Loss Of HBV-DNA Research Articles

Model to predict on-treatment restoration of functional HBV-specific CD8+ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B.

SummaryBackgroundHepatitis B virus (HBV)‐specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off‐treatment HBV control in e‐antigen‐negative chronic hepatitis B (CHBe(−)).AimTo predict this response with variables involved in T‐cell exhaustion for use as a treatment stopping tool.MethodsIn NUC‐treated CHBe(−) patients, we considered a functional response in cases with HBV‐specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off‐treatment follow‐up according to LRM likelihood.ResultsWe developed an LRM that predicted the presence of a proliferative type I cytokine‐secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off‐treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability.ConclusionsShort‐term low‐level antigen exposure and early long‐term NUC treatment influence the restoration of a functional HBV‐specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off‐treatment HBV control and HBsAg decline and loss.

Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B.

Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6months post-treatment and defined as achieving both <2000IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. The median follow-up period was 7.2years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P<.001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P=.01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.

Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients: A Randomized Controlled 48-Week Trial.

To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).

Telbivudine on IgG-associated hypergammaglobulinemia and TGF-β1 hyperactivity in hepatitis B virus-related liver cirrhosis.

As debate rumbles on about whether anti-hepatitis B virus (HBV) nucleos(t)ide analogue treatments modulate host immune system during end-stage liver diseases, we studied effects of two potent anti-HBV agents, telbivudine or entecavir, on humoral immune activities including cytokine secretion, immunoglobulin production, and IgG-Fc agalactosylation, which is known to induce proinflammatory responses, in liver cirrhosis. Serum IgG-Fc N-glycan structures in patients with HBV-related liver cirrhosis, who had received either telbivudine treatment or entecavir treatment for at least 48 weeks were analyzed using liquid chromatography tandem-mass spectrometry. Levels of cytokines and each immunoglobulin isotype were measured using enzyme-linked immunosorbent assays. Results showed that 48 weeks of entecavir treatment caused HBV DNA loss, alanine aminotransferase normalization, and an amelioration of hypergammaglobulinemia in cirrhotic patients; however, telbivudine treatment, though possessing similar efficacies on HBV suppression and an improvement in liver inflammation to entecavir treatment, did not mitigate IgG-related hypergammaglobulinemia. Levels of IgG and transforming growth factor (TGF)-β1 in sera of the cirrhotic patients before and during treatment were positively correlated. In vitro assays revealed that telbivudine treatment induced TGF-β1 expression in human macrophagic cells. Moreover, recombinant TGF-β1 treatment stimulated cell proliferation and IgG overproduction in human IgG-producing B cell lines. Finally, we found that telbivudine treatment enhanced the proportion of serum IgG-Fc agalactosylation in cirrhotic patients, which was associated with enhanced levels of TGF-β1 and IgG. In conclusion, telbivudine therapy was associated with TGF-β1 hyperactivity, IgG-related hypergammaglobulinemia, and IgG-Fc agalactosylation in HBV-related liver cirrhosis.

HBV DNA loss in Bulgarian patients on NUC therapy. Speed related factors

HBV DNA loss in Bulgarian patients on NUC therapy. Speed related factors

HBV DNA loss in Bulgarian patients on NUC therapy. Speed related factors

HBV DNA loss in Bulgarian patients on NUC therapy. Speed related factors

Pegylated interferon-based sequential therapy for treatment of HBeAg reactive pediatric chronic hepatitis B-First study in children.

