Off‐therapy precipitous HBsAg decline predicts HBsAg loss after finite entecavir therapy in HBeAg‐negative patients

Cessation of nucleos(t)ide analogue (Nuc) therapy in HBeAg‐negative patients may increase HBsAg loss rate in patients with sustained remission (SR) and non‐retreated clinical relapsers (CR). To investigate and compare the HBsAg kinetics from end of treatment (EOT) to HBsAg loss in these patients, serial serum samples after EOT from 36 SR and 12 CR with HBsAg loss (study group) and an 1:1 matched control who remained HBsAg‐seropositive (control group) were assayed retrospectively for quantitative HBsAg (qHBsAg). The results showed that study group SR and CR had comparable EOT features except SR had lower EOT qHBsAg (67.5 vs 350.5 IU/mL; P = 0.02; < 100 IU/mL: 58.3% vs 25%; P = 0.09). All showed gradual qHBsAg decrease then “precipitous HBsAg decline” (>0.5 log₁₀ IU/mL in 1 year) prior to HBsAg loss. Patients with EOT qHBsAg <100 showed earlier (<12 months) “precipitous HBsAg decline” (91.7% vs 58.3%; P = 0.017) and sooner HBsAg loss (5.5 vs 21.9 months; P = 0.026). The control group also showed gradual qHBsAg decrease but less frequent “precipitous HBsAg decline” (39.6% vs 100%; P < 0.001) which occurred later (15.1 vs 5.7 months; P = 0.003) and was less steep (slope ?0.6 vs ?1.65 log₁₀ IU/mL/year; P < 0.001). HBsAg loss was achieved in 92.9% of the patients with “precipitous HBsAg decline” >0.76 log₁₀IU/mL in 1 year. In conclusion, both the SR and CR groups showed gradual HBsAg decrease followed by a “precipitous HBsAg decline”, which is a prerequisite for HBsAg loss. Lower EOT HBsAg in the SR group and qHBsAg <100 IU/mL may reflect better immune control hence followed by sooner HBsAg loss.     

Serum HBsAg kinetics and usefulness of interferon‐inducible protein 10 serum in HBeAg‐negative chronic hepatitis B patients treated with tenofovir disoproxil fumarate

The kinetics of serum HBsAg and interferon‐inducible protein 10 (IP10) levels in patients with chronic hepatitis B infection treated with tenofovir are unclear. We evaluated the changes of HBsAg levels and the predictability of IP10 for HBsAg decline in 160 HBeAg‐negative patients receiving tenofovir for ≥12 months. Serum samples taken before and at 6, 12, 24, 36 and 48 months after tenofovir were tested for HBsAg levels. In 104 patients, serum samples before tenofovir were tested for IP10 levels. Compared to before tenofovir, HBsAg levels decreased by a median of 0.08, 0.11, 0.24, 0.33 and 0.38 log₁₀ IU/mL at 6, 12, 24, 36 and 48 months, respectively (P < 0.001). HBsAg kinetics did not differ between nucleos(t)ide analogue(s) naive and experienced patients. The 12‐, 24‐, 36‐ and 48‐month cumulative rates of ≥0.5 log₁₀ HBsAg decline were 8%, 16%, 24% and 41% and of HBsAg ≤100 IU/mL were 9%, 12%, 14% and 18%, respectively. The only factor associated with HBsAg ≤100 IU/mL was lower HBsAg levels before tenofovir (P < 0.001), while HBsAg decline ≥0.5 log₁₀ was associated with higher IP10 levels (P = 0.002) and particularly with IP10 > 350 pg/mL (P < 0.001). In conclusion, tenofovir decreases serum HBsAg levels in both nucleos(t)ide analogue(s) naive and experienced patients with HBeAg‐negative chronic hepatitis B infection. After 4 years of therapy, HBsAg ≤100 IU/mL can be achieved in approximately 20% of patients, particularly in those with low baseline HBsAg levels. HBsAg decline is slow (≥0.5 log₁₀ in 40% of patients after 4 years) and is associated only with higher baseline serum IP10 levels.     

Predictors of hepatitis B surface antigen loss,relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

Reliable predictors of outcomes after treatment discontinuation in HBeAg‐negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon‐inducible protein‐10 (IP10) and hepatitis B core‐related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg‐negative CHB patients who discontinued long‐term antiviral therapy. All HBsAg‐positive (n = 57) patients of the prospective DARING‐B study were included and followed monthly for 3 months, every 2/3 months until month‐12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE‐B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18‐month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month‐1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100‐1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month‐1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE‐B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg‐negative CHB.     

