Neutralizing antibodies to interferon alfa arising during peginterferon therapy of chronic hepatitis B in children and adults: Results from the HBRN trials.

BACKGROUND: Peginterferon-α (PegIFNα) is of limited utility during immunotolerant (IT) or immune active (IA) phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some treated patients are associated with limited/no virological responses. AIM: To determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies. METHODS: Pre-, on- and post-treatment sera from 61 IT trial participants on PegIFNα/ entecavir therapy and 88 IA trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by pre-incubation of sera +/- recombinant-human IFNα (rhIFNα) added to Huh7 cells with measurement of interferon stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated. RESULTS: Pre-incubation of on-treatment serum from 26 IT (43%) and 13 IA (15%) participants with rhIFNα markedly blunted ISG-induction in Huh7 cells. Degree of ISG-inhibition correlated with IFNα antibody titer (p<0.0001; r=0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced qHBsAg and qHBeAg declines (p<0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults (p=0.004) but nAbs in children had less impact on virological responses. CONCLUSIONS: The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.

Factors associated with knowledge and awareness of Hepatitis B in individuals of Chinese descent: Results from a mass point of care testing and outreach campaign in Toronto, Canada.

Background: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine. Methods: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants' level of HBV knowledge. Results: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% (N = 552), were female, and 73.6% (N = 656) have been in Canada for <30 years. The average questionnaire score was 70.7% correct, with 65.2% (N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of $50,000 to <$75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing. Conclusions: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups.

PAGE-B incorporating moderate HBV DNA levels predicts risk of HCC among patients entering into HBeAg-positive chronic hepatitis B.

BACKGROUND & AIMS: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection. METHODS: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed. RESULTS: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001). CONCLUSIONS: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB. IMPACT AND IMPLICATIONS: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Province-to-province variability in hepatitis C testing, care, and treatment across Canada.

Background: Few countries have implemented the necessary policy changes to reduce the number of steps in the cascade of care to achieve hepatitis C virus (HCV) elimination, including Canada. The aim of this study was to describe and compare legislation, scope of practice, and policy as it relates to the provision of HCV care in each province. Methods: We reviewed grey literature and regulatory and legislative documents which affect various aspects of the HCV cascade of care. Findings were verified by content experts. Results: HCV RNA reflex testing ensures those that are antibody positive get an HCV RNA test; however only 80% of provinces have reflex test. Point-of-care antibody testing can be offered in most community non-health care settings, yet many types of health care providers are unable to do this independently. Following a positive test, it may not be feasible to complete venipuncture; however only a single province processes HCV RNA dried blood spot cards. In many provinces, training and verification are required for novice prescribers, and in some provinces prescribing continues to be restricted to specialists. Only a single province has task-shifted treatment to a non-physician non-nurse practitioner model, where pharmacists can prescribe treatment. Finally, 80% of provinces require authorization forms, and 30% require proof of investigations for treatment. Conclusions: No single province is optimizing the use of diagnostic tools and task shifting and decreasing paperwork to expedite treatment initiation. Collaboration between provinces is needed to streamline practice, update policy, and promote equity in HCV diagnosis, care, and treatment.

Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells.

Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand-mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.

Characteristics of Older Patients With Immunotolerant Chronic Hepatitis B Virus Infection.

