Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Bulevirtide with or without pegIFNα for patients with compensated chronic hepatitis delta: From clinical trials to real-world studies.

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, characterised by the greatest increase in risk of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Pegylated-interferon-α (pegIFNα), the only off-label therapeutic option, has been available for the last 30 years but is associated with suboptimal response rates and poor tolerability. Among the new treatment strategies under clinical evaluation, the entry inhibitor bulevirtide (BLV) is the only one that has received conditional approval from the European Medicines Agency (EMA); approval was granted in July 2020 for the treatment of adult patients with compensated CHD at a dose of 2 mg daily. Phase II studies and the week 24 interim analysis of a phase III study demonstrated the efficacy and safety of this treatment as a monotherapy or combined with pegIFNα. This favourable profile has been confirmed by recent real-world studies performed in Europe. As a long-term monotherapy, BLV has been successfully used to treat patients with advanced compensated cirrhosis. These encouraging yet preliminary findings must be viewed with caution as many critical issues related to this new antiviral strategy are still poorly understood, as summarised in this review. While waiting for new anti-HBV and anti-HDV drugs to become available for combination studies, BLV treatment is currently the only available anti-HDV therapeutic option that might improve the long-term prognosis of difficult-to-manage patients with CHD.

Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

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

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

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).

Endo-therapies for biliary duct-to-duct anastomotic stricture after liver transplantation: Outcomes of a nationwide survey.

BACKGROUND: The most appropriate endo-therapeutic approach to biliary anastomotic strictures is yet to be defined. AIM: To retrospectively report on the endo-therapy of duct-to-duct anastomotic strictures during 2013 in Italy. METHODS: Data were collected from 16 Endoscopy Units at the Italian Liver Transplantation Centers (BASALT study group). RESULTS: Complete endo-therapy and follow-up data are available for 181 patients: 101 treated with plastic multistenting, 26 with fully covered self-expandable metal stenting and 54 with single stenting. Radiological success was achieved for 145 patients (80%), that is, 88% of plastic multistenting, 88% of self-expandable metal stenting and 61% of single stenting (P < 0.001 vs plastic multistenting; P < 0.05 vs self-expandable metal stenting). After first-line endo-therapy failure, the patients underwent a second-line endo-therapy with plastic multistenting for 25%, fully covered self-expandable metal stenting for 53% and single stenting for 22% of cases, and radiological success was achieved for 84%, that is, 100%, 85% and 63% with plastic multistenting, self-expandable metal stenting and single stenting (P < 0.05 vs plastic multistenting or self-expandable metal stenting) respectively. Procedure-related complications occurred in 7.8% of endoscopic retrograde cholangiopancreatographies. Overall, clinical success was achieved in 87% of patients after a median follow-up of 25 months. CONCLUSION: Plastic multistenting is confirmed as the preferred first-line treatment, while fully covered self-expandable metal stenting as rescue option for biliary anastomotic strictures. Single stenting has sub-optimal results and should be abandoned.

Treatment of hepatitis B: Is there still a role for interferon?

The treatment of chronic hepatitis B (CHB) patients is based on monotherapy with pegylated-interferon (Peg-IFN) or with one of the three most potent nucleot(s)ide analogues (NUCs) with the best resistance profiles, i.e. entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Long-term NUCs treatment can achieve virological suppression in almost all patients. However, this requires lifelong therapy, is costly and the rate of hepatitis B surface antigen (HBsAg) seroclearance is low. A one-year course of Peg-IFN has the advantage of providing immune-mediated control of the hepatitis B virus (HBV) infection, the possibility of achieving a sustained off-treatment response in nearly 30% of the patients and ultimately, HBsAg loss in approximately 30%-50% of the latter patients during long-term off treatment follow-up. However, the major limitations to the extensive use of this treatment are the need for parenteral therapy and clinical and laboratory monitoring, the side-effects profile and contraindications in certain patients and the limited effectiveness in a large proportion of patients. Nevertheless, the cost-effectiveness of Peg-IFN can be significantly increased by careful patient selection based upon baseline alanine aminotransferase (ALT), HBV DNA levels, viral genotype, host genetic variants and especially by applying early on-treatment stopping rules based upon HBsAg kinetics. Recently, because of the different mechanisms of action of Peg-IFN and NUCs, the strategy of "adding-on" or "switching to" Peg-IFN in patients being treated with NUCs to accelerate the decline in HBsAg and enhance HBsAg seroclearance rates, has provided interesting results.

