New Approaches to the Prevention, Diagnosis, and Treatment of Viral Hepatitis

This monograph is provided as a service to the medical community by the American Digestive Health Foundation (ADHF) in cooperation with the American Liver Foundation. It was developed in consult with the Digestive Health Initiative (DHI) Viral Hepatitis Education Campaign Scientific Advisory Board and Section Chairs: Eugene R. Schiff, MD; Willis C. Maddrey, MD; Emmet B. Keeffe, MD; Gary L. Davis, MD; Jay H. Hoofnagle, MD; Karen L. Lindsay, MD; Harold Margolis, MD; Robert P. Perrillo, MD; Leonard B. Seeff, MD; John M. Vierling, MD; and Teresa L. Wright, MD. The views expressed herein, while consistent with current medical literature, are solely those of the board and section chairs.

The Viral Hepatitis Education Campaign is a DHI program produced by the ADHF in cooperation with the American Liver Foundation to educate healthcare professionals, consumers, and policy makers about prevention, early detection, and treatment of viral hepatitis. The viral hepatitis monograph will help inform primary care physicians (and provide a concise review for gastroenterologists and hepatologists) about the virology, epidemiology, natural history, diagnosis, prevention, and treatment of the most common types of viral hepatitis.

Learning Objectives

After completing the monograph, the participant will be able to:

Identify the critical elements of screening, prevention, and treatment protocols of the most common viral hepatitis strains

Recognize the signs and symptoms of the several forms of viral hepatitis

Explain to patients the importance of preventing viral hepatitis

Improve quality of care and the clinical outcomes of patients with viral hepatitis

Introduction

Type A Viral Hepatitis

• Virology
• Epidemiology
• The Clinical Spectrum of Disease
• Diagnosis
• Prevention

Type E Viral Hepatitis

Type B Viral Hepatitis

• Virology
• Epidemiology
• Natural History
• Diagnosis
• Prevention
• Treatment
• Liver Transplantation

Type C Viral Hepatitis

• Virology
• Epidemiology
• Natural History
• Diagnosis
• Management and Treatment

References

Continuing Medical Education, CME Self-Test and CME Evaluation -- email amanela@gastro.org for details

Viral hepatitis is a major public health concern. It is a source of significant morbidity and mortality, both in the U.S. and around the world, and exacts a substantial cost on society. Viral hepatitis is the most common cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Five primary viruses causing hepatitis have been identified to date, producing five distinct disease entities affecting the liver—hepatitis types A, B, C, D, and E (Figure 1). While hepatitis A virus (HAV) and hepatitis E virus (HEV) cause only acute disease, hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) may produce either acute or chronic illness.

Viral hepatitis has long attracted the attention of physicians, natural philosophers, and those concerned with public health. The ancient Greeks, reporting an outbreak in the 5th century BC, referred to jaundice as a “system complex”; more than a millennium later, Pope Zacharias observed that it might be wise to isolate people with jaundice from those who were well. Notwithstanding our forebears’ relative lack of medical sophistication, these clinical observations and epidemiological precautions still seem eminently practical.

Despite the references to jaundice in ancient Chinese literature, the Hebrew Talmud, and the writings of Hippocrates, the identification and characterization of the particular forms of disease and the agents that cause them are recent discoveries. Hepatitis A and hepatitis B, formerly known as “infectious hepatitis” and “serum hepatitis,” were defined after World War II. In the early 1970s, following recognition of HAV and HBV, scientists found cases of transfusion-associated hepatitis that were not caused by either HAV or HBV. The new disease was called “non-A, non-B” hepatitis until 1989, when Michael Houghton and colleagues at Chiron Corporation sequenced a novel viral genome, and the disease was renamed “hepatitis C.” Of the two remaining viruses, the delta variant was found to be a distinct form requiring co-infection with HBV for its continued replication. Prevalence of hepatitis D in North America is low, save for intravenous drug users or individuals receiving multiple transfusions. Hepatitis E is relatively uncommon in the U.S., although it
is seen more frequently in developing countries; like hepatitis A, it is acute and self-limiting, although women infected during the third trimester of pregnancy are at a heightened risk of liver failure. An additional candidate virus, hepatitis G virus, has been discovered recently and its possible role in causing viral hepatitis continues to be evaluated. Hepatitis G virus and another recently identified variant, hepatitis GB virus, appear to be nearly identical. Their role in the etiology of acute or chronic hepatitis is unclear.

Each year, some 200,000 to 700,000 new acute viral hepatitis infections occur in the U.S. In 1995, these included upwards of 180,000 new infections of hepatitis A; 128,000 of hepatitis B; and 28,000 of hepatitis C (CDC: unpublished data). Of these, there are about 100 deaths per year from fulminant hepatitis A and 150 from hepatitis B; hepatitis C has rarely been implicated as a cause of fulminant hepatic failure (CDC: unpublished data). Although the death rate from acute disease is low, many patients with hepatitis B and C become chronically infected, and a large percentage progress to chronic liver disease. The Centers for Disease Control and Prevention (CDC) estimate that approximately 1-1.25 million Americans are infected with HBV and nearly 4 million with HCV (CDC: unpublished data). Almost 6,000 Americans die each year as a consequence of chronic hepatic disease associated with hepatitis B and 8,000-10,000 with hepatitis C (CDC: unpublished data), and the death rate from hepatitis C is estimated to rise and likely triple by the year 2020.

The costs associated with viral hepatitis are significant, particularly for hepatitis B and C. In 1991, the most recent estimated annual cost (medical care, lost work, and productivity) is well in excess of a billion dollars (CDC: unpublished data). When quality of life is factored into the equation, the costs are even greater.

There has been significant progress in recent years in the understanding of the diagnosis, epidemiology, natural history, prevention, and treatment of viral hepatitis. All cases of HAV and HBV infection are potentially preventable, and while a vaccine to prevent hepatitis C remains an objective of research, new therapies have proven to be beneficial for many patients. This monograph will explore current strategies to prevent, diagnose, and manage the major forms of viral hepatitis seen in the U.S. The aim is to improve the quality of care and the clinical outcomes of patients with these common, yet serious and largely preventable, diseases.

Virology

Hepatitis A is caused by a single-strand ribonucleic acid (RNA) virus belonging to the family Picornaviradae, a group that includes both the polio viruses and the rhinoviruses, sources of the common cold. Hepatitis A virus is non-enveloped and replicates exclusively in the cytoplasm of the host cell. Only one serotype of HAV has been recognized, but multiple genotypes of HAV have been found in infected humans. Unlike the different genotypic forms of HBV and HCV, the HAV variations are closely related antigenically and do not produce clinically important distinctions in the natural history of disease or the response to treatment. The antigenic similarity of HAV helps explain the global protection afforded by immune globulin and vaccination. The virus is heat stable and will survive for up to a month at ambient temperatures in the environment. Hepatitis A virus can be inactivated by ultraviolet radiation, autoclaving, sodium hypochlorite, and iodine.

