HBV DNA and HBsAg Levels at 24 Weeks Off-Treatment Predict Clinical Relapse and HBsAg Loss in HBeAg-Negative Patients Who Discontinued Antiviral Therapy.

BACKGROUND & AIMS: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. METHODS: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. RESULTS: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P < .001) and a lower chance of HBsAg loss (HR, 0.454; P < .001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P < .001) and a lower chance of HBsAg loss (HR, 0.263; P < .001). A combination of both HBsAg <100 IU/mL and HBV DNA <100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg >100 IU/mL and HBV DNA >100 IU/mL (P < .001). CONCLUSIONS: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg <100 IU/mL with HBV DNA <100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.

Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study.

BACKGROUND: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis. METHODS: We analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. RESULTS: The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4). CONCLUSIONS: Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. METHODS: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. RESULTS: We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p = 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p = 0.001). CONCLUSIONS: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. LAY SUMMARY: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.

Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).

BACKGROUND & AIMS: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation. METHODS: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders. RESULTS: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001). CONCLUSIONS: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.

Utility of handgrip strength (HGS) and bioelectrical impedance analysis (BIA) in the diagnosis of sarcopenia in cirrhotic patients.

BACKGROUND: Sarcopenia is associated with disability, mortality, and poorer survival in cirrhotic patients. For the evaluation of muscle volume, computed tomography (CT) is the most accurate tool. Unfortunately, it would be hard to apply a muscle mass measuring CT to daily practice. This research aims to study the utility of handgrip strength (HGS) and bioelectrical impedance analysis (BIA) to detect sarcopenia in cirrhotic patients compared with CT as the reference. METHODS: In cirrhotic patients who met inclusions criteria (age 20-70 years, ascites < grade 2 of International Ascites Club grading system, no active malignancy, and no cardiac implanted device), HGS were measured using a Jamar dynamometer. Subsequently, patients with low muscle strength (defined as JSH criteria, < 26 kg in male, < 18 kg in female) were then underwent CT and BIA (Tanita MC780 MA) on the same day to measure muscle volume, the definition of sarcopenia by CT was according to the Japan Society of Hepatology (JSH). We also collected data from patients with normal HGS whose CT results were available in the study period. RESULTS: From 146 cirrhotic patients who underwent HGS, 30 patients (20.5%) had diagnosed low HSG. Data from 50 patients whose available CT results included 30 low HGS and 20 patients with normal HSG. The HGS was strongly correlated with skeleton muscle index (SMI) by CT (r = 0.81, p < 0.001) and had an excellent diagnostic performance for detecting sarcopenia by using JSH criteria the sensitivity, specificity, NPV and PPV were 88.2%, 100%, 100%, and 98.7% respectively. In contrast, only 6 of 30 patients (20%) met sarcopenic criteria by BIA. Among sarcopenic patients, the result showed a fair correlation between SMI and BIA (r = 0.54; p < 0.002). CONCLUSION: Our study demonstrated an excellent correlation between HGS and SMI by CT in the mixed cirrhotic population from the sarcopenia and non-sarcopenia groups. The HGS using the JSH criteria showed an excellent performance in detecting sarcopenia compared to CT. Nonetheless, for the BIA by using the current cut-offs demonstrated unacceptable rate to detect sarcopenia.

Diagnostic performance of endoscopic ultrasound-guided tissue acquisition by EUS-FNA versus EUS-FNB for solid pancreatic mass without ROSE: a retrospective study.