Our aim was to evaluate the efficacy and safety of sequential therapy using pegylated interferon (Peg-IFN) and nucleos(t)ide analogue (NA) for treatment of children in immunoactive (IA) and immunotolerant (IT) phases of chronic hepatitis B. It was a prospective observational study where those willing for sequential therapy were allocated to group 1 (sequential therapy) and others to group 2 (standard therapy). Sequential therapy included 8weeks of NA followed by 44weeks of combination of NA and Peg-IFN. In group 2, IA children received NA monotherapy, and IT children received no therapy. HBe seroconversion, HBs seroconversion, and loss of HBV DNA were the major outcome measures. A total of 61 children (36 IA and 25 IT) were included in the analysis. Among the IA children, 17 received sequential therapy and 19 received standard therapy; whereas, among the IT children, 12 received sequential therapy and 13 did not receive any therapy. In IA phase, sequential therapy led to higher HBe seroconversion (64.7% vs. 21.05%, p= 0.017) and higher virological clearance (94.12% vs. 52.63%, p= 0.008). In IT children, there was no benefit of treatment with sequential therapy over observation alone. Baseline ALT > 100IU/L predicted response to therapy with 100% sensitivity, 89.5% specificity, and LR+ of 9.52. Sequential therapy leads to higher HBe seroconversion and virological response in children in IA phase. Children with baseline ALT > 100IU/mL are more likely to respond to sequential therapy. There appears to be no role of sequential therapy in children in IT phase.

Higher efficacy of pegylated interferon-α2b add-on therapy in hepatitis B envelope antigen-positive chronic hepatitis B patients on tenofovir monotherapy.

Monotherapy with pegylated interferon-α (Peg-IFNα) or the nucleos(t)ide analogs (NA) currently approved for treating chronic hepatitis B (CHB) has limited efficacy. Studies on the combination of Peg-IFNα/NA have shown conflicting results. We investigated whether sequentially adding on Peg-IFNα to tenofovir enhances serological response rates. Treatment-naïve, hepatitis B envelope antigen (HBeAg)-positive CHB patients with moderately elevated alanine aminotransferase (ALT; 48-200IU/mL) were started on tenofovir (300mg/day) and enrolled at week 12 in a 1:1 ratio to either receive Peg-IFNα2b add-on (1.5μg/kg/week) from week 12 to 36 (n = 53) or continue tenofovir monotherapy (n = 53). Both treatment arms received tenofovir consolidation therapy until week 72. The primary end-point was HBeAg loss at week 72. At week 72, the rate of HBeAg loss was higher in the Peg-IFNα2b add-on group (35.8%) compared to the tenofovir monotherapy group (17%) (P = 0.028; odds ratio, 2.73, 95% confidence interval, 1.09-6.79), and considerably higher in patients with a baseline hepatitis B virus (HBV)-DNA level >6logIU/mL (32.6% vs 11.4%; P = 0.021). Rates of HBV-DNA loss (77.4% vs 71.7%; P = 0.51), ALT normalization (62.3% vs 52.8%; P = 0.32), and sustained virologic response (20.8% vs 11.3%; P = 0.18) at week 72 were comparable between the two groups. Significantly more patients in the add-on group had >3log HBV-DNA reduction at week 36 (92.5% vs 66%; P = 0.001). Four patients treated with Peg-IFNα2b add-on achieved hepatitis B surface antigen (HBsAg) loss compared with one patient receiving tenofovir monotherapy. Decline of HBV-DNA of >2log at week 4 led to higher HBeAg loss at week 72, independent of treatment arm. No patient had treatment-related adverse effects requiring treatment discontinuation. Twenty-fourweeks of Peg-IFNα2b as an add-on sequential regimen to tenofovir is safe and resulted in greater loss of HBeAg and HBsAg compared to tenofovir monotherapy in selected HBeAg-positive patients. Viral load reduction followed by immune modulation is a potentially useful approach.

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community-based real-world study.

Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.

Continuous up to 4 Years Entecavir Treatment of HBV-Infected Adolescents - A Longitudinal Study in Real Life.

