January 30, 2014

Tips for Managing Symptoms Associated with HCV

David Novak
January 30, 2014


Based on research from the World Health Organization (WHO), each year 3 to 4 million people are infected by hepatitis C virus, or HCV, and more than 350,000 die every year because of this chronic disease. Fortunately, due to the introduction of direct-acting antivirals, the treatment for HCV has been dramatically improved. However, some of these medications have troublesome side effects that can interfere with normal daily activities. Here are simple and practical tips that can help in managing and reducing these side effects:

Tiredness and weakness

The majority of people with chronic hepatitis C or HCV will experience extreme tiredness, especially during treatment. Severe fatigue may develop in patients that don’t show any signs of changes, or perhaps small little changes in the liver. The feeling of tiredness and weakness is usually accompanied by a total lack of energy, which can affect daily activities. Peginterferon injections, which is an antiviral drug treatment for HCV, are also known to cause fatigue, which usually worsens 1-2 days after injections. It is best to plan ahead on when is the best time to receive this treatment, and make sure that you’ll be able to rest the next day. It is also important to remain physically active if you’re able, but in some cases it is best to conserve your energy, especially during treatment or if you have advance liver failure.

Pain and soreness

Flu-like symptoms -- such as chills, fever, muscle soreness and joint pain -- are common with HCV. Peginterferon injections can also cause flu-like symptoms that usually subside after two to three weeks of taking the drug. Some choose to take peginterferon injections before bedtime so that they can sleep through the discomfort; however, these same injections can cause insomnia, and in those instances, this tactic isn’t very effective. Drinking plenty of fluids can help in keeping your body hydrated and potentially aid in easing some of the symptoms. There are also medications that can help in managing the pain, but it is best to consult your doctor to avoid further complications.

Eating problems

Loss of appetite is fairly common among patients undergoing HCV treatment, so it’s essential for them to consume highly nutritious foods to avoid serious weight loss and other complications. Eating smaller but frequent meals throughout the day, and drinking clear fruit juices can help in adding extra calories. Add variety to the food choices and take time to make your meals appealing and tasty. Nausea is also one of the side-effects associated with HCV treatment and it can affect the appetite. Make sure to keep track of foods that can cause nausea, so they can be avoided in the future.

Avoid skipping meals because an empty stomach can also trigger nausea. Try to incorporate ginger in your meal because this spice is known to be helpful in keeping nausea at bay. If needed, you can also ask your doctor about anti-nausea medication.

Skin conditions

Almost every patient undergoing HCV treatment may develop some type of skin condition. Porphyria cutanea tarda is one of them, and it’s characterized by fluid-filled blisters on the hands and other areas when exposed to sunlight. Though it’s incurable, it can still be managed through medication. Blotchy skin rashes are another one of the symptoms, actually caused by cryoglobulinemia, which is an autoimmune disorder commonly associated with HCV. Medications are also available to help in suppressing the immune system that usually triggers this condition. Hair loss, or alopecia, is also a side effect caused by peginterferon injections. This repercussion is only temporary, and hair usually grows back when the treatment is over.


In severe cases of HCV, vomiting of blood and bloody bowel movement can be experienced, and these conditions are also linked to cirrhosis and liver failure. Medications can help with constricting open varices, and in severe cases, endoscopic surgery can be performed. Another condition associated with HCV is thrombocytopenia, wherein the body produces a low platelet count. This can be a very serious condition, especially for those with bleeding disorders, so it’s best to consult your doctor if bleeding occurs.

Mood changes

Most HCV patients experience depression, irritability, insomnia and difficulty concentrating. Depression is an emotional state wherein the person feels terribly sad, and this state can last for several weeks or months. There are several antidepressant drugs available to reduce the feeling of depression. Psychological therapy is also proven effective in mood improvement. Meditative exercises such as tai chi and yoga can also help in calming the nerves and relieving stress.

image  David Novak’s byline has appeared in newspapers and magazines around the world. He’s an avid health enthusiast, and frequently is featured in regional and national health publications. He is also a weekly writer for Healthline. To visit his other stories on Healthline, visit http://www.healthline.com/.


Common Conditions Associated with Hepatitis C

David Novak
January 30, 2014


Hepatitis C is a contagious liver condition caused by infection with hepatitis C virus. It is also the most common form of viral hepatitis. Hepatitis C virus can be transmitted through needles that are contaminated, as well as through blood transfusions. Severity of illness can range from mild illness, which could last for several weeks, to serious lifelong condition. According to the World Health Organization or WHO, about 150 million people are chronically infected with hepatitis C virus, and more than 350,000 people die every year because of hepatitis C-related conditions, such as cirrhosis and other liver diseases. Here are several common conditions that are associated with hepatitis C virus:


Cryoglobulinemia is one of the most associated diseases with Hepatitis C. It is a medical condition caused by abnormal proteins called cryoglobulins, which come from the simulation of lymphocytes, or white blood cells, by hepatitis C virus. Cryoglobulinemia is usually characterized by joint pain or swelling, raised purple skin rash, nerve pain and increased sensitivity to weather changes. Cryoglobulinemia can be diagnosed by a special laboratory test to detect cryoglobulins in the blood. Tissue biopsies can also help the diagnosis by uncovering inflammation of small blood vessels.


Cirrhosis is a complication of the liver, resulting in loss of liver cells and irreversible scarring of the liver. It is usually characterized by redness of the skin caused by dilated small blood vessels, shrinking of the muscles, bleeding from enlarged veins in the digestive tract, nose bleeds, weight loss and damage to the brain and nervous system. A combination of tests will help in diagnosing cirrhosis. This includes a physical exam and records of medical history.

Autoimmune Thyroid Dysfunction

There are two conditions of thyroid dysfunction associated with hepatitis C. One is hyperthyroidism, wherein the thyroid gland becomes overactive and secretes an excessive amount of hormones. Symptoms include nervousness, heart racing, anxiety, thinning of the skin and muscular weakness. Another condition is hypothyroidism, wherein the thyroid gland doesn't produce enough hormones, resulting in fatigue, weight gain, poor memory and concentration, hair loss and peripheral edema.

Autoimmune Thrombocytopenic Purpura

This autoimmune disorder is caused by low levels of platelets, which are cells that help the clotting of blood. The immune system produces antibodies that mistakenly destroy platelets, resulting in spontaneous formation of bruises, bleeding and menorrhagia. Autoimmune thrombocytopenic purpura, or ATP, is diagnosed by a full blood count, wherein low platelet count can be observed.

Leukocytoclastic Vasculitis

Leukocytoclastic vasculitis (LCV) is an immune system abnormality, which is characterized by inflammation of blood vessels. The actual cause of this disease is unknown, though it is associated with various infections such as hepatitis, cancers and rheumatic diseases. LCV can be diagnosed through laboratory testing of blood and body fluids. Organ function tests can also be done depending on the degree of the organ involvement.

Lichen Planus

This skin condition is a recurrent, itchy rash with unknown initial triggers. Lichen planus is characterized by shiny, reddish-purple spots on the skin, which can grow to rough, scaly plaques. Rashes can also develop in the lining of the mouth, lips and the lateral border of the tongue. This disorder is also known to affect women more frequently than men.

Those with extensive lichen planus disease appears to be more likely to have hepatitis C virus infection, though it is unclear if it is the main cause of the condition. It is also associated with different liver diseases.

Porphyria Cutanea Tarda

Porphyria cutanea tarda, or PCT, is the most common subtype of porphyria in which the skin shows several abnormalities when exposed to sunlight. It could result in scarring and blistering of skin, as well as onycholysis. Hepatitis C, HIV and estrogens are several environmental factors that can trigger PCT.

Non-Hodgkin’s Lymphoma

Patients with hepatitis C have a 20 to 30 percent higher risk of developing lymphoma, based on research done by the National Cancer Institute. Lymphoma is a type of cancer that affects lymphocytes, which is a white-blood cell generated by the immune system. This disease generally affects the lymphatic system, whose main function is to help the immune system in fighting off infections and diseases by filtering out viruses, bacteria and unwanted substances. Symptoms of non-Hodgkin’s lymphoma include unexplained weight loss, fever, swollen and painless lymph nodes, abdominal pain and itching of the skin.

image  David Novak’s byline has appeared in newspapers and magazines around the world. He’s an avid health enthusiast, and frequently is featured in regional and national health publications. He is also a weekly writer for Healthline. To visit his other stories on Healthline, visit http://www.healthline.com/


Taming the Dragon

by Opiferum
January 30, 2014


The phrase “chasing the dragon” means to inhale the vapour of heated morphine, heroin, oxycodone or opium that has been placed on a piece of foil. On the other hand, the phrase “silent” or “yellow dragon” refers to the hepatitis C virus (HCV). Small difference, big coincidence? After all, hepatitis C is so often cited as a disease that results from opioid drug use, one could easily be mistaken for thinking there is a connection! In Chinese medicine, the liver is represented by a dragon that is said to store anger. This seems like a more plausible explanation, however, it also illustrates how the same word can mean very different things depending on the context. Even though the “dragon” with respect to smoking drugs has no connection to the hepatitis C virus, it just demonstrates how the words used with regard to hepatitis C can also play upon very different meanings depending on the context. Sometimes, the result is not helpful for reducing HCV-related stigma. Perhaps this is why we not only need to “slay the dragon” with medical treatment, but also start “taming the dragon” with language instead.

