Is high intake of whole grains associated with lower risk of developing liver cancer?

Media
Whole grains might help ward off liver cancer
Linda Carroll

(Reuters Health) - Yet another benefit of eating a diet containing high amounts of whole grains may be a reduced risk of liver cancer, a new U.S. study suggests. 

“Consumption of whole grains and dietary fiber, especially cereal fiber, have been associated with lower risk of obesity, type 2 diabetes, and nonalcoholic fatty liver disease, which are known predisposing factors for (liver cancer),” Zhang said. “Besides improving insulin sensitivity, metabolic regulation, and decreasing systemic inflammation, intake of whole grains and dietary fiber may improve gut integrity, and alter gut microbiota composition, thereby leading to increased production of microbiota-related metabolites including short-chain fatty acids, particularly butyrate.” 

Read more: https://in.reuters.com/article/us-health-grains-liver-cancer/whole-grains-might-help-ward-off-liver-cancer-idINKCN1QA2BE

Original Investigation 

JAMA Network OpenFebruary 21, 2019
Association of Intake of Whole Grains and Dietary Fiber With Risk of Hepatocellular Carcinoma in US Adults 
Wanshui Yang, PhD1,2; Yanan Ma, PhD2,3; Yue Liu, MD2,4; et al Stephanie A. Smith-Warner, PhD5,6; Tracey G. Simon, MD7,8,9; Dawn Q. Chong, MD10; Qibin Qi, PhD11; Jeffrey A. Meyerhardt, MD, MPH12; Edward L. Giovannucci, MD, ScD2,5,6; Andrew T. Chan, MD, MPH2,8,9; Xuehong Zhang, MD, ScD2 Author Affiliations JAMA Oncol.

Published online February 21, 2019.
doi:10.1001/jamaoncol.2018.7159

Key Points
Question Is high intake of whole grains and dietary fiber associated with lower risk of developing hepatocellular carcinoma (HCC)?

Findings In this cohort study of 125 455 participants in the United States, including 141 patients with HCC, with an average follow-up of 24.2 years, increased intake of whole grains was associated with a reduced risk of HCC. A nonsignificant inverse HCC association was observed for total bran but not for germ; increased intake of cereal fiber but not fruit or vegetable fiber was associated with a nonsignificant lower risk of HCC.

Meaning Increased intake of whole grains and possibly cereal fiber and bran could be associated with reduced risk of HCC among US adults.

Abstract
Importance Increased intake of whole grain and dietary fiber has been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for hepatocellular carcinoma (HCC). Therefore, we hypothesized that long-term intake of whole grains and dietary fiber may be associated with lower risk of HCC.

Objective To assess the associations of whole grain and dietary fiber intake with the risk of HCC.

Design, Setting, and Participants Cohort study of the intake of whole grains, their subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) in 125 455 participants from 2 cohorts from the Nurses’ Health Study and the Health Professionals Follow-up Study.

Exposures Intake of whole grains, their subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) were collected and updated almost every 4 years using validated food frequency questionnaires.

Main Outcomes and Measures Multivariable hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression model after adjusting for most known HCC risk factors.

Results After an average follow-up of 24.2 years, we identified 141 patients with HCC among 125 455 participants (77 241 women and 48 214 men (mean [SD] age, 63.4 [10.7] years). Increased whole grain intake was significantly associated with lower risk of HCC (the highest vs lowest tertile intake: HR, 0.63; 95% CI, 0.41-0.96; P = .04 for trend). A nonsignificant inverse HCC association was observed for total bran (HR, 0.70; 95% CI, 0.46-1.07; P = .11 for trend), but not for germ. Increased intake of cereal fiber (HR, 0.68; 95% CI, 0.45-1.03; P = .07 for trend), but not fruit or vegetable fiber, was associated with a nonsignificant reduced risk of HCC.

