Pretreatment Hepatitis C Virus RNA Levels Research Articles

1067. Interferon-free Hepatitis C Treatment Increases Surrogates of Cardiovascular Disease Risk in Black Veterans

BackgroundSustained virologic response (SVR) after hepatitis C virus (HCV) treatment with either Interferon (IFN)-based or IFN-free regimens with direct-acting antivirals (DAAs) has been shown to reduce cardiovascular disease (CVD) events in majority white populations stratified by ASCVD score. However, the effect of IFN-free therapy on lipid profiles after SVR, as an indirect measure of CVD risk, is unknown in Black patients.MethodsWe evaluated HCV-infected Veterans from the Baltimore VA who were treated with DAAs between 2015-2019. We performed a retrospective analysis comparing lipid profile changes following SVR among those with early stage (F0-F2) fibrosis and advanced liver disease (ALD, F3-F4 fibrosis) using two-tailed paired t-tests. Independent t-tests were used to assess differences in lipid profiles based on fibrosis stage in patients with HIV and Type II Diabetes Mellitus (DM2).ResultsOf those treated for HCV (n=1,528), 96% (n=1,474) achieved SVR. Demographics are shown in Table 1. Most patients were Black males (75%) and a minority (2.7%) received statin therapy during treatment (Table 1). Of 1,094 patients for whom data was available, an increase in total cholesterol (TC) and LDL (p< 0.01 for both) was seen an average of 17 months after SVR, regardless of fibrosis stage (Figure 1). A significant decrease in triglyceride levels (p=0.04) was also seen in the ALD group after SVR (Figure 1). Mean pre-treatment HCV RNA level was comparable between fibrosis groups (F0-F2: 6.35 logs, F3-F4: 6.37 logs, p=0.46). There were 101 and 436 patients with HIV and DM2, respectively, for whom pre-treatment liver fibrosis data was available. In both groups, there were significant increases in LDL (p=0.008 (HIV), p=0.003 (DM2)) among patients with ALD following SVR.Table 1. Baseline characteristics of treated HCV-infected persons who achieved SVR. Figure 1. Mean lipid profile parameters before and after HCV treatment for patients who achieved SVR. TC was measured a mean of 8.1 months (228 days, SD 333 days) before treatment and 17.4 months (488 days, SD 196 days) after SVR. LDL was measured a mean of 8 months (224 days, SD 284 days) before treatment and 17.5 months (492 days, SD 201 days) after SVR. *=differences in means using paired t-test were statistically significant with p<0.05. HCV= Hepatitis C Virus, SVR= Sustained Virologic Response TC=Total Cholesterol, HDL= High Density Lipoprotein, LDL= Lipoprotein, TG= Triglycerides. ConclusionIn a cohort of mostly Black HCV-infected Veterans, significant increases in TC, driven by increases in LDL, were seen after SVR regardless of fibrosis stage. In addition, patients with ALD and HIV or DM2, who have an inherently higher risk of CVD, had increased LDL levels, suggesting that these patients should be screened and treated for HCV prior to development of ALD. Correlates such as the ASCVD score should be considered in the timing of HCV treatment, in order to reduce the long-term risk of CVD.Disclosures Shyam Kottilil, MD PhD, Arbutus Pharmaceuticals (Grant/Research Support)Gilead Sciences (Grant/Research Support)Merck Inc (Grant/Research Support, Advisor or Review Panel member)

Rapid virologic response in chronic hepatitis C genotype 1: Evaluation of pretreatment factors in patients