Leading up to World Aids Day last year, The Stigma Project released some fantastic projects that promoted the elimination of stigma of HIV & AIDS on a global scale, “through awareness, art, provocation, education and by inspiring a spirit of living HIV Neutral.” This is something that desperately needs to be achieved within the hepatitis C affected community, too. One of the key lessons given by The Stigma Project is how to refer to a person that lives with HIV. Instead of saying that a person is “HIV positive”, for example, the non-discriminating way in which to do this is to refer to someone as “living with HIV”. Haven’t really thought about when you refer to in yourself as hepatitis C positive? Don’t worry, you have probably been labelled as “hep C positive” for so long by doctors or family, that it’s kind of hard to ignore (or deny). However, you have the right NOT to feel that your disease is what makes you who you are, simply because of living with it. Nobody living with the hepatitis C virus needs to carry the “hep C positive” label, which in itself instantly sends to other a fear inducing message that, “I am infectious”. Furthermore, describing a person as “living with hepatitis C” is indeed a more accurate description. After all, it’s not as if people living with cancer are called “cancer positive” or “cancerous”.

Let’s look at some other commonly used terms within HCV-related literature that also adds to unnecessary instances of stigma inducing concepts. The most harmful include “drug abuse” and “drug addict”. Whilst there is no arguing that hepatitis C is an infection that grossly affects people that inject drugs, it is simply unforgiving to refer to “drug abuse” as a way in which hepatitis C is spread. Not sure why? Well, it’s quite simple, really: not all drug use is abuse, and not all drug use is high-risk. As well, just the reference to “drug abuse” with respect to HCV transmission links a person’s conscious to the sordid stereotype image our society associates with a “drug addict” or (even worse) a “junkie”. More importantly, the term “drug abuse” makes no distinction between licit and illicit drug use. Rather, referring to “drug abuse” in relation to hepatitis C always affiliates the disease with illicit drug use: it creates a division based upon ideas related to “lawful” and “unlawful”. As well, it makes the assumption that people that inject drugs must also share needles - by default. With respect to HIV/AIDS education, the distinction between “safe” and “unsafe” sex is commonly accepted. It only seems fair to distinguish between “safe” and “unsafe” injecting drug use.

As well, when referring to “drug abuse” without a second-thought, the common perception is that only illicit drug use can fall under the umbrella of “drug abuse”. After all, how often do we hear the term “alcohol abuse” with respect to cirrhosis of the liver? Instead, we typically hear of “heavy” and “binge” drinking, or “alcoholism”. The terms are not used interchangeably, despite the fact they can all be classified as forms of “abuse” because of the short- and long-term effects. But because alcohol is a legal substance, “alcohol abuse” simply does not exist in our language because “abuse” carries with it a totally different moral discourse.

How successfully we can eliminate the stigma attached to hepatitis C and those that live with the virus is something we can definitely achieve by making better choices of our words. As the old saying goes, Think twice before you speak, because your words and influence will plant the seed of either success of failure in the mind of another. - Napoleon Hill (1883 - 1970)


Mount Sinai researchers identify UHRF1 as oncogene driving liver cancer


Contact: Laura Newman
The Mount Sinai Hospital / Mount Sinai School of Medicine

Finding spurs R&D into epigenetic-modifying drugs for this lethal disease


This shows a 5-day old zebrafish expressing green fluorescent protein in hepatocytes (liver cells) to highlight the liver.

New York, NY – Patients with advanced hepatocellular (or liver) cancer have high mortality rates, with existing drugs demonstrating only a small, but significant survival advantage. By combining a zebrafish model of liver cancer with data from human tumors, researchers from the Icahn School of Medicine at Mount Sinai hope to identify potential genes of interest that can be targeted for new treatments for hepatocellular carcinoma, the most common form of liver cancer to develop from liver cells.

Using transgenic zebrafish as an emerging, powerful whole animal model for cancer gene discovery, in combination with cultured cells and data from human tumors, they found that a gene called UHRF1, which is highly expressed in many types of cancers, can cause liver cancer at an unprecedented rate and incidence – with tumors forming in 75% of fish within 20 days. Results from the study are published online in the journal Cancer Cell.

"This is the first time that UHRF1 has been shown to be sufficient on its own to cause any kind of cancer when it is highly expressed," said the study's senior investigator, Kirsten C. Sadler, PhD, Associate Professor Medicine in the Division of Liver Diseases and of Developmental and Regenerative Biology, and Director of the Zebrafish Research Facility at the Icahn School of Medicine at Mount Sinai. UHRF1 has generated a lot of interest because it is a central regulator of epigenome – which is a collection of reversible modifications to DNA and the DNA packaging proteins – that are important for deciding which genes are expressed and how the DNA is transmitted during cell division. The cancer cell epigenome is dramatically different from normal cells, and the field of cancer epigenetics is exploding because of the hope that these changes could be reversed, and thereby reverse the aggressive nature of cancer cells. "Down the road, we hope to develop drugs to target UHRF1 and thereby reset the cancer epigenome to activate anti-tumor mechanisms and halt liver cancer.," added Dr. Sadler.

\UHRF Levels Important in Human Liver Cancers, Too

When the team analyzed patient-derived liver tumors, they found that high levels of the UHRF1 were also found there, too. Most strikingly, the changes in gene expression caused by high UHRF1 levels in zebrafish were reflected in the human tumors expressing high UHRF1 levels. This points to similar mechanisms underlying UHRF1-driven liver tumor formation in both species. One of these is the ability of the cancer-prone cells to bypass the tumor suppressive mechanisms that are activated in most cells when they receive a cancer-causing stimulus.

Cellular senescence is one such mechanism, and this study found that tumors associated with UHRF1 levels in both fish and humans only those cells that could escape senescence were the ones that could go on to form the tumors. This lays the groundwork to use this model to test new therapies that would target UHRF1 to re-activate the senescence program and halt cancer formation.

Dr. Sadler pointed to several advantages of using zebrafish in preclinical liver disease research. Zebrafish reproduce rapidly and abundantly, they are translucent until about three weeks of age, enabling researchers to directly visualize tumor growth, and the cells in the liver function similarly to those in humans. Zebrafish are also inexpensive to raise, making this study uniquely powerful, as they analyzed nearly 300 fish for tumors in this study– a scope that would be extremely costly using traditional mammalian cancer models.

UHRF1 is overexpressed in around 40%-50% hepatocellular cancers in humans and predict poor outcome. This overexpression is associated with poorer prognosis in terms of high recurrence rate and low term overall survival. "We have little to offer people in the setting of advanced disease – and this points to an entirely new direction," Dr. Sadler said. "It raises the hope that epigenetic drugs could be applied to liver cancer in the future."

Commenting on the research, Scott Friedman, MD, Dean for Therapeutic Discovery, and Fishberg Professor of Medicine, and Chief of the Division of Liver Diseases, at the Icahn School of Medicine at Mount Sinai, said: "Dr. Sadler's team has conducted a remarkable study that combines the power of the zebrafish model with state of the art genomic analysis of a devastating and poorly treated human cancer. This kind of comprehensive study not only uncovers a new approach to treating hepatocellular carcinoma, but also provides a vital roadmap to unlocking cancer's secrets more quickly and effectively."

The need for better treatments for hepatocellular cancer was underscored by Josep M. Llovet, MD, a study coauthor, and Professor of Medicine, and Director, Mount Sinai Liver Cancer Program. "The incidence of hepatocellular cancer is increasing worldwide and the median outcome at advanced stages with the sole effective molecule available, Sorafenib, is one year. Thus, identification of novel targets for HCC therapies are an unmet medical need. The current study points to the fact that UHRF1 is an oncogene driver and a potential target for therapies"


Other researchers contributing to this research from the Icahn School of Medicine at Mount Sinai were Raksha Mudbhary, Yujin Hoshida, Yelena Chernyavskaya, Vinitha Jacob, M. Isabel Fiel, Xintong Chen, Kensuke Kojima, Swan Thung, Anja Lachenmayer, Kate Revill, Ravi Sachidananandam, and Josep M. Llovet. The research team also included investigators from Harvard Medical School's Brigham and Women's Hospital and the IDIBAPS- Hospital Clínic and Institucio Catalana de Recerca, in Barcelona Spain.

