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To: scaram(o)uche who wrote (315)	9/27/1999 11:42:00 AM
From: scaram(o)uche	Respond to of 1169

keep reading, beyond where you first start to say "did he get the wrong thread?"........ Monday September 27, 10:49 am Eastern Time Company Press Release SOURCE: ViroLogic, Inc. Phenotypic HIV Drug Resistance Testing Superior to Treatment History in Predicting Salvage Therapy Success - Late Breaker Study Presented Monday at ICAAC Uses Novel Phenotypic Assay, PhenoSense(TM) HIV - SAN FRANCISCO, Sept. 27 /PRNewswire/ -- A late breaker study presented today at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) by Dr. Michael Saag of the University of Alabama, Birmingham found that phenotypic HIV drug resistance testing is superior to treatment history in predicting sustained HIV suppression in antiretroviral therapy (ART) -experienced patients who are starting new treatment regimens. Today's presentation, ''Predictive Value of HIV Phenotypic Susceptibility Testing in an HIV Clinical Cohort'' (Late Breaker Session, Monday, Sept. 27, 12:00pm, Room 103/104), described the use of ViroLogic, Inc.'s novel phenotypic drug susceptibility assay, PhenoSense HIV. ViroLogic's rapid test directly measures the sensitivity or resistance of a patient's HIV to all available anti-HIV drugs. In the study, Dr. Saag and his colleagues followed 71 ART-experienced HIV patients with plasma viral loads of >5000 RNA copies/ml who were beginning a new salvage regimen. Plasma collected at baseline was tested retrospectively for phenotypic drug susceptibility. Patient data obtained included complete ART history. The data showed that a patient's phenotypic susceptibility profile, as measured by the PhenoSense HIV assay, best predicted sustained virologic suppression in these ART-experienced patients. Therapy history was less predictive of treatment success and did not provide additional predictive value when added to the phenotypic susceptibility information. These results suggest that phenotypic testing should supplement treatment history in selecting salvage regimens for patients. ''Reduced drug susceptibility has become a significant roadblock to successfully treating people with HIV,'' noted lead investigator Dr. Michael Saag of the University of Alabama, Birmingham. ''As we have shown, relying on a patient's treatment history alone to design salvage therapy regimens will be less predictive. Phenotypic susceptibility testing is clearly a useful tool which is superior to a thorough patient history as a predictor of salvage therapy success in heavily treated patients.'' About PhenoSense HIV and ViroLogic PhenoSense HIV directly measures the susceptibility of HIV to each of the currently available antiretroviral drugs, providing highly accurate, reproducible, and individualized drug susceptibility information in two weeks, rather than the nearly 4-6 weeks for other currently available phenotypic resistance tests. The substantial advantage in turnaround time, sensitivity and reproducibility provided by PhenoSense HIV makes phenotypic HIV resistance testing a practical tool for physicians. ViroLogic, a privately held South San Francisco-based biotechnology company, is a leader in the development of novel therapy guidance tools to enable patients, physicians and medical reimbursers to make rational treatment decisions in the management of viral diseases and cancer. The company's proprietary technology is also being used in the fields of viral pharmacogenomics to identify, analyze and select new drug candidates for treating viral diseases and cancer, and in disease management through the development of therapy guidance algorithms to guide patient therapy. Today's study, ''Predictive Value of HIV Phenotypic Susceptibility Testing in an HIV Clinical Cohort,'' is one of seven studies utilizing the PhenoSense HIV assay presented at ICAAC. SOURCE: ViroLogic, Inc. The N88S Amino Acid Substitution in HIV-1 Protease Is Associated with Increased Susceptibility to Amprenavir C.J. Petropoulos, R. Ziermann, K. Limoli, N.T. Parkin ViroLogic, Inc.: San Francisco, CA Background: Amprenavir (Agenerase, 141-W94, VX-478) is an HIV-1 protease inhibitor (PRI) recently approved for marketing in the US for treatment of HIV-1 infection. One potential use for amprenavir may be salvage therapy for patients who have experienced viral load rebound after treatment with other approved PRIs. Since one cause of treatment failure is the development of resistance to PRIs, we performed a study to evaluate patterns of amprenavir cross-resistance in viruses resistant to other PRIs. Methods: Antiretroviral drug susceptibility of 200 viruses from patients failing therapy with IDV or NFV were evaluated using a recombinant virus assay (PhenoSense™ HIV). HIV-1 protease (PR) and reverse transcriptase (RT) regions were amplified by RT-PCR from plasma samples and inserted into a viral vector (derived from pNL4-3) containing a luciferase indicator gene. Drug susceptibility was evaluated by measuring luciferase inhibition activity in a single cycle replication assay. The PR region of recombinant viruses was sequenced using dideoxy-chain termination methods (PE/ABI) to identify drug resistance mutations. Results: Increased (2.5 to 10-fold) susceptibility to amprenavir was detected in 20 viruses. Pronounced increases in amprenavir susceptibility was strongly associated with an N88S substitution in PR. N88S has been described previously in viruses isolated after in vitro passage in the presence of an investigational protease inhibitor, SC-55389A (Smidt et al. Antimicrob. Agents Chemother. 41: 515-522, 1997). Other combinations of mutations were also associated with amprenavir hypersensitivity. Some viruses also exhibited increased susceptibility to saquinavir. Site-directed mutagenesis studies have been used to test directly the effect of the N88S substitution and other mutations on amprenavir and saquinavir susceptibility. Conclusions: The N88S substitution in HIV-1 protease is strongly associated with increased susceptibility to amprenavir. The N88S substitution may be useful in predicting clinical response to amprenavir salvage therapy.

