fibrosis

How do we define “older” in our older patients living with hepatitis B virus (HBV)? What monitoring and treatment options should be considered for these older patients with chronic HBV infection?

Listen as Nancy Reau, MD, discusses strategies and considerations for monitoring and treating older adults with HBV, illustrated with a patient case.

Presenter:

Nancy Reau, MD
Professor of Medicine
Chief, Section of Hepatology  
Associate Director, Solid Organ Transplantation  
Richard B. Capps Chair of Hepatology
Rush University Medical Center
Chicago, Illinois

Link to full program:
https://bit.ly/3T1UImw

You can think of the “D” in HDV as standing for difficult, disadvantaged, and dangerous. Hepatitis delta virus (HDV) is difficult to diagnose, is often diagnosed in disadvantaged patient populations, and leads to dangerous sequelae.

Listen as Dr. Kosh Agarwal and Dr. Graham R. Foster and discuss challenges and opportunities for linking patients to care after a positive test for HDV.

Presenters:

Kosh Agarwal, MD
Consultant Hepatologist and Transplant Physician
Institute of Liver Studies
King's College Hospital NHS Foundation Trust
London, United Kingdom

Graham R. Foster, FRCP, PhD
Professor of Hepatology
The Liver Unit
Consultant Hepatologist
Queen Mary University of London
London, United Kingdom

Link to full program:
https://bit.ly/3tlxa0H

Our week of "Greatest Hits" episodes from the vault continues with Scott Friedman's fascinating presentation on precision medicine in the context of senescent stellate cells and fibrosis, first posted in October 2021. Scott combines erudition and unparalleled knowledge of the subjects he is discussing with a storyteller's ability to paint clear pictures and make complex issues both simple and lively.

Scott, known to some as the "Father of Fibrosis," starts this discussion talking about his own history in fibrosis research and then the history of the stellate cell and its role in where precision medicine is heading. The rest of the episode touches on issues ranging from the importance of omics in learning about the disease and the future of precision medicine to target disease to today, specifically, the downside of being, as Scott puts it, "yoked to biopsy." In the aftermath, listeners (including other leading KOLs) described this episode as a "coup," a "treasure" and "something you can find only at Surfing the NASH Tsunami." If you missed this episode the first time around, download it now and make it your weekend (or vacation week) listen.

Surfing the NASH Tsunami posted on Buzzsprout for the first time on July 23, 2020. Over the past two years, NASH Tsunami has posted 132 episodes and close to 400 posts when we include both episodes and conversations. This week, Jörn Schattenberg and Roger Green review some of the podcast's high points and set the stage for a week of resharing "Greatest Hits" episodes and conversations from the Vault of old postings.

The conversation starts with Jörn and Roger reminiscing about Jörn's first couple of appearances on the podcast, first helping to review the digital ILC 2020 and then coming on a couple of months later to discuss a paper Jörn had recently published looking at why NASH drug trials fail. Jörn and Roger discuss come of the lessons from the paper and how those have translated into changes in drug development and clinical trial strategies.

One interesting side note: Roger asks Jörn about feedback from the original paper. He comments that the authors rarely get feedback, especially those who are not the correspondent author (which Jörn was not for this paper). He commented that he receives more feedback from the discussions on NASH Tsunami, either on the podcast or in subsequent conversations with friends and colleagues who have heard the episode. 

Roger goes on to note that while the "Why Trials Fail" paper touched on challenges around biomarkers and conditional endpoints, we were only at the beginning of learning how many flaws existed in the system of semi-quantitative reads. This serves as a bridge to the specific conversations NASH Tsunami will repost from the Vault during this anniversary week. They address topics ranging from stellate cell activation to the role of NITs to the importance of patient advocacy. As they move from post to post, Jörn and Roger provide context on where each one fits in the history of the podcast and what they learned or experienced as a result. 

Of course, a podcast without Stephen or Louise can provide only so much of the podcast's history and key moments, but for listeners, this episode will give you an opportunity to reflect on your own intellectual journey with NAFLD and NASH and to ask yourself which of the older episodes and conversations you might want to revisit. As we noted earlier, we will post two episodes and six conversations we like to revisit in the week ahead.

