In the beginning of this year, the European Association for the Study of the Liver (EASL) organized two days special consensus meeting about Hepatitis C Virus (HCV). In windy, rainy and cold Paris, on February 26 and 27, numerous experts, mostly from Europe but also from USA, presented different aspects and their experiences with Hepatitis C virus. Very well organized in the Palace of Congress, this meeting was extremely successful. Particularly because, it abounded in professional discussions by its invited lecturers and many of the participants. It gave a lot of answers about Hepatitis C Virus.The Organizer of this meeting was Pr. Patrick Marcellin (Paris, France) and the Secretary of the Scientific Committee was Pr.A.K. Burroughs (London, United Kingdom). Before the the meeting, two Proceeding books were distributed to the participants with the presenting abstracts of invited lecturers. After the meeting, Consensus Panel with Pr. J.P. Benhamou (Paris, France) as the Chairperson, prepared the text of the Consensus Statement of the Conference which was sent to all participants. This full text is also available on the Internet (www.munskgaard.dk/hepatology).
In summary, Consensus Statement contains conclusions of almost all current aspects about Hepatitis C such as: natural course and factors which influence the disease, screening assays, transmission and prevention, optimal treatment as well as the consideration of the main unresolved issues. In this consensus text, Hepatitis C virus is emphasis as the major health problem with the global prevalence of 3% (from 0.1 to 5% in different countries). With approximately 150 million chronic carriers throughout the world, in industrial 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 transplantts. The incidence of new symptomatic infections has been estimated to be 1-3 cases/ 100 000 persons annually but the actual incidence of new infections is obviously much higher. Declining the incidence in last years is a result of two reasons: transmission by blood products of HCV is reduced to near zero and universal precautions measures markedly reduced transmission in medical settings.The main mode of transmission remains intravenous drug use.
The natural history of HCVdisease is slowly progressive in general. Unfortunately, only about 15% of infected individuals recover spontaneously. The majority of the chronic carriers have only mild to moderate necro-inflamatory lesions and minimal fibrosis an probably will not succumb to the liver disease. About 20% of the patients with chronic HCV hepatitis will develop cirrhosis in 10-20 years and may die of complications of cirrhosis in the absence of transplantation. So, the majority of the patients with chronic HCV hepatitis will probably live out their normal life span. Co-factors, which may influence the development of cirrhosis, are next: older age, alcoholism and co-infections with Hepatitis B Virus (HBV) and Human Immunodeficiency Virus (HIV).
The risk factor for hepatocellular carcinoma which incidence is 1-4% per year in patients with cirrhosis, supports regular monitoring of the patients by ultrasonography and measurement of alpha-fetoprotein level. Development of carcinoma in patients without cirrhosis is very rare.
Anti HCV antibodies are recommended to be detected by ELISA tests for initial HCV screening. They are easy to perform and are inexpensive. They are reliable in most immunocompetent patients who replicate HCV but less sensitive in haemodialyzed and immunocopromized patients. In low-risk populations (e.g. blood banks) where ELISA test could be false positive in around 25%, supplemental confirmatory tests such as a strip immunoblot assay is recommended. In those cases, qualitative HCV RNA detection should be performed if anti-HCV positivity is confirmed. This test is recommended also in high-risk populations with clinical features of chronic hepatitis and positive ELISA test. In patients with acute hepatitis, ELISA test should be performed together with tests for Hepatitis A and B viruses first. If all tests are negative, qualitative RNA HCV test must be performed. The same test should be performed in patients with chronic hepatitis of unknown etiology, which is also negative for antibodies to HCV, particularly in haemodialiyzed and immunocompromized individuals. Quantitative HCV RNA testing and genotyping are only recommended prior to the treatment of patients.
Because general screening is not advisable, HCV screening should be limited to following risk-groups: persons who received blood products prior to 1991, hemophiliacs, haemodyalized patients, children born to mothers who have hepatitis C, current or previous i.v. drugs users and donors for organ or tissue transplantation.
The main source of HCV transmission is intravenous drug use. Transmission by administration of blood products has almost completely disappeared since 1991 using second-generation ELISA test. Sexual transmission of HCV infection is very low, particularly in stable heterosexual or homosexual partners. Prevalence of HCV infection is higher in persons with multiple partners when the use of condoms is strongly recommended. HCV infection is not contraindicated for pregnancy nor in pregnancy HCV testing is recommended. The risk of vertical transmission is less than 6% and is greater in women with higher viraemia and HIV co-infection. There is no association between the mode of delivery or breast-feeding and the rate of HCV infection. Since now, there is no recommendation about the risk of vertical transmission of HCV by in vitro fertilization because of insufficient data. Universal precaution measures efficiently prevent nosocomial HCV infection.
