Unmet needs in the clinical management of chronic hepatitis B infection.

The hepatitis B virus (HBV) remains a global problem despite effective tools to prevent, diagnosis, and control it. Unmet needs are identifiable across its clinical care cascade, underlining the challenges providers face in delivering effective care for patients with chronic hepatitis B. The review herein will focus on three timely clinical issues in HBV. This includes efforts to optimize delivery of perinatal HBV care, improve HBV-related hepatocellular carcinoma risk stratification models, and clarify the role of finite therapy in the HBV treatment algorithm. Important developments within these three topics will be addressed with the goal to motivate further investigation and optimization of these treatment strategies for HBV.

Trends and outcomes of combined percutaneous (TAVI+PCI) and surgical approach (SAVR+CABG) for patients with aortic valve and coronary artery disease: A National Readmission Database (NRD) analysis.

BACKGROUND: In patients with severe aortic stenosis (AS) and concomitant severe coronary artery disease (CAD), the relative merits of a combined percutaneous (transcatheter aortic valve implantation [TAVI] and percutaneous coronary intervention [PCI]] versus surgical approach (surgical aortic valve replacement [SAVR] and coronary artery bypass graft [CABG]) remain unknown. AIMS: To determine the utility of combined percutaneous versus surgical approaches in patients with severe AS and CAD. METHODS: The National Readmission Database (NRD) (2015-2019) was queried to identify all cases of TAVI+PCI and SAVR+CABG. The adjusted odds ratios (aOR) of mortality, stroke, and its composite (major adverse cardiovascular events [MACE]) were calculated using a propensity-score matched (PSM) analysis. RESULTS: A total of 89,314 (5358 TAVI+PCI, 83,956 SAVR+CABG) patients were included in the crude analysis. There was a gradual increase in the utilization of TAVI+PCI from 2016 to 2019 by 2%-4% per year. Using PSM, a subset of 11,361 (5358 TAVI+PCI, 6003 SAVR+CABG) patients with a balanced set of demographics and baseline comorbidities was selected. During index hospitalization, the adjusted odds of MACE (aOR 0.72, 95% confidence interval [CI] 0.62-0.83), and all-cause mortality (aOR 0.68, 95% CI 0.57-0.81) were significantly lower in patients undergoing TAVI+PCI compared with SAVR+CABG. However, patients undergoing TAVI+PCI had a higher incidence of MACE (aOR 1.40, 95% CI 1.05-1.87), and mortality (aOR 1.75, 95% CI 1.22-2.50) at 30-days. The risk of index-admission (aOR 0.82, 95% CI 0.62-1.09) and 30-day (aOR 0.88, 95% CI 0.51-1.51) stroke was similar between the two groups. CONCLUSION: In selected patients with severe AS and concomitant CAD, a combined percutaneous approach (TAVR+PCI) compared with SAVR+CABG may confer a lower risk of MACE and mortality during index admission but a higher incidence of 30-day complications.

A little leak goes a long way! 5-Year-outcome after transcatheter aortic valve implantation.

Mild paravalvular leak after TAVR is associated with increased 5-year mortality. Current noninvasive and invasive prediction models for mortality may only hold for short term outcomes. Other imaging modalities aside from transthoracic echocardiography should be strongly considered when assessing paravalvular leak, regardless of severity.

Adverse clinical outcomes in patients undergoing both PCI and TAVR: Analysis from a pooled multi-center registry.

