Monday, March 27, 2017

Would legalizing medical marijuana help curb the opioid epidemic?

Drug and Alcohol Dependence
April 1, 2017 Volume 173, Pages 144–150

Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever
Yuyan Shi

ArQule Announces Top-Line Results of Phase 3 Clinical Study of Tivantinib in Hepatocellular Carcinoma in Japan

ArQule Announces Top-Line Results of Phase 3 Clinical Study of Tivantinib in Hepatocellular Carcinoma in Japan

March 27, 2017
ArQule, Inc. (ARQL) today reported that its partner, Kyowa Hakko Kirin, announced top-line results of the JET-HCC Phase 3 trial of tivantinib in Japan, and that the trial did not meet its primary endpoint of progression free survival (PFS).

JET-HCC is a randomized, double-blind placebo-controlled study that enrolled approximately 190 Japanese patients with c-Met diagnostic-high inoperable hepatocellular carcinoma (HCC) with a history of prior sorafenib therapy, to evaluate the efficacy and safety of tivantinib.

The primary endpoint of the trial is PFS, and the top-line results did not show a significant difference in PFS between the tivantinib group and the placebo group. There were no new safety issues observed in the trial.

The details of the study results will be presented in an upcoming scientific forum.

“I would like to thank our partner, Kyowa Hakko Kirin, and all the participants in their study,” said Paolo Pucci, Chief Executive Officer of ArQule. “The results are disappointing as there is a need for a second-line HCC therapy in Japan.”

Hepatitis C - Medicare Part D: High costs put some drugs out of reach

Medicare Part D: High costs put some drugs out of reach
March 27, 2017 12:45 PM
By Katie Wedell / Dayton Daily News
DAYTON, Ohio — High-priced prescription drugs are driving up the cost of Medicare Part D catastrophic coverage, which is bad news for both patients and taxpayers, according to a new report from the Department of Health and Human Services Office of Inspector General.

Patients on specialty drugs for cancer, hepatitis C, multiple sclerosis and other diseases are seeing higher out-of-pocket costs because of inflated list prices that accelerate their move into a coverage gap known as the “doughnut hole,” the report says.

The government’s spending is only going to grow, as 3 out of 4 hepatitis C patients are baby boomers who are aging into eligibility for Medicare Part D.

Drugs like Harvoni are extremely effective, he said, but are beyond reach for many of those afflicted with hepatitis C....
Continue reading... 

MSF joins Europe-wide action challenging patent on key hepatitis C drug

MSF joins Europe-wide action challenging patent on key hepatitis C drug

Patent opposition aims to increase affordable access to hepatitis C drug sofosbuvir for millions

State Health Registry issues ‘Cancer in Iowa: 2017’ report, highlights increase in liver cancer cases

Increase In Liver Cancer Cases

An excerpt from the report released by the Iowa State Health Registry is provided below, full press release available here

The report, based on data from the Iowa Cancer Registry and the Iowa Department of Public Health, is available online in the “Publications” section on the registry’s website or by calling the registry at 319-335-8609. The report includes county-by-county statistics, summaries of new research projects, and a special section focused on liver cancer.

Liver cancer is the 13th leading cause of cancer deaths in Iowa. However, unlike most other common cancers, both new cases of and deaths from liver cancer are on the rise in Iowa and throughout the U.S.

The rate of new liver cancer cases in Iowa has roughly tripled over the past 35 years, from two cases per 100,000 people in 1975 to 1979 to six cases per 100,000 in 2010 to 2014.

Michael Voigt, clinical professor of internal medicine and a specialist in gastroenterology and hepatology at University of Iowa Hospitals and Clinics, says that chronic infections of hepatitis B or hepatitis C are the major risk factors for liver cancer, and these infections are correlated with the increase in the number of cases.

“Liver cancer is predominantly due to hepatitis B or hepatitis C infection, and chronic viral hepatitis ultimately causes more deaths than breast cancer, heart failure, or prostate cancer,” Voigt says. “Deaths from hepatitis C are at an all-time high, and the number of cases in people under 30 years of age is increasing dramatically in Iowa.”

However, Voigt notes that because there is a vaccination for hepatitis B and effective treatment of both hepatitis B and C, liver cancer is highly preventable. “The Centers for Disease Control and Prevention (CDC) recommends that everyone born between 1945 and 1965 be tested for hepatitis C,” he says. “It is a silent killer, and the majority of people with hepatitis C are unaware of it.”

Though most cases of liver cancer prove to be fatal, national data show that in recent years deaths have been increasing slower than new cases. Iowa data shows a similar trend but has lower rates overall, possibly due to earlier detection and improvements in treatment of chronic hepatitis.