Conclusions and Relevance Increased intake of whole grains and possibly cereal fiber and bran could be associated with reduced risk of HCC among adults in the United States. Future studies that carefully consider hepatitis B and C virus infections are needed to replicate our findings, to examine these associations in other racial/ethnic or high-risk populations, and to elucidate the underlying mechanisms.
https://jamanetwork.com/journals/jamanetworkopen

Nine-year distribution pattern of hepatitis C virus (HCV) genotypes in Southern Italy

Nine-year distribution pattern of hepatitis C virus (HCV) genotypes in Southern Italy
Arnolfo Petruzziello , Rocco Sabatino, Giovanna Loquercio, Annunziata Guzzo, Lucia Di Capua, Francesco Labonia, Anna Cozzolino, Rosa Azzaro, Gerardo Botti
Published: February 20, 2019
https://doi.org/10.1371/journal.pone.0212033

Full-text available online

Download PDF 

In conclusion, the epidemiological framework of Hepatitis C infection in Southern Italy, particularly interesting for the high prevalence of this virus in the general population, seems to highlight the "returning" role of the iatrogenic transmission as risk factor for the diffusion of HCV infection. Furthermore, the small increase of genotype 3a among young people should be more investigated, with a support of a phylogenetic analysis. At support of our hypothesis, some studies report small HCV outbreaks in Europe due to breaches in standards of health and safety practices among health-care workers [56]. Indeed, an interesting case–control study highlighted some unconventional routes of diffusion of Hepatitis C infection such as digestive endoscopy, beauty treatments and professional pedicure/manicure [57]. This suggest not only a necessary evaluation of the safety practices in surgery, but the fundamental importance of not lowering the safety levels, especially among all health-care professionals.

Abstract
Introduction
It has been greatly described that different hepatitis C virus (HCV) genotypes are strictly correlated to various evolution, prognosis and response to therapy during the chronic liver disease. Aim of this study was to outline the changes in the epidemiology of Hepatitis C genotypes in Southern Italy regions from 2006 to 2014.

Material/Methods
Prevalence of HCV genotypes was analyzed in 535 HCV-RNA positive patients with chronic Hepatitis C infection, selected during the period 2012–2014, and compared with our previous data, referred to periods 2006–2008 and 2009–2011.

Results
In all the three periods analyzed, genotype 1b is predominant (51.8% in 2006–08, 48.3% in 2009–11 and 54.4% in 2012–14) while genotype 2 showed an increase in prevalence (27.9% in 2006–08, 31.7% in 2009–11 and 35.2% in 2012–14) and genotypes 3a and 1a a decrease during the same period (6.8% in 2006–08, 4.7% in 2009–11 and 3.2% in 2012–14 and 7.9% in 2006–08, 4.7% in 2009–11 and 2.6% in 2012–14, respectively). Subtype 1b seems to be equally distributed between males and females (52.7% vs 56.6%) and the prevalence in the age range 31–40 years is significantly higher in the 2012–14 period than in both previous periods (53.8% vs. 16.6% in 2009–11, p< 0.001 and 13.4% in 2006–08, p < 0.001).

Conclusions
Genotype 1b is still the most prevalent, even if shows a significantly increase in the under 40 years old population. Instead, genotype 3a seems to have a moderate increase among young people. Overall, the alarming finding is the “returning” role of the iatrogenic transmission as risk factor for the diffusion of Hepatitis C infection.

Intercept - Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

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NASH update: 5 reports on trials, meetings, upcoming collaborations

February 19, 2019

The beginning of 2019 has already seen several significant advancements for the field of nonalcoholic steatohepatitis, from the inaugural NASH-TAG meeting to the recently announced positive results from the phase 3 study of Ocaliva.

Healio Gastroenterology and Liver Disease presents the following reports including trial results for Ocaliva (obeticholic acid, Intercept Pharma), a take-home report from NASH-TAG, and an update for this year’s International NASH Day.

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY

NASH: Fastest-growing cause of liver cancer in transplant candidates

February 5, 2019

Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study

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Press Release

Intercept Announces Positive Topline Results from Pivotal Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

First and largest successful pivotal Phase 3 study in patients with liver fibrosis due to NASH

OCA achieves primary endpoint demonstrating statistically significant improvement in liver fibrosis without worsening of NASH at 18 months (p=0.0002)

Intercept intends to file for regulatory approval in the U.S. and Europe in the second half of 2019

Results to be presented at European Association for the Study of the Liver 2019 International Liver Congress

The International Liver CongressTM
Every year in April, scientific and medical experts from a broad range of fields including hepatology, gastroenterology, internal medicine, cell biology, transplant surgery, infectious diseases, microbiology and virology, pharmacology, pathology and radiology and imaging come together from around the world to learn about the latest in liver research. Specialists share recent data, present studies and findings, and discuss the hottest topics on liver disease. The annual Congress attracts around 10,000 delegates and 250 media representatives from all over the world making this a truly international networking opportunity!

The International Liver CongressTM 2019 #ILC2019 will take place 10-14 April 2019 at the Reed Messe Wien Exhibition & Congress Center, Vienna, Austria.

