What Is the Role of Body Composition Assessment in HCC Management?

In the last decade, body composition (BC) assessment has emerged as an innovative tool that can offer valuable data concerning nutritional status in addition to the information provided by the classical parameters (i.e., body mass index, albumin). Furthermore, published data have revealed that different types of body composition are associated with different outcomes. For example, abnormalities of skeletal muscle, a common finding in cirrhotic and oncologic patients, are associated with poor outcome (i.e., high morbidity and high mortality). The disposition (visceral/subcutaneous adipose tissue) and radiodensity of adipose tissue proved to also be determinant factors for HCC outcome. Despite all the advantages, BC assessment is not part of the standard pre-therapeutic workup. The main reasons are the high heterogeneity of data, the paucity of prospective studies, the lack of a standard assessment method, and the interpopulation variation of BC. This paper aims to review the available evidence regarding the role of BC as a prognostic tool in the HCC population undergoing various therapies.

HCV disease burden and population segments in Switzerland.

BACKGROUND: Switzerland has made strides towards hepatitis C virus elimination, but as of 2019, elimination was not guaranteed. However, political interest in viral hepatitis has been increasing. We sought to develop a better understanding of Switzerland's progress towards HCV elimination and the profile of remaining HCV-RNA-positive patients. METHODS: A previously described Markov model was updated with recent diagnosis and treatment data and run to generate new forecasts for HCV disease burden. Two scenarios were developed to evaluate HCV morbidity and mortality under the status quo and a scenario that achieves the Swiss Hepatitis Strategy Elimination targets. Next, an analysis was conducted to identify population segments bearing a high burden of disease, where future elimination efforts could be directed. RESULTS: At the beginning of 2020, an estimated 32 100 viremic infections remained in Switzerland (0.37% viremic prevalence). Adult (≥18 years of age) permanent residents born abroad represented the largest subpopulation, accounting for 56% of HCV infections. Thirteen countries accounted for ≥60% of viremic infections amongst permanent residents born abroad, with most people currently residing in Zurich, Vaud, Geneva, Bern, Aargau and Ticino. Amongst Swiss-born HCV-RNA-positive persons, two-thirds had a history of IDU, corresponding to 33% of total infections. CONCLUSIONS: In Switzerland, extra efforts for diagnosis and linkage to care are warranted in foreign-born populations and people with a history of drug use. Population-level measures (eg increasing the number of providers, increase screening) can identify patients who may have otherwise fallen through the gaps or avoided care because of stigma.

Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

Nonalcoholic fatty liver disease burden - Switzerland 2018-2030.

As a result of epidemic levels of obesity and diabetes mellitus, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) will contribute to increases in the liver-related disease burden in Switzerland. A Markov model was built to quantify fibrosis progression among the NAFLD and NASH populations, and predict disease burden up to 2030. Long-term trending of NAFLD prevalence was based on changes in the prevalence of adult obesity. Published estimates and surveillance data were applied to build and validate the model projections. The prevalence of NAFLD increased up to 2030 in tandem with projected increases in adult obesity. By 2030, there were an estimated 2,234,000 (1,918,000–2,553,000) NAFLD cases, or 24.3% (20.9–27.8%) of the total Swiss population (all ages). Increases in NASH cases were relatively greater than NAFLD cases. Incident cases of advanced liver disease are projected to increase by approximately 40% by 2030, and incident NAFLD liver deaths to increase from 580 deaths in 2018 to 820 deaths in 2030. Continued growth in obesity, in combination with an aging population, will result in increasing number of cases of advanced liver disease and mortality related to NAFLD and NASH. Slowing the growth in obesity and metabolic syndrome, along with future potential therapies, are required to reduce liver disease burden.  .

The Optimal Timing of Hepatitis C Therapy in Transplant Eligible Patients With Child B and C Cirrhosis: A Cost-Effectiveness Analysis.