About Cancer Gene Discovery in Zebrafish

Researchers in the Liver Cancer Research Program at the Icahn School of Medicine at Mount Sinai use genetic approaches in live zebrafish and in cultured human cancer cells. They collaborate with translational researchers to exploit data from human tumors to identify novels targets for treating hepatocellular carcinoma.

About the Mount Sinai Health System

The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12-minority-owned free-standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.

For more information, visit http://www.mountsinai.org. Find Mount Sinai on: Facebook: http://www.facebook.com/mountsinainyc Twitter @mountsinainyc YouTube:http://www.youtube.com/mountsinainy


The impact of hepatitis C burden: an evidence-based approach

Aliment Pharmacol Ther. 2014 Jan 26. doi: 10.1111/apt.12625. [Epub ahead of print]

Younossi ZM, Kanwal F, Saab S, Brown KA, El-Serag HB, Kim WR, Ahmed A, Kugelmas M, Gordon SC.


BACKGROUND: Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management.

AIM: To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes.

METHODS: An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes.

RESULTS: The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life.

CONCLUSIONS: The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.

© 2014 John Wiley & Sons Ltd.

PMID: 24461160 [PubMed - as supplied by publisher]


Patterns of viral load decline with telaprevir-based therapy in patients with genotype 1 chronic HCV infection

J Clin Virol. 2014 Jan 6. pii: S1386-6532(13)00542-8. doi: 10.1016/j.jcv.2013.12.011. [Epub ahead of print]

Picchio G1, De Meyer S2, Dierynck I2, Ghys A2, Gritz L3, Kieffer TL3, Bartels DJ3, Witek J4, Bengtsson L3, Luo D4, Kauffman RS3, Adda N5, Sarrazin C6.


BACKGROUND: Telaprevir-based therapy is associated with rapid decline in HCV RNA, enabling the application of early futility rules.

OBJECTIVES: To familiarize physicians with this paradigm, a comprehensive analysis of the most frequent HCV viral load profiles observed during treatment with telaprevir/Peg-IFN/RBV in Phase III trials is provided.

DESIGN: HCV RNA profiles were analyzed from 320 HCV genotype 1 treatment-naïve patients enrolled in the ADVANCE study, and 225 prior Peg-IFN/RBV treatment-experienced patients enrolled in the REALIZE study. Patients received 12 weeks of telaprevir with either 24 or 48 weeks of Peg-IFN alfa-2a/RBV. Patients with missing SVR assessments during follow-up, detectable HCV RNA at end of treatment but who did not have viral breakthrough (vBT), or with early vBT who discontinued telaprevir before time of failure were excluded.

RESULTS: All analyzed patients experienced a rapid decline in HCV RNA (>2.0 log10) by Day 14, irrespective of baseline characteristics and/or prior response to Peg-IFN/RBV (relapse, partial response and null response). Subsequently, HCV RNA continued to decline to undetectable levels in most patients. These patients went on to have one of the following outcomes: sustained virologic response, late vBT (after Week 12, i.e. during the Peg-IFN/RBV phase), or relapse. In the small subset of patients with early vBT or meeting a futility rule before Week 12, HCV RNA usually never became undetectable and/or increased rapidly after reaching the nadir.

CONCLUSIONS: HCV RNA profiles with telaprevir/Peg-IFN/RBV are different from those with Peg-IFN/RBV alone. It is important that clinicians understand these HCV RNA profiles and monitor patient viral load in order to apply futility rules correctly.

Copyright © 2014. Published by Elsevier B.V.

KEYWORDS: HCV RNA, Hepatitis C, Stopping rule, Telaprevir, Viral load

PMID: 24462470 [PubMed - as supplied by publisher]


What is the future of ribavirin therapy for hepatitis C?

Antiviral Res. 2014 Jan 24. pii: S0166-3542(14)00017-5. doi: 10.1016/j.antiviral.2014.01.005. [Epub ahead of print]

Koh C1, Jake Liang T2.


With the introduction of direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection, the field is rapidly evolving towards interferon-free regimens with high sustained virologic response (SVR) rates. The ultimate goal of therapy in chronic HCV should include an easily dosed all-oral regimen that is highly effective, inexpensive, pan-genotypic, safe and tolerable, with minimal to no resistance. Various investigational DAA regimens are currently evaluating therapeutic combinations with and without ribavirin (Rbv). With the projected arrival of improved therapies over the next 5 years, the future role of ribavirin comes into question. Despite being plagued by the lack of understanding of its mechanism of action and significant side effects such as anemia, Rbv has been a part of the standard-of-care therapies in chronic HCV infection for almost 10 years. As we look towards the future HCV therapy, Rbv may still have utility in the care of patients infected with HCV because of its low cost and potentially added value in combination with other DAAs. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."

Copyright © 2014. Published by Elsevier B.V.

KEYWORDS: ALT, Alanine Aminotransferase, Antiviral therapy, Chronic hepatitis C, DAA, DNA, Deoxyribonucleic Acid, Direct-Acting Antiviral, Direct-acting antivirals, FDA, Food and Drug Administration, HCV, Hepatitis C, Hepatitis C virus, RNA, RSV, Rbv, Ribavirin, Ribonucleic Acid, SVR, Sustained Virological Response, respiratory syncytial virus

PMID: 24468277 [PubMed - as supplied by publisher]


Chronic hepatitis C: future treatment

Clin Pharmacol. 2014 Jan 8;6:1-17. eCollection 2014.

Wendt A, Adhoute X, Castellani P, Oules V, Ansaldi C, Benali S, Bourlière M.


The launch of first-generation protease inhibitors (PIs) is a major step forward in HCV treatment. However, the major advance is up to now restricted to genotype 1 (GT-1) patients. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors include nucleoside/nucleotide inhibitors (NIs) and non-nucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with protease inhibitors can cure GT-1b null responders in an interferon-free regimen. Besides, several studies demonstrate that interferon (IFN)-free regimens with direct-acting antiviral agent combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, quadruple regimen with PR is able to cure almost all GT-1 null responders. The development of pan-genotypic direct-acting antiviral agents (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment.

KEYWORDS: SVR, cirrhosis, direct antiviral agents, host-targeting agents, interferon-free regimen, pangenotypic activity

PMID: 24470777 [PubMed - as supplied by publisher]

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A New Laboratory Based Algorithm to Predict Development of Hepatocellular Carcinoma in Patients with Hepatitis C and Cirrhosis

Gastroenterology. 2014 Jan 23. pii: S0016-5085(14)00104-8. doi: 10.1053/j.gastro.2014.01.045. [Epub ahead of print]

El-Serag HB1, Kanwal F2, Davila JA3, Kramer J4, Richardson P5.


BACKGROUND & AIMS: Serum levels of α-fetoprotein (AFP) are influenced not only by the presence of hepatocellular carcinoma (HCC) but also by underlying severity and activity of liver disease, which is reflected by liver function tests. We constructed an AFP-based algorithm that included these factors to identify patients at risk for HCC, and tested its predictive ability in a large set of patients with cirrhosis.

METHODS: We used the national Veterans Administration hepatitis C virus (HCV) clinical case registry to identify patients with cirrhosis, results from at least 1 AFP test, and 6 months of follow up. Our algorithm included data on age; levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, creatinine, and hemoglobin; prothrombin time; and numbers of platelets and white cells. We examined the operating characteristics (calibration, discrimination, predictive values) of several different algorithms for identification of patients who would develop HCC within 6 months of the AFP test. We assessed our final model in the development and validation subsets.

RESULTS: We identified 11,721 patients with HCV-related cirrhosis in whom 35,494 AFP tests were performed, and 987 patients developed HCC. A predictive model that included data on levels of AFP, ALT, and platelets, along with age at time of AFP test (and interaction terms between AFP and ALT, and AFP and platelets), best discriminated between patients who did and did not develop HCC. Using this AFP-adjusted model, the predictive accuracy increased at different AFP cutoffs, compared with AFP alone. At any given AFP value, low numbers of platelets and ALT and older age were associated with increased risk of HCC, whereas high levels of ALT and normal/high numbers of platelets were associated with low risk for HCC. For example, the probabilities of HCC, based only on 20 ng/ml and 120 ng/ml AFP, were 3.5% and 11.4%, respectively. However patients with the same AFP values (20 ng/ml and 120 ng/ml) who were 70 y old, with ALT levels of 40 IU/ml and platelet counts of 100,000, had probabilities of developing HCC of 8.1% and 29.0%, respectively.

