The management of liver disease in people with congenital bleeding disorders: guidance from European Association for Haemophilia and Allied Disorders, European Haemophilia Consortium, ISTH, and World Federation of Hemophilia.

People with bleeding disorders (PWBD) have been exposed to the risk of developing chronic viral hepatitis and cirrhosis after replacement therapy. Today, the advent of new pharmacologic strategies for the control of hemostasis and the efficacious antiviral therapies against hepatitis C virus and hepatitis B virus have significantly reduced this risk. However, the definitive success for liver health in this clinical setting is also influenced by other factors, such as the severity of liver disease at the time of hepatitis B virus/hepatitis C virus antiviral therapy and the exposure to highly prevalent factors of chronic liver damage (eg, metabolic dysfunction and/or alcohol) that can cause a residual risk of complications such as hepatocellular carcinoma, portal hypertension, and liver insufficiency. With this background, a group of experts selected among hepatologists, hematologists, PWBD treaters, and patient representatives produced this practical multisociety guidance for the protection of liver health and the prevention and management of liver complications in PWBD based on the most updated protocols of care.

Results from a retrospective case finding and re-engagement exercise for people previously diagnosed with hepatitis C virus to increase uptake of directly acting antiviral treatment.

BACKGROUND: Direct acting antivirals (DAAs) for the Hepatitis C virus (HCV) have shifted the World Health Organisation global strategic focus to the elimination of HCV by 2030. In England, the UK Health Security Agency (UKHSA) led a national 'patient re-engagement exercise', using routine surveillance data, which was delivered through the HCV Operational Delivery Networks (ODNs) with support from National Health Service England (NHSE), to help find and support people with a positive HCV PCR test result to access treatment. We report a quantitative evaluation of outcomes of this exercise. METHODS: Individuals with a recorded positive HCV antibody or PCR result between 1996 and 2017 were identified using UKHSA's records of HCV laboratory diagnosis. Linkage with established health-care datasets helped to enhance patient identification and minimise attempts to contact deceased or previously treated individuals. From September to November 2018 each ODN was provided with a local list of diagnosed individuals. ODNs were asked to perform further data quality checks through local systems and then write to each individual's GP to inform them that the individual would be contacted by the ODN to offer confirmatory HCV PCR testing, assessment and treatment unless the GP advised otherwise. Outcomes of interest were receipt of treatment, a negative PCR result, and death. Data were collected in 2022. RESULTS: Of 176,555 individuals with a positive HCV laboratory report, 55,329 individuals were included in the exercise following linkage to healthcare datasets and data reconciliation. Participants in the study had a median age of 51 years (IQR: 43, 59), 36,779 (66.5%) were males, 47,668 (86.2%) were diagnosed before 2016 and 11,148 (20.2%) lived in London. Of the study population, 7,442 (13.4%) had evidence of treatment after the re-engagement exercise commenced, 6,435 (11.6%) were reported as PCR negative (96% had no previous treatment records), 4,195 (7.6%) had prescription data indicating treatment before the exercise commenced or were reported to have been treated previously by their ODN, and 2,990 (5.4%) had died. The status of 32,802 (59.3%) people remains unknown. CONCLUSIONS: A substantial number of those included had treatment recorded after the exercise commenced, however, many more remain unengaged. Evaluation of the exercise highlighted areas that could be streamlined to improve future exercises.

Changes in the prevalence of hepatitis B and C viral infections in Sindh province, Pakistan: Findings from two sero-surveys in 2007 and 2019.