On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in considering whether the evidence in the new release will be sufficient to get the drug approved.

Stephen starts by noting that we have not heard anything about the results of the REVERSE trial, which evaluated obeticholic acid (OCA) in patients with compensated cirrhosis. As he notes, even if OCA is not approved for cirrhosis, many hepatologists will consider giving this drug to cirrhotic patients, particularly compensated cirrhotics who face a significant worsening of their condition in a fairly short period of time. 

Jörn comments on this briefly to agree that the cirrhosis data will create a complete data set, then returns to the pruritus issue. Mostly, his point about cirrhosis is that given the high placebo rate suggests there is "something about how the question is asked." He finishes this comment by discussing the importance of getting a first drug approved and stating his anticipation of what happens when FDA reviews these data. 

Roger goes on to note that he has a unique experience in this group: he has discontinued a drug therapy based on pruritus (in his case, a cancer drug). Having lived through that experience, he expresses skepticism that pruritus that resolves on discontinuation will be a reason for the drug to be rejected. Stephen concurs, and Roger goes on to state that the perceived cardiovascular risk in 2020 made sense as a reason not to approve, but not pruritus. Stephen and Louise concur that we will not know the entire story until we know the lengths to which providers went to keep patients in this study, but both are hopeful (and pretty much expect) that while there may be boundaries on patient types and guidance on treatment, the case for approval appears likely to succeed. 

During the second half of this conversation, panelists share their common hope that this data will be sufficient to get OCA approved and discuss what this could mean for the entire Fatty Liver stakeholder community.

On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in considering less obvious questions surrounding efficacy and safety.

Stephen starts this conversation by asking the group how important it is for a drug (in this case, obeticholic acid) to show a combined endpoint of fibrosis improvement and NASH resolution. He notes this is a tougher standard to hit but notes that it might be quite important.

Jörn describes this comment as a "good point" that probably was not addressed due to the low level of NASH resolution when viewed as a primary endpoint. Louise says she would need to know more about the diets patients were on while in the trial given the effect diet can have on liver fat. She then goes on to say that one question she would like to have answered is how many patients needed counseling on their pruritus to stay in the study and what exact steps did researchers take to keep these patients in. She points out that knowing the steps necessary to maintain patient adherence is vitally important to caregivers but rarely reported for trials, if ever.

Roger makes two points. His first basically supports Jörn's comment that the low level of NASH resolution as a primary endpoint virtually guarantees that the number of patients achieving the dual endpoint will be minimal at best. His second harkens back to Stephen's earlier point about including a larger post-18 month patient pool in the efficacy analysis. To Roger, it appears that Intercept made the sound commercial decision to reveal only the data necessary to generate the analyses necessary for approval. It felt to him as if Intercept assessed the least risky way to refute each point in the CRL, and then did only the analyses necessary to refute points successfully. In essence, Roger describes the analysis as a way to de-risk the drug and believes they appear to have done so effectively. 

At this point, Stephen shifts direction. He gives Intercept "accolades...they didn't give up. They persevered. They continued to drive forward and they added three different adjudication committees." And while he believes there is more analysis to be done, he describes the contents of the press release as "a very, very positive implication for the field" and "give[s] it two thumbs up." 

After Roger concurs, Stephen goes back to Louise's questions about pruritus and notes that the methodology for evaluating pruritus might have produced overstated results. In essence, the investigator asked patients whether they were experiencing pruritus at every visit, an approach Stephen and Jörn believe was likely to produce an overstatement on itching. Stephen continues this line of thinking to note that investigators were forced to discontinue therapy under certain pruritus reports. As the conversation ends, he notes that he is far more interested in hepatic effects.

On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining how the larger sample and longer time patients were on therapy changed the safety and tolerability profile from the initial analysis.

