Viral Breakthrough Rate Research Articles

Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naïve chronic hepatitis B patients in Japan.

We determined the antiviral potency and viral breakthrough rate after 10years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1logcopies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10years were calculated. The median age was 50years and follow-up period was 5.5years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08logIU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment. Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment.

Effect of Metabolic Syndrome on the Clinical Outcomes of Chronic Hepatitis B Patients with Nucleos(t)ide Analogues Treatment.

No data are available about the effect of MS on oral nucleos(t)ide analogues (NUCs) treatment and clinical outcomes in chronic hepatitis B (CHB) patients. We aimed to elucidate whether coexistence of MS and CHB affects the long-term prognosis of CHB patients with oral NUCs treatment. We performed a retrospective data analysis for a total of 587 CHB patients who started oral NUCs treatment for the first time in our institution from January 2006 to March 2016. Among the 587 patients, 70 (11.9%) had MS, but 517 (88.1%) had no evidence of MS when oral NUCs treatment was initiated. Cumulative occurrence rates of viral breakthrough, genotypic resistance, HCC, disease progression (PD), and overall adverse outcomes (OAO) were significantly higher in CHB patients with MS than in those without MS, although HBV-DNA suppression and cumulative occurrence rates of HBeAg negative conversion and seroconversion were not significantly different between the two groups. The overall survival (OS) was also significantly shorter in CHB patients with MS than in those without MS. Multivariate analysis indicated that the MS was an independent, poor prognostic factor for occurrence of genotypic resistance (adjusted hazard ratio [aHR], 22.3; 95% confidence interval [CI] 6.61-75.02; P < 0.001), HCC (aHR, 3.98; 95% CI 2.07-7.66; P < 0.001), PD (aHR, 6.18; 95% CI 3.43-11.14; P < 0.001), OAO (aHR, 8.10; 95% CI 4.68-14.02; P < 0.001), and OS (aHR, 12.29; 95% CI 2.25-67.24; P < 0.001). MS is an independent determinant of poor prognosis in CHB patients receiving oral NUCs treatment.

Efficacy of entecavir-based rescue therapy in lamivudine-resistant chronic hepatitis B patients in China: a retrospective study.

Limited studies have investigated the antiviral efficacy of entecavir (ETV)-based rescue therapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients. We retrospectively analyzed the efficacy of entecavir (ETV) monotherapy versus ETV-tenofovir disoproxil fumarate (TDF) combination therapy in 220 LAM-resistant CHB patients. Among 220 patients, 114 patients were treated with ETV monotherapy and 106 were treated with ETV-TDF combination therapy for at least 24 months. There were no significant differences between the two groups in baseline characteristics. During the follow-up of 24 months, virologic response (VR) occurred in 146 (66.4%) patients (58 patients belonged to the ETV monotherapy group and 88 patients belonged to the ETV-TDF combination group). The VR rates were different between the ETV and ETV-TDF groups (32.5% vs. 57.5% at 6 months, 50.0% vs. 77.4% at 12 months; and 50.9% vs. 83.0% at 24 months, P<0.001). In addition, both groups showed no difference in terms of the biochemical and HBeAg response. The rates of viral breakthrough at 6, 12 and 24 months were significantly different between ETV and ETV-TDF groups (2.63%, 4.39% and 9.65% vs. 0.00%, 0.94% and 1.89% at 6, 12 and 24 months, respectively). The ETV-TDF group was superior to the ETV group in achieving a virologic response. Moreover, the ETV-TDF was lower than the ETV group in achieving the initial viral breakthrough and genotypic mutations. Therefore, ETV-TDF combination therapy might be a better regimen than ETV monotherapy in the subgroup of LAM-resistant Chinese patients with CHB.