Epidemiology: Risk Factors, Surveillance, and Seroprevalence

Hepatitis A is spread almost exclusively through fecal-oral contact, generally from person to person or via contaminated food or water, with the highest HAV titers found in acute-phase stool samples. Person-to-person transmission is the most important means of dissemination, accounting for the protracted outbreaks that occur in communities, institutions, and day-care centers. It also is the mode best implicated in the high rates of infection found in young children in developing countries. Sewage has been implicated in outbreaks of hepatitis A associated with the ingestion of shellfish and other seafood, and other food-borne community outbreaks, involving such products as fruits and vegetables, have been traced to contami-nation by a food handler.¹ Casual contact, including kissing or the sharing of utensils or cigarettes, is not an efficient source of transmission. While there are reports of cases of hepatitis A transmitted through blood transfusion, the occurrence is rare.²

The figure below details the most common risk factors associated with the acquisition of hepatitis A. It should be noted that injection drug use, which reached a peak of 19 percent of reported cases in 1986, has since declined to two percent of all cases. Generally, the distribution of primary risk factors for hepatitis A has remained relatively stable during the past decade, according to the CDC.³

The rates of hepatitis A have tended to rise and fall sharply every seven to ten years (Figure 3). The increase anticipated in the early 1980s did not materialize, however, as the incidence fell throughout the decade until 1989, when the figure again peaked.⁴ The current rate of reported cases of hepatitis A is approximately 9.1 per 100,000 population; after correcting for underreporting and asymptomatic infections, the CDC estimates 94,000 cases and 180,000 infections occurred in 1995, the most recent year for which data are available (CDC: unpublished data).

Hepatitis A is a disease commonly found in children (age 5-14), who make up almost 30 percent of reported cases.³ As an even larger proportion of children have asymptomatic infections and are contagious, prevention of disease in this population has become a major public health issue. Native Americans report rates ten-fold higher than the other groups, while cases among Hispanics occur at more than twice the rate of Caucasians and Asians.¹ Generally, the prevalence of anti-HAV tends to increase with age, poor personal hygiene, household sanitation, and household sibling size, and to decrease with higher socioeconomic status. (In developing countries, hepatitis A is predominantly a disease of young children.) Gender and immune deficiency have no relation to antibody status.

The Clinical Spectrum of Disease

Hepatitis A is an acute self-limiting disease. The onset of symptoms is abrupt. Early manifestations include fever, malaise, anorexia, nausea, vomiting, and right upper quadrant abdominal discomfort, although the fever typically is short-lived, resolving by the time the patient seeks treatment. The first specific signs of an hepatic process are dark urine, light-colored stool, and scleral icterus, which may be evidenced when the serum bilirubin exceeds 2.5-3.0 mg/dl. These symptoms tend to appear after the illness has begun. Immune globulin can be administered parenterally to household and sexual contacts following exposure to an infected person to prevent disease in individuals who have not already been immunized.

The most noteworthy laboratory findings are marked increases in serum aminotransferases, serum alkaline phosphatase, and serum bilirubin levels (see Figure 4). The rise in serum alanine aminotransferase (ALT) is typically greater than the increase in serum aspartate aminotransferase, customarily exceeding 1,000 IU/dl. Serum aminotransferase activity usually precedes changes in serum bilirubin and alkaline phosphatase.

The period of acute illness may last as long as three weeks. Patients tend to recapture a sense of wellness as elevated serum chemistries return to normal. While serum aminotransferase levels typically resolve before serum bilirubin, in some cases aminotransferase activities may remain abnormal for several months, although the elevation is not marked. These elevations tend not to persist beyond six months and almost always return to normal within a year.

Hepatitis A patients rarely have extrahepatic manifestations, the most common being skin rash and arthralgias. However, three atypical clinical manifestations of hepatitis A have been identified: relapsing hepatitis, cholestatic hepatitis, and autoimmune trigger.⁵

Relapsing hepatitis A is an unusual clinical outcome, in which the disease runs its normal course but is followed several months later by a second cycle of illness. There are reports that patients with relapsing hepatitis A may be replicating virus and have detectable fecal shedding.⁶ However, it is not known if these patients are infectious. Eventually, symptoms diminish over the course of several months. The prognosis is good; chronic hepatitis does not evolve.

Patients with cholestastic hepatitis A characteristically have prolonged jaundice, pruritus, and other manifestations of cholestasis. In certain situations, corticosteroid therapy may hasten recovery. While the mechanism for this response to HAV is unknown, it is believed to be immunological.

One newly recognized atypical manifestation of hepatitis A is the possible “triggering” of autoimmune hepatitis. There are reported cases of patients who had serologic indication of past hepatitis A infection, antibodies to asialoglycoprotein, and defects in T-cell suppressor-inducer cells controlling immune response.⁷ Additional research needs to be done to clarify whether there might be a connection between HAV and autoimmune hepatitis.

The severity of illness associated with hepatitis A increases with age. Children under two years rarely have jaundice and other signs of acute illness. However, nearly 70 percent of infected adults exhibit clinical symptoms or jaundice.⁸ Hepatitis A may be more severe in patients with underlying chronic liver disease of various causes. Fulminant hepatitis A is frequently fatal, especially when it occurs in individuals above the age of 50 and below the age of five. While the actual case fatality rate is difficult to determine, the CDC suggests the death rate is about 30 per 1,000 reported cases in these age ranges. (These numbers may overestimate the fatality rate as many less severe cases are unreported.) Approximately 100 patients per year die of hepatitis A (CDC: unpublished data).

The typical incubation period of hepatitis A is from 15 to 50 days, with an average of 28 days. The two weeks immediately preceding the first signs of jaundice are the most infectious, which complicates attempts at infection control. High concentrations of virus are found in stool samples of infected individuals from the beginning of the incubation period. Viremia is present in the later stages of incubation; nonetheless, it is of low titer and has a shorter duration than fecal excretion. No chronic carrier of HAV has ever been identified, according to the CDC.⁹

Diagnosis of Hepatitis A

The presence of immunoglobulin M (IgM) anti-HAV in serum collected during the acute or convalescent period of the disease (>5 days following exposure) confirms a diagnosis of hepatitis A. In most patients, IgM anti-HAV subsequently declines slowly and becomes undetectable three to six months after infection. Infected individuals also will produce immunoglobulin G (IgG) anti-HAV during the convalescent phase. It will be detectable in serum for the life of the patient and will protect against reinfection. Commercially available diagnostic tests to determine IgM anti-HAV and total (IgM and IgG) anti-HAV levels in serum are quite reliable, offering high specificity and sensitivity.

Prevention of Hepatitis A

During the past decade, the overall incidence of hepatitis A in the U.S. has declined, primarily because of improved hygiene and sanitary conditions. Nonetheless, periodic community outbreaks and the high incidence of disease among select populations demonstrate that hepatitis A remains a serious public health concern.

The availability of hepatitis A vaccines provides a powerful tool to lower disease incidence and potentially eliminate infection by increasing the immunity of high risk individuals. In so doing, the number of individuals susceptible to infection will diminish, as will the pool of virus circulating in the population.

An ideal vaccination strategy would be based on the polio model, allowing both "catch-up", immunization of older children, adolescents, and parents, and routine vaccination of infants and younger children as part of the regular vaccination schedule. However, at the present time there are no data to specify the proper dosing and timing of immunization of children under two years of age. Newer combination vaccines that include an inactivated hepatitis A component, which would help reduce the large number of injections now required, are currently under investigation.

Until the hepatitis A vaccines are approved for children under two years and the optimum strategy can be implemented, the Advisory Committee on Immunization Practices (ACIP) of the CDC, the nation’s primary overseer of immunization practices, recommends pre-exposure vaccination of: ¹

• persons traveling to or working in countries with high or intermediate rates of disease, such as Mexico, the Caribbean, Southeast Asia, South and Central America, and Africa;
• children living in communities with high rates of disease and periodic outbreaks;
• children and young adults living in communities with intermediate rates of disease;
• individuals who engage in high risk behaviors, such as homosexual activities or illegal drug use;
• patients with chronic liver disease;
• individuals with occupational risk of disease, such as primate handlers.

