Kinetics of hepatitis B surface antigen quasispecies during REP 2139‐Ca therapy in HBeAg‐positive chronic HBV infection

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long‐term administration of nucleos(t)ide analogues (NUCs) and peg‐interferon. Nucleic acid polymers (NAPs; REP 2139‐Ca and REP 2139‐Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti‐HBs in response to REP 2139‐Ca, whereas 3 of 12 patients did not show responses (>1 log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the ‘pre‐S/S’ open reading frame including the ‘a’ determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P = .28). However, these responders showed significant decline in viral complexity (P = .001) as REP 2139‐Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P = .99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in ‘a’ determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients’ poor HBsAg response during REP 2139‐Ca therapy.     

Efficacy and safety of continuous 4‐year telbivudine treatment in patients with chronic hepatitis B

In the phase‐III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2‐year treatment in HBeAg‐positive and HBeAg‐negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine‐treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2‐year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per‐protocol population. Amongst 293 HBeAg‐positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg‐negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off‐treatment follow‐up). The cumulative 4‐year resistance rate was 10.6% for HBeAg‐positive and 10.0% for HBeAg‐negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m² (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg‐positive and HBeAg‐negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg‐positive patients.     

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

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

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.     

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.     

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

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

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.     

Elevated serum levels of soluble CD14 in HBeAg‐positive chronic HBV patients upon Peginterferon treatment are associated with treatment response

Pegylated IFNα (PEG‐IFN) is one of the treatment options for chronic HBV (CHB) patients. However, the high patient treatment burden and limited response rate together clearly ask for biomarkers to predict PEG‐IFN response. Soluble CD14 (sCD14) is considered a marker for immune activation and has been shown to predict clinical outcome of HIV infection. However, studies on sCD14 in CHB infection are inconclusive, and its relationship with clinical outcome is largely unknown. Here, we measured sCD14 levels in CHB patients and investigated whether changes in sCD14 level related to PEG‐IFN response. Serum sCD14 levels were determined in 15 healthy controls, 15 acute self‐limited HBV, 60 CHB patients in different disease phases and 94 HBeAg+ CHB patients at week 0 and week 12 of a 52‐week PEG‐IFN treatment. Response to PEG‐IFN treatment was defined as HBeAg seroconversion or HBeAg loss at 26 weeks post‐treatment. The mean sCD14 level in acute HBV patients (3.0 µg/mL) was significantly higher than in CHB patients (2.4 µg/mL) and healthy controls (2.4 µg/mL). In CHB patients receiving PEG‐IFN, a significant increase in sCD14 was found after 12‐week treatment (median week 0:2.1 µg/mL; week 12:3.7 µg/mL). After 12‐week treatment, the fold change (FC = w12/w0) in sCD14 was significantly higher in responders compared to nonresponders (HBeAg seroconversion: median FC_responder = 2.1 vs FC_nonresponder = 1.6; HBeAg loss: median FC_responder = 2.2 vs FC_nonresponder = 1.5). Receiver operating characteristic curves demonstrated that FC‐sCD14_wk12/wk0 levels can be of significant value as a stopping rule to select patients at week 12 who are not likely to benefit from further PEG‐IFN treatment.     

Antiviral effect of entecavir in nucleos(t)ide analogue‐naïve and nucleos(t)ide analogue‐experienced chronic hepatitis B patients without virological response at week 24 or 48 of therapy

We investigated the antiviral effect of entecavir in nucleos(t)ide analogue (NA)‐naïve and NA‐experienced chronic hepatitis B patients without virological response (VR, HBV DNA < 300 copies/mL) at week 24 or 48. A total of 369 NA‐naïve and 181 NA‐experienced patients treated with entecavir monotherapy were analysed. Of the 369 NA‐naïve patients, 34 did not achieve VR at week 48. Of them, patients with HBV DNA ≤2000 copies/mL at week 48 achieved a higher VR rate than those with HBV DNA >2000 copies/mL (18/23 vs 3/11, P = 0.004). Two naïve patients with HBV DNA >2000 copies/mL developed entecavir‐ or lamivudine‐resistant mutants. In 98 lamivudine‐experienced patients without ever having lamivudine resistance, most patients with VR (72/72) and partial VR (300–10⁴ copies/mL; 20/23) at week 24 or VR at week 48 (89/91) could maintain or achieve VR after prolonged therapy. In 75 patients with prior resistance to lamivudine, prolonged entecavir therapy led to low VR rate in those without VR at week 24 (13/45) or 48 (4/34) and high entecavir‐resistance rate in those with or without VR at week 24 (6/30 with and 23/45 without) and 48 (8/41 with and 21/34 without). VR at week 48 was an independent predictor (HR 0.14, 95% CI 0.06–0.33) for entecavir‐resistant mutant development among the 75 patients with prior lamivudine‐resistant mutants. In conclusion, prolonged entecavir treatment resulted in a poor response in naïve patients with HBV DNA >2000 copies/mL at week 48 and patients with prior lamivudine‐resistant mutants without VR at week 24 or 48.     

