Independent Predictor Of Sustained Virological Response Research Articles

Implications of soluble E-cadherin level of antiviral treatment in patients with chronic hepatitis C virus infection

Background and aimsSoluble E-cadherin (sE-cadherin) has been observed elevated in patients with various diseases, and implicated in the occurrence and development of those diseases. The implications of sE-cadherin in chronic hepatitis C virus (HCV) infection are still unclear. The purpose of this study is to explore the significance of sE-cadherin in chronic hepatitis C infection and the correlation with treatment response. Methods87 chronic HCV infected patients and 60 healthy subjects were enrolled in this study. Blood samples from patients receiving the combined treatment of pegylated interferon-a (Peg-IFN-α) with ribavirin (RBV) were collected before treatment, during 4th, 12th therapy weeks, end of the treatment, and 24 weeks post-therapy. Plasma sE-cadherin level was detected by enzyme-linked immunosorbent assay (ELISA) and the relationship between sE-cadherin and antiviral treatment outcome was analyzed. ResultsPlasma sE-cadherin concentrations of Chronic HCV infected patients were significantly higher than that of healthy controls. A strong correlation between sE-cadherin level and the HCV viral load, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and also glutamyl transpeptidase (GGT) level was detected. Chronic HCV infected patients achieving rapid virological response (RVR) and sustained virological response (SVR) had lower baseline sE-cadherin concentrations compared with the non-RVR and non-SVR groups respectively. Univariate and multivariate regression analyses suggested that baseline plasma sE-cadherin level was predictive of therapeutic effect in patients with chronic HCV infection. ConclusionBaseline sE-cadherin level could be considered as an independent predictor of SVR with Peg-IFN-α plus ribavirin therapy in the Chinese Han population chronic HCV infection patients. Effective antiviral therapy might restore sE-cadherin at physiological levels.

Effects of Age on Treatment of Chronic Hepatitis C with Direct Acting Antivirals

Introduction and aim: Data on the efficacy and tolerance of interferon-free treatment in chronic hepatitis C (CHC) in elderly patients are limited in phase II-III trials. Methods: A prospective cohort of adult patients with CHC treated in French general hospitals. Results: Data from 1,123 patients, distributed into four age groups, were analyzed. Of these, 278 were ≥ 64 years old (fourth quartile) and 133 were ≥73 years old (tenth decile). Elderly patients weighed less, were more frequently treatment-experienced women infected with genotype 1b or 2, while they less frequently had genotype 3 or HIV coinfection, but had more frequent comorbidities and drug consumption. Half of the patients had cirrhosis, whatever their ages. The main treatment regimens were sofosbuvir/ledipasvir (37.8%), sofosbuvir/daclatasvir (31.8%), sofosbuvir/simeprevir (16.9%), sofosbuvir/ribavirin (7.8%); ribavirin was given to 24% of patients. The overall sustained virological response (SVR) rate was 91.0 % (95% CI: 89.2-92.5 %) with no difference according to age. Logistic regression of the independent predictors of SVR were albumin, hepatocellular carcinoma and treatment regimen, but not age. The rate of severe adverse events (66 in 59/1062 [5.6%] patients) tended to be greater in patients older than 64 years of age (21/261, 8.1%), but the only independent predictors of SAE by logistic regression were cirrhosis and baseline hemoglobin. Patient-reported overall tolerance was excellent in all age groups, and patient-reported fatigue decreased during and after treatment, independent of age. Conclusions: The high efficacy and tolerance of interferon-free regimens is confirmed in elderly patients in real-life conditions.

Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C.

Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Predictors of treatment efficacy and liver stiffness changes following therapy with Sofosbuvir plus Ribavirin in patients infected with HCV genotype 2

While the combination therapy of ribavirin (RBV) and sofosbuvir (SOF) is effective in genotype 2 HCV infection, the predictors of treatment efficacy and posttreatment changes in α-fetoprotein (AFP) and liver stiffness (markers of hepatocellular carcinoma), remain unclear. In this study, 302 patients with chronic HCV genotype 2 infection were treated with SOF (400 mg) plus RBV (400-1000 mg; based on body weight) for 12 weeks. We evaluated the efficacy and safety of treatment, as well as measured serum AFP, liver stiffness, and controlled attenuation parameter (CAP, a surrogate marker of steatosis) at baseline and within 48 weeks of treatment completion. The intention-to-treat analysis showed a sustained virological response (SVR) rate of 95.7%. None of the patients discontinued treatment due to side effects. Multivariate analysis identified pretreatment (no treatment with interferon), level of AFP (AFP; <10 μg/L), and RBV/body weight (BW) ratio (≥9.0 mg/kg) as independent predictors of SVR. The SVR rate in patients with two predictors of poor response (AFP ≥10 μg/L and RBV/BW ratio <9.0 mg/kg) was significantly lower than in other patients. In the SVR group, posttreatment AFP level and liver stiffness were significantly lower than at baseline. CAP tended to be higher after treatment than at baseline in all patients. SOF plus RBV combination therapy achieved a high SVR rate and was safe in HCV genotype 2 infected patients. Treatment reduced AFP levels and improved liver stiffness, but increased CAP.

Direct-acting antiviral treatment of chronic HCV-infected patients on opioid substitution therapy: Still a concern in clinical practice?

There is limited real-world information on the effectiveness of antiviral treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAA) in people on opioid substitution therapy (OST). This study compared sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST and non-OST patients in the German Hepatitis C-Registry (DHC-R). National multi-centre prospective real-world registry (German Hepatitis C-Registry, DHC-R). Non-OST patients comprised patients with former/current drug use (non-OST/DU) and patients never consuming drugs (non-OST/NDU). A total of 254 medical centres in Germany, including 123 centres providing OST. A total of 7747 chronic HCV patients started DAA therapy (739 OST and 7008 non-OST; 1500 non-OST/DU; 5508 non-OST/NDU) patients. Five hundred and twenty-eight OST and 5582 non-OST patients had completed antiviral therapy and at least one follow-up documentation [intention-to-treat (ITT) population]. Study outcomes were SVR, proportion of LTFU and safety of treatment. SVR (ITT) was documented in 85% (450 of 528) OST patients versus 86% (969 of 1126) in non-OST/DU (P=0.651) and 92% (4113 of 4456) non-OST/NDU (P<0.001) patients. Independent predictors for SVR (P<0.01 in multivariate analysis) included HCV genotype non-3 [adjusted odds ratio (aOR)=1.11; 95% confidence interval (CI)=1.07-1.15], female sex (aOR=1.59; CI=1.30-1.94), platelet counts >90×109/l (aOR=1.51, CI=1.14-2.01), cirrhosis (aOR=0.77; CI=0.62-0.96) and patient group (OST/DI (aOR=0.58; CI=0.42-0.78); non-OST/DU (OR: 0.63; CI=0.50-0.78). In per-protocol analysis (PP), SVR rates were ≥94% in all patient groups. In OST the proportion of LTFU was higher (10.2%) than in non-OST/DU (8.5%) and non-OST/NDU (3.2%, P<0.001) patients. Independent factors for LTFU (P<0.01) were HCV genotype non-3 (aOR=0.92; CI=0.88-0.96), female sex (aOR: 0.7; CI=0.53-0.92), pre-treatment (aOR=0.64; CI=0.50-0.82), OST/DI (aOR=3.35; CI=2.35-4.78) and non-OST/DU (aOR=2.38; CI=1.80-3.14). In Germany, direct-acting antiviral treatment of former or current drug users with or without opioid substitution therapy can achieve equally high sustained virological response rates as in patients with no history of drug use.

Effect of vitamin D supplementation on sustained virological response in genotype 1/4 chronic hepatitis C treatment-naïve patients from India.

