12, 13 ARBs were developed as antihypertensive medications that selleckchem now have utility in a variety of diseases, including heart failure and chronic kidney disease. This versatile therapeutic drug class may also have utility in NASH, because early evidence suggests that they may improve insulin resistance14, 15 and hepatic fibrosis.16 Subsequently, this study was designed to compare the therapeutic efficacy of three treatment regimens in biopsy-proven NASH patients: rosiglitazone

alone, rosiglitazone plus metformin, and rosiglitazone plus losartan. ARB, angiotensin receptor blocker; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BAMC, Brooke Army Medical Center; BMI, body mass index; FDA, the U.S. Food and Drug Administration; HOMA-IR, the homeostasis model assessment for insulin resistance; NAFLD, nonalcoholic fatty liver disease; NAS, Nonalcoholic Fatty Liver Disease Activity Score; NASH, nonalcoholic steatohepatitis; SNPs, single-nucletide polymorphisms; TZD, thiazolinedione. Patients were recruited for this randomized, open-labeled,

prospective, clinical trial from March 2007 to March 2010 from the outpatient Hepatology and Gastroenterology Clinics at Brooke Army Medical Center (BAMC; San Antonio, TX). The protocol was approved by the BAMC Institutional Review Board, MAPK Inhibitor Library cost and all subjects gave written informed consent. The study was investigator-initiated, and no funding was received. Patients 18-70 years of age with biopsy-proven NASH were enrolled. NASH was confirmed on liver biopsy by the presence of steatosis,

hepatocellular TCL inflammation, and hepatocyte ballooning degeneration, with or without fibrosis, utilizing the Brunt criteria.17 Liver biopsy must have been within the 6 months before enrollment, or else a repeat-baseline liver biopsy was required to be eligible for enrollment. Exclusion criteria included the following: patients with New York Heart Association class 3 or 4 heart failure, insulin-requiring diabetics, patients with a history of TZD, metformin, or ARB use in the 3 months before enrollment, alcohol consumption >20 g/day in a female and >30 g/day in a male, serum creatinine on initial screening of greater than 1.4, known hypersensitivity to a study drug, known history of diabetic ketoacidosis, and pregnant or breast-feeding females. Patients were also excluded if there was evidence of coexistent chronic liver disease to include viral hepatitis, Wilson’s disease, autoimmune hepatitis, hemochromatosis, primary biliary cirrhosis, or primary sclerosing cholangitis. Eligible patients were randomly assigned using a computer-generated, random-sequence grid maintained by the principal investigator to one of three treatment arms: rosiglitazone 4 mg by mouth twice-daily, rosiglitazone 4 mg and metformin 500 mg by mouth twice-daily, or rosiglitazone 4 mg twice-daily and losartan 50 mg daily (Fig. 1). All medication doses were selected based on the usual starting does of these medications.

Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic buy XL184 pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods: This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory

patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter, and global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results: Levels of 234 biochemicals were significantly altered in subjects with severe AAH. Random-forest and principal component analyses demonstrated that metabolomic profiles separated the two cohorts RXDX-106 order with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation.

Furthermore, decreased levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in patients with severe AAH, reduced levels of deoxycholate and glycode-oxycholate in severe AAH were consistent with ethanol-related changes in intestinal microbial composition. Metabolomic profiling highlighted several changes in substrate utilization for energy homeostasis, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism in severe AAH. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Using univariable logistic regression, we identified 15 metabolites that were associated with 180-day survival in severe AAH. Conclusion: Severe AAH is characterized

by a distinct metabolic phenotype spanning multiple pathways. Metabolomic profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe Fenbendazole AAH. Disclosures: Lauren N. Bell – Employment: Metabolon, Inc. The following people have nothing to disclose: Vikrant Rachakonda, Charles Gabbert, Amit Raina, Shahid M. Malik, Sara J. Cooper, Jaideep Behari Background: Alcohol induced hepatic steatosis is a significant risk factor for progressive liver disease. Steatotic hepatocytes have increased sensitivity to injury produced by inflammatory cytokines, particularly TNF. Cyclic adenosine monophosphate (cAMP) has been shown to play a significant role in the regulation of both TNF production and lipid metabolism.

