Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies

Regulus Announces Continuation of RG-101 Clinical Hold

FDA requests longer-term follow-up data from ongoing studies

LA JOLLA, Calif., Jan. 27, 2017 /PRNewswire/ -- Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that it received written communication from the U.S. Food and Drug Administration (FDA) that the clinical development program for RG-101 remains on clinical hold. In June 2016, RG-101 was placed on clinical hold following the Company's submission of a second serious adverse event (SAE) of jaundice.

Late last year, Regulus submitted a complete response to the FDA's initial request for information, which included identification of a potential mechanism of hyperbilirubinemia. The Company also submitted a proposal to mitigate this risk. Subsequently, the FDA has requested the final safety and efficacy data from on-going RG-101 clinical and pre-clinical studies before reconsidering the clinical hold. These data will be available once the current study protocols are complete through 48 weeks of follow up, which is anticipated in the fourth quarter. The FDA also requested additional expert review of liver safety data in light of the proposed mechanism of hyperbilirubinemia.

"While we are disappointed that the clinical hold was not lifted at this time, we plan to continue to work with the FDA to address their additional requests as we seek the removal of the clinical hold," said Dr. Timothy Wright, Chief R&D Officer of Regulus.

About Regulus
Regulus Therapeutics Inc. (Nasdaq:RGLS) is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus has leveraged its oligonucleotide drug discovery and development expertise to develop a well-balanced microRNA therapeutics pipeline complemented by a rich intellectual property estate to retain its leadership in the microRNA field. Regulus is advancing several programs in renal, hepatic and central nervous systems diseases, both independently and with our strategic alliance partners, Sanofi and AstraZeneca. Regulus maintains its corporate headquarters in La Jolla, CA. For more information, please visit http://www.regulusrx.com.

About microRNAs
The discovery of microRNAs in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 800 microRNAs have been identified in the human genome, and over two-thirds of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNA expression, or function, has been shown to be significantly altered or dysregulated in many disease states, including oncology, fibrosis, metabolic diseases, immune-inflammatory diseases and HCV. Targeting microRNAs with anti-miRs, chemically modified, single-stranded oligonucleotides, offers a unique approach to treating disease by modulating entire biological pathways and may become a new and major class of drugs with broad therapeutic application.

http://ir.regulusrx.com/releasedetail.cfm?ReleaseID=1009493

Preventing Disease Transmission in Dental Settings

CDC Expert Commentary
Preventing Disease Transmission in Dental Settings

Infection Transmission in Dental Healthcare

Reports of transmission of infectious agents between patients and dental healthcare personnel (DHCP) in dental settings are rare. However, a recent Centers for Disease Control and Prevention (CDC) article in the Journal of the American Dental Association[1] identified three published reports describing the transmission of hepatitis B virus and hepatitis C virus in dental settings since 2003. In addition, the Morbidity and Mortality Weekly Report[2]—published April 8, 2016—described a 2015 outbreak of Mycobacterium abscessus infection at a pediatric dentistry practice.

In most cases, investigators have failed to link a specific lapse of infection prevention and control practice with a particular transmission. However, reported breakdowns in basic infection prevention practices included unsafe injection practices, failure to heat-sterilize dental handpieces between patients, failure to monitor (eg, conduct spore testing of) autoclaves, and failure to maintain dental unit waterlines. These reports highlight the need to improve understanding of and

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Scientists have shed new light on how the common painkiller paracetamol causes liver damage

Paracetamol brand names - Wikipedia

Paracetamol - NHS Choices

Paracetamol study could open door for way to treat liver damage
Scientists have shed new light on how the common painkiller paracetamol causes liver damage.

Their findings may offer valuable insights into poisoning caused by an excess dose, which can be difficult to treat and may prove fatal.

The discovery could inform research into therapies to counteract harm caused by the drug, which is the leading cause of acute liver failure in the Western world.

Scientists at The University of Edinburgh studied the impact of paracetamol on liver cells in human and mouse tissue.

Tests showed that even relatively low doses of paracetamol can damage the liver by harming vital structural connections between adjacent cells in the organ.

When these cell wall connections – known as tight junctions – are disrupted, the liver tissue structure is damaged, cells are unable to function properly and they may die.

This type of cell damage is known to occur in liver conditions including hepatitis, cirrhosis, and cancer, but until now it was not linked to paracetamol toxicity.

Researchers aim now to develop a reliable method of using human liver cells as an alternative to animal testing. They then will seek to examine how varying paracetamol doses and timescales affect toxicity in the liver, and identify potential targets for new drugs.

The study, involving researchers from the universities of Edinburgh and Oslo, and the Scottish National Blood Transfusion Service, was published in Nature Scientific Reports. It was supported in part by the Biotechnology and Biological Sciences Research Council and the Chief Scientist Office.

Nature Scientific Reports
Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver

Dr Leonard Nelson, of The University of Edinburgh’s Hepatology Laboratory and Institute for Bioengineering, who co-led the study, said: “Paracetamol is the world’s preferred pain remedy – it is cheap, safe and effective. However, drug-induced liver damage remains a significant problem. Our findings reinforce the need for vigilance in paracetamol use, and could help discover how harm caused by its adverse use might be prevented.”

Co-author Pierre Bagnaninchi, of the university’s MRC Centre for Regenerative Medicine, said: “Although liver damage cause by paracetamol toxicity has been the subject of intense study for 40 years, developments in biosensor technology are enabling a fuller picture of the biological mechanisms involved, which is a huge step in helping develop ways to manage the risks of an overdose.”

Source - http://www.healthcanal.com/digestive-system/76368-paracetamol-study-could-open-door-for-way-to-treat-liver-damage.html

About BBSRC
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, BBSRC invested £473M in world-class bioscience, people and research infrastructure in 2015-16. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: www.bbsrc.ac.uk.
For more information about BBSRC strategically funded institutes see: www.bbsrc.ac.uk/institutes.

Clinical characteristics, healthcare costs, and resource utilization in hepatitis C vary by genotype

Curr Med Res Opin.

2017 Jan 27:1-24. doi: 10.1080/03007995.2017.1288613. [Epub ahead of print]
Clinical characteristics, healthcare costs, and resource utilization in hepatitis C vary by genotype.
Goolsby Hunter A1, Rosenblatt L2, Patel C2, Blauer-Peterson C1, Anduze-Faris B3.

Received 22 Dec 2016, Accepted 26 Jan 2017, Accepted author version posted online: 27 Jan 2017

Article

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Abstract
BACKGROUND:
In the United States, approximately 3 million people are infected with hepatitis C virus (HCV). Genotypes of HCV variably affect disease progression and treatment response. However, the relationships between HCV genotypes and liver disease progression, healthcare resource utilization, and healthcare costs have not been fully explored.

RESEARCH DESIGN AND METHODS:
In this retrospective study of patients with chronic hepatitis C (CHC), healthcare claims from a large US health plan were used to collect data on patient demographic and clinical characteristics. Main outcome measures also include healthcare resource utilization (HCRU) and healthcare costs. Linked laboratory data provided genotype and select measures to determine liver disease severity.

RESULTS:
The sample (mean age 50.6 years, 63.5% male) included 10,331 patients, of which 79.1% had genotype (GT)1, 12.8% had GT2, and 8.1% had GT3. Descriptive analyses demonstrated variation by HCV genotype in liver and non-liver related comorbidities, liver disease severity, and healthcare costs. The highest percentage of patients with liver-related comorbidities and advanced liver disease was found among those with GT3. Meanwhile, patients with GT2 had lower HCRU and the lowest costs, and patients with GT1 had the highest total all-cause costs. These differences may reflect differing rates of non-liver-related comorbidities and all-cause care. Multivariable analyses showed that genotype was a significant predictor of costs and liver disease severity: compared with patients having GT1, those with GT3 were significantly more likely to have advanced liver disease. Patients with GT2 were significantly less likely to have advanced disease and more likely to have lower all-cause costs.

