Chapter 39. Viral Hepatitis

• Hepatitis A–E cause most recognized cases of acute viral hepatitis; hepatitis B, C, and D cause most recognized cases of chronic viral hepatitis.
• Hepatitis A and E are transmitted by the fecal-oral route; neither causes chronic infection.
• Hepatitis B, C, and D are acquired percutaneously; all can result in chronic infection.
• Hepatitis D can occur only in a host already infected with hepatitis B.
• All five forms can cause fulminant hepatitis, but B, D, and E are common causes, whereas A and C are very rare causes.
• Diagnostic tests appropriate to different clinical situations detect specific viral antigens and antibodies in serum by sensitive enzyme immunoassay or radioimmunoassay and viral DNA/RNA by sensitive amplification assays (eg, polymerase chain reaction).

Although the hepatitis viruses have been characterized extensively, the pathogenesis, diagnosis, and treatment of chronic viral hepatitis continue to be the focus of research. Sensitive and specific assays are available for all five forms (A to E) of viral hepatitis (Table 39–1). Nevertheless, at least approximately 5–10% of cases of acute and chronic hepatitis cannot be attributed to any of the known forms of viral hepatitis and do not appear to result from toxic, metabolic, or genetic conditions. A specific cause cannot be identified for approximately 50% of cases of fulminant hepatitis. Whether additional unidentified viruses cause acute or chronic liver disease remains an unanswered question; to date, despite intense investigation, no other hepatitis viruses have been identified. This chapter focuses on clinical features of the five known viruses that cause almost all recognized cases of acute and chronic hepatitis (Table 39–2).

Acute Viral Hepatitis

Symptoms and Signs

Symptoms of acute viral hepatitis are usually nonspecific and include malaise, fatigue, nausea, anorexia, and arthralgias. Fever, if present, is usually low grade. With disease progression, pruritus, dark urine, scleral icterus, and jaundice may occur.

Laboratory Findings

In any acute viral hepatitis, serum aminotransferase levels typically exceed 500 units/L and often 1000 units/L, with the alanine aminotransferase (ALT) characteristically higher than the aspartate aminotransferase (AST). Elevation of aminotransferase levels begins in the prodromal phase and precedes the rise in bilirubin level in patients with icteric hepatitis. Serum alkaline phosphatase may be normal or only mildly elevated. Serum bilirubin may be normal (anicteric cases) or elevated (icteric cases), but albumin and prothrombin time are generally normal unless the acute hepatitis is sufficiently severe to impair hepatic synthetic function. In most instances, bilirubin is divided equally between conjugated and unconjugated fractions; values above 20 mg/dL that persist late into the course of viral hepatitis are more likely to be associated with severe disease. Prolongation of the prothrombin time (>3 seconds above the control value or international normalized ratio [INR] >1.7) should raise concern and prompt close monitoring of the patient for worsening hepatic function and impending hepatic failure. Neutropenia and lymphopenia are transient and followed by a relative lymphocytosis. Hypoglycemia occurs occasionally in severe acute hepatitis. A mild and diffuse elevation of the γ-globulin fraction is common, especially in patients with acute hepatitis A.

Imaging Findings

Radiologic imaging studies are rarely necessary unless biliary tract disease is suspected. For example, for patients with profound cholestasis (such as occurs in hepatitis A and even more commonly in hepatitis E), ultrasonography may be helpful in excluding extrahepatic biliary tract obstruction.

Histologic Evaluation

Liver biopsy is rarely necessary in acute viral hepatitis except when the diagnosis is questionable or when chronic hepatitis is suspected.

Chronic Viral Hepatitis

Symptoms and Signs

Chronic viral hepatitis may be and is often asymptomatic; many patients are unaware of their condition until the diagnosis is made incidentally or until progression to advanced liver disease results in systemic symptoms and clinical features of hepatic dysfunction.

Laboratory Findings

The most telling laboratory markers are the aminotransferase levels, which may be elevated continuously or may fluctuate; typically, ALT levels are higher than AST levels until cirrhosis develops, when AST levels tend to be higher. Otherwise, laboratory values that reflect hepatic function (bilirubin, albumin, prothrombin time) may be normal.

Imaging Findings

Ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) are useful to evaluate liver parenchyma and to assess for the existence of varices, reversal of portal hepatic flow, ascites, splenomegaly, and other signs of portal hypertension; hepatic vein occlusion and other vascular abnormalities; and focal mass lesions.

Histologic Evaluation

Although its role is evolving, liver biopsy is useful for grading the activity and for staging the progression of disease, for identifying clinically relevant histologic features (eg, steatosis, iron deposition, pathognomonic features of autoimmune liver injury, granulomatous inflammation, etc), or for adding helpful information in diagnostically challenging cases.

