Reduction Of Liver-related Mortality Research Articles

Screening for liver fibrosis: lessons from colorectal and lung cancer screening.

Many countries have incorporated population screening programmes for cancer, such as colorectal and lung cancer, into their health-care systems. Cirrhosis is more prevalent than colorectal cancer and has a comparable age-standardized mortality rate to lung cancer. Despite this fact, there are no screening programmes in place for early detection of liver fibrosis, the precursor of cirrhosis. In this Perspective, we use insights from colorectal and lung cancer screening to explore the benefits, challenges, implementation strategies and pathways for future liver fibrosis screening initiatives. Several non-invasive methods and referral pathways for early identification of liver fibrosis exist, but in addition to accurate detection, screening programmes must also be cost-effective and demonstrate benefit through a reduction in liver-related mortality. Randomized controlled trials are needed to confirm this. Future randomized screening trials should evaluate not only the screening tests, but also interventions used to halt disease progression in individuals identified through screening.

Hepatic recompensation according to Baveno VII criteria is linked to a significant survival benefit in decompensated alcohol-related cirrhosis.

Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the subsequent survival in patients with decompensated alcohol-related cirrhosis. The rate of recompensation was evaluated in patients with decompensated alcohol-related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function. Two hundred and four abstinent patients with decompensated alcohol-related cirrhosis (age: 57.2 [IQR:50.1-63.7] years; 75.0% male; median MELD: 15 [IQR:11-19]) and a median HVPG of 20 (IQR:18-24) mmHg were included. During a median follow-up of 24.4 (IQR:10.9-50.4) months, 37 patients (18.1%) achieved abstinence-induced recompensation. Lower baseline HVPG, lower Child-Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver-related mortality (adjusted HR: 0.091 [95% CI: 0.012-0.677]; p = .019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 [95% CI: 0.084-1.878]; p = .245), yet this finding did not reach statistical significance and requires further investigation. Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG-characterised patients with decompensated alcohol-related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver-related mortality.

Anticoagulation improves survival in patients with cirrhosis and portal vein thrombosis: The IMPORTAL competing-risk meta-analysis

Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome - the effect of anticoagulation on all-cause mortality - was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization. Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49-0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22-5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group. Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding. CRD42020140026. Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation.

100–100–100: a new, ambitious treatment target to end the HIV and hepatitis C epidemics

In 2014, UNAIDS put forth an ambitious target known as 90–90–90, the aims of which included that, by 2020, 90% of all people living with HIV should know their HIV status, 90% of all people with diagnosed HIV should be receiving sustained ART, and 90% of all people receiving ART should have viral suppression.1 In 2016, WHO proposed a global target for the elimination of hepatitis C virus (HCV) by 2030, which included the aims for 80% of eligible people with HCV to be treated, a 90% reduction in incident infections, and a 65% reduction in liver-related mortality.

Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications.

Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia’s progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.

From the Editor’s Desk…

From the Editor’s Desk…

Estimates of people who injected drugs within the last 12 months in Belgium based on a capture-recapture and multiplier method

BackgroundFor Belgium, available estimates of the number of people who inject drugs (PWID) are based on data from more than fifteen years ago and apply only to those who report ever injecting drugs. As a result, no reliable baseline data exist to determine the scale of services for PWID. MethodsWe obtained pseudo-anonymized identifier information from treatment and harm reduction service providers and a fieldwork study between February and April 2019 in Brussels. We estimated the number of PWID, defined as people who injected within the last 12 months, in Brussels using capture-recapture (CRC) methodology. To obtain national estimates, we scaled the proportion of PWID in Brussels to the total number of this population in Belgium based on two existing drug treatment registers, which were then multiplied with the result of the CRC. ResultsThe total population of PWID is estimated to be 703 (95 %CI 538–935) for Brussels and between 6620 (95 %CI 4711 – 8576) and 7018 (95 %CI 4794 – 9527) for Belgium. ConclusionsThese estimates provide crucial information to ensure that services to PWID are adequately maintained. They clearly indicate the need to maximize efforts to achieve the targets set by WHO for 2030 on the provision of 300 sterile needles and syringes per PWID per year, a 90 % reduction of new HCV infections, and a 65 % reduction of liver-related mortality.

