Metabolic dysfunction-associated steatotic liver disease a multisystem disease: Assessing the cost effectiveness of pharmacotherapies.Journal of hepatology • January 28, 2025
Christopher Byrne, Gregory Dore
Wallace and colleagues have aimed to model the US health and economic impact of a hypothetical pharmacologic therapy which halts metabolic dysfunction-associated steatotic liver disease (MASLD) fibrosis progression.1 In their models, therapy which only reverses steatosis had minimal (<1–2%) effect on severe liver disease events prevented and healthcare costs averted. Over a 20-year timeframe (2024-2044), the scenarios in which a hypothetical therapy halts fibrosis progression (70% response rate) resulted in reduced cases of decompensated cirrhosis (11-39%), hepatocellular carcinoma (10-34%), liver-related deaths (8-31%), a 9-31% reduction in cumulative DALYs (disability adjust life years), and $40-$99 B incremental healthcare costs averted. We congratulate them on their work in addressing this extremely complex issue which has now become very relevant for healthcare providers and clinical practice.
MASLD has rapidly become the most common chronic liver disease, causing major adverse liver outcomes, and affects up to ∼38% of the global adult population.2 Thus, MASLD has major implications for healthcare costs and providers of healthcare. A decade ago, we highlighted evidence supporting the notion that MASLD is a multisystem disease, not only affecting the liver; but also having the potential to increase risk of other extrahepatic cardiometabolic diseases.3 Since then, it has become apparent that MASLD also increases the risk of chronic kidney disease (CKD)4 and certain extrahepatic cancers.5 Cardiovascular disease (CVD) is the leading cause of death in people with MASLD, and MASLD is a risk factor for incident type 2 diabetes mellitus (T2DM),6 creating a vicious cycle where MASLD not only increases the risk of T2DM, but the development of T2DM further worsens the risk of liver disease progression.7 Notably, CVD risk may increase further with more severe liver disease, especially with higher fibrosis stages.8 Since MASLD also increases the risk of developing new-onset heart failure9 and atrial fibrillation,10 there is considerable interest in re-purposing drugs shown to reduce body fat and decrease risk of CVD and CKD for the treatment of MASLD. One such potential drug class is glucagon-like peptide-1 receptor agonists (GLP-1RAs) that have considerable utility in attenuating risk of many of these other diseases linked to MASLD.11 Another drug class is sodium-glucose transport protein 2 inhibitors (SGLT2-i), with preliminary evidence of benefit in decreasing adverse liver and cardiovascular events.12,13 Thus, both drug classes have potential utility for liver disease, including attenuating risk of many other diseases linked to MASLD as a complex multisystem disease.11
Wallace and colleagues have modelled the cost effectiveness of GLP-1RAs and SGLT2-i, as well as a future hypothetical therapy that halts fibrosis progression. They used the MASLD disease burden model, a Markov model that incorporates MASLD prevalence, disease progression, mortality and impact. Five scenarios were evaluated: no treatment; antisteatotic therapy of diabetic MASLD F0–F1 patients; and novel antifibrotic therapy for F3, F2–F3, and F2–F4 patients. In the antisteatotic therapy scenario, diabetes diagnosis among the MASLD population remained constant at 22% with treatment constant at 10%. The assumption of constant antisteatotic treatment is problematic as GLP-1RA and SGLT2-i class use is increasing, and will extend into the population without diabetes, because of the need to attenuate a patient’s risk of CVD and CKD and to treat obesity. The authors did assume the total MASLD population will grow as result of obesity trends. Thus, despite constant proportions diagnosed and treated, Wallace and colleagues estimated the number of people on GLP-1RA/SGLT2-i therapies will increase from 2.6 million in 2024 to 3.8 million in 2044. The modelled benefit of GLP-1RA/SGLT2-i drugs was conservative, being limited to antisteatotic effects and use within the F0–F1 population. In the antifibrotic scenarios, progressive increases in diagnosis of MASLD were incorporated, from 3% to 10% for F0-1 to F4 patients at baseline (2022-2024) to 15% to 50% for F0-1 to F4 patients in 2040-2044.
Given the 20-year time frame of analysis and slow progression of the disease14,15), changing treatment assumptions in the F0–F1 population would be expected to have limited effect on outcomes. However, the analysis was undertaken prior to the publication of interim results from the ESSENCE trial. The significant benefit on liver fibrosis in trial participants treated with the GLP-1RA semaglutide in ESSENCE may translate into a sustained impact on liver disease outcomes, at least for this class of drugs.