CONCLUSIONS: We developed and validated an algorithm based on levels of AFP, platelets, and ALT, along with age, which increased the predictive value for identifying patients with HCV-associated cirrhosis likely to develop HCC within 6 months. If validated in other patient groups, this model would have immediate clinical applicability.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: liver cancer, prediction, prognosis, risk factors

PMID: 24462733 [PubMed - as supplied by publisher]


Culture Shock: Web-Based Hep C Tx Guidelines

Published: Jan 30, 2014

By Michael Smith, North American Correspondent, MedPage Today


Practice guidelines are a fact of life in modern medicine. They provide clinicians with the best data and the latest consensus on what the data mean for the care of patients.

But they are -- or have been -- rather slow to react to changes.

Enter HCVguidelines.org, a website that aims to keep up with one of the fastest-moving fields in medicine today – the treatment of hepatitis C virus (HCV) with what are called direct-acting agents.

The website was developed and will be run jointly by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the International Antiviral Society-USA.

A panel of 26 experts will keep clinicians on top of HCV treatment options, spokesmen for the three societies told MedPage Today before the site went live.

For those who haven't been following, HCV therapy for years was a long, difficult course of ribavirin and pegylated interferon. Neither agent actually targets the virus -- interferon is a general immune booster and ribavirin a general anti-viral.

On the other hand, direct-acting agents -- there are now four on the market and about a dozen in late clinical development -- aim at aspects of HCV replication. In general, they appear to be safer and less difficult to take than ribavirin and peginterferon, as well as being markedly more effective.

But the arrival of the new drugs over the next year or so will create a conundrum.

Between 3 million and 4 million Americans are thought to have chronic HCV and could benefit from treatment with the new drugs.

Indeed, for the first time, there is a "promise to cure nearly all" people with chronic HCV, according to David Thomas, MD, of Johns Hopkins University and a spokesman for the infectious diseases society.

The conundrum is that there are not enough specialists to go around, so that nonspecialists will have to fill in. And despite the increased safety and efficacy of the new drugs, actually using them is not going to be a matter of "take these and call me in the morning."

All the drugs are meant to be taken in combination with others, and the combinations have varying efficacy and side-effect profiles depending on such things as the genotype of the virus and the stage of liver disease. Moreover, the data seem likely to change and grow much more rapidly than we have ever seen.

For that reason, the website is "perhaps one of the only guidance documents that is a living document," according to Michael Saag, MD, of the University of Alabama Birmingham and a spokesman for the anti-viral society.

"The ability to be nimble," Saag said during a press briefing, is necessary to keep up with the expected tidal wave of information.

He told MedPage Today that the site will contain information -- not only on approved uses, but also on specific off-label drug combinations that have not been through the FDA approval process.

That's because it's not realistic to get specific approval for all possible combinations in all possible patient types, Saag said. A major advantage of the new website, he said, is that the panel can look at all the evidence and "craft [regimens that] experts in the field would be using."

Indeed, the first iteration of the site suggests a combination of two new drugs -- simeprevir (Olysio) and sofosbuvir (Sovaldi) -- that is not specifically approved by the FDA, although both drugs are on the market, according to Donald Jensen, MD, of the University of Chicago Medical Center and a spokesman for the liver society.

The first iteration of the site will also deal only with what to do once the decision to treat has been made. Other questions -- such as who to treat and when -- will be dealt with later.


Also See: Online Expert Advice for Clinicians Treating Hepatitis C Now Available

Detox the Liver with These Top Five Foods

Michael Healey January 30, 2014

A new report and video released by Detoxdieter.org details the importance of cleansing the liver and shares the top foods that detox the liver

(Newswire.net -- January 30, 2014) Boston, MA -- The liver is one of the most vital organs in the human body, taking care of an estimated 500 essential functions.  The liver also tends to be one of the most misunderstood and mistreated organs.  The Top 5 Foods to Detox the Liver supports the natural detox of this essential organ.

Regulating the chemicals in the blood, breaking down and absorbing fats, and making nutrients easier to process are only a few of the liver’s responsibilities.  As blood flows through the body, it filters through the liver.  Medicines, toxins, poisons and harmful chemicals are filtered from the blood in an effort to protect the body from harmful effects.

The liver also stores and processes glucose, accessing it as needed by the body; removes ammonia from the body; filters toxins, pesticides and chemicals from the blood; and supports the immune system by removing potentially dangerous bacteria from the blood.

Liver disease is often connected to consuming too much alcohol.  Surprisingly, while consuming too much alcohol can cause liver damage, it is not the leading cause.  Excess consumption of sugar has demonstrated to be the leading contributor to liver damage.

Sugar contributes liver damage more often than alcohol.  Approximately one quarter of the people in the United States are affected by fatty liver disease, often leading to cancer or even failure of the liver.

There are many natural ways to protect the health of the liver; eating natural liver cleansing foods is a great start.  The top foods to consider when eating for liver health are detailed in an article and supporting video on Detoxdieter.org.


New Concepts of Sofosbuvir-Based Treatment Regimens in Patients With Hepatitis C


Zoe Mariño, Florian van Bömmel, Xavier Forns, Thomas Berg

Gut. 2014;63(2):207-215.


Since the discovery of HCV in 1989, interferon α (IFNα)-based therapy has been the only treatment approach leading to HCV genotype-dependent sustained virological response (SVR) rates in a significant number of patients. However, the treatment uptake has been generally low due to numerous side effects and contraindications to IFNα-based regimens. Because of these limitations, the overall HCV-related health burden could only gradually be decreased, even though treatment efficacy was increased over recent years. [1,2]

The lack of cell culture systems to grow HCV had been a key limitation for the development of direct acting antivirals (DAAs). Nevertheless, in 1997, only a few years after the discovery of HCV, the first subgenomic HCV replicons were obtained allowing researchers to develop and assay DAAs with a robust methodology. [3–5] In 2004, the safety and efficacy of the first DAA, the protease inhibitor BILN2061, were assessed in a proof-of-concept clinical trial. [6] Now, a few years later, IFNα-containing or IFNα-free regimens based on DAAs showed the potential to cure HCV infection in very high percentages with overall good tolerability. [7]

DAAs targeting two major steps of the HCV life cycle have reached clinical development: (1) inhibitors of the NS3-4A protease, which block HCV polyprotein processing and (2) inhibitors of viral replication, including several drug families, such as nucleoside/nucleotide and non-nucleoside inhibitors of the RNA-dependent RNA polymerase (RdRp), and inhibitors of the NS5A viral protein which have a regulatory role in HCV replication. [8–12]

A perspective of the future treatment landscape for chronic HCV infection is depicted in figure 1. Peg-IFNα-containing regimens with second generation protease inhibitors like simeprevir and faldaprvir or the polymerase inhibitor sofosbuvir will become the first to be licensed for HCV type 1 infection. A significant number of different all oral IFNα-free regimens with pan-genotypic activity by combining different classes of DAAs have entered phase II and III and may become available in the near future (see figure 1).


Figure 1. Selected treatment regimens for chronic hepatitis C infections which are expected to become available in the near future. Future treatments focus on interferon (IFN)α-free, direct acting antiviral-based combination regimens which have shown sustained virological response rates of around 90%. The displayed studies include predominantly patients without liver cirrhosis. (1) Submitted for approval in Japan in 2013; (2) approval expected in Japan and in the USA at the end of 2013; and (3) submission for approval expected in November 2013. NS3/4A PI=second generation protease inhibitor; NUC=nucleosidic polymerase (NS5B) inhibitor; NS5A=NS5A inhibitor; PI/r=ritonavir boosted PI; PR=pegylated-IFNα plus RBV; RBV=ribavirin.

Sofosbuvir is the first nucleotide polymerase inhibitor that will become licensed for the treatment of HCV infection as part of IFNα-containing and IFNα-free regimens. As other nucleoside/nucleotide inhibitors of the RdRp, it shows high antiviral activity against all HCV genotypes and a high barrier to resistance. [12] Sofosbuvir was shown to be safe and overall well tolerated, and no relevant drug–drug interactions (DDI) have to be expected. Due to this favourable pharmacological profile, sofosbuvir has a great potential to become a cornerstone in the management of HCV infection. Especially, the performance of sofosbuvir in IFNα-free treatment approaches may open a new and promising area in the treatment of hepatitis C.