Baseline HBsAg and HBcrAg titres allow peginterferon‐based ‘precision medicine’ in HBeAg‐negative chronic hepatitis B patients

Quantitative hepatitis B core‐related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon‐alpha‐2a (PegIFN)‐based therapy. Sixty‐two HBeAg‐negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut‐offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log₁₀ IU/mL and 3.450 log₁₀ U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post‐treatment follow‐up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI [0.578, 0.855]) for HBsAg and 0.668 (95% CI [0.524, 0.811]) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590–0.947), 0.714(0.533–1.000) and 0.800(0.611–1.000), and NPVs for AUCs(95%CI) were 0.756(0.660–0.899), 0.718(0.630–0.857) and 0.765(0.675–0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log₁₀ IU/mL and qHBcrAg 3.450 log₁₀U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN‐based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN‐based ‘precision therapy’. Our results emphasize that the combination of PegIFN alpha‐2a plus TDF with 53% of SR might be an alternative to finite therapy.     

Long‐term observation on hepatitis B surface antigen seroclearance in therapy experienced HIV/HBV co‐infected Chinese

The aim of this retrospective study was to observe hepatitis B surface antigen (HBsAg) seroclearance and explore predictors of HBsAg loss in HIV/HBV‐co‐infected patients receiving long‐term lamivudine or both tenofovir and lamivudine containing therapies. Quantification of HBsAg, hepatitis B e antigen and HBV DNA before and after initiation of HBV‐active antiretroviral therapy in a total of 268 HIV/HBV‐co‐infected patients started treatment between 2005 and 2017 were performed. Over a median of 65.63 months of follow‐up, 10 (3.7%) were observed HBsAg loss and the quantification of HBsAg in 7 (2.6%) patients were less than 50 IU/mL. With the prolongation of antiretroviral therapy duration time, the rates of HBsAg seroclearance tended to increase gradually, rising from 1.8% (3/163) during 2‐4 years treatment to 29.4% (10/34) after antiretroviral therapy for up to 10 years. Lower baseline qHBsAg and HBV DNA levels and strong 12‐month declines in qHBsAg were significantly associated with HBsAg seroclearance. The event of HBsAg seroclearance is uncommon among Chinese individuals with HIV/HBV co‐infection who have been treated with anti‐HBV containing antiretroviral therapy, and lifelong therapy for HBV is needed for HIV/HBV co‐infected patients. Baseline qHBsAg and HBV DNA levels and qHBsAg decline rate were predictors for HBsAg seroclearance.     

Great and rapid HBsAg decline in patients with on‐treatment hepatitis flare in early phase of potent antiviral therapy

HB sAg decline during nucleos(t)ide analogue therapy in chronic hepatitis B with lower pretherapy ALT is usually small and slow. This study aimed to investigate why ~10% of such patients showed “rapid HB sAg decline” ≥0.5 log₁₀ IU /mL by month 6 of therapy. Patients with persistent pretherapy ALT <5X ULN who had qHBsA g at baseline, months 6 and 12 of entecavir or tenofovir therapy were studied. “On‐treatment ALT elevation” was defined as >10% increase above baseline to >2X ULN during first 6 months of therapy. Of the 256 patients treated, 51 experienced transient “on‐treatment ALT elevation” [group A], including 30 (11.7%) with ALT elevation to 2‐5X ULN [group A‐1] and 21 (8.2%) flared to >5X ULN [group A‐2]. The magnitude of qHBsA g decline and rate of “rapid HB sAg decline” by month 6 was significantly greater and more frequent in group A (?0.446 vs ?0.042 log₁₀ IU /mL ; 45.1 vs 8.8%, respectively, P  =  0.000) than in the remaining 205 patients without on‐treatment ALT elevation (group B), being greatest in patients with hepatitis flare (group A‐2: ?0.559 log₁₀ IU /mL and 57.1%, respectively). In patients with therapy ≥2 years, patients with “on‐treatment ALT elevation” also showed significantly greater annual HB sAg decline, more frequent to <100 IU /mL and 4 times higher HB sAg seroclearance rate. “On‐treatment ALT elevation,” especially flare >5X ULN , during entecavir therapy or tenofovir therapy may enhance/accelerate HB sAg decline, suggesting the effect of immune restoration upon potent viral suppression.     

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.     

Intensification with pegylated interferon during treatment with tenofovir in HIV–hepatitis B virus co‐infected patients

In hepatitis B “e” antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono‐infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long‐term effect of adding PegIFN to tenofovir (TDF)‐containing antiretroviral therapy on seroclearance in HBeAg‐positive patients co‐infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1‐year PegIFN intensification during TDF‐containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time‐dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed‐effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4–59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log₁₀IU/mL, respectively (P>.5 between groups). Median follow‐up was 33.4 months (IQR=19.0–36.3). During intensification, faster average declines of qHBeAg (?0.066 vs ?0.027 PEIU/mL/month, P=.001) and qHBsAg (?0.049 vs ?0.026 log₁₀IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person·years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person·years, P=.7). In conclusion, PegIFN intensification in HBeAg‐positive co‐infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN.     

HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg‐positive patients treated with nucleos(t)ide analogues

HBeAg seroconversion marks an important spontaneous change and treatment end‐point for HBeAg‐positive patients and is a pre‐requisite for HBsAg loss or functional cure. In this retrospective analysis, we aimed to identify predictors of seroconversion using serum quantitative HBsAg and HBcrAg, in HBeAg‐positive patients treated with nucleos(t)ide analogues (NA). Data and samples from 118 HBeAg‐positive adults (genotypes A‐G) started on NA between Jan 2005 and Sept 2016 were retrospectively analysed at several time‐points. The predictive power of on‐treatment levels of HBsAg and HBcrAg was determined using receiver operating curve (ROC) analysis and cut‐off values determined by maximized Youden's index. About 36.4% of patients achieved HBeAg seroconversion after a median of 39 months’ treatment. On treatment kinetics of HBV DNA, HBsAg and HBcrAg differed between HBeAg seroconverters and nonseroconverters. A combination of HBsAg and HBcrAg had the greatest predictive value for HBeAg seroconversion: at 6 months, HBsAg of 3.9 log₁₀ IU/mL and HBcrAg of 5.7 log₁₀ U/mL had a sensitivity of 71.4%, specificity of 79.5%, positive predictive value (PPV) of 65.2% and negative predictive value (NPV) of 83.8%, with AUROC of 0.769 (0.668, 0.869; 95%CI), and at 12 months, HBsAg 3.8 log₁₀ IU/mL and HBcrAg 5.5 log₁₀ U/mL had a sensitivity of 73.7%, specificity of 79.5%, PPV of 63.6% and NPV of 86.1%, with AUROC 0.807 (0.713, 0.901; 95% CI). In conclusion, our results may be used to identify patients who are unlikely to achieve treatment end‐points, which will be important as the future management of chronic hepatitis B looks to therapies that offer functional cure.     

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.     

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).     

Hepatitis B virus mother‐to‐child transmission among HIV‐infected women receiving lamivudine‐containing antiretroviral regimens during pregnancy and breastfeeding

The study included 309 HIV‐infected pregnant women receiving a lamivudine‐containing antiretroviral regimen from week 25 of gestational age until 6 months postpartum, during breastfeeding. Twenty‐seven of them (8.7%) were hepatitis B virus surface antigen (HBsAg) positive; at baseline, hepatitis B virus (HBV) DNA levels >3 log₁₀ IU/mL (with a median level of 6.2 log₁₀ IU/mL) were found in 10 women, who at one, three and six months postpartum had median levels of 5.2 log₁₀ IU/mL, 4.5 log₁₀ IU/mL and 2.8 log₁₀ IU/mL, respectively. Twenty‐four of the 30 breast milk samples evaluated had undetectable HBV DNA and the other six had values between 15 and 155 IU/mL. Median lamivudine concentrations were 1070 ng/mL in serum and 684 ng/mL in breast milk. Among the 24 HBV‐exposed children with available samples, 16 always tested negative, four had a transient infection, one had an undetermined status and three (12.5%) first tested positive at Month 12 or Month 24. Among the children born to the HBV‐uninfected mothers of the same cohort, the rate of HBsAg positivity at 12–24 months was 2% (4/196). Our finding of the absence of significative levels of HBV DNA in the breast milk of co‐infected mothers supports the present recommendations for breastfeeding in HBV‐infected women. Horizontal transmission can be hypothesized for the infections detected in children at 12–24 months. Children born to HBV‐positive mothers remained at higher risk of postnatal HBV acquisition compared to those born to HBV‐negative women.     

Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog

Using commercial quantitative assays, quantitative hepatitis B surface antigen (qHBsAg) has improved our understanding and management of chronic hepatitis B (CHB). The HBsAg level is highest in the immune tolerance phase, starts to decline during the immune clearance phase, and decreases slowly but progressively after hepatitis B e antigen (HBeAg) seroconversion. The HBsAg level is lowest in individuals with an inactive carrier state but higher in those who develop HBeAg-negative hepatitis. It has been shown that a reduction of HBsAg by 1 log IU/mL or more reflects improved host immune control of HBV infection. A combination of HBsAg <1000 IU/mL and HBV-DNA <2000 IU/mL can identify a 3-year inactive state in a genotype D HBeAg-negative carrier population. In the Asian-Pacific region, where HBV genotypes B and C are dominant, HBsAg levels of ≤10–100 IU/mL predict HBsAg loss over time. As to the prediction of disease progression, low-viremic carriers with HBsAg >1000 IU/mL have been shown to be at higher risks of HBeAg-negative hepatitis, cirrhosis, and hepatocellular carcinoma than those with HBsAg <1000 IU/mL. Although qHBsAg has been widely used in CHB patients receiving pegylated interferon therapy, the HBsAg decline is slow and does not correlate with HBV-DNA levels during nucleos(t)ide analogue (NUC) therapy. However, a rapid HBsAg decline during NUC therapy may identify patients who will finally clear HBsAg. A 6- to 12-monthly assessment of HBsAg level could be considered during NUC therapy. Taking these lines of evidence together, qHBsAg can complement HBV-DNA levels to optimize the management of CHB patients in our daily clinical practice.     