From the Editor's Desk…

From the Editor's Desk…

Addition of adjuvant hepatic artery infusion to systemic chemotherapy following resection of colorectal liver metastases is associated with reduced liver-related mortality.

After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS). This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared to adjuvant SYS alone. Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI + SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risk methods. Of 361 eligible patients, 208 (57.6%) received HAI + SYS and 153 (42.4%) received SYS. The median follow up among survivors was 142 months (range = 12-217 months). Ten-year overall survival was 50.6% in the HAI + SYS group compared to 30.9% in those receiving SYS (P = .004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI + SYS group compared to 14.3% in the SYS group (P = .007). The addition of HAI to SYS after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.

Treatment of HCV reduces viral hepatitis-associated liver-related mortality in patients: An ERCHIVES study

Treating HCV infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications is unknown. We identified HCV-positive individuals treated for HCV, and propensity score-matched them to HCV-positive/untreated and HCV-uninfected individuals in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis-associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR). Among 50,674 HCV-positive/treated (Group A), 31,749 HCV-positive/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis-associated liver-related mortality rates per 100 patient-years (95% CI) were: 0.28 (0.27-0.30) for Group A; 1.44 (1.38-1.49) for Group B; and 0.06 (0.05-0.06) for Group C; (p <0.0001 for both comparisons). Among HCV-positive/treated persons, rates were 0.06 (0.05-0.06) for those with SVR vs. 0.78 (0.74-0.83) for those without SVR. In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11; 95% CI 0.09-0.14) and SVR (adjusted hazard ratio 0.10; 95% CI 0.08-0.11) were associated with reduced hazards of liver-related mortality. Treatment for HCV is associated with a significant reduction in viral hepatitis-associated liver-related mortality, which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of the reduction in all-cause mortality reported in previous studies. Treating hepatitis C virus (HCV) infection is known to reduce overall mortality. However, whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications was previously unknown. Herein, we show that while treating HCV with direct-acting antiviral regimens has numerous extrahepatic benefits, a significant benefit can be attributed specifically to the reduction in liver-related mortality.

2896. Reduction in Liver-related Mortality Among HCV Infected Persons Is Driven by Attainment of SVR Independent of the Regimen Used: Results from the ERCHIVES Cohort

BackgroundBeneficial effect of hepatitis C virus (HCV) treatment with directly acting antiviral agents (DAAs) upon overall mortality is well-established. However, the effect of treatment upon liver-related mortality is not well documented.MethodsWe used ERCHIVES database to identify all chronic HCV-infected persons between January 1, 2002 and December 31, 2016. We excluded those with HIV or HBV coinfection or hepatocellular carcinoma. HCV treatment status was defined as prescription of pegylated interferon (PEG)/ribavirin (RBV) for >24 weeks, PEG/RBV plus boceprevir or telaprevir, or a newer DAA regimen for >8 weeks. Propensity score-matched untreated controls were identified for each treated person. We linked HCV+ cases to the National Death Index (NDI) data updated to the end of 2016. Cause of death was retrieved from the underlying cause listed on the death certificate by using ICD‐10 codes. The listed primary cause was assigned as the cause of death. Each cause of death was categorized as “Liver related” or “Not liver related” by two physician members of the study team. Liver-related causes included viral hepatitis-related causes, complications of liver disease, and hepatocellular carcinoma, but excluded any cause where alcohol or any other known liver disease other than viral hepatitis was specified. Discordant results were adjudicated by a third physician member.ResultsAmong 34,412 treated and 21,287 untreated controls, there were 13,098 deaths, of which 2,474 (18.9%) were liver related. Overall liver-related mortality rate per 100 person-years of follow-up was 0.64 in the treated and 1.24 in the untreated group (P). Among the treated group, the liver-related mortality rate per 100 person-years was 0.14 for those who achieved SVR and 1.26 among those who did not achieve SVR. When stratified by treatment regimen, those treated with PG/RBV had a mortality rate of 0.73 vs. 0.24 for those treated with a DAA regimen. However, further stratification by attainment of SVR revealed that the difference between regimens was almost entirely driven by the difference in SVR rates (see table).ConclusionHCV-infected persons who receive treatment have a substantial reduction in liver-related mortality. This reduction is largely driven by attainment of SVR and is independent of the regimen use when stratified by SVR attainment. Disclosures All Authors: No reported Disclosures.

