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Hepatitis C Update 2007
Author: Jennifer V. Sellakumar Tom, MD, Clinical Assistant Professor, Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.
Peer Reviewer: Carol A. Kemper, MD, FACP, Clinical Associate Professor, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center and the Camino Medical Group.
This article originally appeared in Emergency Medicine Reports, April 16, 2007.
Hepatitis C virus (HCV) infection results in both acute and chronic hepatitis. Although the acute infection process is often asymptomatic, HCV typically leads to chronic hepatitis and can frequently result in cirrhosis, hepatic failure and hepatocellular carcinoma (HCC). Approximately 20-30% of chronically infected individuals develop cirrhosis over a two to three decade time period. Chronic HCV is the most common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States. Hepatitis C is present in 1-2% of the population and 1-2% in health care workers as well. The primary care physician needs to be aware of the risk factors, promptly screen patients with appropriate testing, and provide timely referral to specialists who can provide often life-saving treatment. This issue covers the epidemiology, pathophysiology, diagnostic testing, and therapeutic options pertinent for the primary care physician's role in this chronic and insidious disease.
Hepatitis C is a single-stranded RNA flavivirus that was first identified in the late 1980s as the virus responsible for causing most of the cases of non-A, non-B hepatitis. HCV is the most common blood-borne infection in the United States and currently the most common indication for liver transplantation.1-4 Hepatitis C is transmitted through contact with blood and blood products, with injection drug use (IDU) a leading risk factor for infection. More than 170 million people worldwide have been exposed to hepatitis C, and approximately 3.9 million Americans have serologic evidence of HCV. Although most acute HCV infections are asymptomatic, chronic HCV infection may result in serious complications. The risk of chronic disease in HCV infected patients is 50%-85 %. Over 20-30 years, those with chronic HCV infection have a 5-20% risk of progression to cirrhosis and a 1-4% yearly risk of developing hepatocellular carcinoma (HCC).5,6 The standard therapy for hepatitis C infection is a combination of pegylated interferon and ribavirin, which is started after genotype and biopsy results are obtained. The combination of pegylated interferon and ribavirin can clear the virus in more than 50% of patients1,7 and can reduce liver fibrosis progression. Despite advancements in diagnostic testing and treatment, patients with hepatitis C infection continue to develop cirrhosis and hepatocellular carcinoma. Many chronic HCV-infected patients are asymptomatic and unaware they are infected, so they unknowingly continue to spread the virus. These patients would benefit from being tested for HCV based on risk factors and receiving the appropriate treatment. The prevalence of HCV infection among health care workers is 1-2%, the same as among the general population in the United States. Prevention of transmission of the HCV can be achieved by the use of universal health care precautions.
Approximately 3.9 million Americans have been exposed to the HCV infection, and more than 170 million people have been exposed worldwide.1,8 The prevalence of serum antibodies to HCV is 1.8% in the general United States population, most of whom have chronic infection. As per the WHO report of 2001, chronic liver diseases were the cause of 1.4 million deaths, and approximately 20% of the deaths were due to HCV infections (more than 280,000 deaths).7,9,10 In the United States, the 30- to 49-year-old age group is the most commonly affected, with men infected more commonly than women.2
The predominant mode of transmission is parenteral.1,2,11-13 The most common methods of transmission include intravenous and intranasal drug use, vertical transmission during childbirth, through sexual intercourse, occupational exposures, and blood product transfusion prior to 1992. It is estimated that half of those infected with HCV do not have recognized risk factors. Among the recognized risk factors for HCV transmission, injection drug use is the most common.7 The risk of acquisition of HCV from solid organ transplantation and blood/blood product transmission was substantial prior to 1992 and now is rare.2 Since the Red Cross instituted mandatory testing, the risk of transmission of HCV is less than 1:100,000 units of transfused blood. Vertical transmission is the main source of infection in the pediatric population. The risk of transmission from a mother with chronic HCV infection is 5-6% per delivery. There is an increased risk of HCV vertical transmission if the mother is coinfected with HIV. Currently, there are no conclusive data on how the mode of newborn delivery affects the transmission of HCV. HCV is less efficiently transmitted through sexual intercourse than hepatitis B and HIV; however, people with multiple sexual partners have a higher risk of infection with HCV.2 HCV transmission risk in health care workers through percutaneous exposure is 1-3%, as compared to 30% for hepatitis B and 0.3% for HIV. There is also risk of transmission associated with hemodialysis, tattooing, shared body piercing, organ transplantation, sharing contaminated medical equipment in places where the HCV prevalence is high.5 Kissing, hugging, sharing eating utensils or food do not transmit HCV. (See Table 1 and Table 2.)
