Q. I know there is no clear time line with the progression of hep C, but in general, what damage would you expect to see in someone who has had the virus for 20 years (and who was unaware of the fact and hence drinking alcohol during that time). I have not had a biopsy but have been successful with treatment (nearly a year now!) but I'm still anxious about the state of my liver

A. The chance of someone developing cirrhosis within 20 years of infection is quite low (less than 20%). Your doctor should be able to look at your blood tests and give you a good idea of whether or not you have advanced cirrhosis. If you have now cleared the virus there is a very good chance that your liver will recover so I would not be unduly worried.

SPEED OF PROGRESSION OF HCV
Q. I developed cirrhosis 18 years after my exposure to HCV. In your experience is there any difference in the speed with which HCV develops or the severity of damage it causes to the liver between the different methods of infection?

A. It is clear that some people are 'fast fibrosers' and others are 'slow fibrosers' and, sadly, you seem to be one of the fast group. We believe that the mode of infection doesn't affect the rate of fibrosis, although this is still a little controversial

SVR – 5 Years Later
Alan Franciscus, Editor-in-Chief

April 09

Does the health of the liver improve after someone achieves a sustained virological response? That’s what researchers Sarah L. George and colleagues set out to answer with a long-term study of patients who achieved an SVR.

A total of 150 patients who had achieved a sustained virological response (SVR = HCV RNA (viral load) undetectable 24 weeks post-treatment) and who were originally biopsied and scored with fibrosis stage 2 or higher (Ishak system – with 0 being no fibrosis and 6 being cirrhosis) were enrolled in the study between June 1997 and April 2002. The average age at time of study enrollment was 49 years old; 49% were female, 98% were Caucasian and the genotype distribution was similar to the genotype distribution generally seen in the United States. Almost all of the patients (87%) were treated with standard interferon (3 shots a week) plus ribavirin daily. Ninety-eight patients (65%) were treated for one year and the other 35% were treated for 6 months. Out of the original 150 patients enrolled, 128 patients (85%) were followed through their fourth year and 108 patients (72%) were followed for five or more years after achieving an SVR.

Pretreatment and long-term follow-up biopsies were performed in 49 patients and blindly scored – that is the person evaluating the biopsy did not have patient information or knowledge of the previous biopsy score.

Of the patients biopsied, 40 patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in the combined inflammation score. Ten patients (20%) who had follow-up biopsy had near or nearly normal livers.

Two patients with pre-treatment cirrhosis developed hepatocellular carcinoma (HCC-liver cancer) and one patient died. However, all of the other patients with pre-treatment cirrhosis or advanced fibrosis had improved fibrosis scores on their long-term follow-up biopsy.

This was the longest and largest study of its kind and the results are very encouraging. But, the bad news is that one of those patients with pre-treatment cirrhosis died even after achieving an SVR. These results confirm previous findings that have had similar outcomes. The two important messages from this study are:

The vast majority of people who achieve an SVR have improved inflammation and fibrosis scores. But larger and longer studies are needed to confirm these findings.
People with pre-treatment cirrhosis should be closely monitored even when an SVR is achieved because there is a risk that a small minority of patients will continue to have severe disease progression leading to death.

Reference
George, S. et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: A 5-year follow-up of 150 patients. Hepatology. Volume 49 Issue 3

http://www.hcvadvocate.org/news/newsLetter/2009/advocate0409.html#3

STAGES OF DISEASE PROGRESSION

Perspective on the Progression of Hepatitis C

April 07, 2009

DETERMINING DISEASE PROGRESS WITH LIVER BIOPSY

SVR and Disease Progression

IDEAL Trial Results

Treatment of Hepatitis C in Patients with Advanced Fibrosis or Cirrhosis

Natural History of Hepatitis C in Patients with Severe Liver Fibrosis

Natural History of Liver Cirrhosis Due to Hepatitis C

HCV: Progression, Pathology

Stages of Disease Progression

STAGES OF DISEASE PROGRESSION

Like other liver diseases, HCV disease progresses in stages. The usual progression is from inflammation to fibrosis to cirrhosis. Cirrhosis can progress to end-stage liver disease and/or can give rise to liver cancer. Normally, when the liver is damaged, liver cells die but the organ regenerates itself without scarring. This is not the case with Hepatitis C. Treatment with interferon-based therapy, is detrimental before cirrhosis begins.

Studies suggest their is rapid fibrosis progression after having HCV for 20 years and very rapid progression beyond 30 years.