Background and study aimsRapid virologic response (RVR) is defined as undetectable hepatitis C virus (HCV) RNA in serum after 4 weeks of treatment for chronic hepatitis C (CHC). Paritaprevir/ritonavir/ombitasvir (PRO) and/or dasabuvir (D), with or without ribavirin [PRO (D) ± ribavirin], which are direct-acting antivirals (DAAs), is the currently approved treatment regimen for CHC genotype 1; this regimen can also be used in patients with end-stage renal failure (ESRF). In this study, we aimed to evaluate the effect of pretreatment factors on RVR in patients treated with PRO (D) ± ribavirin. Patients and methodsThis study included 60 patients with CHC genotype 1 who were treated with PRO (D) ± ribavirin and achieved RVR. Patients’ demographic data; baseline HCV RNA levels; HCV genotype information; biochemical, histologic, and radiologic results; and previous treatment history were recorded. Patients were categorized into two groups: virologic responses achieved in the first week (group 1) and in the first to the fourth week (group 2). Pretreatment factors were compared between the groups. ResultsPatients in group 1 who achieved ultraRVR (undetectable HCV RNA after 1 week of treatment) had significantly lower mean pretreatment HCV RNA levels and lower prevalence of ESRF than patients in group 2. ConclusionsRVR has been indicated to be a robust positive predictor of sustained virologic response. We concluded that some pretreatment factors such as low HCV RNA level and absence of ESRF might lead to faster RVR and shorter treatment duration with DAAs for CHC.

Real-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan.

The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings. In a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics. More than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%. Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen.

Observed increases in CD4:CD8 and TIGIT expression during sofosbuvir-based therapy in a longitudinal hepatitis C cohort

Abstract Chronic hepatitis C virus (HCV) infection reduces immune function through exhaustion and repertoire reduction. Sofosbuvir-based direct-acting antiviral (DAA) therapies offer &amp;gt;90% sustained virologic response (SVR) for HCV infection, but the extent of immune recovery and relationship with clinical factors are unknown. The longitudinal Alaska Hepatitis C Cohort provides an opportunity to evaluate immune recovery following sofosbuvir-based DAA and determine the influence of an extensive clinical and laboratory history. Forty-two persons (genotype 1; mean age 50 ± 12 years; 69% female) received 8 or 12-week sofosbuvir-based DAA therapy. Mean HCV RNA detection date was 2007 (range: 1994–2017). Pre-treatment HCV RNA levels averaged 4.9×106 IU/L (range: 4.9×104–2.4×107), were not detectable in any person after 4-weeks of therapy, and all achieved SVR. 18% (n=7) of persons had a fibrosis score of ≥F2 (moderate fibrosis to cirrhosis). Peripheral blood mononuclear cells (PBMCs) were evaluated at four time points: Pre-treatment (Pre), 4-weeks treatment (4wk), End of Treatment (EOT), and SVR post 12-weeks EOT (SVR-12) by flow cytometry to evaluate memory, exhaustion, and functional immune markers. Initial analysis revealed a significant increase in the CD4:CD8 from 4wk to EOT (p=0.007). Regulatory T-cells significantly increased at EOT and SVR-12 compared to 4wk (p=0.04 and 0.03, respectively). TIGIT showed a significant increasing trend in T-cells and NK cells throughout sampling timeline. Preliminary analysis indicates sofosbuvir-based DAA supports immune recovery to some extent. Additional analysis of immune recovery markers, determination of estimated date of HCV infection, and correlation of morbidity factors continues.

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon α-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.

Impact of Hepatitis B Virus Integration Into Liver Tissue on the Efficacy of Peginterferon and Ribavirin Therapy in Hepatitis B Virus-negative Chronic Hepatitis C Patients