BACKGROUND: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is an established diagnostic procedure for solid pancreatic mass. However, the diagnostic yield between fine-needle aspiration (FNA) and fine-needle biopsy (FNB) remains unclear. We aimed to evaluate and compare the diagnostic yields between FNA and FNB using conventional FNA and Franseen needles of the same size 22-gauge needle, in patients with solid pancreatic mass who underwent EUS-TA without rapid onsite cytopathology evaluation (ROSE). METHODS: All cases of EUS-TA by FNA or FNB for solid pancreatic mass between January 2017 and October 2020 in a single-centre university hospital were retrospectively reviewed. All procedures were performed without an onsite cytologist. Before the endoscopist finished the procedure, macroscopic onsite evaluation (MOSE) was confirmed. The diagnostic yield and the average number of needle passes between FNB and FNA were then compared. RESULTS: A total of 151 patients (FNA, n = 77; FNB, n = 74) with solid pancreatic mass detected by cross-sectional imaging underwent EUS-TA. The mean age was 62.3 ± 12.8 years, with 88 (58.3%) males. Age, sex, mass location, tumour size and disease stage from imaging were not significantly different between the two groups. The diagnostic performance was higher in EUS-FNB (94.6%) than in EUS-FNA (89.6%). The mean number of needle passes was clearly fewer in FNB than in FNA (2.8 vs. 3.8, p < 0.001). The total procedure time was shorter in FNB (34.7 min) than in FNA (41 min). The adverse event rate between FNB and FNA was not significantly different. CONCLUSIONS: The diagnostic yield of solid pancreatic mass was higher in FNB using the Franseen needle than in FNA using the conventional FNA needle in a centre where ROSE is unavailable, without serious adverse event. In addition, FNB had fewer needle passes and shorter total procedure time.

Hepatitis B surface antigen, core-related antigen and HBV RNA: Predicting clinical relapse after NA therapy discontinuation.

BACKGROUND & AIMS: The safe discontinuation of nucleos(t)ide analogue therapy remains challenging in chronic hepatitis B. We investigated the potential role of quantitative hepatitis B surface antigen, hepatitis B core-related antigen and hepatitis B virus RNA at the end of treatment in predicting off-therapy relapse. METHODS: Patients who fulfilled the stopping criteria of the Asian Pacific Association for the Study of the Liver guideline were enrolled. Virological relapse was defined as hepatitis B virus DNA level greater than 2000 IU/mL, and clinical relapse was defined as virological relapse plus alanine aminotransferase level of more than twice the upper limit of normal. RESULTS: Ninety-two patients participated. The combination of end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA levels was most predictive of clinical relapse. Multivariate analysis revealed that end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA were independently associated with clinical relapse. During follow-up, no patients with undetectable hepatitis B core-related antigen (<3.0 log10 U/mL) and hepatitis B virusRNA (<2.0 log10 copies/mL) at end of treatment developed clinical relapse, in comparison with 22.9% and 62.5% patients with detectable levels of one or both biomarkers respectively. End-of-treatment quantitative hepatitis B surface antigen was linked to a likelihood of hepatitis B surface antigen clearance. CONCLUSIONS: The combined hepatitis B core-related antigen and hepatitis B virus RNA assays at end of treatment were highly predictive of subsequent clinical relapse. These novel biomarkers could potentially be used to identify patients who could safely discontinue nucleos(t)ide analogue therapy.

Real-world effectiveness and safety of sofosbuvir and nonstructural protein 5A inhibitors for chronic hepatitis C genotype 1, 2, 3, 4, or 6: a multicentre cohort study.

BACKGROUND: We investigated real-world effectiveness and safety of sofosbuvir and the nonstructural protein 5A inhibitors in the treatment of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, 4, or 6. METHODS: We analyzed data from 1021 patients with HCV infection (506 with genotype 1; 16 with genotype 2; 314 with genotype 3; 13 with genotype 4; 166 with genotype 6) who received 12 to 24 weeks of daclatasvir plus sofosbuvir (n = 767), ledipasvir/sofosbuvir (n = 197), or sofosbuvir/velpatasvir (n = 57), with or without ribavirin in 12 centers across Thailand to estimate sustained virologic response at post-treatment week 12 (SVR12). RESULTS: Overall, SVR12 rate was 98.0% (95% confidence interval [CI], 96.7-98.8%) with daclatasvir plus sofosbuvir, 97.9% (95% CI, 94.8-99.2%) with ledipasvir/sofosbuvir, and 96.5% (95% CI, 88.1-99.0%) with sofosbuvir/velpatasvir. SVR12 was achieved by 99.2% (95% CI, 97.9-99.7%) of subjects with genotype 1 infection, 100% (95% CI, 78.5-100%) of those with genotype 2 infection, 96.7% (95% CI, 94.0-98.2%) of those with genotype 3 infection, 90.9% (95% CI, 62.3-98.4%) of those with genotype 4 infection, and 96.7% (95% CI 92.5-98.6%) of those with genotype 6 infection. Patients with advanced liver disease were at risk of treatment failure. Only four patients discontinued treatment before week 4 due to non-hepatic adverse events. CONCLUSIONS: In this large cohort of patients with various HCV genotypes managed in the real-world practice setting, daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, and sofosbuvir/velpatasvir achieved high SVR rates with good safety profile, comparable to those observed in clinical trials.