The present article reviews the clinical current knowledge of sofosbuvir as part of IFNα-containing as well as IFNα-free treatment regimes, which have been published in phase II and III studies. We have further tried to estimate its possible use in patients who show difficult-to-treat characteristics. Finally, we were trying to give an outlook on the future role of sofosbuvir in the treatment of chronic HCV infection.

Current Standard of Care

The current standard of care for the treatment of chronic HCV infection is still based on a combination of pegylated (Peg)-IFNα and ribavirin (RBV) but includes a protease inhibitor (either telaprevir or boceprevir) for HCV type 1-infected patients. This triple regimen has increased SVR rates up to approximately 70% and also allows reducing treatment duration in approximately 50% of patients to 24 weeks. [12] However, the antiviral efficiency of triple regimens is low in previous null responders, especially in those with advanced fibrosis or cirrhosis and the addition of a protease inhibitor to the regimen led to a significant increase in the number of side effects. [8–11] Contraindications or status intolerance to IFNα or RBV further limits the number of patients who may benefit from this first generation protease inhibitor-based triple therapy.

Protease inhibitors are not licensed for the use in non-type-1-infected patients for whom the combination of Peg-IFNα and RBV remains the standard of care. After 48 weeks of treatment duration, SVR rates of around 60% can be achieved in HCV genotypes 4, 5 and 6 infection whereas up to 60%–80% of type 2 and 3-infected patients may be cured by a 24-week dual regimen. [13,14]

Pharmacology of Sofosbuvir

Sofosbuvir, a prodrug of 2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a specific nucleotide analogue inhibitor of the HCV NS5B polymerase that acts as a false substrate for the RdRp, leading to chain termination after incorporation into the newly synthesised RNA chain. [15] The drug needs two additional phosphorylations to be activated. Sofosbuvir has a potent antiviral activity covering all HCV genotypes. [16] Dose findings studies showed optimal inhibition of HCV replication by a once daily dose of 400 mg. [17]

Sofosbuvir is a once-daily drug which can be taken with or without food. The drug traverses the GI tract and remains intact during absorption, resulting in high exposure in the liver. [15] It is absorbed rapidly with a median t max of 1 h (range 0.5–3.0 h). The elimination is rapid with median t½ in the range of 0.48–0.75 h. The active metabolite of sofosbuvir, GS-331007, exhibits a longer median t max of 4 h (range 1.5–8) and a half life ranging from 7.27 to 11.80 h. [17]

Sofosbuvir is mainly eliminated by the kidneys at a rate of 76%. Clearance of the drug is rapid, with median half life in the range of 0.48–0.75 h. [17] No dose adjustment seems necessary in patients with renal clearance >30 mL/min, whereas modification of doses or dosing intervals may be required in patients with moderate to severe renal impairment or haemodialysis. [18]

One of the additional advantages of sofosbuvir and other drugs of the same family is their low potential for DDI, because their metabolism is not linked to the CYP3A4 pathway. A recent study conducted in healthy volunteers assessed the potential for pharmacokinetic interactions between sofosbuvir and the immunosuppressants cyclosporine and tacrolimus and revealed that sofosbuvir did not affect the exposure to calcineurin inhibitors and only a slight increase in the concentration of sofosbuvir was observed in individuals who received cyclosporine. [19] In addition, no clinically significant interactions have been observed with methadone or with antiretroviral therapies in HCV/HIV co-infected patients such as the nucleosidic reverse transcriptase inhibitors tenofovir and emtricitabine, the non-nucleosidic reverse transcriptase inhibitors efavirenz and rilpivirine or the protease inhibitors darunavir or ritonavir. [20]

Sofosbuvir Development Programme

IFN-free Sofosbuvir Regimens in HCV type 1-infected Patients: Results From Phase II Trials

IFNα-free strategies have been evaluated in phase II studies in HCV type 1-infected patients which tried to define the efficacy of different treatment combinations for different treatment durations ranging from 8 to 24 weeks. [21–26] These regimens typically consist of combinations based on (1) sofosbuvir plus RBV, (2) sofosbuvir plus a second DAA or (3) sofosbuvir plus a second DAA in combination with RBV, summarised in figure 2A and B. Even though the numbers of type 1-infected patients included in the numerous different arms of the studies were quite often limited and to date not all patients have completed the observation period yet, interesting preliminary conclusions can already be extracted from the presented results.


Figure 2. Phase II trials on sofosbuvir-containing interferon α-free treatments in (A) treatment-naive and (B) treatment-experienced patients with HCV type 1 according to present publication of sustained virological response (SVR) rates.21–26 The study arms were designed to examine the efficacy of sofosbuvir in combination with ribavirin (RBV) (highlighted in blue), in combination with a second direct acting antiviral (DAA) (highlighted in pink) or with both a second DAA and RBV (highlighted in purple) to examine the optimal treatment length, which could be between 8 and 24 weeks. Of note, only few patients in these trials had liver cirrhosis. *One patient was missing in the evaluation 12 weeks after the end of treatment. All patients remaining in the study showed SVR.

Sofosbuvir in Treatment-naive HCV Type 1-infected Patients

In the QUANTUM and ELECTRON studies, sofosbuvir was given for 12 weeks in combination with RBV to overall 50 treatment-naive patients with HCV type 1 infection. [23,27] SVR12 was observed in 56% and 88% of patients, respectively (mean of 70%). Prolongation of this dual combination treatment to 24 weeks seemed not implicitly to increase in SVR rates, as the overall SVR12 rate was 52% and 90%, respectively (mean 67%) in 35 patients of the QUANTUM and NIH SPARE studies. [23,25] These findings were surprising in view of the results from the phase III FUSION trial in HCV type 2 and 3 infection, where treatment extension from 12 to 16 weeks tended to improve SVR rates significantly from 56% to 73%. [28]

Combining sofosbuvir with a second DAA generally led to a much more robust treatment response with higher SVR rates as compared with the sofosbuvir plus RBV regimen, irrespective of whether RBV was added or not (figure 2A and B). [21–25]

The choice of the second DAA—either a non-nucleoside polymerase inhibitor or NS5A inhibitor—did not seem to impact the strength of the response, as far as it can be judged by the present results. A combination of sofosbuvir with another distinct nucleotide analogue (GS-0938) for 12 weeks resulted in SVR12 in 88% out of 25 patients. The SVR4 rates after 12 weeks of combination treatment with sofosbuvir and the NS5A inhibitors daclatasvir or ledipasvir (GS-5885) were as high as 98% and 100% in the 41 and 19 patients which were studied, respectively. [22,24] Whether a prolongation of this combination treatment beyond 12 weeks will be required to further increase the response rates is questionable, as treatment extension to 24 weeks with GS-0938 plus sofosbuvir showed an equally high SVR12 rate of 88%. [23] Even shorter treatment duration seems to be a realistic option, as sofosbuvir and ledipasvir given for 8 weeks already led to SVR8 in 95% of 20 patients in the LONESTAR trial. [22]

Sofosbuvir in Treatment-experienced Type 1-infected Patients

A 12-week sofosbuvir plus RBV regimen was evaluated in the multipart ELECTRON study in 10 HCV type 1-infected patients who previously showed null response to Peg-IFNα and RBV (figure 2B). [21] On treatment, complete suppression of hepatitis C viremia was achieved in all patients, but surprisingly all but one of these patients relapsed after treatment was stopped.

The limitations which sofosbuvir obviously had in these patients when combined with RBV were overruled when sofosbuvir was given with a second DAA for only 12 weeks in patients, which resulted in SVR rates between 90% and 100%. Regardless of the mode of action of the second DAA, being either the NS5A inhibitor ledipasvir or daclatasvir, the protease inhibitor simeprevir or the non-nucleoside polymerase inhibitor GS-9669 this regimen showed equally high SVR rates as in treatment-naive patients (figure 2B). [22,24,26]

Treatment extension to 24 weeks using a combination of sofosbuvir and the NS5A inhibitor daclatasvir was evaluated in the AI444-404 study in 41 patients who failed a previous protease inhibitor-based triple therapy. [24] This study was controlled for the effect of RBV by randomising patients to receive 1000–1200 mg RBV per day or placebo for 24 weeks. Irrespective of the addition of RBV, all patients who were followed for 12 weeks after stopping therapy achieved an SVR.

