Efficacy and safety of entecavir compared to lamivudine in nucleoside-naïve patients with chronic hepatitis B: a randomized double-blind trial in China

Background/Aims

Chronic hepatitis B has a high prevalence (>8%) in China. We compared the safety and efficacy of entecavir with that of lamivudine for the treatment of patients with chronic hepatitis B in China.

Methods

A total of 519 nucleoside-naive Chinese patients with chronic hepatitis B were randomized (1:1) and treated with entecavir 0.5 mg/d or lamivudine 100 mg/d. The primary endpoint was serum HBV DNA <0.7 MEq/ml by bDNA assay and alanine aminotransferase <1.25 × upper limit of normal (ULN) at week 48. Patients with missing week 48 measurements were considered non-responders.

Results

About 90% (231/258) of entecavir-treated versus 67% (174/261) of lamivudine-treated patients achieved the primary endpoint (P < 0.0001). The mean reduction from baseline in HBV DNA was greater with entecavir than lamivudine (5.90 vs. 4.33 log₁₀ copies/ml, P < 0.0001). Greater proportions of entecavir-treated patients achieved undetectable HBV DNA (<300 copies/ml) by polymerase chain reaction assay (76% vs. 43%, P < 0.0001) and alanine aminotransferase normalization (≤1 × ULN, 90% vs. 78%, P = 0.0003). Entecavir and lamivudine achieved comparable rates of HBeAg seroconversion (15% and 18%, respectively). Safety was comparable between the two treatments.

Conclusions

For nucleoside-naïve Chinese patients with chronic hepatitis B, entecavir achieves superior virological and biochemical benefit over lamivudine, with a comparable safety profile.     

A comparison of clevudine and entecavir for treatment-naïve patients with chronic hepatitis B: results after 2 years of treatment

Background

This study was undertaken to compare the efficacy, safety, and resistance profile of clevudine (CLV) and entecavir (ETV) following a 2-year treatment period.

Methods

One hundred and eight Korean patients from the prior 48-week study were followed with continuous therapy for up to 2 years and monitored for hepatitis B virus (HBV) DNA levels, HBeAg seroconversion, serum ALT, emergence of drug-resistant mutant HBV, and drug-related adverse events.

Results

A complete virological response during the 2-year treatment period occurred in 68.0 % in the CLV group and in 84.5 % in the ETV group (p = 0.043). The cumulative percentage of patients with sustained virological responses at 2 years was 54.0 and 77.6 % in the CLV and ETV group, respectively (p = 0.010). Virological breakthrough occurred in 12 patients in the CLV group; however, there were none in the ETV group (p < 0.001). HBeAg seroconversion rates were not different between the two groups. In patients who maintained sustained virological responses at 2 years, the mean reduction in HBsAg titer was ?0.24 and ?0.06 log IU/ml in the CLV and ETV group, respectively (p > 0.05). Clinical myopathy occurred in seven patients in the CLV group; however, this was not observed in the ETV group (p = 0.004).

Conclusions

ETV was associated with a significantly higher virological response rate than CLV at 2 years. ETV was superior to CLV in terms of the drug resistance profile and the development of clinical myopathy. Further studies to see whether the unique characteristic of CLV to reduce HBsAg titer is associated with the removal of ccc-DNA from hepatocytes and the remission of the disease are needed.     

De novo combination of lamivudine and adefovir versus entecavir monotherapy for the treatment of naïve HBeAg-negative chronic hepatitis B patients

Purpose

Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to compare effect of naïve HBeAg-negative CHB patients with either de novo combination of lamivudine (LAM) and adefovir dipivoxil (ADV) or entecavir (ETV) monotherapy.

Methods

HBeAg-negative CHB patients (n = 71) with ALT levels between 2 and 10 times the upper normal limit and HBV DNA levels >10⁴ copies/mL were enrolled. Patients were treated with either LAM 100 mg plus ADV 10 mg per day (n = 31) or ETV 0.5 mg per day (n = 40) for 48 weeks.

Results

The average reduction in HBV DNA level compared with baseline were 5.16 ± 1.69 log in the LAM + ADV group and 5.36 ± 1.70 log in the ETV group by week 48 (P = 0.624). The virological response (VR) rates were 80.65 and 77.5%, the biochemical response (BR) rates were 93.55 and 90.00% at week 48 in the LAM + ADV and ETV groups, respectively. There was no significant difference in the VR and BR between the two groups. During the 48-week treatment period, virological breakthrough and serious side effects were not noted in any patient.