BACKGROUND & AIMS: Most patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years. METHODS: Demographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA >107 IU/mL) were compared by age category, and to those with IA-HBeAg+ CHB in cross-sectional analysis. This study received institutional review board approval at all participating centers. RESULTS: Of 107 adult IT participants, 52 (48%) were <30, 33 (31%) were 30 to 39, and 22 (21%) were ≥40 years old (maximum, 71 years). Among IT groups, the proportion born in Asia and duration of CHB were greater in older IT groups, but virologic and liver disease characteristics were similar. Compared with IA-HBeAg+ participants (n = 192), IT participants were younger, fewer were men, more were Asian, and platelets, qHBsAg, and qHBeAg levels were higher. Similar differences were observed when comparisons were made with the ≥40 years IT group. Among IT participants, 60 (56%) transitioned during 206 person-years of follow-up. The phase transition rate per 100 person-years was highest in the <30 years group (33.0 [95% confidence interval [CI], 23.4-46.7]) vs the 30 to 39 years group (24.8 [95% CI, 15.6-39.4]) and ≥40 group (27.4 [95% CI, 14.8-50.9]), but 95% CIs overlapped. CONCLUSIONS: In a large North American population, over 50% of adults in the IT phase of CHB were ≥30 years and 20% were ≥40 years old, but older IT patients had similar characteristics and rates of transition as younger IT patients.

Birth cohort hepatitis C antibody prevalence in real-world screening settings in Ontario.

Background: Widespread screening and treatment of hepatitis C virus (HCV) is required to decrease late-stage liver disease and liver cancer. Clinical practice guidelines and Canadian Task Force on Preventative Health Care recommendations differ on the value of one-time birth cohort (1945-75) HCV screening in Canada. To assess the utility of this approach, we conducted a real-world analysis of HCV antibody (Ab) prevalence among birth cohort individuals seen in different clinical contexts. Methods: Cross-sectional study of individuals born between 1945 and 1975 who completed HCV Ab testing at multiple participating centres in Ontario, Canada between January 2016 and December 2020. Differences in prevalence were compared by year of birth, gender, and setting. Results: Among 16,672 birth cohort individuals tested, HCV Ab prevalence was 3.2%. Prevalence was higher among younger individuals which increased from 0.9% among those born between 1945 and 1956 to 4.6% among those born between 1966 and 1975. Prevalence was higher among males (4.4%) compared with females (2.0%) and differed by test site. In primary care, the prevalence was 0.5%, whereas the prevalence was highest among those tested at drug treatment centres (28.7%) and through community outreach (14.0%). Conclusions: HCV Ab prevalence remains high in the 1945-1975 birth cohort. These data highlight the need to re-evaluate existing Canadian Preventative Task Force recommendations, to consider incorporating one-time birth cohort and/or other population-based approaches to HCV screening into the clinical workflow as a preventative health measure, and to increase training among community providers to screen for and treat HCV.

Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.

Hepatitis B core-related antigen levels predict pegylated interferon-α therapy response in HBeAg-positive chronic hepatitis B.

BACKGROUND: Serum hepatitis B core-related antigen (HBcrAg) levels reflect intrahepatic HBV replication activity. We aimed to study whether HBcrAg levels predict response to pegylated interferon (PEG-IFN) treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. METHODS: We studied HBcrAg levels in 222 HBeAg-positive patients treated with PEG-IFN with or without lamivudine for 52 weeks in a global randomized trial and compared kinetics across treatment arms and types of response. Optimal HBcrAg cutoffs for stopping therapy were compared to and combined with the currently recommended hepatitis B surface antigen (HBsAg)-based stopping-rules. RESULTS: Baseline HBcrAg levels could not discriminate between responders and non-responders (P=0.91). HBcrAg levels of patients responding to PEG-IFN therapy showed a more pronounced on-treatment decline (mean declines 3.4 versus 1.0 log U/ml; P<0.0001), which was sustained until the end of follow-up (mean declines week 78, 3.8 versus 1.0 log U/ml; P<0.0001). In the PEG-IFN monotherapy group, HBcrAg levels of >8.35 log U/ml at week 24 identified 19 patients (19%) of whom 1 (negative predicitve value [NPV]=95%) achieved a response. The performance of this HBcrAg-based stopping rule alone was not superior to the one based on HBsAg >20,000 IU/ml. Among patients with an HBsAg <20,000 (n=56), 9 (16%) had an HBcrAg >8.35, of whom 8 achieved no response (NPV 89%). CONCLUSIONS: HBeAg-positive CHB patients with a response to PEG-IFN therapy achieve a more pronounced HBcrAg decline. HBcrAg levels at week 24 of therapy could be used to identify non-responders in combination with the established HBsAg-based stopping-rules.

Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study.

OBJECTIVE: A healthy lifestyle is the first-line treatment in non-alcoholic fatty liver disease (NAFLD), but specific dietary recommendations are lacking. Therefore, we aimed to determine whether dietary macronutrient composition is associated with NAFLD. DESIGN: Participants from the Rotterdam Study were assessed on (1) average intake of macronutrients (protein, carbohydrate, fat, fibre) using a Food Frequency Questionnaire and (2) NAFLD presence using ultrasonography, in absence of excessive alcohol, steatogenic drugs and viral hepatitis. Macronutrients were analysed using the nutrient density method and ranked (Q1-Q4). Logistic regression analyses were adjusted for sociodemographic, lifestyle and metabolic covariates. Moreover, analyses were adjusted for and stratified by body mass index (BMI) (25 kg/m2). Also, substitution models were built. RESULTS: In total, 3882 participants were included (age 70±9, 58% female). NAFLD was present in 1337 (34%) participants of whom 132 were lean and 1205 overweight. Total protein was associated with overweight NAFLD after adjustment for sociodemographic and lifestyle covariates (ORQ4vsQ1 1.40; 95% CI 1.11 to 1.77). This association was driven by animal protein (ORQ4vsQ1 1.54; 95% CI 1.20 to 1.98). After adjustment for metabolic covariates, only animal protein remained associated with overweight NAFLD (ORQ4vsQ1 1.36; 95% CI 1.05 to 1.77). Monosaccharides and disaccharides were associated with lower overall NAFLD prevalence (ORQ4vsQ1 0.66; 95% CI 0.52 to 0.83) but this effect diminished after adjustment for metabolic covariates and BMI. No consistent associations were observed for fat subtypes or fibre. There were no substitution effects. CONCLUSION: This large population-based study shows that high animal protein intake is associated with NAFLD in overweight, predominantly aged Caucasians, independently of well-known risk factors. Contrary to previous literature, our results do not support a harmful association of monosaccharides and disaccharides with NAFLD.

Real-world medical costs of antiviral therapy among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Very potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)-based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis. METHODS: This retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) treated with IFN-based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate. RESULTS: In total, 672 interferon-based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323-€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244-€41 892). The costs per SVR were €26 105 (95% CI, €23 068-€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151-€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463-€103 541) among those patients with a platelet count below 100 * 109 /L. CONCLUSIONS: Because of the lower SVR rates, the cost per SVR of IFN-based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN-free therapy could be limited among these patients.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS: Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared with their pre-treatment values (within 6 months prior to the start of therapy). All registered platelet count measurements from 24-week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS: This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 × 10(9) /L (IQR 7-62, P < 0.001). In comparison, patients without SVR showed a median decline of 17 × 10(9) /L (IQR -5-47, P < 0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, P < 0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R = -0.41, P < 0.001). CONCLUSIONS: Among chronic HCV-infected patients with advanced hepatic fibrosis, the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure.

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo.

In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.

Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors.

CD4+ type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC; n = 39) or liver metastases from colorectal cancer (LM-CRC; n = 60) we identify a CD4+FoxP3-IL-13-IL-10+ T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.

Modelling of early viral kinetics and pegylated interferon-alpha2b pharmacokinetics in patients with HBeag-positive chronic hepatitis B.

BACKGROUND: Pegylated interferon alpha2b (PEG-IFN-alpha(2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-alpha2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-alpha2b monotherapy. METHODS: Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-alpha2b with or without lamivudine. RESULTS: After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-alpha2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-alpha2b monotherapy group. Peak PEG-IFN-alpha2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-alpha2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-alpha2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed. CONCLUSIONS: PEG-IFN-alpha2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.