In the novel antifibrotic therapy scenarios, it was assumed the pharmacological agent would be used by 80% of those diagnosed with MASLD and successively halt fibrosis with a response rate of 70%. Such high levels of coverage and response do seem optimistic, although the authors additionally evaluated response rates from 30% to 83%, with relatively low impact on outcomes. The impact of antifibrotic therapy is clearly dependent on fibrosis progression parameter estimates and the time-horizon employed. The overall impact would be enhanced if progression was more rapid than estimated and a lifetime horizon was employed.
The health economic analysis is affected by healthcare costs, including MASLD screening and monitoring costs, and estimation of health-related quality of life at liver disease stages. The cost of following up someone with F0–F1 was not that different from following up someone at much higher risk with more severe disease. The authors comment that reducing annual imaging to a less frequent schedule would produce cost savings without affecting quality of care, due to slow disease progression, particularly in the earlier stages (F0–F2) of disease. Consequently, identification of the subset of patients who are more likely to rapidly progress to advanced disease and those with known risk factors for progression (e.g. T2DM obesity, or hypertension as key metabolic syndrome traits), will be key to ensure those who may require more frequent monitoring receive it. The disability weights for liver disease were only applied to decompensated cirrhosis, hepatocellular carcinoma and liver transplant cases. Thus, fibrosis reversal from antifibrotic therapy intervention for patients with F2–F4 prior to these events had limited impact on DALYs. Again, longer-term follow-up would presumably alter this situation.
Evaluation of the potential impact, including cost effectiveness, of pharmacological interventions for MASLD is a complex undertaking for several reasons. First, liver disease generally resides within a multimorbidity clinical situation, with CVD a particularly important determinant of patient outcomes. Second, the relatively short-term improvements in surrogate markers (hepatic inflammation and fibrosis) may not translate into longer-term clinical event impact, since liver disease progresses slowly. Third, treatment adherence and lifestyle will clearly impact on temporal changes in weight, development or resolution of T2DM, and thereby influence liver disease outcomes.
MASLD as a multisystem disease does however present opportunities, particularly in relation to T2DM diagnosis and management. Among people living with MASLD, T2DM is associated with substantially higher morbidity and mortality, making case finding for MASLD particularly important in this group. Thus, therapeutic targeting of people living with MASLD and T2DM is likely to be more cost effective, particularly if one considers the benefits of these drug classes beyond the liver and on extrahepatic organs and diseases linked to MASLD.
Together with MASLD patient selection for treatment, a key challenge in 2025 is how to monitor liver treatment responses, so that clear stopping rules can be introduced for new and expensive licensed treatments. The emergence of various non-invasive testing modalities, including transient elastography and magnetic resonance-based techniques, has improved the ability to monitor patients; however, the accuracy and reproducibility of these modalities can be affected by obesity, liver congestion and acute inflammation, and access to these diagnostic tools remains variable across healthcare systems.16 Other imaging modalities such as magnetic resonance elastography (MRE) show promise but require further validation for routine clinical use and present additional resource challenges.17 Serum biomarker panels, including the enhanced liver fibrosis (ELF) test, have demonstrated utility in risk stratification, though their accuracy in diagnosing MASH and staging fibrosis vary considerably.18
Following the FDA licensing of resmetirom in 2024, there has been a useful update to the AASLD Practice Guidance in 2025 to introduce guidance on monitoring of therapeutic responses.19 This guidance introduces a ‘traffic light’ system, with a ‘green light’ for continuing resmetirom therapy beyond 12 months (i.e. improvement in vibration-controlled transient elastography [VCTE] kPa by 25% or MRE by ≥20% from baseline or normalization or significant improvement in alanine aminotransferase [ALT]), an ‘amber’ light for re-evaluating therapy (i.e. VCTE kPa improvement by <25%, or MRE improvement <20% from baseline or normalization, and no significant improvement in ALT, or <30% reduction in MRI-PDFF [proton density fat fraction]), and a ‘red’ light for stopping treatment (i.e. worsening of the same imaging or blood-based biomarker tests, or a consistent increase in ALT).19 Although this Guideline mentions the use of MRI-PDFF and MRE, both are costly tests that are not likely to be cost effective. However, the Guideline could be followed with the use of ALT, serum fibrosis biomarkers and VCTE, which is likely to be a more cost-effective strategy for monitoring the efficacy of newly licensed treatments.