LIMITATIONS:
Results may not be generalizable to patients outside the represented commercial insurance plans, and analysis of a prevalent population may underestimate HCRU and costs relative to a sample of treated patients.

CONCLUSIONS:
These results suggest that liver disease progression varies by genotype and that CHC patients with GT3 appear to have more severe liver disease. These findings highlight the importance of effective HCV treatment for all patients and support guidelines for treatment of high-risk patients, including those with GT3.

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Glecaprevir and Pibrentasvir for 12 Wks HCV Genotype 1 and Prior Direct-acting Antiviral Treatment

Hepatology
Viral Hepatitis Glecaprevir and Pibrentasvir for 12 Weeks for HCV Genotype 1 Infection and Prior Direct-acting Antiviral Treatment
Fred Poordad, Franco Felizarta, Armen Asatryan, Mark S. Sulkowski, Robert W. Reindollar, Charles S. Landis, Stuart C. Gordon, Steven L. Flamm, Michael W. Fried, David E. Bernstein, Chih-Wei Lin, Ran Liu, Sandra S. Lovell, Teresa I. Ng, Jens Kort, Federico J. Mensa

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record.

Accepted manuscript online: 27 January 2017

Article - Download Accepted Manuscript

ABSTRACT
Although direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA-containing regimens, particularly those with NS5A inhibitors, are limited, and remain an area of unmet medical need. This phase 2, open-label study (MAGELLAN-1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1-infected patients with prior virologic failure to HCV DAA-containing therapy. A total of 50 non-cirrhotic patients were randomized to three arms: 200 mg GLE + 80 mg PIB (Arm A), 300 mg GLE + 120 mg PIB with 800 mg once-daily RBV (Arm B), or 300 mg GLE + 120 mg PIB without RBV (Arm C). By intent-to-treat analysis, sustained virologic response at post-treatment week 12 (SVR12) was achieved in 100% (6/6, 95% CI 61 – 100), 95% (21/22, 95% CI 78 – 99), and 86% (19/22, 95% CI 67 – 95) of patients in Arms A, B, and C, respectively. Virologic failure occurred in no patients in Arm A, and 1 patient each in Arms B and C (two patients lost to follow-up in Arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin, were observed. Conclusion: The combination of GLE and PIB was highly efficacious and well-tolerated in patients with HCV GT1 infection and prior failure to DAA-containing therapy; RBV coadministration did not improve efficacy. This article is protected by copyright. All rights reserved.
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Browse  Accepted Articles
Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.

AtlasPlus Released: The latest CDC surveillance data on HIV, viral hepatitis, STDs, and TB

The CDC has released AtlasPlus, a tool that gives users the ability to create tables, maps, and charts using over 15 years of HIV, viral hepatitis, STD, and TB surveillance data. AtlasPlus offers significant upgrades from the original version of Atlas including:

Easy, quick access to the latest data by county, state, or U.S. total;

2015 data for HIV, STDs, and TB; 2014 data for viral hepatitis;

An upgrade to the Tables function (Based on user feedback, we made it more intuitive to build tables based on the exact subset of the data you want to view.);

Improved chart capabilities such as line graphs by year, bar charts by states or counties, pie charts for sex, bar charts for age, race/ethnicity, transmission category (HIV), country of birth (TB);

New ability to create two side-by-side maps or charts, e.g., compare two diseases, two race/ethnicity groups, or two age groups; and

Mobile access.
For more information, see our What’s New webpage and visit the new AtlasPlus application!

Sofosbuvir in Combination with Simeprevir +/- Ribavirin in Genotype 4 Hepatitis C Patients with Advanced Fibrosis or Cirrhosis

Research Article
PLoS One. 2017 Jan 26;12(1):e0170933. doi: 10.1371/journal.pone.0170933. eCollection 2017.

Sofosbuvir in Combination with Simeprevir +/- Ribavirin in Genotype 4 Hepatitis C Patients with Advanced Fibrosis or Cirrhosis: A Real-World Experience from Belgium
Delphine Degré , Thomas Sersté, Luc Lasser, Jean Delwaide, Peter Starkel, Wim Laleman, Philippe Langlet, Hendrik Reynaert, Stefan Bourgeois, Thomas Vanwolleghem, Sergio Negrin Dastis, Thierry Gustot, Anja Geerts, Christophe Moreno

Published: January 26, 2017 http://dx.doi.org/10.1371/journal.pone.0170933

Abstract
INTRODUCTION:
Hepatitis C virus (HCV) is a major global health issue and successful treatment has been associated with a reduction of risk of all-cause mortality. Advancements have been made in HCV treatment through the use of interferon-free regimens. Most trials have been conducted in HCV genotype (GT) 1 and data for interferon-free regimens in GT4 patients are limited. The aim of this study was to evaluate the safety and efficacy of sofosbuvir plus simeprevir in a real-world cohort of HCV GT4 patients with advanced fibrosis.

PATIENTS AND METHODS:
Eighty-seven GT4 treatment-naïve or -Interferon (IFN) ribavirin (RBV) experienced patients treated with sofosbuvir and simeprevir +/- ribavirin (RBV) were enrolled in this cohort study (41% severe fibrosis, 59% cirrhosis).

RESULTS:
Patients were 51.7% male, 78.2% IFN/RBV treatment-experienced, and 37.9% received RBV treatment. The overall sustained virologic response at least 12 weeks after treatment (SVR12) rate was 87.4% while patients treated with and without RBV had rates of 87.9% and 87% (p = 0.593), respectively, and patients with advanced fibrosis (F3) and patients with cirrhosis had SVR12 rates of 94.4% and 82.4% (p = 0.087), respectively. SVR12 rates in treatment-naïve patients and in IFN/RBV -experienced patients were 78.9% and 89.7% (p = 0.191), respectively. Treatment failure occurred most commonly in patients with cirrhosis and severe disease. The treatment was well tolerated and no patient died or discontinued treatment due to adverse events.

CONCLUSIONS:
Sofosbuvir in combination with simeprevir +/- ribavirin in GT 4 HCV patients with advanced fibrosis achieved high SVR12 rates and was well tolerated. RBV did not appear to increase the rate of SVR12.

