Benevolent Dictator for Life
წევრი No.: 25854
რეგისტრ.: 20-November 06
გამოგზავნილია: 23 Apr 2007, 17:54 #5409403 · პროფილი · პირადი მიმოწერა · ელფოსტა
A. VIROLOGY AND EPIDEMIOLOGY
1. In the United States approximately 1.8% of the population is HCV seropositive (4 million people), and 2.7 million people are estimated to have ongoing HCV infection, with a peak prevаlence in those aged 40 to 59 years ( Box 34-3 ).
2. The incidence of HCV in the United States has been declining, largely because of improvements in blood donor screening programs; however, a fourfold increase in the number of people diagnosed with hepatitis C is projected over the next decade. HCV is the leading indication for liver transplantation.
3. The hepatitis C virus is a single-stranded RNA flavivirus with six genotypes and more than 50 subtypes. Genotypes 1a and 1b are the most common in the United States.
RISK FACTORS FOR HEPATITIS C INFECTION
Intravenous drug use
Blood transfusions before 1992
Exposure to an infected sexual partner[*]
Frequent exposure to infected blood among health care workers[*]
Folk medicine practices including acupuncture[*]
* Less efficient mode of transmission.
B. CLINICAL PRESENTATION
1. HCV infection is infrequently diagnosed during the acute phase of illness because the majority of patients have few or no symptoms. When they do occur, clinical manifestations typically begin 7 to 8 weeks (range 2 to 26 weeks) after exposure to HCV and generally consist of jaundice, malaise, and nausea. Acute fulminant hepatitis C infection is documented but rare.
2. Spontaneous clearance of viremia, once infection has been established, is rare. Between 55% and 85% of those infected become chronic carriers. Among this group, 5% to 20% develop cirrhosis over the next 20 to 25 years. Once cirrhosis develops, the risk of hepatocellular carcinoma is 1% to 4% per year (see Chapter 35 ).
3. In addition to duration of infection, risk factors associated with progression of fibrosis include older age, male sex, alcohol use, HIV, low CD4 count, high body mass index, and diabetes.  
1. Diagnosis of HCV is based on both serologic testing and viral RNA amplification. HCV antibody testing is extremely sensitive and specific, and it is the initial screening test of choice. Anti-HCV antibodies are present approximately 8 weeks after exposure. False negative results can occur in acute infection, immunosuppressed patients with HIV, and those on chronic hemodialysis. Typical serologic patterns of acute and chronic hepatitis C infection are shown in Fig. 34-3 .
2. HCV RNA testing is used to confirm diagnosis by documenting viremia, which is detectable 1 to 2 weeks after exposure.
3. Biopsy is recommended during the initial assessment of those with chronic hepatitis C and helps stage the severity of disease, grade the degree of necrosis and inflammation, and identify those who may or may not benefit from treatment.
1. Treatment of hepatitis C is generally considered for all patients without specific contraindications but may be prioritized and recommended for patients with a higher likelihood of developing cirrhosis, including those with persistently elevated transaminase levels, detectable HCV RNA greater than 50 U/L, and histologic evidence of fibrosis or inflammation. Treatment is also recommended for patients with significant extrahepatic manifestations of HCV infection.
2. Baseline HCV RNA should be measured before treatment, after 12 weeks of treatment, and at the end of treatment. HCV genotyping should be completed before treatment because viral genotype is the strongest predictor of response.
3. The current standard of care for the treatment of chronic hepatitis C infection is weekly subcutaneous peginterferon alfa paired with daily ribavirin therapy. When compared with patients treated with interferon alfa in combination with ribavirin or peginterferon alone, patients treated with peginterferon with ribavirin demonstrated significantly better end-of-treatment response and sustained virologic response (SVR) ( Box 34-4 ).
4. Patients with genotype 1 HCV infection should be treated for 48 weeks. Patients who do not show early virologic response after 12 weeks of treatment may discontinue therapy because 97% of these patients will also fail to achieve SVR. In patients with genotype 1 infection and low levels of viremia (< 2 million copies/ml), 64% achieve SVR compared with 46% among those with high levels of viremia.
5. Patients with genotype 2 and 3 HCV infections achieve higher SVR rates (74% to 81% depending on low or high levels of viremia) and should be treated with peginterferon plus ribavirin for 24 weeks.
6. Other than genotype, several factors predict higher response rates to HCV treatment: lower pretreatment HCV RNA, younger age, lower body weight, and absence of bridging fibrosis and cirrhosis. African American patients with genotype 1 were recently shown to have significantly lower rates of SVR than non-Hispanic white patients.