Validation of original, expanded Baveno VI, and stepwise & platelet-MELD criteria to rule out varices needing treatment in compensated cirrhosis from various etiologies.

INTRODUCTION AND OBJECTIVES: The Baveno VI criteria to rule out varices needing treatment (VNT) was introduced in 2015. Soon after, the expanded Baveno VI and stepwise platelet-MELD criteria were proposed to be equal/more accurate in ruling out VNT; however, neither has been widely validated. We aimed to validate all 3 criteria in compensated cirrhosis from assorted causes. MATERIALS AND METHODS: We conducted a cross-sectional study including all adult compensated cirrhotic patients who underwent endoscopic surveillance at our center from 2014 to 2018 and had transient elastography (TE), and laboratory data for criteria calculation within 6 months of endoscopies. Exclusion criteria were previous decompensation, unreliable/invalid TE results, and liver cancer. The diagnostic performances of all criteria were evaluated. RESULTS: A total of 128 patients were included. The major cirrhosis etiologies were hepatitis C and B (37.5% and 32.8%, respectively). VNT was observed in 7.8%. All criteria yielded high negative predictive values (NPVs)>95%, missed VNT was observed in 2%, 2.7%, and 2.8% in the original, expanded Baveno VI, and platelet-MELD criteria, respectively. The expanded Baveno VI and the platelet-MELD criteria yielded significantly better specificities and could spare more endoscopies than the original Baveno VI criteria. CONCLUSIONS: All 3 criteria showed satisfactorily high NPVs in ruling out VNT in compensated cirrhosis from various causes. The expanded Baveno VI and the platelet-MELD criteria could spare more endoscopies than the original Baveno VI criteria. From a public health standpoint, the platelet-MELD criteria might be useful in a resource-limited setting where TE is not widely available.

Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B.

In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10-8 ) in single-marker analyses, but suggestive associations (P < 1 × 10-5 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10-8 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10-7 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).

Re-bleeding and its predictors after capsule endoscopy in patients with obscure gastrointestinal bleeding in long-term follow-up.

BACKGROUND: Capsule endoscopy (CE) is the preferred diagnostic test of choice in the investigation of obscure gastrointestinal bleeding (OGIB). Although, a conservative strategy is recommended in the short-term, for cases with a negative result from CE, the impact of CE on long-term re-bleeding still remains unclear. Hence, the aim of this study was to determine the long-term re-bleeding rate along with predictors after CE in patients with OGIB. METHODS: We retrospectively reviewed 216 patients with OGIB, whom had received a CE examination, so as to investigate the cause of obscure GI bleeding; between July 2008 and March 2018. The patient's characteristics, medication use, CE finding, treatments strategy, re-bleeding episodes and follow-up information were collected from the institutional electronic medical chart and CE database. Re-bleeding free survival was evaluated using Kaplan-Meier curves with log rank test, whilst predictors associated with the re-bleeding episodes were analyzed via the use of Cox proportional hazard model. RESULTS: One hundred and thirty-three patients with OGIB, having received CE were enrolled in the analysis. The pool rate of re-bleeding was 26.3% (35/133) during a follow-up duration of 26 months after CE. Patients with positive CE study, without specific treatment, had higher rates of re-bleeding (47.6%) than those with positive study whom received specific treatment (25.7%), and negative study (20.8%) (p = 0.042). Although, the re-bleeding free survival was not significantly different among the groups (log rank test; P = 0.10). Re-bleeding events occurring within 6, 12, and 24 months after CE were 36, 64 and 92%, respectively. The high-frequency re-bleeding etiologies were the small bowel angiodysplasias and abnormal vascular lesions. Furthermore, independent predictors for re-bleeding after CE were patients with cirrhosis (hazard ratio, HR 4.06), incomplete CE visualization (HR 2.97), and a history of previous GI bleeding (HR 2.80). CONCLUSIONS: The likelihood of re-bleeding after CE was higher in patients with positive CE study than those with negative study. Specific treatments, or therapeutic interventions for patients with detectable lesions reduced the probability of re-bleeding episodes in long-term follow-up. Close follow-up for recurrent bleeding is recommeded for at least 2 years after CE.

