Switching to PegIFNα-2b leads to HBsAg loss in patients with low HBsAg levels and HBV DNA suppressed by NAs.
ABSTRACT: Patients with low hepatitis B surface antigen (HBsAg) levels and hepatitis B virus (HBV) DNA suppression by nucleos(t)ide analogues (NAs) achieve high rate of HBsAg loss through switching to PegIFNα in pre-registration study. The aim of this study was to achieve higher rate of HBsAg loss through extended PegIFN treatment. 98 patients with HBsAg < 2,000 IU/ml and HBV DNA < 20 IU/ml were randomized to receive PegIFNα-2b or continuing NA therapy for 60 weeks. At the end of treatment (EOT) and end of follow-up (EOF), only patients who switched to PegIFNα-2b achieved HBsAg loss (32.6%) and HBsAg seroconversion (27.9% and 25.6%). Patients who switched to PegIFNα-2b also achieved higher HBeAg seroconversion rates (65.1%) and HBeAg loss (81.4% and 90.7%) than those who continued NAs treatment. On-treatment HBsAg declines predicted the responses at EOT, and HBsAg declines at post-baseline times predicted the responses at EOF. The rates of responses were not increased through extended PegIFNα treatment. For patients with low HBsAg and HBV suppression with NAs, switching to PegIFNα-2b significantly increased the rates of HBsAg loss and HBsAg seroconversion. HBsAg decline can predict the response of switching to PegIFNα-2b following from NAs.
Project description:The clinical efficacy of nucleos(t)ide analogues (NAs) combined with interferon (IFN) therapy vs. NAs monotherapy for chronic hepatitis B (CHB) remains inconclusive. The aim of this meta-analysis was to determine whether the NAs plus IFN regimen offers synergistic efficacy that justifies the cost and burden of such a combination therapy in CHB patients.Related publications covering the period of 1966 to July 2014 were identified through searching MEDLINE, EMBASE, Cochrane library, Chinese Biomedical Literature Database, WANFANG, and CNKI database. A total of 17 studies were enrolled, including 6 in English and 11 in Chinese. Then, we established a final list of studies for the meta-analysis by systematically grading the quality and eligibility of the identified individual studies. We used hepatitis B antigen (HBeAg) loss, HBV-DNA undetectable rate, HBeAg seroconversion, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, and histological score at the end of treatment for efficacy evaluation. A quantitative meta-analysis (Review Manager, Version 5.1.0) was performed to assess the differences between NAs and IFN combination therapy and NAs monotherapy.Our analysis demonstrated that HBeAg loss (RR = 1.73, 95% CI = 1.32-2.26, p < 0.001), HBV-DNA undetectable rate (RR = 1.58, 95% CI = 1.22-2.04, p < 0.001), HBeAg seroconversion (RR = 1.68, 95% CI = 1.36-2.07, p < 0.001), and HBsAg loss (RR = 2.51, 95% CI = 1.32-4.75, p < 0.001) in the combination therapy group were significantly higher than those in the monotherapy group. However, there were no significant differences in HBsAg seroconversion (RR = 4.25, 95% CI = 0.62-29.13, p = 0.14), sustained virological response rates, and biochemical response rates observed between the two groups. The results showed that the combination therapy group had more improved HBV histology than the NAs monotherapy group (RR = 1.14, 95% CI = 0.93-1.39, p = 0.22).NAs and IFN or Peg-IFN combination therapy had a better efficacy in terms of HBeAg loss, HBV-DNA undetectable rate, HBeAg seroconversion, and HBsAg loss, compared to the NA monotherapy group at the end of treatment; however, there was no significant difference in HBsAg seroconversion between the two regimens.
