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Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients
Lybeck, Charlottea; Brenndörfer, Erwin D.c; Sällberg, Mattic; Montgomery, Scott M.b,d,g; Aleman, Sooe,f; Duberg, Ann-Sofia

SVR is associated with clinical cure and regression of liver fibrosis in most patients after 10 years of FU. However, occult HCV infection can be detected in some patients many years after achievement of SVR; this may have a negative effect on the regression of liver fibrosis, but more studies are needed. Future studies are planned to determine whether the viable virus can be recovered from PBMC. If so, this raises the question of whether those repetitively positive for HCV in PBMC should be retreated. Further, the risk of HCC is not eliminated in all noncirrhotic patients with SVR. Studies of the long-term outcome more than 10 years after IFN therapy and eventually after DAA therapy are needed.

Full-text available online...

Objectives Curing of hepatitis C virus (HCV) infection primarily aims to prevent severe liver complications. Our objectives were to investigate the long-term presence and impact of occult HCV infection (OCI) and to study the outcomes in terms of liver disease after virological cure.

Patients and methods A total of 97 patients with achieved sustained virological response (SVR) during 1990–2005 were followed either by a clinical follow-up (FU) visit with blood sampling and liver elastography (n=54) or through national registries for outcomes (n=43). To diagnose OCI among patients with SVR, a highly sensitive method was used to detect HCV-RNA traces in whole blood. The FU duration was a median of 10.5 years, with samples up to 21.5 years after the end of treatment (EOT).

Results The majority of patients [52 (96%)] were HCV-RNA negative at FU, and regression of fibrosis was statistically significant. OCI was found in two (4%) of them at 8 and 9 years after EOT. These patients had F1 and F2 fibrosis before treatment and F2 at FU, but no other abnormal findings. Three previously noncirrhotic men were diagnosed with hepatocellular carcinoma 8–11 years after EOT.

Conclusion Occult infection could be detected many years after the achievement of SVR but was not associated with serious liver disease. The majority had persistent viral eradication and regression of fibrosis after SVR. However, an increased risk of hepatocellular carcinoma may persist in the long term after SVR even in noncirrhotic patients. Further studies with FU after direct-acting antiviral therapy and on the long-term impact after cure are needed.


European Journal of Gastroenterology & Hepatology: April 2019 - Volume 31 - Issue 4 - p 506–513 doi: 10.1097/MEG.0000000000001316 Original Articles: Hepatology

On This Blog
Read All Posts With The Label Liver Cancer
Review a collection of current research articles extracted from peer-reviewed journals, liver meetings/conferences, and learning activities investigating the natural history of liver cancer, approved therapies, risk factors associated with chronic viral hepatitis, cancer-prevention, including diet, nutrition and physical activity, and trends associated with the rising rate of hepatocellular carcinoma in the U.S.
Begin, here.....

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..... 
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Has a second person with HIV been cured?
Mar. 4, 2019 , 6:05 PM

Timothy Ray Brown, aka the “Berlin patient,” the only person to be cured of HIV, may finally have company. A decade after Brown became famous thanks to a stem cell transplant that eliminated his HIV infection, a similar transplant from a donor who has HIV-resistant cells appears to have cured another man, dubbed the “London patient.”

“This is a big deal,” says Sharon Lewin, who heads the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. “It tells us that Timothy Brown wasn’t a one-off.” Although the interventions that the two patients received could only be used on a tiny fraction of the 37 million HIV-infected people worldwide, their stories point to cure strategies that could be more widely applicable.

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Trio Health and Express Scripts’ Accredo Specialty Pharmacy Form Collaboration to Provide Real World Evidence on Prescription Medicines across Specialty and Rare Diseases

“Our collaboration with Accredo enables us to expand on our experience analyzing real world evidence in evaluating treatments for hepatitis C, oncology, RA, hemophilia and HIV, and review medications covering a broad range of diseases and conditions that are prescribed to millions of patients and cost billions of dollars.”

Trio Health announced today that Accredo Specialty Pharmacy will collaborate with Trio Health on their proprietary technology and analytics platform to provide real world evidence of outcomes on a wide range of medicines. The collaboration is expected to bring unprecedented value-based transparency to a medication’s journey.

“Our healthcare system is comprised of patients, pharmaceutical companies, payers, physicians, pharmacy benefits managers and pharmacies, all with differing interests in terms of innovation, pricing and access to care. The ability to evaluate a complete data set encompassing patient experience and outcomes enables unparalleled insight into medication selection and value, insight that has been missing from our healthcare system,” said Brent Clough, CEO of Trio Health. “We believe once these factors become clearer, patients and biopharma innovators will benefit, as payers adopt a true performance-based model for drug reimbursement.”