George Weiner, director of Holden Comprehensive Cancer Center at the University of Iowa, says that researchers consider the disease from all angles in order to reduce the number of cancer deaths.

“Cancer prevention, early detection, and therapy are all important as we seek to reduce the burden of cancer, including liver cancer,” Weiner says. “We are continuing to make progress through research in all of these areas.”

Continue reading....

The 2017 Hepatitis C Community Summit – a key step on the road to elimination

The 2017 Hepatitis C Community Summit – a key step on the road to elimination
In the lead-up to the annual International Liver Congress (ILC) in Amsterdam, Eberhard Schatz of the Correlation Network writes about the Hepatitis C Community Summit that will be held in Amsterdam on the 18-19th of April to focus on community related initiatives and their key role in the hepatitis C elimination movement. Read more about the Summit and register here.
Next month, April, brings the annual meeting of the European Association for the Study of the Liver (EASL), the International Liver Congress (ILC) 2017 in Amsterdam. The ILC serves as one of the most important international meetings on liver research in the calendar year. This year, also in Amsterdam just prior to the opening day of the ILC, the Correlation Network Hepatitis C Initiative has organized the two-day Hepatitis C Community Summit on the 18th and 19th of April.
It is now critically important to reach out to risk groups, such as networks of people who inject drugs, to involve and inform them about treatment options, to provide barrier-free access, and to meet people where they are.
To face the challenges ahead and to effectively provide access to all patients in need, we think the medical world, hepatologists, and consequently the International Liver Congress, must take into account crucial aspects of public health and community involvement to reach global hepatitis elimination goals.

Due to the fact that treatment with new direct-acting antivirals is quick and effective, it is now critically important to reach out to risk groups, such as networks of people who inject drugs, to involve and inform them about treatment options, to provide barrier-free access, and to meet people where they are: in community centres, harm reduction and low-threshold service settings, opioid substitution treatment centres, etc.

The Hepatitis C Community Summit fills a gap in the world of hepatitis C virus (HCV) research, bringing together diverse partners from Europe to provide a platform for community inclusion with all those involved in HCV treatment, most notably civil society. The Summit will bring attention to bear on hepatitis C from the perspectives of medical experts and researchers, as well as patients and representatives of harm reduction and community services in order.
The Summit aims to provide an overview on existing (community related) initiatives, to address challenges and barriers ahead, and provide a platform for exchange across professional borders.
The Summit aims to provide an overview on existing (community related) initiatives, to address challenges and barriers ahead, and provide a platform for exchange across professional borders. In this regard, we are very happy that EASL, WHO, and other important stakeholders and speakers will be contributing to the event.

In addition to attending community members, patient representatives, service providers in community and harm reduction settings, researchers, and several policy makers, we invite ILC participants to join the two-day programme. There will be a welcome, keynote, short plenary speeches from the full spectrum of knowledge in the hepatitis field, and roundtable discussions on the first day as well as two plenary sessions, parallel workshop-style sessions, and a final reception during the second day.

The Summit will be concluded with the launch of a ‘Community Declaration’, a consensus statement highlighting the importance of community involvement in the process of eliminating HCV. This declaration will initially be endorsed by the Hepatitis C Community Summit organizing partners:
We look forward to seeing you in Amsterdam!

Source -

HIV and Hepatitis C are No Longer the Most Serious Infectious Threats to People Who Inject Drugs

Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases

HIV and ID Observations
An ongoing dialogue on HIV/AIDS, infectious diseases,
all matters medical, and some not so medical.

In Case You Missed It

HIV and Hepatitis C are No Longer the Most Serious Infectious Threats to People Who Inject Drugs

I had dinner with my daughter Mimi the other evening, and was ruminating about how things have changed since I started work as an Infectious Diseases doctor around 25 years ago.

Here’s an excerpt of our chat:

Me:  There are way more cases of endocarditis in young people than there used to be, a complication of injecting drugs. People in their 20s and 30s with life-threatening infections, getting admitted to the hospital, needing antibiotics for weeks, sometimes surgery … it’s awful. [I didn’t mean for this to sound like a cautionary speech to my 21-year-old daughter, but reading it now — guilty as charged.]
Mimi:  Endocarditis?
Me:  Infection of the heart valves. It’s an incredibly serious problem, much more difficult to treat than HIV and HCV. Even with our best antibiotics, some people need major heart surgery — their lives are never the same. And sometimes the infection spreads through the blood to the lungs, spine, brain… Some even die!

Continue reading....

Treat All - Are we nearing the end in the fight against hepatitis C?