Stages in Fatty Liver Disease

Inflammation

Liver inflammation refers to the presence of special cells called inflammatory cells in the liver. Chronic inflammation is inflammation that persists over a long period of time. It leads to changes in liver structure, slowed blood circulation, and the death of liver cells (necrosis). Chronic inflammation eventually causes scar tissue to form, a condition known as fibrosis. By controlling liver inflammation, you can control progression to fibrosis.

Fibrosis

Fibrosis is the harmful outcome of chronic inflammation. Fibrosis is scar tissue that forms as a result of chronic inflammation and/or extensive liver cell death. Your health care provider uses the amount of fibrosis in your liver as one way of evaluating how quickly your disease appears to be progressing. Having knowledge of approximately when you were initially infected with HCV is a great help in determining your rate of disease progression.

FIBROSIS AND DISEASE PROGRESSION

The only way to determine the amount of fibrosis in your liver is to have a liver biopsy. No other available test is able to give you and your health care providers this important piece of information.

Cirrhosis

When fibrosis becomes widespread and has progressed to the point where the internal structure of the liver has become abnormal, fibrosis has progressed to cirrhosis. Cirrhosis is the result of long term liver damage caused by chronic inflammation and liver cell death. The causes of cirrhosis include viral hepatitis, excessive intake of alcohol, inherited diseases, and hemochromatosis (abnormal handling of iron by the body).

Cirrhosis is accompanied by a reduction in blood supply to the liver. The loss of healthy liver tissue and the reduced blood supply can lead to abnormalities in liver function. Even when liver disease has progressed to cirrhosis, it may still be possible for the damage to be at least partially reversed if the underlying cause can be eliminated. Cirrhosis progression can usually be slowed or even stopped with treatment.

The onset of cirrhosis is usually silent, with few specific symptoms to identify this development in the liver. As scarring (fibrosis) and destruction continue, some of the following signs and symptoms may occur: loss of appetite, nausea and/or vomiting, weight loss, change in liver size, gallstones, itching, and jaundice. However, a large number of people live many, many years with cirrhosis without any decompensation or symptoms.

It is important to know that once cirrhosis develops, it is critical to avoid further progression of the disease. The consumption of alcohol in any form, including such things as certain mouthwashes and cough medicines, must be completely avoided by people with cirrhosis.

If you just were diagnosed with HCV and have cirrhosis, treatment may eradicate the virus. If you have been putting of treating, this may be a time to reevaluate your treatment goals. If you have not had interferon-based therapy, you may want to consider it or other available treatments that aim to eradicate the virus. It may also be time to look into other means of improving the health of your liver.

Liver Cancer

Though most people with HCV never develop liver cancer, it is a risk associated with chronic hepatitis C. The presence of cirrhosis and/or having been infected with HCV for more than 20 years further increase the risk. For this reason, frequent liver cancer screening is advisable for people who have cirrhosis.

Liver cancer is life-threatening, so it is important to know the warning signs. Do not delay telling your health care provider about any changes in your symptoms. Symptom changes may indicate a change in your liver histology.

There are effective therapies for liver cancer if it is detected early. If you have developed cirrhosis from HCV, you need to be closely followed by a health care provider who can monitor you with the appropriate liver cancer screening tests.
http://www.hepcchallenge.org/

Genetic Variation May Double Risk of Liver Cancer

Incidence and Predictors of Hepatocellular Carcinoma in Patients With Cirrhosis

Progression and stages of hepatitis C

Progression of Hepatitis C
Stages of Hepatitis C

Progression of hepatitis C

The natural history of hepatitis C looks at the likely outcomes for people infected with the virus if there is no medical intervention. However, the process of trying to predict how hepatitis C will affect the body over time and get a picture of the likely disease progression is complicated by a number of factors:

The laboratory test to identify the virus was only developed in 1989 so this is a relatively short time in which to study a disease. Although a great deal has been learnt about what can take place during the first 20 years of infection with hepatitis C, the prognosis from the third decade on remains largely uncharted.

In order to get a picture of likely progression over time it is necessary to know when people were infected. This is problematic as many people with HCV do not know when or how they were infected.

One of the main conundrums about HCV infection is that people have such different outcomes and experiences. While some people clear the virus in the very early stages, most will develop a long term or chronic infection. The course of the disease then is very variable. One person may have no liver damage after twenty years while another person will develop cirrhosis and sometimes liver failure or liver cancer.

The range and degree of symptoms also varies significantly. Many people remain asymptomatic (without symptoms) for years, while others will experience fatigue, depression, digestive problems and other symptoms among the many varied extra-hepatic (outside of the liver) complications of hepatitis C infection. Confusingly the symptoms people suffer are not necessarily an indication of whether they have liver damage or not. One person may have almost no liver damage and yet their quality of life is severely affected by symptoms, while somebody with extensive scarring of the liver may be symptom free. Existing blood tests for example viral load, liver enzyme levels, or HCV genotype also cannot reliably forecast the outcome of untreated HCV infection.

