Evaluation of TRIM5 and TRIM22 polymorphisms on treatment responses in Iranian patients with chronic hepatitis C virus infection.

The tripartite motif (TRIM)-5 and TRIM22 are involved in innate immune response and show anti-viral activities. The current study aimed at evaluating the association of TRIM5 and TRIM22 polymorphisms with treatment outcomes in patients with chronic hepatitis C virus (CHC). TRIM5 rs3824949 and TRIM22 polymorphisms (rs7113258, rs7935564, and rs1063303) were genotyped using TaqMan polymerase chain reaction (PCR) assay in 425 treatment-naïve CHC patients. Rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR) were found in 54.1%, 74.8%, and 67.1% of the patients, respectively. RVR and SVR were associated with TRIM5 rs3824949 (GG), TRIM22 rs1063303 (GC), and TRIM22 rs7113258 (AA), while there was a relationship between TRIM5 rs3824949 (GG) and EVR. TRIM5 and TRIM22 single nucleotide polymorphisms (SNPs) were strongly associated with increased odds of RVR, EVR, and SVR after an interferon-based therapy in patients with CHC.

Effect of IL15 rs10833 and SCARB1 rs10846744 on virologic responses in chronic hepatitis C patients treated with pegylated interferon-α and ribavirin.

The scavenger receptor type B class I (SCARBI) is known to be involved in the entry of hepatitis C virus (HCV) into the host, while interleukin-15 (IL15) is an important cytokine in both the innate and acquired immune responses against HCV infection. We investigated the association of IL15 rs10833 or SCARB1 rs10846744 polymorphisms with treatment responses in patients with chronic HCV (CHC). SCARB1 rs10846744 and IL15 rs10833 were identified in 365 treatment-naïve CHC patients through genotyping by TaqMan® Real-Time PCR and PCR-restriction fragment length polymorphism (RFLP), respectively. Of these 365 CHC treatment-naïve patients, rapid virological response (RVR), complete early virological response (cEVR), and sustained virological response (SVR) were observed in 53.2%, 76.4%, and 66.0% of the patients, respectively. Multivariate logistic regression analysis revealed that RVR was associated with sex (P=0.016), aspartate aminotransferase (AST) (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P<0.001), while there was a relationship between alanine aminotransferase (ALT) (P=0.013) and IL15 rs10833 (AA) genotype (P<0.001) with cEVR. Age (<40years) (P=0.001), AST (P=0.029), ALP (P=0.028), HCV genotypes (P=0.005), HCV viral load (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P=0.001) were strongly associated with SVR. In conclusion, the SCARB1 rs10846744 (CC) and IL15 rs10833 (AA) genotypes can be considered as powerful predictors of treatment responses in CHC patients treated with an interferon-based therapy.

The impact of genetic variation in IL28B, IFNL4 and HLA genes on treatment responses against chronic hepatitis C virus infection.

Single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B), interferon lambda 4 (IFNL4) and the human leukocyte antigen (HLA) gene are associated with treatment responses in patients with chronic hepatitis C (CHC) virus infection treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). We compared the role of IL28B SNPs (rs12979860, rs12980275, and rs8099917), IFNL4 ss469415590 and HLA rs4273729 with treatment outcomes in patients with CHC virus. A total of 520 Iranian patients with CHC infection were enrolled. SNPs in IL28B, IFNL4 ss469415590 and HLA rs4273729 were genotyped by PCR-restriction fragment length polymorphism, TaqMan® Real-Time PCR and direct sequence. Out of 520 CHC treatment-naive patients, 42.9% were infected with HCV-1a, 15.4% with HCV-1b, 9.8% with HCV-2, and 31.9% with HCV-3a. Rapid virologic response (RVR), complete early virologic response (cEVR), and sustained virologic response (SVR) were 53.3%, 73.8%, and 66.7%, respectively. Multivariate logistic regression analysis showed that IL28B rs12980275 and IFNL4 ss469415590 in all HCV genotypes were associated with RVR. In addition, IL28B rs12979860 and RVR in all HCV genotypes and IL28B rs12980275, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a correlated with cEVR. In patient's achieving-SVR, IL28B rs12980275, and RVR in all HCV genotypes and IL28B rs12979860, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a were the powerful predictor factors. As the first report of its kind published in Iran, we indicated that beside IL28B SNPs and HLA rs4273729, IFNL4 ss469415590 was a powerful predictor factor for RVR, cEVR and SVR. Genotyping these SNPs may be a helpful priority in the treatment of patients with HCV infection, especially in countries where access to triple or double therapy with a viral protease inhibitor is limited.