Telbivudine therapy for chronic hepatitis B: A journey to identify super‐responders and to optimize treatment using the roadmap model

Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so‐called super‐responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log₁₀ copies/mL (2 × 10⁸ IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg‐positive patients and HBV DNA < 7 log₁₀ copies/mL (2 × 10⁶ IU/mL) in HBeAg‐negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre‐treatment characteristics and on‐treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.     

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

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

Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment

The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg‐positive and HBeAg‐negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg‐positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511–9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032–2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV‐infected patients treated with tenofovir exhibit a significant (≥1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg‐positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion.     

Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial

Chronic hepatitis B and its life-threatening sequelae are highly prevalent in China. There is a need for effective new therapies to suppress hepatitis B virus (HBV) replication and ameliorate liver disease. In this study, we compared the efficacy of telbivudine, a nucleoside analogue, with lamivudine in Chinese patients. In this phase III, double-blind, multicenter trial conducted in China, 332 patients with compensated hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B were randomly assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine daily for 104 weeks. The primary efficacy endpoint was reduction in serum HBV DNA levels at week 52 of treatment. Secondary endpoints included clearance of HBV DNA to undetectable levels, HBeAg loss and seroconversion, therapeutic response, and alanine aminotransferase (ALT) normalization. Viral resistance and safety were assessed. At week 52, among 290 HBeAg-positive patients, mean reductions of serum HBV DNA were significantly greater in telbivudine recipients than lamivudine recipients (6.3 log(10) versus 5.5 log(10), P < 0.001), and HBV DNA was polymerase chain reaction-negative in significantly more telbivudine recipients than lamivudine recipients (67% versus 38%, P < 0.001). ALT normalization (87% versus 75%, P = 0.007), therapeutic response (85% versus 62%, P = 0.001), and HBeAg loss (31% versus 20%, P = 0.047) were also significantly more common in the telbivudine group. Treatment effects showed similar patterns in the smaller HBeAg-negative group (n = 42). Viral resistance in telbivudine recipients was approximately half that observed with lamivudine; however, this difference was not statistically significant. Clinical adverse events were similar in the two treatment groups. CONCLUSION: In Chinese patients with chronic hepatitis B, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.     

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.     

Association of baseline vitamin D level with genetic determinants and virologic response in patients with chronic hepatitis B

Aim

The role of vitamin D in individuals with chronic hepatitis B (CHB) is unclear. We aimed to explore the association of baseline vitamin D level with genetic determinants and week‐104 treatment outcome in CHB patients.

Methods

Baseline serum 25‐hydroxycholecalciferol (25(OH)D) levels and genetic polymorphism within GC, DHCR7, and CYP2R1 were determined in stored serum of 560 patients who were enrolled into a multicenter, randomized, controlled study and completed 104 weeks of telbivudine monotherapy or telbivudine‐based optimized therapy. Virologic response was defined as hepatitis B virus DNA <300 copies/mL (52 IU/mL) at week 104.

Results

The mean 25(OH)D value was 29.64 ng/mL. The percentage of patients with vitamin D insufficiency (<30 ng/mL) and vitamin D deficiency (<20 ng/mL) were 55.0% and 20.9%, respectively. Gender, season, latitude, and GC rs2282679 polymorphism were independent factors of vitamin D status. Patients with sufficient vitamin D (≥30 ng/mL) achieved a higher virologic response rate than those with vitamin D insufficiency (81.7% vs. 67.2%, P < 0.001). The area under the curve of 25(OH)D to predict virologic response was 0.65 (P < 0.001; 95% confidence interval, 0.62–0.67). On multivariate analysis, 25(OH)D level was an independent predictor of virologic response, but not associated with hepatitis B envelope antigen (HBeAg) seroconversion or alanine aminotransferase (ALT) normalization.

