Effect of Pegylated Interferon Add-On Therapy to Achieve Disease Remission in Patients with Chronic Hepatitis B

Despite effective vaccination, chronic hepatitis B (CHB) poses a substantial hazard to public health with limited options for finite treatment. A pooled analysis was performed to investigate whether 24-48 weeks of peg-interferon (PEG-IFN) addition could increase response 48 weeks after end-of-therapy compared to continued nucleos(t)ide analogue (NUC)-monotherapy in 234 patients from two investigator-initiated trials. PEG-IFN addition hypothetically increases off-treatment response, particularly after prolonged NUC pre-treatment due to partial immune restoration. Response was observed in 38/118 (33%) patients assigned PEG-IFN addition and 23/116 (20%) assigned NUC-monotherapy (p=0.03). The duration of NUC-monotherapy was associated with HBsAg and HBV DNA, but not directly with response. Re-treating initial non-responders with PEG-IFN add-on did not improve response. PEG-IFN naïve patients with low HBsAg and HBV-DNA levels at randomization achieved the highest response to addition therapy compared with NUC-monotherapy (70% vs. 34%; p=0.01), identifying these as the best candidates for PEG-IFN add-on therapy in clinical practice.M.Sc

Low Rate of Hepatitis B Reactivation Among Patients with Chronic Hepatitis C During Direct Acting Antiviral Therapy

Background and Aims: Hepatitis B virus (HBV) reactivation has been reported in patients co-infected with hepatitis C virus (HCV) during direct acting antiviral (DAA) therapy, leading the United States Food and Drug Administration (U.S. FDA) to issue a black box warning on all DAA drug labels recommending monitoring for HBV reactivation. We conducted a comprehensive evaluation to assess the rate of HBV reactivation among patients with chronic hepatitis C (CHC) during DAA therapy. Methods: Patients with CHC and recovered HBV infection (hepatitis B surface antigen negative (HBsAg)/anti-hepatitis B core positive), treated with DAAs were included if stored sera were available. Samples were tested for HBV DNA, HBsAg, and ALT. HBV reactivation was considered if (1) HBV DNA was undetectable pre-DAA therapy and became detectable post-therapy, or (2) HBV DNA was detectable pre-treatment, but not quantifiable (&lt; 20 IU/mL) and became quantifiable post-treatment. Result: 79 patients with median age of 62 years were included. 68% were male and Caucasian. Various DAA regimens were administered for 12–24 weeks. Reactivation occurred in 8/79 (10%) of patients and occurred more frequently in men compared to women: 6 during treatment and 2 after treatment. Neither an ALT flare nor HBsAg seroreversion were observed. Detectable HBV DNA was transient in 5/8 and could not be determined in 3/8 but ALT flares were not observed in follow-up of these patients. Conclusion: The risk of HBV reactivation was low in CHC patients with resolved HBV during DAA therapy. Our data support testing for HBV DNA only in selected patients with ALT flares or failure of ALT normalization during DAA treatment.</p

Low hepatitis B surface antigen and HBV DNA levels predict response to the addition of pegylated interferon to entecavir in hepatitis B e antigen positive chronic hepatitis B

Background Various treatment combinations of peginterferon (PEG-IFN) and nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the optimal regimen remains unclear. Aims To study whether PEG-IFN add-on increases response compared to entecavir (ETV) monotherapy, and whether the duration of ETV pretreatment influences response. Methods Response was evaluated in HBeAg positive patients previously treated in two randomized controlled trials. Patients received ETV pretreatment for at least 24 weeks and were then allocated to 24-48 weeks of ETV+PEG-IFN add-on, or continued ETV monotherapy. Response was defined as HBeAg loss combined with HBV DNA Results Of 234 patients, 118 were assigned PEG-IFN add-on and 116 continued ETV monotherapy. Response was observed in 38/118 (33%) patients treated with add-on therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest response to add-on therapy compared to monotherapy was observed in PEG-IFN naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below 50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cut-off levels, response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both P < 0.005), but not with response (P = 0.82). Conclusions PEG-IFN add-on to ETV therapy was associated with higher response compared to ETV monotherapy in patients with HBeAg positive CHB. Response doubled in PEG-IFN naive patients with HBsAg below 4000 IU/mL and HBV DNA below 50 IU/mL, and therefore identifies them as the best candidates for PEG-IFN add-on (Identifiers: NCT00877760, NCT01532843)

Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B:Multicentre Randomized Trial (PAS Study)

We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA &gt; 12 months, with HBVDNA &lt; 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 μg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p &lt;.001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p =.01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p =.002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (&lt;10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level &gt; 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels &gt;200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.</p

Early virologic relapse predicts alanine aminotransferase flares after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B

When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) ther-apy before achieving HBsAg loss, flares often ensue which are challenging to pre-dict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 pa-tients from an external, prospective cohort were used for validation. Retreatment criteria were pre- defined. Pre- and post-treatment predictors of alanine aminotrans-ferase (ALT) flare (>5× ULN) were evaluated by Cox proportional- hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5×ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2–8.9]; p= 0.03) and serum HBV DNA (1.2 [1.0–1.8]; p= 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5×ULN (3.4 [1.4–8.4]; p= 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment

The Inflammatory Cytokine Profile Associated With Liver Damage Is Broader and Stronger in Patients With Chronic Hepatitis B Compared to Patients With Acute Hepatitis B

Liver damage in hepatitis B is immune driven and correlates with inflammatory markers in patient serum. There is no comparison of these markers to determine if inflammatory profiles are distinct to different types of liver damage across patients at different stages of disease. We measured 25 inflammatory markers in patients with acute hepatitis B and chronic hepatitis B with hepatitis B e antigen seroconversion and chronic patients stopping nucleoside analogue therapy. Myeloid markers dominated the inflammatory profile in all stages of hepatitis B. More inflammatory markers were detectable in chronic patients, including elevated concentrations of cytotoxic effectors Fas ligand, TRAIL, and TNF-α