Treatment of chronic hepatitis B with nucleos(t)ide analogues

Recently antiviral therapies for chronic hepatitis B using nucleos(t)ide analogues have become standard treatment modalities on the basis of several independent guidelines, starting with those of the American Association for the Study of Liver Diseases (AASLD) and other such organizations and bodies, including the European Association for the Study of the Liver (EASL), the Asian Pacific Association for the Study of the Liver (APASL), and the Japanese Ministry of Health, Labour and Welfare (MHLW)'s research team. The philosophies underlying such treatment strategies are considered basically equivalent. MHLW's guidelines define subjects for medical intervention to be cases measuring alanine aminotransferase (ALT) ≥31 IU/L, with serological hepatitis B virus (HBV) DNA level ≥5 log copies/mL for hepatitis B e antigen (HBeAg)‐positive cases, and serological HBV DNA level ≥4 log copies/mL for HBeAg‐negative cases. These Japanese guidelines advocate entecavir as the first‐line treatment option for nucleos(t)ide‐naïve patients, and combination treatment of lamivudine and adefovir as the basis of treatment for patients with lamivudine‐ and/or entecavir‐resistant viruses. Of particular note for patients undergoing lamivudine treatment with persistent HBV DNA level < 2.1 log copies/mL is the recommendation of a switch to entecavir. Early detection of drug‐resistant virus is desirable after initiation of nucleos(t)ide analogue treatment, but such a procedure is not uniformly available at all medical institutions. Nevertheless, timely estimation of potential early‐stage drug‐resistant virus development is crucial for getting a head start on treatment. HBV core‐related antigen (HBcrAg) level or HBV DNA level are considered useful markers for the appearance of such drug‐resistant viruses.     

Efficacy and safety of entecavir treatment in a heterogeneous CHB population from a ‘real‐world’ clinical practice setting in China

Chronic hepatitis B infection is an important cause of liver‐related mortality in China. This study assessed the efficacy and safety of entecavir in a heterogeneous patient population from a ‘real‐world’ clinical practice setting in China. This prospective, observational cohort provides 48‐week data on 2600 patients from 50 sites in China who received entecavir (0.5 or 1.0 mg) and were assessed for virologic, serologic and biochemical responses. Patients were nucleos(t)ide‐naïve or ‐experienced and had compensated or decompensated liver function. At Week 48, 1545/2424 (64%) patients with compensated liver disease and 30/44 (68%) patients with decompensated liver disease achieved HBV DNA <50 IU/mL. Greater proportions of nucleos(t)ide‐naïve than nucleos(t)ide‐experienced (69% vs 53%), and adefovir‐experienced than lamivudine/telbivudine‐experienced (62% vs 52%) patients achieved this endpoint. Most patients with HBV DNA <50 IU/mL also achieved HBV DNA <12 IU/L (60%, 45% and 61% of nucleos(t)ide‐naïve, nucleos(t)ide‐experienced and decompensated patients, respectively). In patients with compensated liver disease, ALT values normalized in 1532/1792 patients (85%), and HBeAg loss and HBeAg seroconversion were observed in 17% and 15% of treatment‐naïve and 15% and 11% of treatment‐experienced patients. Entecavir was generally well tolerated. Adverse event rates were comparable between treatment‐naïve and treatment‐experienced patients with compensated liver disease, but were higher in decompensated than in compensated patients, consistent with previous reports in these patients with more advanced disease. Four patients discontinued treatment due to adverse events. In a ‘real‐world’ setting, entecavir was efficacious and well tolerated throughout 48 weeks in a heterogeneous Chinese CHB population.     

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B*

Summary. This retrospective analysis was conducted to describe the characteristics of nucleoside‐naïve hepatitis B e antigen (HBeAg)‐positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg‐positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double‐blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off‐treatment follow‐up. Through a maximum duration of 96 weeks on‐treatment and 24 weeks off‐treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside‐naïve HBeAg‐positive patients treated with entecavir, and that HBsAg loss is associated with sustained off‐treatment suppression of HBV DNA.     

