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HCV Advocate Newsletter

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November 2008 HCV Advocate

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New Study - Telaprevir in Treatment Experienced Patients
Alan Franciscus, Editor-in-Chief


HealthWise: What We Eat
Lucinda Porter, RN


Hepatitis C Treatment after Liver Transplantation
Liz Highleyman

Understanding Abstracts
Alan Franciscus, Editor-in-Chief

HCV Snapshots
Alan Franciscus, Editor-in-Chief

HCV - Replication and Damage
Alan Franciscus, Editor-in-Chief


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New Study:  Telaprevir in Treatment Experienced Patients
—Alan Franciscus, Editor-in-Chief

On October 15, 2008 Tibotec announced that it will begin screening patients for a large phase III study to evaluate the combination of telaprevir, pegylated interferon plus ribavirin in treatment experienced patients who did not achieve a sustained virological response to a previous course of treatment with pegylated interferon plus ribavirin.  Tibotec is Vertex’s commercial partner that is conducting clinical trials outside of the United States, Canada and Mexico.

This worldwide study will enroll about 650 HCV patients.  According to the company press release the U.S. centers have begun screening patients, and other global study centers are expected to begin the screening process within the next couple of weeks.  The study will include null responders, partial responders and relapsers. 

The REALIZE Study

The study will include 3 arms:

1.   Telaprevir dosed at 750 mg q8h (every eight hours) for 12 weeks in combination with standard doses of pegylated interferon plus ribavirin, followed by 36 weeks of treatment with pegylated interferon plus ribavirin alone;

2.   Delayed start arm – 4 weeks of treatment with pegylated interferon plus ribavirin, followed by telaprevir dosed at 750 mg q8h for 12 weeks in combination with standard doses of pegylated interferon and ribavirin, followed by another 32 weeks of pegylated interferon and ribavirin alone;

3.   Control Arm – standard doses of pegylated interferon plus ribavirin dosed for 48 weeks.

The study has been named REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes).

Currently, Vertex is conducting another large phase III study of telaprevir in combination with pegylated interferon plus ribavirin for the treatment of genotype 1 treatment naïve patients called the ADVANCE trial.  The ADVANCE trial is expected to enroll about 1050 patients in the U.S., Europe and certain other countries.  It is expected that the results from the ADVANCE study will be used to apply to the Food and Drug Administration for marketing approval of telaprevir in the U.S.  

For more information about the ADVANCE and REALIZE studies visit www.clinicaltrials.gov

Source:  Company Press Release


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HealthWise: What We Eat
Lucinda Porter, RN

The U.S. National Day of Eating, affectionately known as Thanksgiving, is around the corner.  Between leftovers and football snacks, several days are spent consuming food.  This is followed by more holidays.  Food is everywhere – at work, the bank, even the health club. 

Champion eaters say that Thanksgiving is amateur day.  They don’t need a holiday to celebrate food.  If you are an amateur, you will go on a diet in January.  A pro extends the eating opportunity through Super Bowl Sunday.  The elite keep going through Valentine’s Day.

I am a champion eater.  However, as much as I love to eat, nothing tastes as good as feeling good feels. Over the years I have learned to balance my desire for food with my desire to be healthy.  Awareness is the cornerstone.  This means thinking about what I eat before I eat it, developing a practice, maintaining a commitment and getting back on track when I fall off. 

Food is the focus of this month’s column.  What does food have to do with chronic hepatitis C virus (HCV) infection?  Everything.  What we eat can lead to weight problems, fatty liver and type 2 diabetes.  These conditions are associated with a poorer HCV prognosis.  HCV treatment is less likely to be effective for those who are overweight or obese.

Most of us will die with HCV rather than of it.  It makes sense to stack the deck in our favor by making the healthiest choices possible.  Changes in the diet may help or eliminate fatty liver, adult-onset diabetes, and high cholesterol.  Healthy food choices may help us avoid a host of diet and weight-related diseases.

Good nutrition relies on knowing:

•    What to eat
•    How much to eat
•    What is in your food
•    Putting this knowledge into practice

Ask experts what to eat and you will get more responses than there were candidates running for the presidential primaries.  In his book, In Defense of Food, Michael Pollan suggests, “Eat food. Not too much. Mostly plants.” By “eat food,”Pollan advises eating food that hasn’t been processed.  I would add: whenever you can, eat food that is grown locally and make it colorful.  This maximizes your chances of getting adequate nutrition.

