Interferon-a plus lamivudine vslamivudine reduces breakthroughs, but does not affect sustained response in HBeAg negative chronic hepatitis B

AIM: To investigate the efficacy of combination treatment of IFN-α and lamivudine compared to lamivudine monotherapy, after 24 mo of administration in HBeAgnegative hepatitis B patients. METHODS: Fifty consecutive patients were randomly assigned to receive IFN-α-2b (5MU thrice per week, n=24) plus lamivudine (100mg daily) or lamivudine only (n=26) for 24 mo. Patients were followed up for further 6 mo. The primary outcome was the proportion with sustained virological response (undetectable serum HBV DNA concentrations) and or sustained biochemical response (transaminase levels within normal range) at 30 mo (6 mo after the end of therapy). Secondary end-points were timed from initial virological (biochemical) response to VBR (BBR, respectively) and the emergence of YMDD mutants across the two arms. RESULTS: Five of twenty-four (21%) patients in the combination arm vs 3/26 (12%) in the lamivudine arm had sustained response (i.e., normal serum transaminase levels and undetectable HBV DNA by PCR assay) 6 mo after treatment discontinuation. A reduction in the emergence of YMDD mutants and in the development of virological breakthroughs was observed in patients receiving combination treatment (10% vs 46%, P=0.01 and 14% vs 46%, P=0.03, respectively). Time from initial virologic response to virologic breakthrough (VBR) was greater among initial responders receiving combination treatment compared to those receiving lamivudine (22.9 mo vs 15.9 mo, respectively; P=0.005). CONCLUSION: Our results demonstrate that IFN-α plus lamivudine combination therapy does not increase the sustained response, compared to lamivudine. However, combination therapy reduces the likelihood of VBR due to YMDD mutants and prolongs the time period until the breakthrough development.     

Treatment of genotype 2 and 3 chronic hepatitis C virus-infected patients

AIM: Before pegylated interferon alpha (IFN) was introduced for the therapy of chronic hepatitis C virus (HCV)-induced hepatitis, conventional thrice weekly IFN therapy was supplemented by ribavirin. Also, at that time, higher and more frequent doses of IFN were expected to be more effective than the standard regimen of 3 MU thrice weekly. As ribavirin significantly increases side effects and negatively influences the quality of life particularly in young patients, we started a prospective non-randomized study with a daily IFN-2a monotherapy as an initial treatment for chronic hepatitis C. METHODS: Forty-six consecutive chronic HCV-infected patients received 3 MU IFN-2a per day as an initial treatment. Patients with genotype 2 or 3 (n = 12) were treated for 24 wk, and patients with genotypes other than 2 or 3 (n = 34) for 48 wk. Treatment outcome was followed up for 48 wk after the end of treatment (EOT). Virological response was defined as the absence of detectable serum HCV-RNA. Patients without virological response at 12 wk after the start of treatment received low-dose ribavirin (10 mg(kg·d)) additionally. RESULTS: During treatment, three genotype 3 patients were excluded from the study due to incompliance. The remaining patients (n = 9) infected with genotype 2 or 3 showed an initial virological response rate of 100%. Six patients (66.7%) were still found to be virus-free at the end of follow-up period. In these patients, initial virological response was evident already after 2 wk of treatment. In contrast, initial virological response occurred first after 4 wk of treatment in the three patients who relapsed (33.3%). In comparison, patients infected with genotypes other than 2 or 3 (n = 34) showed an initial virological response rate of only 23.5% (n = 8), and even in combination with ribavirin a sustained virological response (SVR) rate of only 11.8% (n = 4) could be achieved. CONCLUSION: In chronic HCV-infected patients with genotype 2 or 3, a SVR can be expected after 24 wk of daily dose IFN-2a treatment without ribavirin, if initial virological response develops early. This finding is worth to be confirmed in a prospective randomized study with pegylated IFN.     

Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B

AIM: To study the sequential changes of serum ferritin levels in lamivudine-treated patients with chronic viral hepatitis B and the clinical implications. METHODS: Thirty-eight patients with chronic viral hepatitis B were prospectively studied during their treatment with lamivudine. Each patient received 100 mg oral lamivudine daily for 12 mo, and was observed and tested for blood biochemistry and hepatitis B virus (HBV) DNA levels and serum ferritin levels at baseline and at 3, 6 and 12 mo during the treatment. Serum HBV DNA levels were quantitatively determined using fluorescent quantitative polymerase chain reaction (FQ-PCR), and serum ferritin levels were measured by radioimmunoassay. The sequential changes of serum ferdtin levels and their relationships with virological, serological and biochemical responses in the patients were analyzed. RESULTS: All the patients had a baseline HBV DNA level higher than 1×10^7 copies/L as determined by FQ-PCR and positive HBsAg and HBeAg and abnormal ALT levels. At the end of the 12-mo treatment, 19 of the 38(50.00%) patients had undetectable serum HBV DNA levels by FQ-PCR, and 12(31.58%) became negative for serum HSeAg and 10(26.32%) had seroconversion from HBeAg to HBeAb. Nineteen out of the 38(50.00%) patients had biochemically normal ALT levels after 12-mo lamivudine treatment. Sequential determination showed bhat lamivudine treatment significantly reduced ferritin levels in chronic hepatitis B patients. When the patients were divided into different groups according to their posttreatment virological, serological and biochemical responses for analysis of the sequential changes of ferritin levels, it was found bhat the decrease of ferritin levels in HBV DNA-negative group was significantly more obvious than that in HBV DNApositive group at 6 mo during the treatment (P=-0.013). Consecutive comparisons showed that ferritin levels at 3 mo of treatment were obviously decreased as compared with the baseline levels (P<0.05) in HBeAg-negative group, and the decrease of serum ferritin levels in patients with normalized ALT was more significant than that in patients with abnormal ALT at the end of the 12-mo treatment (P=0.048). CONCLUSION: Lamivudine treatment can reduce the serum ferritin levels in chronic viral hepatitis B patients and decreases of ferdtin levels can be more significant in patients exhibiting virological, serological and biochemical responses, indicating that dynamic observation of serum ferritin levels in patients with chronic viral hepatitis B during lamivudine treatment might be helpful for monitoring and predicting patients‘ responses to the therapy.     

IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection

AIM To investigate the association between interferoninduced protein with tetratricopeptide repeats 1(IFIT1) polymorphisms and interferon-α(IFNα) treatment efficiency among Chinese hepatitis B virus(HBV) infection patients.METHODS Two hundred and twenty five newly diagnosed chronichepatitis B(CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen(HBe Ag) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms(SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.RESULTS At the end of the treatment, HBe Ag seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218(A G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64(95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response(response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype(response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBe Ag seroconversion, combined response or sustained response was observed.CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.     

Pegylated-interferon alpha 2a treatment for chronic hepatitis C in patients on chronic haemodialysis

AIM: To evaluate the response to pegylated-interferon alpha 2a in chronic hepatitis C patients on chronic haemodialysis. METHODS: Ten patients with chronic C hepatitis were enrolled in this study. All had increased aminotransferases for more than 6 mo, positive antiHCV antibodies and positive PCR HCV-RNA. We administrated Peg-Interferon alpha 2a 180μg/wk for 48 wk. After 12 wk of treatment we evaluated the biochemical and early virological response (EVR). At the end of the treatment we evaluated the biochemical response and 24 wk after the end of the treatment we evaluated the sustained virological response (SVR). We monitored the side-effects during the treatment. RESULTS: Two patients dropped out in the first 12 wk of treatment and 2 after the first 12 wk of treatment. After 12 wk of treatment, 7 out of 8 patients had biochemical response and EVR and 1 had biochemical response but persistent viremia. We had to reduce the dose of pegylated-interferon to 135μg/wk in 2 cases. Three out of 6 (50%) patients had SVR 24 wk after the end of the treatment. Intention-to-treat analysis showed that 3 out of 10 patients (30%) had SVR. Side-effects occurred in most of the patients (flu-like syndrome, thrombocytopenia or leucopoenia), but they did not impose the discontinuation of treatment. CONCLUSION: After 12 wk of treatment with Peg-Interferon alpha 2a (40 ku) in patients on chronic haemodialysis with chronic C hepatitis, EVR was obtained in 87.5% (7/8) of the cases. SVR was achieved in 50% of the cases (3/6 patients) that finished the 48 wk of treatment.     

