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Introduction: Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data. Main Body: The Amyloidosis Forum is a public–private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium (www.arci.org). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities). Conclusion: Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies. [ABSTRACT FROM AUTHOR]

Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review. [ABSTRACT FROM AUTHOR]

The interplay between pathology and human immunodeficiency virus (HIV) expansion in brain tissues has not been thoroughly assessed in the highly active antiretroviral therapy (HAART) era. HIV-associated dementia (HAD) is marked by progressive brain infection due to recruitment and migration of macrophages in brain tissues; however, the cellular and viral events occurring prior to HAD development and death are under debate. In this study, 66 brain tissues from 11 autopsies were analyzed to assess HIV-1 DNA concentration in brain tissues. In most patients without HAD, it was impossible to amplify HIV-1 from brain tissues. Amplifiable DNA was obtained from three cases of patients on HAART who died due to primary pathology other than HAD: (1) cardiovascular disease, a disease associated with HAART therapy; (2) bacterial infections, including Mycobacterium avium complex, rapid occurrence of extreme dementia; and (3) acquired immunodeficiency syndrome (AIDS)-related lymphoma with meningeal involvement. HIV-1 DNA was also amplified from multiple tissues of two HAD patients. Analysis of HIV-1 nef, gp120, and gp41 sequences showed reduced viral evolution within brain tissues for the non-HAD cases relative to patients with clinical and histological HAD. The present study is the first to show a potential correlation between HIV-1 evolutionary patterns in the brain and different neuropathologies. [ABSTRACT FROM AUTHOR]

Purpose of Review: Heart transplant (HT) is the therapy of choice for patients with end-stage heart failure (HF), leading to substantial improvements in quality of life, functional status, and longevity compared to optimal medical therapy for end-stage HF. However, race/ethnic disparities in post-HT survival persist and remain a major concern. The purpose of this review is to describe differences in post-transplant outcomes based on race/ethnicity and to highlight evolving knowledge of the reasons for these persistent disparate outcomes. Recent Findings: Black HT recipients have the highest risk for allograft failure and the worst survival post-HT compared to other race/ethnic groups. Although differences in socioeconomic status, access to medical care, and medical compliance have been cited in the past as reasons for these disparate outcomes, recent research highlights the importance of heightened immune reactivity in black HT recipients as a major cause of allograft loss and death. Novel techniques such as gene expression profiling, detection of donor specific antibodies, and detection of genotypes associated with increased metabolism of immunosuppressive medications highlight the role of immune and inflammatory dysregulation and reduced immunosuppressive drug efficacy as significant contributors to post-HT outcomes. Summary: Race/ethnic disparities in post-HT outcomes are due to a complex interplay of immunologic, clinical, and socioeconomic factors. However, multiple reports that demonstrate that black race confers a survival disadvantage post-HT that is independent of differences in access to care or socioeconomic status highlight the need for more research to understand racial differences in biological and genetic responses to immunosuppressive therapy. [ABSTRACT FROM AUTHOR]