Virological Response In Patients Research Articles

Ultradeep Sequencing Study of Chronic Hepatitis C Virus Genotype 1 Infection in Patients Treated with Daclatasvir, Peginterferon, and Ribavirin

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.).

Impact of comorbid hepatic steatosis on treatment of chronic hepatitis C in Japanese patients and the relationship with genetic polymorphism of IL28B, PNPLA3 and LDL receptor.

The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.

Management of viral hepatitis in liver transplant recipients.

Recurrence of viral hepatitis after liver transplantation (LT) can progress to graft failure and lead to a decrease in long-term survival. Recently, there have been remarkable improvement in the treatment of chronic hepatitis B (CHB) using potent antiviral agents. Combination of hepatitis B immunoglobulin and potent antiviral therapy has brought marked advances in the management of CHB for liver transplant recipients. Post-transplant antiviral therapy for hepatitis C virus infection is generally reserved for patients showing progressive disease. Acheiving a sustained virological response in patients with LT greatly ameliorates graft and overall survival, however this only occurs in 30% of transplant recipient using pegylated interferon and ribavirin (RBV). Direct acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors are anticipated to establish the new standard of care for transplant recipients. In liver transplant recipients, hepatitis E virus infection is an uncommon disease. However, it can lead to chronic hepatitis and cirrhosis and may require retransplantation. Recently, 3-month course of RBV monotherapy has been reported as an effective treatment. This review focuses on the recent management and therapeutic approaches of viral hepatitis in liver transplant recipient.

Expression of selected genes in liver biopsy specimens in relation to early virological response in patients with chronic hepatitis C with HCV mono- and HIV/HCV co-infection

The aim of our study was to evaluate the significance of IL-28B single-nucleotide polymorphism and hepatic expression of IFI27, SOCS3 and miR-122 in order to predict early virological response (EVR) in patients infected with HCV genotype 1 or 4. The study group consisted of 65 patients: 46 with HCV mono- and 19 with HIV/HCV co-infection. Analyses of IL-28B single-nucleotide polymorphism C/T (rs12979860) in the blood and expression of SOCS3, IFI27 and miR-122 in liver biopsy samples obtained before PegIFN and ribavirin treatment were performed by the RT-PCR method. EVR was defined as a >2log decline in HCV viremia at week 12. EVR was associated with a lower expression of IFI27 and a more frequent presence of the IL28BCC genotype. IFI27 expression was lower in patients with the CC genotype, irrespective of EVR. In multivariate logistic regression, only IL28B CC genotype and age above 40 years influenced EVR (OR =5.09 and 0.29 respectively). In contrast to IFI27, expression of miR-122 and SOCS3 in patients with different IL28B genotypes was not statistically significantly different. A correlation between miR-122 and SOCS3 was found (Rho =0.495094 p< 0.0001). Analysis of IFI27, SOCS3 and miR-122 hepatic expression does not provide substantial benefits for the prognosis of EVR. The only independent prognostic factors for EVR are age and IL28B genotype. The prognostic significance of IFI27 expression for EVR is dependent on the genetic polymorphism of IL28B.

6.0 Supporting patients on therapy

6.0 Supporting patients on therapy

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients.

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N=1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50IU/mL] by week 4 of treatment (rapid virologic response) and 24weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p<0.1×10(-30)) was stronger than that between METAVIR (p=3.86×10(-13)) or APRI (p=5.48×10(-6)) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40KD)/ribavirin.

Management of Drug Interactions and Side Effects in Patients with Chronic Hepatitis C Receiving Triple Therapy