In addition, infected individuals who have contact with case-patients should receive prophylactic therapy with either immune globulin or vaccine. In the face of community outbreaks, vaccination also
may be recommended for food service workers and health care providers.

The U.S. Food and Drug Administration (FDA) has licensed two formalin inactivated hepatitis A vaccines, Havrix®10 and VAQTA®.¹¹ Both are highly effective in adults and children. Studies show that the vaccines are effective in controlling outbreaks in communities with high and intermediate rates of disease.^12,13 Cost-benefit analyses indicate that the vaccines can reduce health care expenditures.¹⁴

Travelers to regions where hepatitis A is endemic ideally should receive primary immunization at least one month before departure. For those making a single trip of short duration, immune globulin provides a cost-effective alternative. Immune globulin will provide immediate protection to travelers who are departing within four weeks to regions of high endemicity.

More than 95 percent of healthy adults and children develop antibodies to HAV within a month after the first of the two recommended doses of vaccine.^15,16 While a single dose may not produce detectable antibody titers, the protective levels still exceed those achieved by immune globulin and can be elevated by booster doses to extend the duration of protection. Patients with compensated chronic liver disease respond well to hepatitis A vaccine with adequate antibody levels. Antibody titers may be lower in older individuals, infants born to seropositive mothers, and following concurrent administration of immune globulin. Few data are available for infants, although what is available suggests that similar levels of protection will be conferred on this population.¹⁷ The recommended dosing schedule for both vaccines includes a primary immunization followed by a booster in six to 18 months (Table 1).

Both vaccines have excellent safety profiles. No serious adverse events have been reported. In both adults and children, the most common side effects are pain, tenderness, and warmth at the site of injection. Individuals with a known or highly likely hypersen-sitivity to vaccine components should not receive the agent.^10,11 The safety of the vaccinations during pregnancy is unknown; physicians should weigh the benefits for the mother against the risk to the fetus, which many believe is low. Special precautions need not be taken for the immunocompromised, as the vaccines are inactivated.

Hepatitis E is a second, recently identified, acute, self-contained enterically transmitted viral hepatitis spread most frequently by contaminated drinking water. Unlike hepatitis A, hepatitis E is rarely seen in the U.S.; the disease is most common in the developing nations of Asia, Africa, and the Indian subcontinent, with epidemics typically occurring after the rainy season. While no clinical outbreaks of hepatitis E have been observed in developed nations, a small number of cases of acute non-A, non-B hepatitis serologically related to HEV have been found in individuals returning from visits to regions of high endemicity.

Symptoms of hepatitis E are similar to hepatitis A: jaundice, malaise, anorexia, abdominal discomfort, and liver enlargement. Chronic liver disease or persistent viremia has not been observed. Perhaps the most striking pathologic feature of hepatitis E is the high mortality rate (nearly 20 percent) among pregnant women, especially during the third trimester.¹⁸ The cause is unknown. It is thought that the high incidence of disseminated intravascular coagulation associated with the disease may play a role. Also worth noting is the potential for reinfection. Overt hepatitis E is most prevalent in individuals between the ages of 15 and 40; this disproportionate rate suggests that the protective effects of anti-HEV antibody may wane over time.

A host of laboratory techniques have been used to diagnose HEV infection, including serologic identification of anti-HEV antibodies, identification of HEV particles in stools by electron microscopy, molecular identification of HEV RNA in stool and serum, and immunohistochemical detection of hepatitis E virus antigen in hepatocytes. In recent epidemics, HEV particles were found to be predominantly excreted between four and six days after individuals became anicteric. There also may be no correlation between the presence of HEV particles and ALT or bilirubin serum levels, which may remain unchanged.

At present, the only prophylactic measures available against HEV infection are improved sanitation and sanitary handling of food and water. In the future, the use of protective immunoglobulins produced in areas of high endemicity may have merit in preventing disease, as may the development of a vaccine. (Immunoglobulin produced in areas where the disease is uncommon are not effective.)

Virology

Hepatitis B virus is a double-stranded deoxyribonucleic acid (DNA) containing virus belonging to the class Hepadnaviridae. The viral genome consists of four separate regions, or genes. Each encodes distinct proteins, sometimes referred to as “antigens.” The surface antigen is the outside lipoprotein coat of the virus; neutralizing antibodies are directed to a common “a” epitope in this region. The precore region encodes a soluble protein called the “e” antigen (HBeAg), whose function has not been fully determined. It is thought to induce tolerance of the host’s immune system to itself and the core antigen, thus contributing to the persistence of chronic infection. Hepatitis B virus replicates through an RNA intermediate, or “pregenome”; the hepatitis B core antigen (HBcAg) is important in incorporating the pregenomic RNA. During the replication cycle of the virus, the pregenomic RNA is reverse transcribed to a complimentary DNA strand. A duplicate DNA strand is then made through the action of viral DNA polymerase. The HBx protein has several functions, including transactivation of virus replication and a probable role in hepatic carcinogenesis.

The virus replicates primarily in hepatocytes, releasing into the circulation hepatitis B surface antigen (HBsAg), HBeAg, and intact virions containing HBV DNA. There also is evidence that HBV replicates in extrahepatic reservoirs, albeit at a lower level. These cell types include peripheral mononuclear cells, macrophages, intestinal epithelium, and other organs.¹⁹ Hepatitis B virus is a relatively resilient virus, remaining potentially infectious for months when stored at approximately 32°C and for years at -20°C. Heat, however, is effective to inactivate the virus — 100°C for 30 minutes is recommended.

The hepatitis B virus has a more complicated structure than HAV. Recent developments in the use of polymerase chain reaction and DNA sequencing techniques have enabled researchers to identify a number of mutant viruses. The best described mutation is in the precore region of the virus, which affects the synthesis of HBeAg. As noted above, HBeAg is a marker of viral replication and infectivity, and some studies have shown an association between fulminant hepatitis B and the presence of this precore mutant. Two other viral mutations in the core gene also may have clinical significance. The first involves the core promoter region and has been associated with increased viral replication and a more severe form of hepatitis; the second one occurs upstream in the core gene and has been linked to impairment of cell-mediated immunity to the virus.

Epidemiology: Incidence, Transmission, Seroprevalence, and Risk Factors

Hepatitis B is a major cause of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Of the more than one million Americans with chronic infection, an estimated 15 to 25 percent will die of complications associated with hepatitis B.²⁰ According to World Health Organization statistics, hepatitis B-induced cirrhosis or liver cancer is the ninth most common cause of death worldwide, taking more than 1 million lives each year.²¹

During the past decade, the annual reported incidence of hepatitis B in the U.S. has ranged from 200,000 to 300,000. The level peaked in 1985 and has since declined by nearly 40 percent (CDC: unpublished data). The drop has been attributed to changes in disease transmission patterns – diminishing participation in high-risk activities – and, to a lesser degree, the vaccination of adults, with the largest decrease in incidence occurring in the population aged 15-39 (Figure 5).²²

Percutaneous and mucous membrane exposure to infected bodily fluids, such as serum, semen, and saliva, and perinatal transmission from mother to child are the major sources of chronic HBV infection.²⁰ The incubation period is longer than for hepatitis A: 45 to 160 days, with an average of 120.