BACKGROUND: There is a paucity of data regarding the optimum timing of PCI in relation to TAVR. OBJECTIVE: We compared the major adverse cardiovascular and cerebrovascular events (MACCE) rates among patients who underwent percutaneous coronary intervention (PCI) before transcatheter aortic valve replacement (TAVR) with those who received PCI with/after TAVR. METHODS: In this multicenter study, we pooled all consecutive patients who underwent TAVR at three high volume centers. RESULTS: Among 3,982 patients who underwent TAVR, 327 (8%) patients underwent PCI within 1 year before TAVR, 38 (1%) had PCI the same day as TAVR and 15 (0.5%) had PCI within 2 months after TAVR. Overall, among patients who received both PCI and TAVR (n = 380), history of previous CABG (HR:0.501; p = .001), higher BMI at TAVR (HR:0.970; p = .038), and statin therapy after TAVR (HR:0.660, p = .037) were independently associated with lower MACCE while warfarin therapy after TAVR was associated with a higher risk of MACCE (HR:1.779, p = .017). Patients who received PCI within 1 year before TAVR had similar baseline demographics, STS scores, clinical risk factors when compared to patients receiving PCI with/after TAVR. Both groups were similar in PCI (Syntax Score, ACC/AHA lesion class) and TAVR (valve types, access) related variables. There were no significant differences in terms of MACCE (log rank p = .550), all-cause mortality (log rank p = .433), strokes (log rank p = .153), and repeat PCI (log rank p = .054) in patients who underwent PCI with/after TAVR when compared to patients who received PCI before TAVR. CONCLUSION: Among patients who underwent both PCI and TAVR, history of CABG, higher BMI, and statin therapy had lower, while those discharged on warfarin, had higher adverse event rates. Adverse events rates were similar regardless of timing of PCI.

Percutaneous coronary intervention with transcatheter aortic valve replacement makes no difference! None? Really?

Unless a patient who needs transcatheter aortic valve replacement (TAVR) presents with an acute coronary syndrome, "routine" percutaneous coronary intervention of coronary stenoses does not improve outcomes, even out to 5 years. Randomized clinical trials are needed to sort out the best strategies to treat the complex interaction of coronary disease and aortic stenosis, though they are unlikely to be performed. Without such evidence, patients undergoing TAVR need the judgment of a Heart Team to help strategize whether revascularization for CAD should be performed.

The bicuspid aortic valve: Still a toothy problem.

Transcatheter aortic valve replacement (TAVR) is an acceptable treatment alternative to surgical aortic valve replacement in selected patients with a bicuspid aortic valve. TAVR appears to have acceptable mid-term outcomes in patients with bicuspid aortic stenosis. A large-scale, randomized, clinical trial is necessary to better define the role of TAVR for patients with bicuspid aortic stenosis.

Pacemaker need after TAVR: Still a conundrum.

Seven percent of patients (with no history of intraventricular conduction abnormalities) experienced intraprocedural high-degree Atrioventricular (AV)/complete heart block. High-degree/complete heart block was persistent in 64% of patients who developed significant intraprocedural intraventricular conduction abnormalities. Ninety-seven percent of patients with persistent high-degree AV/complete block ultimately required pacemaker implantation.

Thrombocytopenia after transcatheter aortic valve replacement: What is really going on?

In a multivariate model, the drop-in platelet count (DPC) was significantly higher in patients treated with a balloon expandable valve (BEV) than a self-expandable valve (SEV) (36.3% ± 15.1% vs. 27.7% ± 14.4%, p < .001). In a univariate model, a higher DPC post-transcatheter aortic valve replacement was observed in patients requiring alternate access and lower contrast volume. The platelet count nadir was nearly a day later in patients implanted with a BEV compared with an SEV. At 30 days, there was a higher rate of adverse events and mortality in patients with a high DPC. At 1 year, there was no significant difference in mortality rates between the high DPC group and the low DPC group.

The clipping enigma.

There appears to be lower mortality in patients treated with MitraClip + OMT compared to OMT alone. There appears to be a lower rate of hospitalization in patients treated with MitraClip + OMT compared to OMT alone. There are only two randomized controlled trials (with discordant results) evaluating MitraClip + OMT compared to OMT alone.

Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages.

Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune-mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. CONCLUSION: HBV behaves like a "stealth" virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long "window period" during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779-1793).

Transcatheter treatment of aortic regurgitation: Still enigmatic.

