Complete Virological Response Research Articles

Double-Filtration Plasmapheresis plus Interferon-β for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy

Background and Aims: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment. Methods: Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-β/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-β/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed. Results: Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037). Conclusion: DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.

Toll like receptor 3 expression as a novel predictor of response to treatment in chronic hepatitis C virus patients

Purpose. This work was carried out to study the level of pretreatment hepatic expression of Toll like receptor 3 (TLR3) among chronic HCV patients, aiming to determine if there are consistent differences in gene expression, between those who show complete early virological response (cEVR) at week-12 of Pegylated-Interferon α-2a plus ribavirin treatment and others who are not responding to this combination, also if this could be used to predict treatment outcomes. Method. A total of 61 chronic hepatitis C patients were enrolled in the study. For all of them, baseline hepatitis C virus (HCV) viral load was determined and TLR3 gene expression was examined in their hepatic percutaneous needle biopsy specimens using a real time–polymerase chain reaction technique. Hepatic TLR3 was also traced using immunohistochemistry. All patients followed a 12-week regimen of Pegylated-Interferon α-2a plus ribavirin then post-treatment viral load was assayed. Results. Hepatic expression of TLR3 was significantly increased in the non-responder group as compared to those who showed complete early virological response to the used treatment regimen. Using receiver operator characteristic (ROC) curve analysis, a cutoff level of 1.5 was set for TLR3 expression to distinguish responders from non-responders to the 12-week treatment regimen used. Conclusion. In conclusion, measuring the hepatic expression of the interferon stimulated gene, TLR3 could provide a new molecular marker for pre-treatment prediction of complete early viral clearance, thus helping in patients’ selection and optimizing treatment outcomes.

Early Virological Response with Consensus Interferon and Ribavirin in HCV Genotype 3 Non-Responders and Relapsers to Pegylated Interferon Based Therapy

Purpose: Data regarding effectiveness of consensus interferon (CIFN) among HCV genotype 3 patients who failed to respond to pegylated interferon and ribavirin is scarce. The aim of this study was to assess the efficacy, safety and tolerability of CIFN and ribavirin in these patients. Methods: This ongoing open label investigators' initiated clinical study includes consecutive patients of age ≥ 18 years. All eligible patients who agreed to participate in the study are receiving CIFN 15mcg/day (INFERGEN; Three Rivers Pharmaceuticals, LLC, USA) plus ribavirin 800-1200 mg daily. If the patients have complete early virological response (EVR) at week 12, the dose of CIFN is reduced to 15 mcg thrice a week for a further 36 weeks. However, the patients are considered “non-responder” and treatment discontinued if there is a < 2 log10 reduction in HCV RNA. Patients with partial EVR will continue to receive daily CIFN plus RBV for further 12 weeks. These partial responders who will have undetectable HCV RNA at week 24 will continue to receive CIFN 15 μgm daily + ribavirin for further 24 weeks. Results: Included in this interim analysis are 46 patients; 26 (57%) were nonresponders and 20 (43%) relapsers to previous pegylated interferon and ribavirin therapy. Median age 44 years (range 25-61), males 27 (59%). The median baseline quantitative HCV PCR 424668 IU/ml (range 647-1.9 x 107). Ten patients were clinically cirrhotic Child Class A. Twenty patients underwent a liver biopsy, with majority of patients(n=9) having stage 3 fibrosis. A total of 37 patients have completed 12 weeks of treatment and 9 patients dropped out during the initial 12 weeks. Out of the 37 patients (20 non-responders, 13 relapsers), 33 (89%) achieved a complete EVR and one partial EVR. Normal values of SGPT at the end of 12 weeks were observed in 11 nonresponders and 12 relapsers. Common side effects were fever, anorexia and myalgias (78%). Absolute neutropenia (count <500) was observed in 2 patients who were given G-CSF. Five patients received erythropoetin to raise the hemoglobin. Six patients received SSRIs for mild depressive symptoms. Two patients developed portosystemic encephalopathy and were dropped out of the treatment. Conclusion: Our HCV genotype 3 patients who were non-responders and relapsers to previous treatment with pegylated interferon and ribavirin have shown a good response to Consensus Interferon plus ribavirin as reflected by the achievement of early virological response in the majority of patients. It would also be interesting to observe a sustained virological response in these patients.

Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-α and ribavirin therapy for chronic hepatitis C patients

For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy. Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined. Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR. In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.

Rapid reduction of hepatitis C virus‐Core protein in the peripheral blood improve the immunological response in chronic hepatitis C patients

The extracellular hepatitis C virus (HCV)-antigen, including HCV-Core protein, can suppress immune cells. Recently, the efficacy of double filtration plasmapheresis (DFPP) for chronic hepatitis C (CHC) was reported. However, the mechanism of efficacy of DFPP might not be only the reduction of HCV but also the effect of immune cells via direct and/or indirect mechanisms. The aim of this study is to analyze the virological and immunological parameters of difficult-to-treat HCV patients treated with DFPP combined with Peg-interferon and RBV (DFPP/Peg-IFN/RBV) therapy. Twelve CHC patients were enrolled and treated with DFPP/Peg-IFN/RBV therapy. The immunological, virological and genetic parameters were studied. All patients (4/4) treated with the major IL28B allele (T/T) could achieve complete early virological response (EVR). The amounts of HCV-Core antigen in the peripheral blood of EVR patients treated with DFPP/Peg-IFN/RBV rapidly declined in comparison to those of late virological response (LVR) patients treated with DFPP/Peg-IFN/RBV and EVR patients treated with Peg-IFN and RBV (Peg-IFN/RBV). The amount of IFN-γ produced from peripheral blood gradually increased. On the other hand, the amount of IL10 gradually decreased in the EVR patients. The frequencies of HCV-Core binding on CD3+ T cells rapidly declined in EVR patients treated with DFPP/Peg-IFN/RBV therapy. Moreover, the distributions of activated CD4(+) and CD8(+) T cells and CD16-CD56 high natural killer cells were significantly changed between before and after DFPP. The rapid reduction of HCV-Core antigens and changes in the distribution of lymphoid cells could contribute to the favorable immunological response during DFPP/Peg-IFN/RBV therapy.

Occult HCV or delayed viral clearance from lymphocytes of Chronic HCV genotype 3 patients after interferon therapy

BackgroundA recently discovered occult HCV entity reported by various investigators seems to be highly controversial. Especially, the clinical significance of these findings remains uncertain. For optimal outcome of antiviral therapy, investigation of occult HCV needs a broad-based probe in order to investigate the results of viral therapy and its host/viral interaction. The current study was aimed at determining the prevalence of occult HCV in peripheral blood lymphocytes of predominantly genotype 3 HCV-infected patients after completion of antiviral therapy and to investigate long term outcomes in the presence or absence of PBMC positivity.MethodA total of 151 chronic, antiHCV and serum RNA-positive patients were enrolled in the study. Patients with a complete virological response at the end of treatment were screened for the presence of viral RNA in their PBMCs and were followed for up to one year for the presence of serum and PBMC viral genomic RNA.ResultsOut of 151 patients, 104 (70%) responded to the prescribed interferon treatment and showed viral-clearance from serum. These were screened for the presence of genomic RNA in their PBMCs. Sixteen samples were PBMC-positive for viral RNA at the end of treatment (EOT). All these patients had also cleared the virus from peripheral blood cells after the 6-12 month follow-up study.ConclusionTrue occult hepatitis C virus does not exist in our cohort. Residual viremia at the EOT stage merely reflects a difference in viral kinetics in various compartments that remains a target of immune response even after the end of antiviral therapy and is eventually cleared out at the sustained viral response (SVR).

P67 Switch to other nucleos(t)ide analogues therapy in chronic hepatitis B cohort on long-term de-novo combination therapy with lamivudine plus adefovir: efficacy and safety

IntroductionLong-term de-novo combination therapy with lamivudine (LAM) 100 mg/d + adefovir (ADV) 10 mg/d is highly efficient, with no/minimal drug resistance and good safety profile. Tenofovir (TDF) 245 mg/d or...

