Sunday, January 8, 2017

HCV - Fatty liver disease and genotype 3

Page Updated July 14, 2017 - See "Extrahepatic manifestations of HCV & Treatment" further down this page under: HCV and Hepatic Steatosis

Page Updated April 24, 2017 to include updates from The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017) which took place April 19-23 in Amsterdam.

Also see - Hepatitis C Genotype 3 - FDA Approved And Soon To Be Approved Therapies

HCV: Fatty liver disease and genotype 3
Did you know that in the United States hepatitis C (HCV) and nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease?

The good news is that breakthrough treatments for hepatitis C have increased SVR rates to over 90% and new therapies for fatty liver disease are being investigated.

Recently a study published in Gastroenterology reported that while the burden of liver disease from HCV decreases - lowering the number of patients waiting or undergoing liver transplant - the waitlist for nonalcoholic steatohepatitis (NASH) or alcoholic liver disease (ALD) have increased.

In an analysis of 3 different databases (NHANES, HealthCore, and UNOS), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing, and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis.
Today On The Blog
In this post a collection of journal articles and videos reviewing HCV and fatty liver disease is highlighted; with a focus on individuals afflicted with both conditions. In addition given the development of steatosis (abnormal levels of fat in your liver) is higher in people with HCV and genotype 3, links are provided to current therapies in this difficult to cure genotype. Finishing off with several liver healthy tips.

Nonalcoholic fatty liver disease (NAFLD)
Nonalcoholic fatty liver disease (NAFLD) referrers to people who have fat in their liver but no liver damage. Liver blood tests are either normal, or there may be slight increases in two of the enzymes made by the liver, the serum ALT (alanine aminotransferase) and/or the serum AST (aspartate aminotransferase). NAFLD is more common in people who have certain conditions including obesity and conditions that may be related to obesity, such as type 2 diabetes.

Nonalcoholic steatohepatitis (NASH)
The more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH) in which you have fat in your liver plus inflammation and liver cell damage - the latter can cause fibrosis, or scarring of the liver. NASH tends to develop in people who are overweight or obese, or have diabetes, high cholesterol or high triglycerides. However, some people have NASH even if they do not have any risk factors. Liver enzyme levels in the blood may be more elevated than the mild elevations seen with nonalcoholic fatty liver disease (NAFLD).

HCV and Hepatic Steatosis
Extrahepatic manifestations of HCV & Treatment

Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty
July 14, 2017

Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor

Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia. 

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
Link -  Extrahepatic manifestations of HCV & Treatment - View Complete List of Articles

In a 2006 review article published in International Journal of Medical Sciences, researchers investigated the current relationship between hepatitis C infection and hepatic steatosis, below is an excerpt and overview of the article from Hepatitis C Trust website;

There are two discrete forms of steatosis that may be found in patients infected with hepatitis C virus (HCV). Metabolic steatosis can coexist with HCV, regardless of genotype in patients with risk factors such as obesity, hyperlipidemia, and insulin resistance. The second form of hepatic steatosis in HCV patients is a result of the direct cytopathic effect of genotype 3 viral infections. There have been proposed mechanisms for this process but it remains elusive. Both categories of steatosis tend to hasten the progression of liver fibrosis and therefore prompt recognition and management should be initiated in patients with HCV and steatosis.

On average steatosis is about two and half times more common in people with HCV than in the general population, so it is clear that the presence of the virus in the body can actually trigger steatosis. Biopsy samples in people with HCV who have steatosis tend to show that fat accumulates around the portal areas, rather than in the middle of the lobules of the liver, as is usually the case Non Alcoholic Fatty Liver Disease (NAFLD) which point to the virus being the trigger rather than other factors.

For people with genotype 3 though, the link between steatosis and the virus has now been definitively established. Up to 60-80% of people with genotype 3 have moderate to severe steatosis. It seems that that there is a complex interaction between the core protein of the genotype 3 strand of the virus and liver cells that leads to steatosis. It also seems that the severity of steatosis in these patients is directly related to their viral load. The higher the viral load the greater the amount of steatosis.

Surprisingly people with genotype 3, who achieve sustained virologic response (SVR) through treatment, have a marked decrease in and sometimes a complete resolution of steatosis. If they then relapse steatosis then reappears. 
Review the study, here.

