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Article ; Online: PTG-100, an Oral α4β7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

Sandborn, William J / Mattheakis, Larry C / Modi, Nishit B / Pugatch, David / Bressler, Brian / Lee, Scott / Bhandari, Raj / Kanwar, Bittoo / Shames, Richard / D'Haens, Geert / Schreiber, Stefan / Danese, Silvio / Feagan, Brian / Pai, Rish K / Liu, David Y / Gupta, Suneel

Gastroenterology

2021 Volume 161, Issue 6, Page(s) 1853–1864.e10

Abstract: Background & aims: Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, ... ...

Abstract	Background & aims: Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). Methods: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. Results: PTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. Conclusions: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75).
MeSH term(s)	Administration, Oral ; Adult ; Animals ; Cell Adhesion/drug effects ; Cell Adhesion Molecules/metabolism ; Cell Line ; Colitis, Ulcerative/diagnosis ; Colitis, Ulcerative/drug therapy ; Colitis, Ulcerative/immunology ; Colitis, Ulcerative/metabolism ; Colon/drug effects ; Colon/immunology ; Colon/metabolism ; Disease Models, Animal ; Double-Blind Method ; Female ; Gastrointestinal Agents/administration & dosage ; Gastrointestinal Agents/adverse effects ; Gastrointestinal Agents/pharmacokinetics ; Humans ; Integrins/antagonists & inhibitors ; Integrins/metabolism ; Male ; Mice, Inbred C57BL ; Middle Aged ; Mucoproteins/metabolism ; Peptides/administration & dosage ; Peptides/adverse effects ; Peptides/pharmacokinetics ; Severity of Illness Index ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Time Factors ; Treatment Outcome ; Mice
Chemical Substances	Cell Adhesion Molecules ; Gastrointestinal Agents ; Integrins ; MADCAM1 protein, human ; Madcam1 protein, mouse ; Mucoproteins ; PTG-100 peptide ; Peptides ; integrin alpha4beta7
Language	English
Publishing date	2021-08-30
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2021.08.045
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Article ; Online: Th17 and regulatory T cells: implications for AIDS pathogenesis.

Kanwar, Bittoo / Favre, David / McCune, Joseph M

Current opinion in HIV and AIDS

2010 Volume 5, Issue 2, Page(s) 151–157

Abstract: Purpose of review: The present review discusses recent reports showing that reciprocal changes in T helper interleukin-17-secreting CD4 Th17 cells and CD4CD25FoxP3 regulatory T cells (Tregs) may play a role in the progressive disease caused by the HIV ... ...

Abstract	Purpose of review: The present review discusses recent reports showing that reciprocal changes in T helper interleukin-17-secreting CD4 Th17 cells and CD4CD25FoxP3 regulatory T cells (Tregs) may play a role in the progressive disease caused by the HIV and by simian immunodeficiency virus. Recent findings: Studies in nonhuman primate models of lentiviral infection and in HIV-infected human individuals have shown that pathogenic infection is associated with loss of Th17 cells and an increase in the frequency of Tregs. Because interleukin-17 serves to maintain the integrity of the mucosal barrier, loss of Th17 cells may permit the increase in microbial translocation across the gastrointestinal mucosa that is observed in pathogenic lentiviral disease. It remains unclear, however, whether Th17 cells are preferentially infected or if, instead, their loss is induced by bystander effects of lentiviral infection, for example, the induction of indoleamine 2,3-dioxygenase. Summary: Progressive lentiviral disease is associated with preferential depletion of Th17 cells and loss of Th17/Treg balance. Further analysis of such changes in the composition of subset CD4 T helper and Tregs may shed new light on the immunopathology of HIV disease and suggest new strategies for therapeutic and preventive interventions.
MeSH term(s)	Acquired Immunodeficiency Syndrome/immunology ; Acquired Immunodeficiency Syndrome/pathology ; Animals ; Bacteria/immunology ; Bacterial Translocation ; HIV/immunology ; HIV/pathogenicity ; Haplorhini ; Humans ; Immunity, Mucosal ; Interleukin-17/metabolism ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/pathology ; Simian Immunodeficiency Virus/immunology ; Simian Immunodeficiency Virus/pathogenicity ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Interleukin-17
Language	English
Publishing date	2010-08-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0b013e328335c0c1
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Article ; Online: Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection.

Wirth, Stefan / Rosenthal, Philip / Gonzalez-Peralta, Regino P / Jonas, Maureen M / Balistreri, William F / Lin, Chuan-Hao / Hardikar, Winita / Kersey, Kathryn / Massetto, Benedetta / Kanwar, Bittoo / Brainard, Diana M / Shao, Jiang / Svarovskaia, Evguenia / Kirby, Brian / Arnon, Ronen / Murray, Karen F / Schwarz, Kathleen B

Hepatology (Baltimore, Md.)