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.     

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.     

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.     

Efficacy and safety of telbivudine and tenofovir disoproxil fumarate in preventing hepatitis B vertical transmission: A real‐life practice

Mother‐to‐child transmission (MTCT) is a major obstacle in the elimination of hepatitis B virus (HBV) infection. Telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) are the two most common antiviral medicines for preventing MTCT. However, the efficacy and safety of LdT and TDF in preventing HBV vertical transmission during the second to third trimester have not been compared rigorously. Therefore, we carried out a prospective multicentre cohort study of chronic hepatitis B in mothers with HBV DNA > 10⁶ IU/mL, receiving LdT or TDF during the second to third trimester. Among the 893 mothers enrolled, 857 (LdT/TDF/untreated group (NTx) = 396/325/136) completed consecutive follow‐up with 854 infants (LdT/TDF/NTx = 395/323/136). LdT and TDF treatment resulted in a similar decrease of HBV DNA in mothers at delivery. Multivariate analysis indicated that only HBsAg titre at the baseline correlated with viral DNA decrease (P = 0.015). With intention‐to‐treat analysis, MTCT rates in the LdT, TDF and NTx group were 4.41%, 2.42% and 22.08%, respectively. An increasing vertical transmission rate was found to be closely associated with higher HBsAg titre, 5.32% and 17.65% infection rate was estimated in infants born to mothers with HBsAg > 4 and >5 log₁₀ IU/mL, respectively. No serious side effects were reported in either mothers or infants. LdT and TDF treatments were well tolerated and showed comparable efficacy in reducing MTCT. Higher risk of MTCT was shown in pregnant women with HBsAg > 4 log₁₀IU/mL.     

Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother‐to‐child transmission of hepatitis B virus

The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg‐positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log₁₀ copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive‐active immunoprophylaxis. The HBsAg‐positive rate of all infants at 7‐12 months of age was 5.1% (37/728). Specifically, the HBsAg‐positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti‐HBs levels between the infants aged 7‐12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV‐infected group were higher than those in the uninfected group (5.2 vs 3.4log₁₀ copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive‐active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti‐HBs levels of infants born to HBsAg‐positive mothers with HBV DNA higher than 6log₁₀ copies/mL.     

Switching to peginterferon for chronic hepatitis B patients with hepatitis B e antigen seroconversion on entecavir – A prospective study

Nucleos(t)ide analogues (NA) are effective in suppressing hepatitis B virus (HBV) replication, but most patients require long‐term treatment. This study aimed to investigate switching to peginterferon as a strategy to stop NA. Hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients who developed HBeAg seroconversion during NA treatment were studied. All patients received open‐label peginterferon alfa‐2a 180 μg/wk for 48 weeks, and NA was stopped at week 4 of peginterferon treatment. The primary endpoint was sustained response, which was defined as negative HBeAg, positive anti‐HBe and HBV DNA <2000 IU/mL at week 72. Other secondary endpoints including HBsAg loss at week 72 were also studied. Forty‐one patients treated with entecavir for 56 ± 23 months were recruited. Sustained response was achieved in 30 patients (73%, 95% confidence interval 58%‐84%). At week 72, 31 (76%) patients had HBeAg seroconversion, 56 (23%) patients had undetectable HBV DNA, 31 (76%) patients had normal ALT, and 6 patients (15%) had HBsAg loss. Baseline HBsAg level was the best predictor for both sustained response and HBsAg loss; the best HBsAg cut‐off for sustained response was <1500 IU/mL and that for HBsAg loss was <500 IU/mL by receiver operating characteristic curve analysis. Twenty‐two of 25 (88%) patients with baseline HBsAg <1500 IU/mL had sustained response. Five of 10 (50%) patients with baseline HBsAg <500 IU/mL developed HBsAg loss. Switching to peginterferon can be considered as a treatment option in NA‐treated patients with HBeAg seroconversion, particularly among those with lower HBsAg levels.