|Table 1. Estimated Prevalence of Hepatitis C by Region|
|Table 2. Risk Factors for Hepatitis C Virus (HCV) Infection|
Chronic HCV is a result of an intermediate immune response that induces hepatic cell destruction and fibrosis. However, the immune response often is insufficient to eradicate the virus from its reservoirs.7 Patients with poor immunity often are asymptomatic during the acute phase of the HCV infection and more likely to become chronic carriers than those with strong immune responses. HCV- specific CD8 T cells have decreased effector functions, including secretion of antiviral cytokines and lytic activity. The effectiveness of the current antiviral combination therapy of interferon and ribavirin may be explained by restoration of a specific immune response and their antiviral activity.
The majority of acute HCV infections are asymptomatic or present with a mild flu-like illness with little or no jaundice (60-75%).5,14 People with acute symptomatic HCV infection may develop lethargy, malaise, anorexia, jaundice, abdominal pain, hepatosplenomegaly, arthralgias, and maculopapular rash. The symptoms can last for 2-12 weeks. Patients report a transient intolerance for cigarettes and alcohol during the acute viral hepatitis stage of HCV infection. The differential diagnosis for acute symptomatic HCV infection includes hepatitis A,B,D or E; alcohol or substance abuse; medication use; primary biliary cirrhosis; autoimmune hepatitis; fatty liver; hemochromatosis; Wilson's disease; and alpha 1 antitrypsin deficiency.
Most acutely infected HCV patients will develop chronic infection (50-85%) and a smaller percentage will clear the infection (15-50%). Age at initial infection with HCV, gender, mode of acquisition, immune status, and viral factors may influence the likelihood of developing chronic HCV infection. Although the majority of patients with chronic HCV infection are asymptomatic, a small percentage may experience nausea, abdominal pain, malaise, and have fluctuating alanine transaminase levels. Up to 30% of patients with chronic HCV infection may have persistently normal transaminases. Recent studies have shown that some chronically HCV-infected patients with normal liver enzymes can progress to liver damage or cirrhosis.2,15 Physical examination of patients with chronic HCV may show signs of liver disease including spider angiomata, telangiectasia, and palmar erythema. If patients progress to cirrhosis, they may present with jaundice, splenomegaly, esophageal varices, ascites, hepatic encephalopathy, as well as other end stage liver disease manifestations.
Chronic HCV infection leads to chronic inflammation of the liver, which leads to progression of fibrosis, scarring, and, ultimately, cirrhosis. Patients with cirrhosis commonly present with signs of end stage liver disease including ascites, hepatic encephalopathy, and variceal bleeding from portal hypertension. The median time from infection to cirrhosis is 30 years, with several factors influencing fibrosis rate. Factors that increase the progression to cirrhosis include male gender, older age at infection acquisition, longer duration of infection, immune suppression (HIV-HCV coinfection), chronic hepatitis B coinfection, low CD4 count, moderate to heavy alcohol use, obesity, and diabetes.5,7,16 The risk of cirrhosis is 5-20% in a patient with chronic HCV for 20-30 years.
