EASL from Paris, 26-28 February 1999

This is the latest Consensus Statement from the European medical Community: EASL (The European Association for the Study of Liver Disease) International Consensus Conference on Hepatitis C, Paris, 26-28 February 1999

Consensus Statement
This statement was drawn up by the Consensus Panel

1. What are the Public Health Implications of Hepatitis C?

Hepatitis C is a major health problem. The global prevalence of chronic hepatitis C is estimated to average 3% (ranging from 0.1 to 5% in different countries): there are some 150 million chronic HCV carriers throughout the world, of whom an estimated 4 million are in the USA and 5 million in Western Europe. The prevalence seems to be higher in Eastern Europe than in Western Europe. In industrialized countries, HCV accounts for 20% of cases of acute hepatitis, 70% of cases of chronic hepatitis, 40% of cases of end-stage cirrhosis, 60% of cases of hepatocellular carcinoma and 30% of liver transplants.

The incidence of new symptomatic infections has been estimated to be13 cases/100000 persons annually. The actual incidence of new infections is obviously much higher (the majority of cases being asymptomatic). The incidence is declining for two reasons: (a) transmission by blood products has been reduced to near zero; (b) universal precautions have markedly reduced transmission in medical settings. Intravenous drug use remains the main mode of transmission; but, even here, the rate of transmission is diminishing due to a heightened awareness of the risk of needle sharing and, in some countries, the availability of needle-exchange, programs.

2. What is the Natural History of Hepatitis C? What are the Factors Influencing the Disease?

Hepatitis C is a disease with various rates of progression. In general, its course is slowly progressive. About 15% of HCV-infected individuals recover spontaneously; an additional 25% have an asymptomatic illness with persistently normal aminotransferases and generally benign histological lesions; hence, about 40% of patients recover or have a benign outcome. In those with biochemical evidence of chronic hepatitis, the majority have only mild to moderate necro-inflarnmatory lesions and minimal fibrosis: their long-term outcome is unknown and, probably, most of them will not succumb to the liver disease. About 20% of patients with chronic hepatitis C develop cirrhosis in 10-20 years, and may die of complications of

cirrhosis in the absence of liver transplantation. Thus, hepatitis C is a dichotomous disease in which a subset of patients will die from liver-related causes, but in which the majority will probably live out their normal life span.

Several cofactors play an important role in the development of cirrhosis:

(a) the age at the time of infection (on average, patients who acquire the disease at an older age have a more rapidly progressing disease, while progression is slower in younger patients;

(b) alcoholism (all studies show that alcohol is a very important co-factor in the progression of chronic hepatitis to cirrhosis);

Commentary from Jules Levin-- you will note that there isn't much said here about individuals coinfected cwith HIV and HCV. That's because little actual study research has been conducted. There are a number of questions I've heard raised by various researchers about treating HIV infected individuals with current HCV therapies. For one, in theory AZT and possibly d4T may be antagonistic with ribavarin. This needs further exploration. Two, interferon can reduce platelet counts. Individuals with HIV may have a low platelet count. Ribavarin cam cause anemia which may be a problem for individuals with HIV. A number of studies in HIV infected individuals receiving HCV therapy are starting but nonetheless some people with coinfection cannot wait to begin therapy until the asnsweres to these questions are more readily available. These individuals will have to make the best treatment decisions they can with the available information today.

(d) co-infection with hepatitis B virus.

The incidence of hepatocellular carcinoma is 14% per year in patients with cirrhosis. This risk supports the necessity of regular monitoring by ultrasonography and measurement of alphafetoprotein in patients with established or suspected cirrhosis. Development of hepatocellular carcinoma is rare in patients with chronic hepatitis C who do not have cirrhosis.

3. Diagnostic Tests

ELISA tests are easy to use and inexpensive, and are the best tests for initial screening. These tests are reliable in most immunocompetent patients who replicate HCV They are less sensitive in hemodialyzed and in immunocompromised patients. In low-risk settings, such as blood banks and other general screening situations where approximately 25 of ELISA positive results may be false, a supplemental specificity test, such as a strip immunoblot assay, is recommended to avoid unwarranted notification of false positives.

Then, a qualitative HCV RNA test should be performed if anti-HCV positivity is confirmed. In high-risk populations and in clinical settings where hepatitis C is suspected, a positive ELISA should be confirmed by a qualitative HCV-RNA test.

In patients with acute hepatitis of unknown cause, an ELISA test should be performed first. If hepatitis A and B tests are negative, then a qualitative HCV RNA test must be performed.

In ELISA-negative patients with chronic hepatitis of unknown cause, particularly in hemodialyzed and immunocompromised patients, a qualitative HCV RNA test should be performed.

Genotyping and quantitative HCV RNA tests are only recommended prior to the treatment of patients.

4. Who Should be Screened for Hepatitis C?

General screening is not advisable. Screening should be limited to risk groups:

(a) persons who have (or might have) received blood products prior to initiation (1991) of second-generation ELISA test;

(b) hemophiliacs;

(d) children born to mothers who have hepatitis C;

(e) current or previous users of intravenous drugs; (f) donors for organ or tissue transplantation.

