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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 > 12 months, with HBVDNA < 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 <.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 (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG‐IFN add‐on, whereas an HBsAg level > 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 >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. [ABSTRACT FROM AUTHOR]

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

Background: High-dose peginterferon-α (PegIFN-α) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-α may intensify side effects. Methods: We randomized 53 patients, who previously failed with standard IFN-α±ribavirin, to a high-dose induction and an extended regimen with PegIFN-α-2b [3.0 μg/kg once weekly (q.w.) 12 weeks→2.0 μg/kg q.w. 12 weeks→1.5 μg/kg q.w. 48 weeks] or a standard regimen (1.5 μg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800–1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4–33.3, P=0.01] and γ-glutamyltransferase (GGT) levels <2 × ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5–31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 × ULN (OR: 7.3, 95% CI: 1.4–38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2–76.9, P<0.001) were independently predictive for SVR. Conclusion: Retreatment with PegIFN-α-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome. [ABSTRACT FROM AUTHOR]

Background: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects., Methods: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL)., Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR., Conclusion: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.