NAFLD and NASH in HCV Infection
In a more recent 2016 article the relationship between HCV-associated non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, as well as the impact on HCV treatment response and disease progression is analyzed; NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations.
The data demonstrate that hepatic steatosis is a feature of chronic HCV infections and that liver fatty accumulation seems to be a finalistic condition favoring the persistence and replication of HCV. HCV-associated steatosis, in a degree-dependent fashion, producing hepatic inflammation and oxidative stress, induces a more rapid progression of liver fibrosis and increases the risk of the development of HCC. HCV-associated steatosis also influences the development of some extrahepatic manifestations of chronic HCV infection such as diabetes, metabolic syndrome, and atherosclerosis. In addition, the presence of steatosis impairs the response rate to interferons based anti-HCV treatments and could have a role in the lower response rate observed in HCV genotype 3 treated with new DAAs. Thus, steatosis should be regarded as a marker to individuate patients at higher risk of progression of HCV-associated liver disease, development of extrahepatic diseases, and lower therapeutic response rate, perhaps even in the era of new DAAs
Continue to the full text article, here..

Hepatitis C Treatment
Also see - Hepatitis C Genotype 3 - FDA Approved And Soon To Be Approved Therapies, updated Aug 2017

December 2016
Hepatitis C eradication with sofosbuvir leads to significant metabolic changes
The aim of this retrospective study was to assess the changes in glucose and lipid metabolism in a group of hepatitis C patients treated and cured with a sofosbuvir-containing regimen, published in December 2016 in the World Journal Of Hepatologly; Hepatitis C eradication with sofosbuvir leads to significant metabolic changes.
In our retrospective study, we evaluated the changes in glucose and lipid metabolism in a group of hepatitis C patients treated and cured with a sofosbuvir-containing regimen. We used hemoglobin A1c (HgA1c) and lipid panels to assess those two parameters. Six months post eradication, we found a statistically significant drop in HgA1c and an increase in low-density lipoprotein and total cholesterol. The use of HgA1c, although not perfect, is easy to understand and is frequently used by primary care doctors as a tool to assess glucose control.
Treatment and Genotype 3
Follow the links below to review articles related to treating HCV genotype 3, view all current updates, here...

UPDATED July 18, 2017 - U.S. Food and Drug Administration Approves Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir) for Re-Treatment of Adults with Chronic Hepatitis C Virus
U.S. Food and Drug Administration (FDA) has approved VoseviTM (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) tablets, a single-tablet regimen for the re-treatment of chronic hepatitis C virus (HCV) infection in adults with genotype 1, 2, 3, 4, 5 or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. The approval is based on data from the Phase 3 POLARIS-1 and POLARIS-4 studies, which evaluated 12 weeks of Vosevi in direct-acting antiviral-experienced chronic HCV-infected patients without cirrhosis or with compensated cirrhosis.

July 13, 2017
Sofosbuvir based treatment of chronic hepatitis C genotype 3 infections—A Scandinavian real-life study
We found that sofosbuvir based treatment in a real-life setting could offer SVR rates exceeding 90% in patients with HCV genotype 3 infection and advanced liver disease.

July 5, 2017
Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C- Review Article
Expert commentary
Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy

March 20, 2017
2017 Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV
Summary - NEJM Journal Watch
Researchers examined 42 randomized trials of oral hepatitis C treatments that included at least two direct-acting antivirals. Among the findings:
  • For genotype 1 infection, the most common HCV type, sustained virologic response rates were above 95% for six regimens.
  • For patients with HCV genotype 3 and without cirrhosis, sofosbuvir plus velpatasvir or daclatasvir for 12 weeks seemed to be most effective.
  • For genotype 3 with cirrhosis, velpatasvir-sofosbuvir had higher response rates. That drug combination was also highly effective (99% response rate) for genotypes 2, 4, 5, and 6.
  • Patient groups traditionally considered difficult to treat — including those with HIV, severe kidney disease, or liver transplant — had high response rates and limited adverse events.
Read the study, here..

March 1, 2017
Genotype 3
Video - Genotype 3 Infection - Identification of the Best Direct-Acting Antiviral Regimen for Patients With Hepatitis C Virus
Drs. Drenth and Berden discuss their manuscript "Identification of the Best Direct-Acting Antiviral Regimen for Patients With Hepatitis C Virus Genotype 3 Infection: A Systematic Review and Network Meta-analysis."