Long-term lamivudine treatment for chronic hepatitis B in Japanese patients： A project of Kyushu University Liver Disease Study

AIM:To determine the efficacy of long-term lamivudinetreatment of a large number of Japanese patients withchronic hepatitis B.METHODS:In this retrospective,multi-center trial,318 Japanese patients with chronic hepatitis B received100 mg of lamivudine daily for up to 36(median 21)mo.Virological response was a decline to a serumHBV DNA level less than 3.7 log copies/mL.Virological breakthrough was defined as the reappearance of aserum HBV DNA level to more than 10-fold the minimumduring treatment.RESULTS:Lamivudine produced virological responsein 86.8% of the 318 patients at 6 mo,in 80.2% of252 patients at 12 mo,in 69.2% of 133 patients at 24mo,and in 53.6% of 28 patients at 36 mo.Forwardstepwise logistic regression analysis showed an HBV DNAlevel less than 6.8 log copies/mL(P<0.0001),HBeAgnegativity(P<0.0001),a platelet count of 100×10~9/L ormore(P=0.0162)at baseline,and a decline of the HBVDNA level of more than 3.2 log copies/mL as comparedwith the baseline level at 3 mo after the start oftreatment(P=0.0003)to be significantly associated withvirological response.Among patients with a virologicalresponse,virological breakthrough was seen in 5.3%of 19 patients who responded virologically at 1 mo,in20.7% of 203 patients at 3 mo,in 27.5% of 51 patientsat 6 mo,in 33.3% of 12 patients at 9 mo,and in 100%of 3 patients at≥15 mo.A virological breakthrough wasfound significantly more often in patients with delayedvirological response.CONCLUSION:Lamivudine treatment could suppressserum HBV DNA in most of the tested Japanese patients.Long-term efficacy might be seen in patients withoutHBeAg at baseline,in the absence of cirrhosis,and inpatients with a decline in HBV DNA level soon after thestart of treatment.     

Ribavirin monotherapy increases sustained response rate in relapsers of end treatment virologic responders

AIM: To assess the efficacy of ribavirin monotherapy in patients with biochemical relapse after combination therapy. METHODS: Twenty-four weeks of ribavirin monotherapy was given to biochemical relapsers of end treatment biochemical responders within 6 mo after combination therapy, including non-responders with HCV-RNA level ≤0.2 Meq/mL and end treatment virologic responders (ETVRs) with or without reappearance of HCV-RNA. RESULTS: Sixty-two chronic HCV-infected patients completed 24 wk of interferon-α plus ribavirin combination therapy. Fifty patients (80%) achieved end treatment biochemical response including 16 non-responders and 34 of 36 ETVRs. Twenty-six patients (41.9%) were non-responders. Ribavirin monotherapy was given to 20 biochemical relapsers including 12 non-responders with HCV-RNA levels ≤0.2 Meq/mL, four of eight HCV-RNA reappearing ETVRs, and four HCV-RNA negative ETVRs. After 24 wk of ribavirin monotherapy, one of 12 non-responders, two of four HCV-RNA reappearing ETVRs and all four RNA-negative biochemical relapsers of ETVRs showed sustained virologic response. Two of 12 monotherapy treated non-responders showed persistent normalization of liver function test. In total, 50% (31/62) of patients achieved sustained virologic response. CONCLUSION: Resumption of ribavirin monotherapy in ETVRs at signs of viral rebound and recurrent biochemical abnormalities rather than continuation of monotherapy appears to be the key to success of ribavirin monotherapy after interferon-related combination therapy.     