The risk of developing chronic HBV infection is inversely related to age at the time of infection.²³ Ninety percent of infants infected at birth will become chronically infected with HBV, as will 25-50 percent of children aged one to five and one to five percent of older children and adults. However, only a small percentage of carriers will have a history of acute infection – ten percent of children and 30 to 50 percent of adults. Only a fraction of all acute hepatitis B infections, approximately two percent, are reported among children younger than five years of age, even though this cohort accounts for nearly a third of all individuals with chronic infection.²⁴

Immigrants and ethnic groups from regions where hepatitis B is highly endemic, such as Alaskan Eskimos, Asians, and persons from the Pacific Islands, are at high risk of disease.^24-26 Injection drug use or sexual practices, including receptive anal intercourse or heterosexual promiscuity, also increase the risk of disease. The risk from these activities is heightened by a history of sexually transmitted diseases (STD). Health care workers exposed to blood and blood by-products also have a higher prevalence of infection. The most recent data from the CDC’s Sentinel Counties study (CDC: unpublished data) suggest that heterosexual activity is the most common risk factor for hepatitis B, followed by injection drug use, and male homosexuality, making hepatitis B primarily an STD in the minds of many public health officials (Figure 6). Since 1985, the incidence of hepatitis B among homosexual men has decreased by more than 60 percent and has remained stable since 1988. The frequency of hepatitis B associated with injection drug use has fallen 40 percent since 1988. However, during the same period, the incidence of cases associated with heterosexual activity has risen by more than 50 percent. It should be pointed out that most adolescents and adults at risk of HBV infection are hard to identify prior to infection because they do not belong to well-defined risk populations. As a consequence, immunization strategies that target only the more obvious high risk groups may miss a significant number of cases, making global disease prevention difficult.

Natural History

The development of clinical disease is directly correlated with age. Fewer than ten percent of infected children and infants present with symptoms of disease, but the number increases to more than 30 percent in adults above the age of 30.²³ Symptoms include anorexia; malaise; gastrointestinal distress such as nausea, vomiting, and abdominal pain; and jaundice. In addition, patients may have fever, an urticarial rash, and transient arthritis in distal and large joints of the extremities.

The biological response to HBV infection is often complex, particularly in children. In more than 90 percent of adults, the infection is self-limiting. The serologic loss of HBsAg and presence of anti-HBs demonstrates resolution.²⁷ However, in up to five percent of adults, as well as infants and the immunocompromised, the immune response may be incomplete, which often leads to less severe prodromal disease despite persistent viremia and continuing viral replication (positive HBeAg and HBV DNA).^23,28 Patients who have evidence for persistent viral replication are more likely to develop exacerbations, cirrhosis, hepatic decompensation, death from liver failure, and HCC,²⁹ while those who remain in a low replicative state have a reduced risk of more serious sequelae (Figure 7). Additional risk factors include alcohol abuse and co-existent HCV or HDV infection. Future studies are needed to determine what mechanism turns the immune system on and off, and the extent of the role viral mutants play in the pathogenesis of disease.

The rate of progression from chronic hepatitis to HCC ranges from 0.2 to 0.7 percent per year and from compensated cirrhosis to HCC from 0.2 to eight percent per year.^30,31 While HCC resulting from chronic hepatitis B is a major source of mortality worldwide, in the U.S., the disease is infrequently found. The CDC reports HCC incidence rates of 2.4 per 100,000, compared to 55.8 per 100,000 for lung cancer and 50.5 per 100,000 for colorectal cancer (CDC: unpublished data). The prognosis for patients with newly diagnosed HCC is bleak, though, with one year mortality rates as high as 80 percent.³² All told, upwards of one quarter of all patients with chronic HBV will die prematurely of HCC or cirrhosis.²⁰

Diagnosis

There are three antigen-antibody systems associated with HBV infection that serve as the basis for current serologic tests: HBsAg and antibody to HBsAg (anti-HBs), HBcAg and antibody to HBcAg (anti-HBc), and HBeAg and its antibody (anti-HBe). Hepatitis B surface antigen can be found in serum 30 to 60 days after exposure to HBV and may persist for an additional several months when the infection is uncomplicated. Chronic infection may be presumed to be present when the patient maintains a positive blood test for HBsAg for six or more months. Only one to two percent of these individuals will subsequently convert from HBsAg to anti-HBs positive each year. Chronically infected patients may have normal liver function tests (i.e., are healthy carriers) or they can have abnormal serum aminotransferase levels in association with various degrees of underlying liver injury.

It is important to note that while the presence of HBsAg confirms infection, it does not by itself distinguish between acute and chronic infection. Serologic tests to identify the immunoglobulin M class of anti-HBc are the primary method to differentiate acute and chronic HBV infection. Immunoglobulin M anti-HBc normally is detectable for only six months after the onset of infection; thus, a positive test for this antibody signifies that infection has been recent. Negative results can expedite the diagnosis of chronic infection when the physician is confronted with a newly diagnosed patient with a positive test for HBsAg. Antibody to HBsAg develops after resolution of the acute infection or following vaccination and provides long-term protection. Serologic tests for anti-HBs are most often made to determine prior infection or whether immunization is indicated. Infrequently, in chronically infected individuals, HBsAg and anti-HBs may co-exist. The clinical features and course of these individuals are not different from those with HBsAg alone (Figure 8).

As described earlier, HBeAg is an indicator of ongoing viral replication and infectivity. It is normally detectable for a short period (four to eight weeks) during acute hepatitis B. Antibody to HBeAg usually is detected after the loss of HBeAg. Continued detection of HBeAg beyond the first two months after the onset of infection indicates that chronic infection is likely to occur. Most chronically infected individuals remain HBeAg and HBV DNA positive for several years, occasionally for decades. During this time, approximately one-third to one-half of patients have abnormal serum aminotransferase levels and histologic evidence of chronic hepatitis. Approximately five to ten percent will seroconvert from HBeAg to anti-HBe positive each year and will show a marked improvement in aminotransferase levels. While these patients generally are negative for serum HBV DNA by standard molecular hybridization assays, very sensitive molecular techniques, such as polymerase chain reaction, have identified small amounts of circulating HBV DNA in the majority. (The presence of a minute viral reservoir helps explain why reactivated hepatitis may subsequently occur.) This state of low-level viral replication in HBeAg-negative HBsAg carriers should not be confused with the aforementioned HBeAg-negative precore mutant form of the infection. In certain parts of the world, such as Asia, the Mideast, Italy, and Greece, the HBeAg-negative precore mutant is particularly prevalent. In those locales, a chronic carrier of hepatitis B virus may be negative for HBeAg even though moderate to high levels of DNA in serum are detectable. Patients infected with the precore mutant virus often have biochemical and histologic evidence of underlying chronic hepatitis and frequently progress to cirrhosis if they remain untreated.