April 2017 - Conference Updates
International Liver Congress™ (ILC) 2017
Combo Drug Beats Tough-to-Treat HCV Genotype 3
Anti-viral led to sustained virological response in 95% of trial patients

April 23
Shortened duration triple therapy fails in genotype 3 HCV
AMSTERDAM — Six weeks of triple combination therapy induced sustained virologic response in a cohort of patients with genotype 1 HCV but not genotype 3, according to data presented at the International Liver Congress.

April 21
Glecaprevir/pibrentasvir 95% SVR12 in HCV Geno 3 treatment naïve, non-cirrhotic patients
Study results presented today demonstrate that the oral, once-daily treatment regimen of glecaprevir/pibrentasvir (G/P) resulted in 95% sustained virologic response rates at 12 weeks post treatment (SVR12) in patients with Hepatitis C virus (HCV) genotype 3. In the ENDURANCE-3 study, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, patients infected with HCV genotype 3 without cirrhosis and who had no previous treatment history were treated with the new regimen for eight or 12 weeks, which was well tolerated. G/P had a similar safety profile to the commonly used combination of sofosbuvir and daclatasvir for 12 weeks, to which G/P was actively compared in the study.

Meeting Updates
Updates On This Blog
Hep C 5-minute videos - Summary Of The International Liver Congress™ (ILC) 2017

In The Media
Aug 14, 2017
Steatosis: An Independent Risk Factor for Fibrosis in Chronic HCV
A study recently published in Digestive Disease Science found that hypertension, older age, obesity, and HIV are risk factors and that steatosis is an independent risk factor for liver fibrosis in African-Americans with chronic hepatitis C.

March 6, 2017
Rarer HCV Types Still Need Attention
When compared with other HCV patients, genotype 3 patients are relatively difficult to treat, especially those with cirrhosis. However, studies with sofosbuvir-velpatasvir are "encouraging, with SVR [sustained virologic response] rates of 97% in treatment-naïve patients and 90% in treatment-experienced patients."

February 6, 2017
Hepatitis C Genotype Makes a Difference - Genotype 3 Difficult To Treat.
Patients with genotype 3 had the highest percentage of liver-related comorbidities and advanced liver disease. They were about one-third more likely to have advanced liver disease than were patients with the genotype 1 strain of the virus. The highest rates of steatosis, liver transplant, and hepatocellular carcinoma (the most common form of liver cancer) were also among patients with genotype 3....

Jan 27, 2017
New Genotype 3 Treatments
A collection of research articles presented at AASLD 2016  reported by Jules Levin.
New Genotype 3 Treatments - New HCV Treatments

Daclatasvir Plus Sofosbuvir, With or Without Ribavirin, for Hepatitis C Virus Genotype 3 in a French Early Access Programme
Daclatasvir Plus Sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.
Read the full text article - Download Accepted Article

Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort
Recently a 2016 study published in the Journal Of Viral Hepatitis reported people with genotype 3  and cirrhosis, experienced high cure rates using sofosbuvir-based regimens; sofosbuvir+daclatasvir and sofosbuvir/ledipasvir, with few serious side effects; Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.

(Epclusa) Sofosbuvir plus velpatasvir “best options” for HCV G3
An analysis of published studies on direct acting antivirals (DAAs) found that regimens containing sofosbuvir and velpatasvir were the best option for patients with HCV genotype three (G3).

The analysis indicated that ribavirin significantly increased rates of SVR and should be considered if tolerated.

Researchers at Radboud University Medical Centre in the Netherlands performed a Bayesian network meta-analysis using a random effects model to indirectly compare DAA regimens in HCV G3 patients with and without cirrhosis. They found 27 appropriate studies involving 3,415 patients.

Among patients without cirrhosis, the greatest rates of SVR were estimated for those receiving sofosbuvir + velpatasvir with ribavirin (99%) and without ribavirin (97%), for sofosbuvir + daclatasvir + ribavirin (96%), and for sofosbuvir + peginterferon + ribavirin (95%), all for 12 weeks.

Among patients with cirrhosis, the highest rates of SVR were estimated for those receiving sofosbuvir + velpatasvir for 24 weeks (96%), for sofosbuvir + daclatasvir + ribavirin for 24 weeks (94%), and for sofosbuvir + velpatasvir + ribavirin for 12 weeks (94%).
Ribavirin increases efficacy in patients with and without cirrhosis (odds ratios 2.6 and 4.5).