In conclusion, we are witnessing the dawn of a new era in the treatment of MASLD, with new drug classes not only showing promise for treating liver steatosis, inflammation and fibrosis, but also for having extrahepatic benefits in treating MASLD as a multisystem disease.5 We welcome the work of Wallace and colleagues, but the future challenge will also be to consider the extrahepatic benefits of these drugs, as well as the costs per quality-adjusted life years, in order to develop cost effective strategies for a condition that affects millions across the globe.
Surveillance of Viral Respiratory Infections within Maximum-Security Prison, Australia. Emerging Infectious Diseases • July 24, 2025
Nicolas Legrand, Rowena Bull, Behzad Hajarizadeh, Andrew Lloyd, Kirsty Johnston, Katya Issa, Christine Harvey, Alicia Arnott, Dominic Dwyer, Vitali Sintchenko, Luke Grant, Gregory Dore, John Kaldor, Marianne Martinello
Limited surveillance data have hindered understanding of SARS-CoV-2 transmission within prisons. We integrated routine surveillance data with viral sequencing to investigate transmission dynamics and associated factors during a Delta variant outbreak in a maximum-security prison in Sydney, New South Wales, Australia. Infection incidence and associated factors were determined by using person-time and Cox regression. We generated transmission chains by integrating epidemiologic and viral sequencing data. Of 1,562 patients, SARS-CoV-2 infection was diagnosed in 169 (11%), predominantly acquired in prison and asymptomatic. Prisonwide testing identified substantial unrecognized transmission, and 4 subvariants indicated multiple viral introductions. Infection was associated with housing location, having a cellmate (regardless of infection status), and vaccination status. Our findings underscore the inadequacy of symptom-based testing and the efficacy of entry-quarantine, strategic housing, extensive testing, and vaccination in reducing transmission. This integrated approach to surveillance and genomic sequencing offers a valuable model for enhancing infectious disease surveillance in correctional settings.
Bacterial and fungal infections in persons who inject drugs.Clinical Microbiology Reviews • June 13, 2025
Jeffrey Masters, David Goodman Meza, Danielle Russell, Laura Marks, Erin Mccreary, Brendan Jacka, Kate Seear, Joshua Davis, Gail Matthews, Marianne Martinello, Steven Y Tong, Gregory Dore
SUMMARYPersons who inject drugs are at increased risk of bacterial and fungal injecting-related infections due to many physiological, societal, and structural factors. An estimated 15 million persons inject drugs worldwide, with recent increases in the burden of injecting-related infections. Acquisition of these infections has distinct pathophysiology and microbiology related to drug supply, drug composition, and the process of injecting. Clinical management of these infections is complicated by usual factors such as the need for source control and effective antibiotics, as well as the complex challenges faced by persons who inject drugs while in hospital. These challenges include drug withdrawal, difficult pain control related to opioid tolerance, stigma, discrimination, and lack of access to outpatient parenteral antibiotic therapy, which can lead to high rates of patient-directed discharge and non-completion of treatment with subsequent poor outcomes. This review seeks to provide an evidence-based summary of what is known about the risks, epidemiology, microbiology, and presentation of injecting-related bacterial and fungal infections, as well as provide recommendations for treatment, including pharmacological considerations, opportunistic screening, multidisciplinary team care, and approaches to outpatient therapy. It also provides insight into the medicolegal and ethical considerations of care for persons who inject drugs and a first-person perspective of someone with lived experience.