Prevention

The current goal of the immunization program in the U.S. is the eventual elimination of HBV. In 1991, the ACIP, along with the American Academy of Pediatrics, adopted for hepatitis B the same prevention strategy employed successfully for a number of other vaccines, universal childhood immunization. The committee recommended that all infants born in the U.S. should receive hepatitis B vaccine as part of the routine immunization schedule. One advantage of the strategy is that it provides protection to virtually the entire population born each year; however, with nearly 1.5 million chronically infected individuals and transmission patterns such that most infections are acquired in late adolescence and early adulthood, it will take several decades for the full benefits to be seen. In 1995, the ACIP expanded its recommendations, urging a "catch-up" program targeting 11- and 12-year olds, prevention of perinatal transmission through universal HBsAg screening of pregnant women and immunoprophylaxis of infants born of potentially infectious mothers, and vaccination of high-risk adults. The CDC estimates that coverage of 80 percent of the population could prevent 55,000 new infections, 14,000 chronic infections, and 3,000 deaths each year (CDC: unpublished data).

Other organizations have endorsed the principle of routine immunization, including the World Health Organization, American Academy of Family Physicians, the National Coalition for Adult Immunization, and the Canadian National Advisory Committee on Immunization Practices. In addition, the American College Health Association supports the immunization of all university students, and the American College of Physicians recommends that all adolescents and adults be vaccinated against HBV. By 1995, nearly 58 percent of children under two years of age had received all three doses of HBV vaccine (CDC: unpublished data).

Given the cost of vaccines in the U.S., testing of anti-HBc may be a useful adjunct to hepatitis B immunization in certain circumstances. Preimmunization testing may be cost-effective in settings where the prevalence exceeds 30 percent, such as in the case of persons raised in areas of high endemicity or engaging in high-risk sexual and drug behavior. While rarely warranted, postimmunization testing may be beneficial in persons at high risk of exposure or low risk for an antibody response.³³

Two types of hepatitis B vaccines currently are available. One, which is widely used internationally, contains deactivated virus collected from chronic carriers. The other contains nonglycosylated particles of HBsAg expressed from recombinant DNA in yeast. The latter, which are marketed in the U.S. as Recombivax HB® ³⁴ and Engerix-B®,³⁵ are highly immunogenic and efficacious, and have remarkable safety profiles. Combination vaccines containing recombinant HBsAg and other immunogens used in childhood vaccinations are in development and should help simplify children’s immunization schedule. Newer recombinant vaccines containing other hepatitis antigens also are being investigated as alternatives for those who do not respond to the existing vaccines.

More than 95 percent of healthy infants, children, and young adults who receive three intramuscular does of vaccine given in the deltoid muscle develop protective serum titers of hepatitis B antigen.^34,35 The antigenic response is lower in adults over the age of 40 and in hemodialysis patients and the immunocompromised, who should be given larger doses.^36,37 While the immunization schedule and dosing regimens vary by age and the presence of comorbid conditions, booster doses to achieve higher antibody titers and moere lasting protection are typically given one month after the primary immunization, with a third injection at six months (Table 2). A more rapid schedule may hasten antibody produciton but could reduce peak titers.The two commercially available vaccines are virtually interchangeable: either can be used at its recommended dose to complete a series begun with the other. Nearly half of all individuals who fail to develop antibodies to hepatitis B following three doses will respond to additional immunizations.

Simultaneous administration of vaccine plus post-exposure heptitis B immune globulin will not compromise immunogenicity; neither will coadministration of another vaccine. Immunogenicity is reduced by gluteal and intradermal injection, however.

Persons with antibody titers of at least 10 mIU per milliliter rarely will develop symptomatic hepatitis B. After 10 years, nearly half will lose detectable antibody.³⁸ Even in these patients, an antigenic response may occur. Many will have antibodies to HBV core protein, which is indicative of infection, but will show no signs of disease. Long-term protection likely can be attributed to the lengthy incubation period of the disease, which enables immunized individuals to produce a protective antibody response upon exposure to HBV.

Despite the broad support for routine immunization, a number of issues in the prevention of hepatitis B remain. While insurance coverage of infant vaccination is becoming commonplace and state programs in high-risk communities have reduced the prevalence of chronic hepatitis B infection, increasingly complex immunization schedules and vaccine recommendations could damper the depth and breadth of coverage in the future. Moreover, new combination vaccines could affect the administration and immunogenicity of the primary immunization.

Barriers to HBV vaccination in school-based programs also exist. The cost of the vaccine is a hardship for many programs, hindering the “catch-up” effort. So too, parental consent is difficult to obtain. For high-risk children, such as Asian Pacific Islanders, who are hard to reach on a case-by-case basis, vaccine coverage continues to be very low. Community-based organizations, rather than the schools, may be the preferred means to capture this cohort.

For other high-risk adolescents and adults, significant barriers still must be overcome. Relatively few individuals recognize that hepatitis B is a sexually transmitted disease associated with significant morbidity and mortality. Here, again, the cost of vaccine and clinical follow-up are high, and compliance is low. In addition, there are few relevant health care services offering vaccine to these groups. To date, efforts to vaccinate high-risk adults have been restricted to health care workers. In the future, it may be advantageous to provide vaccination programs in STD clinics, prisons, detention centers, and family planning clinics, and make funding available for vaccine purchase.

Efforts to prevent perinatal transmission of hepatitis B have been blocked by a host of administrative and logistical barriers. First, assessment of maternal infectivity is erratic. Testing of HBsAg is not part of the standard prenatal lab panel, and universal reporting mechanisms have not been developed. Second, maternal HBsAg status is infrequently communicated from the hospital to the provider to the mother, leaving many at-risk infants exposed to infection. Thus, appropriate immunoprophylaxis is infrequently administered. Third, post-vaccination testing is inconsistent. Many parents refuse treatment, and many providers fail to follow-up. When testing is performed, results often are not tracked. Despite the problems, universal prenatal HBsAg screening remains a worthwhile public health goal. Forty to 60 percent of births are identified; ninety percent of those infants receive primary immunization. However, less than 70 percent complete the vaccine series by eight months, and results of post-vaccination testing are infrequently reported (CDC: unpublished data). Public health specialists suggest that the development of a computerized tracking program and universal reporting mechanism could dramatically enhance the effectiveness of perinatal hepatitis B prevention programs.

Treatment

Alfa interferon is the only agent known to have a lasting beneficial effect in the treatment of hepatitis B, and interferon alfa-2b (Intron®A) is the only agent licensed in the U.S. A four-to-six month course of treatment has been shown to produce long-term remission in 25 to 40 percent of patients.³⁹ Furthermore, in a meta-analysis of 15 clinical trials, the overall response rate of patients treated with interferon was 33 percent, compared with 12 percent in controls.⁴⁰ (A successful response was defined as a sustained elimination of HBeAg and HBV DNA from serum.)

Treatment is indicated for patients with persistent elevations in serum aminotransferase concentrations; detectable serum HBsAg, HBeAg, and HBV DNA; chronic hepatitis confirmed by liver biopsy; and compensated liver disease. Liver biopsy is suggested before commencing treatment in order to establish the diagnosis and grade the severity of disease and level of fibrosis. The usual dose of interferon alfa is 5 mIU given subcutaneously daily for four months.³⁹

Patients should be monitored clinically, and serum aminotransferase levels should be assessed once a month or more frequently if needed. Serologic assays for HBeAg and HBV DNA are suggested at the beginning and end of treatment and six months later. Transient increases in serum aminotransferase levels are common, especially in patients whose viral load returns to zero. These flares often represent a wave of clearance of infected cells, which become targets for immune attack during interferon therapy. Dosing should not be changed during a flare, unless the increase is
severe, jaundice ensues, or hepatic function deteriorates.