Following the development of cirrhosis, the risk for hepatocellular carcinoma (HCC) is 1-4 % per year, and the rate is increasing in developed nations. The increased incidence of HCC is thought to be due to the increase in patients with chronic HCV infections who survive to progress to liver failure and hepatocellular carcinoma.2 The average length of survival is 6-20 months following diagnosis of HCC. Resection of malignancy and liver transplantation can be curative if the diagnosis is made early, however HCC generally has a high mortality rate. At present, the recommended screening routine for all patients with hepatitis C includes a liver ultrasound and serum alpha–fetoprotein every 6 months. (See Figure 1.)
|Figure 1. Natural History of hepatitis C Virus (HCV) Infection|
Over the last decade, HCV has been associated with multiple extrahepatic manifestations including dermatologic, hematologic, renal, and autoimmune disorders. One study of 321 patients with chronic HCV infections showed more than one-third of patients had an extrahepatic manifestation.2,17,18 The most frequent HCV-associated extrahepatic manifestations are porphyria cutanea tarda (blistering and easily traumatized sun-exposed skin, which leads to scarring and hypopigmentation), mixed cryoglobulinemia (a systemic vasculitic disease), and membranoproliferative glomerulonephritis.17,19 The mechanism by which the HCV causes extrahepatic manifestations remains unclear. It has been shown that antiviral therapy has effectively treated some of the extrahepatic manifestations, however, the relapse rate is high if the virus is not eradicated.17,20 A recent association of HCV infection, insulin resistance, and diabetes mellitus has been shown.17,21
Diagnostic testing for HCV infection can be divided into serological assays for antibodies and molecular tests for viral particles. Patients generally are screened for risk factors for HCV infection and then are tested for anti-HCV antibodies. Screening assays (based upon antibody detection) have been the reason for the drastic drop in transfusion-related transmission. Once the patient seroconverts, the test usually remains positive. In the small population of HCV-infected patients who spontaneously resolve their infection, the anti–HCV antibodies may decrease in concentration. The current standard is the third generation ELISA, which is a qualitative antibody test, and it has greater than 98% specificity in immunocompetent patients. Antibodies can be detected within 4-10 weeks of infection by ELISA.7 Immunosuppressed patients with HIV, renal failure, or HCV-associated mixed cryoglobulinemia can have false negative HCV-Ab results.
There are qualitative and quantitative tests for HCV and both use PCR (polymerase chain reaction) to amplify HCV RNA. HCV RNA can be detected 1-3 weeks after exposure to HCV. The qualitative PCR assay for HCV RNA is most useful in situations where the ELISA test for anti-HCV antibodies is inconclusive, in immunosuppressed patients, in patients with persistently normal transaminase levels with a positive anti-HCV antibodies, when other causes of liver disease are present (i.e., alcohol abuse), or in acute hepatitis before antibodies have been formed. Knowledge of the viral load (quantitative RNA) helps to predict treatment response and the risk of relapse. The HCV viral load does not correlate with severity of hepatitis.7,22
HCV consists of six genotypes and many subtypes based on the RNA sequence diversity of the genome. Genotypes 1 and 2 are commonly found worldwide, and the remaining genotypes 3, 4, 5, and 6 are typically confined to specific geographic areas. More than 70% of HCV-infected patients in the United States are genotype 1, which typically has a lower response rate to treatment than genotypes 2 and 3.1 When a patient is being considered for treatment, the genotype should be determined. Knowledge of the specific genotype will help to predict the chances of achieving sustained virologic response (persistent absence of HCV RNA 6 months after completion of treatment) and will define the length of treatment.7,22
Liver biopsy is currently indicated for initial assessment of patients with chronic HCV infection. In genotypes 2 and 3, liver biopsy is optional due to high treatment response. Biopsy can assess the severity of liver fibrosis and can aid in ruling out other causes of liver disease. Assessment of the severity of fibrosis through liver biopsy helps to make the decision to treat. Liver biopsies, however, do have major limitations, including sampling variability and the risk of adverse effects1 One study has shown the incidence of severe adverse effects was 0.3% and the mortality rate was 0.03% in 98,445 liver biopsies.1,23