Journal: Expert Review of Gastroenterology & Hepatology

Are we nearing the end in the fight against hepatitis C?
Joel V. Chua & Shyam Kottilil
Received 09 Jan 2017, Accepted 17 Mar 2017
Accepted author version posted online: 24 Mar 2017

View Article
Download PDF

With a robust choice of DAA regimens available, even patients that were in the past considered hard to treat such cirrhotic patients, or those previously excluded from treatment due to chronic kidney disease, now have therapeutic options.  For example, elbasvir-grazoprevir is preferred to be used in HCV-infected patients with chronic kidney disease; while decompensated HCV cirrhotic patient are able to be treated with sofosbuvir-ledipasvir-ribavirin, or sofosbuvirvelpatasvir-ribavirin, or sofosbuvir-daclatasvir-ribavirin regimens.  In addition, highly effective and safe pangenotypic DAA regimens such as the once daily fixed dose combination sofosbuvirvelpatasvir, as well as daclatasvir plus sofosbuvir, increases the breath of those that can be treated and cured.  These advancement in drug therapy against HCV, coupled with increasing availability of generic DAAs [6] outside of the U.S. will increase access to these highly efficacious cure drugs worldwide.

Though having safe and highly effective drug regimens that can “virtually” cure all HCV infected individuals is an integral part of any hepatitis C eradication strategy, it still is just one component to achieving disease elimination..
Continue reading....

Gilead hepatitis C drug patent faces European challenge

Gilead hepatitis C drug patent faces European challenge
International groups representing doctors and patients have launched a fresh challenge to the patent on Gilead Sciences' hepatitis C drug sofosbuvir at the European Patent Office in order to increase access to the treatment.

MSF and MdM, who have been joined by 28 groups from across Europe, said key patents on sofosbuvir had already been revoked in China and Ukraine, and decisions were pending in other countries, including Argentina, India, Brazil, Russia and Thailand.

Continue reading...

Saturday, March 25, 2017

Hep C Weekend Reading: Favorite quote of the week “Fight to treat your patients as early as possible.”

HCV Weekend Reading
Hope you all had a wonderful week, sit back and catch up on what you may have missed over the last week in this issue of Weekend Reading.

In a recent article published in Clinical Infectious Diseases, data suggested that delaying hepatitis C treatment regardless of fibrosis stage may be detrimental to patients, ya think?  Reuters Health reported: "Mortality is increased in patients with moderate or severe liver disease related to chronic hepatitis C, and progression from mild/moderate to severe disease cannot be predicted reliably." Here is a quote from Dr. Cepeda, a key author of the study; “Fight to treat your patients as early as possible.” Read the rest of the article, here.

However, according to a report released this month from Trio Health, after patients are prescribed HCV therapy insurance companies are denying coverage, interim data from the study showed HCV treatment non-starts are up, from eight percent in 2014, to over 30 percent in 2016, for the most part because of payer coverage denials. The HCV regimens evaluated in the study include the following: Sovaldi®/Harvoni® (Gilead), Viekira Pak™ (Abbvie), Zepatier™ (Merck), Daklinza™ (BMS) and Epclusa® (Gilead). Read commentary on the report here, Trio press release here.

Annals of Internal Medicine, reported high cure rates, with few side effects, in a review article on various FDA approved regimens to treat chronic hepatitis C. Sustained virologic response (SVR) for genotype 1 (using different approved HCV regimens) was reported at over 95%. Sofosbuvir plus velpatasvir  or daclatasvir for 12 weeks in genotype 3 patients without cirrhosis appeared to seem most effective, for geno 3's with cirrhosis, a regimen of velpatasvir-sofosbuvir had higher response rates, the latter is  also highly effective (99% response rate) for genotypes 2, 4, 5, and 6, this summary was published in NEJM Journal Watch, read the full text article; Hepatitis C: Down but Not Out - Oral Direct-Acting Agent Therapy for HCV.

Weekly News Coverage
HEP offers hepatitis C research with daily news, a great place to start learning about HCV.
Over at HepCBC, each Friday a nice summary of news is available, read this weeks: Weekly Bull.

Daily news, updates and more over at Healio.
Check out the following March publications as well.
HCV Next
Healio Gastroenterology
Infectious Disease News

News Re-Cap
Author: Richard Pizzi Family Practice News
Publish date: March 21, 2017 - Hepatitis Outlook Late February 2017
Here’s a quick look at some notable news items and journal articles published over the past month, which cover a variety of the major hepatitis viruses.

Week Ending March 22, 2017
Hepatitis C | MD Magazine
Infectious Disease Special Edition
Don't miss recent articles written by your favorite bloggers over at HEP blogs. is a great site for patient resources and personal stories with daily articles.

