February 17, 2014

Complementary and alternative medications in hepatitis C infection

World J Hepatol. 2014 January 27; 6(1): 9-16.
Published online 2014 January 27. doi: 10.4254/wjh.v6.i1.9.

Copyright ©2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Dina L Halegoua-De Marzio and Jonathan M Fenkel.

Dina L Halegoua-De Marzio, Jonathan M Fenkel, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
Author contributions: Halegoua-De Marzio DL and Fenkel JM both outlined, researched the topics wrote, and wrote the manuscript.

Correspondence to: Jonathan M Fenkel, MD, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, 132 S. 10th Street, Suite 480, Main Building, Philadelphia, PA 19107, United States. jonathan.fenkel@jefferson.edu

Telephone: +1-215-9558900 Fax: +1-215-5032146

Received October 9, 2013; Revised December 22, 2013; Accepted January 6, 2014;

Abstract

Chronic hepatitis C (CHC) infection affects almost 3% of the global population and can lead to cirrhosis, liver failure, and hepatocellular carcinoma in a significant number of those infected. Until recently, the only treatments available were pegylated interferon and ribavirin, which traditionally were not very effective and have considerable side effects. For this reason, interest in complementary and alternative medications (CAM) in the management of hepatitis C has been investigated. Some CAM has demonstrated therapeutic potential in chronic hepatitis C treatment. Unfortunately, some CAM has been shown to have the potential to cause drug-induced liver injury. This article will review and evaluate many of the natural molecules that interact with the hepatitis C virus (HCV) life cycle and discuss their potential use and safety in HCV therapy, as well as highlight some important interactions between medical and complementary treatments.

Keywords: Hepatitis C infection, Natural molecules, Direct acting antivirals, Hepatotoxicity, Herbal treatments

Core tip: Over the last 10 years there has been a substantial increase in reports of natural compounds displaying anti-viral activity against hepatitis C. At this time, there is no firm evidence supporting complementary and alternative medications for hepatitis C virus infection. Due to a limited number of trials and small numbers of subjects included in them, it is not possible to fully evaluate the risk of adverse events connected with the use of these products.

INTRODUCTION

Hepatitis C virus (HCV) infection affects an estimated 180 million people globally and is a leading cause of chronic hepatitis, cirrhosis, and liver cancer[1,2]. To prevent the complications of chronic hepatitis C (CHC), the goal of therapy is complete viral eradication. For the past decade, a combination of pegylated interferon-α (peg-IFN) and ribavirin was used to treat CHC with disappointing viral eradication rates. These rates were particularly suboptimal in patients with genotype 1 HCV, which is responsible for approximately 60% of worldwide infections[3]. Sustained virological response (SVR) rates for genotype 1 HCV are approximately 40% following 48 wk of peg-IFN/ribavirin and are even lower in patients with HIV co-infection, high baseline viral load, advanced fibrosis, or those of African descent[4-7].

The life cycle of HCV can be divided into three major steps: (1) entry of the virus into its target cells by receptor-mediated endocytosis; (2) cytoplasmic and membrane-associated replication of the RNA genome; and (3) assembly and release of the progeny virions[8]. In recent years, there has been improvement in SVR rates with the development and approval of the first HCV-specific direct-acting antiviral agents (DAAs), namely boceprevir and telaprevir[9,10]. In contrast to the non-specific antiviral activity of peg-IFN and ribavirin, DAA are designed to inhibit viral proteins involved in the HCV life cycle. Still, the first DAAs require coadministration with peg-IFN and ribavirin, and many patients remain intolerant to treatment-associated side effects, including fevers, influenza-like symptoms, headache, cytopenias, fatigue, anorexia, rash, and depressive symptoms.

CAM is being used increasingly across the globe for many chronic diseases[11,12]. The Cochrane Library included nearly 50 systematic reviews of complementary medicine interventions as of 2003[13]. Many people turn to CAM when conventional medicine fails, or they believe strongly in its effectiveness. During the last few years, a substantial increase of reports on natural compounds displaying an anti-HCV activity has been published. There is data that some of these medicinal herbs might have therapeutic potential in CHC, or may alleviate side effects of conventional therapy[13]. CAM use is common among people with CHC. A survey of 1145 participants in the National Institutes of Health (NIH)-supported HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial found that 23% of the participants used herbal products[14]. Although sometimes thought by the public to be safer then conventional therapy, there are many reports about liver toxicity and other adverse events from some herbal products[11,15]. The aim of this review is to evaluate the efficacy and safety of treating HCV infection using complementary and alternative medicine.