Conclusions

Vitamin D insufficiency was highly prevalent in treatment‐naïve CHB patients in mainland China. Latitude and genetic determinants affect vitamin D status. Baseline vitamin D level can predict week‐104 virologic response, but not HBeAg seroconversion or ALT normalization.     

Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV‐/HBV‐coinfected patients

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV‐/HIV)‐coinfected patients receiving HBV‐active combined antiretroviral therapy (cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV‐active cART in a cohort of 59 HIV‐/HBV‐coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan–Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg‐positive [HBeAg(+); n = 36] and HBeAg‐negative [HBeAg(−);n = 23] patients. HBeAg(+) patients with an HBsAg on‐treatment decline ≥1 log IU/mL per year achieved higher HBsAg loss rates (P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(−) patients, a pretreatment baseline cut‐off level of HBsAg ≤100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(−) HIV‐/HBV‐coinfected patients receiving HBV‐active cART.     

Low efficacy of entecavir therapy in adefovir‐refractory hepatitis B patients with prior lamivudine resistance

Summary. We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir‐resistant mutants during entecavir (ETV) therapy in adefovir‐refractory patients with prior lamivudine resistance. Forty adefovir‐refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for ≥6 months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNA < 50 copies/mL by PCR after 24 weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (P = 0.039) and the presence of the rtL180M mutation (P = 0.038) were associated with an initial virologic response. During a mean follow‐up of 11.4 months, four patients (10%) experienced virologic breakthrough, while ETV‐resistant mutants were detected in six patients (15%). YMDD and adefovir‐resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48 weeks of therapy, 96 and 4% of patients had YMDD and adefovir‐resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir‐refractory patients with prior lamivudine resistance.     

HCV E1E2‐MF59 vaccine in chronic hepatitis C patients treated with PEG‐IFNα2a and Ribavirin: a randomized controlled trial

Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV‐specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy‐eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon‐(IFN)/ribavirin‐(RBV)] were randomly assigned to vaccine (V:23), Peg‐IFNα2a‐180‐ug/qw and ribavirin 1000–1200‐mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0‐4‐8‐12‐24‐28‐32‐36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2‐specific‐CD4 + T cells were performed at week 0‐12‐16‐48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV‐RNA levels (P = 0.026) at week 16. HCV E1E2MF59 vaccine in combination with Peg‐IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies.     

Cure for immune‐tolerant hepatitis B in children: is it an achievable target with sequential combo therapy with lamivudine and interferon?

We prospectively studied the HBsAg seroconversion with sequential combination therapy of lamivudine (LAM) and interferon (IFN) in hitherto untreatable ‘immune‐tolerant’ chronic hepatitis B in children. In this case–control study, 28 children with immune‐tolerant hepatitis B [HBsAg positive for >6 months with near normal aminotransferase level, minimal/no inflammation in liver histology and high viral load (HBV DNA>10⁷ copies/mL)] were treated with LAM alone at 3 mg/kg/day for 8 weeks followed by LAM plus IFN alpha (5 MU/m² three times a week) for another 44 weeks. They were compared with 34 untreated children. HBV markers (HBsAg, HBeAg, anti‐HBe, quantitative HBV DNA) were carried out at baseline, at the end of therapy and 6 monthly thereafter. The mean age was 5.9 ± 3.2 years and 24 were boys. End therapy response: HBe seroconversion was achieved in 11, and of these, five had complete response (HBsAg clearance), 11 did not respond and six had virologic response (DNA undetectable but no HBe seroconversion). Six months after therapy, 10 of the 11 (91%) originally seroconverted children remained seroconverted while one seroreverted. Six of the 28 (21.4%) children lost HBsAg and they remained HBsAg negative and anti‐HBs positive on follow‐up. After a mean follow‐up of 21.1 ± 11.9 months, the status remained same in the responders but one of the nonresponders HBe seroconverted (39.3%). There were no serious side effects of therapy. It is possible to achieve a cure in more than one‐fifth of immune‐tolerant children with hepatitis B with the sequential combination of LAM and IFN.