After reviewing the four key points from Intercept's press release, Stephen Harrison kicks off this conversation by discussing the safety evaluation, which included a far larger population with significantly longer exposure to study drug. After describing the enriched population, he quotes from the press release, "Emergent adverse events treatment, emergent serious adverse events, and deaths were generally balanced across the OTC and placebo treatment groups." He goes on to cite the considerable differences in pruritus across groups (22% in placebo, 33% in 10mg and 55% in 25mg), share the comment that most discontinuation stemmed from pruritus, note that gall bladder-related events occurred in less than 3% of patients and, finally, that OCA 25mg had a higher rate of biliary events. He then asked the rest of the group for comments.

Jörn commented first, noting that this was mostly "recapitulated" data, but with a much broader set of subjects. Because risk:benefit ratio was perceived as the pivotal issue around the time of the original Complete Response Letter (CRL), he describes the data as improved "by a lot."

Louise describes as "reassuring" the idea that the NASH dose could be so much higher than the approved PBC dose (25mg vs. 5 or 10mg) but not demonstrate additional safety concerns. She goes on to declare that practices planning to use OCA should be "planning pathways into delivery" in anticipation that the high level of pruritus will lead to a significant set of discontinuation with a careful approach to patient orientation and management. 

Roger shared his recollection that increases in LDL levels and the implicit associated cardiovascular risk were major issues in the negative risk:benefit assessment, but that this analysis appears to report that levels returned to normal within the first year of treatment. This might increase chances for approval.

At this point, Stephen reads the press release carefully to identify potential safety hazards that are not addressed directly in the document, although, as he notes, one can fit only so much into a press release. As the conversation ends, Stephen asks Jörn if he has "ongoing lingering questions". Jörn notes that he wondered how the reads were done and that he also looked for LDL data. He makes a few other points, but suspects that they may have been covered in the 2019 paper.

On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining the new efficacy analysis and exploring what it means for obeticholic acid, both in terms of the drug's performance and its revised prospects for FDA approval.

After reviewing the four key points from Intercept's press release, Stephen Harrison kicks off this conversation by looking at a broader efficacy picture than mere regression of fibrosis, to ask what percentage of patients experienced no further progression of fibrosis compared to the placebo group. Stephen notes that the clinical value of simply halting fibrosis progression in an F3 patient is tremendously important because it allows an asymptomatic patient to continue life at its current level of quality. He adds, "we can manage co-morbidities" separately. He goes on to wonder why Intercept did not expand the analysis to include the large number of patients who made it past the 18-month biopsy time point but were not part of the original 2019 efficacy cohort.

At this point, Stephen takes a step back from the actual data to describe how the consensus approach worked on histological reads and to praise the approach for providing clear, simple answers. Jörn Schattenberg picks up the conversation by agreeing with Stephen's assessment of the consensus approach, which he describes as emulating how colleagues assess challenging cases or histopathology reports in actual practice. 

Roger joins the conversation to wonder why the consensus reading process would have the effect of reducing the percentage of patients who improve in the placebo group on one reading but not elsewhere. More important to him, he goes on to agree with the idea that if this agent regresses fibrosis in some cases but halts progression in most or all, it might become a valuable part of a combination therapy that includes other agents with a stronger effect against steatosis than fibrosis. 

Thinking from a patient perspective, Louise notes that consensus reads should give the patient greater confidence in the results. In terms of confidence and border reads, Stephen points out that some of the presentations at the recent ILC2022 meeting that drugs that have an impact on NASH might also affect liver volume. (He notes that the open-label cirrhotic cohort of the resmetirom trial MAESTRO-NAFLD 1 also showed spleen volume reduction and an inverse effect on platelet count.) Setting aside the cirrhosis results, he notes that if we start to measure liver volume when conducting biopsies, we can correct estimates of the impact of fibrosis to account for changes in "what we see" based on changes in liver volume. As the conversation ends, he notes that this might be a fruitful topic for future research that can translate into patient treatment.

On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining the new efficacy analysis and exploring what it means for obeticholic acid, both in terms of the drug's performance and its revised prospects for FDA approval.