Identification of the best direct-acting antiviral regimen for patients with hepatitis C virus genotype 3 infection: a systematic review and network meta-analysis.
Berden FA, Aaldering BR, Groenewoud H et al. Clin Gastroenterol Hepatol. 2016 Nov 10 [Epub ahead of print]

Nov 21, 2016
Sofosbuvir/velpatasvir improved patient-reported outcomes, knocked out HCV genotypes 1-6
– When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.

Nov 17, 2016
AbbVie Pangenotypic Combination Cures Hard-to-Treat People with HCV Genotype 3
AbbVie’s pangenotypic combination of glecaprevir and pibrentasvir cured almost all of the hardest-to-treat genotype 3 hepatitis C patients -- those with cirrhosis or previous treatment experience -- in a Phase 2 trial, and looks suitable for use as an 8-week regimen for HCV genotypes 2, 4,5 and 6, according to results of studies presented at the AASLD Liver Meeting last week in Boston.

Nov 15, 2016
AASLD 2016 Grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) highly effective for hard-to-treat genotype 3 hepatitis C patients
A triple regimen of grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) without ribavirin cured 96% of previously untreated and 97% of treatment-experienced people with hepatitis C virus (HCV) genotype 3 and liver cirrhosis, matching...

October 2016
Short-duration Treatment With Elbasvir/Grazoprevir and Sofosbuvir - HCV GT1 or GT3 with or without cirrhosis
This clinical study is the first to examine the treatment of patients infected with HCV GT1 or GT3 with or without cirrhosis with short durations of a novel regimen of EBR/GZR + SOF. Our data confirm that cirrhotic and noncirrhotic patients with HCV GT1 infection can be cured with 6–8 weeks of treatment, and that an 8–12 week regimen of EBR/GZR + SOF is safe and effective in cirrhotic and noncirrhotic patients with HCV GT3 infection, commonly regarded as one of the
most challenging patient populations to treat..

Stay Updated
2017-HCV Genotypes/Treatment
Offered on this page of the blog is research updates with a focus on treating HCV according to genotype using FDA approved and investigational medicines. Information is extracted from news articles, peer-reviewed journals, as well as liver meetings/conferences, research manuscripts and interactive learning activities. 

Fatty Liver - Investigational Agents
Click to view recent updates on this blog.

April 2017
Conference Updates
International Liver Congress™ (ILC) 2017
NASH: It's Fibrosis, Not Fat, that Matters
Analysis sheds new light on what drives disease progression
AMSTERDAM -- It isn't fat but rather fibrosis that drives disease progression in people with advanced non-alcoholic steatohepatitis (NASH), a researcher said here
Continue reading....

March 23, 2017
VIDEO: Physician discusses upcoming noninvasive modalities, treatments for NASH
In this exclusive video from Emerging Trends in Non-Alcoholic Fatty Liver Disease, Zobair M. Younossi, MD, MPH, FAASLD, chairman of the department of medicine at Inova Fairfax Hospital and vice president of research at Inova Health System, discusses topic highlights from the meeting, particularly steatohepatitis and future treatments.

NASH recurrence does not hinder liver transplantation success
“In long-term studies, the highest frequency of graft loss related to recurrence of NASH appears to be around 5%. This is in stark contrast with hepatitis C ... with a 3rd of patients with HCV dying, requiring retransplantation or having cirrhosis due to recurrence of HCV within 5 years,” Michael R. Charlton, MD, of the department of medicine at the University of Chicago, said during his presentation. “Knowing that NASH itself is not an important cause of transplant graft failure and death, those other causes we looked at earlier — cardiovascular disease, neoplasia, renal insufficiency — these are much more common causes of death following liver transplantation, particularly in patients with fatty liver disease.”

NeuroVive furthers development of HCC, NASH inhibitors
February 24, 2017
NeuroVive announced two research agreements designed to further develop the company’s new drug compounds in the pipeline for the treatment of nonalcoholic…

January 2017
Full Text
Therapies in non-alcoholic steatohepatitis (NASH)
Key points
NASH is the more aggressive subtype of NAFLD and may replace hepatitis C as the leading cause of liver transplantation by 2020.
The presence of fibrosis is the strongest predictor of mortality in patients with this disease.
Beside lifestyle changes, there are no FDA-approved medications for patients with NASH.
Common medications that have shown good results in reducing disease activity are vitamin E and pioglitazone, but these have no consistently reliable effect on fibrosis.
There are multiple other promising drugs targeting fibrosis and other elements involved in the pathogenesis of NASH that are currently in various stages of clinical study.
Continue reading..