Here are resources to help you choose a nutrition plan to suit you:

• Harvard School of Public Health www.hsph.harvard.edu/
nutritionsource/index.html

• Oldways www.oldwayspt.org/
med_pyramid.html

• United States Department of Agriculture (USDA) www.mypyramid.gov

How much to eat is tailored to each person.  Our age, size and activity level influence the amount of food we should consume.  Use a food plan as a guideline.  Never use restaurant portions as an authority on how much to eat or you will supersize yourself into a triple by-pass.  For me, how much to eat is a simple equation.  As long as I am maintaining my weight, I am in the correct range.  If I gain weight it is because I am eating too much.  If I lose weight it is because I have leukemia or a tape worm because it certainly won’t be because I ate too little.

How much we eat is as important as what we eat.  For instance, most of us like ice cream.  There is nothing wrong with an occasional indulgence.  However, few realize that a serving of ice cream is about the size of ½ of a baseball.  A serving of meat is the size of a deck of cards.  Eat a pound of steak and you consume more than 5 servings.

Here are some resources to help you gauge your nutritional needs:

• Aim for a Healthy Weight www.nhlbi.nih.gov/health/public/heart
/obesity/lose_wt/index.htm

This website is sponsored by the National Heart Lung and Blood Institute and has excellent tools.

• USDA’s nutrition information www.nutrition.gov

www.caloriecontrol.org  This website is free of advertising and has useful tools. Don’t be fooled by the “.org” – this is funded by the diet food industry. 

www.caloriesperhour.com  – Another commercial website that provides useful tools.

Knowing what is in food is not always straight-forward.  It is easy when the food comes from the produce section or the bulk bins at the organic grocery store.  When it comes in a container, then there is a food label.  Next month’s column will be devoted to reading labels.  For now, the key point is to pay attention to portion size.  Read the label for how many servings are in a container. For instance, those tiny cartons of ice cream look as if they are the perfect size for one person.  Unfortunately, they usually hold 4 to 6 servings.

Putting this knowledge into use is like any new skill.  It gets easier with practice.  Once I knew what I needed and how to maintain a healthy diet, it became routine.  The challenges are the psychological and social aspects of eating.  Although we eat to live, we also eat to celebrate, to mourn, for comfort and for pleasure.  Sometimes this can get out of hand, especially during holidays. 

When I get off track, I try to get back on as soon as possible.  A long time ago, I gave up food-related guilt and remorse.  This helps me settle back into my routine more quickly. Guilt and remorse made the situation worse.

There are some who try and no matter how hard, they cannot consistently master a plan of healthy eating.  If this is true for you, there is help.  Talk to your medical provider. Check out resources such as Overeaters Anonymous or Food Addicts Anonymous.  There are also for-profit programs that may be right for you.

This is easier said than done. For years, I weighed more than I wanted. I tried to lose weight and keep it off, but it was not until I underwent HCV treatment that I was able to drop to a more comfortable range.  The reason I didn’t regain the weight was because of HCV patients.  I had seen them lose weight during treatment and then regain it back. I vowed to keep it off – to live the words I speak.

Having HCV bestows an opportunity to eat responsibly.  It’s an excuse to put down the fork and pick up the walking shoes.  It’s a reason to celebrate life by not overeating rather than over-indulging.  This Thanksgiving, may you be blessed with health and a full heart without a bulging belly.


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Election Day is Tuesday November 4. Vote for your health and the health of the United States.



Hepatitis C Treatment after Liver Transplantation
—Liz Highleyman

Over years or decades, chronic hepatitis C virus (HCV) infection can progress to severe liver disease requiring liver transplantation, including decompensated cirrhosis and hepatocellular carcinoma (HCC).

Unfortunately, HCV almost always recurs soon after a transplant, potentially causing rapid disease progression and failure of the new liver.  Although progression is variable and unpredictable, studies suggest that as many as one-third of HCV-infected liver transplant recipients develop cirrhosis within five years, and that they progress to decompensated disease four times faster than non-transplanted hepatitis C patients.  Recurrent HCV is a leading cause of graft failure, retransplantation, and death in liver transplant recipients, and patients with hepatitis C generally fare worse than individuals transplanted for other reasons. 