Purpose: Triple therapy with pegylated interferon (IFN), ribavirin (RIB), and boceprevir (BOC) has been shown to increase sustained virological response in patients with chronic hepatitis C. However, health care providers are faced with the management of drug interactions and side effects of this new therapeutic regimen. The purpose of this research study is to collect data regarding the management of the drug interactions and side effects in patients with chronic HCV receiving this therapy. Methods: A prospective chart review of 26 patients with hepatitis C, receiving triple therapy with pegylated interferon, ribavirin, and boceprevir was conducted. Pegylated IFN, RIB dosages, hemoglobin (Hgb), white blood cell count (WBC), and platelets levels were reviewed. Anemia was defined as either symptomatic decreases from baseline Hgb or Hgb < 10.5 g/dL, while leukopenia was defined as WBC < 4.0 K/mm3. Side effects were recorded at the time of the visit. Concomitant medication changes occurred at the initial visit and were monitored during the initial 24 weeks of therapy. Results: Mean age of this cohort (17 white, five African-American, four Hispanic) was 57.9 ± 4.9 years. Average initial viral load (VL) was 4.04 million (m) (0.002 - 22.0 m); initial platelet count was 164 K ± 42 K; initial fibrosis stage was 2.5 ± 0.94. Initially, patients received pegylated interferon (IFN) [(IFN 180 μg, n=20), (150 μg n=2), (135 μg, n=2), 120 μg, n=2)], [ribavirin (1200 mg, n = 18), (1000 mg, n=4), (800 mg, n=3), (600 mg, n=1)], and boceprevir 800 mg orally, three times per day. Laboratory values decreased during the initial 24 weeks (Hgb, 15.4 to 10.9 g/dL), (platelets 164 to 124K), and (WBC, 5.9.to 2.7 K/mm3). The average amount of pegylated interferon and ribavirin received also decreased (IFN 127 μg and ribavirin 682 mg) at week 24. Three patients relapsed >24 weeks, and two patients were detected at 24 weeks. The side effects included: flu-like syndromes (n=19), rash (n=17), diarrhea (n=2), nausea/vomiting (n=10), anemia (n=26), and leukopenia (n=26). The most frequent drug interactions requiring discontinuations, reductions, or close monitoring involved the following: phosphodiesterase inhibitors, tramadol, and simvastatin. Conclusion: The majority of patients in this small cohort cleared their virus. Reductions in pegylated interferon and ribavirin were common among the HCV patients with fibrosis; however, virological response was 81% in patients who did not fail or discontinue medications. Initial changes in medication were common in this patient cohort.Table 1

Safety and Efficacy of Metformin in Patients With Type 2 Diabetes Mellitus and Chronic Hepatitis C

To evaluate the safety and efficacy of metformin in patients with type 2 diabetes mellitus (T2DM) and chronic hepatitis C virus (HCV) with or without cirrhosis and hepatocellular carcinoma (HCC). A PubMed (1946-August 2013) search using the keywords type 2 diabetes mellitus, metformin, hepatitis C virus, cirrhosis, and hepatocellular carcinoma was conducted. The references in published articles were reviewed to identify additional references for inclusion. Studies written in English, evaluating metformin use in human patients with T2DM and chronic HCV were included. Eight studies met criteria for inclusion. Two prospective, randomized controlled trials showed increased benefit with metformin on virological response in patients with insulin resistance receiving HCV treatment. A prospective observational study evaluated metformin exclusively in patients with T2DM and HCV and showed significant reductions in the occurrence of HCC, liver-related death, and liver transplant. Four retrospective case control studies showed a decreased risk of HCC with metformin treatment in patients with T2DM and chronic liver disease. Finally, a retrospective cohort study indicated an increased survival rate in patients with diabetes and HCC undergoing radiofrequency ablation. Although diarrhea was increased in patients receiving metformin, no serious adverse effects, including lactic acidosis, were reported. Metformin may provide benefit in the treatment of HCV and in reducing the risk of HCC in patients with T2DM and HCV. Further long-term, randomized controlled trials are needed to adequately assess the safety and efficacy of metformin therapy in patients with comorbid diabetes and chronic HCV.

End of treatment response in chronic hepatitis C patients treated with interferon alpha and ribavirin.

We conducted a study at Combined Military Hospital (CMH), Sialkot, from August 2010 to February 2011 with the objective to determine the frequency of early and end of treatment virological response in patients with chronic hepatitis C infection treated with IFN-a / ribavirin therapy. HCV RNA PCR positive adult patients of either gender were included in the study. A total of 123 patients (56 males and 67 females) were given alpha-interferon ribavirin for 24 weeks. At 12 weeks posttreatment, 82 patients out of 123 (EVR 66.6%) had negative HCV RNA PCR while 85 patients out of 123 were HCV PCR negative at 24 weeks (ETR 69.1%). Conventional alpha-interferon ribavirin therapy should be discontinued in patients who are non responders at 12 weeks of treatment and be offered pegylated interferon to save time, money and minimize the side effects.