Fatty Liver: What Treatment is Available?
by Dr. Joe Galati on 12/04/2016
Fatty Liver Disease is one of the more common conditions we treat at Liver Specialists of Texas. New therapies are being investigated, and we are conducting several research protocols specific for fatty liver patients.

Fatty Liver: What Patients Need to Know
Published on Mar 8, 2016
Fatty liver disease, also called NASH (nonalcoholic steatohepatitis) and NAFLD (nonalcoholic fatty liver disease) is a common disease of the liver. It is caused by truncal obesity, diabetes, elevated cholesterol, hypothyroidism, and hypertension. Together, all of these disorders is called metabolic syndrome.

HCV, Diet and Fatty Liver Disease
Diet and exercise can help improve liver health in both conditions, a small study published in the July 2013 issue of the Journal of Hepatology demonstrated patients with nonalcoholic fatty liver disease who followed the Mediterranean diet for six weeks not only significantly improved insulin sensitivity, but reduced both liver fat and inflammation, more on the study is available over at MedPage Today.

Published on Aug 10, 2016
People always ask what special diet is needed for patients with liver disease? Dr. Joe Galati explains the diet patients with liver disease need to follow. Patients with hepatitis C, fatty liver, cirrhosis, and hepatitis B need to follow a low salt diet.

Mediterranean diet and hepatocellular carcinoma
This is exciting, according to a study found in the Journal of Hepatology, November 2013;
A closer adherence to the Mediterranean diet appears to be protective against HCC (liver cancer). Our results also point to potential benefits from adhering to a Mediterranean dietary pattern for patients chronically infected with hepatitis viruses.
Read the full article over at NATAP, abstract here.

Mediterranean Diet
The program includes a high consumption of olive oil, legumes, unrefined cereals, bread, pasta, rice, nuts with less red meat and dairy products than many other diets. Although, red wine is used in moderation, it has never been advisable for people living with hepatitis C, or advanced liver disease. Other food choices are lots of fresh fruit, vegetables and moderate consumption of fish. Fish is rich in omega-3 fatty acids and low in saturated fats. Omega-3 fatty acids can help lower triglycerides and blood pressure.

Learn More
Mediterranean diet: A heart-healthy eating plan
By The Mayo Clinic Staff

Of Interest
Jan 26, 2017
Editorial - Dietary factors can protect against liver cancer development Abstract
Liver cancer is the third leading cause of cancer mortality worldwide with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Most HCC patients are also suffering from chronic liver disease (CLD). Evidence is emerging that the composition of diet plays an important role in HCC and CLD development and may also have a chemoprotective role. In contrast to other types of cancer, there are few studies investigating the role of diet in hepatocarcinogenesis. From the available data it is evident that high intakes of red meat and dietary sugar positively correlate with HCC occurrence. On the contrary, high consumption of white meat, fish, vegetables, fruits and cereals are inversely associated with HCC risk. This letter discusses the potential role of dietary interventions in the prevention of hepatocarcinogenesis. The increasing HCC incidence and its high fatality are making HCC prevention an urgent matter. Dietary modifications are found to offer protection against HCC, however, new studies from well-designed and large prospective trials are required to confirm these results.
Full Article available, here.

Clinical research has demonstrated adhering to a diet plan with foods named in the Mediterranean diet may help preserve memory as we age, a new study shows that older people who followed a Mediterranean diet retained more brain volume over a three-year period than those who did not follow the diet as closely. The study is published in the January 4, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. But contrary to earlier studies, eating more fish and less meat was not related to changes in the brain.

As mentioned the diet has been shown to reduce both liver fat and inflammation, help protect against liver cancer, may have potential benefits for people chronically infected with hepatitis, reduce the risk for heart attack, stroke and diabetes.

In closing folks, because of my family history with diabetes, heart disease, and my own past history of HCV, I stick to the Mediterranean way of eating, it works for me and my liver.

Stay healthy and happy.
Good Luck

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