Discussion Only
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In this Belgian real-world cohort of HCV GT4 patients with advanced fibrosis, we showed that the combination of SOF + SMV achieved in ITT analysis an SVR12 rate of 87.4%, 87.9% for patients treated with RBV and 87% for patients treated without RBV. After exclusion of patients who did not achieve SVR12 for reasons other than virologic failure, we observed an SVR rate of 91.6%. These results showed that the combination of SOF+SMV is efficacious in HCV GT4 patients with advanced fibrosis and that the addition of RBV did not appear to increase the rate of SVR12 although patients treated with RBV seemed to have a faster decrease of their viral load with a higher rate of negative viral load at week 4 and at the EOT. Interestingly, some patients had detectable HCV RNA but below LLOQ at the EOT but achieved SVR12. We did not observe a significant difference in SVR12 between patients with severe fibrosis F3 and patients with cirrhosis. This may be due to the small size of the cohort. However, all but one patient who failed to achieve SVR12 were patients with cirrhosis and advanced disease. This observation is consistent with results observed previously in other studies [15]. After exclusion of patients who did not achieve SVR12 for reasons other than virologic failure, we observed an SVR12 rate of 87.5% in patients with cirrhosis. This result is comparable to the result of the OPTIMIST-2 study in GT1 patients with cirrhosis treated with SOF + SMV, who achieved SVR12 of 83% [31] while decompensated patients were excluded in this study. One patient with positive viral load after the end of treatment was a patient without cirrhosis but this patient was lost to follow-up during the treatment and no compliance data was available. Finally, SVR12 rate in IFN/RBV experienced patients and treatment naïve patients was not significantly different. Treatment was well tolerated. No patient died or discontinued treatment due to adverse events. Among patients treated with RBV, 18% of patients modified ribavirin dosage. The median baseline hemoglobin levels and the median baseline RBV dosage did not differ between patients who modified ribavirin dosage compared with those patients who did not. However, RBV posology was decreased only in patients with cirrhosis.

Limited data are currently available to guide treatment in chronic HCV GT4 patients especially with advanced fibrosis. However it is important to develop optimal treatment strategies for HCV GT4 patients because this genotype is highly endemic in non-Western parts of the world and its prevalence has increased in several European countries [19–21] Moreover, in real life, patients with advanced fibrosis have an urgent need of treatment and robust data are lacking for this population. Several treatment regimens containing sofosbuvir or simeprevir have been evaluated previously for GT4 HCV patients. The combination of SOF and RBV for 24 weeks in a cohort of Egyptian patients showed an SVR rate of 90% but this cohort included few patients with cirrhosis and the SVR rate in patients with cirrhosis was lower (78%) [32]. Recently, a real life study including HCV GT4 patients with advanced fibrosis showed that SOF/SMV+/- RBV combination for 12 weeks was an effective regimen with an overall SVR rate of 92% [33].Other studies including a few patients with cirrhosis showed that sofosbuvir with ledipasvir [34] had also high SVR rates in GT4 patients. A recent study evaluated the efficacy of the SOF+ ledipasvir+ RBV combination in GT1 and GT4 patients with cirrhosis and seemed to be promising but the number of GT4 patients was low[35]. Other studies have evaluated the efficacy of newer direct-acting antiviral therapies for treatment of HCV GT4 patients including the combination of grazoprevir and elbasvir [36]. This treatment seemed to be efficacious but the results in patients with cirrhosis seemed to be worse [37]. The combination of sofosbuvir and velpatasvir provided high rates of SVR among patients infected with HCV genotypes 1,2,4,5, and 6, including those with compensated cirrhosis [38] and decompensated cirrhosis [39]. However, this study included few GT 4 patients. The AGATE-1 study evaluated the efficacy of the combination of ombitasvir and paritaprevir/ritonavir with ribavirin in HCV GT4 patients with cirrhosis. This study showed that this regimen is very efficacious for GT4 patients with cirrhosis [40]. However, conversely to the SOF-SMV combination, RBV use is obligatory. Moreover, this combination is not allowed in patients with decompensed cirrhosis. Indeed, post-marketing surveillance identified several cirrhotic patients who developed hepatic decompensation or liver failure while receiving this therapy [41].

Our study is subject to several limitations. First, ribavirin treatment was not given after randomization but only at the discretion of the treating clinician and the number of patients with cirrhosis receiving RBV is probably too small to show a potential benefit of RBV treatment in this population. It is thus difficult to make definitive conclusions concerning the role of ribavirin in the efficacy of treatment in our cohort of patients. Moreover, we had no data about resistance associated variants (RAV) which might influence the treatment response. Indeed, in the COSMOS study, the viral relapse rate was mainly correlated with mutations that have previously been associated with simeprevir resistance [11]. However, the Q80K mutation has not been reported in GT4.

In conclusion, we showed in this real-world cohort of GT4 patients with severe fibrosis and cirrhosis that the combination of SOF and SMV is efficacious and well tolerated and represents a good therapeutic option in HCV GT4 patients with advanced fibrosis and compensated cirrhosis. In patients with decompensated cirrhosis, second-generation IFN-free combinations would be better suited.

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Editorial - Dietary factors can protect against liver cancer development

Editorial
World J Hepatol. Jan 28, 2017; 9(3): 119-125
Published online Jan 28, 2017. doi: 10.4254/WJH.v9.i3.119

Dietary factors can protect against liver cancer development

Lemonica Koumbi

Full Article available, here.

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

Food consumption topics discussed in the article:
Red Meat
White Meat and Fish
Milk and Eggs
Vegetable, Fruit and Cereals
Dietary Sugar
Diet In Viral Hepatitis-Induced HCC

Read complete article @ World Journal of Hepatology

Review - Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years

Molecules 2017, 22(2), 191; doi:10.3390/molecules22020191
Review
Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years

Alessandro Federico *, Marcello Dallio and Carmelina Loguercio           

Department of Clinical and Experimental Medicine, Second University of Naples, 80131 Naples, Italy

Received: 6 December 2016 / Accepted: 18 January 2017 / Published: 24 January 2017 

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Abstract:

Silymarin is the extract of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma.

Keywords: silymarin; silybin; antioxidants; alcoholic liver disease; viral hepatitis; non-alcoholic fatty liver disease; hepatocellular carcinoma

Continue to full text article @ Molecules

About This Journal

Molecules (ISSN 1420-3049, CODEN: MOLEFW) is an open access journal covering all aspects of organic chemistry. Originally conceived as a forum for papers on synthetic organic chemistry and natural product chemistry, like the field, Molecules has evolved over its 20 years, with increasing numbers of papers on more theoretical subjects, physical organic chemistry, nanomaterials and polymer chemistry and applied studies. All articles are peer-reviewed and published continuously upon acceptance. Molecules is published by MDPI, Basel, Switzerland.

Hepatitis C Education for the Public: 31 Days of Wellness

Watch - Hepatitis C Education for the Public: 31 Days of Wellness
by Dr. Joe Galati on 01/24/2017

Dr. Joseph Galati discusses a recent presentation on hepatitis C, explaining risk factors for hepatitis C, new drug therapies for hepatitis C, and the complications associated with hepatitis C. These slides were presented at a recent program supported by the American Liver Foundation, in Houston, Texas. New therapies are able to cure hepatitis C, and if left untreated, hepatitis C can lead to cirrhosis, liver failure, liver cancer, and the possible need for a liver transplant.

Watch the video, here....

Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study

Hepatitis C virus infection and the risk of cancer among elderly US adults: A registry-based case-control study
Parag Mahale MBBS, PhD, Harrys A. Torres MD, Jennifer R. Kramer PhD, Lu-Yu Hwang MD, Ruosha Li PhD, Eric L. Brown PhD, Eric A. Engels MD, MPH
First published: 24 January 2017
DOI: 10.1002/cncr.30559

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Abstract
BACKGROUND
Hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC) and subtypes of non-Hodgkin lymphoma (NHL). Associations with other cancers are not established. The authors systematically assessed associations between HCV infection and cancers in the US elderly population.

METHODS
This was a registry-based case-control study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data in US adults aged ≥66 years. Cases (n = 1,623,538) were patients who had first cancers identified in SEER registries (1993-2011). Controls (n = 200,000) were randomly selected, cancer-free individuals who were frequency-matched to cases on age, sex, race, and calendar year. Associations with HCV (documented by Medicare claims) were determined using logistic regression.

