Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg‐positive chronic hepatitis B

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG‐IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg‐positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99‐01 study). Patients received 52 weeks PEG‐IFN monotherapy (n = 136) or PEG‐IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG‐IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG‐IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow‐up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG‐IFN treatment. Early on‐treatment HBV RNA level may be used to predict nonresponse.     

Hepatitis B core‐related antigen monitoring during peginterferon alfa treatment for HBeAg‐negative chronic hepatitis B

Serum Hepatitis B core‐related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG‐IFN) therapy for HBeAg‐negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg‐negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG‐IFN alfa‐2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was ?3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (?2.4 vs ?1.0 log U/mL, P = 0.001), but no cut‐off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg ?2.5 log U/mL; HBV DNA: ?4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI‐95% [0.0.629‐0.855], P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI‐95% [0.629‐0.855] P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI‐95% [0.641‐0.867], P < 0.001). In conclusion, in Caucasian patients with HBeAg‐negative CHB, decline of HBcrAg during PEG‐IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG‐IFN treatment.     

Long‐term follow‐up of patients treated with entecavir and peginterferon add‐on therapy for HBeAg‐positive chronic hepatitis B infection: ARES long‐term follow‐up

Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log₁₀ HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates.     

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.     

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline

There is a lack of knowledge regarding the effect of peginterferon (PEG‐IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty‐two HBeAg‐positive and 67 HBeAg‐negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG‐IFN therapy were studied. After PEG‐IFN therapy, HBeAg‐negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg‐positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post‐treatment, 7 (13%) HBeAg‐positive and 9 (14%) HBeAg‐negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post‐treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg ‐positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg‐negative CHB): 71% vs 5% for HBeAg‐positive (P < 0.001) and 60% vs 16% for HBeAg‐negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg‐positive and HBeAg‐negative CHB, respectively). In conclusion, PEG‐IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.     

Efficacy and tolerability of pegylated interferon-α-2a in chronic hepatitis B: a multicenter clinical experience

Background and Aim: Pegylated interferon‐α (PEG‐IFN) provides potential advantages over nucleos(t)ide analogues in the treatment of chronic hepatitis B (CHB) given its finite course, durability and lack of drug resistance. Much of the evidence is derived from controlled studies and it is unclear whether these results can be replicated in an everyday, non‐controlled setting. The aim of this study was to examine the efficacy and tolerability of PEG‐IFN‐α2A in CHB patients in a clinical setting. Methods: Chronic hepatitis B patients treated with PEG‐IFN‐α2A (180 µg/week, 48 weeks) at five tertiary hospitals were retrospectively identified. Baseline demographic and clinical data, on‐treatment virological and serological responses and adverse events (AE) were recorded. Treatment outcomes were defined as alanine aminotransferase (ALT) normalization, hepatitis B virus DNA < 351 IU/mL and hepatitis B e antigen (HBeAg) seroconversion. Results: Sixty three HBeAg positive patients were identified (65% male, 80% born in Asia, 84% with viral loads > 6log IU/mL, 9.5% advanced fibrosis). Six months after therapy 46% achieved normalization of ALT, 16% had viral loads < 351 IU/mL and 32% achieved HBeAg seroconversion. 29 HBeAg negative patients were treated (75% male, 86% born in Asia, 48% had viral loads > 6log IU/mL, 24% advanced fibrosis). Six months post‐treatment, 55% and 36% maintained a normalized ALT and HBV DNA < 351 IU/mL, respectively. Optimal viral suppression was maintained in 50–75% of patients over 2 years of follow up. 6.5% of all patients discontinued therapy due to AEs. Conclusion: In everyday clinical practice PEG‐IFN therapy in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials.     