Next generation sequencing identifies baseline viral mutants associated with treatment response to pegylated interferon in HBeAg-positive chronic hepatitis B.

Current data of hepatitis B virus (HBV) variants associated with treatment outcome identified by next generation sequencing (NGS) are limited. This study was aimed at determining the role of baseline sequence variations in the enhancer II (EnhII), basal core promotor (BCP) and pre-core (PC) regions of HBV genotype C in patients treated with pegylated interferon (PEG-IFN). Patients with HBeAg-positive chronic hepatitis B (CHB) treated with 48-week PEG-IFN were enrolled. Combined response (CR) at week 96 was defined by HBeAg seroconversion plus HBV DNA < 2000 IU/mL and HBsAg < 1000 IU/mL. Pre-treatment viral mutations were characterized by Sanger sequencing and NGS (Miseq Illumina platform). Among 47 patients (32 male, mean age 32.4 years), CR was achieved in 12 (25.5%) individuals. Overall, NGS was superior to Sanger sequencing in detecting mutations (61.7% vs. 38.3%, P < 0.001). Based on NGS, the prevalence of T1753V (T1753C/A/G) and A1762T/G1764A variants were significantly lower in responders compared to non-responders (8.3% vs. 51.4%, P = 0.009 and 33.3% vs. 68.6%, P = 0.032, respectively). No significant difference between groups was found regarding C1653T and G1896A mutants. The absence of T1753V and A1762T/G1764A mutations were factors associated with CR (OR 11.65, 95%CI 1.36-100.16, P = 0.025, and OR 4.36, 95%CI 1.08-17.63, P = 0.039, respectively). The existence of pre-treatment T1753V, A1762T/G1764A mutations and their combination yielded negative predictive values of 94.7%, 85.7% and 93.8%, respectively. The presence of HBV mutants in the BCP region determined by NGS at baseline was associated with poor treatment outcome in patients with HBeAg-positive CHB receiving PEG-IFN.

Findings from a large Asian chronic hepatitis C real-life study.

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.

Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection.

UNLABELLED: Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV-based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens. CONCLUSIONS: ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials.

Treatment outcomes and validation of the stopping rule for response to peginterferon in chronic hepatitis B: A Thai nationwide cohort study.