Continued Mr. Clough, “Our collaboration with Accredo enables us to expand on our experience analyzing real world evidence in evaluating treatments for hepatitis C, oncology, RA, hemophilia and HIV, and review medications covering a broad range of diseases and conditions that are prescribed to millions of patients and cost billions of dollars.”

Trio Health has the ability to analyze pharmacy, physician, and clinical information within its proprietary database. The resultant patient de-identified data is harmonized to bring a new understanding of the delivery, use and outcomes of prescription medications while optimizing care of real world patients. 

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First patient dosed in phase 2/3 trial of advanced HCC therapy
March 3, 2019

Innovent Biologics announced first patient dosing in a phase 2/3 trial of Tyvyt with IBI305 for patients with advanced hepatocellular carcinoma taking place in China, according to a press release.

"HCC is the fourth most common cancer and the second leading cause of cancer related death in China,” Fan Jia, president of Zhongshan Hospital, said in the release. “The five-year survival rate is about 10%, and only 20-30% of patients have the opportunity for curative surgery. Current targeted therapies have only shown limited responses in HCC. Immune checkpoint inhibitors have brought new hope to patients with this life-threatening disease.”
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No need to discontinue hepatitis C virus therapy at the time of liver transplantation
Catarina Skoglund, Martin Lagging, Maria Castedal

Published: February 22, 2019
 https://doi.org/10.1371/journal.pone.0211437

Abstract
Objectives
Direct antiviral agents (DAA) has dramatically improved the therapy outcome of hepatitis C-virus (HCV) infection, both on the waiting-list and post liver transplantation (LT). DAA are generally well-tolerated in patients with mild to moderate liver and kidney failure, but some DAAs are contraindicated in patients with severe dysfunction of these organs. Today there are few studies of peri-LT DAA use and treatment is commonly discontinued at the time of LT. We report here our experience of DAA therapy given continuously in the perioperative LT period in a real-life setting in Sweden.

Material
In total 10 patients with HCV-cirrhosis, with or without hepatocellular carcinoma, and a median age of 60.5 years (range, 52–65) wsere treated with DAAs on the waiting list for LT, and continued in the early postoperative period without any interruption, on the basis of not having reached a full treatment course at the time of LT. Sofosbuvir and a NS5A inhibitor with or without ribavirin, or sofosbuvir and ribavirin only, were given. The distribution of genotypes was genotype 1 and 3, in 4 and 6 patients, respectively. Six of the 10 patients had previously been treated with IFN-based therapy.

Results
There were no adverse events leading to premature DAA discontinuation. All recipients achieved a sustained viral response 12 weeks after end-of-treatment (SVR12). At the time of LT the median MELD-score was 16.5 (range 7–21), CTP-score 9.0 (range 5–10), creatinine 82.5 μmol/L (range 56–135, reference 60–105), bilirubin 33 μmol/L (range 16–79, reference 5–25) and PK-INR 1.5 (range 1.1–1.8). The median duration of DAA therapy was 60 days (range 18–132) pre-LT, 54 days post-LT (range 8–111 days) and in total 15.5 weeks (range 12–30 weeks).

Conclusion
Interferon-free DAA therapy of HCV-infection given in the immediate pre- and post-operative LT period is safe, well-tolerated and yields high SVR rates.

Full-text available online:
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Prevalence of hepatitis B and hepatitis C among diabetes mellitus type 2 individuals 
Livia Melo Villar , Bruno Geloneze , Ana Carolina Junqueira Vasques , Maria Lucia Elias Pires , Juliana Custódio Miguel , Elisangela Ferreira da Silva , Vanessa Alves Marques , Leticia de Paula Scalioni , Elisabeth Lampe

Published: February 28, 2019
https://doi.org/10.1371/journal.pone.0211193

Abstract
Diabetes mellitus type 2 (DM2) patients have higher risk to be infected with parenterally transmitted viruses, like hepatitis B or C virus. This study aims to determine HBV and HCV infection prevalence in DM2 patients from Northeast and Southeast Brazil. A total of 537 DM2 patients were included, 194 (36.12%) males and 343 (63.87%) females, with mean age of 57.13±11.49 years. HBV and HCV markers were determined using serological and molecular analysis, and risk factors were evaluated in a subgroup from Southeast (n = 84). Two HBV acute (HBsAg+/anti-HBc -) and one HBV chronic case (HBsAg+/anti-HBc+) were found. Six individuals (1.1%) were isolated anti-HBc, 37 (6.9%) had HBV infection resolved (anti-HBc+/anti-HBs+), 40 (7.4%) were considered HBV vaccinated (anti-HBc-/anti-HBs+). Thirteen patients (2.42%) had anti-HCV and 7 of them were HCV RNA+. In the subgroup, anti-HBc positivity was associated to age and anti-HCV positivity was associated to age, time of diabetes diagnosis, total bilirubin, indirect bilirubin, alkaline phosphatase at bivariate analysis, but none of them was statistically significant at multivariate analysis.