Acute Viral Hepatitis

Infections with other viruses, such as cytomegalovirus, Epstein-Barr virus, herpes simplex or zoster, and coxsackieviruses, can result in an acute viral hepatitis syndrome and elevated serum aminotransferase levels. Toxoplasmosis and leptospirosis may also share clinical features with acute hepatitis. If the results of serologic tests for the known hepatitis viruses (discussed later) are negative, and if clinical features are suggestive, serologic tests for these agents should be considered.

Several drugs and anesthetic agents can produce a picture similar to that of acute hepatitis; therefore, taking a careful drug history is important. A past history of unexplained and repeated episodes of hepatitis raises the possibility of underlying chronic hepatitis.

Alcoholic hepatitis is associated with a history of ethanol abuse and usually with clinical stigmata of alcoholism. In patients with alcoholic liver disease, serum aminotransferase levels rarely rise above 300 units/L, and, typically, serum AST levels exceed serum ALT levels.

When abdominal pain is prominent, acute viral hepatitis may be confused with acute cholecystitis, choledocholithiasis, ascending cholangitis, pancreatitis, or other abdominal disorders. Careful clinical and radiologic evaluation will assist in making the correct diagnosis and thereby avoiding unnecessary surgery. Cholestatic viral hepatitis may be confused with obstructive jaundice resulting from pancreatic carcinoma, common bile duct stone, other disorders that obstruct the biliary tree, or hepatic infiltrative disorders (eg, fatty infiltration, primary or metastatic tumor infiltration, extramedullary hematopoiesis, granulomatous disorders).

Clinical features help to distinguish acute hepatitis from congestive hepatopathy and acute ischemic injury, which tend to be associated primarily with aminotransferase, not alkaline phosphatase, elevations. Uncommonly, inherited metabolic disorders, such as Wilson disease, mimic acute viral hepatitis.

Chronic Viral Hepatitis

In the differential diagnosis of chronic viral hepatitis are autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, genetic disorders such as Wilson disease, hemochromatosis, α1-antitrypsin deficiency, alcoholic liver disease, nonalcoholic fatty liver disease, and chronic drug hepatotoxicity. Serology, biochemical testing, and liver histopathology help in arriving at the correct diagnosis in most instances.

Essentials of Diagnosis

• Diagnosis of acute infection depends on the detection of immunoglobulin M (IgM) antibodies to hepatitis A virus (IgM anti-HAV).
• IgM anti-HAV, the primary immune response, is replaced by immunoglobulin G (IgG) anti-HAV, correlating with subsequent lifelong immunity.
• Presence of IgG anti-HAV in a patient with acute hepatitis indicates that the illness is not caused by HAV.

General Considerations

Hepatitis A virus (HAV) is a 27-nm nonenveloped RNA virus (genus Hepatovirus) that is transmitted by the fecal-oral route through ingestion of contaminated food (eg, shellfish, strawberries, onions) or water. The incubation period is 2–6 weeks, the duration of viremia is short (5–7 days), and chronic infection does not occur; therefore, percutaneous transmission is exceedingly rare.

Infection is more prevalent in areas of low socioeconomic status characterized by insufficient sanitation and poor hygienic practices, which facilitate the spread of enteric infections. In developing countries, hepatitis A is endemic, infecting most children before the age of 5–10 years. In developed countries, improved socioeconomic conditions and sanitation have led to an increase in the mean age of infection and a reduction in the prevalence of HAV exposure, as reflected by serum antibodies to HAV (anti-HAV) in the population.

Pathogenesis

As is true for all hepatitis viruses, viral replication of HAV occurs primarily within hepatocytes. Except in extraordinary circumstances, hepatitis viruses are not cytopathic; instead, liver cell damage results from host cell-mediated cytotoxicity. In hepatitis A, the necroinflammatory changes and mononuclear cell infiltrates are prominent in periportal areas, but lobular focal necrosis, ballooning hepatocytes, and apoptosis are regular features as well. In some cases, centrilobular cholestasis may be severe, particularly in adults. Serum neutralizing antibodies protect against HAV infection. HAV antigen can be demonstrated by immunohistochemical staining as fine granules in the cytoplasm of hepatocytes and Kupffer cells.

Clinical Findings

Acute HAV Infection

Although more than 70% of adults infected with HAV have symptoms, approximately 70% of infections in young children are asymptomatic. When hepatitis A is clinically apparent, patients present with fatigue, malaise, right upper quadrant and epigastric discomfort, loss of appetite, and, in icteric cases, dark urine and jaundice. Less commonly, HAV infection may be profoundly cholestatic and accompanied clinically by marked jaundice, acholic stools, and pruritus.

Hepatitis A results very rarely in fulminant hepatitis and does not cause chronic liver disease, although extraordinarily rare reports suggest that acute hepatitis A can trigger autoimmune hepatitis in susceptible persons. Approximately 10% of patients can have a relapsing course lasting several months (resumption of fecal viral excretion and aminotransferase elevation after initial, apparent resolution) and invariably culminating in eventual recovery. Systemic manifestations are uncommon and include arthritis and, very rarely, transverse myelitis, aplastic anemia, and leukocytoclastic vasculitis, although reports of these complications are not linked reliably to hepatitis A. Concomitant meningoencephalitis has been reported rarely. Cholestatic hepatitis with protracted, albeit ultimately self-limited, cholestatic jaundice and pruritus can occur as a variant of acute hepatitis A.