This study evaluated the long-term (up to 4 years) efficacy and safety of entecavir ETV treatment and analysed the significance of baseline and on-treatment factors in long-term ETV outcomes in adolescents with chronic hepatitis B (CHB). We determined the cumulative virological and serological outcomes of 44 adolescents with CHB receiving ETV for up to 4 years. To investigate the dynamics of HBV DNA, ALT activity and hepatitis B e antigen (HBeAg) seroconversion over time and their associations with the considered factors, generalized estimating equation (GEE) models were used. The cumulative rates of undetectable HBV DNA (<20 IU/ml) and HBeAg seroconversion after 4 years were 89.7% and 55.4%, respectively. In the study group, we showed that having undetectable HBV DNA at the 6th or 12th month of therapy predicted the achievement of a sustained response rate (SRR, defined as the loss of HBV DNA, loss of HBeAg and ALT normalization) at year 3 of ETV therapy (P = 0.048, OR = 5.83; P = 0.012; OR = 14.57, respectively). The GEE analysis indicated that of the different factors, the duration of ETV therapy had a strong impact on the achievement of virological suppression, HBeAg seroconversion and SRR in adolescents. Each month after the initiation of therapy, the odds of loss of HBV DNA increased by approximately 5% (OR = 1.05, P<0.0001), on average. Additionally, the GEE analysis revealed that adolescents with an age at infection of ≥10 years had 3 times higher odds of achieving undetectable HBV DNA than patients with a younger infection age (OR = 3.67, P = 0.028). None of the ETV-treated patients reported significant adverse effects. ETV is an effective and safe treatment option for adolescents with CHB. Undetectable HBV DNA in the 6th and/or 12th month of ETV treatment and older age at infection could predict maintained virological suppression.

Entecavir for Patients with Hepatitis B Decompensated Cirrhosis in China: a meta-analysis.

Evidence about the clinical effects of entecavir (ETV) for patients with hepatitis B decompensated cirrhosis remain controversial. Therefore, we perform this meta-analysis to assess the treatment outcomes of ETV in participants with hepatitis B decompensated cirrhosis. Relevant studies were identified by searching databases until the March 2016. A random-effects model was used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs). GRADEprofiler3.6 was used to evaluate the quality of the evidence. A total of 26 studies (involving 2040 patients) were included. The quality of the evidence was classified from very low to high by the GRADED approach for all included RCTs. Meta-analysis showed that patients were more likely to experience HBV-DNA loss (RR:1.85, 95%CIs: 1.41 to 2.43, P < 0.0001 at 48 weeks), have normalized alanine aminotransferase levels (ALT) (P = 0.003 at 24 weeks, P = 0.02 at 48 weeks), and have a low mortality rate at 24 weeks (P = 0.003) when treated with ETV. There was no significant different between ETV and the control groups at the total mortality (P = 0.06) and HBeAg seroconversion (P = 0.14). In conclusion, ETV could be the first line therapy for patients with HBV related decompensated cirrhosis, because ETV could reduce the early mortality and move HBV DNA load down.

Association between clinical features and YMDD mutations in patients with chronic hepatitis B following lamivudine therapy.

The aim of the present study was to investigate the correlation between feature and genotype with regard to the tyrosine-methionine-aspartate-aspartate (YMDD) mutation in chronic hepatitis B patients after lamivudine (LAM) therapy. A total of 30 patients with chronic hepatitis B were recruited, who underwent one year of LAM therapy. The patients' alanine aminotransferase (ALT) level and hepatitis B envelope antigen (HBeAg) seroconversion were evaluated, hepatitis B virus (HBV) DNA was genotyped using a new genotyping method and YMDD mutations were analyzed prior to treatment and at 6 and 12 months after LAM treatment. Furthermore, the secondary protein structure of the HBV DNA polymerase gene (P gene) was analyzed. Following treatment, the results suggested that LAM therapy improved ALT normalization. There was no correlation between clinical effects and ALT level before treatment. After 12 months treatment, the rate of HBeAg loss increased and the rate of HBeAg seroconversion decreased linearly with the rise of baseline ALT level. While ALT normalization and HBeAg seroconversion were highest in patients with HBV genotype B, HBeAg loss and HBVDNA loss were highest in those with genotype C. The effect was predominant in genotype D. No YMDD mutations were identified prior to 6 months of LAM therapy. The rate of YMDD mutations after 12 months LAM therapy was 12.12%. Two patients with rtM204V + rtL180M belonged to genotype C and another patient with rtL180M alone belonged to genotype D. The turn of secondary protein structure of P gene changed to β sheet when a rtM204V mutation occurred, and no change of secondary protein structure was associated with the rtL180M mutation. Thus, the present results indicate that one year of LAM therapy is able to improve ALT normalization. Long-term LAM therapy may induce YMDD mutation and drug resistance.

