Monday, October 15, 2018

Liver Cancer Treatment Paradigm Undergoing Major Overhaul

Liver Cancer Treatment Paradigm Undergoing Major Overhaul
Christine Lehmann, MA
Published Online: Oct 15,2018

Until recently, few systemic therapies had been approved for the treatment of patients with liver cancer, as few agents could demonstrate significant benefit over placebo. Sorafenib (Nexavar) was the first systemic therapy that extended median overall survival (OS) over placebo by nearly 3 months (10.7 versus 7.9 months),1 and, in December 2007, it became the first systemic therapy approved by the FDA for patients with unresectable hepatocellular carcinoma (HCC).

Read the article:

Blog & News Updates: Link between viral hepatitis and liver cancer?

Save The Date
October 16th, 3 p.m. EST
In honor of Liver Cancer Awareness Month we have a few news and blog updates to share with you. On Tuesday, October 16th, join Hepatitis B Foundation for a Twitter chat to discuss the link between hepatitis and liver cancer. Representatives from Hepatitis B Foundation, CDC’s Division of Viral Hepatitis, and NASTAD will co-host the chat at 3 p.m. EST.

In addition check out this years Liver Cancer Awareness Campaign aimed at encouraging individuals with an increased risk for liver cancer to receive ongoing screening, launched by the American Liver Foundation (ALF) and Bayer Healthcare. Find out if you're at risk for liver cancer.

October 23, 2018 2:00 p.m. to 3:00 p.m. EST 

Timothy M. Block, Ph.D.President and Director, Baruch S. Blumberg Institute and the Hepatitis B Foundation
Read More

November 29, 2018 (1:00-2:30 pm ET)
Strategies to Eliminate HCV in Veterans Webinar November 29
Join NVHR on November 29, 2018 (1:00-2:30 pm ET) for a webinar to discuss how government and community organizations are working to treat Veterans living with hepatitis C.
Read More

Blog & Journal Updates Around The Web
Oct 15, 2018 
Liver Cancer Awareness Month
• By Lucinda K. Porter, RN
While the incidence of most cancers are declining in the United States, the rate of hepatocellular carcinoma (HCC or liver cancer) is increasing. More than 40,000 people in this country will be diagnosed this year with primary liver cancer, facing a 5-year survival rate of only 18 percent. According to the National Cancer Institute, liver cancer is the fifth leading cause of cancer death. Worldwide, it is the second leading cause of cancer death.
Read More

Oct 14, 2018
VA Continues Hepatocellular Screening, but Study Questions the Value
by Annette Boyle 
SAN FRANCISCO—Although a recent study determined that screening veterans with cirrhosis for hepatocellular carcinoma did not reduce the risk of death associated with liver cancer, the VA has no plans to change its screening practices.

“The VA currently follows the American Association for the Study of Liver Diseases (AASLD) guidelines for HCC screening among patients with cirrhosis,” explained Maggie Chartier, PsyD, MPH, the VA’s deputy director of HIV, Hepatitis and Related Conditions and associate professor at the University of California, San Francisco. The AASLD recommends screening patients with cirrhosis for HCC using ultrasound (USS) with or without serum alpha fetoprotein measurement every six months
Read More

Oct 10, 2018
..positive impact on HRQoL with improvement in mobility, pain/discomfort, anxiety/depression...

Oct 9, 2018
Paul E. Sax, MD
There’s so much going on no one can cover it all, certainly not me. So here’s a sampling of some (emphasis on some) of the interesting research presentations from last week, a “Mini” Really Rapid Review™ of the conference. Use the comments section to chime in with your favorites.

Oct 9, 2018
What support do people with liver cirrhosis and their families need?
People with liver cirrhosis and their families need more information about their condition and prognosis and greater access to palliative care, a systematic review of studies on the needs of people with cirrhosis of the liver has concluded.

Oct 9, 2018
Malnutrition decreases quality of life, social function in cirrhosis
PHILADELPHIA — Malnutrition as measured by subjective global assessment correlated significantly with decreased health-related quality of life in patients with…

Do you know that the liver doesn’t have any nerve cells? Here are some facts about this amazing organ in honor of Liver Awareness Month...

Alcohol and Increased Cirrhosis-related Deaths
Many of us are well aware that excessive (particularly long-term) consumption of alcohol is not good for our body — and is especially not friendly to our liver. But a newly published research study might very well convince us that the effects of alcohol on our liver health are even worse than we may have initially imagined. What’s the sobering research finding? The likelihood that increased cirrhosis-related mortality rates from 1999 to 2016 may be due to alcohol abuse and alcohol-induced liver disease...

Hepatitis C affects more than just the liver- it can affect many parts of the body, and mental wellbeing... 

Stress is not good for any of us, it can lead to serious health issues and depression. Stress is the..

In a pilot study from the October issue of Clinical Gastroenterology and Hepatology, colony stimulating factor 3 (CSF3, also called GCSF) improved liver function and increased survival times in patients with severe alcohol-associated hepatitis (AH), compared with standard therapy. Addition of N-acetyl cysteine (NAC) to GCSF did not improve patient outcomes... 

To all of you with gluten intolerance, first, let me say: I’m sorry. You’re looking for good food for celiac and liver disease. I worked in the kitchen and saved my life with The Liver Loving Diet, I had no idea what celiac was....

In The News
HepCBC - Weekly Review
Here's the latest issue of the Weekly Bull.

Oct 15, 2018
Liver Cancer Treatment Paradigm Undergoing Major Overhaul

Oct 15, 2018
Study Casts Doubt on Connection Between DAAs and Liver Cancer Risk
“There are no significant differences between DAA regimens in HCC risk after antiviral treatment,” concluded the authors, led by Elijah J. Mun, MD, of the University of Washington.

Oct 10, 2018
Hepatitis C - Vosevi safe, effective in ‘triple-infected’ patients with HCV, HBV, HIV
PHILADELPHIA – The direct-acting antiviral Vosevi demonstrated an average sustained virologic response rate of 87% among patients who were “triple-infected” with hepatitis C genotype 3, hepatitis B and HIV, as presented at the American College of Gastroenterology Annual Meeting.

By Nguyen Quy October 8, 2018 
A report by the World Cancer Research Fund International, a leading organization on cancer-prevention research related to diet, nutrition and physical activity, ranks Vietnam fourth among 25 countries with the highest rates of liver cancer this year. The report is based on the latest statistics from Globocan, an interactive web-based platform with cancer statistics from 185 countries....

Mass. General-led study supports ability of regular aspirin use to reduce liver cancer risk
The results of a study led by Massachusetts General Hospital (MGH) investigators support evidence from previous studies suggesting the regular use of aspirin can reduce the risk of developing primary liver cancer – also called hepatocellular carcinoma (HCC). Their report analyzing data from two long-term epidemiologic studies appears in JAMA Oncology and finds that regular aspirin use – taking two or more 325 mg tablets a week for five years or more – led to a significantly reduced risk of developing HCC, which is the second leading cause of cancer death worldwide...

"Compelling" evidence of link between aspirin use, lower hepatoma risk
NEW YORK (Reuters Health) - Regular, long-term use of aspirin is associated with a reduced risk of developing hepatocellular carcinoma (HCC), according to pooled data from more than 133,000 people. "Animal studies have shown that aspirin can block primary liver cancers from developing. Although these studies have been promising, data in humans have been limited," said Dr. Andrew Chan from Massachusetts General Hospital, in Boston.

Scientists use CRISPR to treat genetic liver diseases in neonatal and adult mice
by Arlene Weintraub
The newest issue of the journal Nature Medicine features two animal studies that show progress is being made towards achieving the holy grail of gene editing: the ability to prevent or treat diseases that are caused by gene mutations. In both cases, the researchers used modified versions of CRISPR-Cas9, the most commonly used gene-editing system.