Integration of hepatitis B virus (HBV) DNA into host hepatic DNA is found in patients without HBV surface antigen (HBsAg). We investigated the prevalence of HBV integration and its association with the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy in HBsAg-negative chronic hepatitis C patients. We analyzed 157 patients chronically infected with hepatitis C virus (HCV) with viral load ≥5.0 log10 IU/mL, who underwent PEG-IFN and ribavirin combination therapy. HBV integration was measured by an Alu-PCR assay with liver specimens obtained by needle biopsy before treatment. HBV integration was identified in 54 of the 157 (34.4%) patients. There were no significant differences between patients with and without HBV integration with regard to baseline characteristics including liver histology, pretreatment HCV RNA levels, and genetic polymorphisms near the IL28B gene. In patients with HCV genotype 1b (n=91), a more favorable viral response was observed in patients with HBV integration during therapy, with higher rates of rapid and complete early virologic response. The rate of sustained virologic response (SVR) was significantly higher in patients with HBV integration than those without (P=0.0098). Multivariate analysis identified HBV integration and IL28B polymorphisms as independent factors associated with SVR. HBV integration was associated with favorable viral responses and a higher SVR rate to combination therapy with PEG-IFN and ribavirin in patients infected with HCV genotype 1b. Further studies will be required to confirm this association and elucidate its underlying mechanisms.

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Characteristics and Outcomes of HCV Genotype-1-Infected Patients Treated with Peginterferon and Ribavirin Combination Therapy with Discordant HCV Responses 4 and 12 Weeks after Starting Therapy

Objective: Some patients with chronic hepatitis C virus (HCV) infection fail to achieve complete early virologic response (EVR) despite a marked decrease in HCV RNA at 4 weeks. We investigated the characteristics and final treatment outcomes of this patient subpopulation. Methods: A total of 516 patients with HCV genotype 1 were enrolled. Background characteristics and final outcomes were compared between patients who achieved complete EVR and those who did not among patients whose HCV RNA levels decreased 3.0 log₁₀ or more at 4 weeks. Results: 78 of 334 patients (23.4%) with a ≥3.0 log₁₀ reduction in HCV RNA levels at 4 weeks failed to achieve complete EVR. Female sex, higher pretreatment HCV RNA levels and lower baseline alanine aminotransferase (ALT) activity were independently associated with failure of complete EVR. The rate of sustained virologic response (SVR) in patients without complete EVR was 47.4%, significantly lower than that in patients with complete EVR (89.7%, p < 0.0001). Conclusions: Female patients, patients with higher pretreatment HCV RNA levels and patients with lower baseline ALT have a high likelihood of failure of complete EVR even when they had a ≥3 log₁₀ reduction of HCV RNA at 4 weeks, resulting in a significantly lower SVR rate.

Effect of Functional Interleukin-10 Polymorphism on Pegylated Interferon-α Plus Ribavirin Therapy Response in Chronic Hepatitis C Virus Patients Infected With 3a Genotype in Pakistani Population

Dear Editor, Pakistan is a low socio economic country having more than 10 million people infected with hepatitis C Virus (HCV) with a major genotype of 3a (GT 3a) (1). Due to high rate of resistance to standard Interferon plus Ribavirin therapy, it is highly needed to identify new marker for response prediction to therapy. Interleukin 10 (IL-10) is a key member of Cytokine, which regulates Th1/Th2 Cytokine balance, a major part of immune system against infection (2). IL-10 production varies inter individually based on functional polymorphism (-1082 G/A, -819 C/T and -592 C/A) in its promoter region. Previously we have shown that IL-10 polymorphic variants play important role in HCV susceptibility/prevention (2). Recently we conducted a study to analyze the impact of functionally important IL-10 polymorphism on outcomes of standard Interferon-α plus Ribavirin therapy. The results of current study strengthen previous findings that IL-10 polymorphism effect disease susceptibility in Pakistan (2-4). Our results showed that high IL-10 producing -1082 GG genotype (P = 0.02; OR = 0.4; 95% CI = 0.2-0.8) and GTA haplotype (P = 0.03; OR = 0.55; 95% CI = 0.3-1) were significantly higher in HCV patients as compared to healthy subjects, while IL-10 -1082 GA genotype (P = 0.03; OR = 1.95; 95% CI = 1.1-3.4) showed protective effect against HCV infection. The current data failed to show any significant corelation between IL-10 polymorphism inheritance and standard therapy response in HCV patients. Age and pretreatment viral load are the parameters which influence therapy response; Patients with sustained virological response (SVR) were younger and had lower pretreatment HCV RNA levels. No gender-based statistical difference was found between chronic hepatitis C patients who achieved SVR or failed to respond. To our knowledge this is the first report from Pakistan to evaluate the role of IL-10 polymorphism on the outcomes of standard antiviral therapy. We are unable to find any corelation between IL-10 polymorphic variants and interferon therapy outcomes, may be due to small number of subjects. This study is a preliminary and is on small scale. We believe that our effort may stimulate some additional personal genetic makeup based studies on larger scale using these and new multi-locus analysis approaches for a deeper analysis of the epistatic interaction of the pro- and anti -inflammatory molecules toward hepatitis C progression. Better understanding of genetic factors that have effect on hepatitis C progression and pathogeneses will provide scientific basis for the development of new immunomodulatory treatments for chronic hepatitis C patients and will also help health care workers about the standard therapy effectiveness.