In Case You Missed It

MD Whistleblower
Medical Marijuana Use - Ready, Fire, Aim!
Michael Kirsch, MD
Promoting medical marijuana use is hot – smokin’ hot. States are racing to legalize this product, both for recreational and medical use. In my view, there’s a stronger case to be made for the former than the latter.

Presently, marijuana is a Schedule I drug, along with heroin, LSD and Ecstasy. The Food and Drug Administration (FDA) defines this category as drugs with no acceptable medical use and a high potential risk of addiction. Schedule I contains drugs that the FDA deems to be the least useful and most dangerous. Schedule V includes cough medicine containing codeine.

Hepatitis C Foundation
How to Find a Liver Specialist Who Really Knows Hepatitis B
March 22, 2017
By Christine Kukka
If you have chronic hepatitis B or are newly-diagnosed, it’s important to see a liver specialist who has experience with hepatitis B.

Having a specialist with hepatitis B expertise on your team not only safeguards your health, it also lessens the stress of having a chronic liver disease. “My specialist gave me all the possible scenarios, but most importantly, he gave me my life back,” one hepatitis B patient recalled.

Date Released: Mar 8 2017
HCV Management In Liver Transplantation
Dr. Robert Brown discusses management of hepatitis C infection in patients undergoing liver transplantation, Dr. Nancy Sokol hosts.
Listen here...

Learning Activity
Watch - Release Date: 3/15/2017
Hepatitis C: New Paradigms for Evaluation & Management
Dr. Naudia Jonassaint discusses the new paradigms in regards to the evaluation and management of Hepatitis C. She reviews the basic epidemiology & scope of Hepatitis C, appropriate screening for Hepatitis C, basic Hepatitis C treatment options , identification of special populations, and post SVR Monitoring
Quick View, watch here...

Healthy You

Behind The Headlines
Overweight young men 'more likely to get severe liver disease'
"Men who are overweight in their late teens have a higher risk of developing liver cancer in later life, new research suggests," reports ITV News. Swedish researchers also found a link to other serious types of liver disease…

Updates On This Blog
HCV vaccines—back to the future?
Effects of Melatonin on Liver Injuries and Diseases
Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?
Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C
Study - Statin use may lead to: Decreased fibrosis and Reduced risk of developing liver cancer
Watch - Hepatitis C Overview
Chronic Hepatitis C And Functional Dyspepsia (FD) - A Feeling Of Discomfort In The Upper Abdomen
HCV - Fatty liver disease and genotype 3
HCV Genotypes/Treatment
Is There A Natural Way To Improve Liver Fibrosis?

Check back for updates, enjoy the rest of your weekend.

HCV vaccines—back to the future?

HCV vaccines—back to the future

Paul Klenerman

Received: 12 February 2017; Accepted: 15 February 2017; Published: 16 March 2017.
doi: 10.21037/aob.2017.02.01

View Full Text Article Online

HCV is a huge global problem. Major advances have been made in recent years in the drug therapy for chronic HCV infection (1). If patients have access to such directly acting antiviral agents, there is a very high chance of cure in most settings, even in patients with advanced disease or with previous treatment failures. However, in order to effectively get on top of the epidemic, such therapy is likely only one weapon, as there is still a substantial amount of ongoing transmission and undiagnosed disease, often in populations that are hard to reach. Virologic cure through the new agents does not lead to host immunity, so approaches to prevention of new or repeat infections are still needed. For this reason, a vaccine for HCV still has an important place at the table (2,3).

The classical approach to vaccines has been to use either a live strain with attenuated pathogenicity—as in the case of smallpox vaccine—or to use a killed or inactivated vaccine. Both approaches have been very effective. Live strains—such as the yellow fever vaccine—produce long lasting immunity, and combine typically cellular immunity with humoral responses. While this is advantageous, for many pathogens there is no clear way of safely attenuating the virus, so the risks outweigh the benefits. Inactivated vaccines, for example the Salk polio vaccine, similar to the toxoids used for tetanus, induce a strong antibody response, although the induction of cytotoxic T cells is limited. In the end, the efficacy of the vaccine depends on the dominant form of protection. In the case of HBV vaccines, a recombinant protein approach is highly effective, as the levels of antibody generated are sufficient to provide robust immunity (4). Recombinant protein approaches mimic the killed vaccines in providing a non-replicating antigen, together with sufficient adjuvant to activate the innate immune responses needed for immunologic priming. For HBV the field is relatively well off as the antibodies represent a clear “correlate of protection”—i.e., their presence predicts efficacy (4). Unfortunately, we do not have very well defined correlates of protection in HCV infection, although there is a wealth of data that innate and adaptive immune responses are important, including a role for T cells. This includes studies of animal models, host immunogenetics, viral evolution and numerous correlative studies in acute and chronic disease, as well as challenge studies (5-7).

