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July 2007 HCV Advocate

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Valopicitabine Results
Alan Franciscus, Editor-in-Chief

Types of Interferon and How They Work
Liz Highleyman

The Emotional Impact of Leaving Work on Disability
Jacques Chambers, CLU

HealthWise: Iron Overload
Lucinda K. Porter, RN, CCRC

DDW 2007 Highlights
Alan Franciscus, Editor-in-Chief

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Valopicitabine Results
by Alan Franciscus, Editor-in-Chief

On June 12, 2007 Idenix released the clinical trial data from their phase II trial of valopicitabine (NM283). 

This was a three-arm partially blinded, randomized study of 117 HCV genotype 1 treatment naïve patients from approximately 20 centers in the United States. 

There was a seven day lead-in phase – study participants were given either valopicitabine or placebo, then on the 8th day were rolled over to one of the three different treatment arms.

A total of 39 patients were enrolled in each treatment arm:

  • Arm A:  Double therapy – 200 mg/day of valopicitabine (one pill a day) and pegylated interferon alfa-2a (once a week),
  • Arm B:  Triple therapy – 200 mg/day of valopicitabine (one pill a day), weight-based ribavirin (daily), and pegylated interferon alfa-2a (once a week), and
  • Arm C:  placebo, pegylated interferon (once a week), and weight-based ribavirin (daily).

The primary endpoint of the study was the pharmacokinetic (the study of how the drug is absorbed, distributed, metabolized, and eliminated by the body) and pharmacodynamic (the study of the action, effect, and breakdown of drugs within the body) drug-drug interaction between valopicitabine and ribavirin after 36 days of treatment. 

After 36 days of treatment there were no pharmacokinetic or pharmacodynamic drug-drug interactions between valopicitabine and ribavirin.

The secondary endpoint of the study was to evaluate the antiviral activity, safety, and tolerability at 12 weeks of therapy. Of the patients who completed 12 weeks of therapy, 72.2% of patients treated with triple therapy valopicitabine, pegylated interferon plus ribavirin(Arm B) achieved undetectable HCV RNA (less than 20 copies/mL) compared to 43.6% of patients who received double therapy of valopicitabine and pegylated interferon (Arm A) and 61.5% of patients who received placebo, pegylated interferon and ribavirin (Arm C).  Please note that these are 12 week treatment results and NOT sustained virological response rates.   

Based on the data from this study, Idenix stated that these results support the further development of valopicitabine in combination with pegylated interferon plus ribavirin.  Idenix stated that it will not move forward with studies of double therapy (valopicitabine plus pegylated interferon).  In addition it was noted that valopicitabine has a low drug resistance profile and that in vitro (test tube) studies suggest that valopicitabine could block or delay viral resistance of other direct antivirals in clinical development to treat hepatitis C.  

Three patients discontinued therapy – one attributed to valopicitabine and two were considered to be pegylated interferon/ribavirin related.  All of the discontinuations were in the triple combination arm.

This trial was designed to study valopicitabine for 12 weeks only, but the trial participants were given the option to continue with pegylated interferon plus ribavirin for the additional 36 weeks of therapy (total therapy duration = 48 weeks).  It was reported that all patients in this study elected to continue on with therapy.  The SVR data (24 weeks post-treatment) will give us a better picture of the durability of the triple combination treatment.  However, this trial was not designed as an efficacy study so SVR information from this study will be important, but a larger phase III study (800-1200 patients) planned for 2008 will give a better picture of the effectiveness of valopicitabine when combined and compared with pegylated interferon plus ribavirin.

Clinical Trial Development
The purpose of clinical trials is to find out information about a new drug including the safety, tolerability and effectiveness in treating a condition or disease.  As more information is obtained from one study, the next study phase is adjusted or redesigned to optimize safety, tolerability and effectiveness.   This is the case for most drugs in development and valopicitabine is no exception.  The initial clinical study tested the effectiveness of valopicitabine when used in combination with pegylated interferon.  In the initial study design, ribavirin was not included.  As a result of information obtained from this study (and information from other studies) it is now clear that ribavirin will have to be included in any new drug combination using valopicitabine to achieve a sustained virological response (SVR) and even more importantly to ensure the durability of an SVR.  It is clear that with any antiviral in development ribavirin and pegylated interferon will remain the backbone of HCV therapy until multiple direct antivirals are developed and tested that improve HCV therapy.  