High rate of hepatitis B viral breakthrough in elderly non-Hodgkin lymphomas patients treated with Rituximab based chemotherapy

BackgroundRituximab-containing chemotherapies are offered to elderlies for treatment of non-Hodgkin lymphomas (NHL). From 0.7 to 27% of patients with “resolved” HBV infection develop HBV reactivation and related hepatitis during Rituximab-containing chemotherapies. Currently, several antiviral drugs are available for the prophylaxis of patients at risk for HBV reactivation, which include lamivudine, tenofovir, entecavir, and adefovir. Viral breakthrough may occur during therapy, which is defined as an abrupt increase in serum HBV DNA levels after a period of persistent suppression. Viral breakthrough occurs with non-compliance to therapy and, also, when drug-resistant mutants emerge. The risk might be higher in fragile patients as elderlies. AimsSince no study addressed this question, we determined the rate of HBV-RS in patients >65years undergoing Rituximab-containing chemotherapies for NHLs. MethodsWe evaluated 85 newly diagnosed NHL patients with resolved HBV infection, receiving Rituximab-containing chemotherapies. All received lamivudine. HBV DNA was checked at baseline, every 4 weeks, for 1year after completion of Rituximab cointaining regimens. ResultsNine patients (10%) had HBV reactivation and HBV related hepatitis. All received entecavir and recovered without consequences. HBV reactivation was more likely to occur after an average of five R-CHOP cycles or during Fludarabine. ConclusionsThe rate of viral breakthrough (VBK), in our study population, is high considering that the patients were HBV DNA negative at baseline and suggest that Lamivudine prevention may not be sufficient in this population.

Rapid In Vitro Evaluation of Antiretroviral Barrier to Resistance at Therapeutic Drug Levels.

Failure of combination antiretroviral (ARV) therapy in HIV-infected patients is often associated with the emergence of drug resistance-associated mutations (RAMs). To facilitate analysis of the barrier to resistance at therapeutically relevant ARV concentrations, we performed fixed-dose in vitro HIV-1 drug resistance selection assays using the immortalized MT-2 T-cell line and primary human CD4+ T cells with a panel of FDA-approved ARVs, each at their respective cell culture equivalent clinical trough concentration (CCE Cmin). At high multiples of its CCE Cmin, emtricitabine (FTC) selected for the rapid emergence of M184I/V, a result consistent with resistance emergence in vivo. While the rate of viral breakthrough in the presence of rilpivirine or efavirenz was delayed relative to FTC, both inhibitors selected for virus with known clinically relevant RAMs. No viral breakthrough was observed for the protease inhibitor atazanavir even at subtherapeutic drug concentrations, which is consistent with its previously characterized high in vivo barrier to resistance. Depending on assay conditions, treatment with integrase inhibitors elvitegravir and raltegravir resulted in breakthrough of both resistant and wild-type virus. The RAMs observed in drug selections were not detected above a 2% threshold by deep sequencing in the in vitro virus inoculum, and only rarely in isolates from treatment-naive HIV+ patients. These new viral breakthrough assays facilitate the analysis of multiple experimental replicates and conditions in parallel and provide a rapid quantitative means to evaluate drug resistance emergence at therapeutically relevant drug concentrations, which should facilitate the identification of new ARVs with a high barrier to resistance.

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial.

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Comparison of the antiviral effects of different nucleos(t)ide analogues in chinese patients with chronic hepatitis B: a head-to-head study.

Background/Aims:To assess the antiviral efficacy of lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and lamivudine and adefovir dipivoxil (CLA) combination in previously untreated hepatitis B patients at different time points during a 52-week treatment period.Patients and Methods:A total of 164 patients were included in this prospective, open-label, head-to-head study. Serum levels of alanine transaminase (ALT), hepatitis B virus (HBV) DNA, and hepatitis B e antigen (HBeAg) were measured at baseline, and at 12, 24, and 52 weeks of treatment.Results:Median reductions in serum HBV DNA levels at 52 weeks (log10 copies/mL) were as follows: LAM, 3.98; ETV, 3.89; LDT, 4.11; and CLA, 3.36. The corresponding HBV DNA undetectability rates were 83%, 96%, 91%, and 89%, respectively. These two measures showed no significant intergroup differences. Clinical efficacy appeared related to HBV DNA level reduction after 24 weeks of therapy. Patients were divided into three groups based on HBV DNA levels at week 24: Undetectable (<103 copies/mL), detectable but <104 copies/mL, and >104 copies/mL. Patients with levels below quantitation limit (QL) were analyzed at 52 weeks for HBV DNA undetectability rate (94%), ALT normalization rate (83%), and viral breakthrough rate (0%). The corresponding values in the QL-104 copies/mL group were 50%, 75%, and 13%, whereas those in the above 104 copies/mL group were 53%, 65%, and 18%. There were significant differences at week 52 for HBV DNA levels and viral breakthrough rate between the three groups.Conclusions:Different nucleos(t)ide (NUC) analogues tested exhibited no significant differences in effectiveness for Chinese NUC-naive HBV patients during 1-year treatment period.