Background & objectives:The effect of vitamin D supplementation on response to antiviral therapy in hepatitis C virus (HCV) genotype 1 and 4 infection still remains unclear, with studies yielding inconsistent results. The aim of the present study was to assess the effect of vitamin D supplementation on treatment outcome in patients with genotype 1/4 chronic hepatitis C (CHC) infection.Methods:Sixty consecutive, treatment-naïve, genotype 1 and 4 chronic HCV patients were included in the study. The patients were randomized into two groups: Vitamin D supplemented group received pegylated (PEG)-interferon α-2a 180 μg per week plus ribavirin (RBV) (1000-1200 mg/d) together with vitamin D3 (2000 IU/d) and control group received identical therapy without vitamin D (32 patients).Results:There were no significant differences between the two groups in terms of age, sex, body mass index and baseline laboratory values. Lower vitamin D levels were associated with higher grades of fibrosis in liver histology (vitamin D >20 ng/ml - 70% vs vitamin D <20 ng/ml - 37%, P<0.05). Vitamin D supplemented group had similar rapid viral response (40 vs 28%, P=0.36), complete early viral response (53.2 vs 40%, P=0.34), end of treatment response (64 vs 46%, P=0.17) and sustained virological response (SVR) (60 vs 44%, P=0.19) as compared to control group. Interleukin 28B polymorphism [odds ratio (OR)-15.37, 95% confidence interval (CI)-2.32-101.76, P=0.04] and baseline serum vitamin D levels (OR-6.36, 95% CI-1.36-29.61 P=0.02) were independent predictors of SVR in genotype 1/4 CHC. Vitamin D supplementation was not found to be predictor of response in genotype 1/4 CHC on multivariate analysis (OR-2.79, 95% CI- 0.63-12.34, P=0.74).Interpretation & conclusions:The present study showed that addition of vitamin D to PEG/RBV combination therapy in treatment-naïve patients who were infected with HCV genotype 1/4 had no effect on the rates of rapid, early and sustained viral responses.

Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals.

In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7)mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60)mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28mg/L was the optimal lower cut-off for achieving SVR and 3.61mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin<10g/dL). In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

The relationship between ITPA rs1127354 polymorphisms and efficacy of antiviral treatment in Northeast Chinese CHC patients.

This prospective study investigated the relationship between 2 inosine triphosphatase (ITPA) polymorphisms (rs7270101 and rs1127354) and the efficacy of ribavirin-based antiviral therapy in hepatitis C virus (HCV)-infected Chinese patients.A total of 906 patients diagnosed with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin combination therapy between January 2011 and January 2014 from 5 hepatitis centers in Northeast China were enrolled. The patients were divided into genotype 1 and non-genotype 1 groups according to the genotype of infected HCV. ITPA single nucleotide polymorphism (SNP) genotyping was performed for all patients. Ribavirin-induced hemolytic anemia and virological response (VR) were monitored during treatment and follow-up. Multivariate regression analysis was used to analyze the predictors for sustained virological response (SVR).IPTA rs7270101 variants were not detected. IPTA rs1127354 variants were detected and showed no difference between the genotype 1 and non-genotype 1 groups. IPTA rs1127354 genotype CC was related to a higher incidence of ribavirin-induced hemolytic anemia. For patients who received >80% of the planned ribavirin dose, rs1127354 variants and related ITPase were related to better SVR. Multivariate analysis showed that IPTA rs1127354 non-genotype CC, HCV genotype, a baseline HCV RNA level <4 × 105 IU/mL, IL-28B rs12979860 genotype CC, and low liver fibrosis were independent predictors for SVR during the combination therapy.IPTA rs1127354 variants and related ITPase were not only related with ribavirin-induced hemolytic anemia but also directly affected the SVR to PEG-IFN plus ribavirin combination therapy in Chinese HCV-infected patients.

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4.

Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real-world clinical practice, showed high rates of sustained virological response (SVR) in non-cirrhotic genotype (GT)-1 and GT-4 patients. These results were slightly lower in cirrhotic patients. We investigated real-life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV-GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January-2014 and December-2015. Demographic, clinical, virological and safety data were analysed. Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109 /L, transient elastography≥21Kpa) showed significantly lower SVR rates (84.4%-91.9%) than patients with less advanced liver disease (93.8%-95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE-associated discontinuation events occurred in 5.9% and 2.6%. In this large cohort of cirrhotic patients managed in the real-world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.