Comparative Effectiveness of Long-Acting Lipoglycopeptides vs Standard-of-Care Antibiotics in Serious Bacterial Infections.JAMA Network Open • May 21, 2025
David Goodman Meza, Robert Weiss, Michelle Poimboeuf, Jeffrey Feng, Tara Vijayan, Marianne Martinello, Gail Matthews, Gregory Dore
Serious bacterial infections such as bacteremia, endocarditis, osteomyelitis, and septic arthritis typically require prolonged intravenous antibiotics. Long-acting lipoglycopeptides (laLGPs), such as dalbavancin and oritavancin, offer extended treatment intervals for gram-positive infections that may benefit populations with barriers to traditional treatment, including persons who use drugs (PWUD individuals). To assess the effectiveness of laLGPs in managing serious bacterial infections in both PWUD and non-PWUD populations compared with standard-of-care (SOC) antibiotics. This comparative effectiveness study using a target trial emulation framework included data extracted from the US Cerner Real World Data platform. Individuals hospitalized and discharged for serious bacterial infections between October 1, 2015, and October 1, 2022, were included in the analysis. Data were analyzed from July 7, 2023, to February 28, 2025. Receipt of an laLGP (dalbavancin or oritavancin) vs SOC antibiotics. The primary outcome measure was a composite of readmission, emergency department visit, and inpatient death or discharge to hospice within 90 days post discharge from the index admission. Analyses were stratified by PWUD and non-PWUD status. Clone censor weighting was used to emulate a per-protocol analysis. Hazard ratios (HR) of time to the composite event and 95% CIs were calculated using bootstrapping. Among 42 067 included individuals, median age was 61 (IQR, 47-73) years, 24 704 were male (58.7%), and 5047 (12.0%) were classified as PWUD. laLGPs were prescribed in 825 individuals (2.0%). There was no statistically significant difference in the composite outcome between the laLGP and SOC groups in both the PWUD (HR, 1.01; 95% CI, 0.88-1.13) and non-PWUD (HR, 0.93; 95% CI, 0.86-1.00) participants. In this study of laLGPs vs SOC, findings suggested that laLGPs were effective as step-down treatment of serious gram-positive bacterial infections, offering comparable outcomes to those of SOC antibiotics in PWUD and non-PWUD individuals. Clinicians may consider laLGPs as alternative step-down options to SOC antibiotics for the treatment of serious gram-positive bacterial infections.
Patient preferences for simplified hepatitis C testing modalities among people at risk of hepatitis C infection in Australia: the SELECT study.The International Journal On Drug Policy • February 06, 2025
Annabelle Stevens, Jake Abbott, Loriate Gribbin, Sarah Ahmed, Mark Montebello, Peter Ellis Jones, Thao Lam, Meryem Jefferies, Mim O'flynn, Joss O'loan, Alex Wade, Anita Hoskins, Laura Johnson, Amie Johns, Victoria Cock, Mary Harrod, David Silk, Alison Marshall, Gregory Dore, Jason Grebely, Evan Cunningham
Background: Understanding patient preferences for hepatitis C virus (HCV) testing is essential to improve uptake and support elimination efforts. Despite innovative testing modalities, limited research examines how preferences influence testing choices. This study compared the uptake of HCV testing modalities when participants were given a choice.
Methods: People at risk of HCV were recruited from community sites in the Australian Hepatitis C Point-of-Care Testing Program. Participants used a visual aid outlining test features, including time to result and collection methods. Those reporting prior HCV infection were offered staff-assisted HCV RNA tests [point-of-care XpertⓇ HCV Viral Load Fingerstick (result in 60 min) or dried blood spot (DBS) (1-2 weeks)]. Participants without prior HCV infection were offered self-administered INSTIⓇ HCV antibody (1 min), staff-assisted INSTIⓇ HCV antibody (1 min), staff-assisted BiolineⓇ HCV antibody (5-20 min), and HCV RNA tests. Participants completed their preferred test, a survey, and received AUD$20 reimbursement. Logistic regression evaluated factors associated with preference for point-of-care RNA testing in those with and without prior HCV infection.
Results: 404 people were enrolled (27% female, 75% ever injected drugs). Among those with a history of HCV (n=129), 91% (n=117) selected point-of-care RNA testing and cited the short time to result (52%) and wanting to find out the RNA result today (21%) as key reasons. Among those without a history of HCV (n=275), 72% (n=199) selected staff-assisted INSTIⓇ antibody testing, 19% (n=51) selected point-of-care RNA testing, and 4% (n=10) chose self-administered INSTIⓇ antibody testing. Key reasons for selecting staff-assisted INSTIⓇ included short time to result (75%) and reduced clinic time (8%). Factors associated with selecting point-of-care RNA testing among those without prior infection included recent injecting drug use, homelessness and recent opioid agonist therapy.
Conclusions: Findings highlight the importance of offering rapid, staff-assisted HCV testing to improve uptake among at-risk populations.