Quadruple Therapy?
Idenix stated that they will evaluate the current trial data and design future clinical trials of valopicitabine in combination with pegylated interferon plus ribavirin as a triple therapy and possibly add another unspecified antiviral (quadruple therapy).  Idenix will work closely with Norvartis to plan the most appropriate clinical trial design.  In the meantime, Idenix will begin a phase IIb dose ranging study of 200 and 400 mg doses of valopicitabine in combination with pegylated interferon plus ribavirin therapy that is slated to begin toward the end of the year in about 300 treatment naïve genotype 1 patients.  It was also stated that future studies of valopicitabine will include medications to treat the GI side effects during the first week of therapy.  It has been found that the GI side effects are usually confined to the first week.  

Full study results will be presented at the American Association for the Study of Liver Disease (AASLD) Conference in November 2-6, 2007 in Boston, MA.
Source:  Company press release and investor conference call

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Types of Interferon and How They Work
by Liz Highleyman

Interferon alpha (especially its pegylated form) is the mainstay of therapy for acute and chronic hepatitis C virus infection, and is also used to treat chronic hepatitis B. But several other types of interferon are also under study for the treatment of viral hepatitis.

What are Interferons?
Interferons are natural chemical messengers, or cytokines, that play an important role in the body’s immune response to foreign pathogens – especially viruses – and cancerous cells. Part of the non-specific immune system, interferons act at the earliest stages of viral infection before the production of antibodies.

Different types of interferons utilize different cell surface receptors, but act via common signaling pathways, of which the JAK-STAT pathway is the most fully understood. In the presence of viruses (in particular, viral double-stranded RNA), interferons are part of a complex cascade of signals that involves toll-like receptors and numerous interferon-signaling genes.

Since they affect the immune system as a whole, interferons cause a variety of side effects – including the familiar “flu-like” symptoms of malaise, fever, fatigue, and muscle aches – that indicate an antiviral immune response. Paradoxically, interferons can both increase susceptibility to certain infections (for example, by causing depletion of white blood cells that fight bacteria) and lead to autoimmune conditions in which the immune system attacks the body’s own tissues.

How Do Interferons Work?
First discovered in the 1950s, interferons have been studied as treatments for a wide variety of viral diseases and malignancies. While their full range of activity is not completely understood, it is known that they work via several mechanisms:

Antiviral activity: When an infected cell dies and releases viruses, interferons “warn” surrounding cells and cause them to release protein kinase R and other messengers that interfere with the production of proteins needed to assemble new virus particles. Interferons also help prevent the entry of viruses into cells. Much of interferon alpha’s effect on HCV is attributed to direct antiviral activity.

• Cytotoxicity: Interferons kill virus-infected cells by enhancing apoptosis, or programmed cell death. While the first phase of rapid HCV decline during interferon-based therapy is likely due to direct antiviral activity, the slower subsequent decrease is thought to be due to enhanced destruction of HCV-infected hepatocytes.

• Immunomodulation: Interferons stimulate the production of cytokines that activate macrophages, natural killer cells (NK), and cytotoxic T-lymphocytes (CTLs or killer T-cells). The immunomodulatory effect of interferon alpha is thought to account for its effectiveness against HBV.

• Enhanced MHC expression: Interferons enhance the expression of major histocompatibility complex (MHC) antigens on the surface of virus-infected cells, which enables CTLs and NK cells to recognize and destroy them.

• Antiproliferative and antitumor activity: Interferons inhibit the excessive reproduction of malignant cells and also enhance CTL activity against tumor cells and inhibit angiogenesis, or production of new blood vessels needed for tumor growth.

Types of Interferon
Interferons were originally categorized into two broad classes, type I (alpha and beta) and type II (gamma). Recently, another group of substances (interleukins 28 and 29) with antiviral activity was recognized as a third class of interferons, type III (lambda). While each class acts through different cell receptors, their activity overlaps to a large degree.