RESULTS
HCV prevalence was higher in cases than in controls (0.7% vs 0.5%). HCV was positively associated with cancers of the liver (adjusted odds ratio [aOR] = 31.5; 95% confidence interval [CI], 29.0-34.3), intrahepatic bile duct (aOR, 3.40; 95% CI, 2.52-4.58), extrahepatic bile duct (aOR, 1.90; 95% CI, 1.41-2.57), pancreas (aOR, 1.23; 95% CI, 1.09-1.40), and anus (aOR, 1.97; 95% CI, 1.42-2.73); nonmelanoma nonepithelial skin cancer (aOR, 1.53; 95% CI, 1.15-2.04); myelodysplastic syndrome (aOR, 1.56; 95% CI, 1.33-1.83); and diffuse large B-cell lymphoma (aOR, 1.57; 95% CI, 1.34-1.84). Specific skin cancers associated with HCV were Merkel cell carcinoma (aOR, 1.92; 95% CI, 1.30-2.85) and appendageal skin cancers (aOR, 2.02; 95% CI, 1.29-3.16). Inverse associations were observed with uterine cancer (aOR, 0.64; 95% CI, 0.51-0.80) and prostate cancer (aOR, 0.73; 95% CI, 0.66-0.82). Associations were maintained in sensitivity analyses conducted among individuals without documented alcohol abuse, cirrhosis, or hepatitis B or human immunodeficiency virus infections and after adjustment for socioeconomic status. Associations of HCV with other cancers were not observed.

CONCLUSIONS
HCV is associated with increased risk of cancers other than HCC in the US elderly population, notably bile duct cancers and diffuse large B-cell lymphoma. These results support a possible etiologic role for HCV in an expanded group of cancers. Cancer 2017. © 2017 American Cancer Society.
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Related
Study shows link between Hepatitis C virus, multiple cancers
The connection between Hepatitis C virus (HCV) and certain cancers has been studied previously, with findings showing that HCV infection causes hepatocellular carcinoma, a type of liver cancer, and subtypes of non-Hodgkin lymphoma. In a paper published in Cancer, Dr. Jennifer Kramer and colleagues examine the link between HCV and other cancers within the U.S. elderly population.

“We found that HCV was more prevalent in the cases than in the controls, and that it was positively associated with multiple cancer types,” Kramer said. “This shows us that HCV is associated with an increased risk of cancers outside of hepatocellular carcinoma and supports a potential causative role of HCV in an expanded group of cancers.”

The cancers associated with HCV other than liver included cancers of the bile ducts, pancreas, anus, non-melanoma non-epithelial skin cancers, diffuse large B-cell lymphoma, and myelodysplastic syndrome.

The study was designed and funded by the National Cancer Institute and led by Dr. Parag Mahale, who conducted the research as part of his doctoral dissertation at the University of Texas Health Science Center in Houston.
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Hepatitis C Virus Genotype 4: Genotype 1's Little Brother

J Viral Hepat. 2017 Jan;24(1):4-12. doi: 10.1111/jvh.12620. Epub 2016 Dec 1.

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother
J. Llaneras; M. Riveiro-Barciela; M. Buti; R. Esteban


Introduction
Chronic hepatitis C virus (HCV) infection affects approximately 130-150 million individuals worldwide.[1] Twenty per cent of chronic HCV infections are caused by HCV genotype 4 (GT4).[2] Infection by this genotype is more common (and highly prevalent), in the Middle East and Africa, where GT4 is responsible for more than 80% of HCV infections. In some Mediterranean European countries, especially Italy, France, Greece and Spain, the prevalence of GT4 has increased, accounting for 10%-20% of HCV infections. This genotype is usually seen in intravenous drugs users, HCV/HIV co-infected patients and immigrants from Africa or the Middle East.[3, 4] The prevalence of this infection in the United States is estimated at around 1%.[5]

In the last 5 years, HCV treatment has undergone a major change due to emergence of the new direct-acting antiviral (DAA) agents. Various therapeutic strategies have been designed to treat several HCV genotypes with these drugs.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved several drugs for the treatment of chronic HCV GT4 infection. The classical therapies for GT4, such as pegylated alpha interferon 2a or 2b (PegIFN) and ribavirin (RBV), are giving way to the new DAA agents. The following combinations have been approved for GT4 therapy: sofosbuvir (SOF), an NS5B polymerase inhibitor[6] plus ribavirin; sofosbuvir plus simeprevir (SMV), an NS3/4A protease inhibitor[7]; sofosbuvir plus daclatasvir (DCV), an NS5A protease inhibitor[8]; ombitasvir (OBV), an NS5A protein inhibitor, plus paritaprevir, another NS3/4A protease inhibitor, boosted with ritonavir (PTV/r)[9]; the fixed-dose combination of sofosbuvir with ledipasvir (LDV), an NS5A protease inhibitor[10]; the fixed-dose combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4A protease inhibitor[11]; and sofosbuvir with velpatasvir (VEL), an NS5A protein inhibitor.[12]

As compared with HCV genotype 1 (GT1), few trials have been performed in GT4 patients, and the samples studied are smaller. All the various DAA combinations have demonstrated effectiveness and safety in the treatment of patients with GT4 infection. However, the AASLD and EASL guidelines do not recommended them all, and rating of the evidence differs because of the type of studies performed, the safety profiles reported, drug–drug interactions, the availability across different countries and the cost of treatment.[13, 14] As in other HCV genotypes, the new DAA agents have led to improvements in the efficacy and safety of treatment in GT4 and have displaced PegIFN combined therapies to a secondary position (Tables 1 and 2).

Table 1. EASL recommended therapies for chronic HCV gentoype 4[13]

Recommendation	Regimen and daily dosing	Duration (weeks)
DCV, daclatasvir; LDV, ledipasvir; OBV, ombitasvir; PTR/r, paritaprevir/ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir. a Patients with compensated cirrhosis with contraindications to the use of ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks without ribavirin.
IFN-free regimens in treatment-naive patients with or without cirrhosis
A1	LDV/SOF (90 mg/400 mg)	12
A1	SOF/VEL (400 mg/100 mg)	12
A1	OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV	12
A1	EBR/GZR (50 mg/100 mg)	12
A1	SOF + SMV (400 mg/150 mg)	12
B2	SOF + DCV (400 mg/60 mg)	12
IFN-free regimens in treatment-experienced patients with or without cirrhosis
B1	LDV/SOF (90 mg/400 mg) + weight-based RBV	12a
A1	SOF/VEL (400 mg/100 mg)	12
A1	OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV	24
B1	SOF + SMV (400 mg/150 mg) + weight-based RBV	12a
B2	SOF + DCV (400 mg/60 mg) + weight-based	12a

Table 2. American Association for the Study of Liver Diseases (AASLD) recommended therapies for chronic hepatitis C virus (HCV) genotype 4

Recommendation	Regimen and daily dosing	Duration (weeks)
a Patients with prior on-treatment virological failure should be treated with 16 weeks and adding weight-based ribavirin.
Treatment-naive or treatment-experienced with or without cirrhosis recommended regimens[14]
A1	OBV/PTV/r (25/150/100 mg) + weight-based RBV	12
A1	SOF/VEL (400/100 mg)	12
B2	EBR/GZR (50/100 mg)	12a
B2	LDV/SOF (90/400 mg)	12

This article reviews the currently available data and the new treatments under development for patients with chronic HCV GT4 infection.

2 Historical Situation
2.1 Interferon-based therapies

Four IFN-based therapies have been approved by the FDA and the European Medicines Agency (EMA). Currently, none of them are recommended by the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines because of the superiority of IFN-free therapies in terms of efficacy and safety.

