Photo Credit: iStock.com/Alena Butusava

Michael Tadros, MD, MPH, discusses how lessons learned from HCV treatment could improve the management of metabolic dysfunction-associated steatohepatitis.

“Metabolic-dysfunction-associated steatohepatitis (MASH) is emerging as one of the leading causes of chronic liver disease globally, coinciding with the decline in hepatitis C virus (HCV) prevalence due to highly effective direct-acting antivirals (DAAs),” Michael Tadros, MD, MPH, tells Physician’s Weekly (PW). “Given the shifting epidemiology of liver disease, it is crucial to guide clinicians and researchers as they navigate this evolving landscape.”

In a review article published in Gastroenterology Insights, Dr. Tadros and colleagues examined why developing therapeutics is more challenging for MASH than for HCV and what lessons from HCV can be applied in MASH.

Advances in MASH Lag Behind HCV

With HCV, factors including its viral etiology, a clear clinical endpoint such as Sustained Virological Response (SVR), and a relatively uniform disease course enabled streamlined clinical trials and DAA development. Decades of HCV treatment advancements led to cure rates over 90%, Dr. Tadros and colleagues noted.

By contrast, MASH therapeutic improvements lag, the researchers continued. The complex metabolic, genetic, and environmental factors associated with MASH can require simultaneous treatments for fat accumulation, inflammation, and fibrosis, making drug development a challenge. The lack of a universally accepted, non-invasive clinical endpoint analogous to SVR complicates trial design and regulatory approval. The wide-ranging variability of MASH severity from simple steatosis to advanced fibrosis and cirrhosis requires larger and longer clinical trials, slowing the pace of drug development.

Available non-invasive MASH diagnostic tools, including ultrasound, vibration-controlled transient elastography (VCTE), magnetic resonance imaging–proton density fat fraction (MRI-PDFF), and serum biomarkers, show promise, but can miss histologic nuances. The gold-standard liver biopsy’s invasive nature limits its use in clinical trials and routine practices.

In their review, Dr. Tadros and colleagues evaluated MASH therapies, including resmetirom and combinations such as pioglitazone and vitamin E, which show potential but offer modest improvements due to MASH’s heterogeneity.

“The limited efficacy of these treatments highlights the need for multi-targeted strategies addressing metabolic and fibrotic components,” they wrote.

Dr. Tadros spoke with PW about how clinicians can improve MASH care, including examining the successful development of HCV therapies.

PW: Building on the development of successful HCV treatments, what takeaways can clinicians use to improve outcomes in MASH?

Dr. Tadros: One of the key lessons from HCV management is the importance of early identification and targeted interventions. Clinicians should prioritize non-invasive tools like transient elastography and biomarker panels to assess fibrosis in patients with MASH. A multidisciplinary approach incorporating lifestyle interventions, pharmacologic advancements, and metabolic management is also critical.

To optimize patient care during this growing health challenge, we need to develop effective, patient-specific therapies that close the gap between MASH and better-managed liver diseases.

Are any strengths or limitations of this review especially noteworthy?

The review’s strength is its comprehensive comparison of MASH and HCV, particularly in pathogenesis and treatment approaches. However, a limitation is the relative paucity of long-term outcome data for emerging MASH therapies, which restricts definitive conclusions about their efficacy. The evolving nature of MASH research necessitates ongoing updates to the literature.

What questions remain unanswered for you?

Despite advancements, significant questions remain about the optimal pharmacologic treatment for MASH and the role of combination therapies. Further research is needed to clarify the mechanisms linking metabolic dysfunction to liver inflammation and fibrosis. Longitudinal studies comparing MASH outcomes with those of HCV are warranted to refine therapeutic targets and predict disease progression.

Informed by the HCV therapeutic success, future MASH trials must aim to identify clear surrogate biomarkers and simplify trial designs to accelerate approval of effective therapies.

What are the primary take-home messages for clinicians?

Clinicians should remain vigilant for MASH in patients with metabolic syndrome, even in the absence of elevated liver enzymes. Education on lifestyle modifications and early adoption of validated non-invasive diagnostic tools are essential. Also, engaging patients in shared decision-making and setting realistic expectations regarding lifestyle changes and treatment goals can significantly enhance outcomes.