Interferon alpha (a family of more than a dozen related proteins) is most widely used in the treatment of hepatitis C, and is also approved for treating chronic hepatitis B and several types of cancer. Many controlled trials have documented the effectiveness of conventional interferon alpha-2a (Roferon-A) and -2b (Intron-A) in reducing HCV RNA levels, decreasing liver inflammation (indicated by elevated ALT and AST levels), and retarding – or even reversing – liver fibrosis. Unfortunately, nonresponse and relapse are common with conventional interferon alpha monotherapy, but some studies suggest treatment may improve fibrosis even in patients who do not achieve sustained virological response (SVR).

Today’s standard of care for chronic hepatitis C is pegylated interferon alpha (Pegasys or PegIntron) plus ribavirin. Pegylation – the addition of polyethylene glycol to conventional interferon alpha – increases the length of time the drug stays in the body, so it can be injected less often. Pegasys and PegIntron have different pharmacokinetic profiles, but appear to have somewhat similar efficacy and side effects.

Consensus interferon alpha, also known as interferon alfacon-1 or Infergen, is a recombinant form developed by determining the most common amino acids at each position of the interferon alpha molecule. Consensus interferon has been extensively studied for the retreatment of hepatitis C in prior interferon alpha nonresponders and relapsers. While SVR rates in most studies have been relatively low – though often higher than those for retreatment with pegylated interferon – consensus interferon does offer some previous nonresponders, and especially relapsers, the chance for an SVR.

Interferon alpha-n1, also known as lymphoblastoid interferon or Wellferon, is a combination of nine subtypes of interferon alpha. Approved for treatment of hepatitis C in Europe but not in the U.S., studies suggest that it is about as effective as conventional interferon alpha, and less so than pegylated interferon.

Albumin interferon, or Albuferon, is a long-acting form of interferon alpha fused with the blood protein albumin that needs to be administered only once every two weeks or less. As reported at the European Association for the Study of the Liver meeting this past April, a randomized Phase IIb study of 458 treatment-naive patients with chronic genotype 1 hepatitis C showed that albumin interferon given once every two weeks plus daily ribavirin worked about as well as once-weekly pegylated interferon, although heavier patients (> 75 kg) with optimal adherence benefited more from albumin interferon. A second Phase II study in subjects with genotype 2 or 3 found that albumin interferon administered only once every four weeks produced an end-of-treatment response rate of 82%. Albumin interferon has also demonstrated promising efficacy in prior nonresponders and relapsers.

Interferon beta, both -1a (Avonex) and -1b (Betaseron) are approved for the treatment of multiple sclerosis. This form of interferon has been studied for chronic hepatitis C, but its efficacy appears no better than that of interferon alpha, though it may produce milder side effects.

Interferon gamma-1b, or Actimmune, is a recombinant version of the sole known type II interferon. In studies to date, interferon gamma-1b has not reduced HCV RNA in prior interferon alpha nonresponders and relapsers. Given its antifibrotic activity, interferon gamma has also been studied in patients with advanced liver fibrosis or cirrhosis. In a recent study of 420 participants with pre- and post-treatment liver biopsies, thrice-weekly interferon gamma did not reduce Ishak fibrosis scores more than placebo, though a subgroup of patients with specific cytokine profiles did seem to benefit.

Interferon lambda (interleukin 28/29) is a newly identified class of type III interferons just entering human clinical trials for hepatitis C. In laboratory studies, it demonstrated antiviral activity against both HBV and HCV, though it was less effective than interferon alpha in mouse studies. Since interferon lambda uses receptors that are not as widely distributed throughout the body, researchers hypothesize that it might cause fewer side effects. In January, ZymoGnetics announced that it had initiated a Phase I safety and pharmacokinetic study of pegylated interferon lambda (IL-29) in healthy volunteers.