Intercept Press Release
NEW YORK, Feb. 19, 2019 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, today announced positive results from its pivotal Phase 3 REGENERATE study of obeticholic acid (OCA) in patients with liver fibrosis due to nonalcoholic steatohepatitis (NASH). In the primary efficacy analysis, once-daily OCA 25 mg met the primary endpoint of fibrosis improvement (≥1 stage) with no worsening of NASH at the planned 18-month interim analysis (p=0.0002 vs. placebo). In the primary efficacy analysis, a numerically greater proportion of patients in both OCA treatment arms compared to placebo achieved the primary endpoint of NASH resolution with no worsening of liver fibrosis, but this did not reach statistical significance. As agreed with the U.S. Food and Drug Administration (FDA), in order for the primary objective to be met, the study was required to achieve one of the two primary endpoints.

“We are thrilled to report the first positive registrational Phase 3 study results in patients with NASH, a devastating disease that is on track to become a leading cause of liver transplant in coming years,” said Mark Pruzanski, M.D., President and Chief Executive Officer of Intercept. “The topline REGENERATE data we are reporting today support our belief that OCA will become the first approved medicine for those living with liver fibrosis due to NASH. We are deeply grateful to the patients, investigators and study staff whose ongoing participation in REGENERATE has brought us one step closer to delivering a much-needed therapeutic option to address the enormous unmet medical need in this population.”

Based on these results, Intercept intends to file for approval in the U.S. and Europe in the second half of 2019. OCA remains the only investigational drug to have received Breakthrough Therapy designation from the FDA for NASH with fibrosis. REGENERATE results will be presented at the European Association for the Study of the Liver (EASL): The International Liver CongressTM 2019.

“Patients with significant fibrosis due to NASH are at the greatest risk of progression to severe liver-related complications, such as liver failure and death, and fibrosis is considered the strongest predictor of liver-related mortality in this population,” said Zobair M. Younossi, M.D., Professor and Chairman of the Department of Medicine at Inova Fairfax Medical Campus, Professor of Medicine at Virginia Commonwealth University, Inova Campus and the Chair of the REGENERATE Steering Committee. “I am very encouraged by these results that demonstrate OCA’s ability to significantly improve fibrosis in patients with advanced disease. As the first successful pivotal trial in NASH, REGENERATE is an important advancement for the liver community.”

Efficacy Results
The primary efficacy analysis (Intent-to-Treat or ITT) assessed efficacy at 18 months in 931 patients with stage 2 or 3 liver fibrosis due to NASH. Overall study discontinuations in the primary efficacy analysis population were balanced across treatment arms: 16% in placebo, 17% in OCA 10 mg and 15% in OCA 25 mg.

An additional pre-specified full efficacy analysis at 18 months added an exploratory cohort of 287 NASH patients with stage 1 liver fibrosis and additional risk factors who were at increased risk of progression to cirrhosis (N=1,218).

Patients with biopsy proven NASH with fibrosis were randomized 1:1:1 to receive placebo, OCA 10 mg or OCA 25 mg once daily. A repeat biopsy was conducted after 18 months for histologic endpoint assessment. Patients without a repeat biopsy due to study discontinuation or other reason were treated as non-responders in the primary and full efficacy analyses. 

Click On Image To Enlarge

Fibrosis Improvement at Month 18

NASH Resolution at Month 18

Safety and Tolerability
The safety population in this planned 18-month analysis of REGENERATE included 1,968 randomized patients who received at least one dose of investigational product (OCA or placebo).

Adverse events were generally mild to moderate in severity and the most common were consistent with the known profile of OCA. The frequency of serious adverse events was similar across treatment arms (11% in placebo, 11% in OCA 10 mg and 14% in OCA 25 mg) and no serious adverse event occurred in >1% of patients in any treatment arm. There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg: glioblastoma) and none were considered related to treatment.

The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to moderate, with severe pruritus occurring in a small number of patients (<1% in placebo, <1% in OCA 10 mg and 5% in OCA 25 mg). A higher incidence of pruritus associated treatment discontinuation was observed for OCA 25 mg (<1% in placebo, <1% in OCA 10 mg and 9% in OCA 25 mg). According to the clinical study protocol, investigator assessed severe pruritus mandated treatment discontinuation.