Treatment of the patient with HCV infection is very complex. Many variables must take into consideration. Before starting therapy, it is appropriate to obtain liver biopsy. There is agreement that patients with moderate/severe necro-inflamation and/or fibrosis should be treated. Decision to treat patients does not strictly depend on the age of patients. More important in elderly patients is their overall health status (e.g. cardiovascular system function and potential risk of a decrease in hemoglobin level because of ribavirin treatment). Also, clinical status may affect the decision to treat with regard to quality of life and studies have shown abatement of symptoms after successful treatment with sustained loss of HCV RNA. Although in patients with high level of HCV viraemia or genotype l there is a relatively less chance to respond, it is not a reason to deny the treatment. Available studies of the treatment with interferon monotherapy in children suggest the same response rate as in adults. However, the effect of interferon on growth must be take into consideration in treating children. Also, patients with compensated cirrhosis may be treated. The reduction in development of decompensation and hepatocellular carcinoma in such patients after treatment is not proven since now and should be assessed in future controlled studies.Patients with persistently normal aminotransferase levels are not candidates for treatment although they have positive HCV RNA. Patients with HCV-related extrahepatic manifestations may require long-term therapy with interferon. Patients with HIV co-infection are candidates for treatment if they stabilized HIV infection but drug interaction and additive blood abnormalities must be taken into consideration. Patients with acute hepatitis C may be treated with interferon but that decision should be individualized as well as the timing and duration of the treatment hence is not clearly established. Patients who are not suitable candidates for current treatment are following: active heavy alcoholics and intravenous drug users and patients with decompensated cirrhosis. Histologicaly proven mild disease and older patients are uncertain about benefits of the treatment.
Starting combination therapy with interferon and ribavirin should be offered to “naïve patients” without contraindications. The duration of the treatment depends of the genotype and level of viremia. In patients with genotypes 2 and 3, the duration of the treatment is 6 months. In patients with genotype 1, the current data suggests that 6 months is effective if the level of viremia is low (less than 2 million copies/ml). Treatment of 12 months is recommended in such patients if level of viremia is high (more than 2 million copies/ml). There is no generally agreement for recommending that combination therapy should be discontinued if HCV RNA is detectable after 3 months. If ribavirin is contraindicated, interferon monotherapy should be recommended in dose of 3 MU or 9 microgram, thrice a week for 12 months. Treatment should be continued only if HCV RNA is nondetectable after 3 months of treatment. Increased dosage or daily administration of interferon is not proven to be more efficient to achieve the sustained response. Patients who have relapsed after interferon therapy have two options for further treatment: higher dose of interferon in duration of 12 months or combination treatment (interferon plus ribavirin) in duration for 6 months. If HCV RNA is still positive after 3 months, both options should be discontinued.
Absolute contraindications for interferon therapy are the following: present or past psychosis or severe depression, neutropenia and/or thrombocytopenia, organ transplantation except liver transplantation, symptomatic heart disease, decompensated cirrhosis and uncontrolled seizures. Relative contraindications are the following: uncontrolled diabetes, autoimmune disorders, especially thyroiditis. Absolute contraindications for ribavirin therapy are the following: end stage of renal failure, anemia, hemoglobinopathies, severe heart disease, pregnancy and no reliable method for contraception. Relative contraindications for ribavirin therapy are the following two: uncontrolled arterial hypertension and old age.
Patients with HCV cirrhosis should be considered for liver transplantation if they develop complications of cirrhosis and have life expectancy of 1-2 years without transplantation. This includes patients with refractory ascites, Child-Pugh C cirrhosis, uncontrolled gastrointestinal bleeding after medical endoscopical and TIPS (transjugular intrahepatic portacaval shunt) procedures, severe encephalopathy or bacterial peritonitis. Patients with hepatocellular carcinoma can be candidates for transplantation if there are less than 3 nodules of 3 cm and if there is no extrahepatic spread, including portal invasion. HCV reinfection after liver transplantation is almost constant although the survival rate after 5 and 10 years is comparable to that of patients transplanted for other non-malignant diseases. After liver transplantation at 3 years, about 50% of the patients have normal liver graft or mild lesions; 45% have chronic hepatitis and only 5% develop severe lesions.
In generally, laboratory tests are not very reliable in monitoring the progression of HCV liver disease. However, checking blood counts and liver enzymes are recommended every 6 months. For assessing progression of fibrosis and cirrhosis, liver biopsy is necessary and repeat liver biopsy every 4-5 years is recommended. The cost of monitoring therapy is still too great. Detection of HCV RNA by PRC is the “gold standard” and is recommended to monitor the treatment. Other tests such as are genotyping and quantitation of viremia are useful but expensive. Those tests must be more generally available. Other combinations of drugs or new specific approaches to treatment such as antisense nucleotides targeted against ribosomal-binding site of the HCV, ribosomes, helicase and protease incibitors are presently under investigation and do not achieve better results then current accepted therapy. A traditional vaccine is unlikely to become available in the near future. So, many themes to overcome many questions about HCV infection in the future include different fields in diagnosis, natural history, virology and therapy.
Assistant Prof. Neda Svirtlih, MD, PhD
Institute for Infectious Diseases,
Medical Faculty University of Belgrade,
Clinical Centre of Serbia, Bul JNA 16,
11000 Belgrade, Yugoslavia
tel. 381-11-683-366; Fax 381-11-684-272
e-mail: [email protected]