IFN-free Sofosbuvir Regimens in HCV Non-type 1-infected Patients: Results From Phase II Trials

To evaluate a possible benefit of adding Peg-IFNα to a 12-week combination treatment of sofosbuvir plus RBV in patients with HCV type 2 or type 3, four treatment arms including 12, 8, 4 weeks or no Peg-IFNα and sofosbuvir plus RBV were included in the phase IIa ELECTRON trial. [21] All patients who were treated for 12 weeks with sofosbuvir and RBV, with or without Peg-IFNα, showed SVR12 giving conclusive evidence that adding Peg-IFNα was not needed for these patients. Also patients who were treated with sofosbuvir as monotherapy for 12 weeks showed undetectable HCV RNA at the end of treatment; however, at week 4 post-treatment, four of the 10 patients had a virological relapse. As a result, in the following phase III studies, monotherapy with sofosbuvir was no longer considered.

Sofosbuvir as Part of Peg-IFNα-containing Regimens in HCV Type 1 and Type 4–6-infected Patients: Results From Phase II Trials

A strong efficacy of the combination treatment of sofosbuvir plus RBV and Peg-IFNα in patients with HCV type 1 was demonstrated in the PROTON and in the ATOMIC phase II studies. [29,30] The PROTON study, in which 400 mg sofosbuvir per day or placebo were given in combination with Peg-IFNα plus RBV for 12 weeks followed by an additional 12 or 36 weeks of Peg-IFNα and RBV, showed 91% SVR12 rates for the sofosbuvir group versus 40% for the placebo group. [29] In the ATOMIC trial, it was investigated whether maintenance treatment is necessary once a response was introduced by a 12-week sofosbuvir-containing triple regimen. Overall, 332 treatment-naive patients with HCV types 1, 4 and 6 without cirrhosis were treated with sofosbuvir 400 mg per day plus Peg-IFNα and RBV given for either 12 or 24 weeks. [30] In the 12-week arms, patients were randomised to either stop treatment or enter a maintenance phase with either sofosbuvir alone or in combination with RBV for additional 12 weeks. Regardless of the treatment arms, SVR rates between 90% and 94% were observed. Therefore, a 12-week combination treatment of sofosbuvir plus RBV and Peg-IFNα was chosen for the phase III NEUTRINO study. [31]

Sofosbuvir as Part of Peg-IFNα-containing Regimens in HCV Type 1 and Type 4–6-infected Patients: Results From the NEUTRINO Phase III Trial

In the NEUTRINO trial, 327 naive HCV type 1, 4, 5 and 6 patients were treated for 12 weeks in an open-label single-arm design with sofosbuvir 400 mg and RBV 1000–1200 mg per day as well as with Peg-IFNα 180 μg per week. [31] The result were compared with the historic SVR12 rates of treated cohorts with Peg-IFNα and RBV over 48 weeks which had a global SVR12 rate settled on 60%. The study included 291 patients with HCV type 1 (89%), and 35 with types 4, 5 and 6 (11%). The overall SVR12 rate was 90% (figure 3), 89% in HCV type 1, 96% in HCV type 4 and 100% in the seven patients with HCV types 5 and 6. Out of the 55 patients with cirrhosis, 80% achieved SVR12. No significant differences in SVR rates were found with respect to other baseline parameters, but slightly higher SVR rates were observed in patients with low viral load, favourable IL28B CC genotype and those being infected with HCV subtype 1a versus1b.


Figure 3. Phase III trials on sofosbuvir-containing treatments in treatment-naive, treatment-experienced patients with contraindications to IFNα. The study arms were designed to examine the efficacy of sofosbuvir in combination with Peg-IFNα and ribavirin (RBV) given for 12 weeks (highlighted in blue) or for 24 weeks (highlighted in orange) in HCV types 1, 4, 5 and 6, and to examine the efficacy of sofosbuvir in combination with RBV (highlighted in light blue) in patients with types 2 and 3. 28,31

Sofosbuvir was well tolerated and did not add side effects to the expected safety profile of Peg-IFNα plus RBV. The rate of discontinuation related to adverse events was 2% which was significantly lower as in the historical controls. Even among patients with cirrhosis, serious adverse events were rare and only one patient had to discontinue treatment. [31]

Sofosbuvir as Part of Peg-IFNα-free Regimens in HCV Type 2 and 3-infected Patients: Results From the Phase III Trials FISSION, FUSION and POSITRON

Combination of sofosbuvir plus RBV given for 12 weeks in phase II trials had led to such convincing SVR rates in HCV type 2 and 3-infected patients that this regimen was further evaluated in phase III. According to prior treatment experience different treatment scenarios were explored in three different phase III trials—the FISSION, FUSION and POSITRON studies. [28,31]

The FISSION trial was designed to assess the efficacy of the combination of an IFNα-free regimen based on sofosbuvir plus RBV given for 12 weeks in 256 treatment-naive type 2 or 3-infected patients in comparison with combination of Peg-IFNα plus RBV given to 243 patients with types 2 or 3 for 24 weeks. [31] About 176 (72%) of the patients had HCV type 3, and 50 patients (21%) had cirrhosis. The rates of SVR were 67% in both arms, confirming the non-inferiority main endpoint of the oral regimen (figure 3). The response rates to the IFNα-free sofosbuvir plus RBV regimen were however significantly lower among patients with HCV type 3 than among those with type 2 (56% vs 97%, respectively; figure 4).


Figure 4. Influence of liver cirrhosis on response to treatment with sofosbuvir plus ribavirin (RBV), and the effect of treatment prolongation from 12 to 16 weeks in treatment-experienced patients with HCV types 2 or 3, as observed in the phase III FUSION trial.28 Extending the treatment duration by 4 weeks increased sustained virological response (SVR) rates especially in patients with type 3 infection, but also in patients with type 2 infection and cirrhosis.

Presence of cirrhosis was another strong negative predictor of response. SVR rates were only 47% in patients with cirrhosis, which was similar to the 38% SVR in the control arm with standard treatment of Peg-IFNα plus RBV (figure 4). In terms of safety, the sofosbuvir plus RBV arm was associated with significantly fewer adverse events than the arm with Peg-IFNα plus RBV.

The FUSION trial aimed at investigating whether the combination treatment of sofosbuvir and RBV was more effective when given for 16 instead of 12 weeks. [28] The studied cohort was conducted in HCV type 2 and 3 patients who had failed previous Peg-IFNα-based therapies. Among these patients, 75% had suffered virological breakthrough or relapse, and 25% were defined as non-responders. [28] Patients were randomised 1:1 to receive either 12 weeks (n=103) or 16 weeks (n=98) treatment with sofosbuvir 400 mg plus RBV 1000–1200 mg per day. The overall SVR rates were 50% in the 12-week and 73% in the 16-week arms (p<0.001), both results comparing favourably with a 25% cure rate which has been estimated for a virtual control group expressing identical characteristics but being treated with Peg-IFNα plus RBV (figure 3). [28]

Again, HCV type 3 and presence of cirrhosis were the main predictors of poor outcome. However, in such cases, the extension of treatment duration from 12 to 16 weeks could improve the results considerably (see figure 4). No increase in adverse events was observed when treatment was extended to 16 weeks. [28]

In the POSITRON trial, the effectiveness of 12 weeks of combination of sofosbuvir and RBV was investigated in 278 patients with HCV type 2 or 3 being ineligible for Peg-IFNα-based therapies due to contraindications and/or unacceptable previous adverse events or unwillingness to receive Peg-IFNα therapy. [28] Patients were randomised 3:1 to receive either sofosbuvir 400 mg plus RBV 1000–1200 mg per day or placebo. Overall, 78% of patients in the treatment-arm and no patient in the placebo group achieved an SVR (figure 3). For HCV type 2 and 3-infected patients, SVR rates were 93% and 61%, respectively. Among the 44 patients with compensated cirrhosis, SVR rates were 94% in HCV type 2 but only 21% in HCV type 3 infections.

Sofosbuvir Resistance

HCV variants which cause resistance against sofosbuvir have been identified in vitro using the HCV replicon system. [32] In these assays, sofosbuvir showed a 9.5-fold increase in EC 50 if the S282T mutation was present. Infection models using HCV types 1a, 1b and 2 could also demonstrate a selection of this mutation in presence of sofosbuvir. In type 1a patients, additional variants as the mutation I434M were shown to be selected by sofosbuvir, although these variants only lead to a small loss of susceptibility.