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.     

Peg‐interferon and nucleos(t)ide analogue combination at inception of antiviral therapy improves both anti‐HBV efficacy and long‐term survival among HBV DNA‐positive hepatocellular carcinoma patients after hepatectomy/ablation

Antiviral therapy has been shown to improve the prognosis of hepatitis B virus (HBV) DNA‐positive hepatocellular carcinoma (HCC) after radical treatment, but antiviral treatments require further optimization. This study aimed to evaluate the efficacies of different antiviral strategies with HCC patients after hepatectomy/ablation. This prospective, randomized, controlled and multi‐centre trial enrolled HBV DNA‐positive primary HCC patients after hepatectomy/ablation between January 2007 and January 2009. Patients were divided into four groups: early combination (entecavir plus Peg‐interferon [IFN]α‐2a co‐administration during year 1); late combination (addition of Peg‐IFNα‐2a for 48 weeks after 1 year of entecavir); nucleos(t)ide analogue[NA] monotherapy; and non‐antiviral treatment. Primary endpoints included recurrence‐free survival and overall survival. A total of 447 patients were enrolled. The 2‐year and 8‐year recurrence‐free survival and 8‐year overall survival rates were significantly higher in the early combination group than in the other two antiviral groups (P < .05). After 48‐week treatment, more patients achieved an HBsAg reduction >1500 IU/mL and the mean HBsAg level was significantly lower in the early combination group compared with the late combination and NA monotherapy groups (P < .05). Multivariate analysis showed that early combination therapy and a reduction in HBsAg by >1500 IU/mL after 48 weeks of therapy correlated with reduced mortality and disease recurrence. Early introduction of combination antiviral treatment may represent a more effective therapeutic strategy for patients with HBV DNA‐positive HCC after hepatectomy/ablation. A reduction in HBsAg by >1500 IU/mL after 48‐week treatment is associated with reduced mortality and disease recurrence of HBV DNA‐positive HCC patients after hepatectomy/ablation.     

Long‐term (96‐week) follow‐up of antiretroviral‐naïve HIV‐infected patients treated with first‐line lopinavir/ritonavir monotherapy in the MONARK trial*

Background

The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral‐naïve patients.

Methods

A total of 136 antiretroviral‐naïve patients, with a CD4 cell count above 100 cells/μL and a plasma HIV RNA below 100 000 HIV‐1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n=83) or lopinavir/ritonavir+zidovudine/lamivudine (n=53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent‐to‐treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n=83), and then focused on patients who had an HIV RNA <50 copies/mL at week 48 (n=56).

Results

At week 96, 39 of 83 patients (47%) had HIV RNA <50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA >400 copies/mL. Focusing on the 56 patients with an HIV RNA <50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA <50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI‐associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96.

Conclusion

By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA <50 copies/mL at week 96. The occurrence in some patients of low‐level viraemia (50–500 copies/mL) may increase the risk of drug resistance. First‐line lopinavir/ritonavir monotherapy cannot be systematically recommended.     

Randomized prospective study showing the non‐inferiority of tenofovir to entecavir in treatment‐naïve chronic hepatitis B patients

Aim

The study aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) and entecavir hydrate (ETV) in nucleos(t)ide analog (NA)‐naïve Japanese chronic hepatitis B (CHB) patients.

Methods

This multicenter, randomized, double‐blinded study assessing the efficacy and safety of TDF 300 mg and ETV 0.5 mg in NA‐naïve CHB subjects was carried out from November 2011 to November 2014, and funded by GlaxoSmithKline. The subjects were assigned to the TDF arm or ETV arm in a 2:1 ratio. The primary efficacy endpoint was the non‐inferiority of TDF to ETV at week 24.