As such, researchers have explored various management strategies for liver transplant recipients with HCV, including interferon-based therapy and modification of immuno-suppressive regimens to prevent organ rejection.  Antiviral therapy can be challenging for such patients, since many have difficulty tolerating interferon/ribavirin side effects, but this group has the most pressing need for effective treatment and therefore stands to gain the most benefit.

When to Start Therapy?
The optimal time to start interferon-based antiviral therapy in patients undergoing liver transplantation remains unclear.  Options include pre-transplant therapy aimed at achieving a sustained virological response (SVR) or “cure,” preemptive therapy started soon after the transplantation to prevent HCV recurrence and damage to the new liver, and post-transplant therapy after recurrent liver disease progression has been determined.

In theory, it would seem best to eradicate HCV prior to transplantation in order to protect the new liver.  But in practice, many patients with advanced liver disease cannot tolerate interferon-based therapy.  Hepatitis C patients with cirrhosis have significantly lower sustained response rates than those with less advanced disease, in part due to frequent dose reductions or discontinuation of therapy.  Due to the high risk of serious adverse events, antiviral therapy is generally contraindicated for individuals with decompensated cirrhosis, though it may be undertaken with careful monitoring, such as in a clinical trial.

Individuals who achieve SVR while awaiting a liver transplant appear to have a significantly lower risk of post-transplant HCV recurrence, and severity may be reduced if recurrence does occur.  In a 2005 study of patients with advanced cirrhosis treated with low accelerating doses of antiviral therapy, 13% of hard-to-treat genotype 1 patients and 50% with other genotypes achieved SVR.  Among 15 participants with undetectable viral load before transplantation, 12 remained HCV RNA negative six months thereafter.  Other studies, however, have found that a significant proportion of patients with undetectable HCV at the time of transplantation nevertheless experience recurrence. 

Treatment after Transplant
If pre-transplant therapy is not attempted or does not produce sustained response, post-transplant treatment is the next line of attack.  Unlike as with hepatitis B, prophylactic therapy using antiviral drugs and/or immune globulins (injected antibodies) around the time of transplantation does not prevent recurrence. 

Researchers have studied preemptive interferon-based therapy within 2-6 weeks after transplantation, with the rationale that treatment may be more successful if started while HCV RNA levels are still low and damage to the new liver has not yet occurred.  However, results have been disappointing, since transplant recipients at this stage have difficulty tolerating antiviral side effects, are at greatest risk for organ rejection, and are often receiving high doses of immunosuppressive drugs to prevent it. 

Many immediate post-transplant patients have blood cell deficiencies, kidney dysfunction, and susceptibility to infection that may be exacerbated by interferon and/or ribavirin.  As such, dose reduction and treatment discontinuation are common, leading to low sustained response rates.  A 2007 review of randomized trials of preemptive therapy using conventional or pegylated interferon (Pegasys or PegIntron) plus ribavirin, for example, found SVR rates ranging from about 10% to about 30%.

The risk of HCV recurrence after transplantation, as well as its severity, increases with the use of immunosuppressive steroids.  To address this issue, researchers have explored alternative immunosuppressive agents such as mycophenolate mofetil, monoclonal antibodies (e.g., daclizumab), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), and thymoglobulin.  So far, however, an optimal regimen for transplant recipients with hepatitis C has not been established.

Watch and Wait
Since preemptive therapy does not appear to significantly reduce the risk of complications or improve survival – although the minority of patients who achieve SVR do seem to benefit – most experts recommend waiting until liver disease progression sets in.  An advantage of this approach is that some transplant recipients will never experience serious recurrent liver damage, and “watchful waiting” allows them to avoid unnecessary treatment.  In addition, patients generally become more clinically stable longer after transplantation, although HCV viral load is usually higher.  It is generally advised that transplant recipients should receive annual biopsies to check for disease progression. 