Mutations in carboxy-terminal part of E2 including PKR/eIF2αphosphorylation homology domain and interferon sensitivity determining region of nonstructural 5A of hepatitis C virus 1b:Their correlation with response to interferon monotherapy and viral load

AIM: To study the amino acid substitutions in the carboxy (C)-terminal part of E2 protein and in the interferon (IFN) sensitivity determining region (ISDR) and their correlation with response to IFN and viral load in 85 hepatitis C virus (HCV)-lb-infected patients treated with IFN. METHODS: The C-terminal part of E2 (codons 617-711) including PKR/eIF2a phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-1b-infected patients treated by IFN monotherapy. RESULTS: The amino acid substitutions in PePHD detected only in 4 of 85 patients were not correlated either with response to IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C-terminal part of E2 was significantly correlated with both small viral load (33.9% vs 13.8%, P = 0.0394) and sustained response to IFN (25.0% vs 6.9 %, P = 0.0429). Four or more substitutions in ISDR were significantly correlated with both small viral load (78.6% vs 16.2%, P < 0.0001) and sustained response to IFN (85.7% vs 2.9%, P < 0.0001). In multivariate analysis, ISDR in nonstructural (NS) 5A (OR = 0.39, P < 0.0001) and N-terminal variable region (OR = 0.51, P = 0.039) was selected as the independent predictors for small viral load, and ISDR (OR = 39.0, P < 0.0001) was selected as the only independent predictor for sustained response. CONCLUSION: The N-terminal variable region in the C-terminal part of E2 correlates with both response to IFN monotherapy and viral load and is one of the factors independently associated with a small viral load.     

Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection

AIM:To evaluate the efficacy and tolerability of lowdose standard or pegylated interferon(PEG-IFN)in hepatitis C virus(HCV)-positive hemodialysis patients.METHODS:In total,19 patients were enrolled in this study,of which 12 received PEG-IFNα-2a 67.5μg 1time/wk(Group 1)and 7 received standard interferonα-2b subcutaneously 1.5×106 U 3 times/wk(Group2).The treatment durations were 48 wk for patients infected with HCV genotype 1 and 24 wk for patients infected with HCV genotype 2/3.All patients were prospectively followed after the completion of therapy.The efficacy and tolerability of the treatment were evaluated based on the sustained virological response(SVR)and treatment-related drop-out rate.RESULTS:In Group 1,11 of the 12 patients completed the treatment.Early virological response(EVR)and sustained virological response(SVR)rates were 83.3%and 91.7%,respectively.One patient withdrew from treatment due to an adverse event(leukopenia).The drop-out rate was 8.3%in this group.In Group 2,5 of the 7 patients completed the treatment with an EVR and SVR of 85.7%and 71.4%,respectively.Two patients withdrew due to treatment-related adverse events(nausea and depression).In this group,the drop-out rate was 28.6%.In total,16 of the patients attained EVR,and 15 of them completed the treatment.The SVR rate for the patients who attained EVR was93.7%.Anemia was the most frequent side effect and was observed in 10/19 patients(55.5%),but could be effectively managed with erythropoietin.CONCLUSION:Low-dose interferon monotherapy,either with PEG-IFNα-2a or standard interferonα-2b,is an effective treatment option for hemodialysis patients with chronic hepatitis C.     

An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation

AIM: To evaluate the efflicacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT).METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 flibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability.RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatmentresponse and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not signif icant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased.CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological responseguided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias.     

Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis

Interferon(IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma(HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus(HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer.Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated(PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.     

HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin

AIM:To analyze hepatitis C virus(HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α(IFN-α)plus ribavirin and CIGB-230.METHODS:CIGB-230 was administered in different schedules with respect to IFN-αplus ribavirin therapy.Paired serum and peripheral blood mononuclear cells(PBMC)samples from baseline and end of treatment were analyzed.The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay,neutralizing antibodies were evaluated by cell culture HCV neutralization assays,PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γsecretion was assessed by enzyme-linked immunospot.Data on virological and histological response and their association with immune variables are also provided.RESULTS:From week 12 to week 48,all groups of patients showed a significant reduction in mean leukocyte counts.Statistically significant reductions in antibody titers were frequent,but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response,and the neutralizing antibody response was enhanced only in patients receiving CIGB-230.Cell-mediated immune responses also tended to decline,but significant reductions in IFN-γsecretion and total absence of core-specific lymphoproliferation were exclusive of the control group.Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens.Importantly,it was demonstrated that thequality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy.Specifically,the administration of 6 doses of CIGB-230 as late addon to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γsecretion,both of which were associated with the sustained virological response.CONCLUSION:CIGB-230,combined with IFN-α-based therapy,modifies the immune response in chronic patients.The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.     