Genetic (KIR, HLA-C) and Some Clinical Parameters Influencing the Level of Liver Enzymes and Early Virologic Response in Patients with Chronic Hepatitis C.

Natural killer cells play an important role as effectors of innate immunity and regulators of adaptive immunity. They are important elements of the innate response to viral infections, which they detect using human leukocyte antigen (HLA) class I-binding receptors. Most polymorphic of these are killer cell immunoglobulin-like receptors (KIRs) which exist as two basic isotypes, activating or inhibitory receptors and are encoded by genes distributed differently in unrelated individuals. We searched for links between selected clinical data (including HCV viremia, liver enzymes level and liver histology parameters) and the presence of genes encoding these receptors and their ligands in hepatitis C virus-infected individuals subjected to pegylated interferon-α and ribavirin therapy. Genomic DNA samples from two hundred and ninety-two chronically infected patients were typed by polymerase chain reaction for the presence or absence of genes for KIRs and their ligands, class I HLA molecules, and clinical data of the patients were collected. Our results suggest an importance of clinical parameters and the contribution of KIR and HLA genes to the course of hepatitis C virus infection and the response to therapy. The study revealed that levels of liver enzymes before therapy were about 30% higher in patients who possessed a variant KIR2DS4 gene with 22-base pair deletion. Decrease of ALT activity after treatment was higher in HLA-C C2-positive than negative individuals. Beside it, patients demonstrated early virologic response to the therapy if the time lag before treatment was short, particularly in women.

Impact of IL28B and PNPLA3 polymorphisms on treatment outcomes in patients infected with genotype 6 hepatitis C virus.

BACKGROUND/AIMS: Interleukin-28B (IL28B) and patatin-like phospholipase domain containing 3 (PNPLA3) gene polymorphisms are associated with hepatitis C virus (HCV) clearance and fatty liver, respectively. We aimed to test if their polymorphisms are associated with virologic responses in Chinese chronic hepatitis C (CHC) patients. METHODS: This was a retrospective-prospective cohort study. Consecutive patients infected by genotype 1 and 6 HCV received antiviral therapy were included. Host IL-28B rs12979860/rs8099917 and PNPLA3 rs738409 genotype were tested. The primary outcome was sustained virologic response (sustained virologic response [SVR]: undetectable HCV RNA 24 weeks post-treatment). RESULTS: From 305 patients had positive antibody to HCV, 52 and 31 patients infected by genotype 1 and 6 HCV, respectively were recruited. Mean age was 58 ± 11 years; 70% were male. Mean baseline HCV RNA was 6.8 ± 2.7 log IU/ml. The SVR for patients infected by genotype 1 and 6 HCV was 67.3% and 90.3%, respectively. The proportions of IL28B genotypes were 78%, 21%, and 1% for TT/TG/GG at rs8099917, and 81%, 18%, and 1% for CC/TC/TT at rs12979860, respectively. The proportions of PNPLA3 rs738409 genotypes were 16%, 36%, and 48% for GG/GC/CC. IL28B genotype was significantly associated with SVR in patients infected by genotype 1 but not genotype 6 HCV, with 80% versus 38% of patients infected by genotype 1 achieved SVR carried TT versus TG/GG at rs8099917, respectively (P=0.003). PNPLA3 genotype was not associated with SVR. CONCLUSIONS: IL28B gene with rs8099917 T allele as an independent predictor of SVR in Chinese CHC patients infected by genotype 1 but not genotype 6 HCV.

Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy.

BACKGROUND & AIMS: Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. METHODS: Patients with HCV infection and thrombocytopenia (platelet count <75,000/µL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. RESULTS: More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/µL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. CONCLUSIONS: Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Hepatocyte expression of TRAIL pathway regulators correlates with histopathological and clinical parameters in chronic HCV infection.