Despite these variations and difficulties an increasing amount has been learnt about how the disease does generally progress.

Stages of hepatitis C

Hepatitis C is considered to have four stages:

The Acute Stage

The Chronic Stage

Compensated Cirrhosis

Decompensated Cirrhosis

Overview of the Stages

The period immediately after infection is called the acute phase. This lasts about six months. If the immune system does not manage to clear the virus by then the disease is considered to have moved into a long-term or chronic phase.

Hepatitis C is classified as a liver disease because of the damage it causes to the liver, however the virus affects other body systems and causes symptoms, illnesses and complications outside of the liver.

Doctors have previously tended to focus mainly on the state of your liver as opposed to symptoms you feel or other complications caused by the virus because they have often been seen as unconnected or unrelated. This has meant that they have been given less attention and been studied less.

The effects of Hepatitis C are described in terms of the changes to the liver as scarring develops. This progression moves from the initial inflammation of the liver caused by the virus hijacking, infecting and killing off liver cells through to the gradual scarring (fibrosis)and then hardening of liver tissue (cirrhosis). Throughout this progression the immune system plays a highly influential role both in stemming the disease but also in accelerating scarring of the liver.

Cirrhosis is severe scarring that alters the structure of the liver and over time will seriously undermine the livers ability to function. Cirrhosis is classified as being either compensated or de-compensated. If the liver can continue to carry out most of its functions despite extensive scarring then this is known as compensated cirrhosis (meaning that the liver can compensate for the damage) If the livers functions are seriously affected then this is called decompensated cirrhosis. The most serious symptoms of this stage are:

Portal Hypertension, (when blood cannot properly flow into the liver and causes bleeding from distended veins (varices) in the oepsphagus and the build up of abdominal fluid (acites)
and Hepatic Encephalopathy. If blood is forced to bypass the liver it is not filtered for poisons and toxins and there is risk of serious mental confusion leading to coma.

Cirrhosis also significantly increases the risk of developing liver cancer. This can develop from either compensated or decompensated cirrhosis.

Recent studies suggest that chronic infection with HCV will almost invariably result in cirrhosis. It is the time that this takes that varies. For those people who develop a chronic or long term infection (between 70-80% of those infected with HCV) around 20-30% will develop cirrhosis within 20 years. For some it may be quicker but for others it may take up to sixty years so they may well die of unrelated diseases beforehand.

http://www.hepctrust.org.uk/hepatitis-c/The+natural+progression+of+hepatitis+C.htm

Perspective on the Progression of Hepatitis C

Those with Hepatitis C likely know that their disease can get worse, but may want to know more about the average speed of liver disease progression.

by Nicole Cutler, L.Ac.

Upon receiving a Hepatitis C diagnosis, learning that the virus progressively damages the liver takes center stage. While there is no formula to compute the speed at which Hepatitis C advances in the body, understanding the stages of illness and whether alcohol is consumed can help someone assess where they lie in the scope of their illness.

Accounting for at least 25 percent of all cases of chronic liver disease, chronic Hepatitis C is a progressive condition. Although a significant portion of those infected have no symptoms, normal liver enzymes and normal liver histology, experts believe the virus still progresses – it just does so more slowly than in others. Because of this steady progression, slowing disease progression is a valid goal in chronic Hepatitis C management.

Once a liver is infected with the Hepatitis C virus, it becomes increasingly damaged. A basic progression of liver disease is described below:

· Inflammation – As the liver tries to fight infection, the liver becomes inflamed, tender and enlarged.

· Fibrosis – Known as fibrosis, an inflamed liver will eventually scar. As excess scar tissue grows, it replaces healthy liver tissue, causing a decrease in liver function.

· Cirrhosis – When the liver becomes so scarred that it can no longer heal itself, cirrhosis has occurred.

· Liver Cancer – With a liver struggling to perform its job of processing toxins, the ideal environment for cells to mutate into cancer exists.

· Liver Failure – Once the liver has completely lost its ability to function, the life-threatening condition of liver failure has arrived.

Chronic Hepatitis C progression is typically evaluated in one of three ways:

1. Retrospectively – A retrospective study identifies patients with established infection and correlates their current stage of liver disease to the duration of their infection. A problematic bias of retrospective studies is their inclination to select participants who have sought medical attention due to their symptoms. Because the actual duration of infection in these patients may be underestimated, disease progression approximates may be inaccurate.