Interferon omega is a novel type I interferon. At the recent Digestive Disease Week 2007 conference in May, researchers presented final 72-week results from a Phase II study comparing interferon omega plus ribavirin to interferon omega monotherapy in 102 treatment-naive patients with genotype 1 chronic hepatitis C. Interferon omega plus ribavirin demonstrated antiviral activity comparable to that of interferon alpha plus ribavirin (SVR rate of 36%). The current formulation must be injected daily, but Intarcia Therapeutics is planning to study a continuous release formulation using an implantable device, on the theory that maintaining continuous drug levels may minimize side effects compared with weekly injections of pegylated interferon alpha.

The Future of Interferons
While interferons continue to comprise the backbone of anti-HCV therapy, targeted agents that attack the virus directly (such as HCV protease and polymerase inhibitors) hold the promise for effective therapy with fewer side effects. Nevertheless, given its multiple modes of action, most experts predict that pegylated interferon alpha – and possibly novel types as well – will play an important role in hepatitis C treatment for the foreseeable future.

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The Emotional Impact of Leaving Work on Disability
by Jacques Chambers, CLU

This may seem like one of those issues that is too basic to spend much time thinking about. Of course, there’s an emotional impact on leaving work for disability. Who wouldn’t be depressed? However, there is frequently more to it than that, and not being prepared for it can put you in a tailspin that can affect your mental well-being as well as your physical health.

In my years of working with clients, I have found that making the transition from work to disability is a major life event, right up there with getting married or moving, and it can have broad repercussions on feelings and emotions. It can also have a dramatic effect on your ability to make decisions objectively and rationally. Clients who recognize this impact and know to expect such feelings are better prepared to deal with them and minimize them.

What will happen?
Don’t worry, you won’t “wig out” or “totally lose it.”  As with medical symptoms the emotional impact will vary from person to person. The emotional repercussions of leaving work on disability often take the form of depression, lack of concentration, inability to focus on a goal and achieve it, as well as general feelings of malaise,  helplessness, and fear of the future. There may be other symptoms both emotional and physical. The important thing to remember is that, uncomfortable as these symptoms are, they are a natural part of this change you are making, and they will pass.

Why does it happen?
Part of it is obvious. You are moving from active work to inactive disability; that’s major and would upset anyone. There are other factors as well, primarily the sense of loss of control and having to battle lifelong messages.

There is frequently a feeling of loss of control over not only the direction of your life, but loss of control over your very own body. Many people feel that stopping work is “giving in” to the medical condition that is now in control of their bodies, and all they can do is watch.

Likewise, the medical condition is now dictating your future. You may feel like you no longer have the power to decide what direction to take or what to do next. Such a feeling of helplessness can be devastating emotionally and can create all sorts of symptoms.

Finally, there are all those good work ethic messages you learned growing up and which you were probably playing back during the early stages of your condition. Who wouldn’t have emotional issues if, in the background of their mind, they keep thinking things like:

  • You’re giving up by stopping work. You’re a quitter.
  • You’re surrendering to the disease.
  • You’re no longer a contributing member of society. 
  • You’re taking a giant step closer to “The End.”
  • You’re “milking the system.”
  • You’re weak, needy, plus many other not-so-nice adjectives.

Of course, none of these are true or even rational, but our emotions don’t react rationally.

These “deep” messages may even be communicated by friends and family. People who haven’t been disabled do not understand the price you must pay for stopping work. I have heard some refer to their disabled friends as “retired” or “taking it easy.” There may even be “jokes” about “how easy your life is.”

What can I do about it?
Fortunately, there’s a lot you can do about it, and all of the suggestions below would come under the overall title of “Take back control of your life.”

Control how and when you leave work – Make your plans; do your research; create your own timetable for stopping work.

Take one step at a time to avoid being overwhelmed – You can do this by breaking down your tasks into smaller steps. First, leave work, then apply for the employer’s disability, then move your health insurance to COBRA, then apply for Social Security, etc. A list or timeline will help you focus your attention on the next small step without being overwhelmed by the entire process.

Build, activate and use your support network – Your family, friends, and caregivers can give you emotional support as well as practical assistance, but you may need to ask for it.

Consider short-term therapy – Perhaps your support network is strong enough that they will give you all the help you need to get through this time. Many clients have also found that a few months with a therapist trained in the emotional issues of the disabled can be of great help as well. 

