Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area: What's new 12 months later?

INTRODUCTION AND OBJECTIVES: The lockdown policy introduced in 2020 to minimize the spread of the COVID-19 pandemic, significantly affected the management and care of patients affected by hepatocellular carcinoma (HCC). The aim of this follow-up study was to determine the 12 months impact of the COVID-19 pandemic on the cohort of patients affected by HCC during the lockdown, within six French academic referral centers in the metropolitan area of Paris. MATERIALS AND METHODS: We performed a 12 months follow-up of the cross-sectional study cohort included in 2020 on the management of patients affected by HCC during the first six weeks of the COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Overall survival were compared between the groups. Predictors of mortality were analysed with Cox regression. RESULTS: From the initial cohort, 575 patients were included (n = 263 Exposed_COVID, n = 312 Unexposed_COVID). Overall and disease free survival at 12 months were 59.9 ± 3.2% vs 74.3 ± 2.5% (p<0.001) and 40.2 ± 3.5% vs 63.5 ± 3.1% (p<0.001) according to the period of exposure (Exposed_COVID vs Unexposed_COVID, respectively). Adjusted Cox regression revealed that the period of exposure (Exposed_COVID HR: 1.79, 95%CI (1.36, 2.35) p<0.001) and BCLC stage B, C and D (BCLC B HR: 1.82, 95%CI (1.07, 3.08) p = 0.027 - BCLC C HR: 1.96, 95%CI (1.14, 3.38) p = 0.015 - BCLC D HR: 3.21, 95%CI (1.76, 5.85) p<0.001) were predictors of death. CONCLUSIONS: Disruption of routine healthcare services because of the pandemic translated to reduced 1 year overall and disease-free survival among patients affected by HCC, in the metropolitan area of Paris, France.

Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area.

BACKGROUND & AIMS: Patients affected by hepatocellular carcinoma (HCC) represent a vulnerable population during the COVID-19 pandemic and may suffer from altered allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of patients with HCC within 6 referral centres in the metropolitan area of Paris, France. METHODS: We performed a multicentre, retrospective, cross-sectional study on the management of patients with HCC during the first 6 weeks of the COVID-19 pandemic (exposed group), compared with the same period in 2019 (unexposed group). We included all patients discussed in multidisciplinary tumour board (MTB) meetings and/or patients undergoing a radiological or surgical programmed procedure during the study period, with curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treat. RESULTS: After screening, n = 670 patients were included (n = 293 exposed to COVID, n = 377 unexposed to COVID). Fewer patients with HCC presented to the MTB in 2020 (p = 0.034) and fewer had a first diagnosis of HCC (n = 104 exposed to COVID, n = 143 unexposed to COVID, p = 0.083). Treatment strategy was modified in 13.1% of patients, with no differences between the 2 periods. Nevertheless, 21.5% vs. 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared with 2019 (p <0.001). In 2020, 7.1% (21/293) of patients had a diagnosis of an active COVID-19 infection: 11 (52.4%) patients were hospitalised and 4 (19.1%) patients died. CONCLUSIONS: In a metropolitan area highly impacted by the COVID-19 pandemic, we observed fewer patients with HCC, and similar rates of treatment modification, but with a significantly longer treatment delay in 2020 vs. 2019. LAY SUMMARY: During the coronavirus disease 2019 (COVID-19) pandemic era, fewer patients with hepatocellular carcinoma (HCC) presented to the multidisciplinary tumour board, especially with a first diagnosis of HCC. Patients with HCC had a treatment delay that was longer in the COVID-19 period than in 2019.

Assessing the cost-effectiveness of hepatitis C screening strategies in France.

