Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.

BACKGROUND AND OBJECTIVES: Age is a traditional risk factor for open-heart surgery. The efficacy and safety of transcatheter edge-to-edge mitral valve repair, using MitraClip (Abbott Vascular), has been demonstrated in patients with severe mitral regurgitation (MR). Since octogenarians or older patients are usually deferred to receive open-heart surgery, the main interest of this study is to elucidate the procedural safety and long-term clinical impact of MitraClip in elderly patients. METHODS: Patients with symptomatic severe MR were evaluated by the heart team. For those with high or prohibitive surgical risks, transcatheter mitral valve repair was performed in hybrid operation room. Transthoracic echocardiography (TTE), blood tests, and six-minute walk test (6MWT) were performed before, 1-month, 6-months, and 1 year after index procedure. RESULTS: A total of 46 consecutive patients receiving MitraClip procedure were enrolled. Nineteen patients (84.2±4.0 years) were over 80-year-old and 27 (73.4±11.1 years) were younger than 80. Compare to baseline, the significant reduction in MR severity was achieved after the procedure and sustained. All the patients benefited from significant improvement in New York Heart Association functional class. The 6-minute walk test (6MWT) increased from 259±114 to 319±92 meters (p=0.03) at 1 year. The overall 1-year survival rate was 80% in the elderly and 88% in those <80 years, p=0.590. Baseline 6MWT was a predictor for all-cause mortality (odds ratio, 0.99; 95% confidence interval, 0.982–0.999; p=0.026) after the MitraClip procedure. CONCLUSIONS: Trans-catheter edge-to-edge mitral valve repairs are safe and have positive clinical impact in subjects with severe MR, even in advanced age.
Aged ; Aged, 80 and over ; Echocardiography ; Heart ; Hematologic Tests ; Humans ; Mitral Valve Insufficiency ; Mitral Valve ; Mortality ; Risk Factors ; Survival Rate

BACKGROUND AND OBJECTIVES: Age is a traditional risk factor for open-heart surgery. The efficacy and safety of transcatheter edge-to-edge mitral valve repair, using MitraClip (Abbott Vascular), has been demonstrated in patients with severe mitral regurgitation (MR). Since octogenarians or older patients are usually deferred to receive open-heart surgery, the main interest of this study is to elucidate the procedural safety and long-term clinical impact of MitraClip in elderly patients. METHODS: Patients with symptomatic severe MR were evaluated by the heart team. For those with high or prohibitive surgical risks, transcatheter mitral valve repair was performed in hybrid operation room. Transthoracic echocardiography (TTE), blood tests, and six-minute walk test (6MWT) were performed before, 1-month, 6-months, and 1 year after index procedure. RESULTS: A total of 46 consecutive patients receiving MitraClip procedure were enrolled. Nineteen patients (84.2±4.0 years) were over 80-year-old and 27 (73.4±11.1 years) were younger than 80. Compare to baseline, the significant reduction in MR severity was achieved after the procedure and sustained. All the patients benefited from significant improvement in New York Heart Association functional class. The 6-minute walk test (6MWT) increased from 259±114 to 319±92 meters (p=0.03) at 1 year. The overall 1-year survival rate was 80% in the elderly and 88% in those <80 years, p=0.590. Baseline 6MWT was a predictor for all-cause mortality (odds ratio, 0.99; 95% confidence interval, 0.982–0.999; p=0.026) after the MitraClip procedure. CONCLUSIONS Trans-catheter edge-to-edge mitral valve repairs are safe and have positive clinical impact in subjects with severe MR, even in advanced age.

Background/Aims: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). Methods: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. Results: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5–40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7–67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1–62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12–2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21–0.81). Conclusions Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.

Background/Aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection. Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. Results: A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were –2.9, –3.3, –3.5 and –0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was –2.9, –2.4, –2.0, and –0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events of mild or moderate severity with no discontinuations, serious AEs or deaths. Conclusions In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.