5. How Can the Transmission of Hepatitis C be Prevented?

The two main sources of Infection are intravenous drug use and administration of blood products. The latter source has almost completely disappeared since 1991.

Sexual transmission is very uncommon: the prevalence of HCV infection in stable partners of homosexual or heterosexual individuals infected with HCV is very low, but is higher in persons with multiple partners. The use of condoms in stable monogamous relationships is not justified; the use of condoms is strongly encouraged in patients with multiple partners.

Pregnancy is not contraindicated in HCV-infected women. Routine HCV screening is not recommended in pregnant women.

HCV vertical transmission is uncommon: the prevalence of transmission from mother to child is less than 6%. The risk of transmission appears to be greater in women with high levels of viremia or HIV co-infection. The mode of delivery (cesarean section/vaginal) does not appear to influence the rate of HCV transmission from mother to child.

There is no association between breast-feeding and transmission of HCV infection from mother to child. There are insufficient data concerning the risk of vertical transmission of in vitro fertilization in patients with hepatitis C to make recommendations at this time. Nosocomial HCV infection is efficiently prevented by the observance of universal precautions.

6. Which Patients Should be Treated?

The decision to treat is a complex issue which must take into consideration numerous variables: age of the patients, general state of health, risk of cirrhosis, likelihood of response, and other medical conditions that may decrease life expectancy or contraindicate the use of interferon or ribavirin.

Commentary from Jules Levin

If a person also has HIV there is an additional group of considerations for deciding upon whether a person is a candidate for HCV treatment. Consultation with a doctor is advisable but it should be a doctor knowledgable in both HCV and HIV and coinifection issues. Since HCV in HIV is an emerging problem many of the issues surrounding HCV treatment inj HIV-infection are not well known. A knowledgable doctor is your best bet.

7. Does the decision to treat depend on the histologic lesions?

It is appropriate and important to obtain a percutaneous liver biopsy before beginning therapy. The liver biopsy provides an opportunity to grade the severity of necro-inflammation and to stage the progression of fibrosis, which may then be considered in relation to the supposed duration of the disease, clinical status and biochemical abnormalities to make therapeutic decisions. The biopsy also provides a baseline in individual patients. There is agreement that patients with moderate/severe necro-inflanimation and/or fibrosis should be treated.

8. Does the decision to treat depend on the age of the patient?

The physiological age of the patient is more important than the chronological age of the patient. Factors to be considered in older patients include overall health status with a special assessment of thcardiovascular system to determine the potential risk of a decrease in hemoglobin level if treatment with ribavirin is being considered.

9. Does the decision to treat depend on the clinical manifestations?

In the early stages, in the absence of advanced cirrhosis, there is a poor correlation between the clinical manifestations and the histological lesions of the disease. Overall, clinical status may affect the decision to treat with regard to quality of life. Studies have shown the abatement of symptoms in patients in whom treatment has induced sustained loss of HCV RNA.

10. Does the decision to treat depend on the level of viremia?

Only patients who have detectable serum HCV RNA are candidates for therapy It is widely recognized that patients who have higher levels of viremia (more than 2 million copies/ml) are relatively less likely to respond to therapy. However, the level of viremia should not be used as a reason to deny treatment.

11. Does the decision to treat depend on the genotype of the virus?

Although it is well-recognized that patients with genotype 1 respond to the treatment less well than patients with genotype 2 or 3, the genotype should not be used as a reason to deny treatment.

12. Should children he treated?

There are no large studies of the treatment of chronic hepatitis C in children. Available studies suggest that children have response rates to interferon monotherapy similar to adults. There are no data on combination therapy with interferon and ribavirin in children. The decision to treat a child must take into consideration the same factors as in adults. There may be additional factors that are unique to young children, in particular the effect of interferon on growth, which require further studies.

13. Should patients co-infected with HIV he treated?

Chronic hepatitis C is frequently found in HIV-infected subjects. It has been established that the progression of chronic hepatitis C is accelerated in co-infected patients. Treatment of hepatitis C may be indicated in those patients in whom treatment has stabilized the HIV infection. Consideration must be given to possible drug interactions and to additive blood abnormalities when treating these co-infected patients.

Commentary from Jules Levin: In theory, AZT and d4T may interact or be antagonistic with ribavarin, which is used in combination with interferon for treating HCV. Interferon monotherapy is an option. Interferon can lower platelet counts. WBC and RBC counts are a concern as well with ribavarin+interferon.

14. Should patients with compensated cirrhosis he treated?

Patients with compensated cirrhosis may be treated. Some potential benefits, such as the reduction in the development of hepatocellular carcinoma and decompensation, are not proven and should be assessed in future controlled studies.

15. Should patients with persistently normal aminotransferases he treated?

Patients who are HCV RNA positive and have persistently normal aminotransferase levels generally have mild disease and an uncertain response to therapy. At present, it is not recommended that these patients undergo therapy, but they should be followed up every 4-6 months or entered into clinical trials.