We thank M. Sudol for providing the YAP cDNA. “
“The purpose of this prospective cohort study

was to compare the serologic response between human immunodeficiency virus (HIV)-infected men who have sex DNA Damage inhibitor with men (MSM) receiving two and three doses of hepatitis A virus (HAV) vaccine and HIV-uninfected MSM receiving two doses of HAV vaccine. Between June 2009 and December 2010, 582 MSM aged 18 to 40 years who were seronegative for HAV were enrolled in the study. HIV-infected MSM received either two doses of HAV vaccine (1,440 enzyme-linked immunosorbent assay units) (n = 140) with the second dose given at week 24 or three doses (n = 225) with the second and third dose given at weeks 4 and 24, respectively, while HIV-uninfected MSM (n = 217) received two doses. The primary endpoint was seroconversion at week 48. The geometric mean concentration (GMC) of anti-HAV antibody was determined at weeks 48 and 72. At week 48, the seroconversion rate was IWR-1 nmr 75.7%, 77.8%, and 88.5% in intention-to-treat analysis for two-dose HIV-infected, three-dose HIV-infected, and two-dose HIV-uninfected MSM, respectively. The GMC of anti-HAV antibody at week 48 for three-dose HIV-infected MSM (2.29 ± 0.73 log10 mIU/mL) was significantly higher than

that for two-dose HIV-infected MSM (1.94 ± 0.66; P < 0.01), but was lower than HIV-uninfected MSM (2.49 ± 0.42; P < 0.01). Multivariate analysis revealed higher CD4 counts (adjusted odds ratio

[AOR] for per 50 cells/μL increase, 1.13; 95% confidence interval [CI], filipin 1.05-1.21) and undetectable plasma HIV RNA load (AOR, 1.90; 95% CI, 1.10-3.28) before HAV vaccination were predictive of seroconversion in HIV-infected patients. Conclusion: Serologic response rate to three and two doses of HAV vaccine was similar in HIV-infected MSM, which was lower than that in HIV-uninfected MSM receiving two doses. HAV vaccination in HIV-infected patients with a higher CD4 count and suppression of HIV replication increased the seroconversion rate. (HEPATOLOGY 2013) Hepatitis A virus (HAV) infection that is transmitted via a fecal-oral route occurs worldwide, especially in countries where sanitary and hygienic conditions are not maintained appropriately. In countries with improved sanitation and access to HAV vaccination, the incidence of HAV infection has declined significantly. The annual incidence of HAV infection has decreased from 12 per 100,000 population in 1995 to 0.6 per 100,000 population in 2009 in the United State after HAV vaccine was licensed in 1995.1 In Finland, the incidence of HAV infections ranged from 0.3 to 3.6 per 100,000 between 1990 and 2007, and most of the cases seemed to be travel-related.

We thank M. Sudol for providing the YAP cDNA. “
“The purpose of this prospective cohort study

was to compare the serologic response between human immunodeficiency virus (HIV)-infected men who have sex Alpelisib with men (MSM) receiving two and three doses of hepatitis A virus (HAV) vaccine and HIV-uninfected MSM receiving two doses of HAV vaccine. Between June 2009 and December 2010, 582 MSM aged 18 to 40 years who were seronegative for HAV were enrolled in the study. HIV-infected MSM received either two doses of HAV vaccine (1,440 enzyme-linked immunosorbent assay units) (n = 140) with the second dose given at week 24 or three doses (n = 225) with the second and third dose given at weeks 4 and 24, respectively, while HIV-uninfected MSM (n = 217) received two doses. The primary endpoint was seroconversion at week 48. The geometric mean concentration (GMC) of anti-HAV antibody was determined at weeks 48 and 72. At week 48, the seroconversion rate was Selleckchem MG-132 75.7%, 77.8%, and 88.5% in intention-to-treat analysis for two-dose HIV-infected, three-dose HIV-infected, and two-dose HIV-uninfected MSM, respectively. The GMC of anti-HAV antibody at week 48 for three-dose HIV-infected MSM (2.29 ± 0.73 log10 mIU/mL) was significantly higher than

that for two-dose HIV-infected MSM (1.94 ± 0.66; P < 0.01), but was lower than HIV-uninfected MSM (2.49 ± 0.42; P < 0.01). Multivariate analysis revealed higher CD4 counts (adjusted odds ratio

[AOR] for per 50 cells/μL increase, 1.13; 95% confidence interval [CI], 4��8C 1.05-1.21) and undetectable plasma HIV RNA load (AOR, 1.90; 95% CI, 1.10-3.28) before HAV vaccination were predictive of seroconversion in HIV-infected patients. Conclusion: Serologic response rate to three and two doses of HAV vaccine was similar in HIV-infected MSM, which was lower than that in HIV-uninfected MSM receiving two doses. HAV vaccination in HIV-infected patients with a higher CD4 count and suppression of HIV replication increased the seroconversion rate. (HEPATOLOGY 2013) Hepatitis A virus (HAV) infection that is transmitted via a fecal-oral route occurs worldwide, especially in countries where sanitary and hygienic conditions are not maintained appropriately. In countries with improved sanitation and access to HAV vaccination, the incidence of HAV infection has declined significantly. The annual incidence of HAV infection has decreased from 12 per 100,000 population in 1995 to 0.6 per 100,000 population in 2009 in the United State after HAV vaccine was licensed in 1995.1 In Finland, the incidence of HAV infections ranged from 0.3 to 3.6 per 100,000 between 1990 and 2007, and most of the cases seemed to be travel-related.