Project description:Some reports have documented the coexistence of Hepatitis B surfage Antigen (HBsAg) and anti-HBsAg antibodies (HBsAb) in patients with chronic hepatitis B (CHB), often in the absence of amino acid substitutions in the HBsAg sequences of the Hepatitis B Virus (HBV) genome able to explain an immunological escape variant.HBV genome has a very compact coding organization, with four partially overlapping open reading frames (ORFs). Because the reverse transcriptase region (rt) of HBV polymerase overlaps the HBsAg ORF, it is possible that some mutations in the HBsAg region correspond to mutations in the rt ORF, conferring resistance to current antiviral therapies. This unique case explores the response to antiviral therapies of a CHB with concurrent HBsAg and HBsAb positivity, and analyse the clinical implications of possible mutations in rt and HBsAg ORFs.Here we describe the case of a 59 year-old Italian man suffering from Hepatitis B envelope Antigen (HBeAg) positive CHB with concurrent HBsAb positivity. By ultra-deep pyro-sequencing (UDPS) technique, mutations conferring immunological escape or resistance to antiviral therapies were found neither in HBsAg nor in HBV rt ORFs, respectively. The patient was unsuccessfully treated with interferon, adefovir monotherapy and adefovir plus entecavir combination. Surprisingly, during entecavir plus tenofovir combination, anti-HBe seroconversion and HBsAg loss were observed, while the titer of HBsAb persisted.Concurrent HBsAg/HBsAb positivity in active CHB is a clinical and virological dilemma. In this setting, there are not consistent data about the response to conventional therapies and the immunological balance between host and virus remains so far unexplained. This is, to our knowledge, the first case described of a CHB with HBsAg/HBsAb positivity, wild type for clinically relevant mutations in HBsAg and rt ORFs, successfully treated with a combination of nucleot(s)ide analogues (NAs).
Project description:INTRODUCTION:Achieving functional cure of chronic HBV infection (Hepatitis B surface antigen [HBsAg] clearance, eventually followed by acquisition of anti-hepatitis B surface antigen [Anti-HBs]) in individuals with HIV and HBV infections is a rare event. In this setting, factors related to HBV cure have not yet been fully characterized. METHODS:HIV-infected individuals with chronic HBV infection enrolled in the French Dat'AIDS cohort (NCT02898987), who started combined antiretroviral (cART)-anti-HBV treatment were retrospectively analyzed for HBsAg loss and Anti-HBs seroconversion. RESULTS:Overall, 1419 naïve-subjects received three different cART-anti-HBV treatment schedule: (1) 3TC or FTC only (n = 150), (2) TDF with or without 3TC or FTC (n = 489) and (3) 3TC or FTC as first line followed by adding/switching to TDF as second line (n = 780). Individuals were followed-up for a median of 89 months (IQR, 56-118). HBV-DNA was < 15 IU/mL in 91% of individuals at the end of the follow-up. Overall, 97 individuals cleared HBsAg (0.7/100 patient-years), of whom, 67 seroconverted for Anti-HBs (0.5/100 patient-years). A high CD4 nadir, a short delay between HBV diagnosis and treatment, a longer time on HBV therapy, an African origin and TDF-based therapy were independent predictors of HBsAg clearance (Probability of odds ratio [OR]>1, >95%) suggested by Bayesian analysis. Also, TDF-based regimen as first line (OR, 3.03) or second line (OR, 2.95) increased rates of HBsAg clearance compared to 3TC or FTC alone, with a 99% probability. CONCLUSIONS:HBsAg clearance rate was low in HIV-HBV co-infected cART-anti-HBV treated individuals, but was slightly improved on TDF-based regimen.