Pakistan harbours a large burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We utilised repeat sero-surveys to assess progress achieved towards hepatitis elimination in Pakistan. Multilevel logistic regression evaluated the change in HBV infection (HBV surface antigen (HBsAg)-positive) prevalence and HCV exposure (HCV antibody (HCV-Ab)-positive) prevalence between two sero-surveys from 2007 and 2019 for Sindh province and associated risk factors. Adjusted odds ratios (aORs) were estimated and population-attributable fractions (PAF) for modifiable risk factors for HCV exposure. The 2007 and 2019 surveys included 8855 and 6672 individuals. HBsAg prevalence decreased from 2.6% (95% confidence intervals (95% CI): 2.2-2.9) in 2007 to 1.1% (95% CI: 0.8-1.3) in 2019, while HCV-Ab prevalence increased from 5.1% (95% CI: 4.6%-5.5%) to 6.2% (95% CI: 5.6%-6.8%). The age and gender-adjusted HBsAg prevalence decreased by 80% (aOR = 0.2, 95% CI: 0.1-0.4) among children and 60% (aOR = 0.4, 95% CI: 0.3-0.6) among adults over 2007-2019, while HCV-Ab prevalence decreased by 60% (aOR = 0.4, 95%CI:0.2-0.7) in children and increased by 40% (aOR = 1.4, 95% CI: 1.2-1.7) in adults. HCV-Ab prevalence was lower in adults with secondary (aOR = 0.6, 95% CI: 0.5-0.8) and higher (aOR = 0.5, 95%CI:0.3-0.8) education compared to illiterates and higher among adults reporting blood transfusion (aOR = 1.7, 95% CI: 1.2-2.4), family history of hepatitis (aOR = 2.5, 95% CI: 1.9-3.3), past year medical injection (aOR = 2.1, 95% CI: 1.6-2.7), being tattooed (aOR = 1.4, 95% CI: 1.0-1.9) and shaved by traditional barber (aOR = 1.2, 95% CI: 1.0-1.5). Modifiable risk factors accounted for 45% of HCV exposure, with medical injection(s) accounting for 38% (95%CI,25.7-48.4%). Overall HCV has increased over 2007-2019 in Sindh province, while HBV prevalence has decreased. Medical injections should be an important focus of prevention activities.

Pilot postal birth cohort HCV Screening in UK primary care.

BACKGROUND: Birth cohort screening has been implemented in some countries to identify the potentially 'missed population' of undiagnosed chronic Hepatitis C Virus (HCV) in people who may not be found through targeted approaches. AIM: To determine uptake of HCV antibody testing using an oral swab screening method, overall yield, whether those testing positive had risk markers in their primary care record, and cost per case detected. DESIGN AND SETTING: Pilot screening study set in general practices in the Southwest, South London and Yorkshire and Humber. METHOD: Participants consenting were sent an oral swab kit in the post and saliva samples were tested for antibody to HCV. RESULTS: 16,436/98,396 (16.7%) patients consented and were sent an oral swab kit. 12,216 (12.4%) returned a kit, with 31 participants (yield 0.03%) testing positive for HCV antibody. 45% of those positive had a risk marker for HCV on their primary care record. Two (yield 0.002%) were confirmed RNA positive and referred for treatment, both had HCV risk markers. Cost per case detected was £16,000 per HCV antibody and £247,997 per chronic HCV. CONCLUSIONS: Wide-scale screening could be delivered and identified people infected with HCV, however most of these individuals could have been detected through lower-cost targeted screening. Yield and cost per case found were substantially worse than model estimates and targeted screening studies. Birth cohort screening should not be rolled out in primary care in England.

Evaluating the effect of direct-acting antiviral agent treatment scale-up on Hepatitis C virus prevalence among people who inject drugs in UK.

BACKGROUND: There is limited empirical work assessing the effectiveness of treatment as prevention (TasP) in reducing HCV prevalence among people who inject drugs (PWID). Here, we used survey data from the UK during 2010-2020, to evaluate the impact of direct-acting antiviral agent (DAA) treatment scale-up, which started in 2015, on HCV prevalence among PWID. METHODS: We fitted a logistic regression to time/location specific data on prevalence from the Needle Exchange Surveillance Initiative in Scotland and Unlinked Anonymous Monitoring programme in England. For each post-intervention year and location, we quantified the effect of TasP as the difference between estimated prevalence and its counterfactual (prevalence in the absence of scale-up). Progress to elimination was assessed by comparing most recent prevalence against one in 2015. RESULTS: In 2015, prevalence ranged from 0.44 to 0.71 across the 23 locations (3 Scottish, 20 English). Compared to counterfactuals, there was an absolute reduction of 46% (95% credible interval [32%,59%]) in Tayside in 2020, 35% ([24%,44%]) in Glasgow in 2019, and 25% ([10%,39%]) in the Rest of Scotland in 2020. The English sites with highest estimated absolute reductions in 2021 were South Yorkshire (45%, [29%,58%]), Thames Valley (49%, [34%,59%]) and West London (41%, [14%,59%]). Compared to 2015, there was 80% probability that prevalence had fallen by 65% in Tayside, 53% in Glasgow and 36% in the Rest of Scotland. The English sites with highest % prevalence decrease compared to 2015, achieved with probability 80%, were Chesire & Merseyside (70%), South Yorkshire (65%) and Thames Valley (71%). Higher treatment intensity was associated with higher reductions in prevalence. CONCLUSION: Conclusion. Real-world evidence showing substantial reductions in chronic HCV associated with increase of HCV treatment scale-up in the community thus supporting the effectiveness of HCV treatmen as prevention in people who inject drugs.