HCV TREATMENT DEFINITIONS
Sustained virologic response: absence of HCV RNA in serum at the end of treatment and 6 mo later.
Early virologic response: 2-log drop or loss of viral HCV RNA 12 wk into therapy.
End-of-treatment response: absence of detectable virus as the termination of treatment.
Nonresponder has stable HCV RNA levels despite treatment.
Partial responder has a declining HCV RNA level, but levels never become undetectable.
HCV, hepatitis C virus.
1. No clinical benefit has been shown with immune globulin prophylaxis, and it is not recommended after exposure. There is no available vaccine for hepatitis C.
2. Needlestick transmission of HCV is an important concern for health care workers. It is not possible to prevent infection after exposure to HCV, and HCV infection will develop in an estimated 2% to 10% of exposed individuals.
3. Because clinical symptoms may be minimal, HCV antibody, HCV RNA, and ALT levels should be measured within several days of exposure and 6 months thereafter.
4. There are no clear recommendations about the timing or duration of treatment for acute hepatitis C infection. Excellent results have been achieved in uncontrolled trials with interferon alone. These results are confounded because most patients present with symptomatic acute infection, which has been associated with higher rates of spontaneous clearance (52%).
ACUTE HEPATITIS C
HCV is an RNA virus that belongs to the family Flaviviridae (genus Hepacivirus). HCV originally was identified by molecular techniques, and the virus has not been well visualized. HCV probably circulates as a double-shelled enveloped virus, 50 to 60 nm in diameter. The genome is a positively stranded RNA molecule, which is approximately 9.6 kb in length and contains a single, large open-reading frame that encodes a large polyprotein that is post-translationally modified into three structural and several nonstructural polypeptides. The structural proteins include two highly variable envelope antigens (E1 and E2) and a relatively conserved nucleocapsid protein ©. HCV replicates largely in the liver and is detectable in serum in titers of 105 to 107 virions/mL during acute and chronic infection.
Hepatitis C is spread predominantly by the parenteral route. At highest risk are injection drug users and persons with multiple parenteral exposures. Sexual transmission of hepatitis C occurs but is not common. Prospective follow-up of spouses and sexual partners of patients with chronic hepatitis C shows the risk of sexual transmission to be low (<1% per year of exposure). Maternal-infant spread occurs in approximately 5% of cases, usually to infants whose mothers have high levels of HCV RNA in serum. Other potential sources of HCV are needlestick accidents and either contamination or inadequate sterilization of reusable needles and syringes. Since the introduction of routine screening of blood for anti-HCV, post-transfusion hepatitis C has become rare. Inactivation procedures performed on plasma products have made transmission of HCV from clotting factor concentrates uncommon. There remain, however, many persons with chronic hepatitis C who were infected with this virus by these means in the past. Current studies of acute hepatitis C indicate that more than 60% of cases are attributable to injection drug use; 15 to 20% of cases to sexual exposure (usually involving multiple sexual partners); and only a small proportion of cases to maternal-infant spread, needlestick accidents, and iatrogenic causes. Approximately 10% of cases have no history of potential exposure and remain unexplained.
The clinical course of acute hepatitis C begins with an incubation period that ranges from 15 to 120 (mean 50) days. During the incubation period, often within 1 to 2 weeks of exposure, HCV RNA can be detected by sensitive assays such as reverse-transcriptase polymerase chain reaction (PCR). HCV RNA persists until well into the clinical course of disease. Antibody to HCV (anti-HCV) arises late in the course of acute hepatitis C and may not be present at the time of onset of symptoms and serum aminotransferase elevations. If the hepatitis is self-limited, HCV RNA soon becomes undetectable in serum; in this situation, titers of anti-HCV are generally modest and eventually may fall to undetectable levels as well.
The major complication of acute hepatitis C is the development of chronic hepatitis. The clinical course depicted in Figure 151-4 is not typical because hepatitis C does not resolve in 70% of cases but rather progresses to chronic infection ( Chapter 152 ). In this situation, HCV RNA remains detectable, and aminotransferases usually remain elevated, although often in a fluctuating pattern. In some instances, aminotransferase levels become normal despite persistence of viremia. Other complications include development of immune complex phenomena and cryoglobulinemia, although these are more typical of chronic disease. Fulminant hepatitis resulting from HCV is rare; in several large surveys of acute liver failure, none of the cases could be attributed to HCV.