BACKGROUND & AIMS: In Europe, hepatitis C virus (HCV) screening still targets people at high risk of infection. We aim to determine the cost-effectiveness of expanded HCV screening in France. METHODS: A Markov model simulated chronic hepatitis C (CHC) prevalence, incidence of events, quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER) in the French general population, aged 18 to 80 years, undiagnosed for CHC for different strategies: S1 = current strategy targeting the at risk population; S2 = S1 and all men between 18 and 59 years; S3 = S1 and all individuals between 40 and 59 years; S4 = S1 and all individuals between 40 and 80 years; S5 = all individuals between 18 and 80 years (universal screening). Once CHC was diagnosed, treatment was initiated either to patients with fibrosis stage ≥F2 or regardless of fibrosis. Data were extracted from published literature, a national prevalence survey, and a previously published mathematical model. ICER were interpreted based on one or three times French GDP per capita (€32,800). RESULTS: Universal screening led to the lowest prevalence of CHC and incidence of events, regardless of treatment initiation. When considering treatment initiation to patients with fibrosis ≥F2, targeting all people aged 40-80 was the only cost-effective strategy at both thresholds (€26,100/QALY). When we considered treatment for all, although universal screening of all individuals aged 18-80 is associated with the highest costs, it is more effective than targeting all people aged 40-80, and cost-effective at both thresholds (€31,100/QALY). CONCLUSIONS: In France, universal screening is the most effective screening strategy for HCV. Universal screening is cost-effective when treatment is initiated regardless of fibrosis stage. From an individual and especially from a societal perspective of HCV eradication, this strategy should be implemented. LAY SUMMARY: In the context of highly effective and well tolerated therapies for hepatitis C virus that are now recommended for all patients, a reassessment of hepatitis C screening strategies is needed. An effectiveness and cost-effectiveness study of different strategies targeting either the at-risk population, specific ages or all individuals was performed. In France, universal screening is the most effective strategy and is cost-effective when treatment is initiated regardless of fibrosis stage. From an individual and especially from a societal perspective of hepatitis C virus eradication, this strategy should be implemented.

Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141).

BACKGROUND & AIMS: In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). METHODS: A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. RESULTS: Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. CONCLUSIONS: Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Long-term effects of an educational seminar on antibiotic prescribing by GPs: a randomised controlled trial.

BACKGROUND: High levels of outpatient antibiotic use remain observed in many European countries. Several studies have shown a strong relationship between antibiotic use and bacterial resistance. AIM: To assess the long-term effect of a standardised educational seminar on antibiotic prescriptions by GPs. DESIGN AND SETTING: Randomised controlled trial of 171 GPs (of 203 initially randomised) in France. METHOD: GPs in the control group (n = 99) received no antibiotic prescription recommendation. Intervention group GPs (n = 72) attended an interactive seminar presenting evidence-based guidelines on antibiotic prescription for respiratory infections. The proportion of prescriptions containing an antibiotic in each group and related costs were compared to the baseline up to 30 months following the intervention. Data were obtained from the National Health Insurance System database. RESULTS: In the intervention group, 4-6 months after the intervention, there was a significant decrease in the proportion of prescriptions containing an antibiotic from 15.2 ± 5.4% to 12.3 ± 5.8% (-2.8% [95% CI = -3.8 to -1.9], P<0.001). By contrast, an increase was observed in controls from 15.3 ± 6.0 to 16.4 ± 6.7% (+1.1% [95% CI = +0.4 to +1.8], P<0.01), resulting in a between-group difference of 3.93% ([95% CI = 2.75 to 5.11], P<0.001). The between-group difference was maintained 30 months after intervention (1.99% [95% CI = 0.56 to 3.42], P<0.01). Persistence of the intervention effect over the entire study period was confirmed in a hierarchical multivariate analysis. CONCLUSION: This randomised trial shows that a standardised and interactive educational seminar results in a long-term reduction in antibiotic prescribing and could justify a large-scale implementation of this intervention.

The burden of liver disease in Europe: a review of available epidemiological data.

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

Non-invasive assessment of liver graft fibrosis by transient elastography after liver transplantation.

