viruses from 20 patients (pts) treated with ascending intravenous doses of PRO 542.
Methods: Viral sensitivity to PRO 542 was examined using PhenoSense Entry assay technology (Virologic, Inc.), which utilizes reporter viruses complemented with HIV-1 envelope glycoproteins. The viral envelopes were obtained by RT-PCR amplification of the env gene from pt viruses. Pt viruses were also obtained by passage on peripheral blood mononuclear cells and analyzed for PRO 542 sensitivity in a whole-virus assay that utilizes a p24 antigen readout. PRO 542 serum levels in longitudinal pt specimens were determined using a validated ELISA assay. Antiviral response was quantified as the area under the normalized viral load-time curve (viral AUC) for defined periods post-treatment. Correlations between in vivo antiviral responses and in vitro parameters were examined by linear regression analysis.
Results: PRO 542 demonstrated dose-proportional pharmacology. The inter-patient variation in viral sensitivity to PRO 542 was comparable across the reporter- and whole-virus assays. The variation for pt viruses, which represent diverse quasi-species, was consistent with prior in vitro studies performed using cloned or biological isolates. Within a given dose cohort, significant correlations were observed between viral AUC and viral sensitivity to PRO 542 (r = 0.78, p < 0.003).
Conclusions: These studies begin to define an inhibitory quotient for PRO 542 based on drug susceptibility and exposure. Phenotypic drug-resistance testing can reveal inter-patient variations in viral sensitivity to PRO 542 in vitro, and correlations can be drawn between in vitro sensitivity and clinical outcome. Viral resistance testing may have prognostic value for HIV-1 attachment and entry inhibitors.