Treatment of children with HBeAg-positive chronic hepatitis B: A systematic review and meta-analysis

BackgroundEffective management of children with chronic hepatitis B is still an unresolved issue. AimTo assess the outcome of different therapeutic regimens among children with HBeAg-positive chronic hepatitis B. MethodsElectronic database searches identified clinical trials that completed specific periods of treatment and follow-up. Sustained response rates were defined by the loss of HBV DNA and HBeAg, and by the normalization of liver enzymes. The loss of HBsAg and seroconversion to anti-HBs were also listed. ResultsOur searches found 20 eligible articles (1112 enrolled patients, 2–18 years old). Interferon-alpha therapy showed significantly higher sustained response rate and loss of HBsAg than no therapy (Odd's ratio 3.0, 95% confidence interval 1.6–5.4; and 2.3, 1.1–11.3, respectively). The sustained response rate was not significantly different between interferon and interferon plus lamivudine, or plus prednisone, or plus hepatitis B vaccine; this rate was significantly higher for interferon compared with combined interferon plus levamisole or vitamin E. ConclusionInterferon-alpha is still the most effective treatment option for children with HBeAg-positive chronic hepatitis B. Randomized trials are warranted for further comparing interferon to newer antiviral agents in terms of efficacy, safety, emergence of mutant variants, and cost/benefit ratio.

Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double‐blinded multicentre trial

Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 μm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 μm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 μm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy

BackgroundImproving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy.MethodsFifty patients with chronic hepatitis B without the loss of HBeAg after ≥96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN α2a therapy, and were then assessed during a subsequent 24-week follow-up period.ResultsForty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN α2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg <20,000 IU/mL, which was significantly higher than 29.4% of patients with HBsAg ≥20,000 IU/mL (P=0.031). For patients with HBsAg levels <1,500 IU/mL at 12 and 24 weeks therapy, the end-of-treatment combined response rate was 68.2% and 69.0%, which were both significantly higher than patients with HBsAg ≥1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA<105 copies/mL (76.2%) compared to patients with HBV DNA ≥105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004).ConclusionRetreatment with PEG-IFN α2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN α2a after 48 weeks of therapy.

HBsAg loss with HBsAg/anti-HBs seroconversion and non-detectable HCV-RNA in a patient with chronic HBV e-minus/HCV hepatitis treated with two cycles of antiviral therapy