MEDICINAL HERBAL AND DIETARY SUPPLEMENTS WITH ANTI-HCV ACTIVITY

Silymarin

An extract of the milk thistle plant, silymarin (Silybum marianum), has been used to treat chronic liver disease since the time of the ancient Greeks[16]. Owing to its purported hepatoprotective properties, it is the most commonly used herbal product by individuals with chronic liver disease in the United States[16,17]. A recent publication from the HALT-C study group indicated that 33% of patients with CHC and cirrhosis reported current or past use of silymarin[14]. A follow-up study found silymarin use among CHC patients was associated with reduced progression from fibrosis to cirrhosis, but had no impact on clinical outcomes[16].

The major active component of silymarin, silibinin (a mixture of the two diastereoisomers silybin A and silybin B), is thought to be responsible for silymarin’s hepatoprotective properties[18]. Silymarin appears to inhibit HCV infection at two or more different levels: (1) it inhibits HCV replication in cell culture; and (2) it displays anti-inflammatory and immunomodulatory actions that may contribute to its hepatoprotective effect[19,20]. The inhibition of HCV replication has been attributed to inhibitory action on the NS5B RNA-dependent RNA polymerase.

Clinical studies that have evaluated milk thistle for a variety of liver diseases have yielded inconsistent results and low bioavailability of oral silymarin components[21]. Studies with IV silibinin have shown substantial antiviral effect against HCV in liver transplant recipients, and even in nonresponders with good safety outcomes[22-24]. Although oral administration of silymarin is not effective for the treatment of HCV, intravenous silibinin formulation may represent a future potential therapeutic option.

Green tea extract

Green tea, made from the unfermented leaves of Camellia sinensis, is comprised of several polyphenolic compounds called catechins, and can be concentrated into a green tea extract (GTE). Epigallocatechin-3-gallate (EGCG) is the most abundant and potent catechin contained within GTE, comprising typically approximately 40% of the total polyphenol content[25]. EGCG is a potent inhibitor of HCV entry in primary human hepatocytes independent of the genotype, by blocking virus attachment. This novel inhibitor may provide a new approach to prevent HCV infection, especially in the setting of liver transplantation of chronically infected HCV patients[26,27]. Beyond its antiviral effect on HCV, EGCG may have potential use as a chemopreventative agent for hepatocellular cancer as EGCG may inhibit cancer cell growth. This mechanism of action is thought to be due to tyrosine kinase inhibition and modulation of target gene expression associated with induction of apoptosis and cell cycle arrest in cancer cells[28-34].

GTE is a common ingredient in several dietary supplements, some of which have been withdrawn from the market due to safety concerns. An example of this is Exolise (Arkopharma, France), a weight loss supplement containing high EGCG levels that was withdrawn from the market in April 2003 due to 13 cases of attributable liver injury[35]. Between 1966 and 2008, 216 case reports of toxicity with green tea extracts were identified by the United States Pharmacopeia, of which 34 were concerning for liver toxicity[36]. Recent animal studies with high doses of GTE and EGCG have described dose-dependent hepatotoxicity resulting in severe morbidity and mortality[37]. However, chronic moderate to high dose daily GTE and EGCG use in healthy human volunteers, and selected patients with cirrhosis, was safe and did not impair liver function[38-40]. Although GTE may be very useful in further treatment of CHC and prevention of HCC, its hepatotoxic potential must be acknowledged and monitored carefully in future studies.

Naringenin

HCV associates with β-lipoproteins [very low density lipoprotein (vLDL) and low-density lipoprotein (LDL)] circulating in blood[41]. In addition, HCV replication can be up-regulated by fatty acids and inhibited by statins; this suggests an interaction between HCV, cholesterol, and lipid metabolism[42]. Recent research has found that of HCV secretion is dependent on both apolipoprotein B (ApoB) expression and vLDL assembly in a chromosomally integrated complementary DNA (cDNA) model of HCV secretion[43].

Naringenin is the predominant flavanone present in the grapefruit and is responsible for its bitter taste. Naringenin has been shown to reduce cholesterol levels both in vitro and in vivo[44,45]. Furthermore, naringenin inhibits ApoB secretion by reducing the activity and the expression of the microsomal triglyceride transfer protein (MTP) and the acyl-coenzyme A cholesterol acyltransferase 2 (ACAT)[44,46]. Due to the close link between HCV assembly/secretion and lipoprotein metabolism, there has been extensive study on the impact of naringenin on the secretion of HCV particles[43]. A dose-dependent decrease of core protein, HCV-positive strand RNA, infectious particles, and ApoB has been observed in the supernatant of infected primary hepatocytes in culture after naringenin treatment[43]. Overall, naringenin blocked the assembly of intracellular infectious viral particles without affecting intracellular levels of the viral RNA or protein. Although still at the cell culture phase, naringenin may offer new insight into a promising and novel HCV therapeutic target.

