Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels

Summary. The association between viral level and the long‐term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow‐up in 104 HBeAg‐negative Japanese carriers with PNALT. During a mean follow‐up period of 6.4 ± 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of ≥5 log₁₀ copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of ≥5 log₁₀ copies/mL and an alanine aminotransferase (ALT) level of >20 to ≤40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of ≥5 log₁₀ copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg‐negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk.     

Response to tenofovir monotherapy in chronic hepatitis B patients with prior suboptimal response to entecavir

Summary. Both entecavir (ETV) and tenofovir (TDF) are potent antiviral agents for hepatitis B virus (HBV). Suboptimal response (SOR) following antiviral therapy is associated with an increased risk of subsequent treatment failure and viral resistance. It remains unclear whether switching to TDF is a reasonable approach in patients with SOR to ETV treatment. This study was aimed to determine how HBV patients with SOR to ETV respond to TDF monotherapy. Data of patients with SOR to ETV (failure to achieve >1 log₁₀ HBV‐DNA reduction during the last 24 weeks of ETV treatment) who were switched to TDF monotherapy during 2005 and 2010 were reviewed. Treatment adherence was assessed by pill‐count. Fourteen patients (2.9%) were identified from a total cohort of 482 ETV‐treated patients. All 14 patients were Chinese and were infected with HBV genotype C (71%) or B (29%). Nine patients were men, and the median age was 41.5 years (19–64). Twelve were treatment naïve (one lamivudine‐ and one peginterferon‐experienced patient); 85.7% were HBeAg positive. The median baseline HBV‐DNA was 7.55 (5.30–9.40) log₁₀ copies/mL, and 57% had abnormal serum alanine aminotransferase (ALT) levels. Precore and/or basal core promoter mutations were detected in four patients, whereas no genotypic resistance was detected at baseline and before switching to TDF. The median duration of ETV treatment was 64.5 (26–126) weeks. The median HBV‐DNA at the time of switching to TDF was 3.69 (3.00–4.90) log₁₀ copies/mL. The median HBV‐DNA reduction from baseline and during the last 6‐month observation period prior to switching to TDF was 4.04 (0.51–6.06) log₁₀ and 0.43 (?0.09–1.13) log₁₀ copies/mL, respectively. After the switching to TDF, all 14 patients (100%) achieved undetectable HBV‐DNA and ALT normalization within a median duration of 30 weeks. In 12 patients who were HBeAg positive, HBeAg seroconversion was observed in two patients after TDF treatment of 75‐ and 84‐weeks duration. There was no virological breakthrough observed after switching to TDF with a median follow‐up period of 50 (24–160) weeks. TDF treatment was safe and well tolerated. In conclusion, suboptimal response to ETV is rare (approximately 3%). TDF monotherapy is safe and very effective in the management of HBV patients with SOR to ETV.     

Efficacy of switching to telbivudine in chronic hepatitis B patients treated previously with lamivudine

Background: Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials. Aims: The present phase IIIb, randomized, double‐blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy. Methods: HBeAg‐positive and HBeAg‐negative adult patients (N=246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log₁₀ copies/ml] under lamivudine treatment for 12–52 weeks were randomized (1:1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24. Results: The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (?1.9 ± 0.18 vs. ?0.9 ± 0.27 log₁₀ copies/ml; P<0.001) and maintained through 1 year. The rate of treatment failure was significantly lower (P<0.001) for patients who switched to telbivudine (5%) compared with those who continued lamivudine (20%) after 52 weeks of treatment. In the telbivudine group, treatment failure occurred in only five patients with >24 weeks of prior lamivudine treatment, all associated with pre‐existent lamivudine‐resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with <24 weeks of lamivudine exposure. Both treatments were well tolerated with similar safety profiles. Conclusions: Early (≤24 weeks) switch to telbivudine improves virological outcomes in CHB patients with persistent viral replication under lamivudine treatment.     