2.1.1 Pegylated interferon plus ribavirin

The first treatment for GT4 patients was PegINF plus ribavirin (RBV), which provided a sustained virological response (SVR) rate of around 45% in treatment-naive patients receiving pegylated alpha interferon (2a or 2b) plus RBV for 24-48 weeks.[15-17] In a large real-world cohort study, PROPHESYS, 317 patients with chronic HCV GT4 infection received this regimen.[18] The overall SVR24 rate (sustained virological response at week 24) was 41%, with a lower value (27%) in patients with cirrhosis. The limitations of this therapy are the lengthy duration, adverse events associated with PegINF, and low applicability in patients with advanced liver disease.

2.1.2 Sofosbuvir plus pegylated interferon plus ribavirin

Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase with activity against all HCV genotypes.[6] SOF plus PegINF and RBV for 12 weeks was evaluated in the NEUTRINO trial,[19] a phase-III study that included 28 patients infected by HCV GT4. SVR12 (sustained virological response at week 12) was achieved in 27 of the 28 patients (96%). The limitation of this regimen is that it is PegIFN-based, with all that this implies.

2.1.3 Simeprevir plus pegylated interferon plus ribavirin

Simeprevir, an NS3/4 inhibitor, is active against genotypes 1, 2 and 4.[7] The RESTORE study evaluated the efficacy and safety of SMV plus PegIFN plus RBV for 12 weeks followed by PegIFN and RBV for an additional period of 12 or 36 weeks in 107 patients HCV infected with GT4, including treatment-naïve and treatment-experienced patients.[20] Overall, 65.4% (70/107) of patients achieved SVR12, with a lower rate in treatment-experienced patients.

2.1.4 Daclatasvir plus pegylated interferon plus ribavirin

Daclatasvir is an NS5A inhibitor with activity against all HCV genotypes.[8] In the phase-III COMMAND-4 study, 124 GT4 patients were randomized to receive DCV plus PegIFN plus RBV for 24-48 weeks or PegIFN plus RBV for 48 weeks.[21] SVR12 rates were 82% (67/82) with DCV plus PegIFN plus RBV vs 43% (18/42) with PegIFN plus RBV.
Although SVR12 rates are higher in DAA plus PegIFN regimens than in PegIFN plus RBV, DAA plus PegIFN regimens do not achieve higher SVR12 rates than the currently available IFN-free combinations, which have the additional advantages of a shorter treatment duration and fewer adverse events.

3 Interferon-Free Therapies

Direct-acting antiviral agents have brought about a revolution in the efficacy and safety of HCV treatment and have enabled treatment of more complex cases: patients with advanced liver disease or decompensated disease, those with IFN contraindications or intolerance and those unwilling to receive IFN treatment.

Among IFN-free therapies, four combinations are recommended in the new, updated AASLD guidelines[14] for treating naïve and experienced patients (with or without cirrhosis): two NS5B inhibitor plus NS5A inhibitor combinations, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir; and two NS5A inhibitor plus NS3/4 inhibitor combinations, ombitasvir/paritaprevir/ritonavir (with RBV) and elbasvir/grazoprevir. In most cases, all these combinations are used in 12-week regimens (Table 3).

Table 3. Interferon-free combination regimens with new DAA agents with activity in GT4

NS3/4	NS5B	NS5A
a Fixed-dose combination.
	Sofosbuvir	Ledipasvira
	Sofosbuvir	Velpatasvira
	Sofosbuvir	Daclatasvir
Simeprevir	Sofosbuvir
Paritaprevir/r		Ombitasvira
Grazoprevir		Elbasvira

3.1 NS5B inhibitor plus NS5A inhibitor

3.1.1 Sofosbuvir/ledipasvir

The NIAID SYNERGY study, a phase-IIA trial, evaluated the combination of SOF/LDV in a cohort of 21 HCV GT4-infected patients.[22] The regimen was SOF 400 mg combined with LDV 90 mg in one pill, once daily for 12 weeks. The cohort included 13 (62%) treatment-naïve patients and eight (38%) treatment-experienced patients; three patients had moderate–severe liver fibrosis (F3 in 2 and F4 in 1). Twenty (95%) patients achieved SVR12 (100% in the protocol analysis). One patient did not complete the 12-week treatment regimen because of nonadherence. There were no treatment discontinuations due to adverse events. The most common side effects were diarrhoea, fatigue, nausea and upper respiratory tract infection. This controlled study showed that this one-pill once-daily treatment was highly effective and safe in GT4-infected patients. Further studies are needed to expand the recommendations for difficult-to-treat patients with GT4 infection.

Abergel et al.[23] evaluated SOF/LDV for 12 weeks in 44 patients infected by HCV GT4, including 10 (23%) with cirrhosis and 22 (50%) who were treatment-experienced. The overall SVR12 rate was 93%. As to NS5A resistance-associated substitutions (RASs), 22 of 27 (89%) patients with NS5A RASs and all those without RASs achieved SVR12. L30R was the most prevalent NS5A resistant-associated substitution (RAS) in the cohort. NS5B RASs were not detected at baseline. Three patients relapsed within the first 4 weeks after completion of treatment. Two were treatment-experienced, and none had cirrhosis. The most common side effects were similar to those seen in other cohorts (asthenia, headache and fatigue).

3.1.2 Sofosbuvir/velpatasvir

Velpatasvir is a pangenotypic HCV NS5A inhibitor with antiviral activity against genotypes 1-6. The EMA and FDA have authorized use of the SOF 400 mg plus VEL 100 mg fixed combination in one pill daily.[12]

Sofosbuvir/velpatasvir was evaluated in ASTRAL-1, a phase-III study that enrolled 624 patients with HCV infection, including some cirrhotic and treatment-experienced patients.[24] Patients previously treated with DAA agents were excluded. Overall, 116 (19%) patients had genotype 4 infection, 121 (19%) had cirrhosis, and 423 (68%) were treatment-naïve. All patients received a 12-week regimen of SOF/VEL. SVR12 rates were 100% (116/116) in GT4-infected patients, regardless of their fibrosis status or whether they had previously received treatment. At baseline, 50 GT4-infected patients had NS5A RASs, but all achieved SVR12. No significant differences were observed in adverse event rates between the SOF/VEL regimen and placebo. The most frequent adverse effects were headache, fatigue and nasopharyngitis.

Although the GT4-infected sample size was small, this 12-week combination regimen was easy to comply with, highly effective, and safe, even in those with advanced liver fibrosis and treatment-experienced patients.