16. Should patients with HCV-related extrahepatic conditions he treated?

Consideration should be given to the treatment of HCV-related extrahepatic conditions, for example symptomatic cryoglobulinemia, glomerulonephritis or vasculitis. However, sustained remission is unlikely, and long-term maintenance therapy with interferon may be required. The efficacy of interferon and ribavirin combination therapy should be assessed.

17. Should patients with acute hepatitis C he treated?

Most experts are in favor of treating patients with acute hepatitis C.

The timing and duration of the treatment have not been clearly established. Patients with acute hepatitis C should be informed of the 15% chance of spontaneous recovery, the 85% risk of chronic hepatitis C, and the side effects of therapy. Treatment decisions should be individualized and, ideally, patients should be entered into clinical trials. Combination therapy has not been evaluated.

18. Which patients should not he treated?

Given the relatively low efficacy and the side effects of the current treatment of hepatitis C, many patients with hepatitis C virus are not suitable candidates for therapy. In particular, patients with active heavy alcohol intake should not be treated because alcohol adversely increases viremia and interferes with the response to treatment. Active intravenous drug users should not be treated due to the risk of reinfection. In addition, compliance with treatment is poor in patients in whom alcoholism has not been interrupted and in whom drug addiction continues. It is potentially dangerous and there is no evidence that treatment is beneficial to patients with decompensated cirrhosis. The benefits of treating patients with histologically mild disease are uncertain, especially older patients, with co-morbid conditions.

7.What is the Optimal Treatment?

In naive patients, the combination of interferon and ribavirin should be offered to those without contraindications. The duration of therapy depends on the genotype and level of viremia. In patients with genotype 2 or 3, the duration is 6 months (regardless of the level of viremia). In patients with genotype 1, the current data suggest that 6 months is sufficient if the level of viremia is low (less than 2 million copies/nil); 12 months of treatment is recommended if the level of viremia is high (more than 2 million copies/mI).

Preliminary data suggest that, with combination therapy, 5-1O% of patients with detectable HCV RNA after 3 months of therapy may nevertherless clear HCV RNA after 6 months of treatment and develop a sustained response after treatment. There has been no consensus for recommending that therapy be discontinued if HCV RNA remains detectable after 3 months of treatment.

In naive patients in whom ribavirin is contraindicated, interferon monotherapy (3 MU or 9 pg thrice a week) should be administered for 12 months, with HCV RNA testing after 3 months of therapy. Therapy should be continued only in patients in whom HCV RNA has disappeared. It is not proven that an increased dosage of interferon, or daily administration, or high-dose induction increases the sustained response rate. Absolute contraindications to interferon are the following: present or past psychosis or severe depression; neutropenia and/or thrombocytopenia; organ transplantation except liver; symptomatic heart disease; decompensated cirrhosis; uncontrolled seizures. Relative contraindications to interferon are the following: uncontrolled diabetes; autoimmune disorders, especially thyroiditis.

Absolute contraindications to ribavirin are the following: end-stage renal failure; anemia; hemoglobinopathies; severe heart disease; pregnancy; no reliable method of contraception. Relative contraindications to ribavirin are the following: uncontrolled arterial hypertension; old age.

In patients who have relapsed after interf_ron mono-therapy- two options can be considered:

(a) treat with a combination of interferon and ribavirin for 6 months if there are no contraindications to ribavirin;

(b) treat with a high dose (more than 3 MU or 9 pg thrice a week) of interferon for 12 months. In both options, HCV RNA should be checked after 3 months and therapy should be discontinued if HCV RNA remains positive.

In patients who have filled to respond to inteferon mono-therapy or combination therapy, there are no clear data to indicate that retreatment will be beneficial.

Liver transplantation is indicated in patients with life-threatening cirrhosis, and those with hepatocellular carcinoma on cirrhosis. Patients with cirrhosis should be considered for transplantation if they develop complications of their cirrhosis and have a life expectancy of 12 years without transplantation. This includes patients with recurrent or refractory ascites, Child-Pugh C cirrhosis, uncontrolled gastrointestinal bleeding after medical, endoscopical and TIPS (trans-jugular intrahepatic portacaval shunt) procedures, severe encephalopathy (spontaneous or after shunt), bacterial peritonitis.

Patients with hepatocellular carcinoma or cirrhosis can be considered for transplantation if there are less than 3 nodules of 3 cm and if there is no extrahepatic spread, including portal invasion.

After liver transplantation, HCV reinfection is almost constant. At 3 years, about 50% of the patients have a normal graft or mild lesions, 45% of the patients have chronic hepatitis and only 5% develop severe lesions. The 5-year rate of HCV-related cirrhosis on the graft is about 10%. The 5- and 10 year patient survival rate in Europe is about 70% and 60%, respectively, which is comparable to that of patients transplanted for other non-malignant liver diseases. Patients should be informed of the risk of HCV recurrence and its potential consequences before transplantation.