2017 Volume 66, Issue 4, Page(s) 1102–1110

Abstract: Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty- ... ...

Abstract	Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. Conclusion: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).
MeSH term(s)	Adolescent ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/therapeutic use ; Child ; Female ; Hepacivirus/genetics ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/virology ; Humans ; Male ; Ribavirin/pharmacokinetics ; Ribavirin/therapeutic use ; Sofosbuvir/pharmacokinetics ; Sofosbuvir/therapeutic use ; Sustained Virologic Response
Chemical Substances	Antiviral Agents ; Ribavirin (49717AWG6K) ; Sofosbuvir (WJ6CA3ZU8B)
Language	English
Publishing date	2017-08-26
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.29278
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Article ; Online: The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection.

Balistreri, William F / Murray, Karen F / Rosenthal, Philip / Bansal, Sanjay / Lin, Chuan-Hao / Kersey, Kathryn / Massetto, Benedetta / Zhu, Yanni / Kanwar, Bittoo / German, Polina / Svarovskaia, Evguenia / Brainard, Diana M / Wen, Jessica / Gonzalez-Peralta, Regino P / Jonas, Maureen M / Schwarz, Kathleen

Hepatology (Baltimore, Md.)

2017 Volume 66, Issue 2, Page(s) 371–378

Abstract: No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in ... ...

Abstract	No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).
MeSH term(s)	Administration, Oral ; Adolescent ; Antiviral Agents/administration & dosage ; Benzimidazoles/administration & dosage ; Child ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Combinations ; Female ; Fluorenes/administration & dosage ; Follow-Up Studies ; Genotype ; Hepacivirus/genetics ; Hepatitis C, Chronic/diagnosis ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/genetics ; Humans ; Male ; Patient Safety ; Risk Assessment ; Severity of Illness Index ; Sofosbuvir/administration & dosage ; Treatment Outcome ; Viral Load/drug effects
Chemical Substances	Antiviral Agents ; Benzimidazoles ; Drug Combinations ; Fluorenes ; ledipasvir (013TE6E4WV) ; Sofosbuvir (WJ6CA3ZU8B)
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.28995
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Article ; Online: SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment.

Hartigan-O'Connor, Dennis J / Abel, Kristina / Van Rompay, Koen K A / Kanwar, Bittoo / McCune, Joseph M

Science translational medicine

2012 Volume 4, Issue 136, Page(s) 136ra69

Abstract: The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a ... ...

Abstract	The mechanisms by which some HIV-infected subjects resist disease progression, whereas others progress rapidly, are incompletely understood. Viral and host genetic factors, such as nef deletions and major histocompatibility complex alleles, explain a portion of the observed variability. However, it has been difficult to identify host immune functions that may be present before infection and that allow resistance to lentiviral disease progression. Here, we show that simian immunodeficiency virus replication in the infected rhesus macaque is limited by the size of the preexisting T helper 17 (T(H)17) cell compartment: Animals with a high representation of such cells in blood and intestinal tissue before infection experienced peak and set-point viral loads about one log unit lower than those with a lower representation of T(H)17 cells. Reciprocally, treatment of macaques with interleukin-2 and granulocyte colony-stimulating factor before infection led to depletion of T(H)17 cells, reduction of the ratio between T(H)17 cells and CD3(+)CD4(+)CD25(+)CD127(low) regulatory T cells, and higher viral loads for 6 months after infection. These results demonstrate that the composition of the host immune system before infection has an influence on the course of disease after infection. Furthermore, to the extent that this influence shapes and interacts with T cell-mediated responses to virus, our findings provide a new framework for understanding interindividual variation in responses to therapies and vaccines against HIV.
MeSH term(s)	Animals ; Macaca mulatta ; Simian Immunodeficiency Virus/immunology ; Simian Immunodeficiency Virus/physiology ; Th17 Cells/metabolism ; Virus Replication/physiology
Language	English
Publishing date	2012-05-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.3003941
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Zs.A 6941: Show issues

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Article ; Online: Cytokine profiles in peripheral blood of children and adults with Crohn disease.

Pak, Seung / Holland, Nina / Garnett, Elizabeth A / Mileti, Elizabeth / Mahadevan, Uma / Beckert, Rachel / Kanwar, Bittoo / Heyman, Melvin B

Journal of pediatric gastroenterology and nutrition

2011 Volume 54, Issue 6, Page(s) 769–775

Abstract: Background: Increasing evidence suggests that cytokine dysregulation in T-helper 1 and T-helper 2 (TH1/TH2) subsets contributes to the pathogenesis of Crohn disease (CD). The present pilot study examines the hypothesis that cytokine profiles differ ... ...

