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

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

SVR “Sustained Virologic Response and Disease Progression
Alan Franciscus, Editor-in-Chief

Ann Intern Med 2007 Nov 20;147: 677

http://www.hcvadvocate.org/news/newsLetter/2008/advocate0208.html#1