Conclusions

Both LAM + ADV combination therapy and ETV monotherapy are effective in naïve HBeAg-negative CHB patients, but further studies are needed to obtain long-term results.     

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

Purpose  

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.     

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

Purpose

Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years.

Methods

Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.

Results

After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of >400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≥1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of >400 copies/mL, 84% (27/32) had ALT of ≥1 × ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares.

Conclusions

Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.     

Interferon-alpha combined with ketoprofen as treatment of naïve patients with chronic hepatitis C: a randomized controlled trial

Summary. In this randomized controlled study, we evaluated the efficacy and safety of interferon-α combined with ketoprofen to that of interferon-α alone in naïve patients with chronic hepatitis C. Forty patients were randomized to receive Interferon-α_2a (3 million units three times a week) and ketoprofen (150 mg twice a day) and 40 to receive only interferon-α_2a at the same dose. Patients were treated for 6 months and followed up for 6 months. Response was defined by undetectable HCV-RNA in serum at the end-of-treatment and after 6 months from the completion of therapy (long term response). At the end of treatment the response was similar in the two group. However, combination treatment showed significantly higher efficacy than monotherapy in achieving long term response (10%vs 32.5%; P = 0.014). Overall adverse events were similar in the two groups. ‘Flu-like syndrome was significantly less common in the ketoprofen plus interferon group which experienced a significantly higher incidence of epigastric pain'. Our results indicate that the combination of ketoprofen plus interferon is significantly more effective than interferon alone in the tratment of naïve patients with chronic hepatitis C and is well tolerated. However this combined treatment appears to be less effective than the association of pegylated IFN and ribavirin which represent the current standard treatment. Thus, the role of ketoprofen in the treatment of chronic hepatitis C needs to be further evaluated against such a treatment.     

Serum HBsAg quantification in treatment-naïve Indian patients with chronic hepatitis B

Background and Aims

There is paucity of Indian data regarding serum HBsAg levels (qHBsAg) in treatment-naïve chronic hepatitis B (CHB). This study was done to determine correlation of qHBsAg with hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels and its ability to independently categorize subgroups of CHB.

Methods

We studied 131 treatment-naive CHB patients and initially classified them based on HBeAg status. The HBeAg-positive group was further classified into immune tolerance (IT) and immune clearance (IC) phases based on serum alanine aminotransferase. HBeAg-negative patients were classified into low replicators (LR) and HBeAg-negative chronic hepatitis (ENH) based on DNA levels. HBsAg quantification was performed using the Architect chemiluminescence system.

Results

HBeAg-positive patients had higher DNA (7.89 vs. 2.69 log₁₀?IU/mL) and higher qHBsAg (4.60 vs. 3.85 log₁₀?IU/mL) compared to the HBeAg-negative group. Good correlation between qHBsAg and DNA was seen in HBeAg-positive (ρ?=?0.6, p?<?0.001) but not in HBeAg-negative CHB (ρ?=?0.2). A qHBsAg level greater than 4.39 log₁₀?IU/mL predicted HBeAg-positive state with 81 % sensitivity and 85 % specificity. However, among HBeAg-negative CHB, qHBsAg failed to discriminate between LR and ENH.

Conclusions

A single point estimation of qHBsAg in treatment-naïve patients could predict replicative HBeAg-positive CHB, but was not helpful in defining replicative status in the HBeAg-negative CHB.     

Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy

AIM:To evaluate the efficacy and safety of lamivudinetreatment of chronic hepatitis B disease in pregnancy.METHODS:The study group was comprised of 38 chronicHBV patients who were diagnosed pregnant duringIamivudine treatment and voluntary to continue the sametherapy.The control group was from documented patientdata in the literatures.We compared the followingparameters with those of a control group:anti-HBV efficacy,complications of pregnancy (abortion,preterm birth,neonatalasphyxia,fetal death,and congenital anomaly),incidenceof HBV-positive babies and developmental anomalies inpregnant women treated with Iamivudine.RESULTS:The blocking rate of lamivudine treatment wassignificantly higher than that of active vaccine immunizationfor babies with double-positive (HBsAg/HBeAg) mothers with30-30-10 μg doses of vaccine (74.07%) and with 30-20-10 μg(64.87%).The natural vertical HBV transmission from motherto infant of “double-positive”mothers was 100% (10/10).No pregnancy complication was noted during the observationperiod,but in the control group the incidences of pregnancycomplication were 16.67% (abortion),43.02%(preterm),15.62% (neonatal asphyxia),and 4.49% (fetal death),10.0% (congenital anomaly).No HBV-positive newborn wasdetected and no developmental anomaly was found in thestudy group.CONCLUSION:Lamivudine is helpful to prevent maternal-infant HBV transmission and may reduce the complicationsof HBV-infected pregnant patients.     

Effect of Qinling granule in treatment of 102 patients with chronic hepatitis B

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A randomized,open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naïve chronic hepatitis B patients

Purpose

Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy.

Methods

Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed.

Results

There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups (p = 0.0376). Biochemical response rates were similar in all groups (78–94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study.

Conclusion

We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study.     

Successful cessation of lamivudine using interferon in a patient with chronic hepatitis?B who received prophylactic lamivudine treatment during chemotherapy

Lamivudine (LMV) prophylaxis is effective in preventing hepatitis B virus (HBV) reactivation in patients with chronic hepatitis B undergoing chemotherapy. However, the optimal duration of LMV prophylaxis remains unclear. We report herein the case of a woman with localized follicular B-cell lymphoma who received chemotherapy with LMV prophylaxis. She achieved complete response to lymphoma, and LMV treatment was continued for 8 months after completion of chemotherapy. HBV status was still inactive. LMV was then stopped, but reactivation of hepatitis developed 1 month after cessation of LMV. LMV was restarted, resulting in successful treatment of reactivated hepatitis. Interferon (IFN) was used for 6 months before withdrawal of LMV, which was successfully ceased without flare hepatitis. This report describes the utility of sequential therapy with LMV and IFN to treat flare after withdrawal of LMV in hepatitis B carriers who receive LMV prophylaxis during chemotherapy and to prevent flare after withdrawal of LMV.     

Polymorphism of estrogen receptor alpha (ESR1) is associated with virological response to entecavir (ETV) in nucleoside-naïve adult patients with chronic hepatitis B

Introduction

Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC).

Materials and methods

To test the hypothesis that polymorphisms in estrogen receptor alpha (ESR1) might influence the virological response to entecavir (ETV) therapy, we examined two polymorphisms (PvuII and XbaI) in 76 nucleoside-naïve chronic hepatitis B (CHB) patients. All of the patients (52 HBeAg-positive and 24 HBeAg-negative) were treated with ETV 0.5 mg daily and followed up for a median time of 96 weeks (range 48–96). Polymorphisms were determined using the polymerase chain reaction–restriction fragment-length polymorphism (PCR–RFLP) method.

Results

Under an additive model, the univariate analysis showed that patients carrying the PvuII T/C genotype might have higher virological responders than those carrying the T/T and C/C genotypes at week 48 (87.7 vs. 57.1 vs. 58.3 %; P = 0.012) and week 96 (96.7 vs. 64.3 vs. 24 87.5 %; P = 0.018), although this difference disappeared with the multiple analysis at week 48 [95 % confidence interval (CI) 0.687–3.841; P = 0.269] and week 96 (95 % CI 0.861–18.016; P = 0.077). Conversely, the univariate analysis suggests statistical significance between the recessive model of PvuII (TT vs. TC/CC) and virological response at week 48 (57.1 vs. 81.1 %; P = 0.033) and week 96 (64.3 vs. 94.7 %; P = 0.017). Multiple regression analysis affirmed the significant and independent association between the recessive model of PvuII and virological response. In other words, patients carrying at least one PvuII C allele (TC/CC) had a better likelihood of achieving virological response compared with those carrying the T/T genotype at week 48 (95 % CI 1.026–14.785, P = 0.046) and week 96 (95 % CI 1.456–57.509; P = 0.018). XbaI polymorphisms were not significantly associated with virological response.

Conclusion

Our results suggest that the PvuII polymorphism may play an important role in determining ETV efficacy after 48 and 96 weeks of treatment, at least in this study population.     