BACKGROUND AND AIMS: Treatment with pegylated interferon-alpha (PEG-IFN) and ribavirin is the backbone of standard therapy of HCV by mechanisms that are not completely understood. Besides a direct antiviral effect, different immunomodulatory and apoptotic effects have been discussed. Tumor necrosis factor-related apoptosis inducing-ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with immunomodulatory as well as pro- and antiapoptotic effects and is putatively involved in control of HCV infection. Thus, we analyzed the expression of the TRAIL/TRAIL-receptor system, caspase-8 and cFLIP and examined their prognostic and predictive value for HCV infection and antiviral therapy, respectively. METHODS: We immunohistochemically analyzed liver biopsies of 116 therapy-naive HCV patients before treatment with PEG-IFNα and ribavirin in comparison to healthy liver tissue. Expression levels of TRAIL, TRAIL-R1 to TRAIL-R4, caspase-8 and cFLIP were correlated with sustained virologic response (SVR), genotype and staging of chronic hepatitis. RESULTS: Caspase-8, cFLIP, TRAIL-R2 and TRAIL-R4 were strongly upregulated in HCV patients, whereas TRAIL-R3 was downregulated. SVR correlated with high expression of TRAIL and pro-apoptotic TRAIL-R2 on HCV infected hepatocytes. CONCLUSIONS: Our results suggest a pathophysiological role of TRAIL in both, HCV infection and therapy. Further studies need to elaborate possible TRAIL-related targets for clinical applications.

NS5A inhibitors in the treatment of hepatitis C.

Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. In addition, currently approved pharmacotherapies achieve suboptimal cure rates and have side effects that result in non-compliance and premature treatment discontinuation. Significant research has been devoted to developing direct-acting antiviral agents that inhibit key viral functions. In particular, several novel drug candidates that inhibit the viral non-structural protein 5A (NS5A) have been demonstrated to possess high potency, pan-genotypic activity, and a high barrier to resistance. Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon-free, all-oral regimens.

Mutations within the interferon sensitivity determining region in Korean patients infected with hepatitis C virus genotype 1b / 대한간학회지

BACKGROUND/AIMS: The treatment response to interferon could differ with mutations in the interferon-sensitivity-determining region (ISDR) in patients infected with hepatitis C virus (HCV) genotype-1b (HCV-Ib). We examined the pattern of ISDR mutations and analyzed whether the number of amino acid substitutions influences the treatment response to peginterferon plus ribavirin in chronic hepatitis or cirrhotic patients infected with HCV-Ib. METHODS: The study population comprised 52 patients who visited Seoul Asan Medical Center and Seoul National University Bundang Hospital from January 2006 to December 2008 and who received peginterferon alpha-2a (n=37) or -2b (n=15) plus ribavirin, and whose serum was stored. We analyzed the early virologic response, end-of-treatment response, and sustained virologic response (SVR), and examined the ISDR using direct sequencing. RESULTS: The proportions of patients with ISDR mutation types of wild (0 mutations), intermediate (1-3 mutations), and mutant (> or =4 mutations) were 50.0%, 42.3%, and 7.7%, respectively, and the corresponding SVR rates were 63%, 50%, and 67% (p>0.05). The SVR rates were 59.4% and 50.0% in patients with or =2 mutations, respectively (p>0.05). On univariate analysis, age was the only predictive factor for SVR (p=0.016). The pretreatment HCV RNA titer tended to be lower in those with SVR, but without statistical significance (p=0.069). CONCLUSIONS: The frequency of ISDR mutations was low in our cohort of Korean patients infected with HCV-Ib. Therefore, ISDR mutations might not contribute to the response to treatment with peginterferon plus ribavirin.

Rapid virological response to peginterferon alfa and ribavirin treatment of chronic hepatitis C predicts sustained virological response and relapse in genotype 1 patients.

The treatment of chronic hepatitis C is a rapidly changing arena with new medications, new guidelines, and an evolving understanding of the virus, host factors and natural history. With the explosion of new information, the educational infrastructure to update clinicians has been outpaced; many feel uncertain if the tools they are using to care for patients are meeting the standard of practice. This review focuses on the most common genotype of the hepatitis C virus and the rules of engagement when treating with pegylated interferon and ribavirin. Viral assessment guideposts are evaluated and put into context for a clinical audience. The expected arrival of newer antiviral therapies is still years away, and maximizing the current treatment regimens is of utmost importance to eradicate virus when feasible, while minimizing toxicity.