2. Prospectively – A prospective study looks at an entire group of people with Hepatitis C from the time they first become infected. These studies typically involve those who received contaminated blood, since their time of viral acquisition can be accurately determined.

3. Retrospectively and Prospectively Combined – Retrospective/prospective studies identify a group of patients who were exposed to Hepatitis C in the past and then follow them prospectively. The advantage of these studies is that there is a head start to the follow-up as compared to a prospective study.

Although the statistics describing Hepatitis C progression are not necessarily straightforward, some generalized assumptions that have resulted from a combination of retrospective, prospective and retrospective/prospective studies include:

· After acquiring the Hepatitis C virus, it takes an average of between 10 to 14 years for biopsy evidence of chronic hepatitis to appear.

· After acquiring the Hepatitis C virus, it takes an average of about 20 years to develop cirrhosis.

· After acquiring the Hepatitis C virus, it takes an average of about 28 years to develop liver cancer.

· About 10 to 25 percent of people with chronic Hepatitis C develop cirrhosis within 10 to 15 years.

· While the overall rate of fibrosis progression in people with Hepatitis C is low, it is increased in those who are older or already have fibrosis as indicated on their index biopsy.

The combined results of dozens of studies confirm that the natural progression of the chronic Hepatitis C virus is slow and, in general, complications develop over decades, not years. Although a timeline for how Hepatitis C evolves covers a wide spectrum, scientists agree on three factors that favor rapid progression of the virus: 1.) alcohol use, 2.) co-infection with another hepatitis virus and 3.) duration of infection. While viral genotypes, co-infection with HIV and gender have been suspected of affecting Hepatitis C progression, these claims lack conclusive evidence.

Understanding how liver disease progresses from inflammation to liver failure confirms the importance of maintaining any healthy liver cells. Thankfully, this progression usually takes many years. If you’ve recently acquired Hepatitis C, this affords plenty of time to protect remaining liver cells. However, if you have been living with Hepatitis C for a long time, the only clear instruction is to completely abstain from alcohol, since it is the only definite route for accelerating Hepatitis C progression.

References:

Ryder, SD, MD, Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study, Gut, 2004.

www.brown.edu, Hepatitis C: Epidemiology, Brown University, 2008.

www.medicinenet.com, Hepatitis C, MedicineNet Inc., 2008.

www.medpagetoday.com, Mortality from Hepatitis C-Related Disease at Near-Record High, Michael Smith, MedPage Today LLC, March 2008.

Posted by Editors at April 7, 2009 10:07 AM

http://www.hepatitis-central.com/mt/archives/2009/04/perspective_on.html

DETERMINING DISEASE PROGRESS WITH LIVER BIOPSY

The most accurate way to check the severity of liver disease is with a biopsy. A liver biopsy is a test in which small pieces of liver tissue are removed so they can be examined under a microscope. The three main things that will be looked for are inflammation, fibrosis, and cirrhosis. The biopsy report may also reveal other histological and pathological findings such as the presence of lymphoid nodules, damage to small bile ducts, and/or the presence of fat

Click below for more help on understanding disease progress with biopsy

Scoring and Grading Liver Biopsies

The question of whether it is the virus or the person infected by the virus that determines how HCV disease will progress is an active area of research. At this point, we know of several personal factors and several viral factors that may influence the rate of HCV disease progression.

Personal factors related to disease progression include some variables you can control. The consumption of alcohol can markedly affect disease progression. The amount of fat in one's diet, and body weight can also influence disease progression and treatment outcomes.

In terms of viral characteristics, we know that the existence of multiple quasispecies can accelerate disease progression. We also know that HCV genotype is a factor in whether or not someone responds to therapy and is therefore able to arrest his or her disease progression.

Based on our current knowledge, it seems that both the person and the virus affect disease progression. Therefore, your environment, diet, exercise plan, lifestyle, and support system may all be important factors that could affect the course of your HCV infection.

Progression of chronic hepatitis C in any given person cannot be predicted. The majority of people will not progress to cirrhosis. However, the seriousness of this disease for people with advanced cirrhosis is beyond question. If you follow the progression of your disease with all the tests available to you, you will be in a better position to make informed decisions about your treatment options.

It is hoped that ongoing research will improve our ability to predict disease progression and intervene more effectively

SVR and Disease Progression (Sustained virological response = (SVR)

Alan Franciscus, Editor-in-Chief

In the January 2008 issue of the HCV Advocate there was a report on 2 large clinical trials that found that the long term use of low-dose pegylated interferon did little to change the clinical outcome of HCV disease progression. Another clinical study published in 2007, “Sustained Virologic Response and Clinical Outcome in Patients with Chronic Hepatitis C and Advanced Fibrosis,” provides hope that successful treatment may indeed prevent disease progression.