Results

A total of 166 subjects (TDF arm, 110; ETV arm, 56) were enrolled. The change (mean ± SE) in serum hepatitis B virus (HBV)‐DNA levels from baseline to week 24 was ?4.63 ± 0.044 and ?4.50 ± 0.063 log₁₀ copies/mL in the TDF and ETV arms, respectively, indicating the non‐inferiority of TDF to ETV (P < 0.0001). The proportion of subjects with undetectable HBV‐DNA increased from 54 to 77% and 39 to 66% in the TDF and ETV arms with continuation of the treatment from week 24 to 48, respectively. Reduction in hepatitis B surface antigen level was greater in subjects with hepatitis B envelope antigen (+) and high alanine aminotransferase levels (≥80 IU/L). Prevalence of drug‐related adverse events at week 48 was 20% and 18% in the TDF and ETV arms, respectively.

Conclusions

The study is the first to report that TDF has non‐inferiority to ETV in treatment effectiveness (lowering of serum HBV‐DNA level) at week 24. ClinicalTrials.gov trial registration nos. NCT01480284 and GSK LOC115409.     

Efficacy of switching to entecavir monotherapy in Japanese lamivudine‐pretreated patients

Background and Aims: To assess the efficacy of switching Japanese chronic hepatitis B patients from lamivudine monotherapy to entecavir 0.5 mg/day. Methods: A retrospective analysis was conducted on 134 patients switched to entecavir between September 2006 and February 2008 for 6 months or more. Patients were divided into three groups based on viral load at entecavir switching point (baseline < 2.6, 2.6–5.0 and > 5.0 log₁₀ copies/mL). Results: At baseline, detection of lamivudine‐resistant virus was highest in patients with higher hepatitis B virus (HBV) DNA (76% vs 23% in ≥ 2.6 and < 2.6 log₁₀ copies/mL, respectively), and in patients with longest previous exposure to lamivudine (52%, 28% and 24% for > 3 years, 1–3 years and < 1 year, respectively). Two years after entecavir switching, HBV DNA suppression to less than 2.6 log₁₀ copies/mL was achieved in 100% (32/32), 92% (12/13) and 44% (4/9) of patients in the less than 2.6, 2.6–5.0 and more than 5.0 log₁₀ copies/mL baseline groups, respectively. Alanine aminotransferase (ALT) normalization occurred in 76–96% and 90–100% of patients following 1 and 2 years of entecavir treatment, respectively. One patient (2.6–5.0 log₁₀ copies/mL) with lamivudine‐resistant mutants at baseline developed entecavir resistance at week 48 during follow up. Conclusion: Switching to entecavir 0.5 mg/day achieves or maintains undetectable HBV DNA levels and ALT normalization over 2 years, especially in patients with viral load less than 5.0 log₁₀ copies/mL.     

Characteristics of adefovir resistance in patients with or without lamivudine‐resistant hepatitis B virus treated with adefovir: a 4‐year experience

Background/Aim: We investigated the 4‐year incidence and predictors of adefovir resistance in chronic hepatitis B patients with or without lamivudine (LAM)‐resistance treated with adefovir dipivoxil with or without short‐term LAM overlapping. Methods: One hundred and two LAM‐resistant patients and 79 without LAM resistance (36 naïve and 43 prior LAM exposure) treated with adefovir for >12 months were prospectively examined. Results: Cumulative incidences of adefovir resistance at month 12, 24, 36 and 48 were 3.9, 21.1, 31.8 and 43% respectively in LAM‐resistant patients. Cirrhosis was a significant risk factor for adefovir resistance. A similar rate of adefovir resistance was observed for LAM‐resistant patients and those with prior LAM exposure without resistance. Regarding LAM‐resistant patients, compared with those having hepatitis B virus (HBV) DNA levels <300 copies/ml, patients having HBV DNA levels >10⁴ copies/ml at week 24 of therapy had a hazard ratio (HR) of 9.8 for adefovir resistance development, while those without LAM resistance having the same HBV DNA levels at week 48 had a similar HR (9.5). Multidrug‐resistant (LAM+adefovir) variants were detected by direct sequencing in three of 35 LAM‐resistant patients treated with a switch to adefovir. Two of them had resistant mutations to both drugs on the same viral genome as determined by molecular cloning and sequencing. Conclusion: The incidence of adefovir resistance was high in LAM‐resistant patients treated with sequential adefovir. High HBV DNA levels at week 24 and 48 of therapy were the strongest predictors for adefovir resistance development in patients with and without LAM resistance respectively.     