After Stephen lists the four major bullet points from Intercept's press release, this conversation focuses on the first point: "The 25mg dose of obeticholic acid met the agreed primary endpoint of improvement in liver fibrosis without worsening of NASH at 18 months." The data behind this bullet point stem from a new interim analysis of the original 931 cases. In the re-analysis, the treatment effect remained constant but the placebo effect dropped slightly. The different results from a different method of analyzing histopathology, one that relied on consensus panel reads instead of an individual histopathologist's interpretation (as was done in the original analysis). Stephen goes on to note that there is a similar small change in the NASH resolution percentages, but, like the original analysis, these do not reach statistical significance. He notes that this submission relied on hitting one of the primary endpoints, not both of them. He then asks the group two questions: "Does this change our perception of OCA in NASH?" and "Does this change our perception of this drug as a driver of the field in drug development for NASH?"

Roger answers first. Taking a narrow focus on the question, he answers that we still see OCA as an effective anti-fibrotic at the same level we did three years ago. If there is a change, it is that if obeticholic acid had a three-year lead on the market, it would have focused a significant amount of research on FXR agonists -- both in terms of developing more FXRs and in considering them the backbone in NASH pharmacotherapy. In 2022, with another very different agent appearing to be fairly close to market, he felt these results would not dramatically change the other directions in which research is heading.

Jörn Schattenberg goes back to the original 2019 paper, which he describes as "groundbreaking" and, quoting Zobair Younossi, "a watershed moment." He notes that the reading method seems more consistent with what FDA wants and says that while others may comment on the small effect size (11%), his view is that this is a positive achievement as the first paper to demonstrate significant effect against fibrosis.

Louise Campbell echoes her colleagues' comments about the successful efficacy results but notes that patients who could have benefitted from OCA's approval two years ago have gone two more years without the benefit of medication.

Stephen concludes the conversation by agreeing with Jörn that this is a watershed moment. He notes how many observers have said that proving efficacy was essentially impossible due to the complexity of the disease and regulators "moving the goalposts." This study, he says, proves that it can be done.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic liver science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." After this extremely rich and engaging discussion of advances in research processes and the findings the group discussed, Roger Green asked the group with the impact of advances like these will be over the next "year, three years, five years."

The answers vary significantly from one panelist to another, in each case reflecting where the panel members touch the healthcare system and product industries. Scott discusses the ability of research to create completely new classes of therapies with previously unimaginable impact on disease, citing CAR-T as one example that is already in use. Louise Campbell makes a vastly different but very important point: it will work better for everyone if we can create more tissue samples, and the ability to generate these kinds of advances will make it easier for providers to ask patients to provide tissue samples and will increase the number of patients who say, "Yes." Scott and Neil both note how good and important a point this is, with Neil stating that the growth in data we can produce from tissue is "exponential," and that this data is key to creating better disease understanding, diagnostics and drugs. Rachel discusses two key areas where the cost of research is decreasing: the availability of open-source data sets and the cost of actual sequencing. Jörn suggests that having a richer understanding of disease will reduce the number of drug failures, partly because we will know how to capitalize on what we are learning and partly because we may not rush into major drug trials where we lack elements of basic understanding. Roger closes with two summary points: (i) that the technologies the group discussed will be applicable not only for NASH but an array of other liver diseases, and (ii) that over the past three years, the field has created a vastly larger number of data points which is starting to look less like scattered points and more like connected dots making an actual picture.

With these final notes of optimism and energy, the group closed the discussion.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." The conversation starts with Roger Green asking the panel how to pay this research off in terms of commercial benefit. Most of the conversation consists of their answers.

Scott Friedman answers Roger's question first. He notes that these advanced techniques will allow us to focus on not only the right type of cell but the right subtype(s). Hitting the right target dead-on will improve the efficacy of drugs and the accuracy of diagnostics. Also important (perhaps more so): we can avoid what Scott calls "off-target effects", which commercial executives might think of as safety, tolerability and side effect issues. 

Consistent with other themes NASH Tsunami visits regularly, Jörn notes that the future of therapy is likely to be individualized, multi-element, and probably multi-phase. The more this basic research can teach us about the disease process stages and how they vary by patient, the better job drug developers can do in developing medicines that resolve specific patients' needs. 