Abstract	Background: Increasing evidence suggests that cytokine dysregulation in T-helper 1 and T-helper 2 (TH1/TH2) subsets contributes to the pathogenesis of Crohn disease (CD). The present pilot study examines the hypothesis that cytokine profiles differ between pediatric and adult patients with CD. Methods: Production of TH1 cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and of TH2 cytokines interleukin-4 (IL-4) and IL-6 was analyzed in peripheral blood of patients with CD and healthy controls (n=20) using flow cytometry after in vitro stimulation. Results: In both pediatric and adult subjects, frequencies of TNF-α CD4+ T cells were higher in patients with CD than in controls (P=0.009 and P=0.047, respectively). Percentages of cells expressing IL-4 were slightly increased (P=0.036), whereas those for IFN-γ were decreased (P=0.009) in pediatric patients with CD compared with controls. As expected, the overall production of TH1 cytokines was higher in adults compared with pediatric subjects. When memory CD4+CD45RO+ T cells were considered, lower IFN-γ expression was observed in pediatric subjects with CD compared with controls (P=0.009), matching the trend seen in the general CD4+ T cell population. The percentage of CD4+CD45RO+ T cells was increased in adult patients with CD compared with pediatric patients with CD (P=0.016). Conclusions: The present study describes a peripheral blood TH1/TH2 cytokine imbalance in CD and suggests different immunological mechanisms in children and adults for disease pathogenesis.
MeSH term(s)	Adolescent ; Adult ; Child ; Crohn Disease/blood ; Crohn Disease/immunology ; Female ; Flow Cytometry ; Humans ; Interferon-gamma/blood ; Interleukin-4/blood ; Leukocyte Common Antigens/metabolism ; Male ; Middle Aged ; Pilot Projects ; Th1 Cells/metabolism ; Th1-Th2 Balance ; Th2 Cells/metabolism ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Tumor Necrosis Factor-alpha ; Interleukin-4 (207137-56-2) ; Interferon-gamma (82115-62-6) ; Leukocyte Common Antigens (EC 3.1.3.48)
Language	English
Publishing date	2011-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603201-1
ISSN	1536-4801 ; 0277-2116
ISSN (online)	1536-4801
ISSN	0277-2116
DOI	10.1097/MPG.0b013e3182455bb3
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Article ; Online: Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor.

Nelson, David / Yoshida, Eric M / Paulson, Matthew S / Hengen, Paul N / Ge, Dongliang / Kanwar, Bittoo / McNally, John / Pang, Phillip S / Subramanian, G Mani / McHutchison, John G / Urbanek, Petr / Lawitz, Eric / Urban, Thomas J

Antiviral therapy

2014 Volume 19, Issue 7, Page(s) 679–686

Abstract: Background: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype ...

Abstract	Background: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial. Methods: Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0-1) versus high (grade 2-4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed. Results: A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed. Conclusions: These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.
MeSH term(s)	Adult ; Aged ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Bilirubin/blood ; Computational Biology ; Female ; Genome-Wide Association Study ; Genotype ; Hepacivirus/drug effects ; Hepacivirus/metabolism ; Hepatitis C/blood ; Hepatitis C/drug therapy ; Hepatitis C/genetics ; Humans ; Male ; Microbial Sensitivity Tests ; Middle Aged ; Organic Anion Transporters/genetics ; Organic Anion Transporters, Sodium-Independent/genetics ; Peptides, Cyclic/pharmacology ; Peptides, Cyclic/therapeutic use ; Pharmacogenetics ; Phenotype ; Phosphinic Acids/pharmacology ; Phosphinic Acids/therapeutic use ; Polymorphism, Single Nucleotide ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Viral Nonstructural Proteins/antagonists & inhibitors ; Young Adult
Chemical Substances	Antiviral Agents ; GS-9256 ; NS3 protein, hepatitis C virus ; Organic Anion Transporters ; Organic Anion Transporters, Sodium-Independent ; Peptides, Cyclic ; Phosphinic Acids ; SLCO1B1 protein, human ; SLCO1B3 protein, human ; Solute Carrier Organic Anion Transporter Family Member 1B3 ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Viral Nonstructural Proteins ; Bilirubin (RFM9X3LJ49)
Language	English
Publishing date	2014
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1339842-8
ISSN	2040-2058 ; 1359-6535
ISSN (online)	2040-2058
ISSN	1359-6535
DOI	10.3851/IMP2747
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Zs.A 4877: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers.

Loke, P'ng / Favre, David / Hunt, Peter W / Leung, Jacqueline M / Kanwar, Bittoo / Martin, Jeffrey N / Deeks, Steven G / McCune, Joseph M

Blood

2010 Volume 115, Issue 15, Page(s) e20–32

Abstract: HIV "controllers" are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we ... ...