Glycyrrhizin

Glycyrrhizin, a natural compound extracted from the roots of Glycyrrhiza glabra, has been used for more than 20 years as a treatment for chronic hepatitis[47]. It has been used for many centuries in traditional Chinese medicine as an anti-allergic agent. Because of its sweet taste it is also used as a food additive, for example in beverages and licorice[48]. In an attempt to use glycyrrhizin as a treatment for “allergic” hepatitis it was found to lower the transaminases. In a study by Suzuki et al[49] in 1977, plasma transaminases activity improved significantly with glycyrrhizin in patients with chronic liver disease compared to a placebo group.

The mechanism by which glycyrrhizin improves the biochemistry and histology in liver disease is unknown. It is thought to have anti-inflammatory, antioxidant and immunomodulatory activities. Due to this there has been much interest in use of glycyrrhizin in CHC. In the only randomized clinical trial of glycyrrhizin, ALT levels declined modestly during treatment, compared with placebo, but this was not sustained after cessation of treatment and there was no significant effect on HCV RNA levels[50]. In the another trial, statistically significant differences in liver enzyme levels, but not viral loads, between treatment groups were identified during treatment, however, again no sustained response occurred at follow-up[51]. Use of glycyrrhizin is not without side effects. It has been found to cause pseudo-aldosteronism, manifested by sodium retention, hypokalemia and hypertension[52]. Cardiac arrhythmia and acute rhabdomyolysis due to severe hypokalemia caused by excess licorice consumption have also been reported[52-54].

Oxymatrine

Oxymatrine is the major alkaloid extract from the root of sophora flavescens, a deciduous shrub native to China, Japan, South Korea and Russia. It is reported to have antiviral activity against HCV in cell cultures and in animal studies[55-57]. Clinical studies have shown that oxymatrine has some hepatoprotective activity in alcohol toxicity and hepatitis B infection, but not carbon tetrachloride, acetaminophen or cadmium chloride-induced acute hepatitis[58,59]. Oxymatrine is considered to be an antifibrotic, likely through inhibition of lipid peroxidation[60-62]. In a study of HCV-infected subjects randomized subjects to receive either an intramuscular injection of oxymatrine 600 mg/d or other support products such as oral vitamins 47% of the treated cases had complete HCV viral suppression after 3 mo, compared with only 5% in the control group[61]. No serious adverse events were reported. The treated group had significantly more ALT normalizations than the control group in the first 2 mo, but this improvement waned by the end of the third month of treatment. While treatment with oxymatrine holds promise, it is difficult to draw conclusions from the small studies currently available.

Traditional chinese herbal medications

The primary goal of Chinese traditional medicine is to create wholeness and harmony within a person, allowing the mind/body/spirit to heal itself. There have been several randomized clinical trials of traditional Chinese medicine in the treatment of hepatitis C, however, the methodological quality of these studies is generally considered poor[63-70]. In two trials of herbal formulations in combination with interferon-alfa, there was a trend toward greater clearance of HCV RNA and ALT normalization with the combination treatment compared with patients receiving monotherapy[63,64]. In the only placebo-controlled trial of solo therapy with traditional Chinese medicine, a significant reduction in ALT levels during treatment occurred, though no virologic effect was identified[69]. Detailed descriptions of adverse events were not provided for most of these trials. The safety of these medicines is unclear due to the individualized nature of many of the herbal compounds involved, the large number of different herbs in each formulation, and the relatively small number of subjects within each clinical trial.

Vitamin D

The traditional role of Vitamin D (Vit D) was thought to be based upon its interaction in calcium homeostasis, via regulation of intestinal calcium absorption and of bone health. However, over the last several years Vit D has been shown to have a much more complex role in many other host functions, including its interaction with chronic hepatitis C. 25-OH Vit D is made in the liver via cytochrome P450 (CYP27A1) activated hydroxylation of Vit D, brought into the body either by intestinal absorption or endogenous synthesis through sun-exposed skin. It is then converted to 1.25 OH Vit D (calcitriol) in the kidneys, the most active form, where it becomes available to bind to Vit D receptors throughout the body[71,72].