BACKGROUND AND AIMS: Peginterferon has demonstrated effectiveness in clinical trials in patients with chronic hepatitis B (CHB). However, its efficacy in real-life settings remains unclear. We investigated the efficacy of peginterferon for CHB and validated the performance of previously identified response predictors in clinical practice. METHODS: We analyzed prospectively collected data from a Thai nationwide cohort of CHB patients treated with peginterferon alfa-2a (180 µg/week, 48 weeks). RESULTS: Among a total of 233 patients, mostly with genotype B or C, sustained response was observed in 23% of 135 hepatitis B e antigen (HBeAg)-positive patients (HBeAg seroconversion with hepatitis B virus [HBV] DNA < 2000 IU/mL) and 42% of 98 HBeAg-negative patients (HBV DNA < 2000 IU/mL with aminotransferase normalization) at 24 weeks after treatment. Age, sex, presence of cirrhosis, genotype, and pretreatment levels of aminotransferase, HBV DNA, and hepatitis B surface antigen (HBsAg) were not identified as significant predictors of sustained response. In HBeAg-positive patients, HBsAg > 20 000 IU/mL at week 12 provided a good stopping rule, with a negative predictive value of 96%. In HBeAg-negative patients, the performance of 12-week stopping rules of no decline in HBsAg with a < 2log10 decline in HBV DNA and a < 10% log10 decline in HBsAg showed modest negative predictive values of 80% and 66%, respectively, for achieving sustained response. CONCLUSION: Outcomes in CHB patients treated with peginterferon in a clinical setting are similar to those demonstrated in clinical trials. Application of the early stopping rule based on HBsAg quantification may allow individualization of therapy, particularly in HBeAg-positive patients.

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

BACKGROUND AND AIMS: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections. METHODS: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events. RESULTS: The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 µg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups. CONCLUSIONS: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665).

A global view of hepatitis C: physician knowledge, opinions, and perceived barriers to care.

UNLABELLED: Chronic infection with the hepatitis C virus (HCV) is a leading cause of global morbidity and mortality. Although recent advances in antiviral therapy have led to significant improvements in treatment response rates, only a minority of infected patients are treated. Multiple barriers may impede the delivery of HCV therapy. The aim of this study was to identify perceived barriers to care, knowledge, and opinions among a global sample of HCV treatment providers. An international, multidisciplinary survey of HCV treatment providers was conducted. Each physician responded to a series of 214 questions concerning his or her practice characteristics, opinions regarding the state of HCV care, knowledge regarding HCV treatment, and perception of treatment barriers. A total of 697 physicians from 29 countries completed the survey. Overall, physicians viewed patient-level barriers as most significant, including fear of side effects and concerns regarding treatment duration and cost. There were distinct regional variations, with Central and Eastern European physicians citing government barriers as most important. In Latin America, the Middle East, and Africa, payer-level barriers, including lack of treatment coverage, were prominent. Overall, the perception of barriers was strongly associated with physician knowledge, experience, and region of origin, with the fewest barriers reported by Nordic physicians and the most reported by Middle Eastern and African physicians. Globally, physicians demonstrated deficits in basic treatment principles, including the role of viral kinetics and the management of treatment nonresponders. Two thirds of surveyed physicians believed that patients do not have adequate access to providers in their community. CONCLUSION: Barriers to HCV treatment vary globally, though patient-level factors are viewed as most significant by treating physicians. Efforts to improve awareness, education, and specialist availability are needed.

Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels.

UNLABELLED: On-treatment levels of hepatitis B surface antigen (HBsAg) may predict response to peginterferon (PEG-IFN) therapy in chronic hepatitis B (CHB), but previously proposed prediction rules have shown limited external validity. We analyzed 803 HBeAg-positive patients treated with PEG-IFN in three global studies with available HBsAg measurements. A stopping-rule based on absence of a decline from baseline was compared to a prediction-rule that uses HBsAg levels of <1,500 IU/mL and >20,000 IU/mL to identify patients with high and low probabilities of response. Patients with an HBsAg level <1,500 IU/mL at week 12 achieved response (HBeAg loss with HBV DNA <2,000 IU/mL at 6 months posttreatment) in 45%. At week 12, patients without a decline in HBsAg achieved a response in 14%, compared to only 6% of patients with HBsAg >20,000 IU/mL, but performance varied across HBV genotype. In patients treated with PEG-IFN monotherapy (n = 465), response rates were low in patients with genotypes A or D if there was no decline of HBsAg by week 12 (negative predictive value [NPV]: 97%-100%), and in patients with genotypes B or C if HBsAg at week 12 was >20,000 IU/mL (NPV: 92%-98%). At week 24, nearly all patients with HBsAg >20,000 IU/mL failed to achieve a response, irrespective of HBV genotype (NPV for response and HBsAg loss 99% and 100%). CONCLUSION: HBsAg is a strong predictor of response to PEG-IFN in HBeAg-positive CHB. HBV genotype-specific stopping-rules may be considered at week 12, but treatment discontinuation is indicated in all patients with HBsAg >20,000 IU/mL at week 24, irrespective of HBV genotype.