Abstract	HIV "controllers" are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV(+) persons with high viral loads and progressive disease ("noncontrollers"). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease.
MeSH term(s)	Adult ; Biopsy ; Colon, Sigmoid/pathology ; Flow Cytometry ; Gene Expression Profiling ; Gene Expression Regulation ; HIV/immunology ; HIV Infections/blood ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Infections/pathology ; HIV Seropositivity/blood ; HIV Seropositivity/genetics ; HIV Seropositivity/immunology ; HIV Seropositivity/pathology ; Humans ; Immunity, Mucosal/genetics ; Immunity, Mucosal/immunology ; Male ; Middle Aged ; Principal Component Analysis ; Rectum/pathology ; Reproducibility of Results ; Reverse Transcriptase Polymerase Chain Reaction
Language	English
Publishing date	2010-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2009-12-257451
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Sofosbuvir plus pegylated interferon and ribavirin in patients with genotype 1 hepatitis C virus in whom previous therapy with direct-acting antivirals has failed.

Pol, Stanislas / Sulkowski, Mark S / Hassanein, Tarek / Gane, Edward J / Liu, Lin / Mo, Hongmei / Doehle, Brian / Kanwar, Bittoo / Brainard, Diana / Subramanian, G Mani / Symonds, William T / McHutchison, John G / Nahass, Ronald G / Bennett, Michael / Jacobson, Ira M

Hepatology (Baltimore, Md.)

2015 Volume 62, Issue 1, Page(s) 129–134

Abstract: Unlabelled: Retreatment of patients who have not achieved sustained virological response (SVR) after treatment with investigational direct-acting antiviral agents (DAAs) has not been extensively studied. We conducted an open-label trial to assess the ... ...

Abstract	Unlabelled: Retreatment of patients who have not achieved sustained virological response (SVR) after treatment with investigational direct-acting antiviral agents (DAAs) has not been extensively studied. We conducted an open-label trial to assess the efficacy and safety of sofosbuvir (SOF) plus pegylated interferon (Peg-IFN) and ribavirin (RBV) in patients with genotype 1 hepatitis C virus (HCV) who participated in previous studies of one or more Gilead investigational DAAs in combination with RBV with or without Peg-IFN. We enrolled 80 patients at 40 sites. All patients received SOF 400 mg once daily plus Peg-IFN-α 180 μg/week and weight-based ribavirin (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 80 patients enrolled, 36 (45%) had received two or more courses of earlier treatment for HCV and 74 (93%) had at least one resistance-associated variant (RAV) at baseline. SVR12 was achieved by 63 of the 80 patients (79%) treated. Rates of SVR12 were similar across patient subgroups. Presence of RAVs at baseline did not appear to be associated with treatment failure. Seventy-one of eighty patients (89%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and nausea. No patients discontinued all treatment because of AEs. Conclusion: These findings suggest that SOF plus Peg-IFN and RBV for 12 weeks is effective and safe in patients who have not achieved SVR with earlier regimens of one or more DAAs plus Peg-IFN and RBV.
MeSH term(s)	Adult ; Aged ; Antiviral Agents/therapeutic use ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Hepacivirus/genetics ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/virology ; Humans ; Interferon-alpha/therapeutic use ; Male ; Middle Aged ; Ribavirin/therapeutic use ; Sofosbuvir ; Treatment Failure ; Uridine Monophosphate/analogs & derivatives ; Uridine Monophosphate/therapeutic use ; Young Adult
Chemical Substances	Antiviral Agents ; Interferon-alpha ; Ribavirin (49717AWG6K) ; Uridine Monophosphate (E2OU15WN0N) ; Sofosbuvir (WJ6CA3ZU8B)
Language	English
Publishing date	2015-07
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.27836
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Article ; Online: Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

Cheng, Laurence E / Kanwar, Bittoo / Tcheurekdjian, Haig / Grenert, James P / Muskat, Mica / Heyman, Melvin B / McCune, Joseph M / Wara, Diane W

Clinical immunology (Orlando, Fla.)

2009 Volume 132, Issue 1, Page(s) 124–131

Abstract: The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are ... ...

Abstract	The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.
MeSH term(s)	Adolescent ; Blood Sedimentation ; Child ; Child, Preschool ; Colonoscopy ; Enterocolitis/blood ; Enterocolitis/etiology ; Enterocolitis/pathology ; Female ; Humans ; Immunologic Deficiency Syndromes/blood ; Immunologic Deficiency Syndromes/complications ; Immunologic Deficiency Syndromes/pathology ; Infant ; Inflammation/blood ; Inflammation/etiology ; Inflammation/pathology ; Male ; Pedigree
Language	English
Publishing date	2009-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2009.03.514
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