First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection.

BACKGROUND & AIMS: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.

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.

Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B.

BACKGROUND AND AIMS: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed. APPROACH AND RESULTS: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log10  IU/mL) independent of HBeAg status. CONCLUSIONS: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931.

Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: During treatment of chronic HBV infections, loss or seroconversion of the HBV surface antigen (HBsAg) is considered a functional cure. HBsAg consists of the large (LHBs), middle (MHBs), and small surface protein (SHBs) and their relative proportions correlate strongly with disease stage. Our aim was to assess the association between HBsAg composition and functional cure during treatment. METHODS: A total of 83 patients were retrospectively analyzed. HBsAg loss was achieved by 17/64 patients during nucleos(t)ide analogue (NA) treatment and 3/19 patients following treatment with pegylated interferon-alfa2a (PEG-IFN) for 48 weeks. Sixty-three patients without HBsAg loss were matched as controls. LHBs, MHBs and SHBs were quantified in sera collected before and during treatment. RESULTS: Before treatment, median MHBs levels were significantly lower in patients with subsequent HBsAg loss than in those without (p = 0.005). During treatment, MHBs and LHBs proportions showed a fast decline in patients with HBsAg loss, but not in patients with HBV e antigen seroconversion only or patients without serologic response. MHBs became undetectable by month 6 of NA treatment in all patients with HBsAg loss, which occurred on average 12.8 ± 8.7 (0-52) months before loss of total HBsAg. Receiver-operating characteristic analyses revealed that the proportion of MHBs was the best early predictor of HBsAg loss before NA treatment (AUC = 0.726, p = 0.019). In patients achieving HBsAg loss with PEG-IFN, the proportions of MHBs and LHBs showed similar kinetics. CONCLUSION: Quantification of HBsAg proteins shows promise as a novel tool to predict early treatment response. These assessments may help optimize individual antiviral treatment, increasing the rates of functional cure in chronically HBV-infected patients. LAY SUMMARY: The hepatitis B surface antigen (HBsAg) is a key serum marker for viral replication. Loss of HBsAg is considered stable remission, which can be achieved with antiviral treatments. We have investigated whether the ratios of the different components of HBsAg, namely the large (LHBs) and medium (MHBs) HBsAg during different treatments are associated with the occurrence of HBsAg loss. We found that LHBs and MHBs decrease earlier than total HBsAg before HBsAg loss and we propose LHBs and MHBs as promising novel biomarker candidates for predicting cure of HBV infection.

Quantitation of large, middle and small hepatitis B surface proteins in HBeAg-positive patients treated with peginterferon alfa-2a.

BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive vs active chronic infection. Interferon alfa may convert hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: Hepatitis B surface proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as HBeAg seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders vs nonresponders at all time points (P < .05) and decreased steadily during the initial 24 weeks treatment (by 1.16 vs 0.86 ng/mL in responders/nonresponders respectively) with unchanged relative proportions. Genotype B had a two-fold higher proportion of LHBs than genotype C (13% vs 6%). HBV DNA, HBeAg, HBsAg and HBs protein levels predicted response equally well but not optimally (area under the receiver operating characteristic curve values >0.70). CONCLUSIONS: Hepatitis B surface protein levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.

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).

Efficacy and Safety of Peginterferon Alfa-2a (40KD) in Children With Chronic Hepatitis B: The PEG-B-ACTIVE Study.

Children with chronic hepatitis B (CHB) represent an area of unmet medical need, attributed to increased lifetime risk of CHB sequelae and limited therapeutic options compared with adult CHB patients. The PEG-B-ACTIVE (NCT01519960) phase III study evaluated peginterferon (PegIFN) alfa-2a treatment in children aged 3 to <18 years with CHB. A total of 161 hepatitis B e antigen (HBeAg)-positive immune-active patients without advanced fibrosis (AF)/cirrhosis were randomized (2:1) to PegIFN alfa-2a (Group A, n = 101) or no treatment (Group B, n = 50); patients with AF were assigned to PegIFN alfa-2a (Group C, n = 10). PegIFN alfa-2a was administered for 48 weeks by body surface area (BSA) category, based on 180 µg/1.73 m2 . HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in Group A (25.7% vs. 6%; P = 0.0043), as were the rates of hepatitis B surface antigen (HBsAg) clearance (8.9% vs. 0%; P = 0.03), hepatitis B virus (HBV) DNA <2,000 IU/mL (28.7% vs. 2.0%; P < 0.001) or undetectable (16.8% vs. 2.0%; P = 0.0069), and alanine aminotransferase (ALT) normalization (51.5% vs. 12%; P < 0.001). Safety, including incidence of ALT flares and neutropenia, was comparable to the established PegIFN alfa-2a profile in HBV-infected adults or hepatitis C virus-infected children. Changes in growth parameters were minimal during treatment and comparable to those in untreated patients. Safety and efficacy outcomes in Group C were in line with Group A. Conclusion: PegIFN alfa-2a treatment of children in the immune-active phase of CHB was efficacious and well tolerated, and associated with higher incidence of HBsAg clearance than in adults. This represents an important advance to the treatment options for children with CHB.