Association between insulin resistance and sustained virologic response in hepatitis C treatment, genotypes 1 versus 2 and 3: systematic literature review and meta-analysis

Background/aimsControversial results have been found in literature for the association between insulin resistance and sustained virologic response to standard chronic hepatitis C treatment. This study aims to provide a systematic literature review with meta-analysis, in order to evaluate if insulin resistance interferes with sustained virologic response in patients infected by the HCV genotype 1 versus HCV genotypes 2 and 3, undergoing treatment with interferon and ribavirin or pegylated interferon and ribavarin. MethodsSystematic search was performed on main electronic databases until May 2012. Primary outcome was sustained virologic response, defined as undetectable levels of HCV-RNA six months after the end of treatment. Meta-analytic measure was estimated using Dersimonian and Laird's method, using Stata software. ResultsThirteen studies involving 2238 infected patients were included. There was a statistically significant association between insulin resistance and lower sustained virologic response rate, and this difference occurred in HCV genotype G1 (OR: 2.23; 95% CI: 1.59–3.13) and G2/G3 (OR: 4.45; 95% CI: 1.59–12.49). In addition, a difference was seen in the cut-offs used for defining insulin resistance by Homeostasis Model Assessment of Insulin Resistance. To minimize this limitation, sub-analysis that excluded the studies that did not use 2 as a cut-off value was performed and the results still demonstrated association between insulin resistance and sustained virologic response, for both genotypic groups. ConclusionThis meta-analysis provides evidence that elevated Homeostasis Model Assessment of Insulin Resistance is associated with a lower sustained virologic response rate in patients with hepatitis C treated with interferon and ribavirin or pegylated interferon and ribavarin, regardless of their genotype.

Sustained virological response after treatment in patients with chronic hepatitis C infection - a five year follow up

Peginterferon alpha-2a and ribavirin combination therapy achieves a sustained virological response (SVR) in patients with chronic hepatitis C. Little is know about long-term durability of hepatitis C virus--Ribonucleic acid (HCV-RNA) negativity in patient treated with pegylated interferon and ribavirin therapy. Aim of this study was to evaluate the durability of virologic response in patients with SVR to anti-viral therapy treated at our centre. A total of 52 patients with chronic hepatitis C virus infection who had obtained SVR after Peginterferon alpha-2a and ribavirin combination therapy were followed up to 5 years with annual HCV-RNA testing. During this follow up period, 4 of 52 patients with initial SVR developed late relapse of hepatitis C virus infection. Relapse was more common in patients who has cirrhosis (3/6 [50%]) vs (1/46 [2.17%]) without cirrhosis. In conclusion, SVR is durable in most patients, but some patients do have late relapse; long-term follow up may be particularly important in a subset of patients with hepatitis C virus infection who have liver cirrhosis.

Interleukin 28B as a Predictor of Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection

Interleukin 28B as a Predictor of Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C

Dysfunctional hepatitis C virus (HCV) specific CD4(+) T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4(+) T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4(+) T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients.

P285 Factors affecting sustained virologic response in patients with chronic hepatitis C receiving Peg-IFN and ribavirin treatment

P285 Factors affecting sustained virologic response in patients with chronic hepatitis C receiving Peg-IFN and ribavirin treatment

Serum apolipoprotein B‐100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b-infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274-24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB-100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype.

Early serum hepatitis B virus large surface protein level: A stronger predictor of virological response to peginterferon alfa-2a than that to entecavir in HBeAg-positive patients with chronic hepatitis B

BackgroundThe response rate to antiviral therapy varies greatly among individuals, and its prediction is still very challenging. ObjectivesTo evaluate the usefulness of serum hepatitis B virus large surface protein (LHBs) levels compared with HBsAg in prediction of the antiviral treatment effect. Study designQuantification of LHBs, HBsAg and HBV DNA was carried out at baseline and during antiviral therapy (weeks 4, 12, 24, 36 and 48) in HBeAg-positive patients treated with peginterferon alfa-2a (n=21) or entecavir (n=41). ResultsThe serum LHBs concentration was correlated positively with HBV DNA and HBsAg (r=0.635 and 0.588, respectively). LHBs and HBV DNA levels decreased significantly in a biphasic manner and HBsAg level tended to decrease slowly in both treatment groups. In peginterferon alfa-2a group, the cutoff of 88.46ng/ml in serum LHBs at week 4 gave the best AUC (=0.96) with positive and negative predictive values of 88.9% and 100%, in association with virological response (VR). Serum LHBs level at week 4 also showed an association with VR in entecavir group (AUC 0.78). The predictive model incorporating LHBs, HBsAg and HBV DNA could discriminate VR at baseline (AUC 0.79) and showed an association with serological response (SR) at week 12 (AUC 0.80) in peginterferon alfa-2a group. ConclusionsOn-treatment quantification of serum LHBs may be a more useful parameter for predicting VR in patients on peginterferon alfa-2a than those on entecavir. Combining LHBs, HBsAg and HBV DNA can predict VR and SR more effectively and earlier.