Australia on Track to Achieve Who HCV Elimination Targets Following Rapid Initial DAA Treatment Uptake: A Modelling Study

Background: Subsidized direct-acting antiviral (DAA) treatment recently became available to all adults living with chronic hepatitis C (HCV) in Australia. An estimated 32,600 people initiated DAA HCV treatment in 2016, an increase from 3,750 (IFN-based) in 2014. Based on this rapid uptake we estimated the impact on HCV epidemiology and mortality in Australia and determined if Australia can meet the WHO HCV elimination targets by 2030. Methods: Used a previously developed mathematical model, we simulated pessimistic, intermediate and optimistic DAA treatment scenarios in Australia over 2016-2030. We assumed treatment and testing rates were initially higher for advanced fibrosis and the same across HCV transmission risk level sub-populations. We compared the results to the 2015 level and a counterfactual (IFN-based) scenario. After 2016, we assumed testing rates and current harm reduction programs remained in place to focus on the impact of DAA treatment uptake. Findings: During 2016-2030, we estimated an intermediate DAA treatment scenario (2016, 32,600 treated; 2017, 21,370 treated; 2018,17,100 treated; 2019 and beyond, 13,680 treated each year) would avert 40,420 new HCV infections, 13,260 liver-related deaths (15,320 in viraemic; -2,060 in cured), and 10,730 HCC cases, equating to a 53%, 63% and 75% reduction respectively, compared to the IFN-based scenario. The model also estimated that Australia will meet the WHO targets of 80% reduction in HCV incidence by 2026 and 80% of eligible people treated by 2028. Time to a 65% reduction in liver-related mortality varied considerably between HCV viraemic only cases (2026) and all cases (2047). Interpretation: Based on a feasible DAA treatment scenario incorporating declining uptake, Australia should meet key WHO HCV elimination targets in 10 to15 years. Despite a reduction in liver-related mortality risk among those who are cured, the pre-DAA escalation in those with advanced liver disease makes the achievement of the liver-related mortality target difficult. Funding: NSW Health, as part of the BBV & STI Research, Intervention and Strategic Evaluation Program (BRISE), and the Australian Government. Declaration of interests: GJD is an advisory board member and receives honorarium from Gilead, Merck, Abbvie, Bristol-Myers Squibb, has received research grant funding from Gilead, Merck, Abbvie, Bristol-Myers Squibb, and travel sponsorship from Gilead, Merck, Abbvie, and Bristol-Myers Squibb. JG is a consultant/advisor and has received research grants from Abbvie, Cepheid, Gilead, Janssen, and Merck. CE and HR have received research grants from the John C Martin Foundation, Gilead Sciences, AbbVie, and WHO. RTG and JAK have provided project advice for Gilead.

Australia on track to achieve WHO HCV elimination targets following rapid initial DAA treatment uptake: A modelling study.

Subsidized direct-acting antiviral (DAA) treatment recently became available to all adults living with chronic hepatitis C virus (HCV) in Australia. Based on rapid uptake (32600 people initiated DAA in 2016), we estimated the impact on HCV epidemiology and mortality in Australia and determined if Australia can meet the WHO HCV elimination targets by 2030. Using a mathematical model, we simulated pessimistic, intermediate and optimistic DAA treatment scenarios in Australia over 2016-2030. We assumed treatment and testing rates were initially higher for advanced fibrosis and the same across HCV transmission risk level sub-populations. We also assumed constant testing rates after 2016. We compared the results to the 2015 level and a counterfactual (IFN-based) scenario. During 2016-2030, we estimated an intermediate DAA treatment scenario (2016, 32600 treated; 2017, 21370 treated; 201817100 treated; 2019 and beyond, 13680 treated each year) would avert 40420 new HCV infections, 13260 liver-related deaths (15320 in viraemic; -2060 in cured) and 10730 HCC cases, equating to a 53%, 63% and 75% reduction, respectively, compared to the IFN-based scenario. The model also estimated that Australia will meet the WHO targets of incidence and treatment by 2028. Time to a 65% reduction in liver-related mortality varied considerably between HCV viraemic only cases (2026) and all cases (2047). Based on a feasible DAA treatment scenario incorporating declining uptake, Australia should meet key WHO HCV elimination targets in 10 to15years. The pre-DAA escalation in those with advanced liver disease makes the achievement of the liver-related mortality target difficult.