In the past decade, there has been a great improvement in therapies for chronic HCV infection. The main objective of treatment is to eradicate the virus and to prevent complications of HCV chronic infection (i.e., cirrhosis and HCC). Other goals include the reduction of extrahepatic manifestations and preventing transmission. When treatment is commenced, its efficacy is assessed by measurement of HCV RNA viral load. The main goal of treatment is to achieve a sustained viral response (SVR), which is persistent absence of the HCV RNA 6 months after completion of therapy. Patients with chronic HCV infection who are considered for treatment have a chronic viremia (quantified by PCR testing) and histologic evidence of hepatic inflammation.1 The current regimen for antiviral treatment of HCV is pegylated interferon in combination with ribavirin. The SVR rate of the combined regimen is 45% for genotype 1 and is close to 80% for genotypes 2 and 3 in patients without HIV co-infection.2 Patients must be monitored closely during treatment for adverse side effects of antiviral therapy. Adverse effects include ribavirin–induced hemolysis, interferon-induced bone marrow suppression, depression, and teratogenicity (patients are counseled to use strict birth control during and 6 months after treatment). (See Table 3.) Adverse effects are severe enough to discontinue combination treatment in up to 17% of patients.1 Alcohol consumption must be avoided during treatment because it negatively effects treatment response.1
|Table 3. Adverse Side Effects from Interferon and Ribavirin|
Nonresponders are patients who have detectable serum HCV RNA at the end of treatment. By 2015, it is expected that the number of nonresponders will exceed the number of patients with HCV infection seeking initial treatment.1 The SVR in nonresponders retreated with the pegylated interferon combination therapy is 4-12%. Preliminary studies have shown some improvement of SVR with the use of interferon alfacon-1 and ribavirin.1
Decompensated cirrhosis from HCV is currently the leading indication for liver transplant in North America.5,7 HCV recurs in the transplanted liver in more than 95% of patients.7 There is a decreased survival rate for transplant recipients with HCV than patients with liver transplants for other indications. In addition, accelerated recurrent HCV infection following transplantation can result in rapid development of cirrhosis and decompensated liver failure. Currently, efforts to treat recurrent HCV in liver transplant recipients are complicated by limited efficacy and adverse effects of the current treatments available.
HIV-HCV Coinifected Patients. As HIV and HCV share the same mode of transmission, coinfection is common.5 Studies have shown that roughly 25%-30% of HIV-infected patients in the United States and Europe are coinfected with HCV.1,24,25 Patients with coinfection appear to have a slightly decreased response rate to combination therapy when compared to patients with only HCV infection. Also, there is a high rate of HCV therapy discontinuation in coinfected patients due to adverse effects. Although the success of HAART (highly active antiretroviral therapy) has dropped HIV morbidity and mortality, HCV-associated liver failure and death has increased in coinfected patients.5 HCV seropositivity is an independent predictor of HIV progression and mortality in HIV-infected patients. Patients with HIV and HCV coinfection should consult with an experienced specialist for treatment.
Pediatric HCV-Infected Patients. In the United States, the prevalence of anti-HCV antibodies in children is 0.2%-0.4%.
In the past, the mode of transmission of HCV in children was through the transfusion of blood and blood products. Today, due to mandatory blood and blood product testing, the main risk factor is perinatal transmission (5-6% of all cases).2 Commonly, pediatric patients with chronic HCV infections have a mild course of the disease; however, it is not clear if the benign course will continue into their adulthood. The current combination treatment regimen is not approved in children, except for those with strong indications (i.e., progressive liver fibrosis) with response rates similar to adults.2
Acute HCV Infection. Acute HCV infection should be considered in patients presenting with acute viral illness with nausea, malaise, anorexia, jaundice, and right upper quadrant pain and active injection or intranasal drug use. It should also be considered in health care workers with occupational exposure. There is a minority of patients who spontaneously clear the HCV infection generally within 12 weeks postexposure. Some studies suggest that early treatment can decrease the rate of developing chronic HCV infection using interferon therapy alone,1 however, combination therapy with pegylated interferon and ribavirin for 6 months is the current treatment of choice for acute HCV infection.