The diagnosis of acute hepatitis C generally is made based on the finding of anti-HCV in serum in a patient with the clinical and biochemical features of acute hepatitis. Some patients do not develop detectable levels of anti-HCV, however, until weeks or months after onset of illness, so retesting for anti-HCV during convalescence or direct tests for HCV RNA are necessary to exclude the diagnosis of acute hepatitis C in a patient who tests negative for all serologic markers. At least one commercial test for HCV RNA is now licensed and is reliable in detecting HCV RNA at levels greater than 100 copies/mL. Tests that quantify the HCV RNA level are also available, but measuring viral levels is not clinically useful in diagnosis or monitoring of acute hepatitis C.
At present, there are no means of prevention of hepatitis C other than avoidance of high-risk behaviors and appropriate use of universal precautions. Injection drug use is currently the most common cause of newly acquired cases of hepatitis C. In this regard, needle exchange programs and education regarding the risks of drug use including intranasal cocaine and the role of reusable equipment are important.
Accidental needlestick exposure is perhaps the most frequent issue in prevention of transmission. At present, neither immune globulin nor preemptive therapy with antiviral agents or interferon is recommended in this situation. Monitoring using aminotransferase levels, HCV RNA, and anti-HCV testing (at 1 and 6 months after exposure) is appropriate. This approach allows for early intervention and treatment.
Therapy with pegylated interferon-α and ribavirin has been shown to be beneficial in chronic hepatitis C ( Chapter 152 ), leading to sustained clearance of virus and resolution of disease in slightly more than 50% of cases. The role of therapy during the acute infection is still unresolved. Because 60 to 75% of patients with acute disease progress to chronic infection, the issue of early therapy often arises. In a single, multicenter study from Germany, more than 95% of patients with acute hepatitis C treated with standard interferon-α for 24 weeks had resolution of disease and a sustained loss of HCV RNA. This study did not have a control group, but the high rate of response to interferon alone (without ribavirin) suggests that early therapy is highly effective in preventing chronic hepatitis C. The study provided little help in deciding which patients should be treated and, perhaps more importantly, when therapy should be started. The role of peginterferon versus standard interferon and the use of ribavirin are unresolved. Until more information is available, recommendations are based largely on inference from natural history studies and experience with therapy in chronic hepatitis C. Therapy of acute hepatitis C is appropriate but probably is best delayed for 2 to 4 months after onset to assess whether the disease is self-limited. If HCV RNA remains detectable, an appropriate regimen is either PEG-interferon alfa-2a (180 µg) or interferon alfa-2b (1.5 µg/kg) once weekly for 24 weeks. The possible roles of ribavirin and of genotyping of HCV in guiding therapy are currently under investigation.
CHRONIC HEPATITIS C
Chronic hepatitis C is caused by infection with the hepatitis C virus (HCV), a small RNA virus classified in genus Hepacivirus, family Flaviviridae. The diagnosis of chronic hepatitis C usually is based on the finding of anti-HCV in a patient with serum aminotransferase elevations or a risk factor for hepatitis C. The typical test for anti-HCV is an enzyme immunoassay, which occasionally can yield a false-positive result. A recombinant immunoblot assay can be used to confirm anti-HCV reactivity. The diagnosis of hepatitis C is confirmed more aptly, however, by a qualitative test for HCV RNA in serum using a sensitive assay, such as a reverse-transcriptase PCR. If anti-HCV is present without HCV RNA, recovery from hepatitis C rather than persistent infection probably has occurred. Several commercial assays are available to quantify HCV RNA levels in serum, but these tests have been difficult to standardize. Most patients with chronic hepatitis C have 105 to 107 IU of HCV RNA in serum, and levels are usually stable over time. HCV RNA levels should be measured before and during therapy, but otherwise there is little clinical value to following levels of HCV RNA.
HCV has marked genetic heterogeneity, with nucleotide variability between different isolates ranging from 1 to 50%. Phylogenetic analyses indicate that there are at least 6 different genotypes of HCV (differing by 30 to 50% in sequence) and more than 90 subtypes (differing by 15 to 30%). Different isolates of a single genotype can vary by 5 to 15%, and virions isolated from a single individual often differ by 1 to 5%, a phenomenon that is termed quasispecies diversity and that may account for the propensity of this virus to lead to chronic infection. The most common genotypes in the United States are 1a and 1b (approximately 75%), 2a and 2b (approximately 15%), and 3a (approximately 7%). Genotype 4 occurs typically in Africa and the Middle East and is uncommon in the United States. Genotype 5 is rare outside of South Africa, and genotype 6 is rare outside of Southeast Asia. Infections with different genotypes do not differ in clinical expression or disease severity, but responses to interferon-based therapies depend on genotype of the infection.