Is telbivudine superior to lamivudine for the treatment of patients with chronic hepatitis B?

This practice point commentary discusses the findings and limitations of a prospective, double-blind, phase III trial conducted by Lai et al. in which patients with chronic hepatitis B (CHB) were randomly allocated to receive telbivudine 600 mg daily or lamivudine 100 mg daily. The trial showed that telbivudine was superior to lamivudine in terms of mean reduction in number of HBV DNA copies/ml from baseline, the number of patients with a reduction in serum HBV DNA to undetectable levels, and rate of HBV drug resistance. This commentary highlights the issues to consider when interpreting and generalizing these results, including the fact that lamivudine is no longer recommended as first-line therapy for patients with CHB and that head-to-head comparisons between telbivudine and its two alternatives-entecavir and adefovir dipivoxil-have not been performed. The importance of selecting patients for treatment according to predictive factors of a good response is also highlighted.     

A randomized trial to assess the efficacy of interferon-alpha daily in combination with ribavirin in the treatment of naïve patients with chronic hepatitis C

Summary. A randomized trial was conducted to assess the efficacy of interferon-alpha (IFN) daily in combination with ribavirin in 301 naïve patients with chronic hepatitis C (CHC). Patients were randomized to receive ribavirin 1.2 g daily (QD) for 48 weeks with either IFN 5 MU (thrice weekly) TIW for 8 weeks followed by IFN 3 MU TIW for 40 weeks (IFN TIW, n  = 154) or IFN 5 MU QD for 8 weeks followed by IFN 3 MU QD for 16 weeks followed by IFN 3 MU TIW for 24 weeks (IFN QD, n  = 147). Treatment discontinuation rates, because of adverse events, were similar in the two arms (14.9% in IFN TIW and 14.3% in IFN QD, P  = 0.87). The proportion of patients with sustained virological response (SVR) was 27.9% for patients treated TIW and 38.8% for those treated QD ( P  = 0.046). According to logistic regression analysis, patients in the IFN QD arm had 1.7 times higher probability of achieving SVR, than those receiving IFN TIW ( P  = 0.038). Low baseline viral load ( P  = 0.017) and genotype non-1 ( P  = 0.036) were associated with higher SVR rates. Combination of IFN/ribavirin for 48 weeks is more effective when IFN is administered daily for the first 24 weeks in naïve patients with CHC.     

Safety and efficacy of two-step peginterferon α-2a treatment in patients of chronic hepatitis B with acute exacerbation

The focus of this study was to evaluate the safety and efficacy of sequential peginterferon α-2a (Pegasys) therapy for chronic hepatitis B with acute exacerbation [ALT > 10 × upper limit of normal (ULN), bilirubin <2.0 mg/dL]. Four groups of patients categorized by HBeAg status and treatment regimens were studied since May 2007. Nineteen HBeAg-positive patients (Group 1) had received entecavir pretreatment (when ALT > 10 × ULN) plus Pegasys (180 μg/kg/week, when ALT was 5-10 × ULN) for 24 weeks. Thirteen HBeAg-negative patients (Group 2) had the same protocol for 48 weeks. In both groups, entecavir was then discontinued 14 days after the initiation of Pegasys. The results were compared, respectively, to 35 HBeAg-positive patients (Group 3) and 24 HBeAg-negative patients (Group 4), all with ALT > 5 × ULN, under continual entecavir monotherapy. The ALT levels of patients in Group 1 and 2 who had received entecavir pretreatment for a duration of 19.63 ± 3.34 days were below four times of ULN following 4 weeks of Pegasys treatment. At week 96, the rates of sustained virological response were 69.2% (9/13) and 80% (8/10), and the relapse rates were 23.1% (3/13) and 11.2% (1/9) for HBeAg-positive and HBeAg-negative patients with two-step Pegasys treatment, respectively. The HBeAg seroconversion rates were 46.2% in Group 1, and 42.1% in Group 3; HBsAg loss rates were 15.4% (2/13) in Group 1, and 30% (3/10) in Group 2, whereas none achieved HBsAg loss with entecavir monotherapy (Group 3 and 4). The two-step Pegasys treatment offers an alternative, other than the nucleos(t)ides, for treating chronic hepatitis B with acute exacerbation and provides a safe, efficacious, short-term and finite strategy.