-
1.
Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients.
Fujita, K, Mimura, S, Iwama, H, Nakahara, M, Oura, K, Tadokoro, T, Nomura, T, Tani, J, Yoneyama, H, Morishita, A, et al
International journal of molecular sciences. 2018;(7)
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.
-
2.
Vitamin D Status and Virologic Response to HCV Therapy in the HALT-C and VIRAHEP-C Trials.
Loftfield, E, O'Brien, TR, Pfeiffer, RM, Howell, CD, Horst, R, Prokunina-Olsson, L, Weinstein, SJ, Albanes, D, Morgan, TR, Freedman, ND
PloS one. 2016;(11):e0166036
Abstract
Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.
-
3.
The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis C outcome.
Jabłońska, J, Pawłowski, T, Laskus, T, Zalewska, M, Inglot, M, Osowska, S, Perlejewski, K, Bukowska-Ośko, I, Cortes, KC, Pawełczyk, A, et al
BMC infectious diseases. 2015;:556
Abstract
BACKGROUD Cytokine response against hepatitis C virus (HCV) is likely to determine the natural course of infection as well as the outcome of antiviral treatment. However, the role of particular cytokines remains unclear. The current study analyzed activation of cytokine response in chronic hepatitis C patients undergoing standard antiviral treatment. METHODS Twenty-two patients were treated with pegylated interferon and ribavirin. Twenty-six different cytokine transcripts were measured quantitatively in peripheral blood mononuclear cells (PBMC) before and after therapy and correlated with therapy outcome as well as with clinical and liver histological data. RESULTS We found that patients who achieved sustained virological response (SVR) showed higher pretreatment cytokine response when compared to subjects in whom therapy was unsuccessful. The differentially expressed factors included IL-8, IL-16, TNF-α, GM-CSF, MCP-2, TGF-β, and IP-10. Serum ALT activity and/or histological grading also positively correlated with the expression of IL-1α, IL-4, IL-6, IL-10, IL-12, IL-15, GM-CSF, M-CSF, MCP-2 and TGF-β. CONCLUSION Pretreatment activation of the immune system, as reflected by cytokines transcripts upregulation, positively correlates with treatment outcome and closely reflects liver inflammatory activity.
-
4.
Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.
Berger, KL, Scherer, J, Ranga, M, Sha, N, Stern, JO, Quinson, AM, Kukolj, G
Antimicrobial agents and chemotherapy. 2015;(10):6017-25
-
-
Free full text
-
Abstract
Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.
-
5.
Improvement of glucose and lipid metabolism with pegylated interferon-a plus ribavirin therapy in Chinese patients chronically infected with genotype 1b hepatitis C virus.
Qing, S, Ji, D, Li, B, Li, F, Wang, Y, Niu, X, Ling, B, Meng, Y, Lau, G, Chen, G
Annals of Saudi medicine. 2015;(4):293-7
Abstract
BACKGROUND Many epidemiological studies have demonstrated a significant association between Type 2 diabetes mellitus and abnormal lipid profiles with chronic HCV genotype 1 (GT1) infection. We examined the impact on glucose and lipid profiles of treating Chinese patients using pegylated interferon (Peg-IFN)-a and ribavirin (RBV). METHODS We conducted a hospital-based clinical study of Chinese patients chronically infected with GT1b HCV. All the patients were treated for 48 weeks (PR48) with Peg-IFN-a (180 micro g once per week) or Peg-IFN-a (1.5 micro g/kg once per week) plus RBV (15 mg/kg per day). Fasting blood glucose (FBG), postprandial blood glucose (PBG-2h), glycosylated hemoglobin (HbA1c), total cholesterol (TC) and triglyceride (TG) levels, were measured at baseline, during therapy, at the end of therapy and at follow-up. In addition, liver stiffness (LS) by transient elastography, HCV RNA and ALT levels were also measured. RESULTS We enrolled 116 patients. At the end of treatment (EOT) (week 48), HCV RNA was negative in all patients, 77.6% (90/116) of patients achieved sustained virologic response (SVR) 24 weeks after EOT, and 22.4% (26/116) did not achieve SVR. All parameters associated with liver inflammation, liver fibrosis, glucose and lipid metabolism had decreased significantly compared with baseline (P < .05) in SVR patients. However, there were no obvious changes in lipid metabolism in non-SVR patients. CONCLUSION PR48 therapy is still the primary treatment for Chinese patients with GT1b HCV infection and will remain so until oral anti-HCV agents are approved. It is beneficial in amelioration of liver histological status and glucose metabolism regardless of post-treatment virologic response.