Speak up, politely but firmly – Do not hesitate to tell those who don’t understand what you are going through that this is not a vacation and you wish you could return to work.

But what will I do once I go on disability?
Many people worry that after they leave work, they will have nothing to do. Some people have an image of themselves lying in bed, face to the wall, doing nothing but waiting. That’s not the way it is. More than one of my clients has worried that they will have too much time on their hands only to return after leaving work to tell me they are so busy, they have no idea how they were able to work full-time.

Initially at least, there’s a lot to do, applications and claims to file, health insurance to adjust, government benefits to apply for.

If you are the type of personality that was always busy before, trust me, you will be as busy as you want and are able to be once you go on disability. Depending on how you feel and your interests, there are classes to be taken, family to be enjoyed, other people or agencies that you could volunteer to assist.

The best thing you can do is to expect some emotional upheaval when leaving work. Recognize it as a natural part of the process and don’t let it scare you into believing that it is more than just a passing reaction to what’s going on with your life at the moment. It will pass; you will move on. Life will continue.

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HealthWise: Iron Overload
by Lucinda Porter, RN

July is Hemochromatosis Awareness Month. House fans will recognize hemochromatosis from one of the May episodes. Hemochromatosis is a metabolic disorder that causes the body to store excess iron. Without early intervention this iron overload may lead to serious consequences, including death. If you are wondering why I am taking up space in a hepatitis C newsletter to write about an iron disorder, keep reading.

When the body stores excess iron, this is referred to as iron overload.  Iron overload can have many causes, the most common being genetic. Other causes include too much iron in the diet (particularly from supplementation), chronic transfusion therapy, iron injections, chronic hepatitis, and other disorders.

The terms iron overload and hemochromatosis are often used interchangeably, but they are not the same. According to the Centers for Disease Control (CDC), “hemochromatosis is a disease that occurs as a result of significant iron overload.” Not all iron overload is hemochromatosis, but all hemochromatosis is iron overload.

The CDC states, “Hemochromatosis can have genetic and non-genetic causes.” However, for the most part, when we talk about hemochromatosis, we are referring to the genetic variety – hereditary hemochromatosis. The next statement may scare you so be sure to read the sentence following it. More than a million people in the U.S. carry the gene for hereditary hemochromatosis. However, carrying the gene is not the same as having hemochromatosis. In fact, the chances of having hemochromatosis are low.

Back to the broader category of iron overload, the CDC estimates that between 1% and 6% of Americans have too much iron. Not everyone with iron overload develops signs and symptoms. However, because the consequences can be so serious, it is important that those with iron overload are monitored and treated accordingly. Prevention of progression is critical.

Why is this important to people living with hepatitis C?  Researchers are interested in the relationship of iron overload in people with HCV. It would seem that liver disease would be more likely to progress in patients who have both conditions.  Some studies have come close to staking that claim. However, the current research findings are inconclusive and open to debate. What we can agree upon is that iron overload, with or without HCV, is a potentially serious condition. Diagnosis and early intervention can prevent disease progression.

Basically, hemochromatosis is the accumulation of iron in the joints and organs, chiefly the liver, pancreas, heart and skin. It takes a long time for symptoms to develop. Men typically show signs beginning in their 40’s; women tend to develop symptoms about 15 years after menopause. The early symptoms of iron overload are vague and similar to the symptoms of HCV. Fatigue, weakness and joint pain are the most common. If the condition progresses, one might experience abdominal pain. Weight loss, diabetes, arthritis, breathing difficulties and hormonal changes may occur as the disease progresses.  A change in skin pigmentation (usually bronze), cirrhosis, and liver cancer are late stage signs.

The CDC does not recommend routine genetic testing for the general population. The genetic test is expensive and inconclusive. The CDC does recommend testing for anyone with a family history of hereditary hemochromatosis and those who have signs or symptoms of iron overload. If you have hepatitis, arthritis, diabetes, and unexplained hormonal changes you should talk to your medical provider. You may request testing if you experience any of the symptoms of iron overload such as unexplained fatigue or weakness.