Entecavir maleate versus entecavir in Chinese chronic hepatitis B predominantly genotype B or C: Results at week 144

Reports on the efficacy and safety of long‐term entecavir treatment in chronic hepatitis B (CHB) predominantly genotype B or C are insufficient. This study presents the efficacy and safety of entecavir maleate in Chinese CHB patients. Patients were randomly assigned to receive 48‐week treatment with either 0.5 mg/day entecavir (group A) or 0.5 mg/day entecavir maleate (group B), and then all patients received treatment with 0.5 mg/day entecavir maleate from week 49. Two hundred and seventy‐five patients with CHB (HBeAg‐positive: 218) were analysed, predominantly (98.5%) with genotype B or C. Baseline characteristics were balanced. For the HBeAg‐positive CHB patients, the mean HBV DNA level decreased similarly (A: by 6.36 log₁₀ IU/mL vs B: by 6.31 log₁₀ IU/mL) between groups at week 144. The percentages of patients who achieved undetectable HBV DNA were similar (A: 70.59% vs B: 66.67%) between groups. Similar HBeAg loss rates (A: 43.53% vs B: 40.23%; P>.05) and HBeAg seroconversion rates (A: 21.52% vs B: 21.18%) were achieved. For the HBeAg‐negative CHB patients, similar reductions in HBV DNA levels from baseline (A: by 6.13 log₁₀ IU/mL vs B: by 5.65 log₁₀ IU/mL) and percentages of patients who achieved undetectable HBV DNA (A: 100% vs B: 100%) were achieved. The overall incidence of adverse events was comparable between groups. In conclusions, 48‐week administration of entecavir maleate and entecavir showed similar efficacy and safety in Chinese patients with CHB. Long‐term entecavir maleate treatment was effective and safe in CHB patients.     

Pegylated interferon alfa for chronic hepatitis B: systematic review and meta‐analysis

Conventional interferon alfa and nucleos(t)ide analogues, such as lamivudine, are frequently used for chronic hepatitis B (CHB) treatment, but are associated with adverse effects and viral resistance. Here we performed a systematic review and meta‐analysis evaluating all studies of pegylated interferon alfa (PEG‐IFNα) treatment in hepatitis B e antigen (HBeAg)‐positive and HBeAg‐negative patients with CHB. We searched electronic databases – PubMed, EMBASE, Cochrane Library and LILACS – for randomized controlled trials evaluating PEG‐IFNα therapy between 1999 and September 2014. Virological response was the primary outcome. We identified 14 studies involving 2829 patients. Our analysis revealed that PEG‐IFNα + lamivudine combination therapy produced better virological and biochemical responses than PEG‐IFNα monotherapy in HBeAg‐positive and HBeAg‐negative patients at the end of treatment. PEG‐IFNα + adefovir dipivoxil achieved better seroconversion rate than PEG‐IFNα in HBeAg‐positive patients at the end of treatment. The present findings demonstrated a beneficial response rate following PEG‐IFNα combination therapy with nucelos(t)ides among HBeAg‐positive and HBeAg‐negative patients with CHB. Further trials are needed to investigate simultaneous and sequential therapy strategies.     

A randomized clinical trial of peginterferon alpha‐2b with or without entecavir in patients with HBeAg‐negative chronic hepatitis B: Role of host and viral factors associated with treatment response

Combining peginterferon (PEG‐IFN) and a potent nucleoside/nucleotide analogue might improve treatment response in patients with chronic hepatitis B (CHB). The aims of this study were to compare the efficacy of PEG‐IFN alpha‐2b with or without entecavir in HBeAg‐negative CHB and to investigate predictors of response. A total of 126 treatment‐naïve patients were randomly assigned to receive monotherapy (n = 63) or combination therapy (n = 63) for 48 weeks. Virological response (VR) was defined as HBV DNA level <2000 IU/mL at week 96. Baseline factors including polymorphisms in the IFNL3 (rs12979860) and HLA‐DPA1 (rs3077) genes and on‐treatment viral kinetics were determined. At week 48, rates of undetectable HBV DNA were lower in the monotherapy than combination groups, but rates of HBsAg clearance and decline were comparable. At week 96, there was no difference between the corresponding groups regarding virological response (41.3% vs 38.1%, P = 0.856), HBsAg clearance (9.5% vs 4.8%, P = 0.491) and HBsAg decline. Baseline HBsAg level [odds ratio (OR): 3.14 (1.34–7.69), P = 0.012] and rs3077 polymorphism [OR: 2.78 (1.27–6.11), P = 0.011] were independent predictors of response. Patients carried GG genotype of rs3077 with low baseline HBV (<1000 IU/mL) had high probability of achieving VR (76.5%) and HBsAg clearance (29.4%). None of the patients without decrease in HBsAg combined with <2 log₁₀ HBV DNA decline at week 12 achieved a virological response. In conclusion, the combination therapy lead to greater on‐treatment HBV DNA suppression but did not improve virological response and HBsAg clearance/decline over monotherapy. Host and viral factors could help optimize decision‐making at baseline and during PEG‐IFN‐based therapy.     