The study was a retrospective study conducted in 5 hepatology centers in Europe and Canada. The total number of participants was 479 of whom 131 patients (27%) received interferon monotherapy, 130 patients (27%) received interferon plus ribavirin, 10 patients (2.1%) received pegylated interferon monotherapy, and 208 patients (43%) received pegylated interferon plus ribavirin. In all, 142 patients (30%) achieved an SVR and 337 (70%) did not achieve an SVR. All patients had biopsy-proven advanced fibrosis or cirrhosis (Ishak 4 to 6).

The purpose of the study was to compare the incidence of outcome events in the SVR group vs. the non-SVR group. An outcome event was defined as liver failure, hepatocellular carcinoma (HCC-liver cancer), and/or liver transplantation.

The authors found that only 4 patients who achieved an SVR had 1 outcome event compared to 83 people in the non-SVR group – with a statistically significant difference between the two groups after 5 years. Death due to hepatitis C occurred in only 1 person in the SVR group compared to 16 people in the non-SVR group. Furthermore, 18 patients in the non-SVR group underwent liver transplantation compared to no patients in the SVR group. Forty-two people developed liver failure in the non-SVR group compared to no patient in the SVR group. HCC or liver cancer developed in 3 patients in the SVR group compared to 32 people in the non-SVR group.

The authors commented that “Our finding that therapy provides long-term clinical benefit for patients with a sustained virologic response may help to change attitudes toward screening persons who are at risk for hepatitis C infection.”

Another important piece of information from this study is that people who are able to achieve an SVR still need to be monitored for potential future complications even though the risk of complications is low.

Ann Intern Med 2007 Nov 20;147: 677

IDEAL Trial Results
Alan Franciscus, Editor-in-Chief

The IDEAL (Individualized Dosing Efficacy vs. Flat Dosing to Assess optimal pegylated interferon therapy) clinical trial results were released by Schering in January 2008. The trial was a Food & Drug Administration (FDA) mandated clinical trial to find out what dose of Peg-Intron (1.5 mcg/kg/week vs. 1.0 mcg/kg/week) is the most effective for the treatment of hepatitis C when combined with ribavirin. In the study design Schering added an arm to compare the effectiveness of Peg-Intron (plus ribavirin) with Pegasys (plus ribavirin). This part of the trial has been promoted as a head-to-head study of the two pegylated interferons, but as I will discuss later in this article it is not a true head-to-head study because the study design was flawed.

There were 3,070 treatment naïve HCV genotype 1 patients enrolled in the study throughout the United States who were randomized into three different treatment arms:

Group A: Peg-Intron: 1.5 mcg/kg/week and Rebetol (ribavirin): 800-1,400 mg/day
Group B: Peg-Intron : 1.0 mcg/kg/week and Rebetol (ribavirin): 800-1,400 mg/day
Group C: Pegasys: 180 mcg/week and Copegus (ribavirin): 1,000/1,200 mg/day

All the trial participants were treated for 48 weeks with a 24 week follow-up period, which is the standard duration of treatment for people with genotype 1. It was reported that there were no significant differences in the patient characteristics.

The sustained virological response (SVR) rates given in the press release were as follows:

Group A: 40%
Group B: 38%
Group C: 41%

It was also stated that the overall adverse events, or side effects, reported were similar between the three arms.

The results released were listed as top line results, which means that no further information was available, just the overall SVR rates. In addition the p-values, or confidence intervals, which would give us a better idea of whether or not the results are truly statistically significant, were not listed. However, it was noted that more of the data will be submitted for peer-reviewed publication and for presentations at upcoming medical meetings. It is expected that Schering will release more information at the upcoming European Association for the Study of Liver Diseases (EASL) that will be held in April 2008.

Bottom line:
The top line results suggest that the effectiveness of Peg-Intron at the lower dose of 1.0 mcg/kg is at least equivalent to the higher dose of 1.5 mcg/kg.

The results comparing Peg-Intron vs. Pegasys have been promoted as a head-to-head study. However, as I pointed out above, the part of the clinical trial comparing Peg-Intron vs. Pegasys was poorly designed because in truth the dose of ribavirin given to trial participants taking Peg-Intron was different than the ribavirin dose given to the people who were taking Pegasys. For instance, in the Peg-Intron arms the dose of Rebetol (ribavirin) was 800 – 1,400 mg/day (weight based), but the dose of Copegus (ribavirin) in the Pegasys arm was 1,000-1,200 mg/day (weight based). In addition, the dose reduction schedule for Peg-Intron was different than the dose reduction schedule for Pegasys. This is an important issue because in the last few years we have learned that taking the optimal dose of ribavirin is one of the most important factors in achieving an SVR. In addition the different ribavirin dose reduction schedule also affects the use of growth factors for the management of ribavirin-related anemia. Finally, it was pointed out in the Roche press release that the study arm with Pegasys was not blinded so there could be a potential for patient or provider bias.