Pegylated interferon plus ribavirin is more effective in post-transplant patients than conventional interferon or interferon monotherapy, but sustained response rates are lower than those of immunocompetent non-transplant patients.  While most studies find overall SVR rates of approximately 50% for genotype 1 and 70%-80% for genotypes 2 or 3, for transplant recipients these rates are closer to 20% and 50%, respectively.

As reported in the August 2008 Journal of Hepatology, M.  Berenguer and colleagues conducted a systematic review of published studies of pegylated interferon plus ribavirin in patients with recurrent HCV-related liver disease after transplantation (preemptive therapy was not included).  They identified 19 studies published between 2004 and 2007, including a total of 611 patients (86% with genotype 1), primarily from Europe and the United States. 

Participants started combination antiviral therapy an average of two years after transplantation, at which point most had mild to moderate liver disease.  The mean SVR rate was 30% (range 0%-50%), rising to 60%-75% for patients with genotypes other than 1.  Just over half (55%) achieved biochemical response, and biopsies generally showed improvement – or at least lack of progression – in histological activity.

About three-quarters of participants required interferon or ribavirin dose reduction, and about 25% discontinued therapy due to side effects.  As with non-transplant patients, low pre-treatment viral load, good adherence, and early response at week 12 predicted sustained response.  In their discussion, the investigators suggested that improvement in monitoring and managing side effects – for example, using growth factors to prevent and treat blood cell deficiencies – would be “useful in optimizing treatment outcomes.”

In a recent study published in the August 2008 European Journal of Gastroenterology & Hepatology, B.  Raziorrouh and colleagues retrospectively assessed antiviral therapy using conventional or pegylated interferon plus ribavirin for 48 weeks in 36 liver transplant recipients with HCV recurrence (27 with genotype 1; 9 with genotypes 2 or 3).  Here, the SVR rate for genotype 1 patients was similar to that observed in other studies (26%), but 100% of genotype 2 or 3 achieved sustained response. 

Another recent study, by A.  Kornberg and colleagues, looked at outcomes of long-term combination antiviral therapy in 30 liver transplant recipients with recurrent hepatitis C; results were reported in the August 15, 2008 issue of Transplantation.  After an average treatment duration of 46 months, biopsies demonstrated that while two-thirds of non-responders experienced fibrosis progression, this did not occur in any patients who achieved sustained HCV clearance.  “Our data indicate that an antiviral combination should aim at viral eradication in liver transplant patients with recurrent hepatitis C, because it improves survival,” the researchers concluded.  Kornberg’s team previously demonstrated that long-term interferon/ribavirin maintenance therapy in non-responder transplant recipients led to reduced liver inflammation and stable fibrosis despite persistent HCV viremia.

Hope for the Future
While SVR rates remain lower for transplant recipients than for non-transplant patients, it is clear that a significant proportion can and do benefit from existing combination therapy.  In the future, directly targeted antiviral agents now in the pipeline (such as HCV protease and polymerase inhibitors) offer the prospect of more effective treatment with fewer side effects.

Selected References

Arjal, R., et al. The treatment of hepatitis C virus recurrence after liver transplantation Alimentary Pharmacology & Therapeutics 26(2): 127-144. July 2007.

Berenguer, M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. Journal of Hepatology 49(2): 274-287. August 2008.

Everson, G.T., et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 42(2): 255-262. August 2005.

Kornberg, A., et al. Antiviral maintenance treatment with interferon and ribavirin for recurrent hepatitis C after liver transplantation: Pilot study. Journal of Gastroenterology and Hepatology 22(12): 2135-2142. December 2007.

Kornberg, A., et al. Transplantation. Sustained clearance of serum hepatitis C virus-RNA independently predicts long-term survival in liver transplant patients with recurrent hepatitis C. Transplantation 86(3): 469-473. August 15, 2008.

Raziorrouh, B., et al. Antiviral therapy for recurrent hepatitis C after liver transplantation: sustained virologic response is related to genotype 2/3 and response at week 12. Eur. J. Gastroenterol. & Hepatol. 20(8): 778-783. August 2008.

Teixera, R., et al. Therapeutic management of recurrent hepatitis C after liver transplantation. Liver International 27(3): 302-312. April 2007.