As conclusion, low prevalence of HBV and high prevalence HCV was found in DM2 patients.

Full-text available online:
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211193
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Estimating the prevalence of hepatitis C among intravenous drug users in upper middle income countries: A systematic review and meta-analysis
Víctor Granados-García , Yvonne N. Flores, Lizbeth I. Díaz-Trejo, Lucia Méndez-Sánchez, Stephanie Liu, Guillermo Salinas-Escudero, Filiberto Toledano-Toledano, Jorge Salmerón

Published: February 26, 2019

Abstract
Aim
This systematic review and meta-analysis characterizes the prevalence of hepatitis C virus (HCV) infection among intravenous drug users (IDUs) in upper middle-income countries.

Methods
Five databases were searched from 1990–2016 for studies that took place in countries with a GDP per capita of $7,000 to $13,000 USD. The data extraction was performed based on information regarding prevalence, sample size, age of participants, duration of intravenous drug use (IDU), recruitment location, dates of data collection, study design, sampling scheme, type of tests used in identifying antibody reactivity to HCV, and the use of confirmatory tests. The synthesis was performed with a random effects model. The Cochrane statistical Q-test was used to evaluate the statistical heterogeneity of the results.

Results
The 33 studies included in the analysis correspond to a sample of seven countries and 23,342 observations. The point prevalence value estimates and confidence intervals of the random effects model were 0.729 and 0.644–0.800, respectively for all seven countries, and were greatest for China (0.633; 0.522–0.732) as compared to Brazil (0.396; 0.249–0.564). Prevalence for Montenegro (0.416; 0.237–0.621) and Malaysia (0.475; 0.177–0.792) appear to be intermediate. Mexico (0.960) and Mauritania (0.973) had only one study with the largest prevalence. A clear association was not observed between age or duration of IDU and prevalence of HCV, but the data from some groups may indicate a possible relationship. The measures of heterogeneity (Q and I2) suggest a high level of heterogeneity in studies conducted at the country level and by groups of countries.

Conclusions
In this systematic review and meta-analysis, we found that the pooled prevalence of HCV was high (0.729) among a group of seven upper middle income countries. However, there was significant variation in the prevalence of HCV observed in China (0.633) and Brazil (0.396). 

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NIH study of brain energy patterns provides new insights into alcohol effects
Assessing the patterns of energy use and neuronal activity simultaneously in the human brain improves our understanding of how alcohol affects the brain, according to new research by scientists at the National Institutes of Health. The new approach for characterizing brain energetic patterns could also be useful for studying other neuropsychiatric diseases. A report of the findings is now online in Nature Communications.

“The brain uses a lot of energy compared to other body organs, and the association between brain activity and energy utilization is an important marker of brain health,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of NIH, which funded the study. “This study introduces a new way of characterizing how brain activity is related to its consumption of glucose, which could be very useful in understanding how the brain uses energy in health and disease.”

The research was led by Dr. Ehsan Shokri-Kojori and Dr. Nora D. Volkow of the NIAAA Laboratory of Neuroimaging. Dr. Volkow is also the director of the National Institute on Drug Abuse at NIH. In previous studies they and their colleagues have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, which is assessed through changes in blood oxygenation.

“The findings from this study highlight the relevance of energetics for ensuring normal brain function and reveal how it is disrupted by excessive alcohol consumption,” says Dr. Volkow.

In their new study, the researchers combined human brain imaging techniques for measuring glucose metabolism and neuronal activity to derive new measures, which they termed power and cost.

“We measured power by observing to what extent brain regions are active and use energy,” explained Dr. Shokri-Kojori. “We measured cost of brain regions by observing to what extent their energy use exceeds their underlying activity.”

In a group of healthy volunteers, the researchers showed that different brain regions that serve distinct functions have notably different power and different cost. They then investigated the effects of alcohol on these new measures by assessing a group of people that included light drinkers and heavy drinkers and found that both acute and chronic exposure to alcohol affected power and cost of brain regions.

“In heavy drinkers, we saw less regional power for example in the thalamus, the sensory gateway, and frontal cortex of the brain, which is important for decision making,” said Dr. Shokri-Kojori. “These decreases in power were interpreted to reflect toxic effects of long-term exposure to alcohol on the brain cells.”

The researchers also found a decrease in power during acute alcohol exposure in the visual regions, which was related to disruption of visual processing. At the same time, visual regions had the most significant decreases in cost of activity during alcohol intoxication, which is consistent with the reliance of these regions on alternative energy sources such as acetate, a byproduct of alcohol metabolism.