BACKGROUND: Liver stiffness measurement (LSM) by transient elastography (TE) (FibroScan) is a validated method of quantifying liver fibrosis in non-transplanted patients with hepatitis C virus (HCV). It could be useful in follow-up after liver transplantation (LT). The aim of this study was to assess the diagnostic accuracy of LSM in evaluating liver fibrosis after LT in patients with and without recurrent HCV. PATIENTS AND METHODS: Forty-three patients (mean age 57.6 ± 9.9 years), 28 (65.1%) HCV-positive patients and 15 (34.9%) HCV-negative patients underwent gold standard liver biopsy and TE 55.8 ± 4.9 months after transplantation. Liver fibrosis was scored on biopsy specimens according to METAVIR (F0-F4). Accuracy of TE and optimal stiffness cut-off values for fibrosis staging were determined by a receiver-operating characteristics (ROC) curve analysis. RESULTS: Median stiffness values were significantly different for METAVIR score less than 2 (5.8 kPa) vs. METAVIR score greater to equal to 2 (9.6 kPa) (P<0.001). The area under the ROC curve was 0.83 for METAVIR score greater to equal to 2 (95%CI: 0.71-0.95). The optimal stiffness cut-off value was 7 kPa for METAVIR scores greater to equal to 2. The results were similar whether the patients had recurrent HCV infection or not. CONCLUSIONS: These results indicate that transient elastography accurately identifies LT recipients with significant fibrosis, irrespective of HCV status. It is a promising non-invasive tool to assess graft fibrosis progression after LT in patients with HCV recurrence, as well as for screening of late graft fibrosis of other etiologies. Transient elastography could reduce the use of invasive protocol biopsies.

Impact of hepatitis C triple therapy availability upon the number of patients to be treated and associated costs in France: a model-based analysis.

OBJECTIVE: The combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor (PI) has been approved in summer 2011 for the treatment of genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially improved efficacy. The aim of this study was to estimate the number of G1 patients to be treated in France in 2012 and associated costs. METHODS: A published model of HCV and data on PEG-IFN sales were used to estimate patients needing treatment using three scenarios. (1) HCV screening rate unchanged versus 2010; proportion of treated F0-F1 patients unchanged, proportion of treated F2-F4 patients increased to the current proportion of treated F2-F4 G2/3 patients. (2) Scenario 1 but the proportion of treated F0-F1 patients increased to the current proportion of treated F0-F1 G2/3 patients. (3) Scenario 2 but a 5% increase in the HCV screening rate. To estimate cost, treatment duration was multiplied by drug unit cost. Probabilities corresponding to treatment duration were estimated based on liver fibrosis stage, treatment-naive or experienced status of the patient and virological response kinetics on treatment. RESULTS: Compared with the 5100 G1 patients treated in 2010, the number of G1 patients receiving treatment in 2012 would be 15,000 in scenario 1, 18,300 in scenario 2 and 19,400 in scenario 3, among whom 2.5-3.7% may receive PEG-IFN/RBV and 96.3-97.5% PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638 million Euros. CONCLUSION: These model-based estimates indicate that new anti-HCV treatments may result in a three- to fourfold increase in the number of G1 patients to be treated in France in 2012.

A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults.

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting.

HEPACOM: multicenter, observational prospective study of outcome and monitoring of HCV positive antiviral-naïve patients managed in the French health care system.

OBJECTIVE: To study management practices in the French health care system for antiviral-naïve patients with chronic hepatitis C virus (HCV) infection. METHODS AND PATIENTS: Two groups of general practitioners, group I (special training and experience in drug addiction) and group II (other general practitioners) enrolled untreated HCV positive patients and noted management practices for a 12-month period. RESULTS: Among 4660 enrolled patients, 2038 enrolled by 462 general practitioners in group I and 1756 enrolled by 588 general practitioners in group II were retained for analysis. These patients were adults, aged 42+/-14 years, who were naïve to antiviral treatment. The male/female ratio was 1: 7. Ten percent were coinfected with HIV, 12% had excessive alcohol intake, and 61% were current drug users, 75% of whom (45% of the total population) were taking replacement therapy. Minimal hepatic lesions (stageor=F2). At the end of the monitoring period, 64% of the patients had been referred to a specialist. Antiviral treatment had been started in 20%, i.e. 32% of the patients who consulted a specialist. Occupational activity (P<0.0001), young age (P=0.007), more recent diagnosis (P<0.0001), lack of HIV co-infection (P=0.015), male gender (P=0.006), lack of replacement treatment (P=0.006), previous liver histology with METAVIR A and F>or=2 (P<0.0001) and enrollment by a group I general practitioner (P<0.007) were the independent predictive factors of initiation of antiviral treatment. CONCLUSION: Only one-third of patients with access to the French health care system started antiviral treatment and some categories of patients, including women, patients co-infected with HIV and patients on replacement therapy, were less likely to be treated than others. The recommendations of the French Consensus Conference, held in the middle of the study period (2002), might have been implemented (probably followed) by a minority of general practitioners.