Consistent with observations from previous NASH studies, OCA treatment was associated with an increase in LDL cholesterol, with a peak increase of 22.6 mg/dL at 4 weeks and subsequently reversing and approaching baseline at month 18 (4.0 mg/dL increase from baseline). Triglycerides rapidly and continually decreased in the OCA treatment arms through month 18. There were few and varied serious cardiovascular events and incidence was balanced across the three treatment arms (2% in placebo, 1% in OCA 10 mg and 2% in OCA 25 mg).

With respect to hepatobiliary events, more patients (3%) on OCA 25 mg experienced gallstones or cholecystitis compared to <1% on placebo and 1% on OCA 10 mg. While numerically higher in the OCA 25 mg treatment arm, serious hepatic adverse events were uncommon with <1% incidence in each of the

Source - Download PDF

MarketWatch 

Intercept Pharmaceuticals is one step closer to getting FDA approval for the first-ever NASH drug

There are no approved treatments for NASH, or nonalcoholic steatohepatitis, a serious liver disease caused by fat accumulation in the liver that can result in chronic inflammation and scarring, or fibrosis. Eventually, the disease can lead to liver failure, cancer and death. 

Intercept’s treatment, obeticholic acid (OCA), is meant to treat patients with liver fibrosis due to NASH. The Phase 3 trial enrolled 931 patients with liver fibrosis who were randomly assigned to be treated with a placebo drug or one of two doses of OCA. 

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Merck's Keytruda fails late-stage study in liver cancer patients

Reuters
Merck's Keytruda fails late-stage study in liver cancer patients
(Reuters) - Merck & Co Inc’s cancer drug Keytruda failed a late-stage trial’s main goals of slowing disease progression and extending the life of patients with a common type of liver cancer, the company said on Tuesday.

The results could hamper prospects for the drug, which had received an accelerated approval from the U.S. Food and Drug Administration in November as a treatment for patients with advanced liver cancer who had been previously treated with Bayer AG’s Nexavar. 

Continue reading...

Press Release

Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma 

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-240 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus best supportive care, for the treatment of patients with advanced hepatocellular carcinoma (HCC) who were previously treated with systemic therapy, did not meet its co-primary endpoints of overall survival (OS) and progression-free survival (PFS) compared with placebo plus best supportive care. In the final analysis of the study, there was an improvement in OS for patients treated with KEYTRUDA compared to placebo, however these OS results did not meet statistical significance per the pre-specified statistical plan (HR=0.78 [95% CI, 0.611-0.998]; p=0.0238). Results for PFS were also directionally favorable in the KEYTRUDA arm compared with placebo but did not reach statistical significance (HR=0.78 [95% CI, 0.61-0.99]; p=0.0209). The key secondary endpoint of objective response rate (ORR) was not formally tested, since superiority was not reached for OS or PFS. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and have been shared with the U.S. Food and Drug Administration for discussion.

“While we are disappointed KEYNOTE-240 did not meet its co-primary endpoints, the results for overall survival, progression-free survival and objective response rate are generally consistent with findings from the Phase 2 study, KEYNOTE-224, which led to the accelerated approval of KEYTRUDA for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We sincerely thank the patients and investigators for their participation in this study and are committed to helping patients diagnosed with this common and difficult-to-treat type of liver cancer.”

KEYTRUDA is being studied across multiple settings and lines of therapy for HCC through our broad clinical program that includes 10 clinical trials sponsored by Merck or in collaborations. As monotherapy in second-line HCC, in addition to KEYNOTE-240 and KEYNOTE-224, KEYTRUDA is being investigated in the ongoing Phase 3, KEYNOTE-394 trial, a randomized, double-blind trial evaluating KEYTRUDA in combination with best supportive care, compared to placebo in combination with best supportive care, in Asian patients with advanced HCC who were previously treated with systemic therapy. In addition, there are several ongoing trials investigating KEYTRUDA in combination with other treatments, including therapies through our collaborations.

About KEYNOTE-240

KEYNOTE-240 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT02702401) evaluating KEYTRUDA plus best supportive care compared to placebo plus best supportive care in patients with advanced HCC who were previously treated with systemic therapy. The primary endpoints are OS and PFS. The secondary endpoints include ORR, duration of response, disease control rate and time to progression. The study enrolled 413 patients who were randomized to receive either KEYTRUDA (200 mg fixed dose every three weeks for up to 35 cycles of treatment [up to approximately two years]) plus best supportive care (including pain management and management of other potential complications including ascites per local standards of care) or placebo plus best supportive care. 