Serologic Assays

The diagnosis of acute HAV infection depends on the detection of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV occurs as a primary immune response and persists for approximately 3 months, sometimes extending to 6 months after acute HAV infection. It is replaced by immunoglobulin G (IgG) anti-HAV, which correlates with subsequent lifelong immunity. Thus, if a patient who presents with acute hepatitis has IgG anti-HAV, the acute illness is not caused by HAV.

Prevention

General measures to prevent the spread of HAV infection include a safe water supply and proper environmental hygiene (eg, sewage disposal, elimination of overcrowded housing, etc). Killed HAV vaccines have a protective efficacy of 94–100% after two doses, with negligible side effects. Two such vaccines were licensed in the United States in 1995–1996 and are available worldwide. Their introduction in the United States coincided with a decline in new, reported cases of hepatitis A in the United States from an annual average of 12 cases per 100,000 population in 1995 to 1 case per 100,000 in 2007. In 2006, because of residual clusters of hepatitis A cases, including severe and even fatal instances in otherwise healthy adults, the Advisory Committee on Immunization Practices recommended routine hepatitis A vaccination of children at 1 year of age. Recommendations for vaccination of other persons in groups at increased risk for hepatitis A are listed in Table 39–3.

Immunoglobulin has also been shown to be safe and effective as both preexposure and postexposure prophylaxis against HAV infection. For preexposure prophylaxis, if immediate protection is required, travelers should receive passive immunization with immunoglobulin and begin a course of active immunization with vaccine; in this setting, preexposure passive immunization requires a single intramuscular dose of immunoglobulin (0.02 mL/kg). For postexposure prophylaxis, the same dose, given within 10–14 days of exposure, has an efficacy of approximately 85% and usually aborts or reduces the severity of, and renders clinically inapparent, HAV infection (yielding a combination of passive immunization and the durable immunity that follows acute infection). In the absence of such concomitant active immunization, the passive protection offered by immunoglobulin lasts only a few months.

Treatment

Treatment is largely supportive and consists of discontinuation of potentially hepatotoxic medications and restriction of alcohol intake. Neither bed rest nor dietary restrictions are effective. Most cases do not require hospitalization, which is recommended for patients with advanced age, serious underlying medical conditions, chronic liver disease, malnutrition, pregnancy, immunosuppressive therapy, hepatotoxic medications, severe vomiting that prevents adequate oral intake, and clinical and laboratory findings that suggest fulminant hepatitis. The occasional patient with fulminant hepatic failure, defined as the onset of encephalopathy within 8 weeks of the onset of symptoms, should be referred for consideration of liver transplantation.

Course & Prognosis

The overall case fatality rate for HAV infection is very low (~0.3–0.8%), although higher in adults older than age 60 years (2.6%). In some reports, morbidity and mortality were increased in the presence of a hepatitis A superinfection in patients with underlying chronic liver disease.

Essentials of Diagnosis

• Diagnosis relies on the presence of hepatitis B surface antigen (HBsAg).
• Presence of IgM versus IgG antibodies to hepatitis B core antigen (anti-HBc) distinguishes acute from chronic infection, and IgM anti-HBc indicates recent infection (previous 6 months).
• Hepatitis B e antigen (HBeAg) appears early in the course of infection and in self-limited cases is replaced within 2–3 months by antibody to HBeAg (anti-HBe).
• During chronic hepatitis B in patients with wild-type HBV infection, viral replication is high, infectivity is substantial, and liver injury is pronounced; this phase gives way to one of lower viral replication, infectivity, and liver injury in which patients become inactive carriers.
• In patients with precore mutations (HBeAg-negative chronic hepatitis B), HBV DNA levels fluctuate, and anti-HBe is detectable in serum.
• Presence of isolated antibodies to HBsAg (anti-HBs) is consistent with vaccine-induced immunity.
• Antibodies to both surface and core proteins (anti-HBs, anti-HBc, and anti-HBe) indicate prior HBV infection.
• Interpretation of isolated IgG anti-HBc positivity is difficult and may represent ongoing, low-level HBV infection, prior HBV infection, or a false-positive test.

General Considerations

More than 350 million people worldwide—5% of the world's population—are currently HBsAg-reactive, indicating that they are currently infected with hepatitis B virus (HBV), and as many as 50% of the world's population have had HBV infection, as reflected by the presence of anti-HBs. HBV is endemic in areas containing 45% of the world's population. In endemic areas, rates of current infection range from 8% to 25%, and exposure rates (based on the presence of anti-HBs) range from 60% to 85%. In low prevalence areas such as the United States, the prevalence of chronic HBV infection is 0.1–0.2% (1.25 million), and the annual incidence of new HBV infections is 200,000–300,000.