Sequential therapy with adefovir dipivoxil and pegylated Interferon Alfa‐2a for HBeAg‐negative patients

Summary. To assess the impact of sequential therapy with adefovir dipivoxil (ADV) and pegylated interferon alfa‐2a (PEG‐IFN) on virological (serum HBV‐DNA) and serological (serum HBsAg) response in 20 consecutive HBeAg‐negative patients. Patients received ADV for 20 weeks, then ADV and PEG‐IFN for 4 weeks and lastly PEG‐IFN for 44 weeks. Serum HBV‐DNA and HBsAg were assessed at baseline, during therapy (weeks 20, 44 and 68) and follow‐up (weeks 92 and 116). Sustained virological response (SVR) was defined as serum HBV‐DNA <10 000 copies/mL (partial) or <70 copies/mL (complete) 24 weeks after stopping treatment. A serological response was defined as a serum HBsAg decrease ≥1 log₁₀IU/mL at the end of treatment. Baseline median serum HBV‐DNA and HBsAg levels were 7.6 log₁₀copies/mL and 3.8 log₁₀IU/mL, respectively. Ten patients (50%) achieved SVR, six of them had partial response and four complete response. Four patients (20%) achieved serological response. Complete SVRs showed a major and steep decline in HBsAg level with a median decrease of 0.5, 1.6 and 2.0 log₁₀IU/mL at treatment week 20, 44 and 68, respectively. Partial SVRs showed a slight and slow decline in serum HBsAg level (0.1, 0.4, and 0.6 log IU/mL at weeks 20, 44 and 68, respectively). On‐treatment serum HBsAg decrease had a high accuracy to predict SVR (AUROC = 0.88). Our results suggest that sequential therapy might be an interesting strategy for HBeAg‐negative patients. Serum HBsAg kinetics seem to be an accurate tool to predict SVR. Large clinical trials are needed to explore this strategy with more potent analogues.     

A survey of chronic hepatitis B patient management practices in the European Union

Summary. The current study sought to evaluate the characteristics of chronic hepatitis B virus (HBV) infection and current management practices in the European Union by surveying physician and patient records. A detailed survey of physician practices and management of patients with CHB was conducted between July and October 2006 in France, Germany, Italy and Spain. A total of 200 physicians participated in the survey, and data were collected from 2023 patients with chronic HBV infection. Most patients were men (69%), who had hepatitis B e antigen (HBeAg)‐negative disease (64%), and demonstrated evidence of significant disease [53%; moderate fibrosis (35%), compensated cirrhosis (14%), or decompensated cirrhosis (4%)]. Among the 1665 HBV‐monoinfected patients surveyed, 1184 (71%) were currently receiving treatment for chronic HBV infection. At treatment initiation, 70% of HBeAg‐positive patients had both pretreatment serum HBV DNA levels ≤9 log₁₀ copies/mL and alanine aminotransferase (ALT) levels ≥2 × the upper limit of normal (ULN), and 81% of HBeAg‐negative patients had HBV DNA levels of ≤7 log₁₀ copies/mL. Among untreated patients, HBV DNA levels ≤5 log_10, ALT levels <2 × ULN, and mild or no liver fibrosis were present in 48% and 84% of HBeAg‐positive and HBeAg‐negative patients, respectively. In conclusion, the majority of European patients with CHB surveyed were HBeAg negative, Caucasian, men, and presented with significant histologic liver disease. At treatment initiation, most HBeAg‐positive patients had pretreatment serum HBV DNA levels ≤9 log₁₀ copies/mL and ALT levels ≥2 × ULN, while the HBeAg‐negative patients had HBV DNA levels ≤7 log₁₀ copies/mL.     

Long-term follow-up of patients with hepatitis B e antigen negative chronic hepatitis B

Background and Aim: After hepatitis B virus (HBV) e antigen (HBeAg) seroconversion, HBV‐DNA continues to replicate, and HBeAg‐negative patients still face the risk of liver disease progression. We investigated the predictive factors for alanine aminotransferase (ALT) elevation, antiviral drug use, and hepatocellular carcinoma (HCC) occurrence in HBeAg‐negative patients. Methods: Age, sex, ALT, platelet counts, HBV‐DNA levels, genotype, antidiabetic drug use, body mass index, smoking, and alcohol consumption were analyzed for a total of 244 HBV carriers who were HBeAg‐negative. Results: Of 244 HBeAg‐negative patients, 158 (64.8%) showed normal ALT levels at baseline. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels and high ALT at baseline as independent risk factors for ALT elevation in the patients with normal ALT at baseline. The threshold ALT and HBV‐DNA levels were determined to be 31 IU/L and 5.3 logcopies/mL, respectively. Seventeen (7.0%) patients used antiviral drugs. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels (threshold, 5.7 log copies/mL), the use of antidiabetic drugs, and daily alcohol consumption at baseline as an independent risk factor for the use of antiviral drugs in HBeAg‐negative patients. In 10 patients (4.1%), HCC was detected, and a low platelet count (threshold, 10.0 × 10⁴/mm³) was associated with the occurrence of HCC. Conclusion: This study identified predictors of future active liver disease in HBeAg‐negative patients, i.e. ALT elevation, unavoidable use of antiviral drugs, and occurrence of HCC.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Loss of HBsAg and antiviral treatment: from basics to clinical significance