Sa1030 Alisporivir Interferon-Free G2/3 Vital-1 Study: Low Rate of Viral Breakthrough and Combination of Multiple NS5A Domain II Mutations Required to Reduce Susceptibility to Alisporivir In Vitro

BACKGROUND: VITAL-1 study assessed safety, tolerability and antiviral activity of the cyclophilin inhibitor alisporivir (ALV) as monotherapy or combination with ribavirin (RBV) compared to IFN/RBV and ALV/IFN in treatment-naive GT2/3 HCV patients. We describe genotypic and phenotypic changes in patients from this study who experienced a viral breakthrough (VB). METHODS: VITAL-1 study patients on IFN-free regimens that did not achieve RVR (, 25 U/ml) at week 4 were administered IFN/RBV/600 mg QD ALV starting at week 6 (IFN-add-on). VB defined as an increase of HCV RNA .1 log10 above nadir. The HCV NS5A gene was analyzed by population sequencing. The entire NS5A region isolated at baseline and at VB was cloned into a JFH1subgenomic shuttle vector for phenotypic analyses. Selected mutations were engineered into a wild type replicon and their impact on replication fitness and susceptibility to ALV and direct acting antiviral drugs were determined. RESULTS: The VB rate with IFN-free or IFN-add-on regimens was 2.7% (7/ 260). Low ALV drug level (Cmin , 20% of group mean; , 100 ng/mL) was observed (5/ 7 VB patients). Genotypic analysis of the NS5A gene revealed amino acid changes in these patients at the time of VB compared to baseline. Replicons bearing NS5A from patients at breakthrough conferred 1.2-16.9-fold shift over baseline EC50 values; 5/7 had impaired replication fitness. No cross-resistance to other classes of HCV inhibitors was observed. Most frequently identified mutations were D320E (D316E in G2), R347W and A349V in Domain II of NS5A, which by themselves decreased ALV susceptibility by 5-, 4, and 8-fold, respectively, in vitro when engineered into wild-type replicon. Combination of multiple mutations decreased susceptibility further, but generally at the cost of replication fitness. CONCLUSION: In treatment-naive G2/3 patients with viral breakthrough, mutations in NS5A domain II were selected, which individually conferred ≤ 8-fold reduced susceptibility to ALV in vitro. The combination of multiple mutations was required to further reduce susceptibility which is consistent with the high barrier to resistance for host-targeting ALV. Observed genotypic changes did not confer cross-resistance to other classes of HCV inhibitors, supporting the use of ALV in future drug combination therapies.

Profile of alisporivir and its potential in the treatment of hepatitis C

Two classes of hepatitis C antiviral agents currently exist, ie, direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis. In conclusion, alisporivir represents an attractive candidate component of future interferon-free regimens.

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure

Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

Efficacy of Lamivudine or Entecavir against Virological Rebound after Achieving HBV DNA Negativity in Chronic Hepatitis B Patients

Nucleos(t)ide analogues (NAs) lead to viral suppression and undetectable hepatitis B virus (HBV) DNA in some individuals infected with HBV, but the rate of virological rebound has been unknown in such patients. We examined the prevalence of virological rebound of HBV DNA among NA-treated patients with undetectable HBV DNA. We retrospectively analyzed 303 consecutive patients [158 entecavir (ETV)- and 145 lamivudine (LAM)-treated] who achieved HBV DNA negativity, defined as HBV DNA < 3.7 log IU/mL for at least 3 months. They were followed up and their features, including their rates of viral breakthrough, were determined. Viral rebound after HBV DNA negativity was not observed in the ETV-group. Viral rebound after HBV DNA negativity occurred in 38.7% of 62 HBe antigen-positive patients in the LAM-group. On multivariate analysis, age was an independent factor for viral breakthrough among these patients (P = 0.035). Viral rebound after HBV DNA negativity occurred in 29.1% of 79 HBe antigen-negative patients in the LAM-group. Differently from LAM, ETV could inhibit HBV replication once HBV DNA negativity was achieved. In contrast, LAM could not inhibit HBV replication even if HBV negativity was achieved in the early phase. Attention should be paid to these features in clinical practice.