Significance of a reduction in HCV RNA levels at 4 and 12 weeks in patients infected with HCV genotype 1b for the prediction of the outcome of combination therapy with peginterferon and ribavirin

BackgroundThe importance of the reduction in hepatitis C virus (HCV) RNA levels 4 and 12 weeks after starting peginterferon (PEG-IFN) and ribavirin combination therapy has been reported to predict a sustained virologic response (SVR) in patients infected with HCV genotype 1. We conducted a multicenter study to validate this importance along with baseline predictive factors in this patient subpopulation.MethodsA total of 516 patients with HCV genotype 1 and pretreatment HCV RNA levels ≥5.0 log10 IU/mL who completed response-guided therapy according to the AASLD guidelines were enrolled. The reduction in serum HCV RNA levels 4 and 12 weeks after starting therapy was measured using real-time PCR, and its value in predicting the likelihood of SVR was evaluated.ResultsThe area under the receiver operating characteristics (ROC) curve was 0.852 for 4-week reduction and 0.826 for 12-week reduction of HCV RNA levels, respectively. When the cut-off is fixed at a 2.8-log10 reduction at 4 weeks and a 4.9-log10 reduction at 12 weeks on the basis of ROC analysis, the sensitivity and specificity for SVR were 80.9% and 77.9% at 4 weeks and were 89.0% and 67.2% at 12 weeks, respectively. These variables were independent factors associated with SVR in multivariate analysis. Among 99 patients who showed a delayed virologic response and completed 72-week extended regimen, the area under ROC curve was low: 0.516 for 4-week reduction and 0.482 for 12-week reduction of HCV RNA levels, respectively.ConclusionsThe reduction in HCV RNA levels 4 and 12 weeks after starting combination therapy is a strong independent predictor for SVR overall. These variables were not useful for predicting SVR in patients who showed a slow virologic response and experienced 72-week extended regimen.

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.

Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome. The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored. Patients with SVR (n=58) and with non-SVR (n=20) differed significantly in pretreatment HCV RNA level (p=0.002), fibrosis score (p=0.047), and cumulative RBV dosage (p=0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p=0.01 for group 1, p=0.004 for group 2, and p=5E-05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258-2306 region were significantly high in SVR compared to non-SVR patients (p=0.01 for group 1, p=0.006 for group 2, and p=0.0006 for combined). Multivariate analyses revealed that core aa 110 (p=0.02), NS5A aa 2258-2306 (p=0.03), and cumulative RBV dosage (p=0.02) were identified as independent variables associated with the final outcome. The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.