The FDA is the government body that approves all clinical trial designs for clinical trials that take place in the United States. Clearly someone at the FDA was asleep at the wheel when they approved the third arm of this study. In the future it is hoped that the FDA will take a more proactive role in determining and approving appropriate studies that will give providers and patients more clinically significant information.
http://www.hcvadvocate.org/news/newsLetter/2008/advocate0208.html

Natural History of Hepatitis C in Patients with Severe Liver Fibrosis

As reported in the July 2007 Journal of Hepatology, British researchers conducted a study to examine the morbidity and mortality of patients with severe liver fibrosis related to hepatitis C virus (HCV) infection, within a population unbiased by tertiary referral.

A total of 150 HCV positive patients were identified from the Trent HCV study who had liver biopsies taken before 2002 that demonstrated severe fibrosis (Ishak stage 4). Follow-up data were extracted from the study database and hospital records. The median follow-up period was 51 months.

Results

• Of the 131 patients with no prior history of hepatic decompensation, 25% either died (n=25) or received a liver transplant (n=8), after a median interval of 42 months.

• Hepatocellular carcinoma (liver cancer) and/or hepatic decompensation were diagnosed in 33 patients (25%), after a median interval of 41 months.

• The probability of survival without liver transplantation was 97% at 1 year, 88% at 3 years, and 78% at 5 years.

• In a multivariate analysis, interferon-based combination antiviral therapy was associated with improved survival.

• Overall, prognosis was not affected by Ishak stage on the initial biopsy.

• However, the 19 patients with previous hepatic decompensation had worse prognosis: 89% either died (n=15) or received a liver transplant (n=2)

Conclusion

In conclusion, the authors wrote, "This study demonstrates that severe liver fibrosis (Ishak stage 4) secondary to hepatitis C is associated with a poor prognosis, that may be improved following combination antiviral treatment."

07/10/07

Reference
A Lawson, S Hagan, K Rye, and others. The natural history of hepatitis C with severe hepatic fibrosis. Journal of Hepatology 47(1): 37-45. July 2007

Treatment of Hepatitis C in Patients with Advanced Fibrosis or Cirrhosis

By Liz Highleyman

Individuals with advanced liver fibrosis typically respond less well to interferon-based therapy, and treatment for those with decompensated cirrhosis is considered contraindicated, due to the risk of serious side effects. Yet this group of patients has the greatest need for effective therapy in order to avoid liver transplantation or death.

Two recent studies looked at treatment of patients with advanced fibrosis and decompensated cirrhosis using pegylated interferon alpha-2b (PegIntron) plus ribavirin.

Study 1

In the first study, published in the December 2006 Journal of Viral Hepatitis, French researchers compared sustained virological response (SVR) rates in 203 chronic hepatitis C patients with severe fibrosis. Participants were randomly assigned to receive PegIntron at either the standard dose of 1.5 mcg/kg/week or a half dose of 0.75 mcg/kg/week for 48 weeks; all patients also received 800 mg/day ribavirin.

Results

" 45 out of 101 patients (44.5%) achieved SVR with the standard dose of PegIntron, compared with 38 out of 102 patients (37.2%) treated with the lower dose (P = non-significant).

In patients with HCV genotypes 1, 4, or 5, SVR was observed in 25.0% of patients who received the standard dose and 16.9% of those who received the lower dose (P = non-significant).

- In patients with these genotypes and low baseline HCV viremia, the SVR rates were again similar (27.3% vs 25.8%; P = non-significant).
- In the high-viremia subgroup, 24.0% and 9.1% of patients, respectively, achieved SVR.

In patients with genotypes 2 or 3, SVR rates were higher, but also similar in the standard and low-dose groups (73.2% vs 73.0%; P = non-significant).

[P]atients with genotypes 2 and 3 and severe fibrosis can be treated with low dose pegylated interferon and ribavirin," the authors concluded, adding that "more studies are needed for patients with genotype 2 or 3 to define the optimal duration (24 or 48 weeks) in patients with severe fibrosis."

Further, they wrote, "this study suggests that patients with genotypes 1, 4, and 5 and high viremia could receive a standard dose of pegylated interferon associated with ribavirin for 48 weeks." However, they noted that "side effects limit the efficacy of the treatment with standard dose pegylated interferon in patients with genotypes 1, 4 and 5 and low viremia."