The initial test is a simple blood test – the fasting transferrin saturation test. In addition to fasting the day of the test, patients should abstain from iron supplements for 24 hours prior. The placebo pill in oral contraceptives sometimes contains iron, so you may need to skip this. Talk to your medical provider about how to prepare for the test.

If the transferrin saturation test is abnormally high, it is usually followed with another blood test – the serum ferritin level. If this is elevated, then your medical provider may advise iron removal. The only way to remove iron is by blood loss. This is done by blood donation – just as if you were donating blood. Good news – this blood is a donation. There is a national shortage of our blood supply. The blood you donate helps you stay healthy and may save someone else’s life. How cool is that!

The blood donation process for iron overload is called de-ironing. You may need to do this once or twice a week for 3 months to a year. Once your body returns to safer iron levels, you may need to do this several times a year. The procedure is safe and free. You should be well hydrated before and after the procedure. Avoid strenuous exercise and alcohol for 24 hours after de-ironing.

If you have iron overload, there are a few measures you can take to help you stay healthy. Avoid iron supplementation, including iron in your multivitamin or multi-mineral. Vitamin C intensifies iron absorption, so limit C to 500 mg daily. It is all right to eat foods that are naturally high in vitamin C. Avoid eating raw shellfish. Avoid alcohol consumption if you have liver damage, hepatitis or other alcohol-limiting diseases. There is no proven supplement that will remove excess stored iron.

If you have hereditary hemochromatosis, tell your blood relatives. The CDC recommends testing and routine surveillance of parents, grandparents, children and siblings. Don’t wait until this treatable condition does irreversible damage. Those who have early testing and treatment for iron overload have the same life expectancy as the general population. Don’t wait until it is too late.

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DDW 2007 Highlights
by Alan Franciscus, Editor-in-Chief

This year’s Digestive Disease Week Conference (DDW) provided a wealth of information about new drugs in development as well as on many HCV-related topics.  Because DDW followed on the heels of the European Association for the Study of Liver Disease Conference (EASL) most of the information about drugs in development was covered in the May 2007 HCV Advocate newsletter, HCV Advocate Web site and many other media sources.  As a result, this article will focus on information presented at DDW that has not been previously covered by the HCV Advocate or on information that has been previously reported, but that warrants a more detailed investigation. 

HCV & Arab Americans
The most common way that HCV is transmitted around the world is from unsafe medical practices, such as the re-use of syringes and the use of unscreened blood products.  In the Eastern Mediterranean countries it is estimated that about 21 million people are infected with HCV.  If you break down the estimated prevalence of HCV by Middle Eastern country it would be Egypt (18.1%), Iraq (0.5%), and Jordan (2.1%), while the prevalence rates are unknown in Syria and Lebanon.  In this country, some immigrant populations have higher rates of HCV compared to the prevalence rate of the general U.S. population.  Selected prevalence studies of the Russian and Vietnamese immigrant communities have found prevalence rates between 15 and 25%.  But what about Arab Americans who have immigrated from Middle Eastern countries?  In the first study of Arab Americans, L.H. Jamil and colleagues (poster # 1024) in cooperation with the Arab American and Chaldean Council (Arab Americans belonging to the Chaldean Catholic Church) tested Arab Americans in Southeast Michigan for hepatitis C.  Southeast Michigan has the largest Middle Eastern community outside of the Middle East estimated at 430,000.

In all, 492 patients were tested – 8 participants were excluded because they were born in the United States.  Of the remaining 484 subjects, 26 patients (5.4%) tested positive for hepatitis C – 46% were male, 61.5% were between the age of 40 and 59, 69% had less than or equal to 12 years of education, and 65% had no health insurance.  The highest prevalence rate was among Jordanians (18.2%) followed by Tunisians (16.7%), and Egyptians (10%).  The self-reported risk factors included IDU (72%), risky sexual behavior (62%), shared personal hygiene products (52%), blood transfusions prior to 1992 (15%), and receiving an injection from a non-sterile needle (13%). 