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Understanding Abstracts
—Alan Franciscus, Editor-in-Chief

This month the HCV Advocate Web site will provide conference coverage from one of the largest and most important conferences on liver disease.  The article below will hopefully be helpful in understanding some of the information presented.  The most important thing to remember is that the posters and abstracts are just snapshots of a study, and that the best information will come from an article published in a prestigious peer-reviewed publication.

Reading – and understanding – an abstract can be very challenging because there are so many pieces of the puzzle to fit together.  This article will focus on tips for reading and understanding an abstract.

General Tips for Reading and Understanding an Abstract:
An abstract is usually divided into seven sections.  Start by reading the entire abstract quickly – highlight or note any important facts that are key points, such as the number of participants, overall effectiveness, etc.  After a quick review go back and read it slowly and carefully.  A natural inclination is to just read the conclusion section, but remember that a conclusion, at times, can be what the author wanted to prove and not necessarily the real facts. 

The abstract below is from the Association for the Study of Liver Diseases (AASLD) Conference 2007.  This particular abstract is about HCV-796 – a drug that is no longer in clinical development due to severe side effects.

1) Title:
A very brief (one brief sentence) description of the study – this will give you an idea of what the study authors are trying to test or prove.

Example: 

Phase 1 evaluation of antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in combination with different pegylated interferons in treatment-naïve  patients with chronic HCV.

2) Authors:
All the authors will be listed and sometimes the affiliations of the authors will also be listed.  Look for reputable authors and medical institutions.  The author and affiliation carry a lot of weight.

Example:

S. Villano; D. Raible; D. Harper; P. Chandra; L. Bazisotto; G. Bichier.

3) Introduction or background:
A brief history of what is known about the topic under study and why the study is important.

Example:

Background:
HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated clinical antiviral activity across multiple HCV genotypes when administered as monotherapy or in combination with pegylated interferon alfa-2b (PEG2b).  We further evaluated HCV-796 when administered with pegylated interferon alfa-2a (PEG2a).

4) Aim:
This is one of the most important sections because it spells out the original intent or design of the study.  The aim should include definite end points that are carefully planned and executed.  Look for prospective studies that are designed in advance with certain clinical outcomes.

• Retrospective studies are studies that look back over time at a previous study or population.  They are important for compiling information for future studies, but they can also be manipulated and do not carry as much weight in evidence based medicine as prospective studies.

As you have probably noticed some abstracts are formatted differently than others.  In the example I have listed the ‘aim’ is included in the background information.   

5) Patients/Methods:
This section will give you information on patient characteristics, drug dosing and other valuable information.

Important questions to ask yourself when reviewing this section:

a. How many patients were enrolled in the study?
Larger studies carry more weight.

b. Outcomes vary widely depending on many factors.  What were the patient characteristics?
Were they evenly matched by age, gender, race, genotype, viral load, degree of liver damage, biochemical markers and other important patient information?

c. Was the clinical trial randomized and blinded to prevent bias?
The gold standard of clinical research on humans is the blinded, randomized control trial.  In this type of trial, patients are randomly selected.  Randomization means that patients are randomly assigned – usually by a computer program – to a particular study group to receive the test drug, a standard of care drug or a placebo.

d. How did the researchers test their hypothesis and what tools did they use?
Are they using sensitive diagnostic tools?

e. Was the study designed to compare one drug against another drug, or against the current standard of care?
Was the dose of medication appropriate in both groups?

Example:

Methods:
Evaluations were performed within a randomized, double-blind, Phase 1 study in adult patients with chronic HCV infection who were naïve to treatment.  In one group, patients were randomized to receive oral HCV-796 or placebo Q12h for 14 days, and all were to receive PEG2b (1.5 mcg/kg) on day -1 (one day before start of HCV-796/placebo) and day 7. In another group, the design was the same except the PEG therapy was PEG2a (180 mcg) on day -1 and day 7.  In each group 12-16 patients were to receive the active HCV-796 (500 mg Q12h) with one of the PEG therapies.

6) Results:
This section reports on the outcome of the study.  It should break the information down by overall results and then by patient characteristics and medication dose.  The results should also report the statistical significance, which is an indicator of how well the drug will work under the same circumstances in a different setting.  This is usually reported as a p-value.  P-value of < 0.05 is considered statistically significant. P=0.05 means that there is a 95% chance the drug will work in a similar patient population and a 5% chance that it will not.