Accurate prediction of the sustained virological response (SVR) to antiviral therapy against chronic hepatitis B (CHB) is still a crucial problem needing profound investigation. In recent years, quantification of hepatitis B surface antigen (HBsAg), a reliable predictor of SVR and an ideal endpoint of treatment, has attracted increasing attention. Serum HBsAg titer may reflect the level of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in most patients, and vary with natural phases of chronic HBV infection, genotypes and variants, antiviral therapy, and other related factors. Serum HBsAg <200 IU/mL or yearly reduction ≥0.5 log₁₀IU/mL may be the optimum cut-off values for prediction of the chance of spontaneous seroclearance of HBsAg. Serum HBsAg <1,000 IU/mL with HBV DNA <2,000 IU/mL may identify most of the inactive HBV carriers from active HBeAg^? hepatitis. Interferon-based therapy can lead to more significant HBsAg decline than therapy based on nucleoside and/or nucleotide analogues. Different patterns or kinetics of HBsAg decline during therapy are related to different probabilities of SVR. A low HBsAg level, <3,000 IU/mL at baseline, or HBsAg level, <1,500 IU/mL at week 12, or a rapid on-treatment HBsAg decline of ≥0.5 log₁₀IU/mL at week 12, may predict higher probability of SVR. However these cut-off values must be further validated for larger cohort of patients across genotypes worldwide. Incorporation of serum HBsAg level, HBeAg status, HBV DNA load, HBV genotypes, and other related factors might help establish new concept of more practical “response-guided treatment (RGT)” rules for antiviral therapy.     

Safety and efficacy of telbivudine in late pregnancy to prevent mother‐to‐child transmission of hepatitis B virus: A multicenter prospective cohort study

Infection of hepatitis B virus (HBV) occurs in ~10% of infants of HBV‐infected mothers with positive hepatitis B e antigen (HBeAg) after immunoprophylaxis. We aimed to evaluate the safety and efficacy of telbivudine used during late pregnancy for preventing mother‐to‐child transmission of HBV. We conducted a multicenter prospective cohort study in 5 hospitals from 2012 to 2014, which enrolled HBV‐infected singleton pregnant women with positive HBeAg. By their choice, women were divided into therapy (telbivudine 600 mg/day, from gestation 28‐32 weeks to 3‐4 weeks postpartum) and control (no antiviral agent) groups. Infants received passive‐active immunoprophylaxis and follow‐up at the age of 7‐14 months. Totally, 328 pregnant women were included: 149 in the telbivudine group and 179 in the control group. Baseline HBV DNA levels were similar in the 2 groups (7.43 vs 7.37 log₁₀ IU/mL, P = .711). At delivery, HBV DNA levels in the telbivudine and control groups were 3.80 and 7.26 log₁₀ IU/mL, respectively (P < .0001). Of the infants, 128 (85.9%) in the telbivudine group and 156 (87.2%) in the control group were followed up. No infant in the telbivudine group had chronic infection, while 2 (1.28%) infants in the control group did (P = .503). Three (2.34%) infants in the telbivudine group, but none in the control group, had severe congenital or developmental abnormalities (P = .090). The data indicate that telbivudine may block perinatal HBV transmission. However, larger studies are required to clarify whether anti‐HBV therapy in pregnancy is associated with severe adverse effects in the foetuses and infants.     

Efficacy and Safety of Tenofovir-Based Rescue Therapy for Chronic Hepatitis B Patients with Previous Nucleo(s/t)ide Treatment Failure

Background/Aims

We investigated the efficacy and safety of tenofovir disoproxil fumarate (TDF)-based treatment in chronic hepatitis B (CHB) patients who failed previous antiviral therapies.

Methods

Seventeen patients who failed to achieve virological responses during sequential antiviral treatments were included. The patients were treated with TDF monotherapy (four patients) or a combination of TDF and lamivudine (13 patients) for a median of 42 months. Hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) were measured, and renal function was also monitored.