Indeed, in the ELECTRON trial, in one of the four patients who suffered a relapse after 12 weeks of sofosbuvir monotherapy, the S282T mutation could be detected after the relapse. Before treatment this variant had not been present in this patient. No mutations associated with resistance to sofosbuvir have been detected in patients who showed a relapse after sofosbuvir combination therapy with either RBV or a second DAA. [33] Moreover, no on-treatment resistance associated viral breakthrough has been observed in any of the patients treated with any sofosbuvir regimens and virtually all patients showed a robust and quite rapid response to the drug. Interestingly, in two patients who experienced a relapse in HCV replication after 12 weeks combination treatment with sofosbuvir and the protease inhibitor simeprevir, the mutation Q80K that is associated with simeprevir resistance was detectable at baseline. One of these patients gained the D168E and I170T simeprevir resistance mutations during combination treatment, but there were no emergent sofosbuvir resistance mutations detectable during the relapse. [34]

The high genetic barrier against resistance created by sofosbuvir may have different reasons. First, replication fitness of the sofosbuvir resistance associated variant S282T is significantly impaired as this mutation within the active site of the RdRp impairs polymerase activity decreasing the replication capacity by approximately 90% in HCV types 1a and 1b as compared with the wild type replicon. Second, the drug was able to suppress hepatitis C viremia to undetectable levels in virtually all patients within 4 weeks of treatment as has been demonstrated in all clinical trials so far. The shutdown of viral replication at these early stages on treatment limits the time for the selection of resistant variants which is in line with the concept: 'no replication=no resistance'.

Predictors of Response and the Problem of Relapse

A rebound of viral replication (a relapse) after stopping sofosbuvir-based therapy accounts for practically all failures to this treatment. The phenomenon that, in spite of fast suppression to undetectable HCV RNA levels in virtually all patients within the first 2–4 weeks of sofosbuvir treatment, HCV replication may relapse in some patients after stopping treatment is poorly understood.

Significant relapse rates (ie, greater than 10%) were however only seen in patients treated with either sofosbuvir alone or in combination with RBV, but not in those treated in combination with a second DAA or Peg-IFNα, and relapse rates were especially high in HCV type 1 and 3-infected patients with previous null response to Peg-IFNα and RBV therapy and those with cirrhosis (figure 4).

There are subtle hints that very early viral kinetics within the first days of treatment may differ between patients who are going to relapse and those achieving a sustained response (figure 5). [20] There remains, however, the intriguing question: why does prior response to a Peg-IFNα-based treatment influence the responsiveness to a IFNα-free regimen like sofosbuvir plus RBV? One might speculate that prior null response to Peg-IFNα and RBV might not only be driven by low IFNα susceptibility but also by non-responsiveness to RBV. According to this concept, re-treatment of these patients with sofosbuvir plus RBV may be basically equivalent to a functional sofosbuvir monotherapy which is not effective enough to eradicate the infection during a short treatment period. A genetic profile associated with an altered innate immune function (ie, IL28B non-CC genotype) predominates in patients showing non-responsiveness to Peg-IFNα and RBV, which also may contribute to the lower likelihood of viral eradication that can be induced during short-term blocking of viral replication by polymerase inhibitors. [35]


Figure 5. Model of the early kinetics of HCV RNA levels including a subgroup of 20 treatment-naive patients with HCV type 1 infection receiving sofosbuvir plus ribavirin in the NIH SPARE study.25 Patients who achieved sustained virological response (SVR) showed a significantly faster decrease of HCV RNA to undetectable levels within the first 7 days of treatment as compared with patients who suffered a relapse after treatment.

RBV reduces in vivo the mRNA levels of a large number of Peg-IFNα-stimulated genes, particularly those which were found to be upregulated in non-responders to Peg-IFNα plus RBV. [36] These epigenetic re-programming properties of RBV could synergise with the potent antiviral activity of sofosbuvir to restore the host innate immunity responses. [37] Furthermore, HCV-specific immune modulation with IFNα-free DAA therapy may occur via inhibition of HCV replication that may be key in order to prevent relapses and induce an SVR. [38]

HCV RNA testing 4 weeks after stopping treatment already allows a high positive prediction of sustained response as it has been shown in both the QUANTUM and the ELECTRON studies. [23,21] SVR24 rates were 99% and 97.1%, respectively, in patients who showed undetectable HCV RNA levels at week 4 of the post-treatment follow-up. [39]

Safety Profile of Treatments Containing Sofosbuvir

Sofosbuvir was generally well tolerated when given alone, in combination with RBV or in combination with Peg-IFNα and RBV.

Sofosbuvir given in Peg-IFNα-free regimens has clearly improved tolerability over Peg-IFNα-based treatments. [40] In a meta-analysis of different studies comprising Peg-IFNα-free arms, the rate of severe adverse events (SAE) was between 4% and 6%, and none of these SAEs was related to sofosbuvir. [40] Only four of 331 patients (1.2%) who received sofosbuvir as monotherapy, in combination with RBV or in combination with the NS5A inhibitor ledipasvir and RBV, discontinued treatment due to adverse events. Also few laboratory abnormalities were found in these patients. In the phase II COSMOS trial, grade 3–4 pancreatic amylase or lipase elevations were observed in five out 52 patients (10%) who had been treated with sofosbuvir in combination with simprevir plus RBV, and in one out of 29 patients (3%) who received sofosbuvir plus simeprevir. However, these laboratory findings were transient and not associated with clinical symptoms. [37]

Safety profile did not differ in patients with well compensated liver cirrhosis who were included in the phase III sofosbuvir trials and no hepatic decompensation was observed while on any of the IFNα-free treatment arms. [27,31]

Sofosbuvir for Difficult-to-Treat Patients

Due to its high antiviral potency, even when given as monotherapy, the favourable safety profile and obvious lack of cumbersome DDIs, sofosbuvir represents a nearly ideal backbone for the treatment of patients who were up to now considered as difficult-to-treat, that is, patients with prior treatment failures to Peg-IFNα-based treatments (including those who failed triple therapy), patients being intolerant or ineligible to Peg-IFNα, patients with extra hepatic HCV manifestations or HCV/HIV co-infection, as well as those with decompensated cirrhosis or liver transplant recipients. [41]

Pilot studies in patients awaiting LT and in liver transplant recipients with aggressive HCV recurrence are currently ongoing to assess efficacy of sofosbuvir in this population (studies NCT01687270 and NCT01779518; for more information see: http://www.clinicaltrials.gov). Sofosbuvir plus daclatasvir combination proof-of-concept therapy was effective to cure a liver transplant recipient with severe recurrent cholestatic hepatitis C. [42] Preventing the infection of the graft by application of sofosbuvir either alone or in combination with a second DAA also appears to become a realistic scenario in the near future.

Treatment efficacy of IFNα-free sofosbuvir regimens in HCV type 1-infected patients with compensated cirrhosis has not been evaluated in a significant number of patients. However, a lower cure rate might be expected given the fact that in HCV type 2 and especially in type 3-infected patients cirrhosis was one of the main risk factors for reduced SVR rates (figure 4). The expected low SVR in these patients has influenced the design of the NCT01687257 in which patients infected with different HCV types who have compensated or decompensated liver cirrhosis receive an extended 48-week combined treatment of sofosbuvir plus RBV. One is inclined to argue that patients with decompensated HCV-induced cirrhosis may profit most from IFNα-free combinations with different DAAs. In some ongoing trials evaluating these treatments, patients with liver cirrhosis may be included; however, data on safety and efficacy are awaited.

Sofosbuvir is currently being investigated in patients with HCV/HIV co-infection in the PHOTON trial (NCT01783678). In this trial, the efficacy of the combination of sofosbuvir plus RBV is investigated over 12 weeks in HCV type 2-infected patients and for 24 weeks in HCV type 1, 2, 3 and 4-infected patients.

Summary and Future Directions

The approval of sofosbuvir can be regarded as a first step towards a radical change in the antiviral management of chronic HCV infection. For the first time, we are about to hold a DAA in our hands that covers all genotypes and shows robust antiviral response in virtually all patients due to high intrahepatocellular concentrations. No viral breakthrough as a consequence of drug resistance has been observed, even when sofosbuvir was given as monotherapy. The excellent safety profile and the lack of significant DDIs will allow the broad use of the drug also in more difficult-to treat situations like co-infections, cirrhosis and the liver transplant setting.

For HCV type 1, 4, 5 and 6 infection, a triple combination containing sofosbuvir plus Peg-IFNα and RBV given for a fixed duration of only 12 weeks will be licensed in the close future that obviously is able to cure 90% of the patients without any response guided modifications. However, Peg-IFNα-containing regimens can be regarded only as a brief 'footnote' in the history of the sofosbuvir development programme, as IFNα-free regimens are close to becoming the standard in HCV type 1 infection.

For HCV type 2 and 3-infected patients, an IFNα-free regimen containing sofosbuvir plus RBV has been established by three different phase III trials showing cure rates that were at least comparable with those observed in dual therapy with Peg-IFNα plus RBV.

As virological relapses account for practically all sofosbuvir treatment failures, the main unresolved issues are now (1) how long the duration of treatment has to be and (2) how many DAAs have to be combined in order to prevent a virological relapse. Also, the role of RBV in the setting of multiple DDA regimens remains uncertain.