SVR Durability
The durability of a sustained virological response (SVR) from HCV treatment has included an on-going debate about whether the use of the ‘cure’ word is appropriate when someone achieves an SVR.  Regardless of the word used to describe treatment success it is clear that the vast majority of people who achieve an SVR continue to be HCV negative long after treatment ends.  Confirmation of the durability of an SVR was presented at DDW in a long-term 5 year follow-up study of trial participants of peginterferon Alfa-2a (40KD) (PEGASYS®) alone or in combination with ribavirin (Copegus®) (poster 444).  M.G. Swain and colleagues presented data from their ongoing study of people who achieved an SVR in 4 different clinical trials (pegylated interferon mono-therapy, and pegylated interferon plus ribavirin in various study populations) from nine randomized trials.  In this follow-up study, HCV RNA was measured annually for up to 5 years from the date of last treatment. To date a total of 997 patients have been followed.  It was found that 989 of 997 (>99%) of patients remained HCV RNA negative up to 5 years after treatment ended (Table 1)

Of the 8 patients who became HCV RNA positive, 1 patient was known to be re-infected because the later genotype was different from the genotype at treatment.  In the other 7 individuals it was unclear if the virus had returned after achieving an SVR or if the return of HCV RNA was due to re-infection.

Treatment (population)
Number of studies N Mean years after treatment Patients with detectable HCV RNA (n)
Monotherapy (elevated ALT)a 4 163 4.6 2
Combination (elevated ALT)a 4 666 4.2 5
Combination (‘normal’ ALT) 1 75 3.2 0
Mono and combination (HIV-HCV co-infection) 1 93 3.2 1

a1 study contained monotherapy and combination therapy arms.

Eltrombopag (GlaxcoSmithKline) is an investigational small-molecule growth factor that is thought to stimulate bone marrow cells to increase blood platelets.  In a previous study (TPL102357) of eltrombopag in people whose platelets counts were too low to start HCV therapy,  it was found that eltrombopag increased platelet counts to greater than or equal to 100,000/Ul, which resulted in two-thirds (49 of 74 patients) of the study participants becoming eligible for and able to start HCV treatment.  A sub-analysis was performed by G.M. Dusheiko and colleagues  (#1044) on the data from TPL102357 to find out if the use of eltrombopag counteracted pegylated interferon induced thrombocytopenia (low platelets). 

It was found that eltrombopag effectively maintained platelet counts above 50,000/uL in up to 81% of the patients during the first 12 weeks of antiviral treatment. The authors concluded that “eltrombopag use avoided the need for PEG-IFN dose modification in approximately 90% of patients during the first 12 weeks of antiviral treatment.”  Based on these results the authors commented that further research of long-term use (48 weeks) of eltrombopag is warranted.  

HAV Vaccination
In people with existing liver disease another hepatitis virus infection could potentially lead to a more severe liver disease and possibly even death.  For this reason, people with any other liver disease should be vaccinated against hepatitis A (HAV) and hepatitis B (HBV) if they have not been previously exposed.  But are these strong recommendations being carried out in actual clinical practice?  To answer this question, S. Dhalla and colleagues (# 1002) recruited 2,038 patients – 715 were identified as uninfected (control group), 121 had HIV, 893 had HCV, and 309 were coinfected with hepatitis C and HIV.  Trial participants were asked to complete a detailed questionnaire during their scheduled visit to either their outpatient primary care or gastroenterology clinic at 3 different study sites.  Information on demographics, personal vaccination history, and barriers to vaccination data was collected. 

Through data collection 1,650 patients were identified who had NOT been previously exposed to HAV.  In this group only 412 (25.0%) reported that they had received the vaccine, 900 (64.5%) were not vaccinated and 338 (20.5%) did not know if they were vaccinated. 

Of the patients who were vaccinated 12.9% were from the uninfected group, 28% from the HIV group, 37.3% from the HCV group and 22.8% from the HIV/HCV coinfected group (P=<0.001).   

A list of the self-reported barriers to receiving the HAV vaccination is summarized in Table 2 below.  

This study makes it very clear that more awareness and education is needed among patients and providers to overcome these barriers to vaccination.