Introduction: Loss of HBsAg is observed in only 3-4% of patients who receive interferon for chronic HBV+HCV hepatitis, and there are few reports of HBsAg loss induced by treatments other than interferon. We report a case of chronic HBV+HCV hepatitis, in which a positive outcome was achieved with a new therapeutic strategy. Case report: The patient was a 49-year-old Caucasian woman found to be HBsAg+ in 1978 and HCVAb+ in 1997. During 2000-2003, the patient had markedly increased AST/ALT, histology grade 5, stage 1 (Ishak) disease with HBsAg positivity, HBV-DNA 1,450 cp/mL, HCV-RNA 7.57x105 IU/mL (genotype 1b). In May 2003 she began a 48-week course of PEG-IFNa2b (80 mg/week) without ribavirin. The latter drug was not used because it had recently been observed that in some HBV/HCV-coinfected patients treated with the two drugs, the hepatic flares preceding the seroconversion to HBsAb caused fulminant liver failure. Neither the HBV and HCV infections responded to this treatment, but during follow-up the HBV-DNA dropped to 40 cp/mL and the patient presented persistently normal transaminase values (6th month) followed by loss of HBsAg (24th month) and the appearance of anti-HBs (36th month). By December 2008, the HBV negativity and HBsAg/anti-HBs seroconversion were well-established, but HCV replication persisted. The decision was therefore made to administer PEG-IFNa2a (180 mg/week) and ribavirin (1,000 mg/day). There was no evidence of an RVR or EVR, so therapy was continued for 48 weeks. At the scheduled 12-month treatment, the patientwas found to be HCV-RNA negative by TaqMan PCR. Conclusions: In our opinion this case is of great interest because: 1) it is the first report of a virological response in a HBV/HCV-coinfected CH patient treated with PEG-IFN; 2) control of the two viral infections was achieved with a new therapeutic strategy that included two phases: a) HBV-DNA loss at 6 months and HBsAg/anti-HBs seroconversion between months 24 and 36, after PEG-IFNa2b mono-therapy, which was administered when the HCV replication seemed to prevail over that of HBV; b) ETR for HCV after 72 weeks of PEG-IFNa2a+ribavirin, which was continued in spite of the lack of an EVR, as this does not preclude the possibility of a SVR.

HBsAg loss with HBsAg/anti-HBs seroconversion and non-detectable HCV-RNA in a patient with chronic HBV e-minus/HCV hepatitis treated with two cycles of antiviral therapy

Loss of HBsAg is observed in only 3-4% of patients who receive interferon for chronic HBV+HCV hepatitis, and there are few reports of HBsAg loss induced by treatments other than interferon. We report a case of chronic HBV+HCV hepatitis, in which a positive outcome was achieved with a new therapeutic strategy. The patient was a 49-year-old Caucasian woman found to be HBsAg+ in 1978 and HCVAb+ in 1997. During 2000-2003, the patient had markedly increased AST/ALT, histology grade 5, stage 1 (Ishak) disease with HBsAg positivity, HBV-DNA 1,450 cp/mL, HCV-RNA 7.57x105 IU/mL (genotype 1b). In May 2003 she began a 48-week course of PEG-IFNα2b (80 μg/week) without ribavirin. The latter drug was not used because it had recently been observed that in some HBV/HCV-coinfected patients treated with the two drugs, the hepatic flares preceding the seroconversion to HBsAb caused fulminant liver failure. Neither the HBV and HCV infections responded to this treatment, but during follow-up the HBV-DNA dropped to 40 cp/mL and the patient presented persistently normal transaminase values (6th month) followed by loss of HBsAg (24th month) and the appearance of anti-HBs (36th month). By December 2008, the HBV negativity and HBsAg/anti-HBs seroconversion were well-established, but HCV replication persisted. The decision was therefore made to administer PEG-IFNα2a (180 μg/week) and ribavirin (1,000 mg/day). There was no evidence of an RVR or EVR, so therapy was continued for 48 weeks. At the scheduled 12-month treatment, the patient was found to be HCV-RNA negative by TaqMan PCR. In our opinion this case is of great interest because: 1) it is the first report of a virological response in a HBV/HCV-coinfected CH patient treated with PEG-IFN; 2) control of the two viral infections was achieved with a new therapeutic strategy that included two phases: a) HBV-DNA loss at 6 months and HBsAg/anti-HBs seroconversion between months 24 and 36, after PEG-IFNα2b mono-therapy, which was administered when the HCV replication seemed to prevail over that of HBV; b) ETR for HCV after 72 weeks of PEG-IFNα2a+ribavirin, which was continued in spite of the lack of an EVR, as this does not preclude the possibility of a SVR.