For HCV type 2-infected patients, a 12-week sofosbuvir plus RBV regimen may soon become the standard of care, whereas in HCV type 3 as well as in type 1-infected patients and in patients with cirrhosis, the high relapse rates that have been seen after this regimen certainly claim for individualised treatment adaptations. Prolonging treatment duration to 16 weeks helped to reduce the relapse rates in HCV type 3. Whether prolongation of sofosbuvir and RBV to 24 weeks may further increase cure rates is currently being evaluated in the ongoing European Valence Study (GS-US-34–0133) in HCV type 3 infection. An alternative approach which is now studied in phase II trials aims to shorten treatment to 12 or even 8 weeks by applying different regimens including either Peg-IFNα and RBV or a second DAA—the NS5A inhibitor ledipasvir or the non-nucleoside inhibitor GS-9669 in combination with sofosbuvir (NCT01260350).

For HCV type 1-infected patients, the combination of sofosbuvir plus a second DAA will probably represent the most promising approach. Gilead Sciences is currently evaluating the combination treatment with its own NS5A inhibitor ledipasvir (formerly GS-5885) in three different phase III trials (ION studies). [43] The ION-1 trial is designed to evaluating a once-daily fixed-dose combination of sofosbuvir plus ledipasvir with or without RBV for 12 or 24 weeks among 800 treatment-naive HCV type 1 patients. The ION-2 is evaluating sofosbuvir with ledipasvir and RBV for 12 weeks or sofosbuvir plus ledipasvir with or without RBV for 24 weeks among 400 treatment-experienced type 1 HCV patients who previously failed to respond to a triple therapy with Peg-IFNα, RBV and either boceprevir or telaprevir. The ION-3 trial is designed to evaluate 8- and 12-week courses of therapy with the combination of sofosbuvir and ledipasvir with or without RBV in 60 treatment-naive non-cirrhotic patients (NCT01851330).

In summary, a 12-week IFNα-free regimen may become the skeletal structure of the future sofosbuvir-based treatment algorithms. Depending on certain host and viral factors, like HCV type, prior treatment experience or presence of cirrhosis, a second DAA, RBV or both will need to be added. Also, shortening or extending treatment duration may become part of the new individualised treatment approach. It is likely that the availability of these Peg-IFNα-free antiviral regimens will lead to a similar shift in the treatment paradigms and outcomes as has been observed when the first polymerase inhibitors became available for patients with chronic HBV infection. However, we have to be aware that the number of treated patients with more 'difficult-to-treat' characteristics is limited, especially of those with cirrhosis who have been successfully cured with the new treatment regimens. Therefore, that a broader use of these new DAAs in the 'real-world' will probably face unprecedented safety and resistance issues cannot be ruled out.


1. Deuffic-Burban S, Deltenre P, Louvet A, et al. Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France. J Hepatol 2008;49:175–83.

2. Deuffic-Burban S, Babany G, Lonjon-Domanec I, et al. Impact of pegylated interferon and ribavirin on morbidity and mortality in patients with chronic hepatitis C and normal aminotransferases in France. Hepatology 2009;50:1351–9.

3. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244: 359–62.

4. Kolykhalov AA, Agapov EV, Blight KJ, et al. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 1997;277:570–4.

5. Yanagi M, Purcell RH, Emerson SU, et al. Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee. Proc Natl Acad Sci 1997;94:8738–43.

6. Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004;127:1347–55.

7. Welsch C, Jesudian A, Zeuzem S, et al. New directacting antiviral agents for the treatment of hepatitis C virus infection and perspectives. Gut 2012;61: i36–46.

J8. acobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16.

9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417–28.

10. Poordad F, McCone J Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195–206.

11. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17.

12. Pawlotsky JM. Treatment of chronic hepatitis C: current and future. Curr Top Microbiol Immunol 2013;369:321–42.

13. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–74.

14. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124–34.

15. Sofia MJ, Bao D, Chang W, et al. Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-20-beta-Cmethyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010;53:7202–18.

16. Hassanein T, Lawitz E, Crespo I, et al. Once daily sofosbuvir (GS-7977) plus PEG/RBV: high early response rates are maintained during post-treatment follow-up in treatment-naive patients with HCV genotype 1, 4, and 6 infection in the ATOMIC study. Hepatology 2012;56:307A.

17. Rodriguez-Torres M, Lawitz E, Kowdley KV, et al. Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naïve patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol 2013;58:663–8.

18. Cornpropst M, Denning J, Clemons D, et al. The Effect of Renal Impairment and End Stage Renal Disease on the Single-Dose Pharmacokinetics of GS- 7977. J Hepatol 2012;56:S433.

19. Mathias A, Cornpropst M, Clemons D, et al. No Clinically Significant Pharmacokinetic Drug-Drug Interactions between Sofosbuvir (GS-7977) and the Immunosuppressants, Cyclosporine A or Tacrolimus in Healthy Volunteers. Hepatology 2012;56:1063A–4A.

20. Kirby B, Mathias A, Rossi S, et al. No clinically significant pharmacokinetic interactions between sofosbuvir (GS-7977) and HIV antiretrovirals Atripla, rilpivirine, darunavir/ritonavir, or raltegravir in healthy volunteers. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), November 9–13, 2012, Boston, MA. Abstract 1877.

21. Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J Hepatol 2013;58:S6.

22. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naïve and previously treated patients with genotype 1 hepatitis C: the LONESTAR study. Hepatology 2013;58:1092A.

23. Lalezari JP, Nelson DR, Hyland RH, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with hCV infection: the QUANTUM study. J Hepatol 2013;58:S236.

24. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.; AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor) with or without ribavirin, in treatmentnaive patients chronically infected with HCV GT 1, 2, or 3. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9–13; Boston, MA. Abstract LB-2.

25. Osinusi A, Meissner EG, Bon D, et al. High Efficacy of Sofosbuvir in Combination with Weight Based Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype-1 Patients. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, March 3–6, 2013. Abstract 157B.

26. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. SVR4 results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GSs-7977) with or without ribavirin (RBV) in HCV GT 1 null responders. Digestive Disease Week, Orlando, May 18–21 2013. Abstract Sa2073.

27. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34–44.

28. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867–77.

29. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013;13:401–8.

30. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013;381:2100–7.

31. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878–87.

32. Lam AM, Espiritu C, Bansal S, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012;56:3359–68.

33. Svarovskaia ES, Dvory-Sobol H, Gontcharova V, et al. Comprehensive Resistance testing in patients who relapsed after treatment with sofosbuvir (GS-7977)- containing regimens in phase 2 studies. Hepatology 2012;56:551A.

34. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of Viral Load through 4 Weeks Post- Treatment Results of a Once-daily Regimen of Simeprevir +Sofosbuvir with or without Ribavirin in Hepatitis C Virus GT 1 Null Responders. 20th Conference on Retroviruses and Opportunistic Infections. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3–6, 2013. Abstract 155LB.

35. Heim MH. Innate immunity and HCV. J Hepatol 2013;58:564–74.

36. Rotman Y, Noureddin M, Feld JJ, et al. Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut 2014;63:161–9.

37. Testoni B, Durantel D, Levrero M, et al. In vivo ribavirin effects on interferon stimulated genes transcriptional regulation involves chromatin remodelling and histone methylation mediated by the G9a methyl-transferase. J Hepatol 2013; 58:S5.

38. Barrett L, Shivasabesan G, Wang C, et al. Altered immune responses during interferon free HCV DAA therapy. J Hepatol 2013;58:S1.

39. Lawitz E, Gane EJ, Lalezari J, et al. High Concordance of SVR4, SVR12, and SVR24 in Patients With HCV Infection who have received treatment with sofosbuvir. J Hepatol 2013;58:S48.

40. Kowdley KV, Hassanein T, Gane EJ, et al. Sofosbuvir Safety and Tolerability in 778 Patients Treated for Up to 24 Weeks in Four Phase 2 Studies. J Hepatol 2013;58:S345.

41. Rodriguez-Torres M, Gonzales M, Rodriguez J, et al. HIV/HCV coinfected and HCV monoinfected patients have similar early HCV viral kinetics with the potent HCV nucleotide polymerase inhibitor sofosbuvir (SOF). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 2012. Abstract H-1921a.

42. Fontana RJ, Hughes EA, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant 2013;13:1601–5.

43. Lawitz E, Rodriguez-Torres M, Denning J, et al. Alloral therapy with nucleotide inhibitors sofosbuvir and GS-0938 for 14 days in treatment-naive genotype 1 hepatitis C (NUCLEAR). J Viral Hepat 2013;20: 699–707.