22 research outputs found
Quality of T-cell responses versus reduction in viral load: results from an exploratory phase II clinical study of Vacc-4x, a therapeutic HIV vaccine
Background
Immunization with Vacc-4x, a peptide-based therapeutic
vaccine for HIV-1, has shown a statistically significant
reduction in viral load set point compared to placebo
during treatment interruption in an exploratory phase II
clinical study enrolling 135 subjects (NCT00659789).
This vaccine aims to induce sustained cell-mediated
immune responses to conserved domains on HIV p24.
Methods
After 6 immunizations on ART over 28 weeks, treatment
was interrupted for up to 24 weeks (Vacc-4x n=88;
placebo n=38). Immunological analyses (ELISPOT, proliferation,
intracellular cytokine staining (ICS)) to HIV p24
were carried out at central laboratories. The HLA class I
profile (Vacc-4x n=73, placebo n=32) was also determined.
Results
For subjects that remained off ART until week 52 (Vacc-4x
n=56, placebo n=25), there was a log 0.44 reduction in
viral load set point between the Vacc-4x and placebo
groups (p=0.0397). There was a similar distribution of
HLA class I alleles in the two treatment arms, with the
exception of the B35 allele (27% of Vacc-4x subjects versus
8% placebo subjects). The viral load of ELISPOT positive
Vacc-4x subjects was significantly lower than that of placebo
subjects (p=0.023). There was no significant difference
in T-cell proliferation responses between Vacc-4x and placebo groups, however, the percentage of subjects showing
proliferative CD4 and CD8 T-cell responses to Vacc-4x
peptides increased over time only for the Vacc-4x group.
ICS analysis showed a predominance of CD8-mediated
T-cell responses to p24 that were significantly increased
from baseline for the Vacc-4x group (p<0.043) but not for
the placebo group(p>0.05). There was also a trend towards
higher numbers of polyfunctional T-cells in the Vacc-4x
group compared to the placebo group (p=0.188).
Conclusion
These findings suggest Vacc-4x immunization can influence
the quality of immune responses to HIV-1 p24 irrespective
of HLA status, and contribute to a reduction in viral load
A Phase IIB, Randomized, Double-Blind, Multicenter, Immunogenicity Study of Vacc-4x Versus Placebo in HIV-1-infected Patients
Background: Vacc-4x is a peptide-based HIV therapeutic vaccine to conserved domains on p24Gag. Recently conserved 'sectors' on HIV p24, critical for virus viability and thereby immunologically vulnerable have been identified. Elite controllers target immune responses to such regions. The Vacc-4x peptides lie within a number of these conserved sectors of HIV p24. The co-primary endpoints of this study were to compare changes in CD4 counts and return to ART between treatmentand placebo groups during a 24 week treatment interruption. Secondary endpoints included safety, viral load and immunogenicity.Methods: This prospective, randomized, double blind phase IIB clinical study (NCT00659789) was carried out in 13 European and 5 US centers recruiting 135 patients on ART. After 6 immunizations on ART over 28 weeks, treatment was interrupted for up to 24 weeks (to week 52) (Vacc-4x n = 88; placebo n = 38). Immunological analyses (ELISPOT, proliferation, intracellular cytokine staining) were carried out at central laboratories.Results: There were no Vacc-4x-related serious adverse events. Of the 135 patients recruited (male n = 92; female n = 43), 126 patients completed the study. Median prestudy CD4 count was 712 (Vacc-4x) and 619 cells/mm3 (placebo), and median CD4 nadir 300 (Vacc-4x) and 285 cells/mm3 (placebo). There was no statistically significant difference between the two groups regarding change in CD4 counts (p = 0.12) or ART resumption (p = 0.89) during treatment interruption. A statistically significant treatment difference between Vacc-4x and placebo groupsfor viral load (VL) was found for patients who achieved a 6 month ART-free period (p = 0.0022). There was a positive correlation between ELISPOT responses and lower viral load in the Vacc-4x group compared to placebo (p = 0.02). Long-term follow-up of patients up t o week 104 was completed in June 2011.Conclusion: Vacc-4x was found to be safe and well tolerated. TheVacc-4x group experienced a significant reduction in viral load compared to placebo
Thrombelastography (TEG® 6s) early amplitudes predict maximum amplitude in severely injured trauma patients
Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG®) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG® 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as <55 mm for Kaolin TEG® and RapidTEG®, and <17 mm for TEG® functional fibrinogen (FF). One hundred eighty-seven patients were included. Median time to MA was 20 (Kaolin TEG®), 21 (RapidTEG®) and 12 (TEG® FF) min. For Kaolin TEG®, the optimal Youden index (YI) was at A5 < 36 mm (100/93% sensitivity/specificity) and A10 < 47 mm (100/96% sensitivity/specificity). RapidTEG® optimal YI was at A5 < 34 mm (98/92% sensitivity/specificity) and A10 < 45 mm (96/95% sensitivity/specificity). TEG® FF optimal YI was at A5 < 12 mm (97/93% sensitivity/specificity) and A10 < 15 mm (97/99% sensitivity/specificity). In summary, we found that TEG® 6s early amplitudes were sensitive and specific predictors of MA in severely injured trauma patients. Intervening on early amplitudes can save valuable time in hemostatic resuscitation
Data-driven Development of ROTEM and TEG Algorithms for the Management of Trauma Hemorrhage:A Prospective Observational Multicenter Study
OBJECTIVE: Developing pragmatic data-driven algorithms for management of trauma induced coagulopathy (TIC) during trauma hemorrhage for viscoelastic hemostatic assays (VHAs). BACKGROUND: Admission data from conventional coagulation tests (CCT), rotational thrombelastometry (ROTEM) and thrombelastography (TEG) were collected prospectively at 6 European trauma centers during 2008 to 2013. METHODS: To identify significant VHA parameters capable of detecting TIC (defined as INR > 1.2), hypofibrinogenemia (< 2.0 g/L), and thrombocytopenia (< 100 x10/L), univariate regression models were constructed. Area under the curve (AUC) was calculated, and threshold values for TEG and ROTEM parameters with 70% sensitivity were included in the algorithms. RESULTS: A total of, 2287 adult trauma patients (ROTEM: 2019 and TEG: 968) were enrolled. FIBTEM clot amplitude at 5 minutes (CA5) had the largest AUC and 10 mm detected hypofibrinogenemia with 70% sensitivity. The corresponding value for functional fibrinogen (FF) TEG maximum amplitude (MA) was 19 mm. Thrombocytopenia was similarly detected using the calculated threshold EXTEM-FIBTEM CA5 30 mm. The corresponding rTEG-FF TEG MA was 46 mm. TIC was identified by EXTEM CA5 41 mm, rTEG MA 64 mm (80% sensitivity). For hyperfibrinolysis, we examined the relationship between viscoelastic lysis parameters and clinical outcomes, with resulting threshold values of 85% for EXTEM Li30 and 10% for rTEG Ly30.Based on these analyses, we constructed algorithms for ROTEM, TEG, and CCTs to be used in addition to ratio driven transfusion and tranexamic acid. CONCLUSIONS: We describe a systematic approach to define threshold parameters for ROTEM and TEG. These parameters were incorporated into algorithms to support data-driven adjustments of resuscitation with therapeutics, to optimize damage control resuscitation practice in trauma