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Publications (4)

  • [Show abstract] [Hide abstract] ABSTRACT: Abstract Treatment of HIV infection with conventional antiretroviral therapy (ART) is a lifelong challenge with significant long-term risks of adverse events and treatment failure-induced HIV resistance being major concerns. One potential alternative to standard treatment is the use of viral decay accelerators, antiviral agents that theoretically can drive the rate of viral mutation beyond the compensatory capacity of the virus, thereby inducing viral extinction. One such drug, KP-1461, was tested in a population of HIV-infected persons not receiving ART to assess the safety, tolerability, and efficacy of the strategy in vivo. Of 24 highly treatment-experienced HIV-infected patients who received at least one dose of KP-1461, 13 completed the planned 4 months of monotherapy. The drug was generally well tolerated; it did not significantly affect either HIV viral load or CD4 lymphocyte count over the period of dosing. Pharmacokinetic sampling suggested adequate drug exposure was achieved. There were no new mutations induced by KP-1461 that changed viral susceptibility to standard antiretroviral agents. After the study was completed, analysis of more than 7 million base pairs of HIV samples from study patients and controls demonstrated changes in the pattern of viral mutations that differed significantly from what would be encountered naturally. The identified alterations were consistent with an effect resulting from KP-1461's proposed mechanism of action. These findings suggest that the novel antiretroviral approach illustrated by this study should be further investigated, particularly given the relatively good tolerability and the demonstrated excellent safety in this limited cohort study.
    Article · Jun 2012 · AIDS research and human retroviruses
  • [Show abstract] [Hide abstract] ABSTRACT: Background: PRO 140 potently inhibits CCR5-tropic (R5) HIV in vitro. In a prior study, single 5mg/kg IV doses reduced HIV RNA by 1.83 log10 in subjects with early-stage disease and R5 virus only. The present study compared 5mg/kg and 10mg/kg IV doses for antiviral activity and tolerability. Methods: Entry criteria included HIV RNA >5,000 copies/mL, R5 virus only, CD4 >300/μL, and no antiretroviral therapy for 12 weeks. Subjects were randomized to receive placebo, 5mg/kg PRO 140 or 10mg/kg PRO 140. They were followed for 58 days post-treatment. An interim analysis was performed on data from the first 15 subjects. Results: Interim enrollment was equally distributed across the treatment groups. Baseline HIV RNA and CD4 averaged 35,480 cps/mL and 403/μL, respectively. Mean maximum log10 reductions in HIV RNA were 0.48 (range 0.15-0.73) for placebo, 1.90 (range 1.44-2.17, p<0.0001) for 5mg/kg PRO 140 and 2.17 (range 2.09-2.26, p<0.0001) for 10mg/kg PRO 140. At Day 12, mean log10 changes in HIV RNA were +0.06, -1.88 (p<0.0001), and -2.01 (p<0.0001) for placebo, 5mg/kg and 10mg/kg, respectively. The mean viral load reduction was >1.5 log10 through Day 22 at 10mg/kg. PRO 140 was generally well tolerated. Trial enrollment has completed, and updated data will be presented. Conclusions: The data confirm the antiviral activity reported previously for 5mg/kg PRO 140. A 10mg/kg dose increased the duration of antiviral effect. The findings indicate the potential for infrequent IV dosing. SC dosing regimens are also being evaluated.
    Conference Paper · Oct 2008
  • [Show abstract] [Hide abstract] ABSTRACT: The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels or =5000 copies/mL, CD4(+) cell counts > or =250 cells/microL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1 RNA level of 0.58 log(10), 1.20 log(10) (P= .0002) and 1.83 log(10) (P= .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of > or =10-fold were observed within 4 days and persisted for 2-3 weeks after treatment. This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. ISRCTN Register: ISRCTN45537485 .
    Article · Oct 2008 · The Journal of Infectious Diseases
  • [Show abstract] [Hide abstract] ABSTRACT: MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration [IC95] = 33 nM in 50% human serum) and good bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4 T-cell counts of at least 100 cells/mm. This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect. Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was -0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences. MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated.
    Article · Jan 2007 · JAIDS Journal of Acquired Immune Deficiency Syndromes