Adherence to Medication Is a More Important Contributor to Viral Breakthrough in Chronic Hepatitis B Patients Treated with Entecavir Than in Those with Lamivudine

Viral breakthrough is related to poor adherence to medication in some chronic hepatitis B patients treated with nucleos(t)ide analogues (NAs). Our study aimed to examine how adherence to medication is associated with viral breakthrough in patients treated with NAs. A total of 203 patients (135 ETV and 68 LAM) were analyzed in this retrospective analysis. Physical examination, serum liver enzyme tests, and hepatitis B virus marker tests were performed at least every 3 months. We reviewed medical records and performed medical interviews regarding to patients' adherence to medication. Adherence rates <90% were defined as poor adherence in the present study. Cumulative viral breakthrough rates were lower in the ETV-treated patients than in the LAM-treated patients (P<0.001). Seven ETV-treated (5.1%) and 6 LAM-treated patients (8.8%) revealed poor adherence to medication (P=0.48). Among ETV-treated patients, 4 (3.1%) of 128 patients without poor adherence experienced viral breakthrough and 3 (42.8%) of 7 patients with poor adherence experienced viral breakthrough (P<0.001). Only 3 of 38 (7.8%) LAM-treated patients with viral breakthrough had poor adherence, a lower rate than the ETV-treated patients (P=0.039). Nucleoside analogue resistance mutations were observed in 50.0% of ETV- and 94.1% of LAM-treated patients with viral breakthrough (P=0.047). Viral breakthrough associated with poor adherence could be a more important issue in the treatment with especially stronger NAs, such as ETV.

468 Preventing Hepatitis B Materno-Fetal Transmission in Late Pregnancy: A Comparative Meta-Analysis of Lamivudine Versus Hepatitis B Immune Globulin

monotherapy. Significantly higher rate of viral breakthrough was observed at 6 months after switching from combination therapy back to monotherapy in the ETV compared to TDF monotherapy cohorts (Figure 1). For those who remained on combination therapy, 4 patients (21%) experienced virologic breakthrough at 6 months after achieving CVS. Two of these patients achieved CVS again on the same therapy, suggesting possible medication nonadherence as the cause of virologic breakthrough. The other two patients are still awaiting additional follow-up on the same therapy. Conclusion: TDFmonotherapymay be a reasonable maintenance therapy option for close to half of patients (40%) with prior PR to ETV who have achieved CVS with combination therapy but not ETV monotherapy. The economic savings and convenience advantage can be considerable for those who can maintain CVS on TDF monotherapy instead of combination therapy with TDF and ETV.

Study on the efficacy and HBeAg seroconversion related factors of telbivudine and entecavir therapy in HBeAg positive chronic hepatitis B patients