Study 2

In the second study, described in the October 20, 2006 electronic edition of the Journal of Hepatology, Italian researchers assessed long-term outcomes in patients with decompensated HCV-related cirrhosis treated with antiviral therapy. Of 129 eligible participants, 66 patients received PegIntron plus ribavirin for 24 weeks, while 63 control subjects remained untreated (currently the standard of care for individuals with decompensated liver disease).

Results

27 patients tolerated therapy, while 26 had their doses reduced due to toxicity, and 13 discontinued due to intolerance.

End-of-treatment response rates were 82.6% for patients with HCV genotypes 2 or 3, and 30.2% for those with genotypes 1 or 4.

Sustained virological response (SVR) rates were 43.5% for genotype 2 or 3 patients, and 7.0% for genotype 1 or 4 patients.

During treatment, odds ratios for severe infections or deaths due to infection were 2.95 (95% CI 0.93-9.3) and 1.97 (95% CI 0.40-9.51) in treated patients compared with untreated control subjects.

During a follow-up period of 30 months off-therapy, decompensation events occurred in 52 control subjects, 33 non-responders to treatment, and 3 patients who achieved SVR.

Odds ratios for ascites, encephalopathy, and esophageal bleeding in treated patients decreased significantly in comparison with untreated control subjects.

The annualized incidence of death was 2.34 per 1000 person-years for untreated controls, compared with 1.91 for non-responders and 0 for sustained responders.

Survival curves showed early separation of sustained responders from both non-responders and untreated controls at approximately 6 months.

In conclusion, the authors wrote, "In decompensated cirrhotics, HCV clearance by therapy is life-saving and reduces disease progression."

12/08/06

References

A Abergel, C Hezode, V Leroy, and others. Peginterferon alpha-2b plus ribavirin for treatment of chronic hepatitis C with severe fibrosis: a multicentre randomized controlled trial comparing two doses of peginterferon alpha-2b. Journal of Viral Hepatitis 13(12): 811-820. December 2006.

A Iacobellis, M Siciliano, F Perri, and others. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: a controlled study. Journal of Hepatology. October 20, 2006

Natural History of Liver Cirrhosis Due to Hepatitis C

Past research has shown that a proportion of patients with chronic hepatitis C go on to develop progressive liver disease including advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) over a period of 10-40 years.

A study published in the June 2006 issue of Hepatology provided further information about the long-term progression of hepatitis C-related liver damage.

The researchers analyzed data from a cohort of 214 patients with compensated hepatitis C-related cirrhosis who were prospectively followed for 17 years. The patients had Child-Pugh class A cirrhosis and no previous clinical decompensation. Follow-up included periodic clinical and abdominal ultrasound examinations.

Results

Over 114 months of follow-up (range 1-199), observed evidence of liver disease progression was as follows:

- HCC developed in 68 patients (32%); annual incidence rate 3.9%
- ascites in 50 patients (23%); annual incidence rate 2.9%
- jaundice in 36 patients (17%); annual incidence rate 2.0%
- upper gastrointestinal bleeding in 13 patients (6%); annual incidence rate 0.7%
- encephalopathy in 2 patients (1%); annual incidence rate 0.1

Clinical status remained unchanged in 154 patients (72%); 45 patients (21%) progressed to Child-Pugh class B and 15 patients (7%) progressed to class C.

HCC was the first complication to develop in 58 patients (27%), followed by ascites in 29 patients (14%), jaundice in 20 patients (9%), and upper gastrointestinal bleeding in 3 patients (1%).

HCC was the major cause of mortality, responsible for 44% of deaths

The annual mortality rate was 4.0% per year, and was higher in patients who had additional potential causes of liver disease (5.7% vs 3.6%; P = .04).

Among the groups with persistently normal, currently high, and

Conclusion

The authors concluded that hepatitis C-related cirrhosis is a "slowly progressive disease that may be accelerated by other potential causes of liver disease." HCC was the first complication to develop, and the dominant cause for increased mortality.

6/16/06

Reference
A Sangiovanni, GM Prati, P Fasani, and others. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 43(6): 1303-1310. June 2006

HCV: Progression, Pathology

Natural History:

Hepatitis C is still a recently diagnosed disease recognized only nine years ago. For this reason, patients have not been able to be followed long enough prospectively to truly know the natural history. Statistics are gained from retrospective analysis and some small short-term prospective studies but the statitstics are still somewhat uncertain.

The course may fluctuate in activity. Specialists in the field of Hep C recognize that enzyme levels fluctuate and the degree of hepatic inflammation may well fluctuate (similar to other chronic viral illnesses such as Herpes Simplex).