IFNL3 (IL28B) polymorphism does not predict long‐term response to interferon therapy in HBeAg‐positive chronic hepatitis B patients

The impact of IFNL3 (IL28B) polymorphism on response to interferon (IFN) treatment in patients infected with hepatitis B virus (HBV) is controversial. We aimed to investigate whether IFNL3 polymorphism (rs12979860) influences the long‐term response of chronic hepatitis B (CHB) treatment to conventional IFN. Design: Ninety‐seven HBeAg‐positive patients treated with IFN were evaluated in this study. Associations were investigated between IFNL3 genotypes and (i) HBeAg seroconversion at the end of treatment (EOT), (ii) sustained virological response (SVR) and (iii) HBsAg seroconversion through long‐term follow‐up (LTFU). Patients were followed for a median of 14 years. The majority of patients were infected with HBV genotype A (69.6%) and were Caucasian (77.9%). Ninety‐five patients were genotyped at rs12979860. Similar IFNL3 distribution was observed among the different ethnicities (P = 0.62) or across HBV genotypes A through G (P = 0.70). Thirty‐six patients experienced HBeAg seroconversion at EOT; HBeAg seroconversion rates were 37.0 and 35.5% in patients with CC and CT/TT genotypes, respectively (P = 0.82). Among the 44 patients (45%) who achieved a SVR, SVR rates were 48.9 and 39.6% in patients with CC and CT/TT IL28B genotypes, respectively (P = 0.80). HBsAg seroconversion occurred through LTFU in 28 patients. HBsAg seroconversion rates were 25.5 and 31.2% in patients with CC and CT/TT genotypes, respectively (P = 0.51). No significant relationship between IFNL3 rs12979860 and fibrosis stage was observed (P = 0.85). IFNL3 genotype was neither associated with SVR, nor with HBeAg seroconversion and long‐term HBsAg seroconversion in HBeAg‐positive CHB patients responding to IFN therapy.     

Hepatitis B surface antigen reduction by switching from long‐term nucleoside/nucleotide analogue administration to pegylated interferon

Hepatitis B surface antigen (HBsAg) reduction during nucleoside/nucleotide analogue (NA) therapy is slow and an alternative strategy for patients receiving ongoing NA to facilitate HBsAg reduction is required. We investigated whether switching to pegylated interferon (PEG‐IFN) after long‐term NA administration enhances HBsAg reduction. Forty‐nine patients who switched from long‐term NA to 48 weeks of PEG‐IFN alfa‐2a were studied. The mean duration of previous NA was 48 months (sequential group). A total of 147 patients who continued NA and matched for baseline characteristics were analysed for comparison (NA continuation group). The treatment response was defined as HBsAg reduction ≥1.0 logIU/mL at the end of PEG‐IFN. HBsAg reduction at week 48 was 0.81±1.1 logIU/mL in the sequential group, which was significantly higher than that in the NA continuation group (0.11±0.3 logIU/mL, P < .001). The treatment response was achieved in 29% and 2% of the sequential group and NA continuation group (P < .001), and the odds ratio of sequential therapy for the treatment response was 19 compared with the NA continuation (P < .001). In patients tested positive for hepatitis B e antigen (HBeAg), HBeAg seroconversion was higher in the sequential group (44% vs 8%, P < .001). In HBeAg‐negative patients, only patients in the sequential group achieved HBsAg loss. No patient needed to resume NA administration because of HBV DNA increase accompanied by alanine aminotransferase flares. In summary, sequential therapy with PEG‐IFN after long‐term NA enhances the reduction of HBsAg and may represent a treatment option to promote HBsAg loss.     