Recommended reading

Evidence does not support statin use for conditions other than heart …
Despite studies suggesting benefits for conditions beyond cardiovascular disease (CVD), the evidence does not support revising current statin …

Early liver disease detection during pregnancy key for improved outcomes
October 7, 2018
PHILADELPHIA — Early detection of liver-related complications and hepatic diseases in patients who are pregnant leads to reduced risks and improved outcomes for…

NAFLD has ‘bidirectional’ course in patients with type 2 diabetes
October 8, 2018
PHILADELPHIA – Nonalcoholic fatty liver disease may have a “bidirectional” nature in patients with type 2 diabetes as NAFLD regressed in 2.2% of patients without any NAFLD-specific interventions despite increase in the prevalence of risk factors, according to a presentation at the American College of Gastroenterology Annual Meeting.

Obesity, Weight Gain Linked to Fibrosis Progression in NAFLD
Medscape Medical News 
October 4, 2018
Obesity and weight gain are independently associated with an increased risk for fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD), a large cohort study has found. Weight loss was negatively associated with fibrosis progression...

At-Risk Teens and Young Adults Overlooked During Opioid Crisis Too Few Tested for Hepatitis C, Research Suggests 
SAN FRANCISCO – Teens and young adults who have injected drugs are at risk for contracting hepatitis C, but most aren’t tested and therefore don’t receive life-saving treatment, according to a national study being presented at IDWeek 2018. The study of more than 250,000 at-risk youth found only one-third of those with diagnosed opioid use disorder (OUD) were tested for hepatitis C...

NEW YORK (Reuters Health) - The risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) treated with tenofovir is lower than in those treated with entecavir, according to a nationwide study from South Korea. "Patients with CHB have about 1% risk of developing HCC," Dr. Young-Suk Lim from the University of Ulsan College of Medicine, in Seoul, told Reuters Health by email. "Once diagnosed with HCC, the overall prognosis of the patients is very poor, with 5-year survival rate of less than 30%. Therefore, prevention of HCC is of utmost importance in the management of CHB patients."

Healthy You
October 13, 2018
Dietary Supplements Can Contain Viagra, Steroids, or Worse
October 13, 2018
You know those sexual enhancement dietary supplements for sale at gas stations and markets across the country? Beware, they might actually be viagra. Or steroids. Or an antidepressant. Many supposed dietary supplements for weight loss, erectile dysfunction, and muscle building may contain actual pharmaceuticals—but you likely have no way of knowing what's in them...

October 13, 2018
Weekend Reading - Baby Boomers and the Flu
Did you know that you are more susceptible to flu-related complications if you're over 65, living with chronic liver disease, or viral hepatitis?

Recommended Reading
How Many Cases of Drug-Induced Liver Injury Are Caused by Herbal and Dietary Supplements?
September 2018
Herbal and dietary supplement-induced liver injury is more severe than other types of drug-induced liver injury (DILI), and re-exposure is more likely, researchers report in the September issue of Clinical Gastroenterology and Hepatology. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses
Read more

Recent Updates
Online learning activity
Screening and Diagnosis of Hepatitis C Infection
Topics; HCV Transmission FAQs, Risk Factors for Acquiring HCV, HCV Disease Burden and more...

Twitter Updates
Open To All
Watch the open access webcasts from #EASL #NAFLDsummit on : 

Check back for updates!

Study Casts Doubt on Connection Between DAAs and Liver Cancer Risk

Study Casts Doubt on Connection Between DAAs and Liver Cancer Risk
OCTOBER 15, 2018
Jared Kaltwasser

“There are no significant differences between DAA regimens in HCC risk after antiviral treatment,” concluded the authors, led by Elijah J. Mun, MD, of the University of Washington.

The finding is significant because it suggests that hepatocellular carcinoma risk does not need to be a determining factor in which DAA a physician prescribes. However, the authors say the takeaway from the study can extend even beyond the question of whether any particular DAA therapy is worse than another when it comes to cancer risk. They argue their study suggests DAAs broadly don’t increase the risk of hepatocellular carcinoma

On This Blog
Sift through current Liver Cancer and Hepatitis C research articles

Liver Cancer After Treatment For Hepatitis C:
Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase? Research is saying no, check out an index of articles here..... 

Saturday, October 13, 2018

Weekend Reading - Baby Boomers and the Flu

Baby Boomers and the Flu 
Did you know that you are more susceptible to flu-related complications if you're over 65, living with chronic liver disease, or viral hepatitis? Yep, I knew it too. 

Currently information on this blog is aimed at people living with or treating hepatitis C, for the most part that is the baby boomer generation; born between 1946 to1964. 

Speaking of baby boomers, if you haven't read the CDC's eye- opening report on last years flu season, it was reported 80,000 flu-related deaths occurred in the US, the highest in 40 years. The death rate among young baby boomers, aged 50 to 64 were shocking as well; 
"Death rates were highest in the over-65 age group, which is typical, but the second most affected group comprised those aged 50 to 64 years old; normally, the second highest death rates occur in children, from birth through age 4 years. The ferociousness of the flu season overall, combined with above-average impacts on younger baby boomers, made 2017-2018 one for the record books."

Liver Disease & The Flu
As we age our immune system is less effective in fighting infections, and new infections can have a severe impact on the liver. This can be especially serious for liver transplant recipients and people who have cirrhosis. Flu-related complications could develop into bronchitis or pneumonia, which in rare cases can also be fatal.

Even though the flu vaccine won’t keep everyone from getting sick, it helps prevent serious flu complications. For instance people over 65 who were vaccinated had a lower rate of flu-related death, according to a 2017 study, found on the CDC's website.
"Flu vaccination reduced deaths, intensive care unit (ICU) admissions, ICU length of stay, and overall duration of hospitalization among hospitalized flu patients; with the greatest benefits being observed among people 65 years of age and older."
In The News
Last Year, The Flu Put Him In A Coma. This Year He's Getting The Shot
October 14, 2018
"I figured [the flu] was something that's dangerous to the elderly and the young, not somebody who is healthy and in their 30s," says Hinderliter, who is 39 and the director of government affairs at the St. Louis Realtors association
"Turns out, I was wrong," he says
Read the article, here.....

Should I or Shouldn't?
September 27, 2018
"People say they never had the flu until they got the shot. That argument doesn’t hold water. Either you got your shot too late, you got a strain of the flu that isn’t covered by the vaccine, or you had a one-day immune response which may make you feel like crap for the day, but isn’t anywhere like having the flu. If you are over 65, high dose flu shots are recommended, and some people feel a bit low and fluish the next day. This is not the flu – it is an immune system reaction"
Read the article: The Flu Shot Debate, written by HCV advocate Lucinda Porter.

CDC Information
People 65 years and older should get a flu shot and not a nasal spray vaccine.
They can get any flu vaccine approved for use in that age group with no preference for any one vaccine over another. There are regular flu shots that are approved for use in people 65 and older and there also are two vaccines designed specifically for people 65 and older:
High Dose Flu Vaccine:
The “high dose vaccine” contains 4 times the amount of antigen as a regular flu shot. It is associated with a stronger immune response following vaccination (higher antibody production). Results from a clinical trial of more than 30,000 participants showed that adults 65 years and older who received the high dose vaccine had 24% fewer influenza infections as compared to those who received the standard dose flu vaccine. The high dose vaccine has been approved for use in the United States since 2009.
Learn more about high dose flu vaccine here.

Adjuvanted Flu Vaccine:
The adjuvanted flu vaccine, Fluad, is made with MF59 adjuvant an additive that creates a stronger immune response to vaccination. In a Canadian observational study of 282 people aged 65 years and older conducted during the 2011-12 season, Fluad was 63% more effective than regular-dose unadjuvanted flu shots. There are no randomized studies comparing Fluad with Fluzone High-Dose. This vaccine was available for the first time in the United States during the 2016-2017 season. Learn more about adjuvanted flu vaccine here.

For Adults with LIVER DISEASE: Important information about a dangerous infection
If you have chronic liver disease, you are more likely to have serious complications if you get pneumococcal disease

Get pneumococcal vaccines 
People who are 65 years of age and older should also be up to date with pneumococcal vaccination to protect against pneumococcal disease, such as pneumonia, meningitis, and bloodstream infections. Talk to your doctor to find out which pneumococcal vaccines are recommended for you. Pneumococcal pneumonia is an example of a serious flu-related complication that can cause death. 

You can get the pneumococcal vaccine your provider recommends when you get the flu vaccine.