Serum HBV RNA as a Predictor of Peginterferon Alfa-2a Response in Patients With HBeAg-Positive Chronic Hepatitis B.

Background: Hepatitis B virus (HBV) RNA is a novel serum biomarker that has the potential to predict treatment response in patients with chronic hepatitis B. We explored whether HBV RNA serum levels can predict hepatitis B e antigen (HBeAg) seroconversion in patients treated with peginterferon alfa-2a. Methods: Serum samples from HBeAg-positive patients previously treated with peginterferon alfa-2a in 2 large randomized controlled trials were retrospectively analyzed. HBV RNA levels were measured using a real-time polymerase chain reaction assay. Ability of individual biomarkers to predict HBeAg seroconversion at 24 weeks posttreatment was evaluated using receiver operating characteristics (ROC) analyses. Results: The study included 131 subjects (70% male, 96% Asians, 35% HBV genotypes B, and 61% C), 76 treated with peginterferon alfa-2a alone and 55 in combination with lamivudine. Median HBV RNA levels were significantly lower, at all timepoints, in patients achieving HBeAg seroconversion. Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (area under ROC scores >0.75, P < .001). A HBV RNA cutoff of >5.5 log10 copies/mL identified 30% of nonresponders at week 12 (negative predictive value >90%). Conclusion: Serum HBV RNA is an early predictor of HBeAg seroconversion in patients treated with peginterferon alfa-2a. Clinical Trials Registration: NCT01705704.

Durability of Response in Children Treated With Pegylated Interferon alfa [corrected] 2a ± Ribavirin for Chronic Hepatitis C.

OBJECTIVES: No long-term data have been published on the durability of response following pegylated interferon (PegIFN) treatment in children with chronic hepatitis C. This prospective, multicenter, long-term follow-up (LTFU) study aimed to assess long-term durability of sustained virological response (SVR), long-term safety and tolerability, and the association between IL28B genotype and treatment response, in children previously treated with PegIFN alfa-2a ± ribavirin (RBV) in the PEDS-C trial. METHODS: A total of 93 patients were assessed for enrollment, and 38 enrolled in the study. Patients attended 2 study visits: 5 (mean 5.6, range 4.1-6.6) and 6 (6.6, 5.1-7.7) years after treatment cessation. Standardized medical history, physical examination, and laboratory testing were performed at these visits. Reminder telephone calls were conducted at 4 and 8 months after the initial visit. RESULTS: The LTFU cohort was the representative of the original PEDS-C cohort because both baseline and treatment characteristics were comparable. Of the 38 participants, 21 achieved SVR (responders) during the PEDS-C trial and 17 had not (nonresponders). All 21 responders maintained undetectable hepatitis C virus RNA during the LTFU (4.4-7.0 years after achieving SVR) in contrast to the nonresponders who demonstrated persistent viremia. IL28B CC genotype was associated with SVR (67% vs 30% in non-CC, P = 0.028). CONCLUSION: Long-term durability of SVR is excellent following PegIFN alfa-2a treatment in children with chronic hepatitis C; SVR is higher in those with IL28B CC versus non-CC.

Long-term growth outcomes in children treated for chronic hepatitis C.

Effects on linear growth were noted in children treated with peginterferon ± ribavirin in the Pediatric Study of Hepatitis C trial. Growth was further examined in a subset of patients followed for up to 6 years post-treatment. No long-term effects on height-for-age z scores were observed that could be attributed to hepatitis C virus treatment.

A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers.

RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

BACKGROUND: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. AIM: To study rates and determinants of clinically significant liver inflammation. METHODS: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). RESULTS: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. CONCLUSIONS: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.

Peginterferon alfa-2a (40 kD) stopping rules in chronic hepatitis B: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Peginterferon alfa-2a (PEG-IFN) treatment stopping rules in chronic hepatitis B (CHB) are clinically desirable. Previous studies exploring this topic contained important limitations resulting in inconsistent recommendations within the current treatment guidelines. We undertook a systematic review and individual patient data meta-analysis to identify the most appropriate PEG-IFN treatment stopping rules. METHODS: Roche's internal database, PubMed and conference abstracts were searched for studies that enrolled >50 treatment-naive patients with CHB who received PEG-IFN treatment for 48 weeks. Stopping rules were identified using receiver-operating characteristic curve analyses and pre-specified biomarker cutoff target performance characteristics (sensitivity >95%, specificity >10%, negative predictive value >90%). Robustness of proposed stopping rules was assessed using internal/external validation analyses. RESULTS: Eight study datasets were included in the meta-analysis (n=1,423; 765 hepatitis B e antigen [HBeAg]-positive, 658 HBeAg-negative patients). In general, performance of hepatitis B surface antigen (HBsAg) and HBV DNA cutoffs at weeks 12 and 24 was similar, and common biomarker cutoffs that met target performance criteria were identified across multiple patient subgroups. For HBeAg-positive genotype B/C and HBeAg-negative genotype D patients the proposed stopping rule is HBsAg >20,000 IU/ml at week 12. Alternatively, HBV DNA level cutoffs of >8 log10 and >6.5 log10 IU/ml, respectively, can be used instead. The proposed stopping rules accurately identify up to 26% of non-responders. CONCLUSIONS: The meta-analysis demonstrates that early PEG-IFN discontinuation should be considered in HBeAg-positive genotype B/C and HBeAg-negative genotype D patients at week 12 of treatment based on HBsAg or HBV DNA levels.