The complex, confusing and poorly understood immune responses to AAV-mediated gene transfer in haemophilia-Is more or less immunosuppression required?

Attempts to achieve a functional cure or amelioration of the severe X linked bleeding disorders haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) using AAV-based vectors have been frustrated by immune responses that limit efficacy and durability. The immune responses include adaptive and innate pathways as well as cytokine mediated inflammation, especially of the target organ cells-hepatocytes. Immune suppression has only been partly effective in clinical trials at ameliorating the immune response and the lack of good animal models has delayed progress in identifying mechanisms and developing more effective approaches to controlling these effects of AAV gene transfer. Here we discuss the arguments for and against more potent immunosuppression to improve factor expression after AAV-mediated gene therapy.

Hepatitis after gene therapy, what are the possible causes?

Hepatitis is a common adverse event following gene therapy for haemophilia, often associated with a loss of transgene expression. Investigating the potential causes and implications of this is crucial for the overall success of treatment. Gene therapy trials using adeno-associated virus (AAV) vectors have demonstrated promising results marked by increases in factor FVIII and FIX levels and reductions in episodes of bleeding. However, hepatocellular injury characterised by elevations in alanine aminotransferases (ALT) has been noted. This liver injury is typically transient and asymptomatic, posing challenges in determining its clinical significance. Proposed causes encompass immune-mediated responses, notably T cell cytotoxicity in response to the AAV vector, direct liver injury from the viral capsid or transcribed protein via the unfolded protein response and pre-existing liver conditions. Liver biopsy data conducted years post-gene therapy infusion has shown sinusoidal infiltration without significant inflammation. The overall safety profile of gene therapy remains favourable with no evidence drug-induced liver injury (DILI) based on Hy's Law criteria. Essential pre-therapy monitoring and identifying patients at high risk of liver injury should involve liver function tests and non-invasive fibroscans, while novel blood-based biomarkers are under exploration. Further research is required to comprehend the mechanisms underlying transaminitis, loss of transgene expression and long-term effects on the liver, providing insights for optimising gene therapy for haemophilia.

Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review.

BACKGROUND: Hepatitis C virus (HCV) is a blood-borne virus which globally affects around 79 million people and is associated with high morbidity and mortality. Chronic infection leads to cirrhosis in a large proportion of patients and often causes hepatocellular carcinoma (HCC) in people with cirrhosis. Of the 6 HCV genotypes (G1-G6), genotype-3 accounts for 17.9% of infections. HCV genotype-3 responds least well to directly-acting antivirals and patients with genotype-3 infection are at increased risk of HCC even if they do not have cirrhosis. AIM: To systematically review and critically appraise all risk factors for HCC secondary to HCV-G3 in all settings. Consequently, we studied possible risk factors for HCC due to HCV-G3 in the literature from 1946 to 2023. METHODS: This systematic review aimed to synthesise existing and published studies of risk factors for HCC secondary to HCV genotype-3 and evaluate their strengths and limitations. We searched Web of Science, Medline, EMBASE, and CENTRAL for publications reporting risk factors for HCC due to HCV genotype-3 in all settings, 1946-2023. RESULTS: Four thousand one hundred and forty-four records were identified from the four databases with 260 records removed as duplicates. Three thousand eight hundred and eighty-four records were screened with 3514 excluded. Three hundred and seventy-one full-texts were assessed for eligibility with seven studies included for analysis. Of the seven studies, three studies were retrospective case-control trials, two retrospective cohort studies, one a prospective cohort study and one a cross-sectional study design. All were based in hospital settings with four in Pakistan, two in South Korea and one in the United States. The total number of participants were 9621 of which 167 developed HCC (1.7%). All seven studies found cirrhosis to be a risk factor for HCC secondary to HCV genotype-3 followed by higher age (five-studies), with two studies each showing male sex, high alpha feto-protein, directly-acting antivirals treatment and achievement of sustained virologic response as risk factors for developing HCC. CONCLUSION: Although, studies have shown that HCV genotype-3 infection is an independent risk factor for end-stage liver disease, HCC, and liver-related death, there is a lack of evidence for specific risk factors for HCC secondary to HCV genotype-3. Only cirrhosis and age have demonstrated an association; however, the number of studies is very small, and more research is required to investigate risk factors for HCC secondary to HCV genotype-3.

Adeno-associated viruses for gene therapy - clinical implications and liver-related complications, a guide for hepatologists.