Hepatitis C is spread largely by the parenteral route, most commonly as a result of injection drug use or receipt of blood transfusions before the introduction of routine screening of blood for anti-HCV (in 1992) or receipt of plasma products before the introduction of inactivation procedures (in 1986). Hepatitis C also occurs after accidental needle sticks and is an occupational hazard for health care workers. In 10 to 30% of patients, a parenteral source of infection cannot be identified, even after careful questioning. These sporadic cases of hepatitis C probably are related to sexual contact or "inapparent" parenteral spread. Sexual spread of hepatitis C can occur, but the risk is low, and sexual transmission has been described primarily in individuals with multiple partners. Maternal-infant spread of HCV occurs in approximately 5% of cases of mothers with chronic hepatitis C. Neither breast-feeding nor type of delivery correlates with transmission.
In the typical course of chronic hepatitis C, HCV RNA becomes detectable soon after exposure and remains present throughout the course of the acute illness and thereafter. Approximately one third of patients experience symptoms during the acute episode, and a similar percentage are jaundiced. Aminotransferase levels vary widely but after the acute episode are usually less than 10 times the upper limit of normal. In 30 to 50% of infected individuals, serum aminotransferase levels decrease and remain in the normal range despite persistence of HCV RNA. These individuals nevertheless have chronic hepatitis on liver biopsy. Anti-HCV rises after the onset of ALT elevations and symptoms, and it usually persists at high titers. Anti-HCV may not become detectable in patients who have renal failure, are immunosuppressed, or have hypogammaglobulinemia or agammaglobulinemia.
The natural history of hepatitis C is highly variable. A small proportion of patients have severe and progressive disease, and cirrhosis and end-stage liver disease develop within a few years; other patients have a benign outcome. In patients followed from the time of acute infection (e.g., after blood transfusion or receipt of contaminated blood products), approximately 55 to 85% have chronic infection, but cirrhosis develops in only 5 to 20% within the first 20 years. In these patients, there is little or no increase in hepatitis C-related mortality rate during the first 2 decades of infection. When patients with established chronic hepatitis C are followed prospectively from the time of initial presentation, 30 to 50% have cirrhosis, however, and morbidity and mortality rates are substantial, with development of end-stage liver disease or hepatocellular carcinoma, particularly in patients with cirrhosis or severe fibrosis indicated on initial liver biopsy. At the time of diagnosis, the average patient probably has had the infection for 10 to 20 years (dating onset from time of presumed exposure).
Factors associated with the risk of development of cirrhosis in chronic hepatitis C include age, male sex, alcohol use, and coinfection with other hepatitis viruses or HIV. Factors associated with increased rate of development of hepatocellular carcinoma are cirrhosis or advanced fibrosis on liver biopsy, age, male sex, and alcohol abuse. In some retrospective studies, treatment with interferon-α, even without a sustained virologic response, has been associated with a lower rate of development of liver cancer.
The pathogenesis of viral persistence and the cause of hepatic injury in chronic hepatitis C infection are unknown, but cytotoxic T lymphocyte-mediated responses are probably important. In general, the degree of liver injury does not correlate with the level or genotype of virus but tends to increase with duration of infection. Nevertheless, some individuals remain infected with HCV for decades yet have minimal changes on liver biopsy. Alcohol ingestion and other causes of liver injury (e.g., iron overload, nonalcoholic steatohepatitis, or concurrent hepatitis virus infection) may augment liver injury in chronic HCV infection.
The extrahepatic manifestations of chronic hepatitis C include cryoglobulinemia ( Chapter 196 ), glomerulonephritis ( Chapter 119 ), mucocutaneous vasculitis ( Chapter 284 ), sicca syndrome ( Chapter 282 ), non-Hodgkin's B-cell lymphoma ( Chapter 195 ), porphyria cutanea tarda ( Chapter 223 ), lichen planus ( Chapter 474 ), and perhaps fibromyalgia ( Chapter 289 ). Cryoglobulinemia, which is the most common and well-defined complication of hepatitis C, occurs in approximately 1% of adults with this infection. Typical manifestations are fatigue, myalgias, arthralgias, skin rash (purpura, hives, and leukocytoclastic vasculitis), neuropathy, and renal disease (glomerulonephritis). Laboratory testing reveals high levels of rheumatoid factor and of cryoglobulins containing anti-HCV and HCV RNA, with low levels of complement. Cryoglobulinemia can be severe and lead to end-stage renal disease or severe neuropathies.