Optimisation of the use of APRI and FIB-4 to rule out cirrhosis in patients with chronic hepatitis B: results from the SONIC-B study.

BACKGROUND: Ruling out the presence of cirrhosis is important for the management of chronic hepatitis B. We aimed to study and optimise the performance of two non-invasive indices for ruling out cirrhosis: the aspartate aminotransferase-platelet ratio index (APRI) and fibrosis score based on four factors (FIB-4). METHODS: We applied established cutoffs to rule in (APRI >2·00; FIB-4 >3·25) or rule out (APRI <1·00; FIB-4 <1·45) cirrhosis to data from eight global randomised trials that required baseline biopsy, and identified new cutoffs aiming for a sensitivity for detection of cirrhosis greater than 90% and a negative predictive value (NPV) of greater than 95% in the same dataset. We externally validated the new cutoffs using data from all consecutive biopsied patients from two tertiary referral hospitals in the Netherlands and Canada. FINDINGS: In the derivation dataset (n=2926; of whom 1750 were Asian); 340 (12%) individuals had cirrhosis. The validation cohort consisted of 1034 individuals (of whom 575 were Asian), with 155 (15%) individuals with cirrhosis. Application of conventional cutoffs for FIB-4 in the derivation dataset yielded unclassifiable results in 686 (23%) individuals, and 139 (41%) of the 340 patients with cirrhosis were misclassified as having no cirrhosis. Similarly, conventional cutoffs for APRI in the derivation dataset yielded unclassifiable results in 706 (24%) individuals, and 153 (45%) were misclassified as having no cirrhosis. An APRI of 0·45 or less had sensitivity of 91·5%, an NPV of 95·4%, and misclassified 29 (9%) of 340 individuals with cirrhosis in the derivation dataset, but performance was reduced in the validation set (22 [14%] of 155 individuals with cirrhosis misclassified). A FIB-4 score of 0·70 had a sensitivity of 90·9%, an NPV of 96·6%, and misclassified 31 (9%) of individuals with cirrhosis in the derivation dataset. In the validation cohort, the same score gave a sensitivity of 94·2%, an NPV of 97·3%, and misclassified nine (6%) of the individuals with cirrhosis. Subgroup analysis indicated that the new FIB-4 cutoff performed acceptably in all subgroups except for individuals aged 30 years or younger. INTERPRETATION: Conventional cutoffs for APRI and FIB-4 should not be used to guide management of patients with chronic hepatitis B due to high rates of misclassification. A newly identified and externally validated cutoff for FIB-4 (≤0·70) can be used to exclude cirrhosis in patients over 30 years of age. FUNDING: Foundation for Liver and Gastrointestinal Research, Rotterdam, Netherlands.

A genotype-specific baseline score predicts post-treatment response to peginterferon alfa-2a in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Peginterferon alfa-2a induces durable responses in some hepatitis B e antigen-negative patients, but robust pretreatment predictors are not available to identify likely responders. In this study we aimed to develop genotype-specific baseline scoring systems to predict response. METHODS: Data from 323 hepatitis B e antigen-negative peginterferon alfa-2a recipients from three studies were analyzed. Scoring systems were developed using generalized additive models and multiple logistic regression analysis. Response was defined as hepatitis B virus DNA <2000 IU/mL alone (virological response) or in combination with alanine aminotransferase normalization (combined response) 48 weeks post-treatment. RESULTS: Points were assigned to genotype B/C patients for: age, alanine aminotransferase ratio, genotype B or C, and hepatitis B surface antigen level; and to genotype D patients for age, hepatitis B surface antigen level and hepatitis B virus DNA level. Higher total scores (range 0-5 for B/C; 0-3 for D) indicated a higher likelihood of response. Among genotype B/C patients with scores of 0-1, 2 and ≥3, respectively, virological response rates were 16.7%, 25.8% and 70.2%, and combined response rates were 12.5%, 21.0% and 57.4%. Among genotype D patients with scores of 0-1, 2 and 3, respectively, virological response rates were 10.1%, 28.0% and 50.0%, and combined response rates were 7.8%, 28.0% and 33.3%. CONCLUSION: Genotype-specific baseline scoring systems can identify hepatitis B e antigen-negative patients with low or high likelihood of achieving sustained responses to peginterferon alfa-2a.