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.

AbstractBackground(Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand.MethodsIn this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients.ResultsOf 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= −0.74, standard error [SE] = 0.16, P = 3.44 ×10–6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10–6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele.ConclusionsAlthough no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.Clinical Trials RegistationNCT01401400.

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 HB eAg‐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 HB eAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response ( HB eAg 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 log 10 HB sAg 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 HB eAg loss than to increased long‐term HB eAg loss rates.

Background:We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy. Methods:This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2000 IU/mL. Patients were randomly assigned in a 1:1 ratio to 48 weeks of peginterferon add-on therapy (n = 39) or continued NA monotherapy (n = 38). Response (defined as HBeAg seroconversion with an HBV DNA load of <200 IU/mL) was assessed at week 48, with responders discontinuing NA therapy at week 72. Results:The primary end point (response at week 96) was achieved in 18% of patients who were assigned peginterferon add-on therapy versus 8% of patients assigned NA monotherapy (P = .31). Among 58 interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon. Conclusion:The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy. Clinical Trials Registration:NCT01532843.

Background— Endovascular infrapopliteal treatment of patients with critical limb ischemia using percutaneous transluminal angioplasty (PTA) and bail-out bare metal stenting (BMS) is hampered by restenosis. In interventional cardiology, drug-eluting stents (DES) have shown better patency rates and are standard practice nowadays. An investigator-initiated, multicenter, randomized trial was conducted to assess whether DES also improve patency and clinical outcome of infrapopliteal lesions. Methods and Results— Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive PTA±BMS or DES with paclitaxel. Primary end point was 6-month primary binary patency of treated lesions, defined as ≤50% stenosis on computed tomographic angiography. Stenosis >50%, retreatment, major amputation, and critical limb ischemia–related death were regarded as treatment failure. Severity of failure was assessed with an ordinal score, ranging from vessel stenosis through occlusion to the clinical failures. Seventy-four limbs (73 patients) were treated with DES and 66 limbs (64 patients) received PTA±BMS. Six-month patency rates were 48.0% for DES and 35.1% for PTA±BMS ( P =0.096) in the modified-intention-to-treat and 51.9% and 35.1% ( P =0.037) in the per-protocol analysis. The ordinal score showed significantly worse treatment failure for PTA±BMS versus DES ( P =0.041). The observed major amputation rate remained lower in the DES group until 2 years post-treatment, with a trend toward significance ( P =0.066). Less minor amputations occurred after DES until 6 months post-treatment ( P =0.03). Conclusions— In patients with critical limb ischemia caused by infrapopliteal lesions, DES provide better 6-month patency rates and less amputations after 6 and 12 months compared with PTA±BMS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00471289.

UNLABELLED:Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. CONCLUSION:Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs.

OBJECTIVE:To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohn's disease (CD).DESIGN:Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohn's Disease Activity Index, Crohn's Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ).RESULTS:Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed.CONCLUSIONS:Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00736983.

OBJECTIVE:Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients. METHODS:All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 μg weekly) ± ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1 ± 0.2 years). Retreated patients were considered nonresponders. RESULTS:Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants). CONCLUSION:About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease.

TLI while in clinical remission.We further confirmed that trough levels are inversely correlated with CRP.The current controlled study will investigate whether long term adjustment of treatment based on IFX levels is a superior strategy.

OBJECTIVES:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon alpha-2a with ribavirin might improve sustained response rates. METHODS:Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon alpha-2a 180 microg weekly plus placebo) or combination therapy (peginterferon alpha-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients. RESULTS:At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia. CONCLUSIONS:Treatment with peginterferon alpha-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.