Project description:As alternative indexes of hepatitis B virus (HBV), covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and peripheral blood RNA known as pgRNA, have been advocated as novel serum markers for prediction of prognosis and treatment response in chronic hepatitis B (CHB). Since the availability of commercial quantitative assays of HBsAg in 2011, HBsAg has been widely used for predicting treatment response of patients with CHB. Patients who received interferon therapy have shown a sharper reduction of HBsAg level than those who received nucleoside drug (NAs) therapy. Upon peginterferon treatment, sustained responders have presented a larger reduction of HBsAg level than the non-responders. An absence of HBsAg decline, together with < 2log reduction in HBV DNA at week 12, can serve as a stopping rule in HBsAg-negative patients infected with genotype D HBV. A sharp reduction of HBsAg titer in the NAs therapy is a predictor of HBsAg clearance in long-term treatment. HBcrAg, which consists of three species of related proteins sharing an identical 149 amino acid sequence, including HbcAg, hepatitis B e antigen (HBeAg), and a truncated 22-kDa precore protein, is still detectable in situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved. Therefore, HBcrAg remains a measurable serum marker to correlate with cccDNA in this situation. The decline in HBcrAg has been observed with NAs therapy and the pattern of decline might provide prognostic information on the risk of HBV post-treatment reactivation. Peripheral blood RNA, which is known as pgRNA, directly derives from cccDNA and reflects intrahepatic cccDNA level. Quantitative pgRNA has been suggested to be helpful in CHB management. However, commercial quantitative assays are lacking. Additionally, the use of simultaneous and continuous clearance of HBV RNA and HBV DNA in serum has been suggested to be a safe stopping rule of NAs therapy for patients with CHB. However, clinical studies of large sample sizes are needed to prove the feasibility and significance of using serum HBV RNA as the assessment standard of antiviral therapy in CHB and the safety of the stopping rule in clinics.
Project description:BACKGROUND:Accurate, rapid, and cost-effective screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may be useful in laboratories that cannot afford automated chemiluminescent immunoassays (CLIAs). We evaluated the diagnostic performance of a novel rapid automated fluorescent lateral flow immunoassay (LFIA). METHODS:A fluorescent LFIA using a small bench-top fluorescence reader, Automated Fluorescent Immunoassay System (AFIAS; Boditech Med Inc., Chuncheon, Korea), was developed for qualitative detection of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HCV (anti-HCV) within 20 minutes. We compared the diagnostic performance of AFIAS with that of automated CLIAs-Elecsys (Roche Diagnostics GmbH, Penzberg, Germany) and ARCHITECT (Abbott Laboratories, Abbott Park, IL, USA)-using 20 seroconversion panels and 3,500 clinical serum samples. RESULTS:Evaluation with the seroconversion panels demonstrated that AFIAS had adequate sensitivity for HBsAg and anti-HCV detection. From the clinical samples, AFIAS sensitivity and specificity were 99.8% and 99.3% for the HBsAg test, 100.0% and 100.0% for the anti-HBs test, and 98.8% and 99.1% for the anti-HCV test, respectively. Its agreement rates with the Elecsys HBsAg, anti-HBs, and anti-HCV detection assays were 99.4%, 100.0%, and 99.0%, respectively. AFIAS detected all samples with HBsAg genotypes A-F and H and anti-HCV genotypes 1, 1a, 1b, 2a, 2b, 4, and 6. Cross-reactivity with other infections was not observed. CONCLUSIONS:The AFIAS HBsAg, anti-HBs, and anti-HCV tests demonstrated diagnostic performance equivalent to current automated CLIAs. AFIAS could be used for a large-scale HBV or HCV screening in low-resource laboratories or low-to middle-income areas.
Project description:Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107? and IFN-? production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- ? secretion and CD107? expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.
Project description:Information on the efficacy of pegylated interferon (PEG-IFN) treatment of chronic hepatitis B (CHB) patients and predictors of the response based on real-world data is limited. Consecutive 201 patients who underwent PEG-IFN treatment for CHB were reviewed. A virological response (VR) was defined as a serum HBV DNA of <2000?IU/mL, and a combined response (CR) was defined a VR accompanied by serological response for hepatitis B e antigen (HBeAg)-positive CHB. For HBeAg-positive CHB patients, the HBeAg seroconversion rate and CR rate were 30.5% and 21.2% at 48 weeks after end of treatment (EOT), respectively. Baseline alanine aminotransferase (ALT) level was associated with HBeAg seroconversion, while baseline hepatitis B s antigen (HBsAg) levels of <250?IU/mL and HBV DNA <2.5?×?10(7)?IU/mL were strongly associated with sustained off-treatment CR. For HBeAg-negative CHB, the VR rates were 85.5%, and 27.7% at EOT, and 48 weeks after EOT, respectively; a baseline HBsAg <1,250?IU/mL was associated with sustained off-treatment VR. PEG-IFN treatment has durable HBeAg seroconversion in HBeAg-positive CHB, but results in a high risk of relapse among HBeAg-negative CHB patients. Pre-treatment HBsAg level is an important predictor of VR in CHB patients undergoing PEG-IFN treatment.