Abbott RealTime PCR assay is useful for evaluating virological response to antiviral treatment for chronic hepatitis C

This study was done to evaluate the utility of the Abbott RealTime PCR assay (ART) for the monitoring of chronic hepatitis C patients. The serum samples of 183 patients infected with hepatitis C virus (HCV) genotype 1b who had completed a 48-week period of pegylated interferon (PEG-IFN) alpha-2b plus ribavirin treatment were prospectively analyzed. Serum HCV RNA levels were measured both by ART and by the Roche COBAS Amplicor Monitor test, version2.0 (CAM) at baseline and at weeks 4, 12, 24, 36, and 48 of treatment, and at 24weeks after the end of treatment (EOT). A significant positive correlation of pretreatment HCV RNA levels was found between ART and CAM (r=0.595, P<0.0001). Of the 183 patients, 66 (36.0%) achieved a sustained virological response (SVR). The logarithmic decline of the HCV RNA level from the pretreatment level determined by ART in SVR patients was significantly higher than that in non-SVR patients at all time points tested. The logarithmic decline determined by CAM in SVR patients was significantly higher than that in non-SVR patients only at week 4, but there was no significant difference at other weeks. Of 124 patients who were HCV RNA-negative at EOT by ART, 58 (46.8%) had a relapse of viremia at 24weeks after EOT, whereas 77 of 143 patients (53.8%) who were HCV RNA-negative at EOT by CAM had a relapse. The relapse rate was lower when determined by ART than by CAM, but not significantly so. ART is more useful than CAM for evaluating the virological response to antiviral treatment for chronic hepatitis C.

Impact of Depressive Symptoms and Their Treatment on Completing Antiviral Treatment in Patients With Chronic Hepatitis C

Interferon-induced depression affects 20% to 40% of patients treated for chronic hepatitis C virus (HCV). The aim of our study was to examine the influence of antidepressant treatment and whether this improves the likelihood of completing therapy. One hundred randomly selected patients with chronic HCV undergoing antiviral therapy at a single center were identified. Patients were categorized as Group 1 (no depressive symptoms during treatment), Group 2 (depressive symptoms without antidepressant therapy), Group 3 (preexisting or prophylactic antidepressants before therapy), and Group 4 (on-demand antidepressant therapy for depressive symptoms). Mean age was 49 years with 72% men. Genotype 1 infection was noted in 65% of patients, and the mean pretreatment HCV RNA level was 1,419,919 IU. Patients without earlier depression receiving on-demand therapy (Group 4) had a significantly higher rate of antiviral treatment completion compared with Group 3 (92% vs. 52%; P=0.01). Patients in groups 1 and 4 with no baseline history of depression had similar treatment completion rates. No significant relationship between the use of antidepressant therapy, SVR or premature cessation of therapy was observed. Preexisting depression was associated with lower antiviral treatment completion rates despite the use of prophylactic antidepressant therapy. In patients without preexisting depression, however, on-demand antidepressant therapy for depressive symptoms was strongly associated with the highest treatment completion rates in the cohort. Antidepressant therapy for new or worsening depressive symptoms independent of baseline depression status did not affect the probability of achieving SVR or stopping treatment prematurely.

Human leukocyte antigen alleles and the response to pegylated interferon/ribavirin therapy in chronic hepatitis C patients

Human leukocyte antigens (HLAs) may play a role in the clinical evolution of hepatitis C virus (HCV) infection. The present study was aimed at elucidating the association between the HLA loci and responses to combination therapy with pegylated interferon-alpha 2a (PEG-IFN) and ribavirin in Taiwanese. We enrolled a total of 208 treatment-naïve Taiwanese chronic hepatitis C (CHC) patients treated with combination therapy. Patients with sustained virological response (SVR) had a significantly higher frequency of genotype non-1b infection, lower pretreatment HCV RNA levels and a higher frequency of mild hepatic fibrosis (fibrosis score: F: 0–2). The HLA A24 and B40 alleles were significantly associated with SVR after adjusted for the other three confounding factors including HCV genotype, hepatic fibrosis and pretreatment serum HCV RNA levels. Haplotypes (B40-DRB1*3, B46- DRB1*9, Cw1- DQB1*3, and Cw1- DRB1*9) were significantly associated with SVR to combination therapy. For 167 patients with genotype 1b infection and viral load < or =5.6 log IU/ml or genotype non-1b infection, the B46 was significantly associated with sustained response with OR (odds ratio) [95% CI (confidence interval) of 0.047 (0.168–0.988)]. Haplotypes B40-DRB1*3, B46- DRB1*9, Cw1- DQB1*3, Cw1- DRB1*9 and DQB1*3- DRB1*9 were found to be associated with SVR to PEG-IFN/ribavirin therapy with OR (95% CI) of 0.179 (0.032–0.989), 0.313 (0.107–0.918), 0.350 (0.145–0.845), 0.282 (0.105–0.759) and 0.412 (0.174–0.978), respectively. We concluded that the virological and the host immunogenetic factors may possibly predict the response to combination therapy in CHC patients.