Efficacy and safety of pegylated-interferon α-2a in hemodialysis patients with chronic hepatitis C

AIM： To evaluate the efficacy and safety of pegylated- interferon alpha-2a in hemodialysis patients with chronic hepatitis C. METHODS： Thirty-six hemodialysis patients with chronic hepatitis C were enrolled in a controlled and prospective study. All patients were treatment naive, positive tested for anti-HCV antibodies, and positive tested for serum HCV-RNA. Twenty-two patients received 135 μg peglyated-interferon α-2a weekly for 48 wk （group A）. The remaining patients were left untreated, eleven refused therapy, and three were not candidates for kidney transplantation and were allocated to the control group （group B）. At the end of the treatment biochemical and virological response was evaluated, and 24 wk after completetion of therapy sustained virological response （SVR） was assessed. Side effects were monitored.
RESULTS： Of 22 hemodialysis patients, 12 were male and 10 female, with a mean age of 35.2 ± 12.1 years. Virological end-of-treatment response was observed in 14 patients （82.4%） in group A and in one patient （7.1%） in group B （P = 0.001）. Sustained virological response was observed in 11 patients （64.7%） in group A and in one patient in group B （7.1%）. Biochemical response parameters normalized in 10/14 patients （71.4%） at the end of the treatment. ALT levels in group B were initially high in six patients and normalized in one of them （25%） at the end of the 48 wk. In five patients （22.7%） therapy had to be stopped at mo 4 due to complications of weakness, anemia, and bleeding.
CONCLUSION： SVR could be achieved in 64.7% of patients on hemodialysis with chronic hepatitis C by a treatment with peglyated-interferon α-2a. Group A had a significantly better efficacy compared to the control group B, but the side effects need to be concerned.     

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

AIM: To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNA- dependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear. METHODS: HCV quasispecies were studied by clon- ing and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or com- bined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their re- sponse to the treatments: 7 with sustained virological re- sponse (SVR) (quasispecies = 150) and 3 non-respond- ers (NR) to IFN-R (quasispecies = 106). RESULTS: Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispe- cies during therapy. Analysis of amino acids substitu- tions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate thetwo groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION: These results suggest that detailed mo- lecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.     

Pegylated interferon alfa-2b plus ribavirin for treatment of chronic hepatitis C

AIM: To study the safety and efficacy of pegylated interferon alfa-2b, indigenously developed in India, plus ribavirin in treatment of hepatitis C virus(HCV). METHODS: One-hundred HCV patients were enrolled in an open-label, multicenter trial. Patients were treated with pegylated interferon alfa-2b 1.5 μg/kg per week subcutaneously plus oral ribavirin 800 mg/d for patients with genotypes 2 and 3 for 24 wk. The same dose of peginterferon plus weight-based ribavirin(800 mg/d for ≤ 65 kg; 1000 mg/d for 65-85 kg; 1200 mg/d for 85-105 kg; 1400 mg/d for 105 kg body weight) was administered for 48 wk for patients with genotypes 1 and 4. Serological and biochemical responses of patients were assessed.RESULTS: Eighty-two patients(35 in genotypes 1 and 4 and 47 in 2 and 3), completed the study. In genotype 1, 25.9% of patients achieved rapid virologic response(RVR): while the figures were 74.1% for early virologic response(EVR) and 44.4% for sustained virologic response(SVR). For genotypes 2 and 3, all patients bar one belonged to genotype 3, and of those, 71.4%, 87.5%, and 64.3% achieved RVR, EVR, and SVR, respectively. In genotype 4, 58.8%, 88.2%, and 52.9% of patients achieved RVR, EVR, and SVR, respectively. The majority of patients attained normal levels of alanine aminotransferase by 4-12 wk of therapy. Most patients showed a good tolerance for the treatment, although mild-to-moderate adverse events were exhibited; only two patients discontinued the study medication due to serious adverse events(SAEs). Eleven SAEs were observed in nine patients; however, only four SAEs were related to study medication.CONCLUSION: Peginterferon alfa-2b, which was developed in India, in combination with ribavirin, is a safe and effective drug in the treatment of HCV.     

Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B

AIM:To study the sequential changes of serum ferritin levelsin lamivudine-treated patients with chronic viral hepatitis Band the clinical implications.METHODS:Thirty-eight patients with chronic viral hepatitisB were prospectively studied during their treatment withlamivudine.Each patient received 100 mg oral lamivudinedaily for 12 mo,and was observed and tested for bloodbiochemistry and hepatitis B virus (HBV) DNA levels andserum ferritin levels at baseline and at 3,6 and 12 moduring the treatment.Serum HBV DNA levels werequantitatively determined using fluorescent quantitativepolymerase chain reaction (FQ-PCR),and serum ferritinlevels were measured by radioimmunoassay.The sequentialchanges of serum ferritin levels and their relationships withvirological,serological and biochemical responses in thepatients were analyzed.RESULTS:All the patients had a baseline HBV DNA levelhigher than 1×10~7 copies/L as determined by FQ-PCR andpositive HBsAg and HBeAg and abnormal ALT levels.At theend of the 12-mo treatment,19 of the 38(50.00%) patientshad undetectable serum HBV DNA levels by FQ-PCR,and12(31.58%) became negative for serum HBeAg and 10(26.32%)had seroconversion from HBeAg to HBeAb.Nineteen out ofthe 38(50.00%) patients had biochemically normal ALT levelsafter 12-mo lamivudine treatment.Sequential determinationshowed that lamivudine treatment significantly reduced ferritinlevels in chronic hepatitis B patients.When the patients weredivided into different groups according to their post-treatment virological,serological and biochemical responsesfor analysis of the sequential changes of ferritin levels,it wasfound that the decrease of ferritin levels in HBV DNA-negativegroup was significantly more obvious than that in HBV DNA-positive group at 6 mo during the treatment (P=0.013).Consecutive comparisons showed that ferritin levels at 3 moof treatment were obviously decreased as compared withthe baseline levels (P<0.05) in HBeAg-negative group,andthe decrease of serum ferritin levels in patients with normalizedALT was more significant than that in patients with abnormalALT at the end of the 12-mo treatment (P=0.048).CONCLUSION:Lamivudine treatment can reduce the serum ferritin levels in chronic viral hepatitis B patients anddecreases of ferritin levels can be more significant in patientsexhibiting virological,serological and biochemical responses,indicating that dynamic observation of serum ferritin levelsin patients with chronic viral hepatitis B during lamivudinetreatment might be helpful for monitoring and predictingpatients' responses to the therapy.     

Effect of SEN virus coinfection on outcome of lamivudine therapy in patients with hepatitis B

AIM:Interactions between hepatitis B virus (HBV) and otherviral hepatitis infections are well known,whether the newlydiscovered SEN virus (SENV) has any effect on lamivudineantiHBV activity is unclear.Our aim was to clarify the effecton treatment outcome of coinfection with SEN virus inpatients with hepatitis B during lamivudine therapy.METHODS:Nested polymerase chain reaction (PCR)amplification was used to detect SENV-D and SENV-Hstrains in serum from 45 patients with chronic hepatitis Btreated with lamivudine 100 mg daily for 12 mo.HBV DNAload was detected with fluorescence quantitative PCR (FQ-PCR) and YMDD (tyrosine,methionine,aspartate,aspartate)motif mutation of HBV DNA was investigated with cDNAmicroarray.RESULTS:SENV DNA was detected in 5 of 45(11.1%) casesafter 12 mo they received lamivudine treatment.SENV-Dand SENV-H were 4.4% and 6.7% respectively.HBV DNAfailed to respond to lamivudine therapy in 4 of 5 SENVcoinfected patients while only 10 of 40 patients becameSENV positive and the difference was statistically significant.Response of ALT and HBeAg to lamivudine had no significantdifference between coinfection patients and single HBVinfection ones.CONCLUSION:Coinfection with SEN virus in chronichepatitis B patients may adversely affect the outcome oflamivudine treatment.     