Vitamin D-related gene polymorphism predict treatment response to pegylated interferon-based therapy in Thai chronic hepatitis C patients

BackgroundPatients with chronic hepatitis C (HCV) infection have high prevalence of vitamin D deficiency. Genome-wide association study data has showed that several genetic variants within vitamin D cascade affect vitamin D function. This study aimed to determine whether genetic polymorphisms of genes in the vitamin D pathway are associated with treatment responses to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection.MethodsThe study included 623 Thai patients from 2 university hospitals diagnosed with chronic HCV infection who were treated with a PEG-IFN and ribavirin. Patients were genotyped for functional variants on vitamin D synthetic pathway including GC (rs4588, rs7041, rs22020, rs2282679), CYP2R1 (rs2060793, rs12794714), CYP27B1 (rs10877012), and DHCR7 (rs12785878). Pre-treatment predictors of sustained virologic response (SVR) at 24 weeks following discontinuation of therapy were identified using a logistic regression analysis.ResultsSVR was achieved by 60.5% of patients (52.9% with HCV genotype 1; 66.7% with HCV non-genotype 1). In 44.6% of HCV genotype 1-infected patients, only the variant rs12785878 in the DHCR7 locus was significantly associated with an SVR. HCV genotype 1 patients who had DHCR7 rs12785878 GT/TT had a higher rate of SVR than those with the GG allele (59.7% vs. 43.4%, P = 0.03), but in HCV non-genotype 1-infected patients, the SVR rate did not differ between the two groups (63.3% and 59.1% for GT/TT and GG allele, P = 0.54). By multivariate analysis, liver fibrosis stage 0–1 (OR = 5.00; 95% CI, 2.02–12.37; P < 0.001), and DHCR7 rs12785878 GT/TT allele (OR = 2.69; 95% CI, 1.03–7.05; P = 0.04) were independent pre-treatment predictors of SVR following PEG-IFN-based therapy in HCV genotype 1 patients. Baseline HCV RNA < 400,000 IU/ml (OR = 1.96; 95% CI, 1.13–3.39; P = 0.02) was the only independent predictor of SVR in HCV non-genotype 1 patients. The polymorphisms of GC, CYP2R1 and CYP27B1 were not associated with treatment outcome even in genotype 1 or non-genotype 1 HCV infection.ConclusionThe DHCR7 polymorphism may be a pre-treatment predictive marker for response to PEG-IFN-based therapy in chronic HCV genotype 1 infection.

The Evaluation of Interferon Lambda 4 rs368234815 as a Predictor Factor in Treated Patients with Chronic Hepatitis C Genotype 1a Infection

Context: Host factors including single-nucleotide polymorphisms (SNPs) in or near interferon lambda (IFNL) gene are the important factors in predicting response to treatment of chronic hepatitis C (CHC). Aims: The aim of this study was to determine the frequency and association of IFNL4 rs368234815 with IFNL3 SNPs rs12979860, rs8099917 and other factors including cholesterol, alanine aminotransferase, fibrosis, viral load, age and body mass index in genotype 1a treated CHC patients, to achieve rapid virologic response (RVR) and sustained virologic response (SVR). Subjects and Methods: A total of 71 hepatitis C virus genotype 1a patients were enrolled from 2013 to 2015. The genotypes of rs12979860, rs8099917 were identified by polymerase chain reaction (PCR) and restriction fragment length polymorphism while the genotype rs368234815 detected by amplification-refractory mutation system-PCR. Results: The rate of RVR and SVR were 43/71 (60.6%) and 46/71 (64.8%), respectively. To achieve an SVR in patients with rs368234815, TT/TT genotype 20/24 (83.3%) was found to be higher than other SNPs. The correlation coefficient of rs368234815 was strongly associated with rs12979860 (r = 0.788, P < 0.001). Multivariate logistic regression showed that the cholesterol (odds ratio [OR]: 0.205, confidence interval [CI] 95%: 0.047–0.891, P = 0.035), age (OR: 0.160, CI 95%: 0.035–0.730, P = 0.018), baseline viral load (OR: 0.167, CI 95%: 0.032–879, P < 0.035) and IFNL4 (OR: 5.453, CI 95%: 1.015–29.293, P < 0.048) could be independent predictors of SVR. Conclusions: The results of these findings emphasise that factors such as age, cholesterol, baseline viral load and IFNL4 rs368234815 are better predictive factors and should be evaluated before CHC treatment.