Uninfected HIV HCV HIV-HCV P-value
My doctor did not offer the vaccine to me 67.0% 69.2% 54.8% 73.8% <0.001
I am afraid of the vaccine 17.5% 15.4% 26.0% 27.7% 0.009
I am afraid of needles 15.0% 28.8% 21.2% 32.3% <0.001
I don’t understand why I need the vaccine 40.4% 25.0% 36.2% 40.0% 0.15
I did not know about a vaccine against HAV 70.7% 78.8% 62.5% 46.9% <0.001
I could not afford to pay for the vaccine 4.4% 11.5% 34.0% 26.9% <0.001

HCV Positive Liver Donors
Even now the amount of healthy livers available for transplantation far exceeds the amount of livers available from donors.  Currently, only about 1/3 of those who need a liver will receive one.  As the population with hepatitis C continues to age there will be an even greater demand for livers for transplantation.   New strategies are needed to help fill the gap between livers needed vs. livers available.  One strategy that has emerged in the last few years is splitting a cadaver (from a deceased person) liver or the use of a portion of a liver from a healthy person (live liver donor).  While both of these strategies are increasing the pool of available livers for transplantation, more livers are needed to improve the availability of livers for transplantation.  Recently, the use of HCV-infected livers for transplantation to HCV-infected persons is gaining attention and acceptance.  A study of HCV-infected donors in liver transplantation was presented at DDW that is giving us crucial information on the use of HCV-infected livers for transplantation.  S. Wilson (#2) presented the results of the largest study to date on the use of HCV-infected livers for transplantation. 

The study compared transplant outcomes for 38 recipients of livers from HCV-infected donors to those of 76 standard, non-extended criteria (ECD) donors (case controls).  

Data was extracted from the transplant center registry, UNOS (United Network for Organ Sharing) data, and from the original on-site donor data charts. Thirty percent of all donors met non-ECD criteria (standard donors) and were included as potential matches for the case-control study. Each HCV-positive liver donor recipient was matched to two standard donor recipients (matched standard donor controls [MSDC]) by recipient age (+/- 10 years), primary diagnosis, cancer stage for those with HCC (liver cancer), recipient MELD (+/- 5), and donor age (+/- 10 years).

Outcomes included graft and patient survival at 3-months, 1-year and 2-years; perioperative (refers to the three phases of surgery preoperative, intraoperative, postoperative) death; and HCV recurrence by 4-month and 1-year fibrosis (F0-F4-Metavir).

The HCV-donor and matched standard donor control groups did not differ for recipient or donor demographics or in cold and warm ischemia (decrease in the blood supply) time. The only difference between the two groups was that the age of the HCV-negative patients in the control group were older than the HCV-positive donors.  Median follow- up time was 36 months. Kaplan-Meier actuarial survival demonstrated improved graft survival for HCV-infected donors with a trend toward significance (p=0.10). 

The authors concluded that the preliminary results from their study suggest that HCV-infected donors may have a slower rate of fibrosis progression at 1-year.  There was also a survival advantage for those receiving HCV-donor grafts compared to the standard donor controls.  The results of the trials were so encouraging that the authors concluded that “the use of HCV-positive donors may be considered as a first line of therapy to increase the available donor pool of organs in those undergoing liver transplantation for HCV-related cirrhosis.” 

TABLE 3: Hepatitis C-Infected Donor Matched Standard Donor Controls (MSDC) p-value
TOTAL N=38 N=76  
90-Day Survival      
   Graft 37/38 (97.4%) 72/76 (94.7%) NS
   Patient 37/38 (97.4%) 72/76 (94.7%) NS
1-Year Survival      
   Graft 30/31 (96.8%) 62/72 (86.1%) NS
   Patient 31/31 (96.8%) 63/72 (87.5%) NS
2-Year Survival      
   Graft 16/19 (84.2%) 49/62 (79.0%) NS
   Patient 17/19 (84.2%) 52/62 (83.9%) NS
Graft Loss within 7 Days 1/38 (2.6%) 1/76 (1.3%) NS
Mean Fibrosis at 4 Months (F0-F4) 0.68 0.33 0.08
Mean Fibrosis at 12 Months (F0-F4) 0.86 1.05 NS
Percent Change in Fibrosis 26% 69%  

More detailed DDW coverage is available at http://www.hcvadvocate.org/news/reports

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