BACKGROUND: Ledipasvir (LDV)/sofosbuvir (SOF) has demonstrated high efficacy, safety, and tolerability in hepatitis C virus (HCV)-infected patients. There is limited data, however, regarding the optimal timing of therapy in the context of possible liver transplantation (LT). METHODS: We compared the cost-effectiveness of 12 weeks of HCV therapy before or after LT or nontreatment using a decision analytical microsimulation state-transition model for a simulated cohort of 10 000 patients with HCV Genotype 1 or 4 with Child B or C cirrhosis. All model parameters regarding the efficacy of therapy, adverse events and the effect of therapy on changes in model for end-stage liver disease (MELD) scores were derived from the SOLAR-1 and 2 trials. The simulations were repeated with 10 000 samples from the parameter distributions. The primary outcome was cost (2014 US dollars) per quality adjusted life year. RESULTS: Treatment before LT yielded more quality-adjusted life year for less money than treatment after LT or nontreatment. Treatment before LT was cost-effective in 100% of samples at a willingness-to-pay threshold of US $100 000 in the base-case and when the analysis was restricted to Child B alone, Child C, or MELD > 15. Treatment before transplant was not cost-effective when MELD was 6-10. In sensitivity analyses, the MELD after which treatment before transplant was cost-effective was 13 and the maximum cost of LDV/SOF therapy at which treatment before LT is cost-effective is US $177 381. CONCLUSIONS: From a societal perspective, HCV therapy using LDV/SOF with ribavirin before LT is the most cost-effective strategy for patients with decompensated cirrhosis and MELD score greater than 13.

Real-world medical costs of antiviral therapy among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Very potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)-based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis. METHODS: This retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) treated with IFN-based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate. RESULTS: In total, 672 interferon-based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323-€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244-€41 892). The costs per SVR were €26 105 (95% CI, €23 068-€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151-€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463-€103 541) among those patients with a platelet count below 100 * 109 /L. CONCLUSIONS: Because of the lower SVR rates, the cost per SVR of IFN-based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN-free therapy could be limited among these patients.

Treatment allocation in hepatocellular carcinoma: Assessment of the BCLC algorithm.

BACKGROUND AND AIMS: The Barcelona Clinic Liver Cancer (BCLC) staging system is the algorithm most widely used to manage patients with hepatocellular carcinoma (HCC). We aimed to investigate the extent to which the BCLC recommendations effectively guide clinical practice and assess the reasons for any deviation from the recommendations. MATERIAL AND METHODS: The first-line treatments assigned to patients included in the prospective Bern HCC cohort were analyzed. RESULTS: Among 223 patients included in the cohort, 116 were not treated according to the BCLC algorithm. Eighty percent of the patients in BCLC stage 0 (very early HCC) and 60% of the patients in BCLC stage A (early HCC) received recommended curative treatment. Only 29% of the BCLC stage B patients (intermediate HCC) and 33% of the BCLC stage C patients (advanced HCC) were treated according to the algorithm. Eighty-nine percent of the BCLC stage D patients (terminal HCC) were treated with best supportive care, as recommended. In 98 patients (44%) the performance status was disregarded in the stage assignment. CONCLUSION: The management of HCC in clinical practice frequently deviates from the BCLC recommendations. Most of the curative therapy options, which have well-defined selection criteria, were allocated according to the recommendations, while the majority of the palliative therapy options were assigned to patients with tumor stages not aligned with the recommendations. The only parameter which is subjective in the algorithm, the performance status, is also the least respected.

Assessment of the Hong Kong Liver Cancer Staging System in Europe.