A growing body of clinical evidence has demonstrated an increased prevalence of Vit D deficiency in patients with CHC. As such, Vit D supplementation has been proposed as an adjunct to current standard regimens for treatment of hepatitis C[72]. One study found that mean 25-OH Vit D serum levels were significantly lower in CHC (25 μg/L) than in the controls (43 μg/L)[73]. Importantly, low Vit D has been linked to increased fibrosis and impaired sustained virologic response (SVR) in IFN-based therapy[71]. One clinical trial demonstrated that the addition of Vit D to the standard IFN plus ribavirin treatment significantly increased SVR in patients with genotype 1 CHC[74]. Regarding the underlying molecular mechanisms, an in vitro study showed that Vit D remarkably inhibits HCV production in Huh7.5 hepatoma cells[75]. These cells express Vit D hydroxylases and can eventually generate calcitriol. Notably, treatment with calcitriol resulted in HCV inhibition through induction of IFN-beta. Overall, 25-OH Vit D levels appear to be an important prognostic marker in helping determine the likelihood of SVR. 25-OH Vit D levels should be checked routinely before HCV treatment and supplementation provided to deficient patients, in an effort to enhance treatment response.

Antioxidants

Antioxidants are one of the most common dietary supplements taken by patients with CHC[14]. The use of these supplements is based on the fact that oxidative stress has been attributed to both host inflammatory processes and induction by viral proteins. By increasing antioxidants, one may be able to decrease oxidative stress and therefore decrease liver injury[76]. Existence of oxidative stress in CHC is well documented, as oxidized protein and nucleic acid markers are increased and antioxidant levels are decreased[77-80]. Studies have shown levels of oxidative stress markers to correlate with disease severity, HCV RNA, iron overload, and insulin sensitivity[78,79]. Oxidative stress has also been shown to be an early event in carcinogenesis and is a risk factor for development of HCC in patients with chronic HCV[81].

Multiple trials have shown antioxidants, such as Vitamin E and N-acetyl cysteine, only lead to small reductions in ALT after chronic administration in some instances[82-93]. Further, the decrease in ALT levels in most studies is marginal and is not sustained after stopping the treatment, raising the question of their clinical significance. No study has shown an improvement in outcome. In addition, no study has shown clear benefit of antioxidants as adjuvant to interferon based therapy of HCV. At the doses studied, these antioxidants appear to be well-tolerated, with no specific adverse events reported in any of the trials. However, very large oral doses of N-acetyl cysteine are commonly associated with nausea and vomiting and intravenous administration of N-acetyl cysteine can result in anaphylactoid reactions, which may be more common in patients with chronic liver disease[94]. Therefore, evidence supporting use of antioxidants as useful therapeutic agents in CHC is lacking.

HERBAL SUPPLEMENTS AND DRUG INDUCED LIVER INJURY IN CHRONIC HCV

Drug-related hepatotoxicity is a serious health problem, with broad implications for patients, healthcare providers, the pharmaceutical industry and governmental regulatory agencies. The Drug Induced Liver Injury Network (DILIN), a federally funded consortium of 12 centers in the United States, recently reported the preliminary results of its prospective study[94]. Dietary supplements were implicated in 9% of reported DILI cases. This may be potentially related to increasing use of herbal or dietary supplements in the US population. The importance of these supplements as a cause of DILI is further underscored by a retrospective Japanese study, in which 10% of 879 cases of single agent DILI from 1997 to 2006 were attributed to dietary supplements and 7% to Chinese herbal drugs[95].

In general, chronic liver diseases such as HCV infection are thought to be associated with an increased incidence of hepatotoxicity induced by several specific drugs. Furthermore, patients with underlying liver disease potentially have worse outcomes than healthy individuals if they do develop DILI[96]. For example, the presence of underlying CHC has been shown to increase the risk of DILI caused by the antituberculosis drugs isoniazid and rifampin, as well as ibuprofen and methimazole[15,97,98]. Due to this, patients with chronic hepatitis C should be counseled and screened by physicians on potential risks associated with herbal medications.

DRUG-CAM INTERACTIONS

Another major area of awareness when patients are considering using CAM is whether or not drug-CAM interactions may exist that could impact the medical therapy. This issue is becoming even more complicated with the addition of new medications for the treatment of CHC infection such as simeprevir and sofosbuvir approved for use in the U.S. in December 2013. St. John’s wort (Hypericum perforatum), a common CAM used for the treatment of depression, is an inducer of cytochrome P450 3A4[99]. This cytochrome is also the primary metabolizer of many medications, including the HCV protease inhibitors: telaprevir, boceprevir, and simeprevir. Additionally, St. John’s wort is a potent intestinal P-gp inducer and may lead to a reduced therapeutic effect of the HCV nucleotide polymerase inhibitor sofosbuvir[100]. Concomitant use of St. John’s wort and these HCV treatments is contraindicated and can lead to treatment failure by reducing blood concentrations. Additionally, concomitant use of milk thistle use is contraindicated with simeprevir. This combination may increase levels of simeprevir by milk thistle CYP3A inhibition leading to possible toxicity[101] (Table 1). Garlic extracts, grapefruit juice, and germander also have cytochrome P450 3A4 interactions[102].