Polymorphisms of HLA-DM on Treatment Response to Interferon/Ribavirin in Patients with Chronic Hepatitis C Virus Type 1 Infection.

Background: HLA-DM gene, which is related to antigen processing and presentation and located in the non-classical class-II region of human leukocyte antigen (HLA) region, may play a crucial role in chronic hepatitis C virus (HCV) infection treatment outcomes. The study was conducted to evaluate the role of the variant of several single nucleotide polymorphisms (SNPs) in HLA-DM gene in HCV treatment outcomes. Methods: We genotyped four SNPs from the candidate genes (HLA-DMA and DMB) in 336 patients who were treated with pegylated interferon-alpha and ribavirin (PEG IFN-α/RBV). Multivariate analysis of factors predicting sustained virological response (SVR) was conducted. Results: HLA-DMA rs1063478 and DMB rs23544 were independent factors of HCV treatment outcomes in Chinese Han population. Individuals who carried favorable genotypes of rs1063478TT and rs23544GG were more likely to achieve SVR {Dominant model: odds ratio (OR) = 2.05, 95% confidence interval (CI) = 1.24–3.41; OR = 2.04, 95% CI =1.23–3.35, respectively}. Rs23544, rs1063478, baseline glucose, baseline platelet and T4 level were independent predictors of SVR. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.740. Conclusions: The genetic variation of rs1063478 and rs23544 are associated with the treatment outcomes in the Chinese Han population.

Favorable efficacy of daclatasvir plus asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older.

The combination of daclatasvir and asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (<20%), pretreatment (failure of treatment except for triple therapy with simeprevir, or treatment naive), and level of viremia (<6.0 log IU/ml) as independent predictors of SVR. Direct sequencing showed a significantly higher rate of NS3-D168 mutation at baseline in non-responders to triple therapy with simeprevir (44%) than others (2%). Alfa-fetoprotein (AFP) level and liver stiffness were significantly lower after end of treatment than at baseline, in both the SVR and non-SVR groups. In conclusion, daclatasvir-asunaprevir combination achieved high SVR in HCV genotype 1b patients, including elderly patients. Viral factors negatively influenced the response to treatment. Treatment improved AFP level and liver stiffness (surrogate markers of hepatocellular carcinoma), regardless of treatment efficacy. J. Med. Virol. 89:91-98, 2017. © 2016 Wiley Periodicals, Inc.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort.

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n=161; pegylated interferon/ribavirin n=76) (30% female, median age 35years, 56% ever injected drugs, median duration of infection 6.2months). Sixteen per cent (n=38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention totreat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P=0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI1.13-4.56, P=0.021), baseline HCV RNA <400000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P=0.041) and age ≥40years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P=0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.

Serum interferon-related microRNAs as biomarkers to predict the response to interferon therapy in chronic hepatitis C genotype 4.