The host and environmental factors that influence the course and progression are:
Factor: Duration of infection
Influence on Outcome: Longer duration may increase rate of progression

Factor: Age of infection
Influence on Outcome: Persons infected over age 50 may have more active disease

Factor: Gender
Influence on Outcome: Women may have less active course than men

Factor: Route of infection
Influence on Outcome: Transfused-related Hep C acquired may have more active course than IVDU acquired

Factor: Hemophilia
Influence on Outcome: Some limited studies suggest less fibrosis in hemophiliacs

Factor: Diabetes
Influence on Outcome: Increased risk of acquiring Hep C

Factor: Iron overload
Influence on Outcome: Increased rate of progression of Hep C

Factor: Alcohol use/abuse
Influence on Outcome: Increased rate of progression

Factor: HBV co-infection
Influence on Outcome: No increased progression to cirrhosis but increase in hepatocellular carcinoma (HCC)

Factor: HIV co-infection
Influence on Outcome: Faster progression to cirrhosis and higher rate of cirrhosis

Factor: Smoking
Influence on Outcome: Possible increased risk of HCC

Factor: Immunosuppression
Influence on Outcome: Steroids do not seem to make Hep C more active

According to present knowledge, the rate of progression is as follows:

- number of acute cases becoming chronic: 80 - 85%

- number of chronic cases developing cirrhosis:
- at 10 years post infection = 5 - 6%
- at 20 years post infection = 12 - 15%
- at 30 years post infection = 18 - 25%

- number of cirrhotics (from Hep C) developing decompensation:
- at 10 years post infection = 0.7%
- at 20 years post infection = 3 - 4%
- at 30 years post infection = 5 - 7%

- number developing Hep C related HCC:
- usually only occurs in patients after development of cirrhosis

- occurrence rate after development of cirrhosis is approximately:
* 3 years: 4% developing HCC
* 5 years: 7% developing HCC
* 10 years: 14% developing HCC
- average time to development is 28 years after infection

What about a liver biopsy?

A liver biopsy is currently the most accurate way of determining activity of disease, extent of fibrosis and assessing prognosis. The CASL (Canadian Association for the Study of the LIver) consensus statement is that "A liver biopsy is not mandatory but is strongly recommended". Because of imperfect treatment, a liver biopsy can assist greatly in making the decision about treatment. If the time of infection is known, the progression from that point to the time of the biopsy will give valuable information about previous and probably future progression. A liver biopsy is relatively safe, particularly the ultrasound guided biopsy.

Statistics relative to biopsy are:
risk of pain: 1/30
risk of serious bleeding: 1/1,000 - 1/3,000
risk of death: 1/10,000 - 1/17,000

Risk of death in the past tended to occur in patients with cirrhosis and with the use of a larger biopsy needle. With ultrasound guidance, pre-biopsy group and screen and smaller needles, death from bleeding should not occur.

Pathology:
The important features in the liver biopsy are the amount of inflammation and the degree of fibrosis. While a number of classifications are used, a practical one is the Ludwig Classification. Note: what was formerly called piecemeal necrosis or limiting plate necrosis is now usually called "interface hepatitis".

Inflammation

Portal:
Grade 0 no inflammation
Grade 1 peri-portal inflammation no hepatocellular necrosis
Grade 2 inflammation with mild interface hepatitis
Grade 3 severe portal inflammation with moderate interface hepatitis
Grade 4 marked inflammation with severe interface hepatitis

Lobular:
Grade 0 no inflammation
Grade 1 minimal, no necrosis (inflammatory cells within the lobule)
Grade 2 moderate inflammatory cells with occasional liver cell necrosis
Grade 3 marked inflammation with severe focal liver cell necrosis
Grade 4 extensive inflammation with bridging necrosis

Fibrosis:
Stage 1 none or mild peri-portal fibrosis
Stage 2 peri-portal fibrosis with/without extension and portal-portal bridging
Stage 3 portal-central bridges but no nodular formation
Stage 4 probable or definite cirrhosis

Other Features:
- lymphoid nodules - fairly specific to Hep C
- damage to small bile ducts
- fatty deposition - fairly frequent

The Hepatitis Knowledge Newsletter is edited by F.H. Anderson, MD., FRCP(C), Natalie Rock, BSN, RN, Susan Campbell, RN. Room B-206, Dept. of Medicine, Van. Gen. Hosp. 855 W 12th. Vancouver V5Z 1M9. Phone:(604)209-9976 Fax: (604)875-4429.

The Newsletter is supported by an educational grant from Schering Canada Inc. and GlaxoWellcome Canada

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