Treatment of chronic hepatitis C in patients with cirrhosis.

This article reviews treatment options of the approved and soon-to-be approved direct-acting antivirals (DAA)-based therapies in individuals with hepatitis C virus (HCV) cirrhosis. DAA-based therapies have been shown to be well tolerated and effective in achieving viral cure in individuals with compensated and decompensated cirrhosis. Preliminary studies suggest that viral eradication arrests fibrosis progression and could lead to fibrosis regression. Long-term benefits of successful HCV treatment in this population translate into less frequent hepatic decompensation and hepatocellular carcinoma development, improvements in liver disease severity, reduction of liver-related mortality, and potential obviation of the need for transplantation. The optimization of viral eradication rates requires longer duration therapy and/or more complex combinations of drugs, including ribavirin. Treatment decisions are guided by HCV genotype, renal function, drug-drug interactions, and the severity of cirrhosis. Safety concerns are paramount in individuals with advanced liver disease and continued vigilance for hepatotoxicity and other complications is warranted, especially in those with decompensated cirrhosis. The availability of high potency DAA-based therapies with excellent safety profiles has transformed the HCV-infected cirrhotic population into a group that is no longer 'difficult-to-treat'. Understanding the pretreatment factors that predict clinical benefits vs. harm remains key in treating this population.

P68 PACIFIC: a phase III, randomised, multicentre, dose escalation, efficacy and safety study examining the effects of treatment with peginterferon alfa-2a in patients with Child's A or B cirrhosis in chronic hepatitis C virus infection

IntroductionTrials have found conflicting results about the efficacy of pegylated interferon α (PIFN), with or without pretreatment including ribavirin, as an antifibrotic agent in patients with established cirrhosis due to...

Highly active antiretroviral therapy in HIV and hepatitis C coinfected individuals: friend or foe?

Highly active antiretroviral therapy dramatically reduces HIV-related morbidity and mortality. Liver disease has subsequently emerged as a major cause of death in HIV/hepatitis C virus-coinfected individuals. Whether HIV therapy also has a favourable impact on the course of liver disease needs to be explored and counterbalanced with toxicity issues related to the extended duration of antiretroviral therapy. Recent cohort studies have shown that highly active antiretroviral therapy is associated with a reduced rate of progression of hepatitis C virus liver disease, with some also showing a reduction in liver-related mortality. Increased mortality from liver disease has been linked with the extended duration of antiretroviral therapy. Highly antiretroviral therapy-associated liver steatosis has been described as an emerging cause of liver cirrhosis. New possibly HIV therapy-related adverse events such as hepatoportal sclerosis have been reported. Studies evaluating the impact of the early initiation of highly active antiretroviral therapy on liver disease in coinfected patients are urgently needed. The safety profile of currently available antiretroviral agents with regard to liver toxicity needs to be further elucidated in order to be able to recommend earlier HIV treatment in this particular patient population.

Early Initiation of Antiretroviral Therapy

Approximately 25% to 35% of HIV-infected persons in developed countries are coinfected with hepatitis C virus (HCV). HCV liver disease is accelerated by HIV coinfection, especially at low CD4 cell counts. Highly active antiretroviral therapy (HAART) dramatically reduces HIV-related mortality, and liver disease has emerged as a major cause of death in HIV/HCV-coinfected persons. Anti-HCV therapy with pegylated interferon plus ribavirin can cure HCV infection in up to 40% of coinfected patients; however, only approximately 10% of coinfected patients are considered candidates. Hence, HCV therapy cures approximately 4% of coinfected patients. Eleven cohort studies have shown that HAART is associated with a reduced rate of progression of HCV liver disease, and 4 of these studies have demonstrated a reduction in liver-related mortality. Although offering HCV therapy to the few eligible HIV/HCV-coinfected patients is important, early initiation of HAART in coinfected patients has a greater public health impact in reducing liver-related mortality than in curing HCV infection in approximately 4% of these patients.

The use of silymarin in the treatment of liver diseases.

The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p < 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.