Interferon alfa therapy can produce an influenza-like acute phase reaction. Patients report fever and chills, headaches, weakness, and muscle soreness beginning six hours following the initial injection and continuing for up to 12 hours. This reaction diminishes with subsequent injections. Chronic side effects may also appear, including fatigue, headaches, irritability, depression, and bone marrow suppression. These adverse reactions require dose reduction in upwards of 40 percent of patients; approximately five percent must be discontinued.^{41, 42} An even smaller percentage had more severe reactions, including bacterial infections, autoimmune disease, seizures, severe depression, cardiac and renal failure, or pneumonitis. Deaths from infection and suicide have been reported, but these generally indicate improper selection of the patient (e.g., individuals with decompensated liver disease or underlying severe depression).

Several biologic, serologic, and clinical features are associated with a positive response to treatment. The most important are high serum aminotranferase levels prior to treatment, low HBV DNA levels, moderate to severe histological activity, and early initiation of therapy.

Patients should be followed when therapy is terminated to assess whether the virus has been eliminated. Therapy can be deemed successful if the patient is negative for HBV DNA and HBeAg and has normal, or near normal, serum aminotransferase levels six months after treatment has ended. A liver biopsy at this time is unnecessary. Several years after a response has been obtained, a third to a half of patients will show no signs of infection.⁴³

There are several groups of patients in which interferon therapy either has been shown to be ineffective, incompletely studied, or associated with a greater likelihood of serious adverse effects (Table 3). Although few studies have been done on children, one recent trial indicated that patients with chronic disease and high serum aminotransferase concentrations have responded to therapy much as adults have.⁴⁴ (The dosing regimen for children is 6 mIU per square meter of body-surface area three times a week for four to six months.) However, patients with chronic disease and atypical serologic profiles, such as the presence of serum HBV DNA but no HBeAg, tend to respond less positively than do those with high serum HBeAg and to relapse frequently.⁴⁵ Nonetheless, long-term remission has been seen in this group.

Patients with decompensated liver disease or cirrhosis are poor candidates for therapy, as are patients with severe depression. Severe side effects, including exacerbation of disease and bacterial infections, have been reported.⁴⁶ However, cirrhosis has been treated successfully in some patients who have decompensated liver disease with a low-dose regimen of interferon alfa – 0.5 mIU to 1 mIU daily – with frequent monitoring and titration as necessary.⁴⁷

A number of new approaches to treating hepatitis B are in development (Table 4). Their objectives are to either inhibit viral proliferation or augment cellular immunity against the virus; in theory, both techniques could be used in combination. Perhaps the most promising therapies at the current time are the new nucleoside analogues, such as famciclovir⁴⁸ and lamivudine,^49-51 which were developed to treat HIV and have been found to have activity against HBV as well. Short-courses of treatment have produced rapid decreases in serum HBV DNA concentrations, and some patients have even shown clearance of HBeAg and reductions in serum aminotransferase levels. However, viral load has returned to pretreatment levels following the end of these short-term regimens, and the amelioration of liver disease has not been sustained. Long-term trials of famciclovir and lamivudine are currently underway, as are studies of combination therapy with interferon alfa. Preliminary reports suggest that the regimens are well tolerated, viral load can be eliminated and often sustained, and improvement in liver histology can be maintained. Nucleoside analogues, alone or in combination with interferon, may have particular benefit in patients who are more difficult to treat with interferon alone (e.g., those with low ALT levels or individuals with chronic hepatitis B following liver transplant). Nevertheless, a number of patents have demonstrated evidence of a mutant virus that is resistant to the effects of lamivudine, and there have even been recent reports of famciclovir resistance. The lamivudine resistant mutants seem to be more common in patients who have been transplanted (see section on Liver Transplantation). However, many experts feel that a combination of nucleoside analogues with or without interferon may discourage viral resistance as has been seen with multi-drug therapy for HIV infection.

Liver Transplantation

In the past, hepatitis B has been a controversial indication for orthotopic liver transplantation (OLT) because the high rate of recurrent infection has limited survival to only 40-50 percent after three years.52 In fact, observed recurrence rates have been 100 percent for recipients with ongoing viral replication and 70-80 percent for those without (HBeAg or HBV DNA positive).⁵² As a consequence, transplantation for hepatitis B was abandoned in some centers in the U.S. and denied reimbursement by the Health Care Financing Administration.

However, recent progress in both the prevention and treatment of recurrent hepatitis B has led to improved outcomes and reauthorization of insurance coverage. Effective prophylaxis can be achieved through long-term administration of hepatitis B immunoglobulin (HBIg).^52-57 In a frequently cited multicenter study⁵³ in which HBIg was administered intravenously to achieve anti-HBs levels greater than 100 IU/l, the rate of recurrent hepatitis B at three years was 58 percent in HBV DNA-negative patients and 83 percent in those who were HBV DNA positive. Moreover, survival at three years was significantly greater in patients receiving long-term HBIg than in patients treated for six months or less (83 percent vs 54 percent). Ongoing studies are exploring whether even better outcomes can be achieved when anti-HBs levels are maintained above 500 IU/l.^{54, 55} (While many transplant centers in the U.S. use HBIg intravenously, other studies showed that intramuscular administration also is effective.^{56, 57})

Experts agree that HBIg must be given indefinitely if the treatment is to be effective. Unfortunately, this regimen is expensive (intravenous HBIg costs $15,000-30,000 for the first year and $5,000-10,000 in subsequent years), the drug supply is limited, and a licensed intravenous preparation is unavailable in the U.S. Investigators are examining whether the nucleoside analogues will provide another option to prevent and treat recurrent hepatitis B.⁵⁸ In preliminary trials, lamivudine monotherapy was shown to be effective in preventing recurrent infection,⁵⁹ and trials combining HBIg and lamivudine also are in progress.⁶⁰ Again, the development of drug-resistant mutants remains a concern. Monotherapy with either lamivudine or famciclovir also has been successful in preventing⁶¹ and treating^{62, 63} recurrent hepatitis B after transplantation. Consequently, most transplant hepatologists recommend that patients with liver failure due to acute or chronic hepatitis B be considered candidates for OLT, irrespective of their initial viral replication status.

Virology

Hepatitis C virus is a spherical, enveloped, single-strand linear RNA genome similar in genetic and virologic makeup to the pestiviruses and flaviviruses that compose the family Flaviviridae. The 5´ end of the virus encodes the structural capsid and envelope proteins. The nonstructural regions are at the 3´ end of the genome and encode the viral proteases, RNA polymerase, and regulatory peptides.

Hepatitis C virus lacks proofreading ability and therefore undergoes genetic changes during replication. Thus, viral populations are extremely heterogeneous. Over the centuries, this diversity has evolved to such a degree that several distinct groupings of virus have formed and are now classified as six major HCV genotypes. Within each of these genotypes are several subtypes. While genotyping of HCV has been reported to be associated with severity of disease and risk of progression, these associations are controversial and by no means certain. However, it is clear that genotype influences the response to short courses of interferon therapy.⁶⁴

The ability of HCV to change its genomic makeup over time also occurs within the infected individual and creates a family of closely related viruses with minor differences, called “quasispecies.” These minor changes may explain the apparent ability of HCV to evade the host’s immune surveillance and persist.⁶⁵ Indeed, antibody produced to one quasispecies does not necessarily afford protection against another. This quasispecies variation, as well as the more significant differences seen with genotypes, will provide a challenge for researchers attempting to construct a polyvalent vaccine.