HBV is transmitted primarily by perinatal, percutaneous, and sexual routes. The virus can also be transmitted by inapparent percutaneous routes and close person-to-person contact, presumably via open cuts and sores, especially among children in endemic areas (eg, sub-Saharan Africa, which has a prevalence of chronic HBV infection of just under 10%). In the United States, most HBV infections occur in adolescence and early adulthood, and the most common modes of transmission are sexual and percutaneous (exposure to contaminated instruments and needles, eg, via injection drug use). In contrast, in Asia, the most common mode is perinatal transmission to infants of mothers with chronic HBV infection; in sub-Saharan African countries, in addition to perinatal spread, another common mode of transmission is horizontal spread between young children. Injection drug users are at high risk of acquiring not only HBV infection but also other blood-borne hepatitis agents, hepatitis C and D (see later sections).

Pathogenesis

HBV is a partially double-stranded, partially single-stranded DNA virus (hepadnavirus type 1) that replicates via reverse transcription through an RNA intermediate. Although HBV is strongly hepatotropic, viral sequences, including HBV replicative intermediates, are present in extrahepatic tissues (lymph nodes, peripheral blood mononuclear cells); however, the vast bulk of—and the only pathophysiologically relevant—HBV replication is confined to the liver. The HBV genome contains four open reading frames that encode four major proteins: (1) the S gene, which codes for the envelope protein, hepatitis B surface antigen (HBsAg); (2) the C gene, which codes for the nucleocapsid proteins hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg); (3) the P (or pol) gene, which codes for the DNA polymerase, which, in turn, catalyzes transcription and reverse transcription steps involved in viral replication; and (4) the X gene, which codes for the X protein, a protein of limited clinical relevance but which upregulates the transcription of host cellular and viral genes, including those of other viruses such as HIV.

The envelope protein of the virus, HBsAg, in serum is the primary marker of HBV infection. In the hepatocyte, HBsAg is expressed in the cytoplasm and can be recognized histologically by the presence of ground-glass hepatocytes. Eight HBV genotypes (A to H) have been identified; the prevalence of HBV genotype varies depending on geographic location. In the United States the prevalences of genotypes A, B, C, D, and others are 35%, 22%, 31%, 10%, and 2%, respectively. Recent data suggest that HBV genotypes may play an important role in progression of HBV-related liver disease as well as in response to interferon therapy. Similar associations have not been clarified definitively in patients treated with oral agents (nucleoside and nucleotide analogs); therefore, the testing of HBV genotype has not yet been adopted routinely as a prelude to antiviral therapy (see later discussion).

The C region has two initiation codons and therefore two gene transcripts (precore and core), the translation of which result in two protein products (HBeAg and HBcAg). HBcAg, the protein expressed on the 27-nm nucleocapsid core particles, is not secreted into serum but is localized predominantly to the hepatocyte nucleus and is expressed also in smaller quantities on the hepatocyte surface membrane. As such, HBcAg is the target of the host immune response to infection, playing an important role in the pathogenesis of HBV-induced liver damage. The other nucleocapsid protein, HBeAg, a low-molecular-weight nonparticulate protein, is encoded by the precore plus core region of the C gene, enters the secretory apparatus of the hepatocyte, and circulates in serum; the presence of HBeAg is indicative of active viral replication and correlates with increased infectivity and liver injury. The products of the same gene, HBcAg and HBeAg, have considerable amino acid homology and immune cross-reactivity at the T-cell level. Antibody to HBcAg (anti-HBc) appears at the onset of clinical hepatitis, shortly after the appearance of HBsAg, and may be the only marker detectable between the disappearance of HBsAg and the appearance of anti-HBs (less likely to be encountered now that the sensitivity of assays for HBsAg and anti-HBs are so high). During acute hepatitis B, anti-HBe appears as clinical symptoms, and aminotransferase levels are waning; its appearance marks a transition to lower viral replication, infectivity, and liver injury.

HBeAg-negative variants result from mutations in the precore region of the C gene, with failure of HBeAg synthesis (the serologic marker linked to active virus replication) yet with continued high-level viral replication and liver injury. "HBeAg-negative" mutant HBV has been associated with fulminant hepatitis (rarely) and chronic hepatitis (commonly).

Liver injury associated with HBV infection is the product of a combination of innate and adaptive immune responses, the latter of which are effected by cytotoxic T cells directed at liver membrane complexes of host histocompatibility antigens and HBcAg. The clinical outcome of HBV infection depends on the balance between viral activity and the host immune response, as reflected by the robustness of the CD8+ cytotoxic T-cell response and the release of antiviral T-cell cytokines; however, other than certain clinical features (eg, age, infection at birth, immunocompetence), what distinguishes those who recover from those who progress to chronic infection remains poorly defined. In perinatally acquired infection, immaturity of the neonatal immune system and the presence of HBV on hepatocytes shortly after birth combine to produce a level of immunologic tolerance to HBV that limits the adequacy of the host immune response to HBV. This state of immunologic tolerance can persist indefinitely. No robust cytotoxic T-cell response occurs against HBV, no clinical illness ensues, but chronic infection is almost invariable (>90%). In contrast, among young adults with acute hepatitis B, the cytotoxic T-cell response to HBV expressed on hepatocyte membranes is substantial and efficient, leading to an acute hepatitis illness and, typically, recovery; chronicity after clinically apparent acute hepatitis B in healthy, immunocompetent young adults occurs in fewer than 1% of cases.