The management of patients with chronic hepatitis C should include counseling to abstain from alcohol and evаluation for hepatitis A and B vaccination. The therapy of hepatitis C is rapidly evolving. Interferon-α (recombinant and natural) has been used successfully to treat chronic hepatitis C for more than a decade, but the overall sustained virologic response rate to a course of interferon-α monotherapy is only 10 to 20%. Combination therapy using interferon-α and ribavirin increases the sustained virologic response rate considerably to 35 to 45%. A 48-week course of the combination of peginterferon and ribavirin yields an overall virologic response rate of 54 to 56%.
Pretreatment factors associated with a beneficial response to combination therapy include short duration of disease, lack of severe hepatic fibrosis or cirrhosis, low level of HCV RNA, and viral genotypes 2 and 3. Sustained virologic responses also correlate with early clearance of HCV RNA (within 3 months of starting therapy) and with more prolonged courses of treatment. Among patients with genotypes 2 and 3, the sustained response rates are 70 to 80%, and these rates can be achieved by a 24-week course of therapy using a lower dose of ribavirin (800 mg daily). In contrast, among patients with genotype 1, sustained responses are more common with a 48-week course of therapy (40 to 45%) than with a 24-week course, and optimal response rates require a full dose of ribavirin (1000 to 1200 mg daily).
The usual criteria used to define a beneficial response to therapy in chronic hepatitis C are (1) eradication of HCV RNA from serum, (2) normalization of serum aminotransferase levels, and (3) improvements in liver histology. The most accurate end point in defining a beneficial response to treatment is absence of detectable HCV RNA (by a reliable and sensitive PCR technique) for at least 6 months after stopping therapy, a sustained virologic response that is highly predictive of long-term remission and resolution of the liver disease and may indicate eradication of the infection.
With combination therapy, HCV RNA levels typically decrease rapidly with starting treatment and, in responders, become undetectable within 1 to 3 months. Serum aminotransferase levels become normal in most patients with virologic response by the end of treatment. In patients who have a relapse, HCV RNA and elevations in serum ALT level reappear soon after therapy is stopped. In nonresponders, ALT levels may decrease and become normal, but HCV RNA remains detectable. In contrast, in some patients HCV becomes RNA-negative during therapy, but aminotransferase levels remain elevated; these patients often have a sustained response, and serum ALT levels may become normal when interferon is stopped.
At present, therapy is recommended for patients with chronic hepatitis C with HCV RNA in serum, raised serum aminotransferase levels, chronic hepatitis of at least moderate severity on liver biopsy specimen (presence of fibrosis or moderate degrees of inflammation and necrosis), and no contraindications to treatment. The contraindications to peginterferon and ribavirin combination therapy are decompensated liver disease, renal failure, severe immunosuppression, solid-organ transplantation, cytopenia, severe psychiatric disease, and active substance abuse. Ribavirin therapy is contraindicated in patients with hemolysis, anemia, significant coronary or cerebrovascular disease, or renal insufficiency. Because ribavirin is teratogenic, it is essential that adequate contraception be practiced during therapy of men and women and for at least 6 months thereafter. Patients with genotype 1 should receive a 48-week course of peginterferon (1.5 µg/kg of alfa-2b, or 180 µg of alfa-2a) weekly in combination with ribavirin in a dose of 1000 mg if body weight is less than 75 kg and 1200 mg if body weight is greater than 75 kg. Patients with genotype 2 or 3 may be able to receive a 24-week course of peginterferon (in the same dose as for genotype 1 patients) and ribavirin in a dose of 800 mg/day. The side effects of interferon and ribavirin must be reviewed carefully before starting therapy. Interferon induces an influenza-like syndrome with the first several doses. Thereafter, the major side effects are fatigue, malaise, depression, difficulty in concentrating, bone marrow suppression, and, in rare instances, bacterial infections or induction of autoimmune disease. Side effects of ribavirin include a dose-related hemolysis that usually results in a 5 to 15% decrease in hemoglobin level, mild itching, and nasal congestion. Dose modification frequently is required during therapy.
Even with combination therapy, the overall sustained virologic response rate to interferon treatment in hepatitis C is only 50%, and many patients find the therapy difficult to tolerate. For patients with decompensated liver disease secondary to hepatitis C, liver transplantation is indicated. Potential future approaches include specific inhibitors of HCV protease, helicase, and polymerase enzymes and agents that block uptake, membrane attachment, or translation initiation of HCV.
"Given enough eyeballs, all bugs are shallow."