CDC - Got Questions?
Flu vaccines recommended this season.

Detailed flu and flu vaccine information specific to the current flu season

If you have HIV, you are at high risk of serious influenza-related complications and should get an injectable influenza vaccine (a flu shot). 

Stay healthy!

Friday, October 12, 2018

Dietary Supplements Can Contain Viagra, Steroids, or Worse

In Case You Missed It
How Many Cases of Drug-Induced Liver Injury Are Caused by Herbal and Dietary Supplements?
September 2018
Herbal and dietary supplement-induced liver injury is more severe than other types of drug-induced liver injury (DILI), and re-exposure is more likely, researchers report in the September issue of Clinical Gastroenterology and Hepatology. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses
Read more

In The News - Wired 
You know those sexual enhancement dietary supplements for sale at gas stations and markets across the country? Beware, they might actually be viagra. Or steroids. Or an antidepressant. Many supposed dietary supplements for weight loss, erectile dysfunction, and muscle building may contain actual pharmaceuticals—but you likely have no way of knowing what's in them.

Between 2007 and 2016, the FDA issued warnings about unapproved pharmaceutical ingredients in 776 dietary supplements, according to a new report in JAMA Network Open. Of those, less than half received voluntary recalls. The authors compiled their data from the FDA’s own warning website. Known as the Tainted Products Marketed as Supplements List, it catalogs any time the FDA reports finding unapproved pharmaceutical ingredients in supplements. The hundreds of offending supplements the FDA found during that nine-year period traced back to 146 companies. These represent only a small fraction of the potentially hazardous supplements on the market.

JAMA - Original Investigation 
Public Health
October 12, 2018
Unapproved Pharmaceutical Ingredients Included in Dietary Supplements Associated With US Food and Drug Administration Warnings
Jenna Tucker, MPH1,2,3; Tessa Fischer, DVM, MPH2,3; Laurence Upjohn, PharmD3; et al David Mazzera, PhD3; Madhur Kumar, MS, PhD3
Key Points Question
What are the trends across adulterated dietary supplements associated with a warning released by the US Food and Drug Administration from 2007 through 2016?

In this quality improvement study, analysis of the US Food and Drug Administration warnings from 2007 through 2016 showed that unapproved pharmaceutical ingredients were identified in 776 dietary supplements, and these products were commonly marketed for sexual enhancement, weight loss, or muscle building. The most common adulterants were sildenafil for sexual enhancement supplements, sibutramine for weight loss supplements, and synthetic steroids or steroid-like ingredients for muscle building supplements, with 157 products (20.2%) containing more than 1 unapproved ingredient.

Potentially harmful active pharmaceuticals continue to be identified in over-the-counter dietary supplements.

Importance Over half of adults in the United States report consuming dietary supplements. The US Food and Drug Administration (FDA) has warned of numerous dietary supplements containing undeclared, unapproved pharmaceutical ingredients. These FDA warnings have not been comprehensively analyzed for recent years.

To summarize trends across adulterated (containing unapproved ingredients) dietary supplements associated with a warning released by the FDA from 2007 through 2016.

Design, Setting, and Participants In this quality improvement study, data were extracted from the FDA’s Center for Drug Evaluation and Research, Tainted Products Marketed as Dietary Supplements_CDER database from 2007 through 2016. Data from each warning were recorded unless multiple warnings were issued for the same product within a 6-month period. Date, product name, company, hidden ingredient(s), product category, source of sample, and warning document type were recorded for each included warning. Data analysis was conducted from February 2017 to June 2017.

From 2007 through 2016, 776 adulterated dietary supplements were identified by the FDA and 146 different dietary supplement companies were implicated. Most of these products were marketed for sexual enhancement (353 [45.5%]), weight loss (317 [40.9%]), or muscle building (92 [11.9%]), with 157 adulterated products (20.2%) containing more than 1 unapproved ingredient. The most common adulterants were sildenafil for sexual enhancement supplements (166 of 353 [47.0%]), sibutramine for weight loss supplements (269 of 317 [84.9%]), and synthetic steroids or steroid-like ingredients for muscle building supplements (82 of 92 [89.1%]). There were 28 products named in 2 or 3 warnings more than 6 months apart. Of these products, 19 (67.9%) were reported to contain new unapproved ingredients in the second or third warning, consistent with the assumption that the FDA found the product to be adulterated more than once. In recent years (2014-2016), 117 of 303 adulterated samples (38.6%) were identified through online sampling and 104 of 303 (34.3%) were identified through the examination of international mail shipments.

Conclusions and Relevance
Active pharmaceuticals continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after FDA warnings. The drug ingredients in these dietary supplements have the potential to cause serious adverse health effects owing to accidental misuse, overuse, or interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement.

Invited Commentary
JAMA Network
2018;1(6):e183329. doi:10.1001/jamanetworkopen.2018.3329
The FDA and Adulterated Supplements 
Pieter A. Cohen, MD1,2
The US Food and Drug Administration (FDA) plays an essential role in ensuring the safety of vitamins, minerals, botanicals, probiotics, amino acids, and glandular extracts sold as dietary supplements in the United States. While the FDA does not assess the safety of supplements prior to market, the agency is tasked with identifying and removing adulterated and hazardous supplements from the marketplace.

Adulteration of dietary supplements typically involves 1 of 2 patterns: economic adulteration, in which a less expensive ingredient is used in place of a more expensive ingredient listed on the label, or pharmaceutical adulteration, in which an active drug is included in a purportedly botanical supplement, for example, sildenafil in a “natural” sexual enhancement supplement. The FDA maintains a public database listing the brands of supplements it has identified as adulterated with drugs and the actions, if any, it has taken to remove the product from commerce.

An analysis of the FDA database of pharmaceutically adulterated supplements is the focus of a new study by Tucker and colleagues.1 The authors found that between 2007 and 2016 the FDA identified 746 brands of supplements adulterated with pharmaceutical agents. The adulterants included prescription medications such as sildenafil and fluoxetine, withdrawn medications including sibutramine and phenolphthalein, and unapproved drugs including dapoxetine and designer steroids. Twenty percent of the adulterated supplements contained 2 or more undeclared drugs, for example, weight loss supplements containing both an anorectic and a laxative. Most supplements adulterated with drugs were marketed as weight loss, sexual enhancement, or sports supplements—the same categories that epidemiologists have found to be responsible for a disproportionate number of the estimated 23 000 emergency department visits attributed to dietary supplements each year in the United States.2

Given the potential public health risks of inadvertently ingesting unknown quantities of pharmaceutical drugs, once an adulterated supplement has been identified by the FDA, the agency frequently requests that the responsible firm voluntarily recall the product and, if the firm agrees, the agency publicizes the recall through email alerts and postings on its website. However, the effectiveness of voluntary recalls for supplements has been questioned.3,4 In one study, investigators found that many supplements previously subject to recalls remained on sale and were still adulterated with pharmaceutical drugs, sometimes years after the initial recall.3 In another study, consumers of a supplement subject to a voluntary recall were not aware of the recall and continued to purchase the product following the recall.4

Despite their limited effectiveness, voluntary recalls are the most common approach used by the FDA to remove adulterated supplements from commerce. In the current study, the agency discovered 746 distinct supplements to be adulterated but announced voluntary recalls for only 360. Only 360 of 746 (48%) were recalled, leaving the majority of adulterated supplements, more than 350 products, available for sale.

The database does not provide information as to why the FDA fulfilled its responsibilities less than half of the time, but it is possible that some firms might have refused to voluntarily recall their products. Warning letters may be used to nudge firms to recall supplements. In the current study, however, more than 140 firms were involved, but the FDA issued only 7 warning letters. The agency has other enforcement tools at its disposal when a firm does not agree to a voluntary recall, including mandating a recall (authority available since 2011 under the FDA Food Safety Modernization Act) or making a referral to the Department of Justice. Tucker and colleagues1 found that the agency seldom uses these enforcement tools: the FDA reported no mandatory recalls and only 1 Department of Justice investigation in response to the 746 brands of adulterated supplements.