IFNL4 rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients.

BACKGROUND & AIM: Robust baseline predictors of interferon (IFN) response in HBeAg-negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/ΔG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN-treated CHB patients. Here we assessed whether IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN-induced HBsAg clearance in CHB patients. METHODS: We sequenced the IFNL4 gene on genomic DNA collected from 126 HBeAg-negative CHB patients treated with IFN and followed up for a median of 11 (1-23) years. RESULTS: The 15-year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes the IFNλ4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFNλ4-S70 protein (39% vs 42%, P = .827). In contrast, these 81 patients, either not producing IFNλ4 or producing an impaired IFNλ4-S70 protein, had a significantly higher 15-year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFNλ4-P70 (42% vs 11% P = .003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70-20.9, P = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39-0.83, P = .003). CONCLUSION: IFNL4 rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg-negative CHB patients.

Optimal therapy of chronic hepatitis B: how do I treat my HBeAg-negative patients?

HBeAg negative chronic hepatitis B (CHB) is a frequent, progressive and difficult-to-cure phase of CHB. The end-point of therapy is to persistently suppress viral replication to halt progression of liver disease. Two different treatment strategies are currently available: a short-term course of pegylated interferon alpha (PEG-IFN) or long-term therapy with nucleot(s)ide analogues (NA), i.e. entecavir or tenofovir. Young patients with mild-to-moderate stages of liver disease can benefit from a 48-week course of PEG-IFN, while NA may be preferred in patients with more severe liver disease, in older patients, and in those who do not respond, are unwilling or have contraindications to PEG-IFN. Nucleot(s)ide analogues provide persistent viral suppression and biochemical normalization in almost all patients, together with the regression of fibrosis and the prevention of decompensation, but the effect on hepatocellular carcinoma rates is limited. Thus, NAs have become the most popular treatment strategy worldwide but lifelong administration is associated with high cost, unknown safety and adherence issues and an unknown risk of drug-resistance over time as well as limited rates of HBsAg seroclearance. On the other hand, PEG-IFN treatment may achieve a SVR in nearly a quarter of patients ultimately leading to HBsAg loss in almost 30-50%. Interestingly, response rates to PEG-IFN may further increase with more careful patient selection based on age, ALT and HBV DNA levels at baseline and by applying early on-treatment stopping rules based on HBV DNA and HBsAg kinetics. The combination of NA and PEG-IFN is not currently recommended but numerous studies are ongoing.

IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B.

UNLABELLED: Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed>10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n=14) in CC compared to 13% (n=7) in non-CC, genotype carriers (P=0.039). Baseline HBV DNA levels<6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P=0.001), ALT levels>136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P=0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P=0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P=0.025) independently predicted HBsAg clearance. CONCLUSIONS: IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV.

HBeAg-negative chronic hepatitis B: why do I treat my patients with nucleos(t)ide analogues?

The aim of chronic hepatitis B (CHB) antiviral therapy is to persistently suppress HBV and improve survival by preventing the progression of liver damage to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing early liver-related death. In HBeAg-negative patients who do not or will not respond to or be treated with pegylated interferon (PEG-IFN), the administration of third generation nucleot(s)ide analogues (NAs), i.e., entecavir (ETV) and tenofovir disoproxil fumarate (TDF), is the treatment of choice. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients after 5 years of treatment with high rates of biochemical normalization, regression of fibrosis and cirrhosis at histology as well as preventing clinical decompensation but not HCC, in compensated cirrhosis and improving survival. No major safety issues have been recorded with either drug. The need for long-term, perhaps indefinite, treatment is the main limitation of NA therapy with possible associated costs, unknown long-term safety and the low rates of HBsAg seroclearance. The latter is important since HBsAg seroclearance is still the best stopping rule for HBeAg-negative NA-treated patients, including those with cirrhosis. For this reason new trials based upon a combination of PEG-IFN and third generation NAs in both naïve and NA-responder HBeAg-negative patients are ongoing.

Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B.

OBJECTIVE: Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population. METHODS: 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 µg PegIFN for 48 weeks (group A, n=51), 180 µg PegIFN for 48 weeks followed by 135 µg weekly for an additional 48 weeks (group B, n=52) or 180 µg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 µg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment. RESULTS: Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events. CONCLUSIONS: In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment. TRIAL REGISTRATION NUMBER: http://ClinicalTrials.gov registration number: NCT01095835.