pylori gene expression are yet to be identified. We thank all members of the laboratory for cooperation, encouragement and helpful discussions

during the study and Kalidas Paul for suggestions and excellent technical support. Raghwan is grateful to the Council of Scientific and Industrial Research (CSIR) for a research fellowship. The work was supported by research grants from CSIR-IICB. The authors have no competing interests. Table S1 Primers used in this study. Table S2 Adherence of H. pylori strains to cell Alvelestat lines. Figure S1 Effect of dpp treatment on amiE and pfr expression in H. pylori. Figure S2 Morphological changes in AGS cells following H. pylori adherence. “
“Background:  Triple therapy with a proton pump inhibitor, moxifloxacin, and amoxicillin has been proven effective in first-line treatment of Helicobacter pylori infection. Aim:  To explore 1, the value of triple therapy with esomeprazole, moxifloxacin, and amoxicillin in second-line or rescue treatment

of Caucasian patients and 2, the impact of treatment duration http://www.selleckchem.com/products/NVP-AUY922.html on eradication success. Methods: H. pylori-infected patients with at least one previous treatment failure were randomized to oral esomeprazole 20 mg b.i.d., moxifloxacin 400 mg o.d., and amoxicillin 1000 mg b.i.d. for either 7 (EMA-7) or 14 days (EMA-14). Eradication was confirmed by 13C urea breath test. Antimicrobial susceptibility testing was performed in all patients at baseline and in patients who failed treatment. Results:  Eighty patients were randomized, and 60% had ≥2 previous treatment failures. Pretreatment resistance against clarithromycin and metronidazole was found in 70.5 and 61.5% of cases, respectively. The intention-to-treat eradication rate was significantly higher after EMA-14 compared with EMA-7 (95.0 vs 78.9%, p = .036). No independent risk factor for treatment failure could be identified. There were

no serious adverse events. Five of the EMA-14 patients (12.5%) compared with none of the EMA-7 patients discontinued prematurely because of adverse events (p = .031). Post-treatment resistance against moxifloxacin was found in one of seven patients with isolated organisms (14.3%). Conclusion:  Second-line/rescue H. pylori eradication therapy with esomeprazole, moxifloxacin, and Ixazomib mw amoxicillin is very effective and well tolerated. Fourteen days of treatment significantly increase the eradication rate but also the rate of adverse events. “
“Objective:  The effect of Helicobacter pylori on Barrett’s esophagus is poorly understood. We conducted a meta-analysis to summarize the existing literature examining the effect that H. pylori has on Barrett’s esophagus. Design:  We performed a comprehensive search to identify studies pertaining to the association between H. pylori and Barrett’s esophagus. We conducted meta-regression analyses to identify sources of variation in the effect of H. pylori on Barrett’s esophagus.

Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular STA-9090 endothelial cells (LMEC) and with LSEC cultured for 42 hours. The LSEC

signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (fold change >7 in at least one comparison); quantitative reverse-transcription polymerase chain reaction confirmation of these genes included numerous family members and signaling pathway-associated molecules. The LSEC differentiation program comprised Temsirolimus cost distinct sets of growth (Wnt2, Fzd4, 5, 9, Wls, vascular endothelial growth factors [VEGFR] 1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1, and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus

freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26-kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced overexpression in MDCK cells, Leda-1 was sorted basolaterally to E-cadherin-positive adherens junctions, suggesting functional involvement in cell adhesion and HSP90 polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. HEPATOLOGY 2010 Endothelial cells (ECs) display marked heterogeneity in different organs and in different segments of the vascular tree. Liver sinusoidal endothelial cells

(LSECs) are a prime example of uniquely differentiated microvascular EC that exert highly specialized functions as professional endocytes1 and participate in induction of hepatic immune tolerance.2 For endocytosis, LSEC express a broad range of different scavenger receptors including Stabilin-1 and Stabilin-2, two members of a novel scavenger receptor gene family selectively expressed in sinusoidal ECs that have been identified and thoroughly characterized by us.3 Stabilin-2 is the major hyaluronan scavenger receptor of the liver, whereas Stabilin-1 mediates endocytosis of acLDL (low density lipoprotein) and SPARC. Stabilin-1 and -2 use the constitutive clathrin-mediated endocytic pathway in LSEC (4); in addition, Stabilin-1 fulfills a second role as an intracellular cargo carrier.

Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular see more endothelial cells (LMEC) and with LSEC cultured for 42 hours. The LSEC

signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (fold change >7 in at least one comparison); quantitative reverse-transcription polymerase chain reaction confirmation of these genes included numerous family members and signaling pathway-associated molecules. The LSEC differentiation program comprised Palbociclib molecular weight distinct sets of growth (Wnt2, Fzd4, 5, 9, Wls, vascular endothelial growth factors [VEGFR] 1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1, and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus

freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26-kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced overexpression in MDCK cells, Leda-1 was sorted basolaterally to E-cadherin-positive adherens junctions, suggesting functional involvement in cell adhesion and Rebamipide polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. HEPATOLOGY 2010 Endothelial cells (ECs) display marked heterogeneity in different organs and in different segments of the vascular tree. Liver sinusoidal endothelial cells

(LSECs) are a prime example of uniquely differentiated microvascular EC that exert highly specialized functions as professional endocytes1 and participate in induction of hepatic immune tolerance.2 For endocytosis, LSEC express a broad range of different scavenger receptors including Stabilin-1 and Stabilin-2, two members of a novel scavenger receptor gene family selectively expressed in sinusoidal ECs that have been identified and thoroughly characterized by us.3 Stabilin-2 is the major hyaluronan scavenger receptor of the liver, whereas Stabilin-1 mediates endocytosis of acLDL (low density lipoprotein) and SPARC. Stabilin-1 and -2 use the constitutive clathrin-mediated endocytic pathway in LSEC (4); in addition, Stabilin-1 fulfills a second role as an intracellular cargo carrier.

Thus, the major objectives of this study were to quantify the risk for sexual transmission of HCV infection from chronically infected subjects to their long-term

heterosexual partners and identify specific sexual practices associated with that risk. CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, injection drug use; PCR, polymerase chain reaction. The recruitment phase of the study was conducted in Northern California sites between January 2000 and May 2003. Recruitment began by first identifying a known HCV-positive subject (referred to as the index subject) from multiple sources, including liver clinics at the University of California at San Francisco, members of Kaiser AZD3965 concentration Permanente Medical Care Plan in Northern California, California Pacific Medical Center and affiliated clinics, other community-based practices in the greater San Francisco Bay Area, and blood donors from Blood Centers of the Pacific/Blood Systems Research Institute. Researchers contacted index subjects for study enrollment, and if eligible based on prescreening, contacted their sexual partner. Criteria for study participation selleck chemical by each couple included a heterosexual relationship for a minimum of 36 months, monogamy

for the duration of the relationship reported by both partners, and a minimum of three sexual contacts by the couple in the preceding 6 months. Couples were excluded

if either partner had known HIV or HBV infection, had prior organ transplantation, or was currently using antiviral or immunosuppressive therapy, or if both partners reported a history of injection drug use (IDU). Partners of each couple were interviewed independently by phone (76%) or in person (24%) by trained interviewers, with no difference in completing a questionnaire by interview type. Detailed information was obtained on sexual (-)-p-Bromotetramisole Oxalate history with the study partner (Supporting Information), nonsexual household exposures (sharing of personal items, including nail grooming tools, razors, and toothbrushes), and all other known risk factors for HCV acquisition. The risk period for sexual transmission was defined using a uniform method to capture sexual activities over the entire duration of the couple’s relationship. Sexual histories were collected in discrete time intervals defined by events in each participant’s sexual history and beginning from the time of first sexual contact with the current partner up to the time of interview. Each participant identified life events such as pregnancy, childbirth, medical illness, and absences that significantly changed sexual activities with their study partner and the corresponding year and age for each life event.

3, 4 The HCV NS5B RNA-dependent RNA polymerase is a key enzyme involved in HCV replication, catalyzing the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA from the minus-strand template and is also an ideal target for inhibiting HCV replication. Ixazomib nmr Direct-acting antiviral agents (DAAs) target the HCV-encoded proteins and when added to Peg-IFN/RBV have resulted in improved SVR rates compared to standard of care.5, 6 Telaprevir and boceprevir are two NS3/4a protease inhibitors for which phase 3 trials are nearing completion. In these trials,5-7 telaprevir and boceprevir are both added to Peg-IFN/RBV, with substantial improvement in SVR rates in both treatment-naive

patients and prior nonresponders. These agents are associated with additional side effects including anemia, skin rash, and gastrointestinal www.selleckchem.com/products/Roscovitine.html symptoms. Both telaprevir and boceprevir have been shown to cause rapid selection of resistance-associated variants when given as monotherapy, and neither DAA should be administered without Peg-IFN/RBV.8