This new evidence is consistent with prior research that has highlighted major deficiencies in the FDA’s regulation of supplements. In a similar study published in 2013, Harel and colleagues5 found that the FDA identified 332 brands of supplements adulterated with pharmaceutical agents during the 9-year period from 2004 to 2012 but only 222 brands (67%) were recalled.5 In another investigation from 2013, the FDA’s analytical chemists uncovered a mixture of synthetic compounds, including an amphetamine analog, β-methylphenylethylamine (BMPEA), in weight loss and sports supplements.6 The FDA did not inform consumers or issue warning letters. An independent study describing the FDA’s inaction was published 2 years later,7 and only then did the FDA begin to take steps to remove the supplements containing BMPEA from the market.

This pattern is currently repeating itself—the FDA has not warned consumers about additional stimulants discovered in weight loss and sports supplements. My colleagues and I informed the FDA in early 2017 that we had identified 2 experimental stimulants, 1,4-dimethylamylamine and octodrine, in dietary supplements.8 One stimulant has never been approved by the FDA for use in humans, and the other was approved for use by inhalation in the 1940s but has since been removed from the US market. Neither stimulant has ever been FDA approved for oral consumption. Our research has since been confirmed by FDA-funded investigators,9 yet as of September 2018 the FDA has not taken any regulatory action to remove these synthetic stimulants from commerce or warn consumers about the novel adulterants.

To counter the perception of regulatory inertia, FDA officials have emphasized their work to eliminate the stimulant 1,3-dimethylamylamine (1,3-DMAA) from supplements. The sympathomimetic 1,3-DMAA was originally introduced by Eli Lilly & Co in the 1940s as a nasal decongestant to compete with amphetamine marketed by Smith, Kline and French.10 By the 1970s, 1,3-DMAA had been withdrawn from the US markets, but it reappeared in the 2000s as a replacement for ephedra in sports and weight loss supplements; by 2012 the stimulant was available in more than 200 brands of supplements.10 The World Anti-Doping Agency banned the stimulant in sport in 2009. In 2011, Health Canada banned 1,3-DMAA from supplements and the US Department of Defense removed 1,3-DMAA supplements from military bases due to safety concerns. The stimulant received prominent media attention as potentially contributing to strokes and deaths of US troops. Only in 2012 did the FDA finally begin to use its full enforcement powers, including warning letters, product seizures, and mandatory recalls, to remove the stimulant from supplements.

More than FDA action will be required to ensure that all adulterated supplements are effectively and swiftly removed from the market. Congress would need to reform the Dietary Supplement Health and Education Act of 1994. One practical change would be to require firms to register supplements with the FDA prior to sale and Congress could provide the FDA with more effective enforcement tools such as immediately revoking a product’s registration if a supplement is found to be adulterated with pharmaceutical drugs. In the meantime, the process that the FDA is required to follow to remove supplements from the marketplace will remain cumbersome and time-consuming; nevertheless, the agency’s failure to aggressively use all available tools to remove pharmaceutically adulterated supplements from commerce leaves consumers’ health at risk.

Article Information
Published: October 12, 2018. doi:10.1001/jamanetworkopen.2018.3329

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Cohen PA. JAMA Network Open.

Egyptian experience, achievements and limitations towards HCV elimination

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In The Journals 
World J Gastroenterol. Oct 14, 2018; 24(38): 4330-4340
Published online Oct 14, 2018. doi: 10.3748/wjg.v24.i38.4330

Towards hepatitis C virus elimination: Egyptian experience, achievements and limitations
Dalia Omran, Mohamed Alboraie, Rania A Zayed, Mohamed-Naguib Wifi, Mervat Naguib, Mohamed Eltabbakh, Mohamed Abdellah, Ahmed Fouad Sherief, Sahar Maklad, Heba Hamdy Eldemellawy, Omar Khalid Saad, Doaa Mohamed Khamiss, Mohamed El Kassas

Worldwide, more than one million people die each year from hepatitis C virus (HCV) related diseases, and over 300 million people are chronically infected with hepatitis B or C. Egypt used to be on the top of the countries with heavy HCV burden. Some countries are making advances in elimination of HCV, yet multiple factors preventing progress; remain for the majority. These factors include lack of global funding sources for treatment, late diagnosis, poor data, and inadequate screening. Treatment of HCV in Egypt has become one of the top national priorities since 2007. Egypt started a national treatment program intending to provide cure for Egyptian HCV-infected patients. Mass HCV treatment program had started using Pegylated interferon and ribavirin between 2007 and 2014. Yet, with the development of highly-effective direct acting antivirals (DAAs) for HCV, elimination of viral hepatitis has become a real possibility. The Egyptian National Committee for the Control of Viral Hepatitis did its best to provide Egyptian HCV patients with DAAs. Egypt adopted a strategy that represents a model of care that could help other countries with high HCV prevalence rate in their battle against HCV. This review covers the effects of HCV management in Egyptian real life settings and the outcome of different treatment protocols. Also, it deals with the current and future strategies for HCV prevention and screening as well as the challenges facing HCV elimination and the prospect of future eradication of HCV.

Full-text article-

Case study of needle exchange programs in the Central Appalachian region of the United States

Qualitative case study of needle exchange programs in the Central Appalachian region of the United States
Stephen M. Davis , Danielle Davidov, Alfgeir L. Kristjansson, Keith Zullig, Adam Baus, Melanie Fisher
Published: October 12, 2018

Due to overwhelming need, PWID are often in the dark regarding the precise outcomes that will be experienced during their next injection. Will it be the sought-after high or a disappointing low? Will it be a fatal overdose or a ‘near-miss’? Similarly, the two West Virginia needle exchange programs described in this case study have been forced to take a shot in the dark and open NEPs in the absence of model programs, adequate funding, and other resources, due to overwhelming need in their small communities. Despite these challenges, such programs have enjoyed robust community support, and have creatively navigated unexpected problems and challenges to effectively implement needle exchange programs in their communities. However, surging participant volumes amidst ongoing funding challenges coupled with location and transportation barriers make the future trajectory of such programs difficult to predict. Additionally, the efficacy of these programs in preventing transmission of blood borne viruses may be compromised from the legal conundrums created by paraphernalia laws and policing behaviors that may promote needle sharing that is the primary risk for acquiring HCV among PWID. Future studies should investigate these potential barriers to using clean needles in people who inject drugs residing in smaller, less populous areas of the United States.

The Central Appalachian region of the United States is in the midst of a hepatitis C virus epidemic driven by injection of opioids, particularly heroin, with contaminated syringes. In response to this epidemic, several needle exchange programs (NEP) have opened to provide clean needles and other supplies and services to people who inject drugs (PWID). However, no studies have investigated the barriers and facilitators to implementing, operating, and expanding NEPs in less populous areas of the United States.

This qualitative case study consisted of interviews with program directors, police chiefs, law enforcement members, and PWID affiliated with two NEPs in the rural state of West Virginia. Interview transcripts were coded inductively and analyzed using qualitative data analysis software. Final common themes related to barriers and facilitators of past program openings, current program operations, and future program plans, were derived through a consensus of two data coders.

Both NEPs struggled to find existing model programs, but benefited from broad community support that facilitated implementation. The largest operational barrier was the legal conundrum created by paraphernalia laws that criminalize syringe possession. However, both PWID and law enforcement appreciated the comprehensive services provided by these programs. Program location and transportation difficulties were additional noted barriers. Future program operations are threatened by funding shortages and bans, but necessitated by unexpected program demand.

Despite broad community support, program operations are threatened by growing participant volumes, funding shortages, and the federal government’s prohibition on the use of funds to purchase needles. Paraphernalia laws create a legal conundrum in the form of criminal sanctions for the possession of needles, which may inadvertently promote needle sharing and disease transmission. Future studies should examine additional barriers to using clean needles provided by rural NEPs that may blunt the effectiveness of NEPs in preventing disease transmission.

Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy

Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy
Yoshihito Uchida, Kayoko Naiki, Jun-ichi Kouyama, Kayoko Sugawara, Masamitsu Nakao, Daisuke Motoya, Mie Inao, Nobuaki Nakayama, Yukinori Imai, Tomoaki Tomiya, Satoshi Mochida Published: October 11, 2018

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Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs.

Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy.

Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011–1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations.

High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy.

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Recommended Reading
Asunaprevir - Wikipedia
Asunaprevir (formerly BMS-650032, brand name in Japan and Russia[1] Sunvepra) is an experimental drug candidate for the treatment of hepatitis C. It is undergoing development by Bristol-Myers Squibb and is currently in Phase III clinical trials.[2] 

Thursday, October 11, 2018

FibroScan after endoscopy found undiagnosed NAFLD, NASH

FibroScan after endoscopy found undiagnosed NAFLD, NASH
October 11, 2018

PHILADELPHIA — FibroScan screening for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis could significantly improve patient diagnosis and care, as data presented at the American College of Gastroenterology Annual Meeting showed that FibroScan found a significant number of undiagnosed cases.
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Meeting Coverage

Gilead to Present 50 Abstracts Across NASH, PSC, HBV and HCV at The Liver Meeting® 2018

Gilead to Present Wide-Ranging New Data on Treatment and Diagnosis of Liver Diseases at The Liver Meeting® 2018

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-- More Than 50 Abstracts Across NASH, PSC, HBV and HCV Reflect Ongoing Commitment to Advancing the Care of People with Liver Disease--

FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 11, 2018-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that data from the company’s liver disease research and development programs in nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection will be presented at The Liver Meeting® 2018 in San Francisco from November 9-13, 2018. The data reflect Gilead’s ongoing commitment to advancing the care of patients with serious liver diseases.

“Gilead has transformed the treatment of viral liver diseases with innovative medicines that have cured HCV and significantly improved treatment of HBV for millions around the world,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research & Development, Gilead Sciences. “Today, we are working to bring this expertise and commitment to other serious liver diseases with significant unmet medical needs, such as advanced fibrosis due to NASH and PSC – two diseases with no or limited treatment options.”

Advanced Fibrosis due to NASH
Individuals with advanced fibrosis, defined as bridging fibrosis (F3) or cirrhosis (F4), are at a significantly higher risk of liver-related mortality. Gilead is advancing multiple investigational compounds for the treatment of advanced fibrosis due to NASH. Data being presented at the meeting further elucidate the potential role and safety profile of three compounds in development.

The non-steroidal FXR agonist GS-9674 leads to significant reductions in hepatic steatosis, serum bile acids, and liver biochemistry in a Phase 2, randomized, placebo-controlled trial of patients with NASH (poster #0736)
Hepatic metabolomics and plasma microRNA analysis of combinations of an ASK1 inhibitor, an ACC inhibitor, and an FXR agonist in the rat choline-deficient high fat diet model reveal reductions in oxidative stress, inflammation and fibrosis (poster #1265)

Currently, liver biopsy is the standard method to diagnose advanced fibrosis due to NASH. This invasive and costly procedure presents challenges to appropriate diagnosis and treatment. Data being presented at The Liver Meeting describe the potential role and sequence of noninvasive tests in the diagnosis of advanced fibrosis due to NASH and patient-reported outcomes from two global Phase 3 trials evaluating the investigational ASK1 inhibitor selonsertib.

Algorithms using noninvasive tests can accurately identify patients with advanced fibrosis due to NASH: Data from STELLAR clinical trials (late-breaking poster #LB-10)
Routinely available noninvasive tests discriminate advanced fibrosis due to NASH in the Phase 3 STELLAR trials of the ASK1 inhibitor selonsertib (poster #1674)
Severe impairment of patient-reported outcomes in patients with advanced fibrosis due to NASH (poster #1683)
Advanced fibrosis based on noninvasive tests in NASH is associated with impairment of patient-reported outcomes (poster #1991)

Data will be presented from a Phase 2 trial evaluating the investigational non-steroidal farnesoid X receptor (FXR) agonist GS-9674 in PSC. PSC is a rare and chronic condition that causes inflammation and scarring of the bile ducts, which can lead to liver failure. There are limited treatment options currently available for patients with PSC.

The non-steroidal FXR agonist GS-9674 improves liver biochemistry and decreases serum bile acids in patients with PSC: A Phase 2, randomized, placebo-controlled trial (oral presentation #0043)

HBV Functional Cure
Data will also be presented from Gilead’s ongoing program directed at achieving a functional cure for HBV by maintaining viral suppression without ongoing therapy. GS-9688, an investigational oral selective toll-like receptor 8 (TLR8) agonist, is the subject of several studies to be presented, including first-in-human clinical results and Phase 1b results from evaluation in patients with chronic hepatitis B. 

First in human study of GS-9688, an oral Toll-like Receptor 8 (TLR8) agonist, in healthy volunteers: assessment of safety, tolerability, pharmacokinetics, pharmacodynamics and food effect (poster #0390)
Pharmacodynamic response to oral administration of the selective toll-like receptor 8 agonist GS-9688 in healthy volunteers (poster #0456)
Safety, pharmacokinetics and pharmacodynamics of oral TLR8 agonist GS-9688 in patients with chronic hepatitis B: a randomized, placebo-controlled, double-blind Phase 1b study (poster #0401)

GS-9674, selonsertib and GS-9688 are investigational compounds and are not approved by the U.S. Food and Drug Administration (FDA) or any other regulatory authority. Their safety and efficacy have not been established.

Viral Hepatitis Treatment
Viral hepatitis presentations include studies of Epclusa® (sofosbuvir 400mg/velpatasvir 100mg) and Harvoni® (ledipasvir 90mg/sofosbuvir 400mg) in difficult to cure HCV populations and data demonstrating the role of Vemlidy® (tenofovir alafenamide 25mg, TAF) in the management of chronic hepatitis B.

Sofosbuvir/velpatasvir for 12 weeks is safe and effective in patients undergoing dialysis (late-breaking poster #LB-15)
Ledipasvir/sofosbuvir for 12 weeks is safe and effective in children 3 to <6 years old with chronic HCV infection (oral presentation #0184)
Three year efficacy and safety of TAF compared to tenofovir disoproxil fumarate (TDF) in HBeAg-negative and HBeAg-positive patients with chronic hepatitis B (poster #0404)
Safety and efficacy at 1 year in post liver transplant patients with chronic kidney disease receiving tenofovir alafenamide for HBV prophylaxis (poster #1225)

EPCLUSA and HARVONI are each indicated in the U.S. for the treatment of chronic HCV infection in patients with no cirrhosis or compensated cirrhosis: EPCLUSA for adults with genotypes 1-6; and HARVONI for patients 12 years and older with genotypes 1, 4, 5 and 6. VEMLIDY is indicated for the treatment of chronic HBV infection in adults with compensated liver disease. The US product labels for EPCLUSA, HARVONI, and VEMLIDY each contain a BOXED WARNING: for EPCLUSA and HARVONI, the risk of hepatitis B reactivation in HCV/HBV co-infected patients; and for VEMLIDY, the risk of post-treatment acute exacerbation of HBV. See below for U.S. Important Safety Information.

The safety and efficacy of EPCLUSA in HCV patients undergoing dialysis and HARVONI in HCV patients ages 3 to up to 6 years of age have not been established.

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Behind The Headlines - Young people turning their backs on alcohol

What is Behind the Headlines?
Each day the NHS Choices team selects health stories that are making headlines. These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information. Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Wednesday October 10 2018

"Shunning alcohol becomes 'mainstream' among young people as a third are now teetotal," reports The Independent.

A study involving nearly 10,000 young people in the UK found that the proportion of 16- to 24-year-olds who say they never drink alcohol rose from 18% in 2005 to 29% in 2015. The study also found that young people who did drink alcohol were drinking less nowadays and that binge drinking rates were falling.

The researchers said the drop in numbers of young people drinking suggested a shift in attitudes towards alcohol. They say this could be due to increased awareness of the health risks of alcohol, as well as changes in the way young people spend their leisure time.

The researchers observed a decrease in drinking in most groups of young people, including those in employment, in education, and with generally healthy lifestyles, and across all income groups.

However, there was no decrease among smokers, some ethnic groups and people with poor mental health. This may indicate a need to reach out with more support to certain groups.