Hepatocellular Carcinoma

Epidemiologically and clinically, chronic HBV infection is linked strongly to the development of hepatocellular carcinoma (HCC), which can occur in up to 50% of patients with HBV-induced cirrhosis following life-long infection acquired perinatally (see Chapter 49). The mechanism of viral oncogenesis has been studied extensively; viral integration into the host genome is required, but no consistent sites of integration have been identified (eg, adjacent to a host tumor promotor or suppressor gene). Cell turnover associated with chronic inflammation likely contributes to the pathogenesis of HCC, as do such cofactors such as alcohol use and environmental aflatoxin exposure.

Hepatitis B Virus Variants

Precore Mutants or HBeAg-Negative Chronic HBV

A precore nucleotide mutation or core-promoter mutation can lead to premature termination of the precore protein, preventing production of HBeAg. HBeAg-negative HBV is found more frequently in HBV genotypes other than genotype A, and its prevalence was concentrated initially in Mediterranean countries. Currently, HBeAg-negative chronic hepatitis B is the predominant form of chronic hepatitis B in Europe and represents a growing proportion (~40%) of chronic hepatitis B infections in the United States. Wild-type (HBeAg-positive) chronic hepatitis B is associated with higher levels of HBV replication (≥106 virions/mL) than HBeAg-negative chronic hepatitis B (≤105 virions/mL), whereas HBeAg-negative chronic hepatitis B is more likely to be associated with fluctuating levels of HBV DNA and aminotransferase activity. In addition, in HBeAg-negative chronic hepatitis B, patients treated with antiviral therapy (see later discussion) cannot experience treatment-induced HBeAg seroconversion, which, in HBeAg-positive chronic hepatitis B, can be used as a treatment end point. Therefore, the ideal duration of therapy remains undefined in HBeAg-negative chronic hepatitis B.

S Mutants

A mutation in the S gene has been reported in infants who are born to HBV-infected mothers but acquire HBV infection after vaccination and in liver transplant recipients who acquire breakthrough HBV reinfection despite treatment with hepatitis B immunoglobulin (HBIG). These mutations alter the antigenicity of the HBV envelope, evading neutralizing anti-HBs. Fortunately, the frequency of such mutations is limited.

P Mutants

Mutations in the polymerase gene are associated with resistance to HBV antiviral agents such as lamivudine, adefovir, and telbivudine (see later discussion).

Clinical Findings

Acute Hepatitis B

The incubation period of acute hepatitis B is between 4 weeks and 6 months. Clinical symptoms are similar to those described earlier for acute hepatitis A (eg, fatigue, anorexia, jaundice), and aminotransferase elevations are the biochemical hallmark of illness. In 5–10% of patients with acute hepatitis B, a serum sickness-like syndrome with arthralgias, rash, angioedema, and, rarely, proteinuria and hematuria may develop in the prodromal phase. In children, hepatitis B may present rarely as anicteric hepatitis associated with a nonpruritic papular rash on the face, buttocks, and limbs (papular acrodermatitis of childhood).

Chronic Hepatitis B

Progression from acute to chronic hepatitis may be suggested by the persistence of anorexia, weight loss, and fatigue, although most patients with chronic hepatitis B are asymptomatic. Physical findings may include hepatomegaly and splenomegaly. Laboratory findings include persistence of HBsAg, detectable HBeAg in HBeAg-positive hepatitis, and elevations of aminotransferase, bilirubin, and globulin levels. Histologic features include the presence of portal inflammation, bridging or, in severe cases, multilobular hepatic necrosis, and the presence of fibrosis.

Many patients with chronic HBV infection are inactive carriers who have no symptoms, normal serum aminotransferase activity, low-level HBV DNA (≤103 virions/mL), circulating anti-HBe, and normal or near-normal liver histology.

Extrahepatic manifestations, when they occur, may include arthralgias, arthritis, Henoch-Schönlein purpura, generalized vasculitis (polyarteritis nodosa), glomerulonephritis, pleural effusions, pericarditis, and aplastic anemia (the latter not definitively linked to HBV infection, however). Uncommon complications of HBV infection include pancreatitis, myocarditis, atypical pneumonia, transverse myelitis, and peripheral neuropathy.