Interferon‐α treatment in children and young adults with chronic hepatitis B: a long‐term follow‐up study in Taiwan

Background/Aims: The short‐ and long‐term benefits of interferon (IFN)‐α therapy in young patients with chronic hepatitis B (CHB) acquiring infection perinatally or during early childhood have been questioned. Methods: Twenty‐one Taiwanese hepatitis B envelope antigen (HBeAg)‐positive CHB patients aged 1.8–21.8 years (median 14.0 years) with alanine aminotransferase (ALT)>80 IU/L at entry were enrolled for IFN‐α therapy. They received IFN‐α therapy with a dose of 3 MU/m²/day three times a week for 24 weeks. A control group included untreated 21 CHB patients closely matched for gender, age, duration of ALT >80 IU/L and HBeAg status. All 42 patients were prospectively followed for 6.5–12.5 years after the end of therapy. Results: The cumulative rate of virological response [anti‐HBe seroconversion and serum hepatitis B virus (HBV)‐DNA <10⁵ copies/ml] was not different between the IFN‐treated patients and control patients at 1 year (41 vs 44%) and at 6 years (88 vs 89%) after stopping treatment. Serum hepatitis B surface antigen loss occurred in two (9.5%) treated patients and in one (4.8%) control patient. Patients with a successful treatment response (anti‐HBe seroconversion, HBV‐DNA <10² copies/ml and ALT normalization at 1 year after stopping treatment) were younger than those without a successful response (P=0.03). A lower pretreatment serum HBV‐DNA level (<2 × 10⁸ copies/ml) is not only a significant factor to predict successful treatment response (P=0.008) but also has a beneficial effect on the long‐term cumulative rate of virological response in IFN‐treated patients (P=0.021), but not in control patients. Genotype difference or emergence of a precore stop codon mutant before treatment was not predictive for HBeAg clearance. Conclusion: For young CHB patients in Taiwan with infection occurring perinatally or in early childhood, the real advantage of IFN‐α therapy was not observed. IFN‐α therapy showed a beneficial effect on short‐ and long‐term virological outcomes only in those with a lower pretreatment serum HBV‐DNA level.     

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.     

Effect of nucleoside analog‐interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B

Aim: Nucleoside analog (NA)‐interferon (IFN) sequential therapy may enable the long‐term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA‐IFN sequential therapy for acute exacerbation of CHB. Methods: A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN‐α 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN‐α alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results: Four out of nine (44.4%) HBeAg‐positive and all three HBeAg‐negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core‐related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion: NA‐IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment.     

HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

Combining peginterferon‐alfa‐2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow‐up. In the initial study, 92 CHB patients (44 HBeAg‐positive, 48 HBeAg‐negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 μg/week and 10 mg adefovir dipivoxil daily. For the long‐term follow‐up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg‐positive, 38 HBeAg‐negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg‐positive patients and 16% (6/38) of HBeAg‐negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5‐year cumulative Kaplan‐Meier estimate for HBsAg loss was 17.2% for HBeAg‐positive patients and 19.3% for HBeAg‐negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow‐up developed anti‐HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg‐positive and 71% (27/38) of HBeAg‐negative patients were retreated with nucleos(t)ide analogues during follow‐up. The cumulative Kaplan‐Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow‐up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti‐HBs antibodies.     