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Understanding Liver Disease with Dr. Joe Galati

Understanding Liver Disease with Dr. Joe Galati

In this timeless patient-friendly video, Dr. Joe Galati will explain medical jargon used to describe common and possible severe symptoms of liver disease, relaunched this month by Liver Specialists of Texas, located in Houston.

Topics
Varices
Encephalopathy - Video
Ascites
Peritonitis infection of ascitic fluid
Fever
Abdominal Pain
Shortness of breath
Chest Pain
Headache
Jaundice
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Links
View additional videos on Dr. Galati's YouTube Channel, connect on Facebook, follow on twitter, or visit both his blog and website.

The Year in Viral Hepatitis: Part 1

Gastroenterology & Endoscopy News

The Year in Viral Hepatitis: Part 1

Feb 18, 2019

Although 2018 saw no major drug approvals or dramatic breakthroughs for viral hepatitis, researchers continued to make progress against these infections. We asked Drs. Ira Jacobson and Saikiran Kilaru for an overview of the most important findings reported last year.

Continue reading: https://www.gastroendonews.com/In-the-News/Article/02-19/The-Year-in-Viral-Hepatitis-Part-1/54073

*** Free registration may be required to view article

Hepatitis C and HIV/AIDS Medications Costliest Group of Outpatient Prescription Drugs for Medicaid

Kaiser Family Foundation
Analysis Finds that Medications for Hepatitis C and HIV/AIDS Are the Costliest Group of Outpatient Prescription Drugs for Medicaid, While Diabetes Drugs Have Posted the Sharpest Rise in Costs 
Chris Lee
Published: Feb 15, 2019
Antiviral medications, including those that treat hepatitis C and HIV/AIDS, cost the Medicaid program more money (before rebates) than any other group of outpatient prescription drugs for each year from 2014 to 2017, according to a new KFF analysis.

The analysis of utilization and spending trends finds that antivirals accounted for more than 13 percent of the $63.6 billion in Medicaid outpatient drug spending pre-rebates in 2017 — a level disproportionate to their utilization and a reflection of the high cost of these drugs. Drugs for diabetes were the second most costly group that year, accounting for 10 percent of Medicaid outpatient drug spending before rebates. Spending for diabetes drugs rose faster than for any other group, nearly doubling from 2014 to 2017 — largely due to the rising price of insulin.

Read the complete article: https://www.kff.org/medicaid/press-release/analysis-finds-that-medications-for-hepatitis-c-and-hiv-aids-are-the-costliest-group-of-outpatient-prescription-drugs-for-medicaid-while-diabetes-drugs-have-posted-the-sharpest-rise-in-costs

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Direct-acting antivirals reduce risk of premature mortality and liver cancer for people with chronic hepatitis C

Page updated with additional links on Feb 14, 2019

The Lancet
Published: February 11, 2019
DOI: https://doi.org/10.1016/S0140-6736(18)32111-1

Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study
Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.
Continue to "full-text article"

PDF shared on twitter by @HenryEChang

Direct-acting antiviral treatment for hepatitis C - Linked Comment
Writing in a linked Comment, Dr Raymond T Chung, Director of the Liver Center at Massachusetts General Hospital, USA, says: 

"The study by Carrat and colleagues offers substantive evidence that cure of HCV delivered by all-oral direct-acting antiviral regimens is associated with clinical benefits. These findings firmly counter those of a Cochrane review of direct-acting antiviral treatment trials that could neither confirm nor reject if direct-acting antivirals had an effect on long-term HCV-related morbidity and mortality. They also provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection. Finally, they provide credence to the achievability of the goals set out by WHO, not only to eliminate HCV but also to substantially reduce its complications." 

Read full comment here....

Media Coverage

Patient-friendly article
Feb 14, 2019

At Last, Strong Evidence That Treating Hep C Offers Major Benefits
By Benjamin Ryan 

Scientists have firmly established an association between direct-acting antiviral treatment and a lower risk of liver cancer and death.

Read more: https://www.hepmag.com/article/last-strong-evidence-treating-hep-c-offers-major-benefits

Feb 11, 2019

Direct-acting antivirals reduce risk of premature mortality and liver cancer for people with chronic hepatitis C 

Professor Fabrice Carrat of the Sorbonne Université, France, said: "Taking a large cohort like this provides the opportunity to evaluate the effect of direct-acting antiviral therapy on the long-term outcomes of patients with hepatitis C. We saw a reduction of risk for complications related to the disease, and to mortality, and believe this treatment should be considered for all patients with chronic hepatitis C infection."