Table 1 Herbal supplements to discontinue and/or avoid while taking hepatitis C virus treatment
Herbal Product Effect
Milk thistle (Silybum marianum) Concomitant use of milk thistle may result in increased plasma concentrations of simeprevir
St. John’s wort (Hypericum perforatum) Concomitant use of St. John’s wort may result in decreased plasma concentrations of telaprevir, boceprevir, simeprevir and sofosbuvir

CONCLUSION

Many human studies have shown improvements in subjective symptoms and liver biochemistries in HCV patients with CAM, but there is no convincing data to suggest a definite histological and/or virologic improvement with any of the herbal agents currently available. Vit D seems to have the best available data as adjunctive therapy to antiviral medications in patients with Vit D deficiency. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature.

The safety profiles of the interventions discussed within this review are encouraging at the doses studied. However, the long-term safety for use in the treatment of hepatitis C, either alone or in combination with conventional medicines, has not been established. Comparative and placebo-controlled trials suggest that patients experience no more adverse events with these interventions than with placebo or comparative medications, although short-term clinical trials are not designed to detect rare or delayed adverse events. Physicians need to be cognizant of known or occult use of CAM by their patients because hepatotoxicity and drug interactions may occur with many herbal medications, and may occur more frequently in patients with chronic liver disease.

There is an undoubted need for further research into the treatment of hepatitis C, and this review has identified several promising compounds, including Vit D, silymarin, oxymatrine, naringenin, and GTE. Some or all of these may be integral components of future HCV management.

Footnotes

P- Reviewers: De Ponti F, Julie NL, Sunbul M S- Editor: Wen LL L- Editor: A E- Editor: Liu XM

References

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Posted by: Mike Nace February 17, 2014

Hepatitis-C-cure-308x400

Leading world health organizations agree that the global rise of Hepatitis is an alarming health issue — one that may have already eclipsed AIDS in many parts of the world. It is estimated that at least 150 million people have Hepatitis C worldwide — nearly 5 times the number of people who suffer from HIV. Hepatitis C is a particularly ravaging disease since, if left untreated, it can eventually cause liver damage and lead to cancer. While drug development for a Hepatitis B cure to complement the already-developed vaccine continues to progress, the good news forHepatitis C is that a cure already exists. The issue, however, is not the cure, but its price.

In countries like India, where Hepatitis C is a major health issue, the high cost of the cure is a sticking point between drug developers looking to get value for their product and health officials who see curing the disease as the only consideration in pricing the treatment. According to a recent article in the New York Times by Donald G. McNeil, Jr., the simple pill regimen for curing Hepatitis C — a drug called sofosbuvir developed by Gilead Sciences under the brand name Sovaldi in the U.S. – costs American patients and healthcare companies an estimated $84,000 per treatment.

The price tag for Sovaldi is clearly priced for the hyper-inflated U.S. healthcare market, which often prices high-performance drugs, surgeries, and other specialized medical procedures higher than anyone could ever pay on their own in the U.S., let alone the developing world. In a country like India, however, $84,000 per treatment for Hepatitis C isn’t even a consideration.

For their part, Gilead has suggested a path toward licensing the treatment to Indian drug companies that they believe would get the price of sofosbuvir down to a $2,000-per-treatment version — a mere 2.3% of the U.S. price.

However, worldwide health advocates are lobbying for Gilead to do what it takes to make their Hepatitis C cure widely affordable and available to those who have the disease in the developing world. McNeil’s piece highlights Doctors Without Borders’ efforts to exhort Gilead to craft sofosbuvir-based treatments for $250 or less, and is lobbying the World Health Organization “to put sofosbuvir on its list of drugs the agency tests for countries too poor to have their own drug regulatory agencies.”

Rohit Malpani, a Doctors Without Borders policy advisor, outlines the organization’s position on the pricing issue, and reveals just how far apart the two sides are on getting to a price that satisfies everyone involved: ”We think a $2,000 price tag, although a discount from U.S. prices, is not going to get the job done,” he noted. “It’s a discount from a price we think is absolutely outrageous. The way we look at it is, how much does this drug cost to make and what is patients’ ability to pay?”

Critics of Gilead’s pricing scheme say, that they believe the Hepatitis C treatment could be offered to countries like India for as low as $68 to $136 for a 12-week treatment course.

“We know from our experience treating HIV over the past decade and a half that treatment needs to be simple and affordable,” Malpani says in a Doctors Without Borders statement. “Full hepatitis C treatment needs to be available for no more than $500 per person.”