For HCV, there have been limited attempts to date to develop preventive vaccines, compared for example to HIV, and there are no simple live-attenuated avenues to explore (3,8,9). HCV is persistent, highly mutable, and difficult to grow in culture. It is also in many patients a relatively poor inducer of immune responses, partly because of its hepatotropism. In common with other complex infections such as HIV and malaria, a viral vector approach has been taken by a few groups, using HCV antigens expressed in the context of another virus, such as a poxvirus or adenovirus. This allows the immunogen to be presented in an optimal form to generate cellular immune responses, and in humans, adenoviral vectors have been shown to be quite effective at priming both CD4+ and CD8+ T cell responses (10,11). Currently a preventive HCV vaccine based on priming with a chimpanzee adenoviral vector expressing HCV non-structural proteins 3-5B, and boosting with a modified vaccinia Ankara (MVA) vector expressing the same proteins is in phase 2 trials in the USA (

Antibodies also have a role to play in protection against HCV, and in an ideal world a vaccine that induced a high-titre antibody response capable of blocking infection of a wide range of HCV strains—so-called broadly neutralising antibody (bNAbs)—would be very effective. Attempts have been made to generate antibodies using recombinant HCV envelope proteins, and bNAbs have been generated with this approach (12,13). However, high level production of these protein targets is not trivial and so this area is still open for development, including attempts to focus the antibody response on targets within envelope which are highly conserved and block infection (14).

On this background the recent study by Yokokama et al. in Gut is of interest as it combines new and old approaches to try and induce protective immunity against HCV (15). While it is not possible to routinely culture HCV, certain strains—notably JFH, first generated by Wakita, a co-author on the current study—can replicate in specific cell lines, and this technology has been further developed to allow different genotypes to be cultured (16). The authors were able to make high level stocks of a cell culture strain (HCVcc), purify it and then inactivate it using UV light for safe use as a vaccine. In order to improve its immunogenicity, they combined it with different adjuvants, one the classical album, and a second, based on stimulation by DNA motifs known as CpG presented in nano-particulate form. CpG motifs bind Toll like receptor 9 (TLR9) and induce strong innate immune activation, enhancing immunogenicity—in particular when presented in nanoparticulate form (17). They analysed immunogenicity of such a vaccine in mice and then in marmosets.

The study showed a number of important features. Animals receiving vaccinations using the alum based vaccine did generate some antibodies against HCV, although the levels of neutralisation were overall quite low. However, using the CpG based nanoparticle adjuvant K3-SPG, the same inactivated HCVcc preparation did induce neutralising antibody which was able to block infection. The levels of neutralisation in vitro reached around 60%, so blockade was not complete, but interestingly the sera did block infection by strains bearing envelopes from diverse genotypes, which would be an important attribute of any vaccine. There was also some evidence of T cell responses against components of the vaccine, capable of making interferon-gamma (IFNg). Analyses of marmoset T cell responses is difficult, so the overall levels of such responses are hard to gauge compared to human studies, but once again they were much more evident using the CpG based nanoparticle adjuvant K3-SPG. Induction of IFNg in response to HCV antigens does correlate with successful immune control of HCV in many human studies, was an important readout in the challenge studies performed previously using virally vectored vaccines, and remains the major measure immunogenicity in the development of HCV T cell vaccines in human trials (11).

This vaccine approach therefore is in many ways classical, but also relies heavily on the new adjuvant for its immunogenicity. The issue is to assess the potential for protection. This was not addressed in the marmoset model, although such animals can be infected with chimeric HCV/GBV-C viruses and that may be one possible approach (18). Additional pre-clinical models also include transgenic mouse strains which support HCV infection, some of which are immunologically intact (19). Given the lack of a clear correlate of protection, it would be very valuable to have more preclinical data before engaging in human studies. However, if it is possible to scale up and provide a highly robust safety profile for such a vaccine, immunogenicity studies in humans, followed by trials in populations at risk are really the only way to answer the question regarding protection. Possibly the blend of old and new approaches used in this study could pave the way for such future vaccines.

Friday, March 24, 2017

Healio Updates Non-Alcoholic Fatty Liver Disease (NAFLD) - Non-alcoholic steatohepatitis (NASH)

Non-Alcoholic Fatty Liver Disease (NAFLD) - Non-alcoholic steatohepatitis (NASH)
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.

VIDEO: Debate continues NAFLD treatment clinical trials’ construction
WASHINGTON — In this exclusive video from Emerging Trends in Non-Alcoholic Fatty Liver Disease, Kris V. Kowdley, MD, FAASLD, of the Swedish…

VIDEO: Hispanic patients at higher risk for developing fatty liver disease
“There are substantial differences in the likelihood of having fatty liver disease across various ethnicities,” Sanyal said. “People of Hispanic origin, or particularly those who are not of European origin, have a high prevalence of fatty liver disease. Not only do they have more fatty liver disease, but it can progress faster to cirrhosis, and this is closely linked to the prevalence of obesity and type 2 diabetes in this population.”

Imaging modalities provide confirmative results of NAFLD, NASH
Imaging modalities, such as magnetic resonance imagining and magnetic resonance elastography, provided significantly confirmative…

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.”

Children diagnosed with non-alcoholic fatty liver disease between the ages 7 and 12 years presented with worse steatohepatitis and other factors than…

View all updates, here....

Effects of Melatonin on Liver Injuries and Diseases

Review article
Effects of Melatonin on Liver Injuries and Diseases
Jiao-Jiao Zhang, Xiao Meng  Ya Li, Yue Zhou, Dong-Ping Xu, Sha Li 2 and Hua-Bin Li

Int. J. Mol. Sci. 2017, 18(4), 673; doi:10.3390/ijms18040673

View Full Text Online Or Download PDF

This review summarizes the effects of melatonin on liver injuries induced by various factors and liver diseases, including liver steatosis, non-alcohol fatty liver, hepatitis, liver fibrosis, liver cirrhosis, and hepatocarcinoma, focusing on the mechanisms of action, such as antioxidant, anti-inflammation, anticancer, antiproliferation, and pro-apoptosis.

Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

Continue to full text article...

Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?

Resistance testing for the treatment of chronic hepatitis C with direct acting antivirals: when and for how long?
Pérez AB, Chueca N, García F.

GERMS 2017;7(1):40-44. doi: 10.18683/germs.2017.1107

View Full Text Article

The need to test for resistance associated substitutions (RAS) has been intensively debated in the past two years. In the absence of pangenotypic combinations, it seems reasonable that, if available, RAS testing in the NS5A gene at baseline for genotypes 1a and 3 may help to avoid overtreatment in terms of ribavirin usage and/or prolonged treatment duration. When patients fail treatment, RAS testing may also be useful to guide the selection of the new regimen, especially for those that need urgent retreatment and that have failed a combination including an NS5A inhibitor. However, there are new drugs in the pipeline that in combination are pangenotypic, very potent and with a high genetic barrier to resistance. In this new scenario, RAS testing may not play such an important role.

Keywords: HCV, RAS, DAA, baseline, failure, new drugs

The key to achieve sustained viral response (SVR) in the treatment of chronic hepatitis C with direct anting antivirals (DAAs) is to eliminate all the hepatitis C virus (HCV) quasispecies that infect the patient; if this is achieved, and the entire viral population has been eradicated, there is no opportunity for viral relapse and the patient is cured of HCV infection. Achieving SVR is a multifactorial event relying not only on virological factors, but also on factors related to the host and the drugs used for treating chronic hepatitis C.1 Being infected by genotypes 1a or 3, cirrhotic, and previously exposed to interferon-containing regimens are predictors of non-response. Among other virological factors that may impact SVR, the presence of resistance associated substitutions (RAS) may be clinically relevant, both before the patient is going to start the first DAA regimen and when the patient has failed treatment.

Although phenotypic tests may be performed to assess resistance to DAAs, genotyping (e.g. sequencing of the HCV genomic region of interest) is considered the gold standard to detect RASs. Next generation sequencing is now available for DNA sequencing and many laboratories have adopted this technology; however, unlike other scenarios, next generation sequencing has not been proven clinically relevant for HCV RASs testing; in fact, the detection of RASs present with a low relative frequency in the quasispecies viral population, below a 15% cutoff, failed to demonstrate any impact on SVR.2,3 In addition, to score resistance in HCV, the type of RAS is also critical, especially for the NS5A inhibitors, where class RASs (all substitutions in NS5A with a fold-change (FC) greater than 2.5X to any drug in the class) do not necessarily have the same impact as drug specific RASs (specific RASs for each drug in the class, in general with FC values above 100X).

The need to test for RASs at baseline has been highly debated through the last two years. In general, expert opinion at major conferences has always been that baseline RAS testing has no or a minimum impact on SVR, and therefore baseline RAS testing was not needed for clinical practice.

However, clinical guidelines from the American Association for the Study of Liver Diseases4(AASLD) recommend testing for Q80K in genotype 1a prior to using simeprevir in interferon-containing regimens, and more recently in cirrhotic patients that are going to start sofosbuvir (SOF) and simeprevir (SIM). For NS5A inhibitors, AASLD guidelines recommend to test for RASs in NS5A if the combination grazoprevir (GZR) and elbasvir (EBR) is going to be used, as the detection of clinically relevant RASs against EBR will aid to decide if prolonging treatment to 16 weeks and adding ribavirin (RBV) is necessary.

For other regimens, such as the AbbVie combination (paritaprevir/r-dasabuvir-ombitasvir, known as 3D) RAS testing is not necessary as there is no impact for HCV genotype 1b treatment, as there also isn´t for all the other DAA combinations and genotype 1b. For genotype 1a, the 3D approved regimen always includes RBV to make the regimen more potent and overcome the effect of RASs. Guidelines from the European Association for the Study of Liver diseases5 (EASL) have been updated September 2016; EASL panel state that if RAS testing is accessible, reliable and interpretable, then testing for baseline RAS for HCV genotypes 1a, 4, 5 and 6 will help to decide on extending treatment duration and adding RBV for any of the SOF and ledipasvir (LDV), SOF and daclatasvir (DCV) combinations, and as AASLD for GZR/EBR for genotype 1a.

Very recently, Zeuzem et al.3 clearly showed that HCV genotype 1a infected patients starting SOF/LDV with LDV specific RASs (15% cutoff) and prior interferon treatment experience, irrespective of the cirrhosis status, and those interferon-naïve with cirrhosis, are prone to achieve lower SVR rates when compared to HCV genotype 1b infected patients or treatment-naïve non cirrhotic genotype 1a, who achieve SVR rates of 96-98%.

Results for treatment-naïve and treatment-experienced genotype 1 infected patients, with and without liver cirrhosis are illustrated in Figure 1.

Figure 1. SVR12 rates achieved considering LDV specific RAS and a 15% cutoff. Data are presented in relation to prior interferon treatment (TN=treatment naïve; TE= treatment experienced), and cirrhosis status (C=cirrhosis; NC=non cirrhosis)

HCV genotype 3 is also difficult to treat with currently available DAAs. NS5A baseline RAS, especially Y93H, may condition lower SVR12 rates (75%) when starting SOF/DCV in real life conditions.6Data from the ASTRAL 3 study,7 where SOF and velpatasvir (VEL) were used for the treatment of genotype 3 infected patients, have also shown the impact on SVR12 of the Y93H RAS in NS5A (88%). In fact, AASLD guidelines recommend testing for Y93H before genotype 3a cirrhotic patients start any SOF/NS5A inhibitor combination, to decide whether extending treatment duration and adding RBV may be necessary.

Regarding patients that have failed a prior DAA regimen, and that are in urgent need of retreatment, there is a general consensus that RAS testing provides added value for clinical practice. Lawitz et al.8 addressed the retreatment with SOF/LDV and RBV for 24 weeks in patients that had failed a previous course of SOF/LDV for 8-12 weeks ± RBV; although only 41 patients were studied, the results showed a clear impact of the number and the type of RAS in NS5A on SVR12: patients that had no RASs at failure achieved 100% SVR12 rates when they were retreated with the same regimen they had failed, but with a 24 week duration and with RBV. Some other trials such as QUARTZ-I9 and CSWIFT-retreatment10 have also addressed the retreatment of patients failing the 3D regimen or GZR/EBV with the addition of SOF and RBV, with excellent results. Real-life studies have also addressed the importance of resistance testing for the retreatment of patients who have failed a first line DAA therapy: Vermehren et al.11showed excellent results in a German real life cohort when retreatment was resistance-guided; in a similar way, Cento et al.12 and Perez et al.13 also show data on resistance-guided retreatment of first line DAA failures in large Italian and Spanish cohorts, respectively.

Although resistance has been proven to play a role on both initial treatment and retreatment, there are some important caveats for the introduction of resistance testing in clinical practice that need to be highlighted. As EASL guidelines underline, the test needs to be reliable and interpretable. Reliability is certainly an issue, and only accredited laboratories with sufficient expertise both on technical issues on DNA sequencing and HCV RAS interpretation should provide results. Variability of interpretation is also important, as no clinically validated rules of interpretation are available so far. Although the Lontok et al. consensus14on HCV interpretation may help for a uniform interpretation of the results, the document is now outdated, as new drugs that are currently available, and new RASs that have been described, are not in the text. Several actions aiming to provide guidance on sequencing methods and RAS interpretation are currently being evaluated for publication in high impact HCV journals and will soon be available for public use. Hopefully, these guidance documents may help to make resistance testing for HCV more reliable and interpretable, and will certainly contribute to improve access to resistance testing in many settings.

New combinations of drugs, including very potent and pangenotypic drugs, such as voxilaprevir (VOX), glecaprevir (GLE), pibrentasvir (PIB), ruzasvir (RZR), uprifosbuvir (MK-3682), are currently in different phases of drug development and have entered phase II/III clinical trials. Some of these combinations are proving to be extremely efficacious for the treatment of interferon treatment-experienced, cirrhotic patients infected with the difficult to treat genotypes 1a and 3, and have already shown excellent SVR rates for treating patients that have also failed interferon free DAA containing regimens (Table 1). Presumably, when these combinations become available, RAS testing may not play an important role for clinical practice. However, we do not know yet how these drugs will be used, and how will they be rolled-out across different countries. In the meantime, until they are here, there is a clear role of RAS testing in the clinical practice, and a need to improve access to reliable testing and interpretation. HCV infected patients will certainly benefit from it.

Table 1. New drug combinations that have demonstrated high SVR rates in patients who have failed a prior course of interferon free DAA regimen

Authors’ contributions statement: ABP and NC drafted the paper; FG reviewed and edited the paper. All authors read and approved the final version of the manuscript.

Conflicts of interest: all authors – none to declare.

Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C

World J Hepatol. 2017 Mar 8;9(7):352-367. doi: 10.4254/wjh.v9.i7.352.

Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C.
Ponziani FR1, Mangiola F1, Binda C1, Zocco MA1, Siciliano M1, Grieco A1, Rapaccini GL1, Pompili M1, Gasbarrini A1.

Published online: March 8, 2017
Full Text
View Online

Core tip: The approval of new direct acting antivirals with high rates of virological clearance and excellent tolerability has dramatically improved hepatitis C virus (HCV) infection curability, especially for patients with advanced liver disease and for liver transplant recipients. The aim of this review is to draw the possible future scenery in HCV-related liver disease, focusing our attention on the impact of second generation direct acting antivirals on liver fibrosis, hepatocellular carcinoma and liver transplantation.

Hepatitis C virus (HCV) infection has been a global health problem for decades, due to the high number of infected people and to the lack of effective and well-tolerated therapies. In the last 3 years, the approval of new direct acting antivirals characterized by high rates of virological clearance and excellent tolerability has dramatically improved HCV infection curability, especially for patients with advanced liver disease and for liver transplant recipients. Long-term data about the impact of the new direct acting antivirals on liver fibrosis and liver disease-related outcomes are not yet available, due to their recent introduction. However, previously published data deriving from the use of pegylated-interferon and ribavirin lead to hypothesizing that we are going to observe, in the future, a reduction in mortality and in the incidence of hepatocellular carcinoma, as well as a regression of fibrosis for people previously affected by hepatitis C. In the liver transplant setting, clinical improvement has already been described after treatment with the new direct acting antivirals, which has often led to patients delisting. In the future, this may hopefully reduce the gap between liver organ request and availability, probably expanding liver transplant indications to other clinical conditions. Therefore, these new drugs are going to change the natural history of HCV-related liver disease and the epidemiology of HCV infection worldwide. However, the global consequences will depend on treatment accessibility and on the number of countries that could afford the use of the new direct acting antivirals.

Continue to full text article....

Study - Statin use may lead to: Decreased fibrosis and Reduced risk of developing liver cancer

Rationale for the use of statins in liver disease
Robert Schierwagen, Frank Erhard Uschner, Fernando Magdaleno, Sabine Klein, Jonel Trebicka

Published 9 March 2017
Full Text Article
Download PDF

Statin drugs are widely used to manage high cholesterol and reduce the risk of cardiovascular disease. But in a new review of more than 50 studies, researchers cite reductions in liver inflammation and improvements in other related factors as reasons why statins make good candidates for treating chronic liver disease. The article is published ahead of print in the American Journal of Physiology—Gastrointestinal and Liver Physiology.

Reducing cholesterol can have a positive effect on many chronic liver disorders, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, as well as in biliary disorders. In some studies, the research team found that statins reduced inflammatory molecules that are typically elevated with liver disease and improved inflammation in the endothelium (cells that line the blood vessels). Statin use may also lead to:
  • Decreased fibrosis (hardening or scarring of tissue),
  • Less development of fatty liver,
  • Slowed or halted spread of hepatitis C virus,
  • Improvement of portal hypertension (high blood pressure in the liver's blood vessels),
  • Destruction of existing liver tumor cells, and
  • Reduced risk of developing liver cancer.
The researchers acknowledge that statin drugs can contribute to liver damage in some people, but for people with advanced liver disease, "[s]tatins are cost-effective, generally well-tolerated by patients and the benefits of statin treatment in most patients outweigh their potential hepatotoxic risk."

Download PDF
Robert Schierwagen et al. Rationale for the use of statins in liver disease, American Journal of Physiology - Gastrointestinal and Liver Physiology (2017). DOI: 10.1152/ajpgi.00441.2016