Serologic Assays

The diagnosis of HBV infection relies on the presence of HBsAg. Acute and chronic infections are distinguished by the presence of IgM versus IgG antibodies to HBcAg (anti-HBc). The presence of IgM anti-HBc indicates recent infection, generally within the previous 6 months. HBeAg appears early during acute hepatitis B, while viral replication is at peak levels, and in self-limited cases is replaced within 2–3 months by antibody to HBeAg (anti-HBe).

During chronic hepatitis B, in patients with wild-type HBV infection, the presence of HBeAg corresponds to a relatively highly replicative period, during which levels of HBV DNA exceed 106 virions/mL, infectivity is substantial, and liver injury is pronounced. Over time, this highly replicative phase gives way to a relatively low replicative phase, characterized by low-level HBV DNA (≤103 virions/mL) and negligible infectivity and liver injury. Patients in this phase are considered inactive carriers.

In patients with precore mutations (HBeAg-negative chronic hepatitis B), HBV DNA levels fluctuate between undetectable and approximately 105 virions/mL, and anti-HBe is detectable in serum. In chronic hepatitis B, anti-HBc is of the IgG class (except, rarely, during reactivation of chronic hepatitis B [eg, sero-reversion from anti-HBe-reactive back to HBeAg-reactive or during reactivation of clinically quiescent HBeAg-negative chronic hepatitis B], when IgM anti-HBc may reappear transiently). The presence of isolated anti-HBs is consistent with vaccine-induced immunity. Antibodies to both surface and core proteins (anti-HBs, anti-HBc, and anti-HBe) indicate prior HBV infection.

Interpretation of isolated IgG anti-HBc positivity is difficult and may represent ongoing, low-level HBV infection, prior HBV infection, or a false-positive test. Isolated anti-HBc with ongoing low-level HBV infection is more common in persons from high-prevalence areas, in persons with a history of injection drug use, and in patients with HIV infection.

Prevention

Hepatitis B vaccine is protective in over 90% of normal adults and in almost 100% of newborns. Recombinant vaccines have largely supplanted the original plasma-derived vaccine in most parts of the world. Common adverse effects are local reactions at the injection site (soreness, tenderness, pruritus, and swelling). The immunogenicity of hepatitis B vaccines is reduced in adults older than 40 years; among younger healthy adults, approximately 2.5–5% do not acquire protective antibodies, and such nonresponsiveness has been shown to be genetically determined.

Despite the availability of highly effective vaccines for 30 years, targeted vaccination programs for those at highest risk of infection have failed to reduce the frequency of HBV infection in the U.S. population. Currently, the U.S. Public Health Service recommends universal vaccination of all neonates and prepubertal teenagers. In addition, HBV vaccination is currently recommended for immunocompromised patients; hemodialysis patients; patients with coexisting chronic liver disease of other causes, including chronic hepatitis C; health care workers; injection drug users; and those with high-risk sexual exposures (see Table 39–3). Currently, booster immunization is not recommended routinely, although it may be useful in immunosuppressed persons who have lost detectable anti-HBs or in immunocompetent persons who sustain HBsAg inoculation after losing detectable antibody (although this subgroup appears to be protected even after loss of detectable anti-HBs).

Treatment

Fulminant Hepatitis B

In fulminant hepatitis B, intensive care in a specialized unit and early consideration for orthotopic liver transplantation likely reduces mortality. Only 25% of patients who have fulminant hepatitis B will survive without liver transplantation. Patients should be supported by maintaining fluid and electrolyte balance and cardiorespiratory function, controlling bleeding, treating prophylactically with broad-spectrum antibiotics, monitoring for cerebral edema, and managing other complications. Although antiviral treatment with interferon has not been shown to be of benefit in fulminant hepatitis B, treatment with oral nucleoside or nucleotide agents (described later) may be of benefit and would be recommended in most specialized treatment centers.

Corticosteroid therapy is not only ineffective but harmful, as demonstrated in clinical trials. Similarly, exchange transfusions, plasma perfusion, human cross-circulation, porcine liver cross-perfusion, and extracorporeal liver-assist devices have not been proven to be effective.

Orthotopic liver transplantation is being performed with increasing frequency, with excellent long-term results. Thus, patients should be supported maximally until spontaneous recovery or until prognostic factors indicate worsening outcome necessitating transplantation; the threshold for referring to a liver transplantation center should be very low. During and after transplantation, measures should be taken to prevent HBV infection of the graft (see later discussion).

Chronic Hepatitis B

The objectives of treatment for chronic hepatitis B are to suppress HBV replication and reduce liver injury. Among the end points of therapy are (1) profound reduction in circulating HBV DNA, preferably to levels undetectable by highly sensitive amplification assays; (2) in HBeAg-positive chronic hepatitis B, HBeAg seroconversion (loss of HBeAg and acquisition of anti-HBe); (3) normalization of ALT levels; (4) improvement in liver histology (reduction in the grade of necroinflammatory activity and limiting progression of, or even improving, the stage of fibrosis). Although not proven conclusively, data suggest that successful antiviral therapy has the potential to prevent or delay progression to cirrhosis, hepatic decompensation, and even HCC. Recommendations for patients with chronic hepatitis B who are candidates for treatment are summarized in Table 39–4; seven therapies are approved and currently available for treatment of chronic hepatitis B (Table 39–5).