Complete Early Virological Response Was Highly Achieved by Double Filtration Plasmapheresis Plus IFN‐Beta Induction Therapy for HCV‐1b Patients With Relapse or No Response After Previous IFN Therapy

The efficacy of double filtration plasmapheresis (DFPP) plus interferon (IFN)-β induction therapy was preliminarily investigated in re-treated patients with chronic genotype 1b hepatitis C and high viral load (patients with relapse or non-response to previous IFN therapies). In eight patients with chronic hepatitis C, DFPP was performed five times over 2 weeks during IFN-β therapy, and 3 MU of IFN-β was administered twice a day for 2 weeks. Combination therapies with ribavirin and pegylated IFN-α2b (PEG-IFN-α2b) or pegylated IFN-α2a (PEG-IFN-α2a) were subsequently used. After 4 weeks, hepatitis C virus (HCV)-RNA tended to be more greatly decreased with DFPP combination therapy than with previous IFN therapy (4.5 ± 2.0 log(10) IU/mL vs. 2.9 ± 1.2 log(10) IU/mL). Rates of both rapid virological response and complete early virological response were significantly higher with DFPP and IFN-β induction therapy than with previous IFN therapy. DFPP plus IFN-β induction therapy produced a great reduction of viral load during the early stage of treatment and achieved a high early virological response, suggesting that this combination therapy may be useful as a new treatment modality for chronic hepatitis C patients in difficult-to-treat states. This combination may contribute to sustained virological response (SVR). The effects of DFPP on SVR and its significance remain to be clarified.

Ribavirin Priming Improves the Virological Response to Antiviral Treatment in Transplanted Patients with Recurrent Hepatitis C: A Pilot Study

Patients with hepatitis C recurrence after liver transplantation represent a clinical challenge. Antiviral treatment in transplant patients has usually poor tolerability and limited efficacy, with a mean sustained virological response (SVR) of 30%. Our pilot study was aimed at evaluating whether 8-week ribavirin pre-treatment could increase either adherence or antiviral effect of a 48-week combination therapy. Ribavirin pre-treatment (8 weeks) was started with 600 mg daily and increased to 10.4 mg/kg/day. After pre-treatment, 1.5 μg/kg/week pegylated interferon-α2b was added for 48 additional weeks of combination therapy. Blood count, liver function tests and plasma HCV-RNA were examined monthly. Ribavirin plasma concentrations were determined by HPLC. Thirteen patients (mean age 53±2 years, 11 males) were treated: eight were HCV genotype 1/4; five were genotype 2/3. The median baseline HCV RNA level was 6.5 log(10) (range 5.84-7.42 log(10)). During ribavirin pre-treatment the median HCV RNA levels decreased significantly (5.7 log(10) ; P=0.023). During combination therapy 6/13 (46%) patients exhibited a rapid virological response (RVR) and 10/13 (77%) patients a complete early virological response, two were non-responders. A decline of 0.5 log(10) HCV RNA during pre-treatment predicted RVR. SVR occurred in six patients (46%): four were genotype 2/3. Stable ribavirin dose reduction was required in only two patients (15%) in whom transient interferon reduction was also required. This proof-of-concept study indicates that ribavirin pre-treatment increased the tolerability of the antiviral treatment, and improved its efficacy in liver transplant patients. Moreover, the degree of HCV RNA decline during pre-treatment allowed one to predict on-treatment response.

Fibrosing Cholestatic Hepatitis in HIV/HCV Co-Infected Transplant Patients—Usefulness of Early Markers After Liver Transplantation

We characterized fibrosing cholestatic hepatitis (FCH) in a large cohort of HIV/HCV co-infected patients. Between 1999 and 2008, 59 HIV infected patients were transplanted for end-stage liver disease due to HCV. Eleven patients (19%) developed FCH within a mean period of 7 months [2-27] after liver transplantation (LT). At Week 1 post-LT, the mean HCV viral load was higher in the FCH group: 6.13 log(10) IU/mL ± 1.30 versus 4.9 log(10) IU/mL ± 1.78 in the non-FCH group, p = 0.05. At the onset of acute hepatitis after LT, activity was moderate to severe in 8/11 HIV+/HCV+ patients with FCH (73%) versus 13/28 (46%) HIV+/HCV+ non-FCH (p = 0.007) patients. A complete virological response to anti-HCV therapy was observed in 2/11 (18%) patients. Survival differed significantly between the two groups (at 3 years, 67% in non-FCH patients versus 15% in FCH patients, p = 0.004). An early diagnosis of FCH may be suggested by the presence of marked disease activity when acute hepatitis is diagnosed and when a high viral load is present. The initiation of anti-HCV therapy should be considered at this point.