Serum NGAL can act as an early renal safety biomarker during long‐term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B

Tubular renal toxicity is a side‐effect of long‐term therapy with nucleos(t)ide analogue(s) (NA) in chronic hepatitis B (CHB). There are no established surrogate markers in plasma of early NA‐related toxicity. Neutrophil gelatinase‐associated lipocalin (NGAL) is a protein produced by tubular cells following renal damage. We aimed therefore to retrospectively compare conventional renal markers (estimated glomerular filtration rates (eGFR) and urinary protein/creatinine ratio uPCR) with a sensitive biomarker (NGAL) in CHB patients on long‐term NA therapy and assess the ability of new markers to predict NA‐related renal toxicity (new onset of nonalbumin proteinuria). A total of 192 naïve CHB patients (median age 41 years, 78% males, 25% HBeAg+, 35% cirrhosis) were NA treated for at least 5 years (median 8.34 years, range 5.54‐11.1 years). The eGFR and uPCR were compared at baseline and last clinical visit with serum NGAL concentrations measured by ELISA at same time‐points and assessed according to the presence/absence of nonalbumin proteinuria at last visit. While baseline and last visit eGFR were similar (median:78 vs 84 mL/min), serum NGAL concentrations increased during therapy (median:9.4 vs 16.4 ng/mL, P < .05). The proportion of patients with proteinuria (uPCR > 15) increased between baseline and last visit (4.6% vs 21.4%, P < .05), with 30 (16%) patients having de novo nonalbumin proteinuria at last visit. High baseline NGAL concentrations were exclusive to patients with de novo nonalbumin proteinuria (median:31.7 vs 7.8 ng/mL, P < .01) and baseline NGAL levels >25 mg/mL were predictive of nonalbumin proteinuria at last visit (AUROC = 0.813). In conclusion, serum NGAL can act as a surrogate marker of early renal injury (de novo nonalbumin proteinuria) in CHB on long‐term NA therapy.     

Comparison between clevudine and entecavir treatment for antiviral‐naïve patients with chronic hepatitis B

Background and Aims: There has been no study comparing the clinical efficacy of clevudine and entecavir in antiviral‐naïve patients with chronic hepatitis B (CHB). Methods: A total of 128 antiviral‐naïve CHB patients were included to receive clevudine 30 mg (n=55) or entecavir 0.5 mg (n=73) once daily for a mean follow‐up period of 18.4 months. Results: Thirty‐three (60.0%) in the clevudine group and 40 (54.8%) in the entecavir group were HBeAg positive (P>0.05). At 6 months from the baseline, the mean decreases in HBV‐DNA were 4.86 and 4.72 log₁₀ copies/ml in the clevudine and entecavir groups respectively (P>0.05). The proportion of patients with undetectable serum HBV‐DNA (<300 copies/ml) at 6 months was 65.5 and 74.0% in the clevudine and entecavir groups respectively (P>0.05). The proportion of patients with normal alanine aminotransferase levels at 6 months was 74.5 and 84.9% in the clevudine and entecavir groups respectively. During the mean follow‐up of 18.4 months, genotypic resistance was noted in three patients (5.5%) in the clevudine group and no cases in the entecavir group. Eight patients (14.6%) in the clevudine group experienced symptoms, signs and laboratory abnormalities relevant to clevudine‐induced myopathy. Conclusions: Clevudine and entecavir treatment effectively suppresses HBV replication in most antiviral‐naïve patients with CHB. During a mean follow‐up of 18.9 months, a small proportion (5.5%) of patients in the clevudine group developed genotypic resistance. However, a substantial proportion (14.6%) of patients in the clevudine group had an adverse effect of clevudine‐induced myopathy.     

Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues

The clinical relevance of viral blipping during nucleos (t) ide analogue (NA) treatment is unclear in chronic hepatitis B (CHB). We investigated the prevalence, risk factors and clinical outcomes for those with viral blipping during NA treatment. A retrospective cohort study investigated consecutively treated CHB patients from May 2008 to February 2015 on the NAs such as entecavir (ETV), tenofovir (TDF) and lamivudine (LAM). Included patients were previously treatment naive. Viral blipping was defined as serum HBV DNA >20 IU/mL on one occasion, and not >200 IU/mL, with subsequent measurement returning to undetectable levels, that is <20 IU/mL. A total of 242 treatment‐compliant CHB patients were included with 44 (18.2%) experiencing viral blipping. In multivariable Cox regression, Asian race (HR=7.40, 95% CI 1.01–54.29, P<.049), LAM therapy (vs ETV/TDF, HR=2.53, 95% CI 1.29–4.95, P<.007), higher creatinine (per SD, HR=1.47, 95% CI 1.21–1.79, P<.001), HBeAg positivity (HR=2.68, 95% CI 1.39–5.03, P<.003) and longer time to achieve undetectable HBV DNA (per month, HR=1.05, 95% CI 1.02–1.08, P=.001) were associated with an increased risk of viral blipping. Viral blipping did not show any significant association with viral breakthrough, HBsAg loss, ALT flares or disease progression. Viral blipping is a frequent event during NA therapy; however, it did not lead to any clinically significant outcomes. Thus, it may not require more frequent blood work and patient visits in clinical practice.     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

Association of on‐treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e‐antigen positive chronic hepatitis B

Aim: This study evaluated the on‐treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off‐treatment sustained virological response (SVR). Methods: Fifty‐one consecutive patients with hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off‐treatment without reappearance of HBeAg. Results: Twenty‐two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off‐treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off‐treatment. A decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86–142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18–185.73 [P = 0.036]; respectively). Conclusion: On‐treatment serum HBsAg level predicted early off‐treatment SVR to NUC therapy in patients infected with genotype C.     

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.     

Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation

Newer nucleos(t)ide analogues (NUCs) have better resistance profiles making hepatitis B immunoglobulin (HBIG)‐sparing protocol an attractive prophylactic approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). We evaluated the risk of HBV recurrence after withdrawal of HBIG in patients who had been under HBIG plus NUCs after LT. Stable patients without HBV recurrence after LT while receiving combination of HBIG plus NUCs for at least 12 months were eligible for HBIG discontinuation. The patients were at low risk for HBV recurrence (only 4.5% had detectable HBV DNA at the time of LT, and 32% had HBV/hepatitis D virus co‐infection). All patients were followed up with HBV serum markers, HBV‐DNA, and evaluation of renal function, including glomerular filtration rate. Forty‐seven recipients discontinued HBIG and were maintained on newer NUCs. Median follow‐up post‐HBIG withdrawal was 24 months (range: 6–40 months). Twenty‐eight (60%) patients continued on lamivudine in combination with adefovir dipivoxil (n = 23, 82%) or tenofovir (n = 5, 18%); 10 (21%) and 9 (19%) of the 47 patients continued on tenofovir and entecavir monoprophylaxis, respectively. Although 3 (6.3%) patients developed detectable hepatitis B surface antigen, all of them had undetectable HBV DNA and no clinical manifestations of HBV recurrence. Renal function was similar between the different groups of patients. In conclusion, maintenance therapy with newer NUCs after discontinuation of HBIG prophylaxis was effective, but further studies in larger cohorts with longer follow‐up are needed.     

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%.     

Add‐on peginterferon alfa‐2a to nucleos(t)ide analogue therapy for Caucasian patients with hepatitis B ‘e’ antigen‐negative chronic hepatitis B genotype D

Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D‐infected patients. We conducted an open‐label study of peginterferon alfa‐2a 180 μg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)‐negative, genotype D‐infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48‐week add‐on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per‐protocol population) was 67.4% (29/43) at week 48 (95% confidence interval [CI]: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa‐2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5‐log₁₀ and ≥1‐log₁₀ were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma‐induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa‐2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg‐negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).