-
6.
Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.
Song, M, DiPaola, RS, Cracchiolo, BM, Gibbon, DG, Hellmann, M, Nieves-Neira, W, Vaidya, A, Wagreich, AR, Shih, WJ, Rodriguez-Rodriguez, L
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2014;(9):1636-41
-
-
Free full text
-
Abstract
OBJECTIVE Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.
-
7.
Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin.
Murakami, E, Imamura, M, Hayes, CN, Abe, H, Hiraga, N, Honda, Y, Ono, A, Kosaka, K, Kawaoka, T, Tsuge, M, et al
Antimicrobial agents and chemotherapy. 2014;(4):2105-12
-
-
Free full text
-
Abstract
Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.).
-
8.
1(OH) vitamin D3 supplementation improves the sensitivity of the immune-response during Peg-IFN/RBV therapy in chronic hepatitis C patients-case controlled trial.
Kondo, Y, Kato, T, Kimura, O, Iwata, T, Ninomiya, M, Kakazu, E, Miura, M, Akahane, T, Miyazaki, Y, Kobayashi, T, et al
PloS one. 2013;(5):e63672
Abstract
OBJECTIVE 1,25(OH)2 vitamin D3 can affect immune cells. However, the mechanism responsible for the favorable effects of 1(OH) vitamin D3, which becomes 1,25(OH)2 vitamin D3 in the liver, is not clear. The aim of this study is to analyze the immunological response of 1(OH) vitamin D3 supplementation in CH-C patients. DESIGN Forty-two CH-C patients were treated with 1(OH) vitamin D3/Peg-IFNα/RBV. Forty-two case-matched controls were treated with Peg-IFNα/RBV. The expression of Interferon-stimulated genes (ISGs)-mRNA in the liver biopsy samples and JFH-1 replicating Huh-7 cells were quantified by real-time PCR. Ten kinds of cytokines in the plasma were quantified during treatment by using a suspension beads array. A trans-well co-culture system with peripheral blood mononuclear cells (PBMCs) and Huh-7 cells was used to analyze the effect of 1(OH) vitamin D3. The activities of the Th1 response were compared between subjects treated with 1(OH) vitamin D3/Peg-IFN/RBV and those treated with Peg-IFN/RBV therapy alone. RESULTS 1(OH) vitamin D3/Peg-IFN/RBV treatment could induce rapid viral reduction, especially in IL28B T/T polymorphism. Several kinds of cytokines including IP-10 were significantly decreased after 4 weeks of 1(OH) vitamin D3 treatment (p<0.05). Th1 responses in the subjects treated with 1(OH) vitamin D3/Peg-IFN/RBV were significantly higher than those treated with Peg-IFN/RBV at 12 weeks after Peg-IFN/RBV therapy (p<0.05). The expression of ISGs in the patient's liver biopsy samples was significantly lower than in those treated without 1(OH) vitamin D3 (p<0.05). CONCLUSION 1(OH) vitamin D3 could improve the sensitivity of Peg-IFN/RBV therapy on HCV-infected hepatocytes by reducing the IP-10 production from PBMCs and ISGs expression in the liver.
-
9.
Impact of peginterferon alpha and ribavirin treatment on lipid profiles and insulin resistance in Hepatitis C virus/HIV-coinfected persons: the AIDS Clinical Trials Group A5178 Study.
Butt, AA, Umbleja, T, Andersen, JW, Sherman, KE, Chung, RT, ,
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2012;(5):631-8
-
-
Free full text
-
Abstract
BACKGROUND The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. METHODS We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. RESULTS Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log(10 )IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR],150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. CONCLUSIONS Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. Clinical Trials Registration. NCT00078403.
-
10.
S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders.
Feld, JJ, Modi, AA, El-Diwany, R, Rotman, Y, Thomas, E, Ahlenstiel, G, Titerence, R, Koh, C, Cherepanov, V, Heller, T, et al
Gastroenterology. 2011;(3):830-9
-
-
Free full text
-
Abstract
BACKGROUND & AIMS Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved. METHODS Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses. RESULTS The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log(10) IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding. CONCLUSIONS The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection.