Response to Cochrane Collaboration review in to Hepatitis C medicines

Update - June 13, 2017
The Guardian published a response to their original article that reviewed a report by Cochrane Collaboration suggesting there was no evidence new HCV treatments improve outcomes in patients infected with the virus.

The Guardian June 13, 2017
Hepatitis C antiviral drugs are effective
The Cochrane analysis casting doubt on this life-saving therapy is flawed and may deter patients from seeking it, say clinicians and scientists
We are clinicians and scientists who have studied and treated patients with chronic hepatitis C virus infection over many years and patient groups that represent those affected by hepatitis C. We write in response to your article on the effectiveness of antiviral therapy (Hepatitis ‘wonder drug’ may be clinically ineffective, say experts, 9 June). The Cochrane review that you highlight analysed clinical trials, which are by nature short term, where the sole purpose was to evaluate the virological efficacy of new antiviral drugs. The trials were neither designed, nor powered, to assess mortality, so it is hardly surprising that the Cochrane review was unable to identify any impact on mortality.
Continue reading....

Recommended Reading
In July Newsletters - Rebuttal over Cochrane Review of DAAs
View each rebuttal and all ongoing media coverage.
In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.
Begin here....

Of Interest

Research article suggested by Graham Cooke‏ @grahamscooke
Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response
The results suggest that there is a significant survival benefit of achieving an SVR compared with unsuccessful treatment in a range of populations infected with hepatitis C virus.

Response to Cochrane Collaboration review in to Hepatitis C medicines

​​​​​​This review was reported in the Guardian​ on Thursday 8 June.

Dr Paul Catchpole, Director of Value & Access, at the ABPI said:

'It can take decades for a person to realise that they are infected with Hepatitis C, by which time their liver may have been significantly damaged.

As such, the objective of clinical trials is to demonstrate clearance of the virus in the blood (SVRs) to predict the effectiveness of treatment, rather than studying mortality which would require studies to run over periods of up to 30 years. This objective measure, along with other 'surrogate markers', are an internationally recognised and accepted benchmark used by medicines regulators, clinicians and researchers alike.

There is also a wealth of evidence which demonstrates the impact of being infected with the Hepatitis virus on progression - from early cirrhosis of the liver through to end stage liver failure and liver transplant or liver cancer. This is why the markers that measure how much virus a patient is carrying, and whether the virus has been eradicated, are of crucial importance.

All of this is taken into account by NICE as part of their strict assessment process.

Our concern is that the Cochrane Collaboration research has been reported in a way that only tells half of this story, which is unhelpful for patients who are currently living through the pain of progressive liver disease or end stage liver failure.'

http://www.publicnow.com/view/60EF3687B2F4B4E01EC3578590FD9ABAB965E53F?2017-06-09-17:31:29+01:00-xxx8318

ABPI - The Association of the British Pharmaceutical Industry

06/08/2017 | Press release | Distributed by Public on 06/09/2017 09:48

Media enquiries​
ABPI Press Office
​Email: pressoffice@abpi.org.uk​
Telephone (24hrs): +44 (0) 20 7747 7147​​ About the ABPI

The ABPI represents innovative resea​rch-based biopharmaceutical companies, large, medium and small, leading an exciting new era of biosciences in the UK.

Our industry, a major contributor to the economy of the UK, brings life-saving and life-enhancing medicines to patients. We represent companies who supply more than 80 per cent of all branded medicines used by the NHS and who are researching and developing the majority of the current medicines pipeline, ensuring that the UK remains at the forefront of helping patients prevent and overcome disease.

Globally our industry is researching and developing more than 7,000 new medicines.

The ABPI is recognised by government as the industry body negotiating on behalf of the branded pharmaceutical industry for statutory consultation requirements including the pricing scheme for medicines in the UK.​​​​​​​​​

Why do we continue to put our children at unnecessary risk of liver cancer?

Why do we continue to put our children at unnecessary risk of liver cancer?
On International Children’s Day (1June), the World Hepatitis Alliance calls for widespread coverage of the hepatitis B birth dose vaccine to protect our children’s futures.

By Raquel Peck, CEO of the World Hepatitis Alliance

Children are our future. It’s an utter cliché, but it’s true. Children are our future adults, leaders, carers. And so, we have a duty to provide children with the best start in life possible, and that means ensuring their health and wellbeing from day one. A no-brainer, right?

Worldwide, almost two out three babies are being denied access to the hepatitis B birth dose vaccine, a simple measure which can avert a virus that can cause cirrhosis and liver cancer and accounts for over 880,000 deaths a year, globally.

Despite the alarming figures, inexplicably not all children are receiving this life-saving intervention. Across the globe 84% of infants receive three doses of the hepatitis B vaccine. It’s a good start but to ensure full protection, the vaccine must be given shortly after birth to prevent both infection that may occur early in life and to protect against potential mother-to-child transmission if the mother is living with hepatitis B.

In the South-East Asia region only 34% receive the birth dose vaccine; in the Eastern Mediterranean region just 23% of babies are vaccinated and in the African region as few as just 10% receive the birth dose. There are many reasons for this: vaccines are unavailable, health services are poorly provided or inaccessible, populations live in remote locations, or because families are uninformed about the importance of vaccination.

As a mother myself, I know it might be hard to imagine putting a newborn baby through the pain of a shot but this small prick is a crucial first step to protecting a child against a deadly disease for life. What’s more, where vaccination has been implemented, it has already proven a success. The proportion of children under 5 years of age who are chronically infected with hepatitis B has fallen from 4.7% in the pre-vaccine era to 1.3% now. The fact that the majority of those living with hepatitis B are adults born before the hepatitis B was available and that the prevalence of hepatitis B among children under 5 is still at 3% in the African region shows just how crucial vaccination is in protecting children’s futures.

The 257 million people currently living with chronic hepatitis B infection were denied this protection, but we cannot deny our children protection. In May 2016, 194 governments committed to increasing coverage of the hepatitis B birth dose vaccine to 90% by 2030.

Today on International Children’s Day, we call on all governments to uphold their commitment by implementing vaccination programme for infants from day one. Let’s join together and raise our voices to ensure that every baby across the world gets the best possible start in life. Now, that’s a no-brainer.

http://www.worldhepatitisalliance.org/news/jun-2017/why-do-we-continue-put-our-children-unnecessary-risk-liver-cancer

Researchers identify how class of drugs blocks Hepatitis C virus replication

Researchers identify how class of drugs blocks Hepatitis C virus replication
Findings reveal a difference between strains of HCV

Date:June 8, 2017
Source: University of North Carolina Health Care
Summary: For the first time, researchers show how the antiviral class of drugs called NS5A inhibitors interacts with the hepatitis C virus, and these findings show a difference between strains of HCV.

Globally, an estimated 71 million people are living with chronic hepatitis C virus (HCV). Over decades of infection, chronic HCV infection results in progressive damage to the liver and an increased risk for end stage liver disease and liver cancer, making the virus the leading cause of liver-related deaths in the United States today.

While effective combination therapies have recently been developed, HCV can evolve to become resistant to these antiviral drugs, potentially resulting in treatment failures. Resistance is particularly important for one class of medications used in treatment, for which the mechanism by which it stops growth of the virus is poorly understood. For the first time, researchers at the University of North Carolina at Chapel Hill have identified how the class of antiviral drugs known as NS5A inhibitors interacts with the virus, and their findings show a difference between strains of HCV. These results were published in PLOS Pathogens.

"When HCV infects a liver cell, it establishes replication complexes (RCs) within the cell," said David McGivern, Ph.D., lead-author and an associate professor in the UNC Division of Infectious Diseases. "These may be thought of as factories that replicate the virus genetic material. We wanted to understand how long these factories persist in an infected cell after treatment with an NS5A inhibitor."

The research team has shown previously NS5A inhibitors block the formation of new RCs, but do not affect existing RCs, which are ultimately lost from the cell during treatment. The team used NS5A inhibitors to estimate the half-life of the existing RCs and found a difference in the speed of decline depending upon the strain of HCV.

"The majority of people who undergo antiviral treatment clear their HCV infection," said McGivern. "But about 5 percent of people experience treatment failure, often associated with drug resistance. Our findings have potentially important implications for this group of people. Did the treatment fail because replication complexes turned over more slowly? Do some strains of HCV need longer treatment? A better understanding of these issues may lead to more effective therapies active against a broader range of viruses."

Story Source:
Materials provided by University of North Carolina Health Care. Note: Content may be edited for style and length.

Journal Reference:
NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains
Tiffany Benzine, Ryan Brandt, William C. Lovell, Daisuke Yamane, Petra Neddermann, Raffaele De Francesco, Stanley M. Lemon, Alan S. Perelson, Ruian Ke, David R. McGivern
PLOS Pathogens, 2017; 13 (6): e1006343 DOI: 10.1371/journal.ppat.1006343

https://www.sciencedaily.com/releases/2017/06/170608202150.htm

Liver Cancer, Fastest-Growing Cause of Cancer Death in U.S. Incidence, rising since the 1970s, expected to continue through at least 2030

Death Rate From Liver Cancer in US Now Double That in 1980s
Mortality rates from liver cancer in the US are increasing faster than for any other cancer, with considerable disparities across ethnic groups.

Medscape Medical News, June 9, 2017

Report Looks at Liver Cancer, Fastest-Growing Cause of Cancer Death in U.S. Incidence, rising since the 1970s, expected to continue through at least 2030
A new report provides an overview of incidence, mortality, and survival rates and trends for liver cancer, a cancer for which death rates have doubled in the United States since the mid-1980s, the fastest rise of any cancer in the U.S.

The report notes that liver cancer incidence has been rising in the U.S. since at least the mid-1970s, a trend that is expected to continue through at least 2030. One major factor contributing to the increase is a higher rate of hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Among this age group, HCV prevalence is approximately 2.6%, a rate 6-fold greater than that of other adults. A rise in obesity and type II diabetes over the past several decades has also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. Despite improvements in liver cancer survival in recent decades, only one in five patients survives five years after diagnosis.

The report appears in CA: A Cancer Journal for Clinicians, and says differences in major risk factors as well as inequalities in access to care have led to significant racial disparities in liver cancer mortality.

The American Cancer Society estimates that liver cancer will account for about 41,000 new cancer cases and 29,000 cancer deaths in the United States in 2017. It is the fifth leading cause of cancer death in men and the eighth leading cause of cancer death in women. About 1.0 percent of men and women will be diagnosed with liver cancer in their lifetimes.

The report notes that liver cancer incidence has been rising in the U.S. since at least the mid-1970s, a trend that is expected to continue through at least 2030. One major factor contributing to the increase is a higher rate of hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Among this age group, HCV prevalence is approximately 2.6%, a rate 6-fold greater than that of other adults. A rise in obesity and type II diabetes over the past several decades has also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. Despite improvements in liver cancer survival in recent decades, only one in five patients survives five years after diagnosis.

The report identifies substantial disparity in liver cancer death rates by race/ethnicity, ranging from 5.5 per 100,000 in non-Hispanic whites to 11.9 per 100,000 in American Indians/Alaska Natives. There are also wide disparities by state, with the lowest death rates in North Dakota (3.8 per 100,000), and the highest in the District of Columbia (9.6 per 100,000). The report says the wide racial and state disparities in liver cancer mortality reflect differences in the prevalence of major risk factors and, to some extent, inequalities in access to high-quality care. “However, most liver cancers are potentially preventable,” write the authors. “Interventions to curb the rising burden of liver cancer and reduce racial/ethnic and geographic disparities should include the targeted application of existing knowledge in prevention, early detection, and treatment, including improvements in [hepatitis B virus] vaccination, screening and treatment of HCV, maintaining a healthy body weight, access to highquality diabetes care, prevention of excessive alcohol drinking, and tobacco control.
Article: Disparities in Liver Cancer Occurrence in the United States by Race/Ethnicity and State, CA Cancer J Clin 2017: doi: 10.3322/caac.21402.
Disparities in liver cancer occurrence in the United States by race/ethnicity and state
Farhad Islami MD, PhD, Kimberly D. Miller MPH, Rebecca L. Siegel MPH, Stacey A. Fedewa PhD, MPH, Elizabeth M. Ward PhD, Ahmedin Jemal DVM, PhD

Full Text Online
First published: 6 June 2017

Abstract

Liver cancer is highly fatal, and death rates in the United States are increasing faster than for any other cancer, having doubled since the mid-1980s. In 2017, it is estimated that the disease will account for about 41,000 new cancer cases and 29,000 cancer deaths in the United States. In this article, data from the Surveillance, Epidemiology, and End Results (SEER) Program and the National Center for Health Statistics are used to provide an overview of liver cancer incidence, mortality, and survival rates and trends, including data by race/ethnicity and state. The prevalence of major risk factors for liver cancer is also reported based on national survey data from the Centers for Disease Control and Prevention. Despite the improvement in liver cancer survival in recent decades, only 1 in 5 patients survives 5 years after diagnosis. There is substantial disparity in liver cancer death rates by race/ethnicity (from 5.5 per 100,000 in non-Hispanic whites to 11.9 per 100,000 in American Indians/Alaska Natives) and state (from 3.8 per 100,000 in North Dakota to 9.6 per 100,000 in the District of Columbia) and by race/ethnicity within states. Differences in risk factor prevalence account for much of the observed variation in liver cancer rates. Thus, in contrast to the growing burden, a substantial proportion of liver cancer deaths could be averted, and existing disparities could be dramatically reduced, through the targeted application of existing knowledge in prevention, early detection, and treatment, including improvements in vaccination against hepatitis B virus, screening and treatment for chronic hepatitis C virus infections, maintaining a healthy body weight, access to high-quality diabetes care, preventing excessive alcohol drinking, and tobacco control, at both the state and national levels.
CA Cancer J Clin 2017. © 2017 American Cancer Society.

View Full Text Article, here....

Cochrane Database of Systematic Reviews - Direct-acting antivirals for chronic hepatitis C

Cochrane Database of Systematic Reviews  - Direct-acting antivirals for chronic hepatitis C

In July Newsletters - Rebuttal over Cochrane Review of DAAs
View each rebuttal and all ongoing media coverage.

In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

Begin here....

Cochrane Review

Cochrane Database of Systematic Reviews

Cochrane Database Syst Rev.2017 Jun 6;6:CD012143.

doi: 10.1002/14651858.CD012143.pub2. [Epub ahead of print]

Direct-acting antivirals for chronic hepatitis C

Janus C Jakobsen, Emil Eik Nielsen, Joshua Feinberg, Kiran Kumar Katakam, Kristina Fobian, Goran Hauser, Goran Poropat, Snezana Djurisic, Karl Heinz Weiss, Milica Bjelakovic, Goran Bjelakovic, Sarah Louise Klingenberg, Jian Ping Liu, Dimitrinka Nikolova, Ronald L Koretz, Christian Gluud

Abstract

Background
Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications.

Objectives
To assess the benefits and harms of DAAs in people with chronic HCV.

Search methods
We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016.

Selection criteria
Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language.

Data collection and analysis

We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE.

Main results

We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn (or discontinued) DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.

Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.

Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20% and when one trial with an extreme result was excluded then the meta-analysis result showed no evidence of a difference.

Withdrawn DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I2 = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I² = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.

DAAs seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I² = 77%, 6886 participants, 32 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.

Only 1/138 trials assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).

The majority of all outcome results were short-term results, so we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma).

Authors' conclusions

Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

Plain language summary

Review question

To assess the beneficial and harmful effects of direct-acting antivirals (DAAs) for chronic hepatitis C.

Background

Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Numerous previous interventions have been used for hepatitis C, but none of these interventions have proven effective on patient-centred outcomes. DAAs are relatively new but expensive interventions for hepatitis C, and preliminary results have shown that DAAs seem to eradicate hepatitis C virus from the blood (sustained virological response). However, it is questionable if an eradication of hepatitis C virus in the blood leads no hepatitis C in the body and improved survival and fewer complications. In this Cochrane Review, the authors assessed the evidence on the clinical effects of DAAs for hepatitis C.

Study characteristics

The authors included 351 publications of 138 randomised clinical trials. All included trials were at high risk of bias. The 138 trials used 51 different DAAs. Of these, 84 trials assessed DAAs on the market or under development; 57 trials were on DAAs withdrawn from the market. Trials were conducted from 2004-2016. The trials were from all over the world including 34 different countries. We included 17 trials where all the participants had previously been treated for hepatitis C (treatment-experienced) before being included in the trial. There were 95 trials that included only participants who had not been previously treated for hepatitis C (treatment-naive). The intervention periods ranged from one day to 48 weeks with an average of 14 weeks. The combined intervention period and follow-up period ranged from one day to 120 weeks with an average of 34 weeks.

Key results

DAAs do not seem to have any effects on the risk of hepatitis C-related morbidity or all-cause mortality. In fact, there were no data on hepatitis C-related morbidity and very few data on mortality (15 deaths/2377 direct-acting antiviral participants (0.63%) versus 1 death/617 control participants (0.16%) resulting in an odds ratio of 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2996 participants, 11 trials, very low-quality evidence). DAAs do not seem to have any effects on the risk of serious adverse events (376/13,574 (2.77%) direct-acting antiviral participants had one or more serious adverse events versus 125/2,243 (5.57%) control participants during the observation period resulting in an odds ratio of 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 66 trials, very low-quality evidence). When analysed separately, simeprevir was the only direct-acting antiviral that showed evidence of a beneficial effect when assessing risk of a serious adverse event. Our analyses, however, showed that the validity of this result is questionable and that 'play of chance' might be the cause for the difference. There was not enough information to confirm or reject if DAAs have clinically relevant effects on other clinically relevant outcomes. Our results confirm that DAAs seem to have an effect on the risk of no sustained virological response, but all of the trial results were at high risk of systematic error ('bias'), and the clinical relevance of results on virological response is questionable. The lack of valid evidence and the possibility of potentially harming people with chronic hepatitis ought to be considered before treating people with hepatitis C with DAAs.

Quality of the evidence

Due to several limitations, we assessed the quality of the evidence in this review as very low quality. First, all trials and outcome results were at high risk of bias, which means that our results presumably overestimate the beneficial effects of DAAs and underestimate any potential harmful effects. Second, there were limited data on most of our clinical outcomes, that is, there were only relevant clinical data for meta-analyses on all-cause mortality and serious adverse events, and for these, data were sparse. Third, most trials primarily focused and assessed the effects of DAAs on sustained virological response; however, it is questionable if sustained virological response has any clinical relevance to the person with chronic hepatitis C (see ‘Background’ in this Plain language summary).
Continue reading full article

Take a coffee or tea break to protect your liver

In Case You Missed It

Take a coffee or tea break to protect your liver

New study indicates that drinking even a few cups a day may prevent hardening of the liver, reports the Journal of Hepatology

J Hepatol. 2017;doi:10.1016/j.jhep.2017.03.013.

Amsterdam, The Netherlands, June 6, 2017 -

Chronic liver diseases rank as the 12th cause of death worldwide and many of these disorders are associated with unhealthy lifestyles. Conversely, a healthier lifestyle can help prevent or reverse liver disease. Liver-related mortality is closely related to the development of cirrhosis, the final consequence of progressive fibrosis, i.e. scarring of the liver resulting from chronic inflammation. According to a new study published in the Journal of Hepatology, researchers found that drinking coffee and herbal tea may protect against liver fibrosis, estimated as the degree of liver stiffness, which is high in extensive scarring of the liver. Because these beverages are popular, widely available, and inexpensive, they could have the potential to become important in the prevention of advanced liver disease.

"Over the past decades, we gradually deviated towards more unhealthy habits, including a sedentary lifestyle, decreased physical activity, and consumption of a 'Happy Diet'," explains lead author Louise J. M. Alferink, MD, of the Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands, "This Happy Diet, also known as the Western diet, is typically rich in unhealthy foods including processed foods lacking nutrients and artificial sugars. This has led not only to an obesity epidemic, but also to a rapid increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), which is due to extensive accumulation of fat in the liver and resembles alcoholic liver disease in people who do not exceed two drinks a day of alcohol. In this context, examining accessible and inexpensive lifestyle strategies that have potential health benefits, such as coffee and tea consumption, is a viable approach to finding ways to halt the rapid increase of liver disease in developed countries."

Sarwa Darwish Murad, MD, PhD, principal investigator of the study and hepatologist at the Erasmus MC University Medical Center, continues "There is quite some epidemiological, but also experimental data suggesting that coffee has health benefits on liver enzyme elevations, viral hepatitis, NAFLD, cirrhosis, and liver cancer. Beyond the liver, coffee has been demonstrated to be inversely associated with overall mortality in the general population. The exact mechanism is unknown but it is thought that coffee exerts anti-oxidant effects. We were curious to find out whether coffee consumption would have a similar effect on liver stiffness measurements in individuals without chronic liver disease."

Data was gathered on 2,424 participants of the Rotterdam study, a large population-based cohort study including participants 45 years or older living in a suburb of Rotterdam, The Netherlands. All participants underwent an extensive physical work-up, including data collection for anthropometrics, blood sampling, hepatological imaging using abdominal ultrasound and Fibroscan®, which quantitatively measures liver stiffness. In addition, they completed an externally validated 389-item Food Frequency Questionnaire, which included detailed information on coffee and tea consumption.

Coffee and overall tea consumption was divided into three categories: none, moderate (>0-3 cups per day), and frequent (?3). Tea consumption was categorized by herbal, green, or black tea and further into none (0) or any (>0) consumption.

Investigators found that frequent coffee consumption was significantly associated with lower odds of high liver stiffness values (?8 kPa as proxy for liver fibrosis), i.e. less scarring of the liver, independent of lifestyle, metabolic, and environmental traits. When they looked at the whole range of liver stiffness values, they found that both frequent coffee and any herbal tea consumption, even in small amounts, were significantly associated with lower liver stiffness values. Finally, while no direct association was found between either coffee or tea and the presence of fat accumulation in the liver (NAFLD) per se, the effect of coffee on lowering the liver stiffness was significant in both the group with and without liver fat. The authors therefore concluded that frequent coffee and herbal tea seem to have beneficial effects on preventing liver scarring even before overt liver disease has developed.

However, some caution in the interpretation of the results is necessary, as underlined in an accompanying editorial by Salvatore Petta, MD, PhD, of the Section of Gastroenterology and Hepatology, Di.Bi.M.I.S., University of Palermo, Italy, and Giulio Marchesini, MD, of the Department of Medical and Surgical Sciences (DIMEC), ''Alma Mater" University, Bologna, Italy., In fact, the study included only an elderly Caucasian population and there were few participants in the no-coffee or no-tea control groups, which limit a straightforward conclusion about the effect of coffee and tea on the liver.. The amount of tea consumed was generally low, making estimation of any protective effect difficult. Further, they note that more than 100 components are present in coffee and tea, including polyphenols and caffeine, which are contained in both beverages in very different and variable amounts.

Hence, when asked "Should we add regular coffee and tea breaks to our daily life? Dr. Petta's and Dr. Marchesini's conclusion is, "Before this policy can be recommended, prospective studies are needed to identify the optimum amounts and the type(s) of coffee and tea leading to more favorable liver outcomes."

IMAGE: Using data from the Rotterdam Study researchers determined that frequent coffee and herbal tea consumption were inversely related with liver stiffness but not steatosis in the general population.

Credit: L. Alferink and S. Darwish Murad

WHO Essential Medicines List - New advice on use of antibiotics; adds meds for hep C, HIV, tuberculosis, cancer

WHO updates Essential Medicines List with new advice on use of antibiotics, and adds medicines for hepatitis C, HIV, tuberculosis and cancer

6 June 2017 | Geneva - New advice on which antibiotics to use for common infections and which to preserve for the most serious circumstances is among the additions to the WHO Model list of essential medicines for 2017. Other additions include medicines for HIV, hepatitis C, tuberculosis and leukaemia.

The updated list adds 30 medicines for adults and 25 for children, and specifies new uses for 9 already-listed products, bringing the total to 433 drugs deemed essential for addressing the most important public health needs. The WHO Essential Medicines List (EML) is used by many countries to increase access to medicines and guide decisions about which products they ensure are available for their populations.

"Safe and effective medicines are an essential part of any health system," said Dr Marie-Paule Kieny, WHO Assistant Director-General for Health Systems and Innovation. "Making sure all people can access the medicines they need, when and where they need them, is vital to countries’ progress towards universal health coverage."

New advice: 3 categories of antibiotic
In the biggest revision of the antibiotics section in the EML’s 40-year history, WHO experts have grouped antibiotics into three categories – ACCESS, WATCH and RESERVE – with recommendations on when each category should be used. Initially, the new categories apply only to antibiotics used to treat 21 of the most common general infections. If shown to be useful, it could be broadened in future versions of the EML to apply to drugs to treat other infections.

The change aims to ensure that antibiotics are available when needed, and that the right antibiotics are prescribed for the right infections. It should enhance treatment outcomes, reduce the development of drug-resistant bacteria, and preserve the effectiveness of "last resort" antibiotics that are needed when all others fail. These changes support WHO's Global action plan on antimicrobial resistance, which aims to fight the development of drug resistance by ensuring the best use of antibiotics.

WHO recommends that antibiotics in the ACCESS group be available at all times as treatments for a wide range of common infections. For example, it includes amoxicillin, a widely-used antibiotic to treat infections such as pneumonia.

The WATCH group includes antibiotics that are recommended as first- or second-choice treatments for a small number of infections. For example, the use of ciprofloxacin, used to treat cystitis (a type of urinary tract infection) and upper respiratory trct infections (such as bacterial sinusitis and bacterial bronchitis), should be dramatically reduced to avoid further development of resistance.

The third group, RESERVE, includes antibiotics such as colistin and some cephalosporins that should be considered last-resort options, and used only in the most severe circumstances when all other alternatives have failed, such as for life-threatening infections due to multidrug-resistant bacteria.
WHO experts have added 10 antibiotics to the list for adults, and 12 for children.

"The rise in antibiotic resistance stems from how we are using – and misusing – these medicines," said Dr Suzanne Hill, Director of Essential Medicines and Health Products. "The new WHO list should help health system planners and prescribers ensure people who need antibiotics have access to them, and ensure they get the right one, so that the problem of resistance doesn’t get worse."

Other additions
The updated EML also includes several new drugs, such as two oral cancer treatments, a new pill for hepatitis C that combines two medicines, a more effective treatment for HIV as well as an older drug that can be taken to prevent HIV infection in people at high risk, new paediatric formulations of medicines for tuberculosis, and pain relievers. These medicines are:

• two oral cancer medicines (dasatinib and nilotinib) for the treatment of chronic myeloid leukaemia that has become resistant to standard treatment. In clinical trials, one in two patients taking these medicines achieved a complete and durable remission from the disease;
• sofosbuvir + velpatasvir as the first combination therapy to treat all six types of hepatitis C (WHO is currently updating its treatment recommendations for hepatitis C);
• dolutegravir for treatment of HIV infection, in response to the most recent evidence showing the medicine’s safety, efficacy, and high barrier to resistance;
• pre-exposure prophylaxis (PrEP) with tenofovir alone, or in combination with emtricitabine or lamivudine, to prevent HIV infection;
• delamanid for the treatment of children and adolescents with multidrug-resistant tuberculosis (MDR-TB) and clofazimine for children and adults with MDR-TB;
• child-friendly fixed-dose combination formulations of isoniazid, rifampicin, ethambutol and pyrazinamide for treating paediatric tuberculosis; and
• fentanyl skin patches and methadone for pain relief in cancer patients with the aim of increasing access to medicines for end-of-life care.

http://www.who.int/mediacentre/news/releases/2017/essential-medicines-list/en/

Improvements in brain and behavior following eradication of hepatitis C

Update June 26, 2017
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The effect of SVR on the risk of extrahepatic manifestations of HCV infection
 Compared with HCV-infected individuals who did not receive treatment, SVR attainment was associated with a reduced risk of mixed cryoglobulinaemia, glomerulonephritis, porphyria cutanea tarda, non-Hodgkin's lymphoma, diabetes mellitus and stroke, but not lichen planus or coronary heart disease. Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, porphyria cutanea tarda and diabetes.
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Journal of NeuroVirology, Inc. 2017
First Online: 30 May 2017
Improvements in brain and behavior following eradication of hepatitis C
Taylor Kuhn1,2 & Philip Sayegh3 & Jacob D. Jones1,2 & Jason Smith2 & Manoj K. Sarma1 & A. Ragin1 & Elyse J. Singer4 & M. Albert Thomas1 & April D. Thames1 & Steven A. Castellon1,2 & Charles H. Hinkin1,2

Abstract
Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus(HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV− controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV− controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.

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