Scott notes that if we can hypothesize which patients will respond best to a specific intervention, we can streamline clinical trials, possibly reduce sample sizes, separate respondents from non-responders better and/or shorten trial durations. All these possible outcomes stem from the increasingly demonstrable reality that NAFLD or NASH is actually a set of related diseases rather than a single, uniform disease process.

As the session begins to wind down, Roger invites Scott to discuss any other topics that emerged from the abstract session. Scott mentions the last paper in the session, where researchers from Heidelberg explored a specific receptor whose acronym is RAGE (Receptor for Advanced Glycation End-products). RAGE drives what Scott terms "a very important response," seen both in NASH and cholestatic disease, in which bile ducts proliferate. This is called a ductular reaction. As Scott notes, both the cause of this reaction and its relationship to fibrosis have been "a bit hazy." Now, this group has identified some players that might be involved in this process...and identified them in such a way that therapeutics are being developed against RAGE. This will benefit NASH and, even more clearly, cholestatic diseases.

As the last question before wrapping up, Roger asks the rest of the panel if they have comments about the meeting aside from this session. Neil points to the optimism and energy caused not only by the new methods but also by the sharing of knowledge AND larger data sets, all of which can lead to molecular pathology-based approaches that will help us define the multiple diseases in the NAFLD galaxy better. Jörn goes almost to the other extreme, commenting on presentations demonstrating the value of FIB-4 as a first-line screening tool and others challenging FIB-4 the same way. To Jörn, this identifies the need for a better first-line screening test, which the kinds of research covered in this session might produce. Roger closes the conversation by noting that the two outstanding benefits of FIB-4 are its low cost and wide availability, which suggests the next steps we are more likely to see is a staged approach to diagnosis and screening.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This conversation centers on papers with similar methods and processes for researching stellate cells.

Scott begins this conversation by describing this process, which is based on another Nobel Prize-winning methodology. In this technique, the researchers start by forcing an adult mature skin cell (or any cell, for that matter) o express a cluster of very well-defined genes and transcription factors, which the researcher then turns into a generalized, Induced Pluripotent Stem (IPS) cell. Researchers have found ways to convert these IPS cells into stellate cells. The developer of this technique posited that it will enable us to explore the proteome. 

To Scott, this process of converting a generalized cell to a stellate cell we can analyze via proteomics to find new targets is more important and noteworthy than the result of this specific study (researchers identified a novel nuclear receptor called RORalpha). To quote Scott, "they're much closer to the action when they find a protein rather than just the mRNA that encodes it." He goes on to discuss a second study from Insitro (a company with which he consults) about their work seeking to optimize the IPS-derived stellate cells to find the one that most closely resembles cells in vivo. 

When Scott finishes, Neil notes that single-cell proteomics is not "coming, but it's not there yet." Neil anticipates we will have this pivotal tool available in a 1-2 year time horizon. Next, Jörn anticipates and asks about the next stage in the process: identifying a protein related to this process we can find in peripheral blood given that, as Neil noted, tissue sampling in the clinical setting will not be possible. Scott discusses a recent paper that seems to provide a solution to this issue in breast cancer. While he notes that the work has to be validated first, it clearly suggests researchers are close to finding proteins we can identify in blood in at least one cancer-related case. 

From there, Scott turns to Rachel for feedback, since this is the area in which her business is building its research. Her answer has several elements to it, but the main point is that proteomic development lags behind some of the other techniques but is making rapid advances as the costs of some key analytical processes come down. She then goes on to provide a description of epigenetics, the area in which she works most intensively.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This presentation centers around two papers that explore stellate cell dynamics related to the progression and regression of fibrosis, both of which rely on methods pioneered by Neil and his colleague Prakesh Ramachandran to take individual cells from tissue (in this case, the liver), use transcriptomic to interrogate the mRNA and infer how cells interact in different processes.

The first presentation, which takes up the bulk of this conversation, centers around scar formation in mouse livers under injurious assault and then scar healing when the assault ceases. Before discussing the study itself, Scott provides a brief but extremely rich background of the research technique that are driving progress in this area, including Neil's work and other advances that have been recognized with Nobel prizes.