Multi-center evaluation of the Abbott RealTime HCV Assay for monitoring patients undergoing antiviral therapy for chronic hepatitis C

Background Hepatitis C virus (HCV) RNA monitoring during antiviral therapy is essential for early prediction of treatment success and failure to peginterferon alfa/ribavirin (PEG-IFN/RBV) therapy. Objectives In this multi-center study we assessed the clinical utility of the Abbott RealTime HCV assay for monitoring patients undergoing antiviral therapy for chronic infection with HCV genotypes (GT) 1–3. Study design We analyzed serum from 361 patients with chronic hepatitis C who had been treated with PEG-IFN/RBV. The predictive value of rapid virologic response (RVR), partial (≥2 log 10 decline) and complete (HCV-RNA undetectable) early virologic response (pEVR/cEVR) based on RealTime HCV for achieving sustained virologic response was evaluated. In addition, the utility of RealTime HCV to tailor treatment duration according to individual virologic responses was studied in a subset of 136 GT 1 patients and compared to the reference tests, Versant HCV Quantitative 3.0 (bDNA) and Qualitative (TMA) assay. Results At week 4 of therapy, patients with RVR had a 100% and 93.5% probability to achieve an SVR in GT 1 and GT 2/3 patients, respectively. At week 12, patients who did not achieve a pEVR had a 97.2% and 100% probability of not achieving an SVR. In addition, assignment of GT 1 patients to abbreviated or extended treatment durations based on low baseline HCV-RNA (<800,000 IU/mL) and RVR or pEVR was highly concordant between RealTime HCV and bDNA/TMA assays (97.8% and 91.9%, respectively). Conclusions The RealTime HCV assay is suitable for monitoring virologic response to PEG-INF/RBV therapy and tailoring treatment duration accordingly.

OL-008 The Diagnostic and prognostic significance of intrahepatic transforming growth factor-β1, angiotensin converting enzyme-2, alpha smooth muscle actin and endoglin in liver fibrosis associated chronic HCV infection

Results: 43.9% of patients achieved a rapid virological response (RVR) and 69.1% of patients had a complete early virological response (cEVR). The serum alanine aminotransferase (ALT) normalization rates were 70.9% and 86.2% at week 4 and 12. Analyzing IL-28B variation (rs12979860), more proportions of patients with the CC genotype (46.7% or 75.3%) achieved a RVR or a cEVR respectively, compared to patients with the CT/TT genotypes (23.8% or 35.3%). However, in a multivariable logistic regression model, the IL-28B genotype was not shown statistically to be a predictive value for RVR or cEVR. Baseline predictive factors for RVR included the serum HCV RNA <4×105 IU/mL (OR: 0.16) and gender (in females, OR: 0.39). The HCV genotype was only a predictive factor for cEVR (2a vs 1b, OR: 8.80). The treatments for 28 patients were discontinued due to adverse events such as anaemia and fatigue. Conclusion: The recombinant IFNa-2b therapy demonstrated a potent anti-virus effect and a significant biochemical improvement. It has good tolerance and safety profiles. The serum HCV RNA, gender and the HCV genotype were identified as valuable predictors for patients who responded to IFN/RBV treatments in the present study.