Current UK guidelines advise men and women to drink no more than 14 units of alcohol a week; equivalent to 6 pints of average-strength beer or 10 small glasses of low-strength wine.

Find out about calculating units of alcohol.

Where did the story come from?
The researchers who carried out the study were from the Department of Epidemiology and Public Health, University College London.

The study was funded by grants from Alliance House Foundation, an organisation that promotes "temperance" or not drinking alcohol. It was published in the peer-reviewed medical journal BMC Public Health and is free to read online.

The story was widely reported. The Telegraph is one of several media outlets that speculated about the reasons for the drop in drinking, suggesting in its headline that "millennials are shunning alcohol" because they think "getting drunk is no longer cool".

But the study didn't actually look into the reasons for the decrease in drinking. More research is needed to investigate the reasons why young people are less likely to drink alcohol.

What kind of research was this?
This was an analysis of repeated cross-sectional surveys of people aged 16 to 24 in England.

The researchers wanted to see how alcohol consumption had changed over time among young people in different subgroups. They also wanted to see how the increase in non-drinking related to the amount of alcohol consumed by those young people who did drink.

Cross-sectional research shows a snapshot of people's behaviour at any one time. Although behaviour can then be linked with factors such as income levels or health habits, we cannot tell from cross-sectional research what causes the behaviour observed. In other words, this study can't tell us what's causing more young people to abstain from drinking.

What did the research involve?
Researchers used data from the Health Survey for England 2005 to 2015, an annual nationwide survey that asks questions about a wide range of health behaviours. For this study, researchers looked only at information from the 9,699 participants aged 16 to 24.

People were asked whether they drank alcohol. If they answered no, they were asked if they had ever consumed alcohol, had previously drunk alcohol or occasionally drank alcohol.

People who said they did drink alcohol were asked if they had done so in the past week, and how many units they had drunk on their heaviest drinking day.

The researchers also looked at:
body mass index (BMI)
smoking status
fruit and vegetable consumption
physical activity levels
wellbeing and mental health
whether the participants had any long-term illness

They looked at the results broken down by:
age group (16 to 17 or 18 to 24)
ethnic background
region where participants lived
whether they lived in a town, city or village
deprivation level of their local area
household social class
whether they were in full-time education or employed

What were the basic results? 
Overall the researchers found that between 2005 and 2015:
the numbers of people aged 16 to 24 who described themselves as non-drinkers rose from 18% to 29%
the numbers who had never drunk alcohol rose from 9% to 17%
the numbers who hadn't had a drink in the last week rose from 35% to 50%
the numbers who drank above recommended weekly limits fell from 43% to 28%
the numbers who had engaged in binge-drinking fell from 27% to 18%

The increase in non-drinking was seen in most subgroups, including both age groups and genders, north and south of the country, urban and rural areas, deprived and non-deprived areas, and those in and not in education or employment.

The numbers of non-drinkers rose among white young people but not among those from ethnic minorities. However, 68% of young people from ethnic minorities described themselves as non-drinkers in 2015, compared to 20% of white young people.

People with different health behaviours showed some difference in terms of drinking. Non-drinking increased among non-smokers but not among young people who smoked. It also increased among those who did high levels of physical activity, but not those who did less exercise.

This may suggest differences in health awareness, though non-drinking rates did increase in people with low fruit and vegetable consumption and regardless of BMI.

The researchers did not see an increase in non-drinking among people with lower scores of health and mental wellbeing.

How did the researchers interpret the results?
The researchers said their results "might suggest that the norms around non-drinking are changing, and this behaviour is becoming more mainstream among young people".

They said "increasing rates of non-drinking among young people are to be welcomed" and noted that the decline in drinking "may influence lower average consumption overall, which tends to reduce problematic drinking".

They said it is "difficult to pinpoint a single factor" behind the decline in drinking, but speculated it may be because of stricter licensing laws, increased awareness of the harms of alcohol, and changes in the way young people spend their leisure time – for example, using social media rather than meeting in a pub or bar.

We don't know for sure from this study why young people are increasingly turning away from drinking alcohol. However, the figures suggest a robust trend, which may or may not continue in future.

The decline in drinking could be due to increasing health awareness among young people and people making healthier lifestyle choices. From a public health point of view, this is probably good news, not least because the numbers of young people engaging in harmful binge drinking is also in decline.

The study has some limitations:
Some of the subgroups considered were quite small, which means the data for these groups may be less reliable. 

Although the participants were surveyed every year, not all of the health questions were asked each year. So in some years there's missing data for the amount of exercise people took, the amount of fruit and vegetables they ate, or for their mental health status. 

Cross-sectional surveys show only a snapshot or series of snapshots in time, so we don't know how the findings relate to changing habits among individuals over time.

Despite the drop in numbers of young people drinking, 28% of young people still reported drinking above recommended levels on at least 1 day in the week they were surveyed, in 2015. The lack of change in drinking habits among young people who smoked was also notable. There are still issues to address and people who may benefit from more support to reduce their alcohol intake.

Current UK guidelines advise men and women to drink no more than 14 units of alcohol a week; equivalent to 6 pints of average-strength beer or 10 small glasses of low-strength wine.

Find out about calculating units of alcohol.

Analysis by Bazian
Edited by NHS Website

Genetic Achilles heel hurts humans fighting hepatitis C

Not all people are equally vulnerable to hepatitis C – new study
The hepatitis C virus (HCV) infects around 1% of the human population and is a devastating pathogen. In most people, it silently infects the liver for decades, often causing life-threatening inflammation, scarring and even cancer. How the virus achieves this feat has long puzzled scientists.

In our latest study, published in PLOS Pathogens, we found that a molecule that defends against HCV and other pathogens is weaker in humans than in our closest relative, the chimpanzee. This weakened molecule might have made it easier for some viruses, such as HCV, to infect humans and cause disease.
Read the article....

Genetic Achilles heel hurts humans fighting hepatitis C 
An antimicrobial signaling molecule called IFNλ4 has lower activity against the hepatitis C virus in the vast majority of humans compared with chimpanzees and African hunter-gatherer Pygmies, according to a study published October 11 in the open-access journal PLOS Pathogens by John McLauchlan's research team at the MRC-University of Glasgow Centre for Virus Research in the UK, and colleagues. 

As antimicrobial signaling molecules, type III or lambda interferons (IFNλs) are critical for defending against infection with diverse pathogens, including bacteria, fungi and viruses. Counterintuitively, a natural mutation that prevents IFNλ4 production improves hepatitis C virus clearance in humans. However, the underlying mechanisms remain poorly understood. To further understand how genetic variation affects IFNλ4 function, McLauchlan and his colleagues screened a comprehensive panel of all natural human IFNλ4 variants for their antiviral potential and carried out a comparative analysis with related species. 

Remarkably, the most common form of human IFNλ4 is less able to protect cells from pathogenic virus infection than the equivalent protein from our closest living relative, the chimpanzee, due to a single amino acid substitution. African hunter-gatherer Pygmies also have a more active IFNλ4, which was likely reacquired following the divergence of chimpanzees and humans. The findings suggest that the evolution of the interferon lambda 4 (IFNL4) gene has placed humans at a disadvantage when infected with pathogens such as hepatitis C virus. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose in Africa very early during human evolution between six million and 360,000 years ago. 

John McLauchlan and Connor Bamford, the first author on the paper, commented, "We were astonished that humans were the only species to carry this mutation and it remains a mystery as to why the human population has evolved an antiviral gene that is less able to control viral infections compared to our closest ancestors." 

Wednesday, October 10, 2018

Pathways to ensure universal and affordable access to hepatitis C treatment

In Case You Missed It

Pathways to ensure universal and affordable access to hepatitis C treatment 
Caitlin H. Douglass, Alisa Pedrana, Jeffrey V. Lazarus, Ellen F. M. ‘t Hoen, Radi Hammad, Ricardo Baptista Leite, Andrew Hill and Margaret Hellard
BMC Medicine201816:175
Received: 27 February 2018Accepted: 29 August 2018Published: 9 October 2018

History records very few opportunities to eliminate a chronic infection. In the DAA era, eliminating hepatitis C as a public health threat is possible, yet it can only be achieved with affordable access to DAAs worldwide. Case studies of Australia, Portugal and Egypt demonstrate that comprehensive public health-based viral hepatitis plans facilitate negotiations with pharmaceutical companies. Shifting from individual-focused hepatitis C treatment to elimination requires strong political will and advocacy. If price negotiations with pharmaceutical companies do not produce reasonable prices for DAAs, governments can utilise flexibilities in patent law to ensure access to low-priced generic sources.