Results

Prior to TDF therapy, 180 M, 204 I/V/S, 181 T/V, 236 T, and 184 L mutations were detected. After TDF therapy, the median HBV DNA level decreased from 4.6 log₁₀ IU/mL to 2.0 log₁₀ IU/mL and to 1.6 log₁₀ IU/mL at 12 and 24 months, respectively. HBV DNA became undetectable (≤20 IU/mL) in 14.3%, 41.7%, and 100% of patients after 12, 24, and 48 months of treatment, respectively. HBeAg loss was observed in two patients. Viral breakthrough occurred in five patients who had skipped their medication. No significant changes in renal function were observed.

Conclusions

TDF-based rescue treatment is effective in reducing HBV DNA levels and is safe for patients with CHB who failed prior antiviral treatments. Patients'' adherence to medication is related to viral rebound.     

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels

Summary. Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on‐treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty‐two patients with HBeAg‐positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on‐treatment factors, on‐treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log₁₀ IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940–1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On‐treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut‐off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log₁₀ PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on‐treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg‐positive CHB patients with entecavir treatment.     

Combined pre‐S deletion and core promoter mutations related to hepatocellular carcinoma: A nested case‐control study in China

Aim: To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) in Qidong, China. Methods: A total of 2387 males (aged 20–65 years) who were seropositive for the hepatitis B surface antigen (HBsAg), but had not been diagnosed with HCC, were recruited to a community‐based HCC screening study from August, 1996. Evaluation of virological parameters at recruitment was determined for 196 HCC patients during 10 years of follow‐up and 323 controls. Results: After adjustment for age at recruitment, history of cigarette smoking and alcohol consumption, alanine aminotransferase (ALT) elevation, alpha‐fetoprotein (AFP) levels >20 ng/mL, hepatitis B e antigen positive, HBV DNA levels ≥4.00 log₁₀ copies/mL, pre‐S deletion, T1653 mutation, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with subsequent risk of HCC. A significant biological gradient of HCC risk by HBV DNA levels from less than 2.69 log₁₀ copies/mL to 6.00 log₁₀ copies/mL or greater was observed. HBV with a complex mutation combination pattern (pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations) rather than a single mutation was associated with the development of HCC. The longitudinal observation demonstrated a gradual combination of pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC. Conclusions: AFP levels >20 ng/mL, high HBV DNA levels, pre‐S deletion, and T1762/A1764 double mutations at recruitment were independent risk factors of HCC. Combination of pre‐S deletion and core promoter mutations increased the risk of HCC.     

Kinetic Changes of Viremia and Viral Antigens of Hepatitis B Virus During and After Pregnancy

Whether pregnancy may influence the replication of hepatitis B virus (HBV) remains unknown. The authors aimed to clarify this issue by observing the kinetics of HBV deoxyribonucleic acid (DNA) and viral antigens in women during and after pregnancy.Total, 371 pregnant women with positive hepatitis B surface antigen (HBsAg) were enrolled. Serial sera collected during and after pregnancy were quantitatively measured for HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg).Total, 34 HBeAg-positive women underwent alanine aminotransferase (ALT) elevation during or after pregnancy; levels of HBV DNA and HBsAg in them showed no obvious change between second trimester or delivery and 7 to 12 months postpartum (P > 0.05). The 337 others had normal alanine aminotransferase levels during pregnancy and postpartum. In 147 HBeAg-positive women with follow-up 7 to 12 months postpartum, the average levels of HBV DNA (>7.0 log₁₀ IU/mL), HBsAg (>4.0 log₁₀ IU/mL), and HBeAg (>3.0 log₁₀ S/CO) were longitudinally constant during pregnancy and postpartum, respectively. In 173 women with follow-up 4.8 years postpartum, neither HBV DNA levels nor antigen titers showed significant difference between second trimester and 4.8 years postpartum, regardless of the HBeAg status. In addition, levels of HBV DNA and viral antigens in second trimester, around delivery, 6 to 8 weeks and 7 to 12 months postpartum showed no marked fluctuations, respectively.Serum levels of HBV DNA and viral antigens in HBsAg-positive women are highly constant during pregnancy and postpartum, regardless of the HBeAg status and alanine aminotransferase levels. This demonstrates that pregnancy has little influence on the HBV replication and antigen expression.     