Studies with both drugs have shown that optimal doses of RBV are needed to maximize SVR rates and minimize the development of resistance-associated variants. The resistance profile of triple therapy with boceprevir is similar to that of telaprevir in patients who fail to achieve SVR,5 and cross-resistance against other NS3 protease inhibitors may occur.8, 9 These resistant strains have been found to persist after withdrawal of therapy with telaprevir and boceprevir in combination with Peg-IFN/RBV and can persist up to 3 years.8, 9 The INFORM-1 (Interferon-Free regimen for the Management of HCV)

trial is the first randomized, double blind, placebo-controlled, dose escalation trial performed in six centers in New Zealand and Australia. This trial was designed to examine the safety of two new direct-acting antiviral drugs: RG7128 and danoprevir. RG7128 is a 3′5′-di-isobutyric acid ester prodrug of the cytosine nucleoside analogue β-D-2′-deoxy-2′-fluoro-2′C-methylcytidine. Thymidine kinase This compound’s triphosphate form inhibits HCV NS5b RNA polymerase. Danoprevir is a macrocyclic inhibitor of HCV NS3/4A protease, which differs from the linear protease inhibitors telaprevir and boceprevir. The addition of RG7128 to danoprevir is an important milestone as the combination of DAAs in the treatment of hepatitis C has the potential to reduce the emergence of resistant associated variants. Moreover, therapies that can be effective in patients with hepatitis C genotype 1 infection without Peg-IFN/RBV will make treatment possible for the many patients who have contraindications to Peg-IFN therapy. Eighty-eight genotype 1–infected Caucasian patients without cirrhosis who had a minimum HCV RNA of 105 IU/mL were randomized in the INFORM-1 trial, including both treatment-naïve (n = 66) and treatment-experienced patients (n = 22).

3, 4 The HCV NS5B RNA-dependent RNA polymerase is a key enzyme involved in HCV replication, catalyzing the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA from the minus-strand template and is also an ideal target for inhibiting HCV replication. Erlotinib Direct-acting antiviral agents (DAAs) target the HCV-encoded proteins and when added to Peg-IFN/RBV have resulted in improved SVR rates compared to standard of care.5, 6 Telaprevir and boceprevir are two NS3/4a protease inhibitors for which phase 3 trials are nearing completion. In these trials,5-7 telaprevir and boceprevir are both added to Peg-IFN/RBV, with substantial improvement in SVR rates in both treatment-naive

patients and prior nonresponders. These agents are associated with additional side effects including anemia, skin rash, and gastrointestinal Ponatinib concentration symptoms. Both telaprevir and boceprevir have been shown to cause rapid selection of resistance-associated variants when given as monotherapy, and neither DAA should be administered without Peg-IFN/RBV.8

Studies with both drugs have shown that optimal doses of RBV are needed to maximize SVR rates and minimize the development of resistance-associated variants. The resistance profile of triple therapy with boceprevir is similar to that of telaprevir in patients who fail to achieve SVR,5 and cross-resistance against other NS3 protease inhibitors may occur.8, 9 These resistant strains have been found to persist after withdrawal of therapy with telaprevir and boceprevir in combination with Peg-IFN/RBV and can persist up to 3 years.8, 9 The INFORM-1 (Interferon-Free regimen for the Management of HCV)

trial is the first randomized, double blind, placebo-controlled, dose escalation trial performed in six centers in New Zealand and Australia. This trial was designed to examine the safety of two new direct-acting antiviral drugs: RG7128 and danoprevir. RG7128 is a 3′5′-di-isobutyric acid ester prodrug of the cytosine nucleoside analogue β-D-2′-deoxy-2′-fluoro-2′C-methylcytidine. Buspirone HCl This compound’s triphosphate form inhibits HCV NS5b RNA polymerase. Danoprevir is a macrocyclic inhibitor of HCV NS3/4A protease, which differs from the linear protease inhibitors telaprevir and boceprevir. The addition of RG7128 to danoprevir is an important milestone as the combination of DAAs in the treatment of hepatitis C has the potential to reduce the emergence of resistant associated variants. Moreover, therapies that can be effective in patients with hepatitis C genotype 1 infection without Peg-IFN/RBV will make treatment possible for the many patients who have contraindications to Peg-IFN therapy. Eighty-eight genotype 1–infected Caucasian patients without cirrhosis who had a minimum HCV RNA of 105 IU/mL were randomized in the INFORM-1 trial, including both treatment-naïve (n = 66) and treatment-experienced patients (n = 22).