Epidemiology: Incidence, Transmission, Seroprevalence, and Risk Factors

It is currently estimated that 3.9 million people in the U.S. are infected with HCV. Fortunately, the CDC estimates that the number of new cases each year has fallen during the past decade, from close to 200,000 to 28,000. Most of these new cases are found in young adults between the ages of 20 and 45 (CDC: unpublished data). This population also has the highest seroprevalance of HCV infection. Notwithstanding the decline in new cases, there remains a large number of chronically infected Americans who may serve as a potential source of transmission and who are at risk of the serious sequelae of chronic infection.

Transmission patterns have changed in recent years. Prior to the discovery of HCV, there was a strong correlation found between hepatitis and a recent history of blood transfusion. Injection drug use, employment in health care, sexual/household exposure, promiscuous sexual behavior, and low socioeconomic status also were important risk factors. Although direct percutaneous exposure through a transfusion of blood or blood product remains an efficient means of transmission, currently most HCV infections are acquired outside the transfusion setting.⁶⁶ Elimination of paid donors, initiation of donor unit testing using both surrogate and viral specific tests, viral inactivation of clotting factor concentrates, and other changes in transfusion practices since 1992 have nearly eliminated the risk of hepatitis C for the transfusion recipient. As a consequence, injection drug use has emerged as the most common cause of HCV infection. While the number of acute cases of infection among injection drug users also has declined since 1987, the risk in this population remains high, accounting for more than half of all new and chronic infections. Efficiency of transmission is high among injection drug users as well. More than 75 percent of all new injection-drug users become seropositive for HCV within one year after beginning drug use (CDC: unpublished data). While it is difficult to design effective prevention campaigns for this population, needle distribution and exchange programs may be useful.

Today, among patients with presumed acute hepatitis C, the most commonly identified risk factors are injection drug use; hemodialysis; sexual or household exposure to an infected contact, multiple sexual contacts, or perinatal exposure; and health care employment (CDC: unpublished data). In up to 40 percent of cases, individuals with acute infection deny having an exposure to a recognized risk factor in the six months prior to infection, and as many as 20 percent deny a contact during their lifetime. Nonetheless, more than 60 percent have participated in some high-risk behaviors at some point during their lives, including past drug use, a history of STDs, body piercing, tattoos, intranasal cocaine use, or a prison stay (CDC: unpublished data). Low socioeconomic status, which is a common risk factor for other percutaneously transmitted infections, also remains a risk factor for hepatitis C (Figure 9).

Natural History

The clinical course of hepatitis C has been controversial, in large part because the onset of acute disease rarely is identified, and the evolution to cirrhosis and complications, if it occurs, usually requires decades. Moreover, many of the studies have investigated patients at different points in the course of disease, making comparisons difficult and further confounding the clinical picture. Nevertheless, despite the broad range of presentations and outcomes, and the lengthy history, there are a number of milestones and risk factors that help clarify the natural history of hepatitis C (Figure 10).

The mean incubation period from infection to onset of acute hepatitis, as manifested by elevated serum ALT levels and detectable HCV RNA, is seven weeks, with a range of three to 20 weeks. Prospective studies beginning from recognized exposure have indicated that a third of infected patients become icteric and symptomatic. In contrast, among persons identified as HCV-positive through routine screening, as many as 90 percent do not recall an episode suggesting the onset of acute disease. When recognized, the acute illness typically lasts from two to 12 weeks. In up to 15
percent of cases, the disease is self-limiting; symptoms resolve, HCV RNA becomes undetectable, and ALT levels return to normal. At least two-thirds of all patients are asymptomatic. Jaundice is uncommon, and diagnosis during the acute illness is unusual. Unfortunately, more than 85 percent of patients with acute disease become chronically infected (HCV RNA+) and 65-85 percent develop chronic hepatitis (elevated ALT).⁶⁶ Symptoms of chronic hepatitis usually are mild, intermittent, and nonspecific although they can affect quality of life. The most commonly reported are fatigue, abdominal pain, fever, and arthralgias. As a consequence, many patients do not present or are not tested for hepatitis until years after infection.

Approximately 30 percent of chronically infected patients have persistently normal ALT levels, and in some others, the ALT may be elevated only occasionally. On liver biopsy, these individuals usually have only mild histological changes. Generally, the prognosis is excellent in these patients, although the natural history has not been completely studied.

Chronic hepatitis C must be considered a progressive liver disease. However, disease progression usually evolves over decades and, in many patients, may be so slow that it does not result in increased morbidity or mortality (Figure 11).⁶⁷ The rate of progression relates best to the degree of inflammation and fibrosis seen on liver biopsy⁶⁸ (Figure 12) and to alcohol use.⁶⁹ However, it is very difficult to predict accurately the course in individual patients.

There are several important extrahepatic manifestations of HCV infection, including essential mixed cryoglobulinemia (EMC), arthritis, membranoproliferative glomerulonephritis, keratoconjunctivitis sicca, lichen planus, and porphyria cutanea tarda. Hepatitis C is the most common cause of EMC, which is characterized by the presence of cryoglobulins in serum, hypocomplementemia, and symptoms such as fatigue, muscle and joint pain, arthritis, dermatitis, and neuropathy.

Approximately 20 percent of hepatitis C patients develop cirrhosis during the first two decades of disease, although in rare cases, cirrhosis can develop within the first two years.⁷⁰ Symptoms usually become more noticeable in cirrhotic patients and may include severe fatigue, marked muscle soreness and neuralgia, fluid retention, jaundice, dark urine, upper intestinal hemorrhage, and itching. Many patients, however, will remain asymptomatic until a major complication, such as variceal hemorrhage or ascites, occurs (Figure 13). The risk of developing cirrhosis appears to accelerate in patients over the age of 50-55 years and in the presence of alcohol intake.⁶⁹ Thus, it is recommended that alcohol ingestion be strongly discouraged in all patients with hepatitis C.

Chronic hepatitis C, accompanied by cirrhosis and hepatic failure, is the leading indication for liver transplantation in adults in the U.S., accounting for 30-50 percent of cases at some large transplant centers.⁷¹ While nearly all recipients will remain positive for HCV RNA following transplantation, liver disease usually is mild and only slowly progressive. Five-year survival in these patients is similar to recipients transplanted for other disease.

Diagnosis

Serological tests are the primary screening tools for hepatitis C. The most important technique for detecting antibodies to HCV is the second-generation enzyme-linked immunoassay (EIA-2). The test is simple, automated, easily reproducible, and inexpensive. It is useful in both low- and high-risk settings; in populations with high-seroprevalence, such as injection drug users or patients with elevated serum ALT levels, the sensitivity and accuracy are both greater than 90 percent, and a positive test is sufficient for diagnosis.⁷² A more sensitive third generation assay, with sensitivity and specificity exceeding 95 percent, will be available soon.⁷³

However, in low-seroprevalence populations, such as healthy blood donors with normal serum ALT levels, the EIA-2 assay may produce false positive results. To help resolve these findings, two supplemental assays, the radioimmunoblot assay-2 (RIBA-2) and qualitative reverse transcription-polymerase chain reaction (RT-PCR) assay for HCV RNA are most commonly employed. While the RT-PCR technique is more sensitive, it has been difficult to standardize; wide variation of results from different laboratories has lessened confidence in the reliability of the assay. In populations with low-seroprevalence, only 50 percent of individuals who are HCV EIA-2 positive are reactive with supplemental assays (i.e., are truly positive for hepatitis C). By comparison, in high seropositive populations, the positive predictive value of the screens is higher, nearly 90 percent.⁷² Supplementary testing for infection with HCV should always be performed on asymptomatic individuals from low-risk settings who are anti-HCV positive. Individuals in high-risk groups with positive EIA-2 results do not usually require supplementary testing to confirm the diagnosis.