HCV Screening. The primary care physician has a central role in identifying and screening patients with risk factors for HCV. If a patient is found to have HCV infection, he or she should be referred to an infectious disease or hepatic specialist for further evaluation and treatment. Many studies have shown that there are barriers to achieve optimal care for HCV-infected patients in primary care clinics.2,26 One large university based study found that only 1% of patients were asked about risk factors for HCV at their initial visit and only 16% of those at risk without signs of liver disease were tested. Also in the same study, 23% of HCV RNA positive patients with elevated transaminases were not referred to specialists.2 These studies suggest there is a significant population of HCV-infected individuals who remain undiagnosed and do not have access to treatment. In the late 1990s, the health care cost of HCV infection exceeded $ 1 billion/year.2 As the population of HCV-infected patients rises, there is an expected increase of the financial cost of this disease. Preventing and slowing the disease progression can decrease the expected financial burden. Patients screened as high risk for hepatitis C should be instructed to follow up with their primary care physician (or referred to a physician for those who lack a physician) where they can be treated for HCV.
Patient Prevention and Education
Patients with risk factors for HCV infection should be tested and counseled on modifying risky behavior. Patients with HCV infection should be instructed on modifying factors that affect disease progression. Excessive alcohol intake and HCV infection have a synergistic effect on liver damage, and therefore all patients with HCV infection should be educated on alcohol abstinence or limiting alcohol ingestion. As the clinical course for HCV-infected patients with acute hepatitis A or B is more severe, vaccination for hepatitis A and B should be considered. Patients should also be educated on the increase of disease progression associated with obesity and other uncontrolled metabolic disorders (i.e., diabetes).7,27 NSAIDs should be avoided, especially in patients with cirrhosis. Kava and other hepatotoxins should be avoided. Infected patients should be instructed not to donate blood/blood products or to share sharp items (i.e., razors, nail clippers, toothbrushes) potentially contaminated with blood. Sexual partners should be informed of the small risk of transmission and are encouraged to be tested. In order to decrease the social isolation associated with diagnosis of HCV infection, it is important that patients understand that routine social and household contacts have not been shown to transmit the HCV.
There are many treatments for HCV currently being studied in early clinical trials, including HCV vaccine, immunomodulators, alternative interferons, and therapy directed against specific HCV targets. However, no new drugs are expected to be available for the next several years and treatment will most likely remain based upon a core of interferon therapy.
HCV and the Health Care Worker
Health care workers are at risk for exposure to blood and body fluids that may be contaminated with infectious agents. The prevalence of HCV infection in health care workers is 1-2% (similar to the general population) and the risk of HCV seroconversion following percutaneous needlestick exposure is 1-3%. Universal precautions are to be used for all patients as issued by the CDC.6 Health care workers can effectively reduce their risk of exposure during invasive procedures by using contact precautions (i.e., gloves, gowns, goggles). The Occupational Safety and Health Administration (OSHA) mandates the use of personal protective equipment during invasive procedures to prevent exposures. The usage of needleless intravenous systems and safety devices can reduce the rate of percutaneous exposure.
Patients with occupational exposure to HCV should be advised to seek immediate medical attention. For significant exposures, the source should be tested. If a patient was exposed to an HCV-infected source, the patient should be tested for anti-HCV antibodies and serum transaminases levels with repeated testing in 6 months.
HCV infection is found in roughly 3.9 million people in the United States. Chronic infection with HCV is a leading cause of cirrhosis and is the most common indication for liver transplant in the United States. There have been many advancements in diagnosis and treatment of HCV in the past decade. Peginterferon and ribavirin therapy have been shown to achieve sustained viral response in almost 50% of patients. However death from hepatitis C is still rising due to inadequate detection and treatment. Primary care physicians can help identify, counsel, and refer patients to specialists for treatment. Continued awareness of factors that promote HCV transmission and disease progression is important in both patients and health care providers so that HCV-infected patients may be detected and referred for treatment. Transmission of HCV in the health care setting may be prevented by the use of appropriate personal protective equipment during invasive procedures and the use of safety devices.
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