If the abstract is testing a new medication, there should also be a brief overview of the side effects. 

In this example you will note that the authors reported that the side effects of HCV-796 were typical of the side effects reports for Peginterferon therapy.  However, we now know that early studies with small patient populations provide limited information and that studies conducted over a longer period of time with large patient populations give us the best information.  

Example:

Results:
The mean baseline HCV RNA level was 6.4-6.5 log10 in each group and 71% of patients were infected with HCV genotype 1.  For both PEG therapies, combination with HCV-796 reduced plasma HCV RNA levels to a greater extent than either PEG alone.  At day 14, the mean reduction in HCV RNA for HCV-796+PEG2b was 3.4 log10 vs. 1.6 log10 for PEG2b alone.  The mean reduction for HCV-796+PEG2a was 3.7 log10 vs. 1.1 log10 for PEG2a alone.  For both groups, activity differed by HCV genotype.  Mean HCV RNA reductions at day 14 for genotype 1 was 2.9 log10 for HCV-796+PEG2b and 3.2 log10 for HCV-796+PEG2a.  For genotype non-1 the respective reductions were 4.4 vs. 4.7 log10.  Combination of HCV-796 with either PEG therapy was generally well-tolerated. Common adverse events in all groups were those typically associated with interferons, including headache, chills, and myalgia.

7) Conclusion:
Be careful because the conclusion can be greatly manipulated to fit the author’s needs.  Refer back to the results and compare the results with the author’s conclusions.

The example we used is very straight forward and appropriate for the intent of the study.  Always be careful, though, reading the conclusion – it is always better to understand the information in an abstract and come to your own interpretation and conclusion. 

Example:

Conclusions:
The combination of HCV-796 with either PEG2b or PEG2a provides similar antiviral activity across multiple HCV genotypes over 14 days of therapy.  Results support clinical studies of more long-term administration of HCV-796 with either PEG therapy.

The more you practice reading an abstract the more you will be able to understand the information presented.  Always use your critical mind when trying to interpret scientific data or any other source of information.  And don’t be afraid to ask questions!

Recommended links:



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HCV Snapshots
—Alan Franciscus, Editor-in-Chief

In this month’s column I will discuss a study on revaccination of prior HBV vaccine non-responders, two studies on disease progression in people with hepatitis C and persistently normal ALT levels, and a retrospective study on the increased risk of complications for people with hepatitis C who take Tylenol.

HBV Vaccine Non-Responders
It is estimated that approximately 5 to 10% of people who receive the hepatitis B vaccine do not respond or develop protective antibodies.  Non-response to standard doses of HBV vaccination is even higher in people with a compromised immune system, such as people living with HIV.  Clearly other dosing strategies are needed to protect individuals at risk for becoming infected with hepatitis B.  In a study that was published  in the Journal of Infectious Diseases, researchers Kristina Cardell and colleagues in Sweden, treated 68 individuals (48 vaccine non-responders, 20 previously unvaccinated) with a double dose of Twinrix (combination HAV/HBV vaccine).  The study found that of the 44 vaccine non-responders, 26 (59%) developed protective HBV antibody titers after the first dose and 42 (95%) developed protective titers after the third dose.  In the 20 people who were previously unvaccinated, 10% developed protective HBV antibody titers after the first dose and 100% after the third dose.  All participants also developed protective HAV antibody titers. 

The authors concluded that the increased response rate was the result of the higher doses of the vaccine, and proposed that “a double dose of combined hepatitis A and B vaccine can be safely and effectively used to induce protective levels of anti-HBs in nonresponders to traditional hepatitis B vaccine among those nonimmune to hepatitis A.”

HCV Patients with NormalALTs
Two new studies are helping to fine-tune our understanding of the meaning of HCV patients with persistently normal ALT levels, although the studies did not necessarily reach the same conclusions.  In the past, it was believed that people with persistently normal ALT levels had little or no HCV disease progression.  However, this has been challenged in the last 5 years because some studies have found that a subset of patients with normal ALT levels do, in fact, have disease progression that could lead to cirrhosis.  