Interferon-α2b

The first antiviral drug for hepatitis B, interferon-α2b (IFN-α), was approved by the U.S. Food and Drug Administration (FDA) in 1992. In patients with compensated chronic hepatitis B (including those with early cirrhosis), detectable HBeAg, and elevated aminotransferase activity, subcutaneous IFN-α injections of 10 million units three times per week or 5 million units daily for 16–24 weeks resulted in HBeAg loss in approximately 30% (along with suppression of HBV DNA to levels undetectable by relatively insensitive hybridization assays) and HBeAg seroconversion in approximately 18–20%. Patients with HBeAg-negative chronic hepatitis B should be treated for at least 12–24 months. In this early experience with interferon, almost 10% of HBeAg-reactive patients cleared HBsAg after their initial course of therapy; however, such high rates of HBsAg seroconversion have not been observed in more recent experiences. The strongest predictor of response to IFN-α in HBeAg-positive patients is a high pretreatment ALT level, but other factors favoring a response include a high histologic activity index, low HBV DNA level, and HBV genotypes A and B. Retreatment of nonresponders with a second course of IFN-α is unlikely to be of any clinical benefit.

In patients with HBeAg-negative hepatitis B, short courses of IFN-α are of little benefit and do not yield durable suppression of HBV DNA and ALT; in this patient group, long-term treatment (eg, 12–18 months) is preferable, but the durability of treatment effect is degraded over time to less than 20%, 5 years after therapy. Compensated cirrhotic patients respond as do patients with precirrhotic chronic hepatitis B; however, in decompensated cirrhosis, IFN-α may precipitate hepatic failure or be complicated by life-threatening infection or psychiatric effects and, therefore, is not recommended.

Side effects of interferon, which, in addition to the need for injection, are the major limitation to its use, include (1) flulike symptoms of fever, myalgias, fatigue, and headache; (2) marrow suppression (leukopenia, neutropenia, and thrombocytopenia); (3) anxiety, emotional lability, or depression; and (4) autoimmune disorders, primarily of the thyroid. IFN-α is accompanied by a flare in ALT in 30–40% of patients, and although flares are considered to be predictive of a favorable response, in patients with advanced or marginally compensated cirrhosis, an acute flare can precipitate decompensation.

Contraindications to IFN-α therapy include immune suppression or autoimmune disease, and severe, uncontrolled psychiatric disease or depression.

Before the availability of newer antiviral agents, IFN-α was considered a good therapeutic choice for patients with mild liver disease, low levels of HBV replication, and high serum aminotransferase levels. Some authorities recommend interferon-based therapy for young persons, based on the assumption that an approximately 30% chance of HBeAg loss with a time-confined course of therapy might be preferable for a young person to indefinite therapy with an oral agent (see later discussion). An equally compelling argument might be made to spare a young person the inconvenience and side effects of IFN-α therapy in favor of a side effect–free oral agent, which might require an extra half year to a year to achieve the same benefit as a course of IFN-α.

For all practical purposes, IFN-α as been supplanted by long-acting, once-weekly pegylated interferon for those favoring interferon therapy and by the several highly potent polymerase inhibitors for those who favor oral agents. What early studies of IFN-α have shown is that successful antiviral therapy can improve the natural history of chronic hepatitis B, improving survival and complication-free survival.

Pegylated Interferon Alfa (Peg IFN-α)

Pegylated interferons are produced by binding of a large, inert polyethylene glycol moiety to the interferon molecule, thus increasing the molecular weight of the compound, decreasing its renal clearance, altering its metabolic degradation, and increasing its half-life. Therefore, pegylated interferons can be administered by subcutaneous injection once weekly.

PEG IFN-α2a is the only pegylated interferon approved for the treatment of chronic hepatitis B in the United States. Clinical trials have demonstrated that the efficacy of PEG IFN-α2a is similar to or slightly better than that of standard IFN-α, in addition to its more convenient administration. For HBeAg-positive patients, the most definitive trial represented a comparison of 48 weeks of PEG IFN-α2a alone, versus lamivudine alone, versus combination therapy. During the 48 weeks of therapy, the level of HBV DNA suppression was highest in the combination-treatment arm, and HBeAg seroconversion occurred in a similar percentage of the three groups: 27%, 20%, and 24%, respectively. Twenty-four weeks after treatment was stopped, however, seroconversion was maintained in 32%, 19%, and 27% of the three groups, respectively, indicating that 48 weeks of PEG IFN-α2a monotherapy was superior to 48 weeks of lamivudine monotherapy as well as 48 weeks of combination therapy. In a study of HBeAg-negative patients, PEG IFN-α2a monotherapy was compared with lamivudine monotherapy versus combination therapy for 48 weeks; a sustained response, defined as suppression of HBV DNA to below 105 copies/mL or to undetectable by polymerase chain reaction (PCR) amplification (102 copies/mL) and a return to normal of ALT, was comparable in patients who received PEG IFN-α2a alone or in combination with lamivudine (100 mg), which were both better than lamivudine alone. In both HBeAg-reactive and HBeAg-negative studies, a small proportion of PEG IFN-α2a-treated study subjects experienced HBsAg seroconversion during (in the HBeAg-negative trial) or after (in the HBeAg-positive trial) therapy. Side effects and predictors of treatment response are similar to those of standard IFN-α therapy, but PEG IFN-α2a is better tolerated by most subjects.

