News from the 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy in Toronto, which started on Sunday.

HIV Research

¿ ViroLogic Inc., of South San Francisco, presented data at ICAAC that cast doubt over the reliability of genotypic prediction in identifying resistance to antiretroviral drugs in several common HIV mutations. The results support the theory that anti-HIV therapy resistance rises from a complex interaction of genetic mutations in the virus, and that genotypic resistance testing, which relies on interpretation of mutations to predict resistance and guide HIV treatment decisions, differs significantly from direct and quantitative measurement by challenging the virus' ability to replicate in the presence of antiretrovirals. Using ViroLogic's PhenoSense HIV assay, authors of the study, "Discordance Between Genotype-Based Predictions of HIV-1 Protease Inhibitor Susceptibility and Actual Phenotype in HIV Isolates Containing Mutations at Positions 82 or 90," found that 73 percent of viruses with mutations at position 82 were still sensitive to at least one drug that genotyping had labeled ineffective, and 47 percent of viruses with the common mutation L90M were susceptible to at least one drug predicted to be ineffective. Other data from ViroLogic presented at ICAAC showed that patients with previous HIV treatment experience expressed hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTIs), a common class of AIDS drug. That study showed hypersusceptibility can lead to improved treatment response. A further study concluded that the newest class of HIV/AIDS drugs, intergrase inhibitors, showed no cross-resistance with other drug classes.

¿ DuPont Pharmaceuticals Inc., of Wilmington, Del., reported data indicating that the anti-HIV drug Sustiva (efavirenz), when substituted for a protease inhibitor, maintains viral load suppression longer in patients who already have achieved a specific level than continued protease inhibitor therapy. Viral load suppression level cutoff was set at less than 50 copies per milliliter for the study. Of 226 patients randomized to change from protease inhibitor therapy to Sustiva administration while maintaining two nucleotide reverse transcriptase inhibitors (NRTIs), 3 percent had virologic rebound to greater than 50 copies/ml at 24 weeks, as compared to 10 percent of the 120 patients randomized to maintain their original regimen of a protease inhibitor plus two NRTIs. P value for the statistically significant data was .011.

¿ Triangle Pharmaceuticals Inc., of Durham, N.C., with partner Abbott Laboratories Inc., of Abbott Park, Ill., said data from their Phase I/II trial of the novel dioxoland purine nucleoside reverse transcriptase inhibitor DAPD showed decreases in viral loads in a cohort of five HIV-infected patients who were failing at their anti-retroviral regimens. Baseline viral load ranged from 15,000 copies/ml to 475,000 copies/ml. The addition of DAPD in two 500 mg doses twice a day to current regimens produced, at 15 days, a baseline viral load reduction ranging from 1.29 log10 to 2.25 log10 (99 percent).

¿ Gilead Sciences Inc., of Foster City, Calif., presented results from a Phase II dose-ranging clinical trial evaluating safety and efficacy of once-daily tenofovir disoproxil fumarate. The study confirmed earlier efficacy results, indicating significant and sustained antiviral activity, and the study further confirmed a lack of evidence of drug-related toxicities. The 48-week double-blind, dose-ranging study enrolled 189 treatment-experienced patients who were on a stable antiretroviral regimen for at least eight weeks prior to entering the study.

¿ Boehringer Ingelheim Group Inc., of Ingelheim, Germany, initiated research indicating that substitution of a non-nucleotide reverse transcriptase inhibitor for a protease inhibitor-based regimen maintained suppression of HIV for up to one year and longer. The NNRTI used in the majority of patients in the study was Viramune, an Ingelheim compound.

¿ University of California, San Francisco researcher Donald Abrams will present preliminary data from the largest-ever clinical trail on the safety and efficacy of interleukin-2 in treatment of HIV. The immune system protein that stimulates CD4+ T-cell production showed that IL-2 can increase CD4+ T-cell levels in some patients receiving antiretrovirals; however, the study also raised the possibility that IL-2 could increase the amount of HIV in the blood. The study was conducted as part of the NIAID's Community Programs for Clincial Research on AIDS.

¿ Bristol-Myers Squibb Co., of Madison, N.J., said updated results from an ongoing Phase II clinical trial show that BMS 232632 is safe, effective and well tolerated when administered once a day. BMS 232632 is an investigational protease inhibitor. Results also showed that BMS 232632 is the first protease inhibitor to have no impact on cholesterol and triglyceride levels in treatment-naive patients at 24 weeks of therapy.

Antibacterials Research

¿ Versicor Inc., of Fremont, Calif., said it will report data from its major discovery programs, including data on the potential of deformylase inhibitors as a novel class of antibacterial agents. In early data researchers plan to present to the conference, inhibition of peptide deformylase (PDF) is shown to lead to novel broad-spectrum antibacterial agents with in vitro and in vivo activity against several resistant bacteria.

¿ TAP Pharmaceutical Products Inc., of Lake Forest, Ill., presented data from a study designed to determine effectiveness of Spectracef (cefditoren pivoxil) in treatment of patients with acute bacterial exacerbations of chronic bronchitis. The Phase III study, designed to show equivalence between Spectracef 400 mg and clarithromycin 500 mg, produced a clinical cure rate for evaluable patients of 81 percent for Spectracef 200 mg, 78 percent for Spectracef 400 mg and 83 percent for clarithromycin 500 mg at seven to 14 days after final dosing. Spectracef is currently under review by the FDA.

¿ Intermune Pharmaceuticals Inc., of Burlingame, Calif., presented results on the therapeutic effect of antibodies to the PcrV protein in a mouse model of Pseudomanas aeruginosa-induced pneumonia indicating administration of a single dose of anti-PcrV up to four hours following a lethal-dose intratracheal instillation of an animal model of bacterial pneumonia resulted in a marked improvement of survival rates. All mice injected with a 50-mg or 100-mg dose of anti-PcrV four hours after instillation of P. aeruginosa survived, compared to only 20 percent of mice injected with 100 mg of control antibody.

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