To: scaram(o)uche who wrote (315)	9/27/1999 11:47:00 AM
From: scaram(o)uche	Read Replies (1) \| Respond to of 1169

Differences in Protease Inhibitor (PI) Phenotypic Susceptibility after Failure of the First PI-Containing Regimen R. Haubrich1, C. Kemper2, M. Witt3, P. Keiser4, M. Dube5, D. Forthal6, J. Currier7, J. Hwang1, D. Richman1, N. Hellmann8, G. Heilek8, Y. Lie8, J.A. McCutchan1 1Univ. of California, San Diego: San Diego, CA; 2Santa Clara Valley Med. Ctr.: San Jose, CA; 3Harbor- UCLA: Los Angeles, CA; 4Univ. of Texas: Dallas, TX; 5Univ. of Southern California: Los Angeles, CA; 6Univ. of California, Irvine: Irvine, CA; 7Univ. of California, Los Angeles: Los Angeles, CA; 8ViroLogic: South San Francisco, CA Objective: To evaluate differences in protease inhibitor susceptibility after failure of the first PI containing regimen. Design: Baseline PI susceptibility was determined in an ongoing strategy trial of susceptibility testing (ViroLogic PhenoSenseTM assay) and expressed as the fold change (FC) in IC50 from control. A > 2.5 FC was defined as resistant for this analysis. Results: Of 82 patients (median CD4 = 281, median HIV RNA = 4.1 log10, median months NRTI = 34, median months PI = 15), 13 were PI naïve and had no reduction in susceptibility to PI. Forty-four had prior NFV, 16 IDV, 5 SQV, 3 RTV and 1 APV. In PI experienced patients, the mean baseline protease inhibitor FC was significantly different between IDV, NFV, RTV, APV and SQV (4.9, 20, 7.0, 2.1, and 3.1 respectively; p < 0.001 by repeated measures ANOVA). The percent of patients with drug susceptible virus (< 2.5 FC) was 83% for APV, 84% for SQV, 71% for RTV, 68% for IDV and 26% for NFV. Compared to patients with other prior PI, prior therapy with NFV was associated with infrequent cross resistance: APV (7% vs 36%, p = 0.006), IDV (16% vs 60%, p < 0.001) and RTV (14% vs 56%, p < 0.001). Multiple LR models were constructed to predict individual PI resistance based on baseline values (CD4, HIV RNA, prior therapy, and AIDS diagnosis). For the best model (NFV, p = 0.0001), correct prediction of resistance was obtained for 81% of cases. 11% (2/18) of patients predicted to be NFV-sensitive were actually resistant while 22% (14/64) predicted to be NFV-resistant were actually sensitive. Conclusion: In this population treated predominately with NFV, viral isolates remained susceptible to APV and SQV in the majority of cases. NFV, used as the first PI, was associated with less cross resistance than other prior PIs. LR modeling (using prior history) did not accurately predict PI resistance.