Direct-acting antivirals (DAAs) have dramatically changed the landscape of hepatitis C treatment and prevention. The World Health Organization has called for the elimination of hepatitis C as a public health threat by 2030. However, the discrepancy in DAA prices across low-, middle- and high-income countries is considerable, ranging from less than US$ 100 to approximately US$ 40,000 per course, thus representing a major barrier for the scale-up of treatment and elimination. This article describes DAA pricing and pathways to accessing affordable treatment, providing case studies from Australia, Egypt and Portugal. Pathways to accessing DAAs include developing comprehensive viral hepatitis plans to facilitate price negotiations, voluntary and compulsory licenses, patent opposition, joint procurement, and personal importation schemes. While multiple factors influence the price of DAAs, a key driver is a country’s capacity and willingness to negotiate with pharmaceutical companies. If negotiations do not lead to a reasonable price, governments have the option to utilise flexibilities outlined in the Agreement on Trade-Related Aspects of Intellectual Property Rights. Affordable access to DAAs is underpinned by collaboration between government, civil society, global organisations and pharmaceutical companies to ensure that all patients can access treatment. Promoting these pathways is critical for influencing policy, improving access to affordable DAAs and achieving hepatitis C elimination.

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On This Blog

The controversy over expensive new drugs for hepatitis C
Link to a collection of research articles addressing the high cost of HCV medications, insurance restrictions; private insurers/Medicaid and availability of generic versions/India, Egypt and other lower-income countries, or through online "buyers clubs"

The British HIV Association is calling for accelerated efforts to cure hepatitis C virus in all those living with HIV

BHIVA statement

The British HIV Association (BHIVA) calls for accelerated efforts to prevent and cure hepatitis C infection in all those living with HIV 
10 October 2018

The British HIV Association (BHIVA) is calling for accelerated efforts to cure hepatitis C virus in all those living with HIV. New treatments for hepatitis C, direct acting agents (DAAs,) have transformed the potential for cure in patients when compared to older, interferon based, therapies. Curing hepatitis C can not only reduce the risk of cancer and liver cirrhosis, but also reduces the risk of cardiovascular disease, diabetes and other associated conditions. Until recently, access to these expensive treatments was limited but with treatment now widely available on the NHS, the new priority is to ensure all those with the virus are diagnosed, linked to services and cured.

Ambitious targets
As part of a concerted and collective effort towards eliminating hepatitis C as a major public health threat, BHIVA will be working closely with local services over the coming year to ensure all patients co-infected with HIV and hepatitis C are linked to care and treatment. We propose the following ambitious targets:
80% of all patients with diagnosed HIV and hepatitis C co-infection cured of hepatitis C by April 2019 (with 100% of patients assessed for therapy)

90% of all patients cured of hepatitis C by April 2020

100% of all patients cured of hepatitis C by April 2021.

In contrast to recent rapid progress in treating the majority of those diagnosed with HIV and hepatitis C co-infection, we expect the achievement of 100 per cent cure to be slower. This is because services will have to treat a small number of particularly vulnerable patients who struggle to make appointments and take medicines. In the short term, many services are likely to need additional staff and new ways of delivering care to ensure all those with the virus can be cured. Achieving this is likely to require plans tailored to individuals being delivered in different settings across the UK.

At the same time as increasing the uptake of treatment, it is important to maintain hepatitis C prevention initiatives and regular testing in those at risk (see BHIVA guidelines, particularly given the potential of bridging networks between those most vulnerable in the HIV positive and other at-risk communities. Patients continue to be diagnosed with new HCV infection, even after cure, and in some settings there remain policies restricting treatment of these patients until chronic infection is established. These groups are particularly likely to pass on infection and such policies have the potential to undermine progress being made towards hepatitis C microelimination (elimination within a particular group of patients) within people living with HIV (PLWHIV). We would urge all health commissioners to ensure treatment continues to be available for all who need it to stop the epidemic re-emerging in PLWHIV.

BHIVA will work closely with public health agencies to monitor progress in all parts of the UK. For example, with support from Public Health England, BHIVA estimates there were approximately 3,300 people living with diagnosed HIV and hepatitis C in England at the beginning of 2016, and that over half of these patients have now been cured for hepatitis C as a result of treatment with DAAs. In some regions (for example, the North East of England and Tayside in Scotland) 100 per cent cure is already close to being achieved.

The UK can be the first country to achieve microelimination of hepatitis C in those living with HIV, well ahead of WHO targets. We should seize this opportunity. 

1. WHO Global health sector strategy on viral hepatitis 2016-2021. Geneva June 2016

2. Stanaway et al The global burden of viral hepatitis from 1990-2013: findings from the Global Burden of Disease Study 2013 Lancet. 2016 Sep 10;388(10049):1081-1088. doi: 10.1016/S0140-6736(16)30579-7. Epub 2016 Jul

3. Platt et al Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Lancet Infect Dis. 2016 Jul;16(7):797-808. doi: 10.1016/S1473-3099(15)00485-5

4. Cooke and Hallett HCV and HIV: shared challenges, shared solutions Lancet Infect Dis. 2016 Jul;16(7):755-756

5. Public Health England Hepatitis C in England 2018 report March 2018

6. Hepatitis C Trust Eliminating Hepatitis C in Scotland: a call to action

Current noninvasive liver reserve models do not predict histological fibrosis severity in hepatocellular carcinoma

Nature Research Journal - Scientific Reports
Current noninvasive liver reserve models do not predict histological fibrosis severity in hepatocellular carcinoma 
Shu-Yein Ho , Po-Hong Liu, Teh-Ia Huo

...No study to date has specifically evaluated the relationship and accuracy between noninvasive liver reserve models and the severity of liver fibrosis in HCC. We aimed to investigate the correlation of the currently used noninvasive liver function models and histological fibrosis in HCC patients undergoing surgical resection...

The Ishak scoring system has been used to stage liver fibrosis. Ten noninvasive liver reserve models were proposed to assess the severity of liver fibrosis, but their performance in hepatocellular carcinoma (HCC) is unknown. We aimed to evaluate the correlation between these models and severity of fibrosis in patients with HCC. A total 464 patients with HCC undergoing surgical resection were retrospectively analyzed. Multivariate logistic regression analysis was performed to determine independent factors associated with advanced fibrosis (Ishak score 4 or higher). There were no significant correlations between all noninvasive models and severity of fibrosis in HCC (p for trend all >0.1). In subgroup analysis, cirrhosis discriminant index (CDS) and Lok’s index in hepatitis B-, and fibrosis index based on 4 factors (FIB-4), CDS and Lok’s index in hepatitis C-associated HCC, best correlated with the severity of liver fibrosis. Low platelet count, prolonged prothrombin time, hepatitis C and multiple tumors were independently associated with advanced fibrosis. Among the 10 models, CDS was the best model to predict cirrhosis. Currently used noninvasive liver reserve models do not well correlate with severity of histological fibrosis in HCC. New noninvasive models are required to improve the predictive accuracy of liver fibrosis in HCC.

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Impact of successful HCV treatment on health-related quality of life

Impact of successful treatment with direct-acting antiviral agents on health-related quality of life in chronic hepatitis C patients 
Regina Juanbeltz , Iván Martínez-Baz, Ramón San Miguel, Silvia Goñi-Esarte, Juan Manuel Cabasés, Jesús Castilla
Published: October 9, 2018 

Direct-acting antivirals (DAA) have demonstrated high efficacy to achieve sustained virological response (SVR) in chronic hepatitis C patients. We aim to assess the change in health-related quality of life (HRQoL) among patients successfully treated, and to identify predictors of this variation.

In a prospective observational study, patients with chronic hepatitis C who started DAA therapy between May 2016 and April 2017 completed the EQ-5D-5L questionnaire at baseline and 12 weeks after the end of therapy before knowing the virological result. Analysis included all patients with SVR.