Why do I treat HBeAg-negative chronic hepatitis B patients with pegylated interferon?

Chronic hepatitis B (CHB) in serum HBeAg negative patients is a difficult to cure, progressive disease leading to end-stage liver disease and hepatocellular carcinoma. Currently, there are two different treatment strategies for such patients: a finite course of Pegylated interferon (PEG-IFN) or long-term administration of the more potent and less resistance-prone nucleot(s)ide analogues (NUC), i.e. entecavir and tenofovir. Although NUC may ensure persistent viral suppression by preventing disease progression in most patients, they require lifelong administration with the hypothetical disadvantages of cost, lack of long-term safety data and, most important, the null rates of HBsAg seroclearance. On the other hand, 1 year of PEG-IFN has the advantage of providing an immune-mediated control of hepatitis B virus (HBV) infection, with the possibility of achieving a sustained off-treatment response in 20% of the patients, ultimately leading to HBsAg loss in approximately 50% of these. However, these sustained response rates can be significantly increased by carefully selecting candidates for PEG-IFN therapy based upon baseline ALT and HBV DNA levels, viral genotype and IL28B polymorphisms, by extending PEG-IFN therapy beyond 48 weeks and, most importantly, by applying early on-treatment stopping rules based upon HBsAg kinetics. Overall, PEG-IFN is an ideal treatment strategy in selected patients with HBeAg-negative CHB, because of its well-recognized and predictable safety profile and a unique mechanism of antiviral activity leading to long-lasting immune control. Because of these features, new therapeutic trials based upon a combination of PEG-IFN and third generation NUC such as entecavir and tenofovir, in both naïve and NUC-exposed patients, are ongoing to further increase the rates of HBsAg seroclearance, which remains the 'ideal end-point' in all HBeAg-negative CHB subjects.

Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a.

BACKGROUND & AIMS: It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. METHODS: HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. RESULTS: The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). CONCLUSIONS: We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy.

Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis.

BACKGROUND & AIMS: The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. METHODS: HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. RESULTS: Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. CONCLUSIONS: IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.

Treatment of HBeAg-negative chronic hepatitis B with pegylated interferon.

Serum HBeAg-negative chronic hepatitis B, which is usually a late stage of chronic hepatitis B virus infection, is difficult to treat, because it is characterized by fluctuating alanine transaminase values resulting in hepatitis flares, accelerated progression to cirrhosis and liver cancer. Antiviral treatment, either long-term nucleot(s)ide therapy or 1-year administration of pegylated interferon (PEG-IFN), is therefore necessary to limit the course of the disease. A sustained virological response to PEG-IFN is achieved in approximately 1/4 of the patients, with significant rates of HBsAg seroclearance. While waiting for the results of several studies whose goal is to improve the long-term efficacy of PEG-IFN, the treatment strategy can be optimized by a careful selection of patients, discontinuation of PEG-IFN as early as possible in primary non-responders and extended therapy (up to 96 weeks) in responders.

Final analysis of the international observational S-Collate study of peginterferon alfa-2a in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma. METHODS: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up. RESULTS: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions. CONCLUSIONS: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics.

The course of inactive hepatitis B in hepatitis-C-coinfected patients treated with interferon and ribavirin.

BACKGROUND: Interferon (IFN) combined with ribavirin (RBV) is an effective therapy for hepatitis C virus (HCV)-infected patients. Those who are coinfected with hepatitis B virus (HBV), however, might suffer from HBV reactivation. The aim of this study was to assess HBV reactivation in HCV-coinfected inactive HBV carriers following IFN/RBV. METHODS: A total of 32 HBV carriers with 4 log(10) copies/ml (range 5.2-6.5 log(10) copies/ml); however, these patients had no ALT flare either on treatment (n=2) or off treatment (n=1). During follow-up, 8 (36%) treated patients and 4 controls lost serum hepatitis B surface antigen (HBsAg; annual rate 6.5% versus 6.9%; P-value non-significant), whereas 4 and 2 patients seroconverted to antibodies against HBsAg, respectively. Hepatocellular carcinoma developed in 1 patient with SVR and 1 non-responder under nucleoside therapy for HBV, both with cirrhosis. No patient clinically decompensated. CONCLUSIONS: Inactive HBV carriers coinfected with HCV might achieve an SVR following IFN/RBV. Combination therapy carries a low risk of on- and off-treatment HBV reactivation and does not prevent HBsAg seroclearance.