Hepatitis C virus recurrence after liver transplantation:A 10-year evaluation

AIM: To evaluate the predictors of 10-year survival of patients with hepatitis C recurrence. METHODS: Data from 358 patients transplanted between 1989 and 2010 in two Italian transplant centers and with evidence of hepatitis C recurrence were analyzed. A χ2, Fisher's exact test and Kruskal Wallis' test were used for categorical and continuous variables, respectively. Survival analysis was performed at 10 years after transplant using the Kaplan-Meier method, and a log-rank test was used to compare groups. A P level less than 0.05 was considered significant for all tests. Multivariate analysis of the predictive role of different variables on 10-year survival was performed by a stepwise Cox logistic regression.RESULTS: The ten-year survival of the entire population was 61.2%. Five groups of patients were identified according to the virological response or lack of a response to antiviral treatment and, among those who were not treated, according to the clinical status(mild hepatitis C recurrence, "too sick to be treated" and patients with comorbidities contraindicating the treatment). While the 10-year survival of treated and untreated patients was not different(59.1% vs 64.7%, P = 0.192), patients with a sustained virological response had a higher 10-year survival rate than both the "non-responders"(84.7% vs 39.8%, P 0.0001) and too sick to be treated(84.7% vs 0%, P 0.0001). Sustained virological responders had a survival rate comparable to patients untreated with mild recurrence(84.7% vs 89.3%). A sustained virological response and young donor age were independent predictors of 10-year survival. CONCLUSION: Sustained virological response significantly increased long-term survival. Awaiting the interferon-free regimen global availability, antiviral treatment might be questionable in selected subjects with mild hepatitis C recurrence.     

Durability of viral response after off-treatment in HBeAg positive chronic hepatitis B

AIM:To evaluate the durability in hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients who discontinued antiviral treatment. METHODS:A total of 48 HBeAg positive chronic hepatitis B patients who were administered nucleoside analogues and maintained virological response for ≥ 6 mo [hepatitis B virus (HBV) DNA 300 copies/mL and HBeAg seroconversion] before cessation of treatment were enrolled between February 2007 and January 2010. The criteria for the cessation of the antiviral treatment were defined as follows:(1) achievement of virological response; and (2) duration of consolidation therapy (≥ 6 mo). After treatment cessation, the patients were followed up at 3-6 mo intervals. The primary endpoint was serologic and virologic recurrence rates after withdrawal of antiviral treatment. Serologic recurrence was defined as reappearance of HBeAg positivity after HBeAg seroconversion. Virologic recurrence was defined as an increase in HBV-DNA level 104 copies/mL after HBeAg seroconversion with previously undetectable HBV-DNA level. RESULTS:During the median follow-up period of 18.2 mo (range:5.1-47.5 mo) after cessation of antiviral treatment, the cumulative serological recurrence rate was 15 % at 12 mo. The median duration between the cessation of antiviral treatment and serologic recurrence was 7.2 mo (range:1.2-10.9 mo). Of the 48 patients with HBeAg positive chronic hepatitis, 20 (41.6%) showed virological recurrence. The cumulative virologic recurrence rates at 12 mo after discontinuing the antiviral agent were 41%. The median duration between off-treatment and virologic recurrence was 7.6 mo (range:4.3-27.1 mo). The mean age of the virological recurrence group was older than that of the non-recurrence group (46.7 ± 12.1 years vs 38.8 ± 12.7 years, respectively; P = 0.022). Age ( 40 years) and the duration of consolidation treatment (≥ 15 mo) were significant predictive factors for offtreatment durability in the multivariate analysis [P = 0.049, relative risk (RR) 0.31, 95% CI (0.096-0.998) and P = 0.005, RR 11.29, 95% CI (2.054-65.12), respectively]. Patients with age (≤ 40 years) who received consolidation treatment (≥ 15 mo) significantly showed durability in HBeAg positive chronic hepatitis B patients (P = 0.014). These results suggest that additional treatment for more than 15 mo after HBeAg seroconversion in patients who are ≤ 40 years old may be beneficial in providing a sustained virological response. CONCLUSION:Our data suggest that HBeAg seroconversion is an imperfect end point in antiviral treatment. Long-term consolidation treatment (≥ 15 mo) in younger patients is important for producing better prognosis in HBeAg positive chronic hepatitis B.