The first prospective, longitudinal study investigating treatment of chronic hepatitis C with direct-acting antivirals finds that the treatment is associated with reduced risk of mortality and liver cancer, according to a study published in The Lancet.

The research is the first to demonstrate the clinical effectiveness of direct-acting antivirals on the disease and suggests that they should be considered for all patients with chronic hepatitis C infection.

For ethical reasons a trial with a control arm is not possible and researchers approached this by setting up an observational study of around 10,000 patients. At follow up, about three-quarters had been treated with direct-action antivirals and a quarter were untreated. The incidence of death and hepatocellular carcinoma - the most common form of liver cancer - were significantly decreased in patients who were treated. Their risk of decompensated cirrhosis was not reduced by the treatment.

Around the world, an estimated 71 million people are chronically infected with the hepatitis C virus (HCV). The infection causes complications such as cirrhosis, liver disease, hepatocellular carcinoma, and many people die as a result. Over the last 15 years, these complications have tripled and models predict they will peak between 2030 and 2035. The World Health Organization (WHO) has set targets for the elimination of hepatitis C, and a reduction of related complications. Recently, a modelling study published in The Lancet found that major progress towards these targets by 2030 is possible, but will require vast improvements in screening, prevention, and treatment [1].

Previous work has shown there is a reduction of risk for complications and mortality in patients who are treated with interferon or direct-acting antivirals, but few studies have compared treated and untreated patients. The aim of direct-acting antiviral drugs is to achieve a sustained virological response, meaning that the virus is undetectable in the blood of the patients. A recent Cochrane Review [2] found no evidence for or against the treatment having a long-term effect on death and disease, so this large study is timely, and may help doctors and patients with treatment plans.

In this study, 10,166 patients were recruited from 32 centres in France. At a median of 33 months, 9,895 patients had available follow up information and were included in the analysis, with 7,344 treated with direct-acting antivirals and 2,551 untreated. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated).

Overall, the study finds that direct-acting antiviral treatment is associated with reduced risk for global mortality and hepatocellular cancer, but not decompensation of cirrhosis. The researchers initially found an increase in risk associated with treatment with direct-acting antiviral treatment, but once they had adjusted for variables such as age, sex, body-mass index, severity of liver disease, geographical origin, infection route and other factors, they found a reduced risk.

Patients who were treated were 52% less likely to die prematurely than people who were not treated (the estimated adjusted risk of death at one year in untreated patients in the cohort is 84 deaths per 10,000 patients, and in those who were treated was 40 per 10,000), and 33% less likely to present with hepatocellular carcinoma (the estimated adjusted risk of developing hepatocellular carcinoma within a year in untreated patients in the cohort was 129 cases per 10,000 patients, and 86 per 10,000 in people who were treated). [3]

In a subgroup of 3,045 patients with cirrhosis at baseline, the same association was found for mortality and hepatocellular cancer, provided the patients achieved an undetectable level of HCV in their blood. The researchers believe this is because the treatment induces a sustained virological response, allowing the liver to regenerate which decreases risk.

Professor Fabrice Carrat of the Sorbonne Université, France, said: "Taking a large cohort like this provides the opportunity to evaluate the effect of direct-acting antiviral therapy on the long-term outcomes of patients with hepatitis C. We saw a reduction of risk for complications related to the disease, and to mortality, and believe this treatment should be considered for all patients with chronic hepatitis C infection." [4]

In the study, only a few patients underwent liver biopsy to confirm cirrhosis, with platelet levels or prothrombin time - a blood test - used to classify whether a patient had cirrhosis or not. A validation study using other non-invasive markers of fibrosis suggested that their methods correctly classified cirrhosis in the patients.

Patients who received more than one course of direct-acting antivirals were considered to have had continuous exposure, even where there may have been a lag time or if the first course may not have been associated with sustained virological response. This should have underestimated the response to the drugs rather than overestimated them so does not affect the result.

The study excluded patients with a history of decompensated cirrhosis and liver transplantation and these are the patients who would be at highest risk for complications. The potential benefits of treatment in this group could be underestimated because of their exclusion, as trial data shows improvements in liver function in patients with decompensated cirrhosis who achieved a sustained virological response.
https://www.eurekalert.org/pub_releases/2019-02/tl-pss020819.php

Recommended Reading

Full-text
Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model

lastair Heffernan, MResProf Graham S Cooke, DPhilShevanthi Nayagam, PhDProf Mark Thursz, MDProf Timothy B Hallett, PhD

Jan 28, 2019
The revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met.