Perfiles de expresión génica en las primeras doce semanas de tratamiento en pacientes con hepatitis C crónica

Gene expression profiling in the first weeks of treatment of patients with chronic hepatitis C may contribute to better evaluate the response to interferon-based therapy. The objective of this study was to evaluate the gene expression profiles of early responders and non-responders before, and after 12 weeks of treatment with peginterferon alfa and ribavirin. Gene expression profiles were analysed in 12 patients with chronic hepatitis C, and scheduled for treatment with peginterferon alpha and ribavirin. Of the 12 patients studied, six showed a complete early virological response, while six failed to control viremia. In early responders, treatment with peginterferon and ribavirin induced an increased expression of a larger number of interferon-induced genes (ISG15, IFI6, IFI44L, IFI27, MX1, OASL, IRF7, IFIT3, IFITM1, EIF2AK2, HERC5 and APOBEC3) than in non-responders (ISG15, IFI44L, IFI27, IRF7, USP18) in the first twelve weeks of treatment (P<0.05). In both groups, there were changes in the levels of certain genes poorly described in the treatment of hepatitis C so far. The gene expression profiles described in this study provide a new insight to understanding the pathogenesis of the disease and treatment effect. The more marked effect of the treatment on the expression of interferon-response genes observed in early responders could explain their better control of viral load.

Adefovir serum levels do not differ between responders and nonresponders

Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well-defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14-59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2-8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus-DNA >10,000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.

A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B

Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy. Treatment-naïve CHB patients who received 30mg of clevudine or 0.5mg of entecavir a day were analyzed. Mean reduction of hepatitis B virus (HBV) DNA levels, complete virological response (cVR, undetectable HBV DNA by real-time PCR), biochemical response (recovery to normal ALT level), and hepatitis B e antigen (HBeAg) seroconversion rate at the 48th week of treatment were assessed. A number of 59 patients in clevudine group and 61 patients in entecavir group were included. Mean HBV DNA reductions from baseline were similar in the clevudine and entecavir groups, -6.4 versus -6.8 log(10) copies/mL in HBeAg-positive (p=0.417) and -6.9 versus -7.0 log(10) copies/mL in HBeAg-negative patients (p=0.640). The proportion of patients who achieved cVR was not different between the two groups, 53 versus 55% in HBeAg-positive (p=1.000) and 100 versus 95% in HBeAg-negative patients (p=0.452). Biochemical response rates and HBeAg seroconversion rates were also similar in both the groups. Two (3.4%) patients in clevudine group showed virologic breakthrough with rtM204I mutation using direct sequencing analysis. Clinical myopathy occurred in two (3.4%) patients in clevudine group. Mean reduction of viral loads was similar between clevudine and entecavir groups during 48weeks. However, virologic breakthrough and significant myopathy were noted only in clevudine-treated patients. Therefore, more attention should be paid to patients receiving clevudine.

Virological response to adefovir monotherapy and the risk of adefovir resistance

To evaluate virological response to adefovir (ADV) monotherapy and emergence of ADV-resistant mutations in lamivudine (LAM)-resistant chronic hepatitis B patients. Seventy-seven patients with documented LAM resistance who were treated with 10 mg/d ADV for > 96 wk were analyzed for ADV resistance. At week 48 and 96, eight (10%) and 14 (18%) of 77 LAM-resistant patients developed the ADV-resistant strain (rtA181V/T and/or rtN236T mutations), respectively. Hepatitis B virus (HBV) DNA levels during therapy were significantly higher in patients who developed ADV resistance than in those who did not. Incidence of ADV resistance at week 96 was 11%, 8% and 6% among patients with complete virological response (HBV DNA level < 60 IU/mL); 0%, 5% and 19% among patients with partial virological response (HBV DNA level ≥ 60 to 2000 IU/mL); and 32%, 34% and 33% among patients with inadequate virological response (HBV DNA levels > 2000 IU/mL) at week 12, week 24 and week 48, respectively. HBV DNA levels > 2000 IU/mL at week 24 showed best performance characteristics in predicting ADV resistance. Development of ADV resistance mutations was associated with HBV DNA levels, which could identify patients with LAM resistance who are likely to respond to ADV monotherapy.