In recent comments on the issue, Gilead does not appear to be ready to capitulate to these calls for lower prices. Instead, the company has indicated that, once it finalizes licensing for the drug in India, it would be incumbent upon Indian generic producers to offer competitive pricing on Solvadi, not only to make it more affordable, but also to gain a market advantage in India: ”We’ll be working probably with three to five different companies,” Gregg Alton of Gilead told The Hindu Business Line. “We leave it up to the Indian companies to bring the price down, should they choose to do that.”

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February 11, 2014
N-195 2013-14

Despite a number of social/behavioral intervention and educational programs, the spread of hepatitis C (HCV) in people who inject drugs (PWIDs) remains a chronic problem. Now, researchers affiliated with New York University’s Center for Drug Use and HIV Research (CDUHR) are focusing on intervention strategies that highlight the lesser-known dangers of HCV transmission through the sharing of other injection equipment such as cookers, filters, drug-dilution water and water containers.

Their article, “The Staying Safe Intervention: Training People Who Inject Drugs in Strategies to Avoid Injection-Related HCV and HIV Infection,” published in the 2014 March-April issue ofAIDS Education and Prevention, explores the feasibility and efficacy of their “Staying Safe Intervention,” a strengths-based social/behavioral intervention conducted with small groups of PWID, designed to facilitate long-term prevention of HIV and HCV.

“The Staying Safe Intervention seeks to reduce injection risk by intervening upstream in the causal chain of risk behaviors by modeling, training in, and motivating the use of strategies and practices of long-term risk-avoidance,” said Dr. Pedro Mateu-Gelabert, the study’s Principal Investigator, at the NYC-based National Development Research Institutes.

Dr. Mateu-Gelabert and his NDRI-CDUHR team evaluated 68 street-recruited injectors from the Lower East Side of Manhattan. The objective was to reduce participants’ injection risk behaviors, empower and motivate behavioral change, and teach tactics to help reduce drug intake.  The current program was built upon findings of their 2005 study, “Staying Safe,” which looked at the behaviors and strategies of individuals who had injected drugs for long periods of time (8–15 years) but had not contracted HIV or HCV.

“The Staying Safe Intervention does not focus exclusively on the moment of injection,” explains Dr. Mateu-Gelabert, “but on the upstream determinants of risk behavior, such as stigma, risk networks, social support and income, while encouraging injectors to plan ahead in order to better manage the drug-related risk contexts they are likely to face.”

The social/behavioral intervention showed substantial improvement in motivation and planning to avoid injection-related risks, increased use of stigma management strategies, and decreases in drug withdrawal episodes (known to reduce safe injection practices) and number of weekly injections. The research team also noted that participants in the study have been spreading the word on safer drug use within their communities.

The Centers for Disease Control and Prevention estimate that not only do nine percent of new HIV infections originate from drug use, but 18 percent of PWID are HIV positive and up to 70-77 percent of PWIDs have HCV.

“Given the substantial reductions observed among Staying Safe participants in key injection-related risk behaviors associated with HCV transmission, the Staying Safe Intervention may have the potential to contribute to sufficient additional risk reduction to help address the seemingly intractable rates of HCV transmission among PWID,” said Dr. Mateu-Gelabert.

Currently, Dr. Mateu-Gelabert’s team is researching HCV and HIV risk associated with nonmedical prescription opioid use. Future research will evaluate the effectiveness of the Staying Safe Intervention in preventing HIV and hepatitis C infection among young prescription opioid users who have transitioned to heroin injection.  “The goal is to implement the Staying Safe approach with this new generation of young injectors, so they do not get infected with HIV or HCV,” said Dr. Guarino, a Co-investigator in the project.

The project described was supported by Award Numbers R21DA026328, R01DA019383, R01DA031597, and R01DA035146 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

The research team members are: P. Mateu-Gelabert, M.V Gwadz, H. Guarino, M. Sandoval, C.M Cleland, A. Jordan, H. Hagan, H. Lune, S.R Friedman. Affiliations: National Development Research Institutes Inc. (PMG,HR,MS,SRF), New York, NY USA; College of Nursing (MVG,CMC,AJ,HH), New York University; Hunter College (SRF), City University of New York, NY USA.

About CDUHR

CDUHR, funded by the National Institute on Drug Abuse, is the first center for the socio-behavioral study of substance use and HIV in the United States. The Center is dedicated to increasing the understanding of the substance use-HIV/AIDS epidemic, particularly among individuals in high-risk contexts. The Center's theme is "Discovery to Implementation & Back: Research Translation for the HIV/Substance Use Epidemic." The Center facilitates the development of timely new research efforts, enhances implementation of funded projects and disseminates information to researchers, service providers and policy makers.

About New York University College of Nursing
NYU College of Nursing is a global leader in nursing education, research, and practice. It offers a Bachelor of Science in Nursing, a Master of Arts and Post-Master’s Certificate Programs, a Doctor of Philosophy in Research Theory and Development, and a Doctor of Nursing Practice degree.  For more information, visit www.nyu.edu/nursing.

This Press Release is in the following Topics:
College of Nursing, NYUToday-feature

Type: Press Release

Press Contact: Christopher James | (212) 998-6876

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PRESS RELEASE February 17, 2014, 10:35 a.m. ET

More than 100 Walgreens Pharmacies Designated Hepatitis C-Specialized to Meet Projected Patient Care Management Needs and Improve Medication Adherence

DEERFIELD, Ill.--(BUSINESS WIRE)--February 17, 2014--

With new advances in treatment therapy now available for hepatitis C patients, Walgreens (NYSE:WAG) (Nasdaq:WAG) today announced it is expanding access to Walgreens Connected Care(sm) hepatitis C program through its more than 100 hepatitis C-specialized pharmacies. Walgreens Connected Care is an education and support plan designed to help patients achieve a sustained virologic response (SVR) and improved quality of life through medication adherence.

The expansion comes at a critical time, as the once potentially life-threatening condition affecting more than 3.2 million Americans is now increasingly curable due to recent advances in therapy.(1) Also, a growing number of Americans with hepatitis C infection are expected to have access to health insurance based on the provisions of the Affordable Care Act.

Walgreens now offers more than 100 hepatitis C-specialized pharmacies with new hepatitis C virus (HCV) medications available and pharmacists specially trained on next generation oral therapies. Walgreens hepatitis C specially-trained pharmacists are also qualified to identify HCV-associated health concerns and can provide hepatitis C patient care for those with a HIV co-infection or other comorbid conditions, such as diabetes or high blood pressure. The specialized support has been proven to benefit patients, contributing to 90 percent adherence for patients who completed past treatments(1) .

"While recent hepatitis C therapy advances can be more effective and present fewer side effects, some patients, with high instance of comorbidity, can experience difficulty in managing care and an increased cost of therapy," said Glen Pietrandoni, Walgreens director specialty products and services, virology. "Walgreens Connected Care(sm) hepatitis C program, delivered through our hepatitis C- specialized pharmacies, is designed to meet the holistic needs of people diagnosed with hepatitis C -- before, during and after HCV treatment. This can help patients achieve SVR and an improved quality of life through medication adherence, while continuing to manage other health outcomes."

Patients in Walgreens Connected Care(sm) hepatitis C program receive support services including 24-hour access to specially trained pharmacists, help verifying insurance and identifying financial assistance options, convenient access to or delivery of medication and pharmacist-led regimen check points to monitor response to therapy and encourage medication adherence.

Walgreens hepatitis C specially trained pharmacists work with patients to determine the best method of delivery. HCV medications can be picked up at a Walgreens hepatitis C specialized pharmacy or a designated local Walgreens pharmacy. Delivery is also available through hepatitis C specialized pharmacies or Walgreens Specialty Pharmacy locations.

"As the most common blood transmitted infection in the U.S. largely affecting an aging population with high instance of other health concerns, careful holistic patient pharmaceutical care and supported comprehensive therapy treatment plans are critical to maintain total medication adherence," said Pietrandoni.

About Walgreens

As the nation's largest drugstore chain with fiscal 2013 sales of $72 billion, Walgreens (www.walgreens.com) vision is to be the first choice in health and daily living for everyone in America, and beyond. Each day, Walgreens provides more than 6 million customers the most convenient, multichannel access to consumer goods and services and trusted, cost-effective pharmacy, health and wellness services and advice in communities across America. Walgreens scope of pharmacy services includes retail, specialty, infusion, medical facility and mail service, along with respiratory services. These services improve health outcomes and lower costs for payers including employers, managed care organizations, health systems, pharmacy benefit managers and the public sector. The company operates 8,206 drugstores in all 50 states, the District of Columbia, Puerto Rico and the U.S. Virgin Islands. Take Care Health Systems is a Walgreens subsidiary that is the largest and most comprehensive manager of worksite health and wellness centers, provider practices, and in-store convenient care clinics, with more than 750 locations throughout the country.

(1) Ghany, M. G., Nelson, D. R., Strader, D. B., Thomas, D. L. and Seeff, L. B. (2011), An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology, 54: 1433-1444. doi: 10.1002/hep.24641.

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February 17, 2014

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Through an exome-wide association study, researchers led by Jonathan Cohen, a professor at the University of Texas Southwestern Medical Center in Dallas, uncovered three variants linked to nonalcoholic fatty liver disease.

As the researchers reported in Nature Genetics yesterday, two of those variants were located in a gene previously linked to disease while one was in the TM6SF2 gene, whose function they traced to the secretion of very-low-density lipoprotein. The variant itself appeared to be associated with higher levels of alanine transaminase, which typically rises in response to liver injury, as well as with lower levels of low-density lipoprotein-cholesterol, triglycerides, and alkaline phosphatase, another marker of liver disease.