3.2 NS5A inhibitor plus NS3/4 inhibitor
3.2.1 Ombitasvir/paritaprevir/ritonavir

Ombitasvir is a NS5A inhibitor and paritaprevir a NS3/4A protease inhibitor that is coadministered with low-dose ritonavir to increase paritaprevir serum levels.[9] This combination was analysed in the multicentre phase-IIb, PEARL-I study[25] including 135 noncirrhotic GT4 patients, 86 (63.7%) of whom were treatment-naïve. Treatment-experienced patients had failed PegINF plus RBV. Treatment-naïve patients were randomly assigned to a 12-week regimen of OBV plus PTV/r with or without weight-based RBV. All treatment-experienced patients received a 12-week regimen of OBV plus PTV/r with weight-based RBV. In treatment-naïve patients, SVR12 rates were 100% (42/42) in the RBV-containing regimen and 91% (40/44) in the RBV-free regimen, with no significant differences. All treatment-experienced patients achieved SVR12 (49/49). Two patients in the treatment-naïve group with an RBV-free regimen prematurely discontinued treatment: one was lost to follow-up and the other experienced viral breakthrough at week 8 of treatment. Two other patients in the same group relapsed within 12 weeks post-treatment. All were subtype GT4d, and all had RASs at the time of failure that were not present at baseline. The predominant NS3 RAS was D168V, and the NS5A RASs were L28S or L28V. The regimen was found to be safe. The most common adverse effect was headache, but there were no adverse event-related discontinuations or dose interruptions.
The efficacy and safety of this regimen in cirrhotic patients was evaluated in the multicentre, phase-III AGATE-I study,[26] including HCV GT4-infected treatment-naïve or treatment-experienced patients with compensated cirrhosis. Patients were randomized into two arms; one received a 12-week regimen of OBV plus PTV/R with weight-based RBV once daily and the other a 16-week regimen with the same combination. Preliminary results showed SVR12 rates of 97% (57/59) in patients with the 12-week regimen vs 98% (60/61) with the 16-week regimen. One patient receiving the 12-week regimen who did not achieve SVR12 had discontinued treatment on day 1. The other was a man with HCV subtype GT4a and a previous null response to PegINF plus RBV. At baseline, he had the P58L NS5A RAS and no NS3 RASs. At failure, he showed newly emergent NS5A RASs: L28M and Y93H. Thirty-six patients in the AGATE-I cohort had RASs at baseline, and all but one achieved SVR12. In the 16-week regimen arm, SVR12 results could not be reported for one patient because of missing data. This combination was well tolerated, with no discontinuations due to adverse events. The most important events recorded were asthenia, fatigue, headache and anaemia, which were more common in the lengthier, 16-week arm.

AGATE-II is a phase-III trial carried out in Egypt, evaluating OBV plus PTV/r with RBV for GT4-infected patients, including those with compensated cirrhosis.[27] In total, 160 patients were enrolled, 100 noncirrhotic and 60 compensated cirrhotic patients. Half were treatment-experienced (61% prior null responders, 24% prior relapsers and 15% partial responders). Noncirrhotic patients received co-formulated OBV plus PTV/R once daily plus weight-based RBV for 12 weeks. Patients with compensated cirrhosis were randomized into two arms with the same regimen for 12 weeks and 24 weeks, respectively. SVR12 rates were high 94% (94/100) in the noncirrhotic arm: one patient failed while on treatment, one discontinued by withdrawing consent, data were missing in another, and three patients relapsed. SVR12 in the 12-week cirrhotic arm was 97% (30/31), with a single patient failing on treatment, and SVR12 in the 24-week arm was 96% (27/29), with missing data in one patient during follow-up and one on-treatment failure. The most common adverse events were fatigue (12%) and headache (15%). Extension of therapy to 24 weeks did not provide any additional benefits in cirrhotic patients, and there were more adverse events and a higher haemoglobin decrease in this arm.

3.2.2 Elbasvir plus grazoprevir

Elbasvir is an NS5A inhibitor, active against genotypes 1, 2a, 3, 4, 5 and 6. Grazoprevir is an NS3/4 protease inhibitor that is active against HCV genotypes 1, 2, 4, 5 and 6.[11]
The C-EDGE treatment-naïve study was an international, randomized, blinded, placebo-controlled trial investigating the combination of EBR 50 mg plus GZR 100 mg in one daily pill for 12 weeks in treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, genotype 4 and genotype 6 infection.[28] The overall SVR12 rate for all genotypes was 95%. SVR12 in GT4 treatment-naive patients was 100% (18/18). RASs were analysed in GT4 patients at baseline. NS3 RASs were present in seven of 18 (39%) patients, NS5A RASs in nine of 18 (50%) patients, and both RASs (NS5A and NS3) were found in two patients. In this study, the presence of RASs did not have an impact on SVR12 in GT4 patients. The most common adverse events in the cohort were headache (17%), fatigue (16%) and nausea (9%).

The C-EDGE treatment-experienced study evaluated the efficacy of a 12-week or 16-week regimen in HCV-infected patients who had failed PegIFN treatment. Patients received a one-pill regimen of EBR plus GZR with or without weight-based RBV.[29] SVR12 rates in GT4 patients receiving the 12-week regimen without or with RBV were 78% (7/9) and 93% (14/15), respectively. SVR12 rates in those receiving the 16-week regimen without or with RBV were 60% (3/5) and 100% (8/8), respectively. Baseline RASs and subgenotypes did not seem to have an impact on SVR12 rates.
Asselah et al.[30] reported data from phase-II and phase-III studies including a total of 103 GT4-infected patients treated with EBR/GZR. Sixty-six treatment-naïve patients were enrolled to receive EBR/GZR for 12 weeks and another 10 patients received the same regimen plus weight-based RBV for 12 weeks. Ninety-six (54/56) patients achieved SVR12 in the RBV-free regimen, one patient was lost to follow-up, and other relapsed. In the RBV regimen, SVR12 rates were 100% (10/10). Treatment-experienced patients were divided into four arms, 12 weeks or 16 weeks of treatment with or without weight-based RBV. SVR12 rates were higher in the 16-week regimens and RBV-associated regimens than in the 12-week regimens or RBV-free regimens. Two patients in the 12-week regimen relapsed, one in the RBV-associated regimen and the other in the RBV-free regimen. The other two patients failed on treatment in the 16-week regimen without RBV. All treatment-naive patients who had NS5A RASs at baseline achieved SVR12. In total, 81% (13/16) of treatment-experienced patients who achieved SVR12 had NS5A RASs at baseline, and 100% of treatment-experienced patients with NS3 RASs at baseline achieved SVR12.

The 12-week regimen without RBV is an attractive combination for treatment-naïve patients and PegIFN relapsers, including patients with compensated cirrhosis. In treatment-failed patients, 16-week therapy duration is associated with a higher SVR12 (Table 4).

Table 4. (a) SVR12 in GT4 hepatitis C virus (HCV)-infected patients without liver cirrhosis treated with IFN-free regimens. (b) SVR12 in GT4 HCV-infected patients with liver cirrhosis treated with IFN-free regimens. (c) SVR12 in GT4 HCV-infected patients with and without liver cirrhosis treated with IFN-free regimens