BACKGROUND & AIMS: European and American guidelines have endorsed the Barcelona Clinic Liver Cancer (BCLC) staging system. The aim of this study was to assess the performance of the recently developed Hong Kong Liver Cancer (HKLC) classification as a staging system for hepatocellular carcinoma (HCC) in Europe. METHODS: We used a pooled set of 1693 HCC patients combining three prospective European cohorts. Discrimination ability between the nine substages and five stages of the HKLC classification system was assessed. To evaluate the predictive power of the HKLC and BCLC staging systems on overall survival, Nagelkerke pseudo R2, Bayesian Information Criterion and Harrell's concordance index were calculated. The number of patients who would benefit from a curative therapy was assessed for both staging systems. RESULTS: The HKLC classification in nine substages shows suboptimal discrimination between the staging groups. The classification in five stages shows better discrimination between groups. However, the BCLC classification performs better than the HKLC classification in the ability to predict overall survival (OS). The HKLC treatment algorithm tags significantly more patients to curative therapy than the BCLC. CONCLUSIONS: The BCLC staging system performs better for European patients than the HKLC staging system in predicting OS. Twice more patients are eligible for a curative therapy with the HKLC algorithm; whether this translates in survival benefit remains to be investigated.

Erlotinib and sorafenib in an orthotopic rat model of hepatocellular carcinoma.

BACKGROUND & AIMS: The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. METHODS: The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 µM) and erlotinib (1-5 µM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. RESULTS: In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 µM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. CONCLUSIONS: Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.

[Liver transplantation - when and for whom it should be performed]. / Der leberkranke Patient - wann und bei wem eine Lebertransplantation?

During the past two decades, orthotopic liver transplantation (OLT) emerged to the treatment of choice for patients with end-stage liver disease. In Switzerland, about 100 liver transplantations are performed every year, while the shortage of cadaveric organs considerably outmatches the demand. Common indications for OLT include cirrhosis due to alcoholic liver disease or chronic viral hepatitis related to hepatitis B or C, and hepatocellular carcinoma. With the advent of the new allocation policy in Switzerland in 2007, patients listed for OLT are mainly stratified based on the Model of End-stage Liver Disease (MELD) score. Using a patient's laboratory values for serum bilirubin, serum creatinin, and the international normalized ratio for prothrombin time (INR), the MELD score accurately predicts three-month mortality among patients on the waiting list. Compared to the pre-MELD era, patients with significantly higher MELD scores undergo transplantation which leads in turn to more complications and higher costs yet with a comparable outcome. Timely referral of potential candidates to a transplant center is crucial since thorough evaluation to rule out contraindications such as uncontrolled infection, extrahepatic malignancy or advanced cardiopulmonary disease is essential. Taken together, every patient presenting with acute liver failure, decompensated cirrhosis or suspected hepatocellular carcinoma should be evaluated in a center with liver transplantation capability.

Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial.

Recent controlled trials on the efficacy of an amantadine/interferon combination in treatment-naive patients with chronic hepatitis C yielded contradictory results. We therefore conducted a large, double-blind, placebo-controlled, multicenter trial in naive patients with chronic hepatitis C: 246 patients were randomized to receive interferon alfa-2a (6 MIU sc thrice weekly for 20 weeks, then 3 MIU sc thrice weekly) and either amantadine sulphate (2 x 100 mg p.o. QD) or placebo. Treatment continued for a total of 52 weeks, if HCV-RNA in serum polymerase chain reaction (PCR) had fallen below detection limit (1,000 copies/mL) at treatment week 10, and stopped otherwise. All patients were followed for 24 weeks off therapy. After 10 weeks of treatment, 66/121 patients treated with amantadine (55%) and 78/125 treated with placebo (62%) had lost HCV-RNA (n.s.). After 24 weeks of follow-up, 25 patients in the amantadine (21%) and 17 (14%) in the placebo group remained HCV-RNA negative (n.s.). During therapy, virologic breakthroughs occurred less often in the amantadine than in the placebo group [14 (12%) vs. 27 (22%) patients; P =.04]. Multivariate logistic regression analysis revealed genotype, viremia level, age, and amantadine therapy [risk ratio 0.4 (95%CI 0.2-1.0), P =.05] as predictors of sustained virologic response. Adverse events and impact of therapy on quality of life were similar in amantadine and placebo treated patients. Compared with current standard treatment (interferon/ribavirin), the interferon/amantadine combination was not cost-effective. In conclusion, amantadine does not add to a clinically relevant extent to the treatment of naive patients with chronic hepatitis C.