To investigate the efficacy of Telbivudine and Entecavir for therapy of HBeAg positive chronic hepatitis B for 52 weeks. In this random and control study, the efficacy of Telbivudine and Entecavir treatments were compared in 180 patients with HBeAg positive chronic hepatitis B.The patients were randomly assigned to a daily 600 mg Telbivudine treatment group or daily 0.5 mg Entecavir group for 52 weeks. At week 52, HBV DNA undetectable rate was better in the Entecavir-treated group than in the Telbivudine-treated group, but didn't reach statistical significance. The viral breakthrough rates were significantly lower in the Entecavir-treated group than in the Telbivudine-treated group (x2 = 4.09, P <0.05). The clearance and seroconversion of HBeAg and the mean reductions of HBeAg from baseline at week 52 were significantly greater in the telbivudine-treated group than in the entecavir-treated group (x(2) clearance = 4.63, x(2) seroconversion = 4.80, (t-mean) reductions = 2.02; P < 0.05). The HBeAg seroconversion rates were not associated with both baseline ALT and baseline HBV DNA in both groups (P more than 0.05). In Telbivudine-treated group, the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 1 log at week 12 and the HBeAg baseline were independent factors correlated to HBeAg seroconversion rates at week 52 by Binary Logistic analysis, and also in entecavir-treated group the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 2 log at week 36 and the HBeAg decline is more than 2 log at week 12 were independent factors correlated to HBeAg seroconversion rates at week 52. Significant difference of HBeAg seroconversion rates at week 52 existed between Telbivudine-treated group and Entecavir-treated group. Entecavir is significantly superior to Telbivudine with less resistance to nucleosides. HBeAg decline is more than 2 log at week 24 is the best predicting factor for HBeAg seroconversion at week 52.

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Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial

Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1.5 mug/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670. Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group. In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. Merck.

PP-100 Prevalence of infection with delta virus in patients positive for hepatitis B surface antigen

Purpose: To study the anti-HBV effect of lamivudine and telbivudine on biochemistry, virology and hepatohistology. Method: Patients are randomized into 2 groups, oral lamivudine and oral telbivudine, for 2 years of observation during which AST, ALT, HBV quantification and changes in hepatohistology before treatment and at week 52 were examined periodically. Results: After treatment of lamivudine and telbivudine, AST and ALT returned to normal levels; HBVDNA negative rates at week 24, week 52 and week 104 for the two drugs were high, HBVDNA levels decreased significantly at week 24, and 52 for telbivudine drug group. HBeAg negative rates (p = 0.032) and 52 week therapeutic response (p = 0.0155) were significantly higher for telbivudine. Viral breakthrough rate at 52 week is low in telbivudine group. And the liver biopsy showed inflammatory change (G) and fibrosis (S) both improved in two group (P< 0.05), but improvement of inflammatory change (G) is more significantly in telbivudine group (P< 0.05). Conclusion: Lamivudine and telbivudine exhibit good antiviral function yet telbivudine is superior to lamivudine in the inhibition of HBVDNA replication, drug resistance rate, the rebound of viral replication rate and also the improvement of liver tissues.

Virologic Response at 12 Months of Treatment Predicts Sustained Antiviral Efficacy in Patients with Adefovir-Treated Lamivudine-Resistant Chronic Hepatitis B

The aim of our study was to define the potential role of virologic response at 12 months of treatment (VR12) in predicting subsequent virologic and clinical outcomes in adefovir (ADV)-treated lamivudine-resistant chronic hepatitis B. Two hundred and four patients with lamivudine-resistant chronic hepatitis B virus (HBV) treated with ADV monotherapy were included. Serum HBV DNA was quantified by real-time polymerase chain reactions. VR12 was defined as a HBV DNA level of less than 4 log(10) copies/mL after 12 months of ADV treatment. VR12 was observed in 110 of the 204 patients (54%). The mean HBV DNA reductions from baseline after 12 months of ADV treatment were 3.8 and 1.9 log(10) copies/mL in patients with and without VR12, respectively (p<0.001). The hepatitis B "e" antigen (HBeAg) seroconversion rates in patients with and without VR12 were 32% and 14% at 12 months treatment, respectively (p=0.018), and 40% and 27% at 24 months of treatment (p=0.032). The genotypic mutation rates to ADV in patients with and without VR12 were 0% and 6% at 12 months of treatment, respectively (p=0.033), and 21% and 42% at 24 months (p=0.012). The rates of viral breakthrough in patients with and without VR12 were 0% and 7% at 12 months of treatment, respectively (p=0.072), and 9% and 25% at 24 months (p=0.006). Patients without VR12 may need to switch to or add on other potent antiviral drugs in their medical regimens.

