Hepatitis C is a relatively common disease.
An estimated 3% of the world population has a chronic infection with the hepatitis C virus (HCV) and HCV accounts for about 20% of cases of acute hepatitis and 70% of cases of hepatitis chronic.
Chronic hepatitis C is a major cause of cirrhosis and primary liver cancer (hepatocellular carcinoma). In addition, decompensated cirrhosis related to hepatitis C is the leading cause of liver transplant in Europe.
The silent evolution of the disease and the high rate of chronicity explain the existence of a large infected tank. Thus, although HCV is not very contagious, it is transmitted widely, mainly parenterally.
Acute hepatitis C is usually asymptomatic, which explains that the diagnosis is rarely made during the acute stage of the disease.
Chronic hepatitis is usually asymptomatic and diagnosis is fortuitous in most cases, sometimes at an advanced stage of the disease. The severity of liver disease associated with HCV is highly variable but can in some cases be responsible for cirrhosis and hepatocellular carcinoma, in a period ranging from several years to several decades.
HCV is transmitted primarily by blood.
The post-transfusion hepatitis C acute has become extremely rare and most patients are now infected by use of intravenous drugs. The clinical presentation of acute hepatitis C was mainly described in transfused patients. Also, the characteristics of acute hepatitis C linked to other modes of infection, such as the use of intravenous drugs or nosocomial or occupational exposure, are poorly known.
The incubation period and severity of acute hepatitis may be related to the importance of the inoculum. The average incubation, after post-transfusion prospective studies, is 7 to 8 weeks, but can be very variable (2-26 weeks). The prodromal phase is uncommon. Acute hepatitis C is jaundiced and in a minority of cases (20%) and is anictérique with no or few symptoms in most cases (80%).
The symptoms are nonspecific: fatigue, nausea, pain in the right upper quadrant, followed by the appearance of dark urine and jaundice.
They are similar to those observed in other viral hepatitis. Thus, the clinical diagnosis of acute hepatitis C is rarely done.
Diagnosis is based on viral serology.
Severe acute hepatitis is rare. In symptomatic patients, the disease usually lasts 2 to 12 weeks.
The first marker of HCV infection is the appearance of detectable HCV RNA in serum by PCR (Polymerase Chain Reaction) in the first week after infection (5-7). The anti-HCV antibodies are detectable in acute hepatitis in most cases but in some cases, seroconversion occurs late, one to several weeks after the peak transaminases. Transaminases rise before the onset of symptoms.
The peak of transaminases is usually greater than 10 times normal, although lower values can be observed.
If healing of acute hepatitis C, transaminases normalize and viral RNA becomes undetectable; anti-HCV antibodies decline very gradually but remain detectable for many years. If chronicity, transaminases may normalize or remain discreetly or moderately high.However, the viral RNA remains detectable.
Spontaneous recovery from acute hepatitis C was observed in 20% of cases.
In most patients, the infection becomes chronic. The frequency of chronicity is of the order of 80%. The high frequency of chronicity is related to the high genomic variability of HCV. The multiplication of the virus, whose genome is RNA, causes permanent changes that allow it to evade the immune response.
There are three forms of chronic hepatitis C chronic hepatitis with normal transaminases;
– Minimal chronic hepatitis;
– Moderate or severe chronic hepatitis.
Chronic hepatitis with normal transaminases:
A number of patients with chronic HCV infection have normal transaminases permanently despite the presence of a detectable viremia (detectable HCV RNA by PCR in serum). These patients are often identified through screening.This group represents about 25% of chronic HCV patients. The definition of this group of patients must be strict: positive anti-HCV antibody positivity of HCV RNA by PCR and strictly normal transaminases. This requires at least three assays transaminases over a period of at least 6 months.
These patients usually have no symptoms, but about 90% of them have chronic hepatitis lesions on liver biopsy.
However, liver histological lesions are usually minimal and severe damage, especially cirrhosis, are rare in the absence of other hepatotoxic factors (excessive alcohol use history, HIV co-infection). Virological characteristics of these patients (genotype and viral load) do not seem different from those observed in patients with chronic hepatitis C with elevated transaminases. The long-term evolution of this group of patients is not known, and regular monitoring of transaminases (twice a year) is recommended, although the prognosis seems a priori quite favorable.
Mild chronic hepatitis:
Another group of patients with chronic hepatitis C is characterized by minimal liver disease with detectable viral RNA in serum by PCR and very moderately elevated transaminases, sometimes fluctuating transiently normal. Liver biopsy shows activity lesions and minimal fibrosis.