When the focus reverts to the actual papers, Neil notes that this presentation is unusual in that most research devotes far more attention to scar formation than to regression whereas this note looks at both processes (In Season 2, Episode 50, Lars Johansson noted similarly that researchers spend far more time researching "what shouldn't be in the liver" than what should be there.) He continues that we can research these issues far more effectively in mice than in people, in part because we do not biopsy people with healthy or healed livers. This leads to another brief discussion of methods, in this case, spatial transcriptomic. Jörn asks a clinician question: if there are, as this paper suggests, 14 different states of activation, how do we know which are druggable? 

NOTE: The researcher presenting this paper at ILC2022 noted that the research was funded in part by Novo Nordisk.

As the discussion closes, Scott mentions a different paper that touches on the role of peroxidation an antioxidant process, in fibrosis progression. and regression.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This presentation centers on the relationship between Circadian rhythms and stellate cells.

It is widely known that we all function under a set of Circadian rhythms tied to day/night changes. Original work in this area focused on physiological changes linked to the central nervous system. In recent years, researchers have learned that other tissues in the body operate on their own Circadian rhythms, presumably tied in some way to the central nervous system. But as Scott exclaims when beginning this discussion, "who would have thought that that included the lowly little hepatic stellate cell, a fibrogenic cell that contains the same mechanisms and the same machinery to regulate circadian rhythm as all those more specialized neuronal tissues." 

Scott goes on to provide greater detail on the mechanisms through which stellate calls control fibrogenic activity in a cyclical manner. When he concludes, the rest of the group shares comments. Neil Henderson notes that Circadian rhythms are strongly tied to fibrogenic processes throughout the body. Jörn Schattenberg, Louise Campbell and Rachel Zayas comment in different ways on the relevance of circadian rhythms to elements of patient care today, and Roger Green asks a question that leads Scott to note that TGF beta, which he described as "the mother of all fibrogenic cytokines," was the signaling mechanisms for this process.

Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). This episode focuses on an abstract session Scott Friedman chaired on Thursday afternoon discussing advancing in the basic science of researching and understanding mechanisms surrounding fibrosis.

Scott starts by describing the session he co-chaired with Sophie Lotersztajn of INSERM as "one of the most exciting groups of presentations I've seen in many years." During this episode, he leads the rest of the panel through exploration of all six presentations. These include:

--Targeting the liver circadian clock by REV-ERB-alpha activation improves liver fibrosis by circadian gating of TGF-beta signaling, Atish Mukherji, University of Strasbourg. Scott describes this presentation, which demonstrates that stellate cells have a circadian clock, as "one of the most surprising results" in that circadian activity can be linked to the  "lowly stellate cell."  This paper generated significant conversation among the group, ranging from Neil Henderson's observation that circadian regulation is a powerful regulator of fibrotic processes to Jörn Schattenberg's observations about what this might mean for treating patients in the clinic to Roger Green asking whether this concept might be germane to specific drugs in development (Scott had mentioned that signalling occurred through TGFbeta.  Louise Campbell and Rachel Zayas  add comments about the relevance of circadian rhythm to care today and ways this paper might yield exciting new areas for research.

--Stellate cell dynamics in progression and regression of hepatic fibrosis, Laura Almale del Barrio, Denmark. This presentation, funded in part by Novo Nordisk, focused on how mouse livers respond when researchers stop injuring them. It leads Neil to comment on how little attention researchers pay to scar healing relative to how much more they pay to the process of scar creation and injury. In response to a question from Scott, Neil also discusses how advances in spatial transcriptomic will make questions like these easier to research in the not-too-distant future. After this, Jörn goes on to note that the paper discussed 14 different stellate cell states, which he interprets as involves activation and transitioning processes. He asks what this might imply for treating patients in the clinic.