"[Our] data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to [nonalcoholic fatty liver disease]," Cohen and his colleagues said.

Nonalcoholic fatty liver disease, or NAFLD, comprises a range of conditions stemming from the accumulation of fat into the liver. The researchers noted that some 30 percent of adults have excess fat in their liver, stored as triglycerides, and that while the condition can be benign, it can also lead to chronic inflammation and cirrhosis. The US National Institute of Diabetes and Digestive and Kidney Diseases reports that NAFLD is becoming more common in the US, possibly due to the increasing number of people with obesity.

Cohen and his colleagues searched for variants associated with hepatic triglyceride content in 2,736 participants from the Dallas Heart Study, sifting through some 138,400 polymorphic sequence variants while adjusting for ancestry, age, body mass index, and gender.

From this, they identified three variants linked to hepatic triglyceride content — two variants in the PNPLA3, which they had previously found to be associated with hepatictriglyceride levels, and one variant in the TM6SF2 gene, whose function was unknown.

The TM6SF2 variant, an adenine-to-guanine substitution leading to lysine replacing glutamate at residue 167, was more common in people of European ancestry than in African Americans or Hispanics, the researchers said. They also noted that the non-substituted form, Glu167, is highly conserved among mammals. People with the variant, though, had elevated hepatic triglyceride content no matter their ancestry.

Additionally, the TM6SF2 variant wasn't linked to other hepatic steatosis risk factors like BMI, insulin resistance, or alcohol consumption. It was also independent from the PNPLA3 variants.

RT-PCR analysis of cDNA from a range of human tissues found that TM6SF2 is highly expressed in the small intestine, liver, and kidneys, though it is found at lower levels in other tissues as well. The TM6SF2 variant is also linked to an increase in serum ALT, a marker of liver injury.

The researchers also confirmed the link between the TM6SF2 variant and NAFLD by drawing two cohorts, one from the Dallas Biobank and one from Copenhagen, including from the Copenhagen City Heart Study and from the Copenhagen General Population Study, with more than 82,000 samples. In both cohorts, the TM6SF2 variant encoding p.Glu167Lys was connected with signifi¬cantly higher activity of ALT in serum.

"These findings further support the hypothesis that the TM6SF2 variant encoding p.Glu167Lys is associ¬ated with NAFLD and are consistent with the notion that the vari¬ant compromises hepatic integrity," Cohen and his colleagues noted.

Further, in all three cohorts, the TM6SF2 variant was linked to lower levelsof triglycerides and LDL-C made in the liver.

By expressing the wild-type and variant forms of the protein in a hepatic cell line, the researchers found that wild-type and variant mRNA levels were comparable, but also that much less — 46 percent less — of the variant protein was expressed. This, the researchers said, suggests that the variant protein is misfolded and quickly degraded within the cell.

To determine how that affects hepatic triglyceride content, Cohen and his colleagues developed recombinant adeno-associated viral vectors that expressed short hairpin RNAs targeting TM6SF2 in mouse livers. Two different shRNAs aimed at TM6SF2 led to a more than 90 percent reduction in TM6SF2 mRNA in mouse livers, but not in other tissues, the researchers said.

Inhibiting TM6SF2 in mouse liver led to a three-fold increase of hepatic triglyceride content while also leading to lower plasma cholesterol levels — LDL, HDL, and the triglyceride content of VLDL were reduced, the researchers reported. ALT levels, though, were unchanged.

This, the researchers said, is consistent with a defect in VLDL secretion. To see just how knocking down TM6SF2 affects VLDL secretion, the researchers inhibited the enzyme — intravascular lipoprotein lipase — that breaks down the triglyceride con¬tent of VLDL and measured how quickly plasma triglycerides built up in plasma. In the knockdown mice, the rate of accumulation was much lower than in the control mice.

"These data indicate that TM6SF2 normally acts to promote VLDL secretion and suggest that the increased HTGC associated with the Glu167Lys TM6SF2 variant in humans results from a reduction in TM6SF2 function," Cohen and his colleagues said.

They noted that diets high in sucrose appear to intensify the effect that knocking down TM6SF2 had on hepatic triglyceride content.

Cohen and his colleagues further hypothesized that TM6SF2 might work in the intestine, where it is also expressed, to influence ALP activity. They said that they are currently exploring whether TM6SF2 is involved in lipoprotein synthesis and ALP activity in the intestine as well as the connection between lower ALP levels and increased hepatic triglyceride content linked to the TM6SF2 variant encoding p.Glu167Lys.

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