Predicting the costs of allogeneic sibling stem-cell transplantation: results from a prospective, multicenter, French study.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is a widely used, cost-intensive procedure. Our purpose was to estimate costs and determine cost predictors. METHODS: We used data from a prospective French study comparing four doses of immunoglobulins. Resource use of hematopoietic stem-cell transplant recipients during the first 6 months posttransplant, both inpatient and ambulatory costs, in 85 patients from five centers were collected prospectively and costed. Baseline data and clinical events were retrieved. Protocol-driven costs were excluded. Multivariable analysis evaluated the association between costs and patient's pretransplant status and transplant-related complications. Because of the absence of differences in outcome among the four randomization groups, cost data for all patients were pooled. RESULTS: Total costs per patient were the following: mean 76,237 Euros; standard deviation 32,565 Euros; median 69,516 Euros; range 183,758 to 14,761Euros. The major cost driver was hospital days. No association was found between costs and baseline status. The "predictors" of higher costs (adding an average 20,000 Euros/patient) were the occurrence of transplant-related complications: graft-versus-host disease and repeated infections that were unpredictable before transplant in this homogeneous group of patients. CONCLUSION: Our data highlight the discrepancy between the Diagnosis Related Group prospective payment system and actual costs. The actual cost of geno-identical stem-cell transplantation results from posttransplant complications that cannot be predicted prospectively and require ex post cost adjustment.

Geographic disparities in access to organ transplant in France.

BACKGROUND: Allocation of organs is organized on a regional basis in France. We assessed regional differences in access to organ transplant. MATERIAL AND METHODS: We used the recipient database and the waiting list database from the year 1994 onward. We estimated median waiting time by region and organ. The probability of receiving a transplant was estimated using the Kaplan-Meier method. Between-region comparisons used the log-rank test, with adjustment for blood type and disease category. RESULTS: At the end of a 4-month follow-up period, 49% of 3,553 patients had received transplants: 64% of 797 benefited from liver transplants, 52% of 549 from heart transplants, and 22% of 2,207 from kidney transplants. Death rates on the waiting lists were 10%, 14%, and 1% for patients selected for liver, heart, and kidney transplant, respectively. Transplantation percentage (all organs) decreased from 63% in the West to 43% in the Paris region and mortality increased from 2% in the West to 7% in the Southeast. All tests of inter-regional differences were statistically significant. CONCLUSION: Factors explaining geographic differences related to the background of transplant teams, activity of organ procurement, and severity of patients on the list.

The costs of septic syndromes in the intensive care unit and influence of hospital-acquired sepsis.

OBJECTIVE: To document the costs and outcomes of the various forms of the septic syndromes [systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock), particularly those associated with infection acquired in an intensive care unit (ICU). DESIGN: Prospective data collection for all septic patients admitted to a medical ICU during a 1-year period. Costs were computed from the viewpoint of the hospital. RESULTS: Mean total hospital costs were Euro 26,256, Euro 35,185, and Euro 27,083 for patients with sepsis, severe sepsis, and septic shock, respectively. Total costs varied slightly according to the site of infection and the severity of sepsis but were influenced mostly by its mode of acquisition: patients having sepsis associated with ICU-acquired infection incurred total costs about three times those of patients presenting with infection and sepsis on ICU admission (from Euro 39,908 in patients with ICU acquired sepsis to Euro 44,851 in patients with ICU-acquired septic shock). Stratifying patients by the presence of ICU-acquired infection also showed that a first episode of infection complicated by ICU-acquired sepsis incurred at least 2.5 times more costs than a single episode of sepsis. CONCLUSIONS: In this series the medical costs of sepsis were not markedly influenced by its severity but by its mode of acquisition. Due to wide variations in ICU costs cost-effectiveness analyses of treatments for sepsis should document the case-mix of patients and the contribution to this of nosocomial infections.