Reassessing the role for lamivudine in chronic hepatitis B infection: a four-year cohort analysis

BACKGROUND/OBJECTIVES:

Lamivudine is readily available and inexpensive. Guidelines recommend other antiviral medications because they achieve superior virological suppression with less resistance. These data are based on clinical trial populations and may not be representative of typical hepatitis B virus (HBV) populations. The authors assessed lamivudine in maintaining long-term viral suppression in an adherent, frequently monitored, noninvestigational HBV-infected population.

METHODS:

All HBV patients (n=369) between 2000 and 2010 were evaluated in a retrospective, single-centre study. Virological response was defined by complete suppression of HBV DNA (<400 copies/mL) and was assessed at six to 12 month intervals over four years. Enzymatic and serological outcomes, as well as treatment failures were assessed.

RESULTS:

Forty-seven patients (36 men; mean age 44 years, mean alanine aminotransferase level 123 U/L; METAVIR stage 3/4 [n=21], treatment naive [n=41]) received lamivudine 100 mg to 300 mg daily. The mean pretreatment viremia was 5.19 log₁₀ copies/mL, and was above the limit of detection (>6.91 log₁₀ copies/mL) in 11 patients (23%). The mean (± SD) dosing duration was 32±22 months. Virological suppression was achieved in 45 (96%) patients. Mean viremia declined to 3.06 log₁₀ copies/mL (n=27) and 2.68 log₁₀ copies/mL (n=18) at 12 and 48 months, respectively, with 78% and 88% with undetectable viremia at these time points, respectively. The mean alanine aminotransferase level declined to 31 U/L and 36 U/L at 12 and 48 months, respectively. Seven of 13 (54%) hepatitis B e antigen-positive patients seroconverted. The treatment failure rate was 11%.

CONCLUSIONS:

In a selected group of HBV patients, successful long-term viremia suppression was achieved with low treatment failure rates. With strict dosing adherence and monitoring for virological breakthrough, sustained virological suppression can be reliably achieved with lamivudine in carefully selected patients.     

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon‐based therapy in patients with hepatitis B e antigen‐negative chronic hepatitis B

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long‐term outcome of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG‐IFN)‐based therapy. Serial serum samples from 91 patients with HBeAg‐negative CHB previously treated with PEG‐IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post‐treatment follow‐up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre‐treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut‐off 2.0 log₁₀ copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut‐off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log₁₀ copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG‐IFN‐based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising “stopping rule” in patients infected with HBV genotypes B or C.     

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.     

A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B

BACKGROUND & AIMS: A previous 4-week trial of telbivudine in patients with chronic hepatitis B indicated marked antiviral effects with good tolerability, leading to the present 1-year phase 2b trial. METHODS: This randomized, double-blind, multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/day and telbivudine 400 or 600 mg/day plus lamivudine 100 mg/day (Comb400 and Comb600) compared with lamivudine 100 mg/day in hepatitis B e antigen (HBeAg)-positive adults with compensated chronic hepatitis B. RESULTS: A total of 104 patients were randomized 1:1:1:1:1 among the 5 groups. Median reductions in serum hepatitis B virus (HBV) DNA levels at week 52 (log(10) copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05. At week 52, telbivudine monotherapy showed a significantly greater mean reduction in HBV DNA levels (6.01 vs 4.57 log(10) copies/mL; P < .05), clearance of polymerase chain reaction-detectable HBV DNA (61% vs 32%; P < .05), and normalization of alanine aminotransferase levels (86% vs 63%; P < .05) compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31% vs 22%) and less viral breakthrough (4.5% vs 15.8%) (P = NS for both). Combination treatment was not better than telbivudine alone. All treatments were well tolerated. In exploratory scientific analyses, clinical efficacy at 1 year appeared related to reduction in HBV DNA levels in the first 6 months of treatment. CONCLUSIONS: Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with lamivudine. Results with the combination regimens were similar to those obtained with telbivudine alone. These data support the ongoing phase 3 evaluation of telbivudine for treatment of patients with chronic hepatitis B.     

Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir

Registration studies show entecavir (ETV) to be effective and safe in NUC‐naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg‐positive and HBeAg‐negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty‐nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log₁₀ IU/mL. Ninety‐two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti‐HBe positive; 14% became HBsAg negative and 13% anti‐HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off‐treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off‐treatment, 3 of them showed HBeAg reversion and 4 lost anti‐HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.