Treatment regimen	Duration (weeks)	No	Prior HCV treatment	SVR12 rate % (no SVR/total)	Virological failures (no of cases)
EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTR/R, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced patients; TN, treatment-naive patients; VEL, velpatasvir. a Regimen without ribavirin. b Regimen with ribavirin.
(a) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]	12	89	Treatment-experienced Treatment-naive	100% (89/89)	—
SOF/LDV (NIAID SYNERGY)[22]	12	14	Treatment-experienced Treatment-naive	93% (13/14)	—
SOF/LDV Abergel et al.[23]	12	34	Treatment-experienced Treatment-naive	91% (31/34)	Relapsers: 3
NS5A/NS3/4
OBV/PTV/r (PEARL-1)[25]	12	135	Treatment-experienced Treatment-naive	91% (40/44) TNa	Virological breakthrough: 1 Relapsers: 2
				100% (42/42) TNb
				100% (49/49) TEb
OBV/PTV/r + RBV (AGATE-II)[27]	12	100	Treatment-experienced Treatment-naive	94% (94/100)	Breakthrough: 1 Relapsers: 3
(b) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]	12	27	Treatment-experienced Treatment-naive	100% (27/27)	—
SOF/LDV (NIAID SYNERGY)[22]	12	7	Treatment-experienced Treatment-naive	100% (7/7)	—
SOF/LDV Abergel et al.[23]	12	10	Treatment-experienced Treatment-naive	100% (10/10)	—
NS5A/NS3/4
OBV/PTV/r + RBV (AGATE-I)[26]	12 16	120	Treatment-naive Treatment-experienced	97% (57/59) 12 weeks 98% (60/61) 16 weeks	Virological breakthrough: 1
OBV/PTV/r + RBV (AGATE-II)[27]	12 24	60	Treatment-naive Treatment-experienced	97% (30/31) 12 weeks 96% (27/29) 24 weeks	Virological breakthrough: 2
(c) NS5A/NS3/4
GZR/EBR (C-EDGE TN)[28]	12	18	Treatment-naive	100% (18/18)	—
GZR/EBR (C-EDGE TE)[29]	12 16	37	Treatment-experienced	78% (7/9) 12 weeksa 93% (14/15) 12 weeksb 60% (3/5) 16 weeksa 100% (8/8) 16 weeksb	—
GZR/EBR Asselah et al.[30]	12 16	103	Treatment-experienced Treatment-naive	TN 96% (54/56) 12 weeksa 100% (10/10) 12 weeksb TE 78% (7/9) 12 weeksa 93% (14/15) 12 weeksb 66% (3/5) 16 weeksa 100% (8/8) 16 weeksb	Relapsers: 3 Virological breakthrough: 2

3.3 Other interferon-free regimens accepted for treating HCV GT4 infection

3.3.1 Sofosbuvir plus ribavirin

Sofosbuvir plus RBV was the first IFN-free therapy used for GT4 infection, but it is no longer recommended. In a phase-II study, 60 patients of Egyptian ancestry with chronic HCV GT4 infection received a combination of SOF plus RBV.[31] Half of the patients had been previously treated. Patients were randomly allotted 1:1 to receive SOF 400 mg and weight-based RBV in both groups, but with treatment durations of either 12 or 24 weeks. SVR12 was achieved in 68% of patients in the 12-week group and 93% in the 24-week group. The most common adverse events were headache, insomnia and fatigue. A larger number of adverse events were reported in the 24-week group due to the longer treatment duration. This study had a limited sample, and it included only a few difficult-to-treat patients.

Another trial carried out in Egypt analysed the efficacy and safety of the same combination in 103 patients,[32] 52% treatment-experienced and 17% with cirrhosis at baseline. Patients were randomly assigned to one of two arms: SOF 400 mg and a weight-based daily dose of RBV for 12 or 24 days. SVR12 was 90% in the 24-week group and 77% in the 12-week group. Patients with cirrhosis had lower SVR12 rates than those without cirrhosis in both arms.
Despite the favourable SVR12 rates at 24 weeks, this combination is suboptimal compared with combinations including two DAAs, which allow shorter duration and show fewer associated side effects, particularly in patients with cirrhosis.

3.3.2 Sofosbuvir plus simeprevir

PLUTO is a multicentre Spanish study including 40 patients with HCV GT4 infection.[33] This single-arm study evaluated the efficacy and safety of a 12-week regimen of SOF 400 mg plus SMV 150 mg daily. All patients achieved SVR12 regardless of their baseline characteristics (18% cirrhosis and 68% treatment-experienced). Adverse events occurred in 50%; all were grade 1 and grade 2. The most common adverse event was headache (20%).

The preliminary efficacy results of the phase-IIa OSIRIS study are in line with those seen in the PLUTO study.[34] OSIRIS is being conducted in Egypt and includes 63 treatment-naïve or experienced patients with and without cirrhosis. All have HCV GT4 infection and are under treatment with SMV 150 mg plus SOF 400 mg daily. High SVR4 rates (95%-100%) have been seen with 12 weeks of treatment regardless of the prior PegIFN plus RBV response or cirrhosis stage. The initial safety data show no discontinuations due to adverse events, and no grade 3 or 4 treatment-related adverse events. The study remains open pending SVR12.

The SOF plus SMV regimen has also been evaluated in the real world. In the French HEPATHER cohort, 34 HCV GT4 patients (82% with compensated cirrhosis and 73% treatment-experienced) were treated with SOF 400 mg plus SMV for 12 or 24 weeks with or without RBV.[35] SVR12 was attained in all patients receiving RBV in their regimen. In a study conducted in the Netherlands, HCV GT4-infected patients were treated with SOF plus SMV (with or without RBV) for 12 weeks. Treatment-naive and treatment-experienced patients were included, and SVR12 was achieved in 49 of 53 patients (92%).[36]

Regarding these results, SOF plus SMV would be a combination option for HCV GT4 infected patients. RBV addition could be considered in treatment-experienced patients.

3.3.3 Sofosbuvir plus daclatasvir

The ATU study investigated a French cohort including 215 patients with HCV GT4 infection and characteristics associated with a low response to treatment, such as moderate liver fibrosis, extrahepatic manifestations, recurrence following liver transplantation and placement on the liver or kidney transplant lists.[37] Among the total, 110 (52%) patients were treated with a 24-week regimen including SOF 400 mg and DCV 30 mg daily, and 63 (30%) patients received the same regimen for 12 weeks. RBV was added in eight patients in the 12-week regimen group and in 31 patients receiving the 24-week regimen. The overall SRV12 rate in HCV GT4 patients was around 91%. SVR12 in patients with cirrhosis (including decompensated cirrhosis) was 90%. The 12-week regimen group showed the highest number of treatment failures. This is a safe regimen with few discontinuations (1%), and the most common adverse event was asthenia in 10% of patients.

4 Treatment of Decompensated Cirrhosis

There are few available studies using the new DAA agents in GT4-infected patients with decompensated cirrhosis. The phase-II SOLAR-I study enrolled GT1- and GT4-infected patients with cirrhosis and moderately or severely impaired liver function, and liver transplant recipients with or without cirrhosis and mild, moderate or severe liver impairment, or fibrosing cholestatic hepatitis.[38] Patients were randomized into two arms to receive 12 or 24 weeks of LDV/SOF plus RBV, respectively. In total, 337 patients were enrolled, and 1% (4/337) had HCV GT4. Overall SVR12 rates in patients with moderate hepatic impairment were 87% in the 12-week regimen and 88% in the 24-week regimen. In liver transplant recipients, SVR12 was lower in those in Child–Turcotte–Pugh class C, with 60% and 75% in the 12- and 24-week regimens, respectively, compared noncirrhotic transplant recipients, with SVR12 rates of 96% and 98%, respectively. Treatment had to be discontinued prematurely in 4% patients because of adverse events. Ten patients died, mainly from complications related to hepatic decompensation. LDV/SOF plus weight-based RBV was associated with high SVR12 rates and good tolerance in decompensated and severe liver impairment, but there were only four GT4 patients in the cohort.