MicroRNAs are messengers during interferon-virus interplay and are involved in antiviral immunity, however, little is known about interferon-related microRNAs regarding their detection in serum and their potential use as non-invasive diagnostic and prognostic biomarkers in chronic hepatitis C (CHC). To elucidate some of the molecular aspects underlying failure of pegylated interferon-α/ribavirin therapy, we investigated pretreatment expression profiles of seven selected interferon-related microRNAs (miR-146a, miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296) by quantitative RT-PCR custom array technology in serum of Egyptian CHC genotype 4 patients and whether their pretreatment levels would predict patient response to the combination therapy. One hundred and six CHC patients and forty matched healthy controls were included. Patients were divided into sustained virological response (SVR) and non-responder (NR) groups. Serum miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296 were upregulated, whereas serum miR-146a was downregulated in CHC compared to controls. Significant correlations were found between expression levels of studied microRNAs and also with clinical data. Pretreatment levels of miR-34a, miR-130a, and miR-195 were significantly higher, whereas miR-192 and miR-296 levels were significantly lower in SVR than NR patients. miR-19a and miR-146a levels were not significantly different between the two groups. miR-34a was superior to differentiate CHC from controls, whereas miR-296 was superior to discriminate SVR from NR patients by receiver operating characteristic analysis. Multivariate logistic analysis revealed miR-34a and miR-195 as independent predictors for SVR and miR-192 as an independent variable for non-response. In conclusion, pretreatment expression profiles of five interferon-related microRNAs are associated with treatment outcome in CHC. Of these, miR-34a, miR-195, and miR-192 could predict treatment response. The profiling results could be used as novel non-invasive diagnostic and prognostic pharmacogenetic biomarkers for treatment personalization in CHC and could help to identify new microRNA-based antivirals.

Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection.

Background & AimsHepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C.MethodsBaseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells.ResultsIn the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment.ConclusionsOxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.

IL28B genetic variations are associated with treatment response of patients with chronic hepatitis C in a Chinese Han population.

This study aimed to investigate the association between interleukin 28B (IL28B) single nucleotide polymorphisms (SNPs) and sustained virological response (SVR) in Chinese Han patients with chronic hepatitis C (CHC) and to analyze the correlations between IL28B SNPs and their personal, virological and clinical characteristics. Altogether 631 Chinese Han individuals, including 297 CHC patients treated with pegylated interferon α plus ribavirin, 14 spontaneous responders to hepatitis C virus (HCV) and 320 healthy controls were enrolled in the study. Two main SNPs of IL28B, rs12979860 and rs8099917, were genotyped using an SNaPshot Multiplex Assay. Associations between IL28B, treatment outcomes and the patients' characteristics were assessed by multivariate logistic regression. The proportion of individuals with the rs12979860 CC or rs8099917 TT genotype was similar in the healthy controls and the CHC patients, although all spontaneous responders presented with both genotypes. Patients with IL28B genotypes had a significantly high rate of rapid virological response (RVR) and SVR. Multivariate analysis revealed that the IL28B SNP rs12979860 CC genotype, being aged <40 years and having a non-genotype 1 (G1) were independent predictors for SVR. The rs12979860 CC genotype and rs8099917 TT genotypes were predictors for RVR. The rs12979860 CC and rs8099917 TT genotypes were more prevalent in patients with a non-G1 genotype than those with G1 genotype. IL28B rs12979860 CC genotype is a significant predictor for SVR and RVR in Chinese Han patients with CHC. Non-G1 HCV genotype is associated with favourable IL28B genotypes.

High sustained virological response to pegylated interferon and ribavirin for recurrent genotype 3 hepatitis C infection post-liver transplantation.