Association between the influential factors and the effectiveness of pegylated interferon alpha-2a plus ribavirin as a combination treatment for chronic hepatitis C patients

To evaluate the efficacy and to investigate the association between the length of the treatment period and the cumulative dose of pegylated interferon alpha-2a (PegIFN alpha-2a) plus ribavirin (RBV) and the effectiveness of antiviral therapy. We analyzed data from 117 patients treated for 48 weeks with PEG-IFN alpha-2a (135mug or 180mug/week) plus weight-based RBV (800 mg/d for patients is less than or equal to 65 kg, 1000 mg/d for patients 65-75 kg and 1200 mg/d for patients is more than or equal to 75 kg) under care at West China Hospital. HCV RNA was assessed at baseline, Week 4, 12 and 24, the end of treatment (EOT) and after 24 weeks follow-up (sustained virological response; SVR) with a test range of 1.0*10(3) to 5.0*10(7) IU/ml. Patients were stratified by age, gender, weight, route of transmission, duration of infection, baseline HCV RNA level and PegIFN alpha-2a or RBV dosage. HCV genotype was assessed in 29 patients (genotype 1b, 21; genotype 2a, 7; genotype 1b/2a, 1). Rapid virological response (RVR; HCV RNA negative at week 4), complete early virological response (cEVR; HCV RNA negative at week 12), EOT response, and SVR were achieved in 88 (75.2%), 110 (94%), 114 (97.4%) and 96 (82.1%) patients, respectively. Younger age, lower weight and shorter speculated infection years were associated with higher SVR rates (91.4% vs 72.9%, x2=6.796, P value is less than 0.05; 85% vs 50%, x2=5.433, P value is less than 0.05; 96.7% vs 77%, x2=5.852, P value is less than 0.05). SVR significantly increased with treatment length (38.5%, 66.7%, and 88.8% for is less than or equal to 29 weeks, 29-38 weeks, and is more than or equal to 38 weeks, respectively). SVR significantly increased with total cumulative treatment doses (38.5%, 66.7% and 88.8% for is less than or equal to 60%, 60%-80% and is more than or equal to 80% of PegIFN dose respectively; 33.3%, 85.3% and 96.8% for is less than or equal to 60%, 60%-80% and is more than or equal to 80% in RBV dose respectively) in all patients. Less than 80% of standard dose of RBV was not sufficient even if given enough PegIFN (is more than or equal to 80% cumulative treatment dose) in patients who achieved RVR. Chinese patients treated with peginterferon alpha-2a plus ribavirin have high rates of SVR. It is important to complete the target length of treatment and to continue the target dosage to achieve SVR.

Outcome of Treatment With Pegylated Interferon and Ribavirin in Heart Transplant Recipients With Chronic Hepatitis C

Background/aim The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC. Methods From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies. Results All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score ≥ 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction. Conclusions Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.

Prognostic Models to Predict Survival In Indolent and Aggressive Non-Hodgkin's Lymphomas Associated with Hepatitis C Virus Infection: a Multicenter Italian Study on 1,043 Patients.