In the algorithm of diagnostic testing for individuals suspected of HCV infection, a negative EIA-2 test rules out infection in low-risk populations. A positive result would indicate a need for supplementary RIBA-2 testing. Indeterminate test results require HCV RNA testing by PT-PCR. For those with positive findings by both measures and persistently normal ALT, a liver biopsy is usually unnecessary unless antiviral therapy is a consideration.

For those with biochemical or clinical signs of liver disease, a positive EIA-2 finding will be sufficient to make the diagnosis. However, supplementary tests can be used to confirm if the clinician suspects that the test might be falsely positive, as in the patient with marked hyperglobulinemia. Disease activity and staging can be assessed only by liver biopsy.

As mentioned previously, serum ALT levels are elevated in the majority of patients with liver disease due to chronic hepatitis C. However, ALT levels do not correlate well with the histologic extent of the liver disease. Thus, only liver biopsy can provide information about the severity of liver disease, and is usually indicated to stage the disease, especially if treatment is being considered.

Management and Treatment

Currently, interferons are the only agents with proven efficacy in the treatment of HCV infection. In 1991, the U.S. Food and Drug Administration cleared the first alfa interferon, interferon alfa-2b (Intron®A), for the treatment of chronic hepatitis C.³⁹ Five years later, the agency licensed a second drug, interferon alfa-2a (Roferon®-A).⁷⁴ A third compound, interferon alfacon-1 (Infergen®), a synthetic consensus interferon, followed in 1997.⁷⁵ Other interferons under investigation include a leucocyte interferon, a lymphoblastoid interferon, and an interferon beta.

The usual response to interferon treatment is lowering of the serum ALT level and reduction of serum HCV RNA. This occurs within the first few weeks and is usually maximal by the twelfth week of therapy. It is unusual for a response to occur after that time. Thus, it is currently recommended that treatment be stopped if the serum ALT has not returned to normal after the first 12 weeks of treatment. An exception may be the patient with non-detectable HCV RNA by RT-PCR and elevated ALT levels, in whom treatment may be continued. Response to interferon is defined as biochemical (normalization of serum ALT) and virologic (loss of detectable HCV RNA by RT-PCR), and is evaluated at the end of treatment (ETR) and at least six months following discontinuation of treatment (sustained response, or SR).⁷⁶

A recent meta-analysis⁷⁷ of all published randomized controlled clinical trials reported that the currently recommended regimen of 3 million units (MU) administered subcutaneously three times per week for at least 12 months resulted in a biochemical ETR in 50-54 percent of patients and a SR in 28-34 percent. These results compare to 44-53 percent and 14-22 percent, respectively, with the previously recommended therapeutic regimen of six months. Higher doses increased the ETR to 66-69 percent and SR to 46-49 percent when used for 12-18 months, but did not have an advantage if used for shorter durations. Higher doses are also associated with lower patient tolerance.

Patients receiving interferon therapy should have regular monitoring, including complete blood count, ALT and thyroid stimulating hormone levels, and viral load. At three months, serum ALT and HCV RNA levels should be determined. Patients who show no response at this time should discontinue treatment, because the likelihood of future response is negligible.

Side effects of interferon therapy include flu-like symptoms, such as fever, chills, headache, tachycardia, myalgia, and arthralgia. These tend to diminish over the first few days of treatment. Bone marrow suppression, neuropsychiatric problems (depression, cognitive impairment, and irritability), and fatigue may occur later in treatment. Side-effects can sometimes be ameliorated by nocturnal administration of interferon and, in the case of early-phase flu syndrome, by pre-treatment with acetaminophen or non-steroidal anti-inflammatory drugs. Nearly 10 percent of patients require dose reduction because of adverse events; as many as five percent must discontinue therapy. Fewer than two percent of patients suffer more serious side effects, including thyroid disorders or severe depression. Rare adverse events, including seizure disorder, acute cardiac and renal failure, hearing impairment, sepsis, interstitial pulmonary fibrosis, and retinopathy, have been reported.^{39, 74, 75}

The recent panel at the National Institutes of Health Consensus Development Conference on the Management of Hepatitis C⁷⁶ concluded that the indications for interferon treatment were unequivocal in patients with moderate-to-severe inflammation or fibrosis on liver biopsy, as they have the highest risk for progression to cirrhosis. It further recommended that the need for treatment be considered on an individual basis in patients with histologically less severe disease and those with cirrhosis (Figure 14). The NIH consensus panel recommended that patients with decompensated cirrhosis not be treated, but rather be considered for liver transplantation. In addition, the panel recommended that patients with normal serum ALT levels should not be treated, as there is no evidence of lasting benefit and some patients may develop elevated liver enzymes on treatment. The role of interferon therapy in immunosuppressed patients, such as those with HIV/HCV co-infection or transplant recipients is unclear and requires further study.

Interferon also is effective in the treatment of acute HCV infection. In the aforementioned meta-analysis, a three-month course of treatment was associated with a sustained virological response (absence of HCV RNA 12 months after treatment) of 41 percent compared to four percent in untreated controls.⁷⁷ Unfortunately, it is uncommon for patients to present during acute infection. In view of the high response rate to interferon therapy, efforts should be made to identify these patients.

Other agents hold promise for the treatment of hepatitis C. Ribavirin is a nucleoside analogue that has in vitro antiviral activity against several viruses. As monotherapy, ribavirin lowers serum ALT levels in many patients with chronic hepatitis C, but has no effect on serum HCV RNA levels. However, when used in combination with interferon, it reduces post-treatment relapse.^78,79 Several controlled studies are underway to confirm these results. Newer agents that are in development and will eventually require clinical consideration include viral enzyme inhibitors such as protease and HCV RNA polymerase inhibitors, oligopeptides including ribozymes and antisense oligonucleotides, therapeutic vaccines, and other immunomodulators. Studies of corticosteroids, ursodeoxycholic acid, iron reduction therapy, and alpha thymosin either have shown no effect or are inconclusive.

Regardless of other treatment considerations, all patients with hepatitis C should be vaccinated against hepatitis A and hepatitis B as these infections may cause significant morbidity and mortality when superimposed on pre-existing liver disease. In addition, chronic hepatitis C patients with cirrhosis should be monitored for the development of hepatocellular carcinoma by annual alpha fetoprotein determination and ultrasound.

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The Viral Hepatitis Education Campaign is a Digestive Health Initiative (DHI) program produced by the American Digestive Health Foundation in cooperation with the American Liver Foundation to educate healthcare professionals, consumers, and policy makers about prevention, early detection, and treatment of viral hepatitis.

The Digestive Health Initiative is comprised of three educational campaigns: the Ulcer Education Campaign, Colorectal Cancer Education Campaign, and the Viral Hepatitis Education Campaign. The DHI is made possible through an unrestricted educational grant from founding sponsor Astra Merck Inc. The activities of the Viral Hepatitis Education Campaign are made possible by major educational grants from Amgen Inc., Chiron Corporation, Schering-Plough Corporation, and Glaxo Wellcome Inc.