Quantification of HBsAg and HBV-DNA during Therapy with Peginterferon alpha-2b plus Lamivudine and Peginterferon alpha-2b Alone in a German Chronic Hepatitis B Cohort

Peginterferon alpha-2b (PEG-IFNa2b) and lamivudine are efficient treatment options for chronic hepatitis B virus (HBV) infection. We assumed that a combination therapy of PEG-IFNα-2b plus lamivudine will be more effective than PEG-IFNα-2b alone concerning loss of HBV-DNA, HBeAg seroconversion, and HBsAg reduction. Patients with chronic hepatitis B were randomised to nine months treatment with PEG-IFNα-2b 1.5 µg/kg o. i. w. or PEG- IFNα-2b plus lamivudine 100 mg/d. The study was designed with 60 patients per treatment arm. The primary endpoint was defined as loss of HBV-DNA (< 400 copies/mL) 24 weeks after the end of therapy. HBV-DNA (PCR), HBsAg (Architect, Abbott), and HBeAg (Axsym, Abbott) were determined prior to and at the end of treatment as well as at follow-up. HBV-genotypes were determined by Innolipa (Innogenetics). Only 32 patients were randomised to combination therapy and 27 individuals to monotherapy due to low recruitment rates. On treatment reduction of HBV-DNA was significantly higher during combination therapy compared to PEG-IFNa-2b monotherapy (- 4.60 ± 2.71 vs. - 2.41 ± 2.17 log; p = 0.003). However, there was no difference in the number of cases achieving HBV-DNA < 400 copies/mL, ALT normalisation, or HBeAg seroconversion at follow-up. None of the parameters was significantly related to HBV-genotypes. In a post-hoc analysis serum HBsAg levels were analysed as an additional prognostic parameter for treatment response (n = 29). Combination therapy showed a stronger, but not significant HBsAg decline during (- 0.7 ± 1.17 log IU/mL vs. - 0.26 ± 0.61 log IU/mL; p = 0.35) and after therapy (- 0.68 ± 1.29 log IU/mL vs. - 0.24 ± 0.56 log IU/mL; p = 0.82). Two of three cases with a 2-log HBsAg decline to HBsAg levels < 100 IU/mL eliminated HBsAg during long-term follow-up. The study was underpowered with respect to the primary endpoint due to low recruitment rates. However, in the post-hoc analysis HBsAg decline was over two-fold stronger at the end of treatment and follow-up after combination therapy and did not rebound after lamivudine withdrawal. These results may indicate the usefulness of future combination therapies without discontinuation of nucleos(t)ide analogues.

HBV DNA Loss within 24 Weeks Predicts Late Viral Breakthrough in Chronic Hepatitis B

Sustained HBV DNA reduction is necessary for biochemical remission, histological improvement, and prevention of complications. We analyzed the time taken from HBV DNA loss to viral breakthrough after antiviral treatment in patients with chronic hepatitis B (CHB). The early fall of the HBV DNA level to undetectable levels assessed really whether it is related to late breakthrough. A total of 91 patients whose HBV DNA levels dropped below undetectable levels were chosen from lamivudine-treated 306 patients and were analyzed retrospectively. The patients were divided into 4 groups (A≤12, 12<B≤24, 24<C≤48, D>48 wk) according to the time taken for the HBV DNA to decrease below undetectable levels. HBV DNA level was determined every 3 months. The mean time taken for loss of HBV DNA was 34±28 wk. The baseline ALT differed significantly among groups (A: 382±274, B: 340±30, C: 166±92, D: 54±100 IU/L) (p=0.007). Fifty nine of the 91 patients (64.8%) experienced viral breakthrough. The mean interval between HBV DNA loss and viral breakthrough was 65±40 wk and differed significantly between group A, B (82±43 wk) and group C, D (56±28 wk) (p=0.015). In multivariate analysis, only HBV DNA loss within 24 wk, was found to be independently associated with late viral breakthrough (p=0.035). Undetectable HBV DNA after 24 wk was associated with high odd ratio of 3.24 (95% CI, 1.09-9.67). HBV DNA loss within 24 wk after antiviral treatment could predict the late breakthrough.

Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia.

Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.