AbstractAbstract 2821Epidemiological studies demonstrated that HCV is associated with B-cell NHL. A precise prognostication of HCV+ NHL is not available; in particular, the impact of liver toxicity on the outcome of pts treated with (immuno)-chemotherapy is not fully clarified. Aim of the present study was to analyse clinical and virological characteristics, toxicity and prognosis of a large series of indolent and aggressive HCV+ NHL. We studied 1,043 pts with HCV+ NHL diagnosed and treated from January 1993 to December 2009 in 15 italian hematologic institutions; 539 cases were aggressive NHL (522 DLBCL) and 504 indolent NHL (265 MZL). All pts were HIV negative, 3% carried HBsAg and 91% were HCV-RNA+. Thirteen out of 56 HCV-RNA negative pts cleared HCV by means of antiviral therapy before NHL diagnosis. An (immuno)-chemotherapy regimen was administered as first-line treatment in 859 pts: 537 received CHOP-like regimen (+ Rituximab 243), 66 III generation regimen, 174 alkylators, 30 purine analogues, 31 other regimens, 21 R alone. Doses of chemotherapy since first cycle were reduced in 31% of pts. A watch-and-wait policy was adopted in 82 pts, other treatments in 68 pts and anti-HCV antiviral therapy in 34 pts with indolent NHL (12 of whom obtained both a complete virologic and hematologic response). Hepatic toxicity was evaluable in 597 patients: among 347 pts with normal ALT at NHL diagnosis, 52 (15%) developed WHO hepatic toxicity ≥ grade 2; among 250 pts (42%) with abnormal ALT, 26 (11%) experienced ALT increase >3.5 times baseline value. Overall, a significant liver toxicity developed in 78 pts (13%) (15% of aggressive NHL and 10% of indolent NHL). Use of Rituximab was not associated with significant liver toxicity (p=0.4); particularly, in DLBCL, R-CHOP and CHOP showed the same rate of significant hepatic toxicity (15%, p=ns), although maximum grade of liver toxicity was registered earlier in patients treated with R-CHOP than in those treated with CHOP (before 3rd cycle respectively in 57% vs 41%, p=0.006). Planned treatment was not completed in 134 pts (29 for liver toxicity). After a median F-UP of 2.6 years, 321 pts died (24 for liver failure). 5-yrs OS was 76% for indolent NHL and 62% for DLBCL. In indolent NHL, the parameters associated with a shorter OS in univariate analysis were: elevated LDH (p<0.001), ECOG ≥2 (p<0.001), AA stage III-IV (p=0.04), age > 60 yrs (p<0.001), B symptoms (p<0.001), serum albumin <3.5 g/dl (p<0.001), Child score (p=0.003), HCV-RNA >106 UI/ml (p<0.02), no antiviral therapy at any time (p<0.001). According to a forward stepwise multivariate Cox regression analysis on OS the following parameters retained statistical significance: ECOG ≥2 (HR 2.82, p=0.005), age > 60 yrs (HR 2.11, p=0.02), AA stage III-IV (HR 2.0, p=0.04), no antiviral therapy at any time (HR 2.56, p=0.01). In DLBCL, the parameters associated with a shorter OS in univariate analysis were: elevated LDH (p<0.001), ECOG ≥2 (p<0.001), AA stage III-IV (p<0.001), age > 60 yrs (p=0.003), liver involvement by lymphoma (p=0.02), B symptoms (p<0.001), serum albumin <3.5 g/dl (p<0.001), INR >1.7 (p=0.01), Child score (p<0.001), HCV-RNA >106 UI/ml (p<0.001), HBsAg+ (p=0.01), HAI grade >9 and/or fibrosis stage >2 at liver biopsy (p=0.03). Moreover IPI, aaIPI and R-IPI were predictive for OS (p<0.001). According to a forward stepwise multivariate Cox regression analysis on OS the following parameters retained statistical significance: ECOG ≥2 (HR 3.12, p=0.001), HCV-RNA >106 UI/ml (HR 3.59, p=0.001), serum albumin <3.5 g/dl (HR 2.53, p=0.01), while other IPI factors (age, AA stage, LDH, extranodal sites) were excluded from the final model. We combined the 3 factors significantly associated to a worse OS (ECOG, albumin, HCV-RNA load) in a new HCV Prognostic Score (HPS) able to discriminate 3 categories of risk (low=0; intermediate=1; high risk ≥2 factors) (p<0.001) (Fig. 1). After adjusting by IPI in multivariate Cox regression analysis, the HPS retained prognostic effect (p<0.001), while IPI itself did not. In conclusion, a significant proportion of pts with HCV+ NHL, when treated with conventional (immuno)-chemotherapy, develops severe liver toxicity. In indolent NHL, employment of antiviral therapy at any time during lymphoma history ameliorates OS. In HCV+ DLBCL, addition of rituximab to CHOP scheme does not increase hepatic toxicity; moreover, the new score HPS performs better than IPI in discriminating different risk categories. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001

Adenovirus infection is a serious and often fatal complication in hematopoietic stem cell transplant patients. There are currently no FDA-approved therapies for adenovirus infection, with only anecdotal, off-label uses described for a variety of anti-viral agents or immune therapies. We report the first case of successful eradication of disseminated adenovirus infection by the novel antiviral agent CMX001 in a severely immunocompromised pediatric stem cell transplant recipient following failure to respond to intravenous cidofovir. Complete clinical and virologic response was documented; virologic and pharmacokinetic data are reported. CMX001 is a promising new oral antiviral agent under development for the prophylaxis and treatment of severe infections caused by double-stranded DNA viruses including adenovirus in immunocompromised patients.