Clevudine Demonstrates Potent Antiviral Activity in Naïve Chronic Hepatitis B Patients

Objectives: Clevudine has demonstrated antiviral potency in the treatment of naïve chronic hepatitis B patients in pivotal studies. The objectives of this study were to evaluate the safety and efficacy of a 1-year treatment with clevudine in chronic hepatitis B patients. Methods: This is a post-marketing surveillance using case report forms which were submitted to the health authorities. Results: Analysis of individual data showed that hepatitis B virus (HBV) DNA after a 1-year treatment was <141,500 copies/ml in 96% of hepatitis B e antigen (HBeAg)-positive and 100% of HBeAg-negative patients. The proportion of patients with HBV DNA <2,000 copies/ml after a 1-year treatment was 74%: 71% of HBeAg-positive and 93% of HBeAg-negative patients. Most of the patients with HBV DNA below the detection limit with each assay at week 24 showed sustained viral suppression up to week 48. The proportion of patients who showed normal alanine aminotransferase at week 48 was 86% in HBeAg-positive patients and 87% in HBeAg-negative patients. The rates of HBeAg-loss were 21%. Two patients showed viral breakthrough during treatment. Conclusion: Clevudine monotherapy demonstrates potent antiviral activity as well as biochemical and serological response with a 0.7% rate of viral breakthrough in naïve chronic hepatitis B patients.

Factors associated with response to lamivudine: retrospective study of 233 patients with chronic hepatitis B

To identify factors associated with response to lamivudine in chronic hepatitis B patients. Clinical data of 233 chronic hepatitis B patients treated with lamivudine 100mg daily (91 patients were switched to Adefovir 10mg daily or Adefovir 10mg in combination with lamivudine 100mg daily) were retrospective. HBV DNA level and serum HBV markers were detected by polymerase chain reaction and enzyme-linked immunosorbent assay. Kaplan-Meier, long-rank, t test were conducted to evaluate the data. (1) The rates of HBV DNA loss, ALT normalization, viral breakthrough(VB), HBeAg loss and seroconversion were 63.4% , 83.8%, 30.9%, 30.9%, and 14.3%, respectively, in HBeAg(+) patients; and these were 84.6%, 81.3%, 14.3%, respectively in HBeAg(-) patients.(2) The rates of HBV DNA loss, HBeAg loss, HBeAg seroconversion, viral breakthrough (VB) were 55% and 66.7% (P more than 0.05), 55.0%, and 66.7% (P less than 0.05), 17.5% and 33.3% (P less than 0.05), 50% and 34.3% (P less than 0.05) in HBeAg(+) patients with baseline ALT less than 2.5 ULN and HBeAg(+) patients with baseline ALT is more than or equal to 2.5 ULN, respectively. (3) For HBeAg(+) patients, viral breakthrough rate was significantly lower in patients with baseline HBV DNA less than 10(6) copies/ml than that in patients with baseline HBV DNA more than 10(6) copies/ml patients (23.4% VS 46.3%, P less than 0.05) among HBeAg(+) patients. (4) The rate of HBV DNA loss, HBeAg loss, HBeAg seroconversion and viral breakthrough for the patients with IVR at week 24 were 76.3%, 72.3%, 40.8% and 28.9% compared to 47.6% (P less than 0.01), 46% (P less than 0.01), 12.7% (P less than 0.01) and 47.6% (P less than 0.05) for those without IVR. (4) For the 44 patients with viral breakthrough, 32 were switched to Adefovir monotherapy or adefovir in combination with lamivudine therapy, and 12 continued to receive lamivudine monotherapy. HBV DNA loss, HBeAg seroconversion were 40.6%, 21.9% for those switch/add group compare to 16.7%, 16.7% for the lamivudine monotherapy group. There were no significant differences in the background factors (sex, diagnosis, antiviral period, pre-tx ALT, pre-tx HBV DNA) between these two groups. Both the baseline ALT and HBV DNA are associated with the efficacy of lamivudine in chronic hepatitis B patients. Patients with baseline ALT is more than or equal to 2.5*ULN and (or) HBV DNA level of less than 1*10(6) copies/ml have better efficacy and lower rate of breakthrough rate. IVR at week 24 is an important predictive factor of a favorable response to lamivudine therapy. For the patients with viral breakthrough, those switched to/added on Adefovir have a favorable result.