Gene therapy has garnered increasing interest over recent decades. Several therapies employing gene transfer mechanisms have been developed, and, of these, adeno-associated virus (AAV) vectors have demonstrated viability for use with in vivo gene therapy. Several AAV-based therapeutics have received regulatory approval in the last few years including those for retinal disease, spinal muscular atrophy or aromatic L-amino acid decarboxylase deficiency. Lately, with the introduction of novel liver-directed AAV vector-based therapeutics for the treatment of haemophilia A and B, gene therapy has attracted significant attention in the hepatology community, with the liver increasingly recognised as a target for gene therapy. However, the introduction of foreign DNA into hepatocytes is associated with a risk of hepatic reactions, with raised ALT (alanine aminotransferase) and AST (aspartate aminotransferase) being - so far - the most commonly reported side effects. The complete mechanisms underlying the ALT flairs remain to be determined and the long-term risks associated with these new treatments is not yet known. The liver community is increasingly being asked to support liver-directed gene therapy to mitigate potential liver associated harm. In this review, we focus on AAV vector-based gene therapy, shedding light on this promising technique and its remarkable success in haemophilia, with a special focus on hepatic complications and their management in daily clinical practice.

HepFREEPak: protocol for a multi-centre, prospective observational study examining efficacy and impact of current therapies for the treatment of hepatitis C in Pakistan and reporting resistance to antiviral drugs: study protocol.

BACKGROUND: Pakistan has one of the highest burdens of Hepatitis C virus (HCV) infection globally. To achieve the World Health Organization's goals for HCV elimination, there is a need for substantial scale-up in testing, treatment, and a reduction in new infections. Data on the population impact of scaling up treatment is not available in Pakistan, nor is there reliable data on the incidence of infection/reinfection. This project will fill this gap by providing important empirical data on the incidence of infection (primary and reinfection) in Pakistan. Then, by using this data in epidemic models, the study will determine whether response rates achieved with affordable therapies (sofosbuvir plus daclatasvir) will be sufficient to eliminate HCV in Pakistan. METHODS: This prospective multi-centre cohort study will screen 25,000 individuals for HCV antibody (Ab) and RNA (if Ab-positive) at various centers in Pakistan- Karachi (Sindh) and Punjab, providing estimates of the disease prevalence. HCV positive patients will be treated with sofosbuvir and daclatasvir for 12-weeks, (extended to 24-weeks in those with cirrhosis) and the proportion responding to this first-line treatment estimated. Patients who test HCV Ab negative will be recalled 12 months later to test for new HCV infections, providing estimates of the incidence rate. Patients diagnosed with HCV (~ 4,000) will be treated and tested for Sustained Virological Response (SVR). Questionnaires to assess risk factors, productivity, health care usage and quality of life will be completed at both the initial screening and at 12-month follow-up, allowing mathematical modelling and economic analysis to assess the current treatment strategies. Viral resistance will be analysed and patients who have successfully completed treatment will be retested 12 months later to estimate the rate of re-infection. CONCLUSION: The HepFREEPak study will provide evidence on the efficacy of available and widely used treatment options in Pakistan. It will also provide data on the incidence rate of primary infections and re-infections. Data on incidence risk factors will allow us to model and incorporate heterogeneity of risk and how that affects screening and treatment strategies. These data will identify any gaps in current test-and-treat programs to achieve HCV elimination in Pakistan. STUDY REGISTRATION: This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

The tolerability of sofosbuvir/velpatasvir for 12 weeks in patients treated in the ASTRAL 1, 2 and 3 studies: A pooled safety analysis.

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

Liver-related aspects of gene therapy for hemophilia: need for collaborations with hepatologists.

Adeno-associated virus-based gene therapies hemophilia allow long-term transgene expression with reduced annual bleeding rates. Various liver-related aspects are involved in the different phases of gene therapy, such as assessment of liver health in the pretherapy period, patient selection and follow-up, maintenance of liver health after gene therapy, and management of potential short- and long-term adverse events. Increase in alanine aminotransferease is a common adverse event that requires rapid evaluation and an immunosuppressive approach. It is therefore important that hemophilia treaters and hepatologists collaborate at all stages of gene therapy to assess potential safety issues and ensure the long-term success of gene therapy. Special attention should be given to patients with not well-defined conditions, e.g. patients with some degree of liver fibrosis or fatty liver disease, patients with a history of hepatitis C and hepatitis B infection, patients with HIV infection, and patients taking medications that may affect liver function.

Evaluation of CirrhoCare® - a digital health solution for home management of individuals with cirrhosis.