HBV DNA level could predict significant liver fibrosis in HBeAg negative chronic hepatitis B patients with biopsy indication.

BACKGROUND: Non-invasive models and methods to substitute liver biopsy in chronic hepatitis B (CHB) patients were investigated but their roles as predictors of significant liver histology for diagnosis of HBeAg-negative CHB patients who had indication for liver biopsy according to The American Association for the Study of Liver Diseases (AASLD) and The Asian Pacific Association for the Study of the Liver (APASL) guidelines are still unknown. This study was designed to identify predictors of significant liver necroinflammation as defined by a Histology Activity Index of necroinflammatory score ≥ 4 or Metavir necroinflammatory activity score ≥ 2 and significant liver fibrosis as defined by a Metavir fibrosis score ≥ 2 in HBeAg-negative CHB patients that had a hepatitis B virus (HBV) DNA level ≥ 2,000 IU/ml and age ≥ 40 years or elevated alanine aminotransferase level between 1-2 times the upper limit of normal. METHODS: Twenty-two patients were prospectively included and performed liver biopsies. Clinical and laboratory parameters including age, gender, underlying disease, family history of cirrhosis or hepatocellular carcinoma, body mass index (BMI), HBV DNA level, HBsAg level, liver function test, complete blood count, aspartate aminotransferase-to-platelet ratio index and transient elastography were collected and analyzed with liver histology profiles. RESULTS: Five patients (23%) had significant liver inflammation and 7 patients (32%) had significant liver fibrosis. Factors associated with significant liver inflammation were a lower BMI and higher alkaline phosphatase level while a factor associated with significant liver fibrosis was lower age. On multivariate analysis, only HBV DNA level > 5.5 log IU/ml could predict significant liver fibrosis (odds ratio 28.012, 95% CI, 1.631-481.240, p = 0.022) and its sensitivity, specificity, positive predictive value and negative predictive value were 71.4%, 93.3%, 83.3% and 87.5% respectively. CONCLUSIONS: An HBV DNA level of > 5.5 log IU/ml was able to predict significant liver fibrosis for treatment of HBeAg-negative CHB patients that had indication for liver biopsy as recommended by AASLD and APASL guidelines.

Influence of meal intake on liver stiffness in patients with chronic hepatitis B and C.

BACKGROUND: Transient elastography (TE) is a non-invasive test for evaluation of fibrosis in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Meal intake has been found to affect liver stiffness (LS) values in CHC patients, but there is still lack of data in CHB patients. OBJECTIVE: Evaluate the influence of meal intake on LS values by TE in non-cirrhotic CHB patients and compare its effect with non-cirrhotic CHC patients. MATERIAL AND METHOD: Forty-five CHB patients and 37 CHC patients were included LS measurements by TE were done at three different times including 4-hour fasting immediately, and 60 minutes after finishing 500 kcal meal. RESULTS: Mean fasting LS values in CHB patients were 5.40--1.7 kPa. LS values in CHB patients significantly increased at both immediately and 60 minutes after finishing meal by 0.31?0.1 kPa (p = 0.035) and 0.33 +/- 0.1 kPa (p = 0.018), respectively Difference in the peak changes of LS values after meal were not significant between CHB and CHC patients (CHB 0.72 +/- 0.1 vs. CHC 1.16 +/- 0.1, p = 0.076). No other variables associated with the changes ofLS values after meal in either CHB patients or CHC patients. CONCLUSION: Meal intake significantly increases LS values in CHB and CHC patients. It was considered to be a confounding factor in LS measurements. An appropriate time offasting should be done before LS measurement in both CHB and CHC patients.