Response‐Guided Therapy for Chronic Hepatitis C Virus Infection in Patients Coinfected with HIV: A Pilot Trial

To study the feasibility of a response-guided therapy for chronic hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus (HIV) in a tertiary care hospital. Treatment duration was individualized on the basis of week 4 and week 12 virologic response. Sixty patients were enrolled and received pegylated interferon alfa-2b (1.5 microg/kg per week) plus weight-based ribavirin (800-1400 mg/day). Patients who achieved a rapid virologic response, defined as viral load <50 IU/mL at treatment week 4, completed 24 weeks of therapy. Patients who did not achieve a rapid virologic response were reassessed at treatment week 12. Patients with a complete early virologic response, defined as an HCV RNA level <600 IU/mL, were treated for 48 weeks. Patients with a partial response, defined as a decrease in the viral load > or = 2 log10 and an HCV RNA level > or = 600 IU/mL, who attained an undetectable viral load at week 24 were treated for 60 weeks. The primary efficacy end point was sustained virologic response, defined as HCV RNA <50 IU/mL, 24 weeks after the end of treatment. Overall, 33 (55%) of 60 patients achieved a sustained virologic response: 11 (44%) of 25 patients with HCV genotype 1, 3 (27%) of 11 patients with genotype 4, and 19 (79%) of 24 patients with genotype 3. One-third of patients showed a rapid virologic response. Of patients with genotype 1, there was a rapid virologic response in 4 (16%) of 25; with genotype 4, in 1 (9%) of 11; and with genotype 3, in 14 (58%) of 24. Of the 19 patients with a rapid virologic response, 17 (89.5%) eradicated the virus after 24 weeks of therapy. The rate of sustained virologic response was significantly higher among patients with genotype 3 and low pretreatment HCV RNA levels. A high relapse rate (46%) after 48 weeks of therapy occurred among patients infected with genotypes 1 or 4 who first achieved undetectable viral load at treatment week 12. A response-guide therapy is feasible and may be useful to optimize the individual outcome of HCV treatment in patients coinfected with HIV.

Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients

Insulin resistance (IR) might be associated with hepatitis C virus (HCV) infection. This study aimed to elucidate impact of IR and beta-cell function on the response to peginterferon-alpha (PEG-IFN)/ribavirin combination therapy in chronic hepatitis C (CHC) patients. Three hundred and thirty patients without overt diabetes were treated with combination therapy with (PEG-IFN)/ribavirin for 24 weeks. The IR and beta-cell function were evaluated by homeostasis model assessment of IR (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-beta) before treatment. HCV genotype, pretreatment HCV RNA level and pretreatment HOMA-IR, but not HOMA-beta, were independent factors associated with sustained virologic response (SVR). In 150 patients with genotype 1b infection, pretreatment HCV RNA level, HOMA-IR and age were independent predictors for SVR. The significantly lower SVR rate in high HOMA-IR patients was observed in 76 patients with high HCV RNA levels (>or=400,000IU/mL) who were defined as 'difficult-to-treat' patients. The mean HOMA-IR of 'difficult-to-treat' patients was significantly lower in 42 sustained responders than in 34 non-responders. IR was associated with SVR to (PEG-IFN)/ribavirin therapy for CHC, especially among 'difficult-to-treat' patients. These findings suggested clinical application of pretreatment HOMA-IR could enable treatment outcome to be predicted and treatment regimens to be determined.