Median baseline EQ-5D-5L scores of the 206 enrolled patients were 0.857 utility and 70.0 visual analogue scale (VAS). Following SVR, a reduction occurred in the proportion of patients with mobility problems (35% vs 24%, p = 0.012), pain/discomfort (60% vs 42%, p<0.001) and anxiety/depression (57% vs 44%, p = 0.012), with an increase in utility (+0.053, p<0.001) and VAS (+10, p<0.001). Score improvements were also observed in cirrhotic (+0.048 utility, p = 0.027; +15 VAS, p<0.001) and HIV co-infected patients (+0.039 utility, p = 0.036; +5 VAS, p = 0.002). In multivariate analyses, middle age (45–64 years) and baseline anxiety/depression were associated to greater improvement in utility after SVR, and moderate-advanced liver fibrosis and cirrhosis to greater increase in VAS score. Low baseline values were associated to greater improvements in utility value and VAS score.

The cure of chronic hepatitis C infection with DAA has a short term positive impact on HRQoL with improvement in mobility, pain/discomfort, anxiety/depression, utility value and VAS score. Patients with poor baseline HRQoL were the most beneficed.

Discussion & Conclusion
Full-Text Article - PDF Download  Or View Online 
Successful treatment with DAA on health-related quality of life in patients with chronic hepatitis C was associated to significant improvement in the majority of HRQoL domains measured by the EQ-5D-5L instrument. Improvement of HRQoL started shortly after the initiation of therapy and enhanced after achieving SVR, including cirrhotic and HIV co-infected patients, classically considered “difficult to treat” populations. Main improvements occurred in mobility, pain/discomfort and anxiety/depression dimensions, as well as in the health utility and VAS score. Although evidence from “real life” setting is lacking [23], patient reporting outcomes with DAA in clinical trials also suggest benefit after treatment [3336]. Relationship between SVR and HRQoL improvement has not been elucidated, but viral clearance has been suggested to result in cytokines and inflammatory biomarkers reduction in periphery and central nervous system, leading to a positively impact on patients’ experience [37, 38]. The improvement observed in the well-being of patients cured with DAA reinforces the idea that chronic HCV infection, far from being a purely hepatic disease, presents a clearly systemic component and impaires HRQoL [39,40]. According the Spanish National Health Survey 2011/12 [41], the general population aged 45–54 years referred a VAS score of 77.2 and utility value of 0.928, being higher figures than those referred by our patients before treatment, 70.0 and 0.875, respectively. Lower scores in our patients suggest a HRQoL impairment associated to chronic hepatitis C infection [7, 29].

In the first 4 weeks of treatment, the median VAS score increased 5 points and improved health dimensions that were negatively affected with interferon treatments [42]. This early improvement in HRQoL has been described for DAA [35], contrary to what happened with peg-IFN + RBV and triple therapy with boceprevir or telaprevir [10,17,43,44], which seems to relate HRQoL deterioration during treatment to interferon and not to second generation DAA. The use of RBV was not associated with significant disutility, a fact that suggests a lower impact of side effects such as anaemia and pruritus, when administered in combination with DAA compared to when administered with interferon. This aspect reinforces the idea of the good tolerability of DAA in real life conditions [45,46].

In clinical practice, patient reporting outcomes constitute useful tools in the evaluation and monitoring of health interventions, since they provide information on patient perception and needs [47]. Knowing the predictors of HRQoL improvement after the treatment of hepatitis C can help to strengthen patient adherence and motivation. Middle age, baseline anxiety-depression, advanced fibrosis and cirrhosis were found to be the most consistent predictors of HRQoL improvements after SVR. Precisely, those factors have been previously associated with impairment in HRQoL among chronic hepatitis C patients [4,29,48] and appear to be key determinants for HRQoL deterioration prior to therapy [14]. The high prevalence of depression and anxiety in HCV patients before treatment initiation [49] would reinforce the need for psychosocial screening, even more when considering that a greater HRQoL improvement may occurs in those patients after SVR. In our study, patients with worse baseline HRQoL score showed more significant improvements, a common finding in all types of clinical trials [50]. This result is consistent with the greater improvement in HRQoL in cirrhotic patients, with comorbidity or HIV co-infection, observed in the stratified analysis of the study.

This study provides useful information for cost-effectiveness analysis. Utility values allow to obtain quality adjusted life years, and to estimate incremental cost-utility ratios in pharmacoeconomic analysis. Since the advent of second-generation DAA, some cost-utility analyses have been published to assess their efficiency [5154], with more or less favourable incremental cost-utility ratios depending on the degrees of liver fibrosis, the cost of the drugs and the previous treatment experience. More favourable treatment efficiency in patients with a high degree of fibrosis is derived from the potential more imminent progression to severe stages, associated with greater disutility and greater consumption of health resources [51,52]. According to our results, the more significant HRQoL improvement in cirrhotic patients after the SVR reinforces this idea. In any case, a decline in the cost of drugs and the possibility of currently treating patients with a low degree of liver fibrosis with short 8-week regimens, would reduce the incremental cost-utility ratios and improve the efficiency of treatment in all patient subpopulations.

This real-life prospective study included hepatitis C patients who received treatment in a regional reference hospital in northern Spain. Although the epidemiology of HCV infection and the introduction of DAA have been relatively homogeneous in Spain, we can not rule out some geographical differences which would affect representativeness of our study. However, patients were infected by all HCV genotypes with a distribution similar to that of the population in our environment [55], in the different stages of the disease, treated with all available combinations of DAA and without excluding patients with comorbidity. The indication and choice of treatment was based on the same protocol, developed according to clinical and efficiency criteria. HRQoL was analysed including subpopulations of patients usually underrepresented in clinical trials, such as those with psychiatric disorders or persons co-infected with HIV [23], which represent one third of the population in this study. All the interviews were carried out by the same investigator, in order to minimize the potential bias of the interviewer. The timing of the interview may affect the results. The post-12 interview was conducted in our study before knowing the SVR result, in order to avoid the possible overestimation on patient’s HRQoL self-assessment secondary to the euphoria experienced at that moment [43,56]. However, when patients know HCV become negative after treatment, the worry about the complications of the disease probably decrease and an improvement in the anxiety dimension could be greater than that observed in our study. A long-term evaluation of HRQoL after SVR would contribute to understand the effect of timing on HRQoL results.

Two possible shortcomings of our study need to be considered. First, the population size, although similar or greater than that of other observational studies [35,14,57] was not large enough to obtain conclusive results in some subanalyses. In any case, the patients included accounted for 78% of the patients who received treatment successfully during the study period. Second, the EQ-5D-5L is a generic questionnaire. Although it has been used in many scenarios, including chronic hepatitis C and its treatment, its combination with a disease-specific questionnaire would have been desirable. Time-related limitations in terms of patient care in the consulting room and of personnel related to completing the interviews discouraged the use of other questionnaires. However, studies that use both types of tools for measurement of patient reporting outcomes in patients treated with DAA therapy obtained similar results and good correlation between the generic and HCV-specific questionnaires [10,35]. EQ-5D-5L version was used in this study, as it has demonstrated to be a valid extension of EQ-5D-3L, providing more precise measurement at both individual and group level [5861]. Since no 5L value sets were yet available in Spain, the crosswalk value set was used in this study, as the EuroQol recommended [31].

The new antivirals available recently seem to improve even more the treatment outcomes, being expected this same effect on quality of life.

In summary, this study shows a short-term positive impact of SVR on the HRQoL of patients with chronic hepatitis C treated with interferon-free DAA. The greatest impact was on health dimensions of mobility, pain/discomfort, anxiety/depression, and in utility values and the VAS of the EQ-5D-5L questionnaire. The treatment did not produce disutility, nor did the use of RBV. Predictors of greater improvements in HRQoL with SVR may be baseline depression, anxiety, moderate-advanced fibrosis and cirrhosis; which may help to give priority to patients for treatment. The results obtained provide the patient's perspective in the assessment of DAA and information on patient reporting outcomes to be incorporated in cost-utility studies.