They conclude that despite widespread decreases in glucose metabolism in heavy drinkers compared to light drinkers, heavy drinking shifts the brain toward less efficient energetic states. Future studies are needed to investigate the mechanisms contributing to this relative inefficiency.

“Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction, as the measures of power and cost may provide new multimodal biomarkers for such disorders,” says Dr. Shokri-Kojori.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol use disorder. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at: https://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference
Shokri-Kojori E, Tomasi D, Alipanahi B, Wiers CE, Wang GJ, Volkow ND (2019). Correspondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain. Nat Commun. 10(1):690.
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Recommended Reading
High response and re-infection rates among people who inject drugs treated for hepatitis C in a community needle and syringe programme
We show that it is feasible to recruit people who inject drugs(PWID) from a community-basedneedle and syringe programme (NSP) onto HCV treatment, and achieve over 80% SVR-12 andimpressive treatment adherence.

Commentary
HCV reinfection as a positive indication of high‐risk population treatment access
Gregory J Dore

First published: 25 February 2019
https://doi.org/10.1111/jvh.13092

Strategies to address HCV reinfection and limit its overall impact on HCV elimination are required, but the most important of these is ongoing engagement with high- risk individuals to enable detection of HCV reinfection and its retreatment without stigma and discrimination.

Download full-text article:

Article shared via Twitter by Henry E. Chang‏.
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Towards a blood test for early-stage liver disease
Researchers uncover a set of proteins that are enriched in pre-symptomatic non-alcoholic fatty liver disease

Heidelberg, 1 March 2019 – One in four people in Western and Asian societies develop a build-up of fat in the liver as a result of an unhealthy diet. This disease – referred to as non-alcoholic fatty liver disease (NAFLD) – causes no symptoms initially but can develop into end-stage liver cirrhosis with limited treatment options. A discovery, published today in Molecular Systems Biology, paves the way for a simple blood test to detect early stages of NAFLD, opening up the possibility of preventing the development of liver cirrhosis through lifestyle changes or pharmaceutical intervention.

The liver is an important organ, filtering toxic substances from the body and producing proteins required for digestion, blood clotting, and other important physiological functions.

“The liver is very resilient and capable of regenerating itself, which may be the reason why liver damages due to excessive fat deposition can go undetected for a long time,” says EMBO Member Matthias Mann of the University of Copenhagen, Denmark, and the Max Planck Institute of Biochemistry in Martinsried, Germany, who led the study. However, when damage accumulates liver function eventually starts to fail.

To date, the standard procedure for diagnosing NAFLD is liver biopsy – a cumbersome and costly procedure that can lead to complications. Non-invasive methods that reliably detect early stage NAFLD are therefore urgently required.

Mann and his colleagues investigated the plasma proteome – the entire set of proteins present in the blood plasma – of NAFLD patients. Using sophisticated mass spectrometry technologies, they uncovered a set of proteins that accumulate in the plasma of patients with non-symptomatic NAFLD.

In a first set of experiments, they determined that the blood proteome of patients in a late stage of the disease differed considerably from that of healthy controls. Many proteins that were altered in the patients’ blood proved to be associated with known aspects of the disease, such as thrombosis, vitamin A and D deficiency, or defects in glucose metabolism. These observations show the validity of the procedure to find new disease-related proteins.

In the next step, comparing the proteome of patients in early stage NAFLD with that of healthy individuals, the researchers found only minor differences. They did, however, succeed in identifying six proteins that were significantly associated with early stage NAFLD.

“One of the proteins we uncovered, termed PIGR, is of special interest,” says Mann. “Individuals with NAFLD who do not show any symptoms have increased levels of PIGR in their blood. And the concentration of the protein increases the further the disease progresses, making PIGR an interesting biomarker candidate for the inclusion in liver damage tests.”

While current blood tests only detect liver damage at a late stage in disease development, the present study is an important step towards developing new diagnostic tools to identify patients with NAFLD in a much earlier, pre-symptomatic phase.

Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease

Molecular Systems Biology
Lili Niu, Philipp E. Geyer, Nicolai J. Wewer Albrechtsen, Lise L. Gluud, Alberto Santos, Sophia Doll, Peter V. Treit, Jens J. Holst, Filip K. Knop, Tina Vilsbøll, Anders Junker, Stephan Sachs, Kerstin Stemmer, Timo D. Müller, Matthias H. Tschöp, Susanna M. Hofmann, Matthias Mann

DOI: 10.15252/msb.20188793
Read the paper: http://msb.embopress.org/cgi/doi/10.15252/msb.20188793
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