An open-label phase 1 clinical trial of the anti-α4ß7 monoclonal antibody vedolizumab in HIV-infected individuals.

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4ß7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4ß7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4ß7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4ß7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4ß7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study.

BACKGROUND: Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy. METHODS: We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility. RESULTS: Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation.

State-of-the-Art Workshops on Medical Countermeasures Potentially Available for Human Use Following Accidental Exposures to Ebola Virus.

The ongoing outbreak of Ebola in West Africa has raised a general awareness that at present there are no Ebola-specific medical countermeasures (MCMs) with proven effectiveness. This paper recapitulates discussions held at the 6th International Filovirus Symposium in March 2014 as well as the subsequent design of a randomized clinical trial design for treating Ebola virus-infected patients evacuated from West Africa to the United States. A number of different drugs or biologics were critically reviewed and 3 different postexposure strategies were identified as being farthest along in development; passive immunotherapy with monoclonal antibodies, postexposure vaccination with constructs involving viral vectors (such as vesicular stomatitis virus), and antisense compounds directly targeting the viral genome such as modified phosphorodiamidate morpholino oligomer-based compounds and small interfering RNA products. At the time of the meetings, there were no investigational new drugs (INDs) in place for the candidate MCMs. Developers and sponsors of these candidate products were strongly encouraged to prepare pre-IND packets and submit pre-IND meeting requests to the Food and Drug Administration. Some of these investigational products have already been used under emergency authorizations to treat patients in Africa as well as patients evacuated to the United States or Western Europe.

Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dimer that are not associated with plasma HIV-RNA levels.

OBJECTIVE: To determine the effects of interleukin (IL)-2 treatment on inflammatory and thrombotic biomarkers in chronically HIV-infected adults receiving antiretroviral therapy. METHODS: Cryopreserved plasma was evaluated retrospectively for C-reactive protein (CRP) and D-dimer at baseline, end of an IL-2 cycle, and long-term follow up from two randomized, controlled trials: 57 IL-2-naive adults receiving either three to six cycles of IL-2 as well as antiretroviral therapy (nucleoside analogues) or antiretroviral therapy alone for 12 months, and 40 IL-2-experienced adults on highly active antiretroviral therapy who either interrupted or continued therapy for 6 months after a baseline IL-2 cycle. High-sensitivity CRP (hsCRP) was measured by immunonephelometry (detection limit 0.175 mg/l) and D-dimer by latex agglutination (detection limit 0.20 mg/l). Median within-group differences and pre and post-IL-2 changes between groups were assessed via nonparametric Wilcoxon signed-rank and Mann-Whitney U-tests. Spearman's rank test was used to assess correlations between changes in hsCRP, D-dimer, and HIV-RNA viral load. RESULTS: Significant increases in hsCRP (study 1: 138.6 mg/l; study 2: 58.9 mg/l) and D-dimer (study 1: 3.1 mg/l; study 2: 0.4 mg/l, all P < 0.0001) occurred by the end of the initial IL-2 cycle, returning to baseline by the end of study. No correlations were seen between changes in hsCRP or D-dimer and HIV-RNA, CD4 T-cell count, or proliferation (Ki67 expression). No thrombotic or cardiovascular serious adverse events occurred during these study periods. CONCLUSION: IL-2 dosing caused transient increases in plasma hsCRP and D-dimer levels, regardless of HIV-RNA viral load, suggesting the possibility of increased risk for thrombotic events.

Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial.

OBJECTIVE: To evaluate whether interleukin (IL)-2 in patients with chronic HIV infection can maintain CD4 T cell counts during 6 months of HAART interruption. DESIGN: Prospective, randomized, controlled, open-label phase II noninferiority trial comparing IL-2 with HAART interruption or continuous HAART. METHODS: Forty-one IL-2-experienced (three or more prior cycles) HIV-1-infected adults with CD4 cell count at least 500 cells/microl were randomized in the ratio 2: 1 to interrupted (I = 27) or continuous (C = 14) HAART for 6 months following an initial IL-2 cycle. Subsequent IL-2 cycles were triggered by CD4 T cell counts less than 90% of baseline. Immune, metabolic, and quality of life indices were compared (Mann-Whitney and Fisher's exact tests), defining noninferiority as a percentage difference (C- I) in treatment success (CD4 T cells > or =90% of baseline at 6 months) with a 95% confidence interval (CI) lower limit greater than -20%. RESULTS: Demographic and immune parameters were similar between the groups at baseline. Median CD4 T cell count, HIV viral load, and treatment success differed significantly at 6 months (I: 866 cells/microl, 39,389 copies/ml, 48.1%; C: 1246 cells/microl, <50 copies/ml, 92.3%; P < or = 0.001). Group I was inferior to C (% difference = -44.2%; 95% CI: -64.2%, -11.2%; P = 0.013). Minor statistically significant differences in HgbA1c and energy level occurred at 6 months (I > C). Following HAART interruption, single cases of acute retroviral syndrome, secondary syphilis, non-Hodgkin's lymphoma, and Kaposi's sarcoma recurrence were observed. CONCLUSION: IL-2 alone was inferior to IL-2 with HAART in maintaining baseline CD4 T cell counts. HAART interruption had a small impact on metabolic parameters and quality of life.