IL-10 promoter gene polymorphisms and sustained response to combination therapy in Taiwanese chronic hepatitis C patients

Host genetic factors may affect clinical outcomes of hepatitis C virus (HCV) infection; however, the possible mechanisms remain largely unknown. The role of immunopathogenesis in chronic hepatitis C leads to extensive exploration of host immunity including inflammatory cytokines. We examined interleukin 10 (IL-10) promoter gene polymorphisms at positions -1082, -819, and -592 relative to transcription start site and studied their association with response to 24 weeks of pegylated interferon plus ribavirin treatment in 143 chronic hepatitis C patients, of whom 97 (67.8%) achieved a sustained virologic response (SVR). In addition, 134 healthy adults were used as controls. Of chronic hepatitis C patients, 111 (77.6%) were genotype 1 infection, 32 (22.4%) were genotype 2 infection. Patients with sustained virologic response were younger and had higher pretreatment ALT levels than those without. No statistical difference was found between chronic hepatitis C patients who achieved SVR or not in terms of gender, HCV genotype, pretreatment HCV RNA levels, and severity of liver disease. The serum IL-10 levels were comparable between healthy controls and chronic hepatitis C patients as well as between HCV patients with and without SVR. The distribution of IL-10 promoter gene polymorphisms at positions -1082, -819, and -592 relative to transcription start site was comparable between HCV patients and healthy controls as well as HCV patients with and without SVR. A high frequency of ATA haplotype of common IL-10 promoter gene SNPs was found in both chronic hepatitis C patients (70.3%) and healthy controls (69.8%). However, ATA haplotype was not associated with SVR in chronic hepatitis C patients. Our data fail to demonstrate the influence of IL-10 promoter gene polymorphisms on the response to combination therapy in Taiwanese chronic hepatitis C patients. The impact of genetic variations in IL-10 haplotype on the response to anti-HCV treatment among different ethnic populations deserves further examination.

Pegylated interferon 2a and 2b in combination with ribavirin for the treatment of chronic hepatitis C in HIV infected patients.

Coinfection with hepatitis C virus (HCV) and HIV is an increasingly recognized clinical dilemma, particularly since the advent of highly active antiretroviral therapy. Several studies of this population have demonstrated both more rapid progression of liver disease and poorer overall prognosis compared to HCV monoinfected patients. Consensus guidelines, based primarily on the results of 4 major randomized trials, recommend treatment with peginterferon and ribavirin for 48 weeks in coinfected patients. However, this current standard of care is associated with lower response rates to therapy than those seen in monoinfected patients. Important predictors of response include HCV genotype, pretreatment HCV RNA level, and presence of rapid virologic response (RVR) and early virologic response (EVR). Use of weight-based ribavirin dosing appears to be safe and enhances the likelihood of sustained virologic response (SVR). Adverse effects most commonly encountered are anemia and weight loss. Mitochondrial toxicity can occur in the setting of concomitant nucleoside reverse transcriptase inhibitor use, especially didanosine, abacavir, and zidovudine, and these should be discontinued before initiation of ribavirin therapy. Discontinuation of therapy should be considered in patients failing to demonstrate EVR, though ongoing trials are investigating a potential role for maintenance therapy in these patients. Peginterferon combined with weight-based ribavirin is appropriate and safe for treatment of HCV in HIV - HCV coinfected patients. This review summarizes the data supporting these recommendations.

Pegylated interferon α-2a versus standard interferon α-2a for treatment-naïve dialysis patients with chronic hepatitis C: a randomised study

Background:Chronic hepatitis C virus (HCV) infection is prevalent in dialysis patients, and standard interferon monotherapy is the current standard of care for such patients.Aim:To investigate whether pegylated interferon has a...