The other four presentations engender a similar level of exploration. They include:
--Peroxidasin deficiency re-programs macrophages toward pro-fibrolysis function and promotes collagen resolution in liver, Mozhdeh Sojoodi, Mass General Hospital and Harvard. 
--Machine learning methods for detailed characterization of TGF-beta-induced signatures in a large iPSC-derived hepatic stellate cell cohort, Kara Marie Liu, Insitro, United States
--The proteomic analysis of hepatic stellate cell differentiation from iPSCs identifies RORalpha as an antifibrogenic target, Raquel A. Martinez Garcia de la Torre, Spain
--Biliary epithelial cell-specific RAGE controls ductular reaction-mediated fibrosis during cholestasis, Macrina Lam, Germany

In each case, Scott starts by discussing the historic of scientific progress that predates the particular paper and topic, places the presentation properly within that context, and invites the others to comment. Each Surfer has unique (and uniquely interesting) comments in their own areas of expertise.

Next week, >10,000 Fatty Liver stakeholders are expected to journey to London (rail strike and all) for the International Liver Congress (#ILC2022), the first meeting at this level since the pandemic started to include an in-person attendance option. This week, NASH Tsunami identifies some of the most important and intriguing non-embargoed presentations at #ILC2022. This conversation explores two of these: OS097, Machine learning algorithms identify novel biomarker combinations for NAFLD, from Jenny Lee (Netherlands); and FRI094, Clinical and economic evaluation of community-based preventative screening strategies for NAFLD in people with Type-2 diabetes melllitus, from Roberta Forlano (UK).

Jörn Schattenberg selected OS097 as the first paper for the Surfers to discuss due to its robust dataset (720 liver-biopsied patients recruited prospectively at centers across Europe; 53% with NASH, 26% with advanced fibrosis and 7% with cirrhosis.) and intriguing task (identify the most robust biomarkers for predicting levels of steatosis, ballooning, inflammation and fibrosis independently). The AUCs for fibrosis were robust (0.90 in the test group and 0.84 in the validation set), while the AUCs for the steatosis measures were weaker (0.79 and 0.74, respectively.) Jörn notes that the histological markers vary between the four targets, with steatosis and ballooning predicted most strongly by BMI, inflammation by hemoglobin and fibrosis by VCTE. After questions, Jörn goes on to note that the CK-18 M 30 emerges as a predictor for both steatosis and fibrosis.

The key question comes from Stephen, who asks how diabetes came into this equation in terms of metric, severity and length of disease. Jörn states that the only diabetes metric in the set was A1c, which was the 5th strongest for fibrosis. He also notes that length of disease is exceptionally challenging to determine in a study that relies on patient self-reports.
Louise Campbell responds next, selecting FRI094, a clinical and economic assessment of community-based screening of Type 2 diabetes mellitus patients for Fatty Liver disease. This study began at Imperial while Louise still worked there. The study reported 17% of NAFLD patients with "significant" fibrosis (kPa>8.1 by VCTE), 11% had advanced fibrosis and 3% had cirrhosis (defined as kPa >12,1 by VCTE.) Any of these patients might have been defined by clinical, radiological or histological means.

After questions, Louise would go on to note that all approaches were determine to be cost effective against a metric of 20,000 English pounds.

Again, the pivotal question came from Stephen, who suggested that a kPa of 12.1 (the definition of cirrhosis here) would fit half of his practice. He used this point to remind listeners of the poor positive predictive value of VCTE as a single measure.

When Stephen and Louise finish this point, Louise notes the positive recommendation on cost-effectivesness of community screening while acknowledging the issue around scoring of cirrhosis. Jörn then closes the discussion of this paper (and the conversation) by agreeing with Stephen's comment on the VCTE kPa and cirrhosis, but noting that the high levels indicate a serious challenge (even if not a level of cirrhosis).

Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in the basic science and technology of defining, diagnosing and treating NAFLD and NASH. This conversation focuses largely on the implications of potentially exciting future technologies such as the mRNA/CAR-T therapy described in Conversation 17.1 on NASH drug development today.

After the earlier discussion of the potential future mRNA/CAR-T therapy, Scott Friedman turns to Neil Henderson and asks this question: "What cell type and what receptors on those cells do you hone in on or do you do more than one? And how do you use single cell genomics to help you sort through that complex question?"