Project description:Background:None of the current guidelines recommend antiviral therapy for inactive hepatitis B virus (HBV) carriers (IHCs). Methods:In this real-world, multicenter, nonrandomized study, 32 participants meeting the inclusion criteria were enrolled 1:1 for treatment with peginterferon ?-2b or monitoring without treatment based on participant preference. The expected treatment duration was 48 weeks. The primary end point was hepatitis B surface antigen (HBsAg) loss. The HBV vaccine could be injected after HBsAg loss. Results:All patients had HBsAg levels of <20 IU/mL. The mean baseline HBsAg levels were 6.6 IU/mL and 5.8 IU/mL in the treated and untreated groups, respectively. Fifteen (93.8%) participants achieved HBsAg loss, 5 obtained HBsAg seroconversion after undergoing a mean of 19.7 weeks of therapy in the treated group, and no one in the follow-up group achieved HBsAg loss during a mean follow-up time of 12.6 months (P < .0001). Generally, the therapy was well tolerated. Nine of 11 individuals who exhibited HBsAg loss benefited from receiving the HBV vaccine. Conclusions:This study provides justification for further studies of short-course peginterferon ?-2b for the functional cure of IHCs with low HBsAg levels. Additionally, HBV vaccine injection is beneficial after interferon-induced HBsAg loss.
Project description:BACKGROUND:As an important anti-HBV drug, pegylated interferon ? (PegIFN?) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. METHODS:We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFN?-2a or PegIFN?-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. RESULTS:HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value?<?0.05). HBV RNA???1000 copies/mL was an optimized cutoff at week 12 that offered better prediction than other HBV biomarkers. This optimized cutoff plus patient age, HBV genotype B, and HBeAg offered a strong estimation of HBeAg seroconversion (accuracy 95.2%, true negative rate 99.8%). CONCLUSION:HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.
Project description:Background and Aims: Data are limited on the use of pegylated-interferon alpha-2a (peg-IFN?) in Chinese patients with chronic hepatitis B virus (HBV) infection (CHB). We evaluated the effectiveness and safety of peg-IFN? in Chinese patients with hepatitis B envelope antigen-negative CHB in routine clinical practice. Methods: In this prospective, multicenter, observational, non-interventional cohort study, patients were assessed for up to 1 year after peg-IFN? treatment cessation. Treating physicians established the dosing and treatment duration according to Chinese clinical practice. Effectiveness of peg-IFN? treatment was measured by the percentage of: patients with HBV DNA <2000 IU/mL and loss of hepatitis B surface antigen (commonly known as HBsAg); HBV DNA level at end of treatment (EOT), and 6 months and 1 year posttreatment; and time course change in quantitative HBV DNA and HBsAg. Results: At EOT, 6 months posttreatment, and 1 year posttreatment, the percentage of patients with HBV DNA <2000 IU/mL was 90.0%, 81.8%, and 82.2%, and that of patients with HBsAg loss was 6.5%, 9.4%, and 9.5%, respectively. The HBV DNA level decreased from 5.61 log IU/mL at baseline to 2.48 log IU/mL at EOT and 2.67 log IU/mL at 1 year posttreatment. The HBsAg level decreased from 3.08 log IU/mL at baseline to 2.24 log IU/mL at EOT and 2.10 log IU/mL at 1 year posttreatment. The incidence of adverse events was 52.0%. Conclusions: Peg-IFN? has the potential to provide functional cure (HBsAg loss) for CHB and is well tolerated in hepatitis B envelope antigen-negative CHB patients in routine clinical practice in China. Clinical Trial Registration: ClinicalTrials.gov (NCT01730508).