BACKGROUND & AIMS: Individuals with cirrhosis discharged from hospital following acute decompensation are at high risk of new complications. This study aimed to assess the feasibility and potential clinical benefits of remote management of individuals with acutely decompensated cirrhosis using CirrhoCare®. METHODS: Individuals with cirrhosis with acute decompensation were followed up with CirrhoCare® and compared with contemporaneous matched controls, managed with standard follow-up. Commercially available monitoring devices were linked to the smartphone CirrhoCare® app, for daily recording of heart rate, blood pressure, weight, % body water, cognitive function (CyberLiver Animal Recognition Test [CL-ART] app), self-reported well-being, and intake of food, fluid, and alcohol. The app had 2-way patient-physician communication. Independent external adjudicators assessed the appropriateness of CirrhoCare®-based decisions. RESULTS: Twenty individuals with cirrhosis were recruited to CirrhoCare® (mean age 59 ± 10 years, 14 male, alcohol-related cirrhosis [80%], mean model for end-stage liver disease-sodium [MELD-Na] score 16.1 ± 4.2) and were not statistically different to 20 contemporaneous controls. Follow-up was 10.1 ± 2.4 weeks. Fifteen individuals showed good engagement (≥4 readings/week), 2 moderate (2-3/week), and 3 poor (<2/week). In a usability questionnaire, the median score was ≥9 for all questions. Five CirrhoCare®-managed individuals had 8 readmissions over a median of 5 (IQR 3.5-11) days, and none required hospitalisation for >14 days. Sixteen other CirrhoCare®-guided patient contacts were made, leading to clinical interventions that prevented further progression. Appropriateness was confirmed by adjudicators. Controls had 13 readmissions in 8 individuals, lasting a median of 7 (IQR 3-15) days with 4 admissions of >14 days. They had 6 unplanned paracenteses compared with 1 in the CirrhoCare® group. CONCLUSIONS: This study demonstrates that CirrhoCare® is feasible for community management of individuals with decompensated cirrhosis with good engagement and clinically relevant alerts to new decompensating events. CirrhoCare®-managed individuals have fewer and shorter readmissions justifying larger controlled clinical trials. IMPACT AND IMPLICATIONS: As the burden of cirrhosis grows worldwide, increasing demands are being placed on limited healthcare resources, necessitating the adoption of more sustainable care models that allow for at-home patient management. The CirrhoCare® management system was developed to fill this care gap, deploying a novel combination of hardware, apps, and algorithms, to monitor and intervene in individuals at risk of new decompensation. This study highlights the possibility of reducing hospital readmissions for cirrhosis by optimising specialist community care, reducing the need for interventions such as paracentesis, while providing a more sustainable care pathway that is acceptable to patients. However, given the pilot and non-randomised nature of this study, the outcomes require further validation in a larger randomised controlled trial, to assess both clinical effectiveness and cost-effectiveness. Moreover, the data generated will also facilitate data modelling and further research to refine the CirrhoCare® algorithms to increase their detection sensitivity and utility.

The economic case for hospital discharge services for people experiencing homelessness in England: An in-depth analysis with different service configurations providing specialist care.

There are long-standing concerns that people experiencing homelessness may not recover well if left unsupported after a hospital stay. This study reports on a study investigating the cost-effectiveness of three different 'in patient care coordination and discharge planning' configurations for adults experiencing homelessness who are discharged from hospitals in England. The first configuration provided a clinical and housing in-reach service during acute care and discharge coordination but with no 'step-down' care. The second configuration provided clinical and housing in-reach, discharge coordination and 'step-down' intermediate care. The third configuration consisted of housing support workers providing in-reach and discharge coordination as well as step-down care. These three configurations were each compared with 'standard care' (control, defined as one visit by the homelessness health nurse before discharge during which patients received an information leaflet on local services). Multiple sources of data and multi-outcome measures were adopted to assess the cost utility of hospital discharge service delivery for the NHS and broader public perspective. Details of 354 participants were collated on service delivery costs (salary, on-costs, capital, overheads and 'hotel' costs, advertising and other indirect costs), the economic consequences for different public services (e.g. NHS, social care, criminal justice, housing, etc.) and health utilities (quality-adjusted-life-years, QALYs). Findings were complex across the configurations, but, on the whole, there was promising evidence suggesting that, with delivery costs similar to those reported for bed-based intermediate care, step-down care secured better health outcomes and improved cost-effectiveness (compared with usual care) within NICE cost-effectiveness recommendations.