Treatment outcomes of recurrent HCV genotype 3 (GT-3) after liver transplantation (LT) are ill-defined. To determine efficacy, predictors, and long-term survival after treatment of recurrent HCV GT-3 infection, post-LT, with a combination of pegylated interferon (PEG) and ribavirin (RBV). We studied all LT recipients (LTR) in our program treated with PEG and RBV for recurrent HCV GT-3 between Jan 1st 2002 and Dec 31st 2013. Antiviral therapy (AVT) was started if histology showed recurrent HCV with ≥ stage 2 fibrosis. Treatment was intended for 24 or 36 weeks, depending on early virologic response, and/or 24 weeks consolidation. Primary endpoint was sustained virological response (SVR). We also studied predictors of SVR and long-term patient survival. Among 492 LT for HCV-related cirrhosis and/or hepatocellular carcinoma performed during the study period, 110 (22%) had HCV GT-3 infection. Fifty-two (10.5%) HCV GT-3 patients had indications for AVT. Six were unable to complete the AVT, three because of clinical decompensation and one each because of metastatic disease involving the brain, lung cancer, and ductopenic rejection. Forty-seven (90%) patients achieved early virological response (EVR) and 37 (71%) achieved SVR. Predictors of SVR were EVR (p < 0.001), stage ≤ 3 fibrosis (p = 0.008), and 36 weeks treatment duration (p < 0.001). Less advanced fibrosis ≤ 3 was independent predictor of SVR (OR 0.18, 95% CI 0.05-0.67). SVR patients had actuarial (Kaplan-Meier) 1, 3, and 10 year post-treatment survival of 100, 100, and 95%, compared with 87, 78, and 20% for non-SVR patients (p < 0.001, log rank test). Efficacy of AVT for recurrent HCV GT-3 post-LT is high, and comparable with that for non-transplant patients. Less advanced fibrosis is an independent predictor of SVR. SVR improves long-term survival.

Significance of miRNA‐122 in chronic hepatitis C patients with serotype 1 on interferon therapy

Peginterferon (PEG IFN) and ribavirin combination therapy is a curative treatment for chronic hepatitis C virus (HCV) infection, and virological response to IFN therapy has been strongly associated with genetic variation in IL28B single nucleotide polymorphisms (SNP). Recently, miRNA122 (miR-122), which is the most abundant miRNA in the liver, has been reported to be important for the replication of HCV RNA. Therefore, we investigated the correlation of miR-122 expression with virological response to IFN and other clinical data. A total of 51 patients with HCV infection who were treated with IFN therapy at Nagasaki University Hospital from 2006 to 2011 were included in this study. We investigated the correlation of miR-122 expression in liver biopsy specimens with virological response to IFN therapy and other predictors of response, including IL28 SNP. miR-122 expression did not correlate with IL28 SNP. However, a significant difference was observed in miR-122 expression between patients who showed a sustained virological response (SVR) and those who did not (P < 0.05). Multivariate analysis indicated that miR-122 is an independent predictor of SVR. miR-122 expression could be a marker for predicting the outcome of IFN therapy. Therapies targeting miR-122 may have positive effects not only by directly inhibiting viral propagation but also by ameliorating cholesterol and lipid abnormalities.

IFNL3 polymorphisms predict response to therapy in chronic hepatitis C genotype 2/3 infection

Single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3, previously known as IL28B) region are the strongest baseline predictors of sustained virologic response (SVR) to pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) genotype 1 infection. Whether IFNL3 SNPs influence treatment response in genotype 2 and 3 (HCV-2/3) infection remains controversial. This study sought to clarify in a large cohort, whether SNPs in the IFNL3 region are associated with treatment response in HCV-2/3 patients. The cohort comprised 1002 HCV-2/3 Caucasians patients treated with pegylated interferon-alpha and ribavirin who underwent genotyping for the SNPs rs12979860 and rs8099917. Overall, 736 (73.5%) patients achieved SVR (81.9%, 67.9%, and 57.8% for rs12979860 CC, CT, and TT [p = 0.0001]; 78%, 68.7%, and 46.3% for rs8099917 TT, TG, and GG [p = 0.0001]). By logistic regression, both rs12979860 CC and rs8099917 TT were independent predictors of SVR with an odds ratio (OR) of 2.39 (1.19-3.81) p = 0.0001 and OR 1.85 (1.15-2.23) p = 0.0001, respectively. IFNL3 responder genotypes were more frequent in relapsers than null-responders (p = 0.0001 for both SNPs). On-treatment rapid virological response (RVR) was predictive of SVR only in those individuals with IFNL3 non-responder genotypes (rs12979860 CT/TT and rs8099917 TG/GG). This adequately powered study in patients with HCV genotypes 2 or 3 infection clearly demonstrates that IFNL3 genotypes are the strongest baseline predictor of SVR, in keeping with the known association for genotype 1 infection. IFNL3 genotyping can aid in therapeutic decision making for these patients.