In the thirty patients with aortic regurgitation in the Jupiter Postmarket Registry, initial device success of JenaValve implantation showed a high success rate of >95% with a device success rate of ∼89%. At one year transvalvar aortic gradients were an acceptable ∼13 mm Hg. Aortic regurgitation in patients in the Jupiter Postmarket Registry continued to be reduced at one-year follow-up with no/trace aortic regurgitation in 50% (though numbers are small). Patients with aortic regurgitation constitute a small number (∼10-15%) of patients with symptomatic aortic valve disease, and follow-up numbers in the Jupiter Postmarket Registry are small (30 patients) with one year echo data in only 23 patients, making broad conclusions about JenaValve results for patients with aortic regurgitation problematic.

Septal rupture closure: Still a challenge.

Review of the Medicare database shows that over the past 16 years the incidence of post- myocardial infarction (MI) ventricular septal rupture (VSR) has decreased but mortality for all post-MI VSR hospitalizations remains unchanged and high During the study period, the 30-day VSR repair rate decreased from 49.9% in 1999 to 33.3% in 2014. Unadjusted mortality was lower for patients undergoing repair procedures than for those not undergoing repair both at 30 days and at 1-year. Most VSR patients underwent surgical repair (82.9%) and only a minority underwent transcatheter repair (17.1%). Regardless of the approach, outcomes remain unsatisfactory.

Paravalvular leak after transcatheter aortic valve replacement: Avoid it or treat it if you can!

Paravalvular leaks (PVL) were more severe and frequent with medtronic core valves (MCV) when compared with Edward Sapien valves (ESV) immediately after transcatheter aortic valve replacement (TAVR). Severity and frequency of PVL improved in MCV overtime, but not in ESV. The decrease in frequency of PVL in MCV valves was earlier and more robust in the area surrounding the commissure between noncoronary cusp (NCC) to right coronary cusp (RCC) compared with other areas. Such preferential reduction of PVL was not seen in ESV.

Supra-annular valve strategy for an early degenerated transcatheter balloon-expandable heart valve.

Currently, there are no recommendations regarding the selection of valve type for a transcatheter heart valve (THV)-in-THV procedure. A supra-annular valve design may be superior in that it results in a larger effective orifice area and may have a lower chance of valve thrombosis after THV-in-THV. In this report, we describe the use of a supra-annular valve strategy for an early degenerated THV.

Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions.

BACKGROUND & AIMS: One major obstacle of hepatitis B virus (HBV) research is the lack of efficient cell culture system permissive for viral infection and replication. The aim of our study was to establish a robust HBV infection model by using hepatocyte-like cells (HLCs) derived from human pluripotent stem cells. METHODS: HLCs were differentiated from human embryonic stem cells and induced pluripotent stem cells. Maturation of hepatocyte functions was determined. After HBV infection, total viral DNA, cccDNA, total viral RNA, pgRNA, HBeAg and HBsAg were measured. RESULTS: More than 90% of the HLCs expressed strong signals of human hepatocyte markers, like albumin, as well as known host factors required for HBV infection, suggesting that these cells possessed key features of mature hepatocytes. Notably, HLCs expressed the viral receptor sodium-taurocholate cotransporting polypeptide more stably than primary human hepatocytes (PHHs). HLCs supported robust infection and some spreading of HBV. Finally, by using this model, we identified two host-targeting agents, genistin and PA452, as novel antivirals. CONCLUSIONS: Stem cell-derived HLCs fully support HBV infection. This novel HLC HBV infection model offers a unique opportunity to advance our understanding of the molecular details of the HBV life cycle; to further characterize virus-host interactions and to define new targets for HBV curative treatment. LAY SUMMARY: Our study used human pluripotent stem cells to develop hepatocyte-like cells (HLCs) capable of expressing hepatocyte markers and host factors important for HBV infection. These cells fully support HBV infection and virus-host interactions, allowing for the identification of two novel antiviral agents. Thus, stem cell-derived HLCs provide a highly physiologically relevant system to advance our understanding of viral life cycle and provide a new tool for antiviral drug screening and development.