This group of patients currently represents approximately 50% of patients with chronic hepatitis C.
These patients are usually asymptomatic but may complain, in some cases, abnormal fatigue. This type of chronic hepatitis C usually develops very slowly and the risk in the long term, to develop cirrhosis is low. The mild chronic hepatitis is the most common form of chronic hepatitis C in young patients. However, a minority of these patients may eventually develop further a progressive disease.
Chronic hepatitis moderate or severe:
The third group of patients with moderate or severe chronic hepatitis represents approximately 25% of patients with chronic hepatitis C. These patients are difficult to distinguish from those with mild chronic hepatitis. Clinically, although liver disease is more severe, most patients are asymptomatic and, if there is fatigue, the intensity of the latter is not correlated with the severity of the disease.
The physical examination is usually normal. Furthermore, although these patients tend to have higher transaminases than patients with mild chronic hepatitis, transaminase levels is not a prognostic factor for a given patient. Increased GGT, ferritin or immunoglobulins, or thrombocytopenia are indications of more severe disease, but they are not always present. Hepatic ultrasound may provide useful information but is usually normal. Thus, liver biopsy is the most reliable examination to distinguish moderate or severe chronic hepatitis of mild chronic hepatitis. It helps establish the prognosis and the treatment indication.
Liver biopsy shows more pronounced lesions of activity and a more or less extensive fibrosis. This form of chronic hepatitis C is more common and is growing faster in elderly patients, in men and in patients with a co-factor such as alcohol or immune deficiency. In particular, in patients with HIV-HCV co-infection, fibrosis progresses faster. It is estimated that 20% of patients with chronic hepatitis develop cirrhosis in 20 years. In some cases, the biopsy done at the first assessment already shows the existence of cirrhosis. The reliability of serum fibrosis markers is being evaluated.
Cirrhosis and hepatocellular carcinoma:
Cirrhosis caused by chronic hepatitis C can remain silent for many years. The signs of portal hypertension or liver failure appear late. And cirrhosis, usually asymptomatic, is most often discovered during liver biopsy. In other cases, cirrhosis is diagnosed during a complication (bleeding from variceal, ascites, jaundice, encephalopathy).
In some cases, cirrhosis diagnosis is made at stage of hepatocellular carcinoma.
The clinical examination, ultrasound and liver tests may suggest the presence of cirrhosis.
In patients with cirrhosis due to chronic hepatitis C, mortality related to portal hypertension, liver failure or hepatocellular carcinoma is of the order of 2% to 5% per year. Decompensated cirrhosis due to chronic hepatitis C is the second leading cause of liver transplantation in France (after alcoholic cirrhosis) and the leading cause in Europe.In cirrhosis, the incidence of hepatocellular carcinoma is high (3% to 10% per year) and warrants routine screening with ultrasound and determination of alpha-fetoprotein every 6 months. Hepatocellular carcinoma is exceptional in the absence of cirrhosis; it usually occurs in compensated cirrhosis and remains asymptomatic for a long time.
Many extrahepatic manifestations have been described in association with HCV infection. Some are well demonstrated while others could be fortuitous (Table I).
The HCV-related disease is most clearly mixed cryoglobulinemia. Although detectable cryoglobulinaemia is common in patients with chronic hepatitis C (50% of cases), it is usually asymptomatic.
The clinical syndrome cryoglobulinemia with arthralgia, Raynaud syndrome and purpura (legs) is rare (1% to 5% of cases). Glomerulonephritis and neuropathy are rare and can be severe. The HCV infection favors the clinical expression of the late cutaneous porphyria. HCV may also play a role in certain non-Hodgkin lymphoma of low grade.For other associations, such as autoimmune thyroiditis and lichen planus, the cause and effect with HCV has not been proven.
Principles of treatment:
Currently, in the patient with hepatitis C, the use of combination therapy with pegylated interferon alpha and ribavirin provides sustained response in about 55% of cases. With hindsight, it appears that the SVR is durable and it is associated with histological benefit and probably a decreased risk of cirrhosis and hepatocellular carcinoma.Optimization of treatment of these patients requires a better knowledge of antiviral treatments currently available (pegylated interferon and ribavirin).
The primary goal of treatment is to eradicate the virus, allowing healing of the infection.
The other objective is to prevent, stabilize or even improve hepatic fibrosis lesions.