SOLAR-II was a multicentre study that extended data on the LDV/SOF plus RBV regimen in GT4 decompensated cirrhotic patients.[39] In total, 333 patients with advanced liver impairment were enrolled, 37 of whom (11%) were HCV GT4. LDV/SOF plus weight-based RBV were administered in 12- or 24-week regimens. SVR12 rates in GT4 were 78% (14/18) in the group receiving a 12-week regimen and 94% (16/17) in those treated for 24 weeks. The discontinuation rates were similar to those of SOLAR-I. Seventeen patients died due to complications of hepatic decompensation.
The phase-III study, ASTRAL-4, enrolled treatment-naive and treatment-experienced patients with decompensated cirrhosis infected with HCV genotypes 1 (78%), 2 (4%), 3 (15%), 4 (3%) and 6 (<1%).[40] Patients were randomized at a 1:1:1 ratio to receive SOF/VEL once daily for 12 weeks, SOF plus RBV once daily for 12 weeks or SOF/VEL once daily for 24 weeks. Overall SVR12 rates were 83% in patients receiving 12 weeks SOF/VEL (100%, 4/4 in GT4 patients), 94% in those receiving SOF/VEL plus RBV (100%, 2/2 in GT4 patients) and 86% in those with 24 weeks of SOF/VEL (100%, 2/2 in GT4 patients). All GT4-infected patients achieved SVR12. There were no significant differences in SVR rates between the three groups. NS5A RASs were detected in 72 of 255 patients (28%). Of these 72 patients, 64 (89%) achieved SVR12 compared with 169 of 183 patients (92%) without RASs. Serious adverse events were observed in approximately 16%-18% of patients in each group.

Real-life data are scarce in GT4-infected patients with decompensated cirrhosis. Welzel et al.[41] reported on 49 decompensated HCV patients receiving SOF plus DCV with or without RBV. The overall SVR12 was 92% (45/49). Three patients had GT4 infection, and all achieved SVR12. According to the Child–Turcotte–Pugh scoring system for cirrhosis, 15 were classified as B and eight as C. SVR12 rates in these patients were 80% and 88%, respectively. Please note the low representation of genotype 4 in this cohort.
The benefits of this treatment are unclear, particularly in patients with an advanced Child–Turcotte–Pugh score, because viral clearance seems to have little impact on liver impairment or liver complications.

5 HCV/HIV Co-Infected Patients

The efficacy and safety of treatment for HCV GT4 infection in the HIV co-infected population has been evaluated in a few studies.

ION-4 is a multicentre study involving patients co-infected with HIV-1 and HCV genotypes 1 or 4.[42] All patients received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir. In addition, all received LDV 90 mg plus SOF 400 mg in a single pill once daily for 12 weeks. In total, 335 patients were enrolled, 20% had cirrhosis, and 55% had received prior HCV treatment. SVR12 was achieved in 96% of the total cohort and in all patients (8/8) with GT4 infection. SVR12 rates were similar in the various subgroups regardless of treatment experience or cirrhosis stage. There were no cases of HIV-1 virological rebound, and none of the patients discontinued treatment because of adverse events.

The ALLY-2 study analysed 203 HCV/HIV co-infected patients (three patients had GT4) receiving 12 or 8 weeks of SOF 400 mg plus DCV 60 mg, daily.[43] SVR12 rates were 97% after 12 weeks of treatment and 76% after 8 weeks. All GT4-infected patients achieved SVR12.
A subanalysis by antiretroviral regimen class reported that SVR12 was 97% and was similar across the antiretroviral regimens included.[44] SOF plus DCV is an attractive combination for HCV/HIV co-infected patients, but further data in GT4-infected patients are needed.

The phase-III C-EDGE CO-INFECTION study is a multicentre trial including HIV patients co-infected with HCV genotypes 1, 4 and 6.[45] In total, 218 patients were enrolled and all received GZR/EBR for 12 weeks. The SVR12 rate in patients with GT4 infection was 96% (27/28), with only one relapse, occurring in a noncirrhotic patient. This RBV-free combination achieved a high SVR12 in HCV/HIV co-infected patients without RBV adverse events.

There is little information on GT4 HCV/HIV co-infected patients treated with ombitasvir and paritaprevir regimens. This would likely be an effective, safe combination, as indicated in genotype 1 by the TURQUOISE-I study,[46] but additional data are needed to recommend this combination in this specific population.

6 DAA Failures
6.1 Genotype 4. Resistance-associated substitutions

Only 2% to 5% of HCV GT4 patients fail DAA treatment. Pawlosky et al. reviewed the profiles of patients who experienced treatment failure in each of the major studies using any type of combination therapy. Most of the information came from HCV GT1-infected patients and very little from HCV GT4.

The emergence of HCV RASs is determined by the genetic barrier to the drug, the fitness of the resistant viral population and blood levels of the drug. The dynamics of RASs after discontinuation of DAAs differs depending on the antiviral agent. NS3/4 protease inhibitor RASs disappear within some time after completion of treatment. However, NS5A RASs persist for years and could impact on the selection of retreatment strategies.[47]

RASs to NS5A inhibitors at baseline did not demonstrate a significant impact on SVR12 in combination regimens of SOF/LDV, SOF/VEL or SOF plus DCV, except in treatment-experienced GT1a patients, with or without cirrhosis, in whom lower SVR12 rates were observed. Very limited data are available in GT4 infection. In patients with NS5A RASs failing DAA treatment, the current recommendation is to extend treatment to 24 weeks and add RBV. This is based on the findings from small studies showing a higher SVR12.[48] Although there are no available data in GT4 infection, NS5A inhibitor resistance did not have an impact on SVR12 in GT1 patients receiving an OBV/PTV/R regimen with RBV. Similar results were found for the EBR/GZR combination, with the exception of GT1a patients and treatment-experienced GT1b patients, in whom SVR12 rates were lower. Hence, associated RBV and 16-week or 18-week duration are required in these patients. Again, no resistance data are available in GT4 for this combination. NS3 RASs at baseline do not appear have impact on SVR12.

Presence of the Q80K NS3 resistance substitution does not affect SVR12 in GT4 infection, unlike what occurs in GT1a patients, especially treatment-experienced ones.[49]
Some re-treatment strategies after failing DAAs have been explored in a small number of patients. In a recent study, 15 GT1- and GT4-infected patients who failed a DCV-based regimen (DCV plus PegIFN plus RBV, with or without asunaprevir) received SOF plus SMV without RBV for 12 weeks. Thirteen (87%) achieved SVR12, including all those with GT4 infection.[50] Further data on re-treatment of GT4 patients are needed before a strong recommendation can be established. In the meantime, one re-treatment approach could be a combination of SOF with a DAA of a different class than that previously used plus RBV, and extending therapy to 24 weeks.

7 Summary

In summary, the treatment options for HCV GT4 are now continually growing. The lower SVR rates reported in the past have been eliminated since the development of the new DAA agents. The NS5B-inhibitor, sofosbuvir, has been and remains the cornerstone of the current IFN-free therapies, achieving high SVR12 rates with a good safety profile. Combinations of NS5B inhibitors with NS5A or NS3/4 may be optimal strategies for the treatment of GT4-infected patients with compensated cirrhosis and those previously treated with PegIFN/RBV regimens. Nonetheless, other combinations without NS5B inhibitors, such as NS5A plus NS3/4-inhibitors, have shown SVR rates and safety profiles similar to those of the sofosbuvir combination. Despite the paucity of studies in HCV GT4 infection, some cohorts have provided information of promising SVR12 rates and safety profiles in special populations, such as HCV/HIV co-infected patients and patients with decompensated cirrhosis. These limited data encourage more aggressive use of DAA agents in these populations.
Unfortunately, data on re-treatment strategies for GT4-infected patients who fail IFN-free therapy are nonexistent. We need a greater representation of GT4 patients in real-life studies to provide GT4 infection with a proper identity and remove it from the shadow of GT1.

Disclosures

Maria Buti and Rafael Esteban have received grant for Gilead, MSD, Abbvie and BMS. Mar Riveiro-Barciela has received grant for Gilead. Jordi Llaneras has no personal interests to declare.

References

Source - http://onlinelibrary.wiley.com/doi/10.1111/jvh.12620/full