A study was recently published in the World Journal of Gastroenterology by Sobesky and colleagues who found that of 76 untreated HCV patients with persistently normal ALT levels the majority (66%) had little or no disease progression after 4 years.  Of those who developed fibrosis progression, subsequent elevated ALT levels and being overweight (BMI >25) were both factors involved in fibrosis progression.   The authors recommended that these patients should be offered HCV antiviral therapy and counseled about weight reduction and diabetes.

In the other study published in Liver International, Faisal and colleagues compared HCV disease progression of 65 patients (group A) with normal ALT levels to a group of 66 patients (group B) with elevated ALTs.  The two groups were well matched by age, sex and degree of baseline liver fibrosis.   The study period was from June 2001 to June 2006. 

The authors found that the degree of inflammation did not significantly differ between the two groups (group A=2.0±0.68 vs. group B=2.09±0.67), and mean fibrosis scores (group A=2.11±0.87 vs. group B=2.24±1.04).  In addition bridging fibrosis was seen in 24.6% (group A) compared to 37.9% (group B) and cirrhosis was seen in 6.2 (group A) compared to 7.6% (group B).  Steatosis or fatty liver was also evaluated and it was found that both groups had similar rates 0.94±0.86 (group A) compared to 1.0±1.02 (group B) although the degree of inflammation and fibrosis was not related to the level of steatosis.    The only factor that predicted normal ALT levels was increasing age.  The authors of this study concluded that “This study demonstrates that ALT is a poor surrogate marker for inflammation and fibrosis in HCV patients.”  The authors suggested that these findings would justify HCV treatment without a need for liver biopsy.

So why did the study authors find different outcomes and conclusions in these studies?  Part of the answer is that both studies included a small patient population over a short time period.  Hopefully, the study authors will follow the patients over a longer period of time.  However, one conclusion is that it is clear that most people will have little or no disease progression.  A better approach would be to monitor people more carefully with normal ALT levels and offer everyone with HCV the opportunity to receive HCV treatment to prevent the possibility of liver damage. 

HCV and Tylenol
A study of patients with HCV who take acetaminophen (brand name Tylenol) suggests that people with HCV who take Tylenol may be at higher risk for liver injury.  In this country it is estimated that there are approximately 112,000 calls to Poison Control Centers, 56,000 emergency room visits, 26,000 hospitalizations and 450 deaths from an overdose of Tylenol every year, which account for 50% of all cases of acute liver failure.  Mixing alcohol and Tylenol is a well known factor for increasing the risk of complications.  In addition alcoholics and people with chronic liver disease are at increased risk for developing complications when taking Tylenol.  But the risk for people with hepatitis C has not been previously studied until now.  

Nguyen and colleagues released a study in Hepatology recently that will hopefully help us understand this issue better.  In their retrospective analysis, the authors analyzed hospital data between 1998 and 2005 and estimated that there were 210,436 hospitalizations due to acetaminophen overdoses.   The prevalence of HCV in this population increased from 0.5% in 1998 to 1.5% in 2005.  The rate of acute liver injury was 7.2%.  After excluding for cirrhosis, the risk for acute liver injury increased with HCV, nonalcoholic fatty liver disease, alcoholic liver disease, and malnutrition.  The authors concluded that HCV was associated with a greater risk of progression to severe liver failure.  However, the authors pointed out that these study results need to be confirmed with prospective studies before any concrete recommendations can be made.  This study sheds light on the potential of liver injury for someone with hepatitis C especially if Tylenol is mixed with alcohol, having decompensated cirrhosis, and/or fatty liver.  It is also important to remember that Tylenol is in over 600 products including prescribed and over-the-counter medications.  At any rate, talk with your medical provider about taking Tylenol and what are safe doses to take.


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Organ and Tissue Donor Registry: New England

   History tells us that the Pilgrims would not have survived without the help of the native people who already lived in what is now known as New England.  This kindness grew into our annual tradition – Thanksgiving.  Now we have the opportunity to modernize this tradition by declaring our intention to become organ and tissue donors in the event of our death.