核苷(酸)类似物序贯干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者的临床观察

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者在核苷(酸)类似物抗病毒治疗基础上序贯聚乙二醇干扰素α-2a(PEG IFNα-2a)治疗48周血清HBsAg的变化.方法 6例HBeAg阳性CHB患者中,3例采用核苷(酸)类似物序贯PEG IFNα-2a治疗48周,3例维持原核苷(酸)类似物治疗方案,每12周采用实时PCR定量检测HBV DNA,采用时间分辨免疫荧光分析法检测HBsAg、抗-HBs、HBeAg、抗-HBe及抗-HBc.结果 核苷(酸)类似物序贯PEG lFNα-2a治疗48周后,3例序贯治疗患者血清HBsAg均消失,而维持原核苷(酸)类似物治疗患者血清HBsAg效价为100～320 IU/mL.结论 对核苷(酸)类似物治疗产生较好应答反应且伴有血清HBsAg效价明显下降的HBeAg阳性CHB患者,在核苷(酸)类似物抗病毒治疗基础上序贯PEG IFNα-2a治疗48周能有效促进血清HBsAg下降,并出现血清HBsAg消失的现象.     

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%.     

Impact of ribavirin priming on viral kinetics and treatment response in chronic hepatitis C genotype 1 infection

Ribavirin amplifies the interferon‐alpha (IFN) signalling cascade. As ribavirin needs 4 weeks to reach steady state, ribavirin priming may optimize hepatic IFN sensitivity before starting a pegylated (PEG)‐IFN/ribavirin combination therapy. This study investigated potential benefits of ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy on viral kinetics, on‐treatment and sustained virological response (SVR) in chronic hepatitis C virus (HCV) genotype 1 infection. Sixty‐eight treatment naive patients were randomized 2:2:1 to ribavirin (ribavirin arm) or placebo (placebo arm) or PEG‐IFN2a (PEG‐IFN2a arm) for 6 weeks prior to 12 weeks of PEG‐IFN2a/ribavirin combination therapy within a double‐blind, placebo‐controlled trial. Then, standard PEG‐IFN2a/ribavirin combination therapy according to the German guidelines was continued under the responsibility of the investigators. Ribavirin was given according to body weight and PEG‐IFN2a at a dose of 180 μg subcutaneously once/week. During ribavirin priming, HCV RNA showed a decline of −0.58 log₁₀ IU/mL (P < 0.001) that was unrelated to the IL28B rs12979860 genotype (CC vs CT/TT, P = 0.244). Ribavirin priming did neither increase the PEG‐IFN2a‐induced first‐ or second‐phase viral decline (P values >0.100) nor on‐treatment response or SVR (HCV RNA undetectable at week 12 of combination therapy: ribavirin arm 56%, placebo arm 38%, PEG‐IFN2a arm 50%; SVR: ribavirin arm 41%, placebo arm 54%, PEG‐IFN2a arm 50%; P values >0.300). In conclusion, ribavirin monotherapy showed a significant antiviral activity that was not influenced by the IL28B genotype. Ribavirin priming prior to PEG‐IFN2a/ribavirin combination therapy did neither increase the first‐ or second‐phase viral decline nor on‐treatment response or SVR.     

Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss

Viral load reduction facilitates recovery of antiviral T‐cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg‐positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T‐cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post‐treatment (at 4‐week intervals). Before and at week 12 of treatment, paired liver biopsies were analysed for intrahepatic HBV‐DNA and cccDNA via real‐time fluorescent PCR. In situ detection of CD4⁺, CD8⁺ T cells and NK cells was analysed by immunohistochemistry. With viral load reduction, HBV‐specific IFN‐γ‐producing CD4⁺ T cells in patients with HBeAg loss were greatly enhanced and reached the highest level at week 12, with further increase observed between week 36 and week 48. After 12 weeks of treatment, total intrahepatic HBV‐DNA and cccDNA had significantly decreased; however, there was no difference in the viral loads or extent of reduction between patients with and without HBeAg loss. Paralleling reduction in viral load, intrahepatic CD8⁺T lymphocytes increased in patients with HBeAg loss compared with baseline values. Only one patient without HBeAg loss exhibited similar results. Increased immune cells were observed in certain patients along with reduced hepatic viral loads during the second phase of HBV‐DNA decline, which could promote the recovery of antiviral immunity and facilitate HBeAg loss.