The indications for treatment are primarily based on the evaluation of the severity of the histological lesions of the liver and the risk of progression to cirrhosis. The indications for treatment should be modulated by taking into account individual factors such as age of the patient, his general condition, response opportunities, comorbidities (Fig. 3). Furthermore, side effects and the decrease in quality of life during treatment should be taken into account.The benefit of treatment is not proven for patients with mild chronic hepatitis.
Maintenance treatment can be discussed in patients with no virological response but with biochemical response.
The indications for treatment are primarily based on the evaluation of the severity of the histological lesions (prognosis). The indications for treatment should be modulated by taking into account individual factors such as physiological age of patient comorbidities, response opportunities (genotype). Furthermore, side effects and the decrease in quality of life during treatment should be taken into account.
Treatment results: SVR
Association pegylated interferon and ribavirin:
Recent studies have shown the superiority of the combination pegylated interferon (PEG-IFN) and ribavirin compared to IFN and ribavirin.
Two randomized trials included a total of 2651 patients with an overall SVR of 55%. For both studies, the SVR rate was about 80% in case of infection with genotype 2 or 3, and the order of 50% in case of infection with genotype 1. In infected with genotype 2 or 3, a 24-week treatment with ribavirin 800 mg daily results in a sustained virological response of approximately 80% with no difference compared to a 48-week treatment. If genotype 1 if the measure viral load at week 12 of treatment showed a disappearance or reduction of more than 2 log of the original viral RNA.Otherwise, if the aim is viral eradication, this treatment can be stopped because of the high probability of virological failure.
Predictive factors of response to treatment:
Predictive factors of pretreatment processing efficiency are mostly related to the virus (genotype non-1 and low viral load) and to a lesser degree to the patient: female, young age and mild liver disease (minimal fibrosis or moderate).
Side effects of interferons and pegylated interferons:
Side effects are frequent, numerous, but generally mild and reversible upon discontinuation of treatment. The most common is the flu-like syndrome (fever, arthralgias, headache, chills). It is usually mild and well controlled by paracetamol. Other possible side effects include asthenia, weight loss, hair loss, sleep disorders, mood disorders with an irritability that can affect in daily life, difficulty concentrating and dry skin .
Some rare side effects can be serious and should be anticipated such as psychiatric disorders. Depression may occur in about 10% of cases. This must be detected and treated because it can have serious consequences (suicide attempt).
preexisting psychotic decompensation may occur. Hypo- or hyperthyroidism may occur. The IFN treatment is cons-indicated during pregnancy.
The safety of PEG-IFN monotherapy is generally comparable to that of standard IFN.
Severe side effects, especially mental, are not more frequent.
ILI and inflammatory skin lesions at the injection site and neutropenia are a little more frequent. The dosage is reduced slightly more often with PEG-IFN with IFN primarily due to neutropenia.
Take charge of anemia associated with ribavirin:
The main side effect of ribavirin is anemia. Anemia led to discontinuation in about 5% of cases. Decompensation of coronary artery disease or heart disease underlying, related anemia may occur. A cardiology consultation is recommended prior to initiating therapy in patients with a history of heart disease or systematically if age is above 50 years.
Treatment with ribavirin is against-indicated during pregnancy. Effective contraception is required before startup and during treatment. The adverse reactions occurring in the combination IFNribavirine appear moderate and seem to correspond to the addition of the known side effects for each of the two molecules. All-cause discontinuation of treatment is needed in less than 10% of cases. The tolerability to combination therapy with PEG-IFN seems little different from the standard combination therapy. Dose reduction is a little more often observed without stopping treatment is more common.
Holding the right dose of ribavirin in the first quarter of treatment is essential to obtaining a good SVR. Ribavirin reduction in the first 12 weeks of the impact has sustained virological response only if the dose of ribavirin is less than 60%.
The management of a patient with chronic hepatitis C should be comprehensive, looking for all the factors associated with a poorer response to treatment (such as excessive alcohol consumption, obesity, insulin resistance) to treat. It seems that the likelihood of effective treatment increases if started at optimal dose with close monitoring to rapidly adjust the dose to avoid stopping treatment. Good adherence is fundamental.
You should know ahead of potential psychological problems (depression). We must quickly diagnose side effects too often bringing lower doses. Growth factors and erythropoietin are a solution for anemia.
It should also improve the effectiveness of treatments.
Although the combination of ribavirin to IFN-PEG is definitely an important step, the results are still unsatisfactory with poor tolerance. It is likely that better use of available drugs can achieve superior results.
The development of new molecules is necessary, such as inhibitors of viral enzymes (proteases, polymerases and helicases).