Neil immediately connects the question and the technology to the need for precision medicine in NASH. He points out that one challenge with NASH is hitting a single target is always challenging, particularly when the target is as "evolutionarily conserved" as fibrosis. To Neil, this suggests that if the mRNA/CAR-T therapy comes to fruition, it will become one element -- an important one, but not the only one -- in what he describes as "multimodal combinatorial therapy" which combines medicines and technology to attack fibrosis, perhaps all at once or possibly in stages.

Stephen Harrison says this information leaves him feeling like he is "very much at the very tip of the archeological dig" into what we know about treating Fatty Liver disease. He points out that one rule in drug development today is "if you get rid of the fat, the liver will take care of itself." Following this logic, he suggests the best place for something like the mRNA/CAR-T approach might be in cirrhotic or pre-cirrhotic patients with the goal of regressing fibrosis sufficiently that other more metabolic drugs might become appropriate and adequate as therapy

Scott points out that 90% of all fatty livers never go on to develop cirrhosis. Given this fact, one key focus of learning must be determine why it is that some livers progress and others do not. This would allow us to develop therapies targeted at the livers that progress and the cellular or genetic factors that lead them to do so. This, Scott points out, leads us back to the question of how we can use single cell technologies to learn the role that each cell type plays at different points in disease progression. This leads to a discussion between Neil, Scott and Stephen about the specific challenges of obtaining the liver tissue necessary for these kinds of assessments.

In this episode from the series “Key Decisions in HIV Care,” Jonathan Appelbaum, MD, FACP, AAHIVS, and Jens D. Lundgren, MD, DMSc, discuss important considerations for antiretroviral therapy (ART) use in older patients with renal and hepatic impairment.

• European AIDS Clinical Society guideline screening recommendations for kidney disease in people with HIV
• Antiretroviral dose adjustment recommendations based on estimated glomerular filtration rate
• Data on the use of full-dose lamivudine with renal impairment
• Data on the use of 2-drug nucleos(t)ide reverse-transcriptase inhibitor–sparing ART regimens, including GEMINI-1 and -2, TANGO, and SALSA for dolutegravir/lamivudine; SWORD-1 and -2 for dolutegravir/lamivudine; and ATLAS and FLAIR for long-acting cabotegravir plus rilpivirine
• US Department of Health and Human Services recommendations on the use of ART agents with hepatic impairment
• Recommendations from the American Gastroenterological Association on screening and diagnosis of nonalcoholic fatty liver disease (NAFLD)
• Prevalence of NAFLD, nonalcoholic steatohepatitis, and liver fibrosis in people with HIV
• Overlapping risk factors between HIV and NAFLD

Presenters:

Jonathan Appelbaum, MD, FACP, AAHIVS
Laurie L. Dozier Jr, MD, Education Director
Professor of Internal Medicine
Chair, Department of Clinical Sciences
Florida State University College of Medicine
Tallahassee, Florida 

Jens D. Lundgren, MD, DMSc
Professor
Rigshospital, University of Copenhagen
Director
Centre of Excellence for Health, Immunity and Infection (CHIP)
Rigshospital, University of Copenhagen
Copenhagen, Denmark 

Content based on an online CME program supported by educational grants from Gilead Sciences, Inc.; Janssen Therapeutics, Division of Janssen Products, LP; and ViiV Healthcare.

Follow along with the slides at:
https://bit.ly/3gAsu19

Link to full program:
https://bit.ly/3fOl0XX

El Dr. Ricardo Del Olmo médico neumonólogo del Hospital María Ferrer invita al Dr. Juan Engelmayer médico neumonólogo especialista en enfermedades intersticiales para hablar sobre fibrosis pulmonar. 

En primer lugar, conversan acerca de las certezas y las incertidumbres respecto al tratamiento de la neumonía aguda por SARS-CoV2 y la fibrosis pulmonar post-covid. El estudio RECUPERACIÓN reunió la evidencia para apoyar la terapéutica con corticoide sistémico de la neumonía aguda; sin embargo aún no se cuenta con suficiente evidencia para definir el tratamiento de la fibrosis pulmonar post CoviD-19. 

Por último, el Dr. Enghelmayer nos comparte una mirada actualizada sobre la terapéutica de la Fibrosis Pulmonar Idiopática.