A Risk for Hepatocellular Carcinoma Persists Long-term After Sustained Virologic Response in Patients With Hepatitis C–Associated Liver Cirrhosis

The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

483 IL28B POLYMORPHISM IS ASSOCIATED WITH NECROINFLAMMATORY ACTIVITY AND ADVANCED FIBROSIS IN PATIENTS INFECTED WITH CHRONIC HEPATITIS DUE TO GENOTYPE NON-1 HCV

Background & Aims: We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin. Methods: Patients (n = 159; 94 men; age, 41.7 ± 11.1 years) with chronic hepatitis C (genotype 1, n = 113; non-1 genotype, n = 46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated. Results: A sustained virological response was associated with lower age, insulin resistance index, body mass index, and γ-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P = .0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49–8.3; P = .001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08–3.06; P = .012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01–1.84; P = .029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%–43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%–75.1%) genotype 1 patients without insulin resistance (P = .007; odds ratio, 3.12, 95% confidence interval, 1.42–6.89). Conclusions: Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.

Role of Interleukin-28B Polymorphism as a Predictor of Sustained Virological Response in Patients with Chronic Hepatitis C Treated with Triple Therapy: A Systematic Review and Meta-Analysis

Chronic hepatitis C represents an important health problem. The aim of our meta-analysis was to establish the role of reference single nucleotide (rs) 12979860 allele of interleukin-28B (IL28B) CC versus CT+TT genotype (the most researched allele of IL28B) as a predictor of sustained virological response (SVR) in patients with chronic hepatitis C treated with triple therapy. The PubMed, MEDLINE, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases as well as abstract books from important gastroenterology and hepatology meetings were searched for all studies published until 15 July 2012 that analysed the relationship between the polymorphism of IL28B and SVR in patients with chronic hepatitis C, genotype 1, treated with pegylated interferon + ribavirin + direct antiviral agents (telaprevir or boceprevir). The following keywords were used: IL28B polymorphism, chronic hepatitis C, sustained virological response, SVR, triple therapy, telaprevir, boceprevir. Odds ratios (ORs) with 95 % confidence intervals were pooled from five study populations (1,641 cases) using a random-effects model. The SVR rate was significantly higher in patients with the CC genotype of IL28B than in those with non-CC genotypes (CT and TT): OR = 3.91 (95 % CI 2.11-7.28), p < 0.0001. Higher SVR rates were obtained in chronic hepatitis C patients with the CC genotype of IL28B, regardless of their therapeutic status (naïve patients: OR = 3.99 [95 % CI 1.67-9.51], p < 0.0001; and previously treated ones: OR = 2.15 [95 % CI 1.35-3.43], p = 0.001). IL28B polymorphism seems to influence the SVR rate in patients with chronic hepatitis C treated with triple therapy, but further studies are needed to clarify the mechanism and the influence of other factors on the SVR rates.

Rapid downregulation of programmed death‐1 and interferon‐γ‐inducible protein‐10 expression is associated with favourable outcome during antiviral treatment of chronic hepatitis B

The dynamics of programmed death-1 (PD-1) as well as cytokine/chemokine expression and its correlation with virological response in patients with chronic hepatitis B (CHB) is unclear. This study was conducted in 29 treatment-naïve patients undergoing telbivudine treatment for 52 weeks. The results showed that PD-1 expression on both CD4+ and CD8+ T cells was positively correlated with hepatitis B virus (HBV) DNA levels (r = 0.621, P < 0.0001; r = 0.548, P = 0.002, respectively), and in virological responders, this decrease was directly correlated with a decrease in HBV DNA levels (r = 0.664, P = 0.002; r = 0.572, P = 0.01, respectively). Furthermore, at the end of 52 weeks, in virological responders, the decreased rate in the frequency of PD-1+ CD8+ T cells was significantly higher than in non-virological responders (58.3% vs 25.7%, P = 0.001), and at weeks 24 and 52, in virological responders, PD-1 expression on CD4+ and CD8+ T cells was lower than in non-virological responders (P = 0.01 and P = 0.035; P < 0.0001 and P < 0.0001, respectively). In 34 cytokines/chemokines detected in serum, IP-10 expression was positively correlated with viral load, level of ALT and PD-1 expression on CD8+ and CD4+ T cells at baseline (r = 0.36, P = 0.055, r = 0.635, P < 0.0001, r = 0.414, P = 0.026, and r = 0.402, P = 0.030, respectively). Moreover, the decrease in IP-10 in serum directly correlated with a decrease in ALT levels (r = 0.751, P < 0.0001). At weeks 24 and 25, IP-10 expression was significantly lower than baseline in virological responders (both P = 0.005); however, this was not observed in nonresponders. Based on the above findings, PD-1 and IP-10 may be used as predictors for virological response, and blockade of their pathway may improve the outcome of patients with CHB.