   Only one of the six New England states maintains its own organ and tissue registry – Connecticut.  Although Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont do not have registries, residents of those states may still designate their wishes to be donors.  Simply indicate your wishes when you apply for or renew your driver’s license or official identification card.  It is always a good idea to notify your family of your wishes.  What better way to celebrate Thanksgiving! http://donatelife.net


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HCV:  Replication and Damage
—Alan Franciscus, Editor-in-Chief

Viruses are extraordinary organisms!  They have one purpose in life – survival!  Viruses use many different modes to infect and replicate in humans.  For instance, the hepatitis A virus spreads by the fecal-oral route, but the infection itself is limited to cells in the digestive tract and the replication process takes place in the liver.  Hepatitis B is spread by blood and bodily fluids, and mainly infects liver cells.  Hepatitis C virus (HCV) transmission is similar to hepatitis B transmission, but transmission is mainly confined to the blood-to-blood route.  The hepatitis C virus mainly infects the liver. 

The hepatitis C virus is a single stranded RNA virus of the Flaviviridae family of viruses.  Other diseases in the Flaviviridae family include yellow fever, West Nile virus, and dengue fever.  The exact mechanism of how the hepatitis C virus replicates has been largely a mystery because scientists have not been able to replicate the virus in a test tube.  However, with the development of a culture to grow the hepatitis C virus in healthy liver cells (HCV Advocate, August 2008) we will hopefully learn a lot more about the replication process in the very near future.  Until the exact process is nailed down, we know that all RNA viruses share certain replication processes that will help us to understand the ‘big picture’ of HCV replication, and, coupled with what we do know about the HCV replication process, we can make educated guesses to fill in the blanks.    
 
HCV Replication
The hepatitis C virus mainly infects hepatocytes or liver cells.  The liver is an excellent source for viral replication because it is a very large organ with over 200 billion liver cells that HCV can use to replicate.  It has been estimated that the hepatitis C virus can infect 50% or more of the cells in a single liver with a daily replication rate of up to 10 trillion new hepatitis C viruses.   

The hepatitis C virus uses blood to transport itself to the liver where it will begin the replication process.  The hepatitis C virus is an enveloped single-stranded virus that attaches itself to a liver cell – then inserts its genetic code into the cell.  During this process the virus is able to ‘shut down’ the normal cell processes and set up a sort of ‘viral factory’ that will make new hepatitis C viruses.  Once the new virions are made they burst out of the cell and make their way to another healthy liver cell to start the replication cycle all over again.  

HCV Quasispecies
The hepatitis C virus is a high error prone virus – that means that when it replicates it is constantly mutating and slightly altering its genetic code.  The natural mutation process allows the virus to escape the body’s natural immune system response (antibodies) that is mounted to kill off the virus.  The process of viral mutation produces quasispecies.  This constant mutation process is the reason why it has been difficult to develop a protective vaccine, and it is also one of the reasons why the majority of people initially infected with HCV will develop chronic infection.  It has also been theorized that HCV quasispecies development may be the reason why some people respond to HCV medications and other don’t and why some people progress on to serious liver disease more quickly while others remain relatively healthy.  

Everyone who has been infected with hepatitis C will test positive for HCV antibodies.  It is important to remember that HCV antibodies are made by the immune system, but unlike other types of antibodies like hepatitis A antibodies, HCV antibodies will not protect someone from becoming re-infected.  Also of note antibodies will always be present even if someone naturally clears the hepatitis C virus out of their body or if someone is able to eliminate HCV through treatment with HCV medications. 

Liver Cell Damage
One of the most interesting aspects of hepatitis C infection is that the virus does not directly cause liver damage. It is believed that the actual damage or death of the liver cell is caused by the immune system trying to kill the virus that has invaded the cell.  But instead of just killing the virus, the immune system attacks and kills the entire liver cell.  The process of cell death can lead to general inflammation of the liver that will eventually result in a form of light scarring of the liver (fibrosis).  After many years of the immune system constantly attacking and killing HCV-infected liver cells, the fibrotic tissue within the liver begins to connect with other fibrotic tissue and after many years lead to extensive scarring of the liver (cirrhosis).  If the process continues, the damage can be so extensive that it will change the overall architecture of the liver.  By this time the liver is so damaged that it can not perform the many functions that keep us healthy, and this could lead to possible death unless a person is able to receive a new liver.


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