Although some patients may choose a year of PEG IFN-α2a therapy, such therapy requires a year of weekly injections and clinically intense monitoring as well as willingness to accept interferon side effects. In these trials of PEG IFN-α2a, treatment was confined to a finite, 48-week period, which is typical of the way PEG IFN-α2a is used but not the way oral agents are used. Instead, oral agents, very well tolerated, are administered for longer periods (eg, until after HBeAg seroconversion or to maintain responsiveness in HBeAg-negative patients). In fact, the same HBeAg seroconversion rates achieved with 48 weeks of PEG IFN-α2a injection therapy occur when oral agent therapy is extended to 18–24 months. In addition, suppression of HBV DNA and ALT after interferon-based therapy in HBeAg-negative patients is lost gradually over time in the vast majority of patients. Therefore, the advantages of a year of PEG IFN-α2a therapy may be outweighed by the advantages of slightly longer treatment with substantially better tolerated oral agents. The recommended dose of PEG IFN-α2a is 180 mcg weekly for 48 weeks.

Lamivudine

Lamivudine, an oral nucleoside analog that inhibits viral DNA synthesis by blocking reverse transcriptase and that is cleared renally, was approved by the FDA originally for the treatment of HIV (150 mg daily) in 1995 and then for the treatment of hepatitis B (100 mg daily) in 1998.

Several large, randomized controlled trials of HBeAg-positive patients treated for 1 year documented HBeAg seroconversion (with suppression of HBV DNA to undetectable levels as determined by insensitive hybridization assays) in 16–20% of treated patients (HBeAg loss in up to a third) compared with 4–6% spontaneous seroconversion in control subjects. Furthermore, loss of detectable HBV DNA occurs in the majority of patients, normalization of ALT in ≥50% of patients, and improvement in necroinflammatory histology scores in 49–56% of patients compared with 23–25% of control subjects. Recent studies in which lamivudine was the comparator arm for new oral nucleoside analogs, demonstrated that lamivudine suppresses HBV DNA by approximately 5.5 log10 copies/mL. Reductions in the progression of fibrosis and progression to cirrhosis have also been demonstrated. After HBeAg seroconversion, this serologic status is maintained in approximately 80% of patients as long as a period of consolidation therapy follows the seroconversion (at least 6 months in Western patients, longer in Asian patients). For patients who do not achieve HBeAg seroconversion during the first year of therapy, HBeAg seroconversion rates increase with extended courses of therapy, but the optimal duration of treatment with lamivudine, as with other oral agents, remains to be defined.

In HBeAg-negative patients, lamivudine suppresses HBV DNA by approximately 4.5 log10 copies/mL, suppresses HBV DNA to undetectable levels (as determined by sensitive amplification assays) in approximately 70%, and reduces ALT to normal in approximately 75%. When therapy is discontinued, however, generally, the therapeutic effect is lost as HBV DNA and ALT return to baseline levels. Therefore, almost all HBeAg-negative patients and the majority of HBeAg-positive patients require extension of therapy indefinitely beyond the first year.

Lamivudine is safe to use in patients with cirrhosis. Clinical trials have demonstrated that lamivudine therapy for several years can reverse cirrhosis and that, unlike interferon, this drug can be used in patients with hepatic decompensation, salvaging them from a further decline and leading to reversal of decompensation. In addition, a prospective trial of lamivudine versus placebo in compensated patients with advanced fibrosis and cirrhosis demonstrated the principle that such antiviral therapy can prevent the incidence over time of hepatic decompensation; in this important study, a trend was apparent in the prevention of, or delay in, the development of HCC.

Selection of lamivudine-resistant mutations is the main concern with lamivudine monotherapy. Genotypic resistance can be detected in 14–32% of patients after 1 year of lamivudine treatment and increases to 60–70% after 5 years of treatment. The most common mutation involves substitution of methionine for valine or isoleucine in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV DNA polymerase. Factors associated with resistance include long duration of treatment, high pretreatment serum HBV DNA, and, most importantly, high levels of residual virus (>103–104 virions/mL) after initiation of treatment. Although in vitro the YMDD mutation actually decreases replication fitness of HBV, compensatory mutations restore the fitness of mutant HBV, and clinical benefit is lost eventually after lamivudine resistance emerges. Lamivudine resistance is usually detected by virologic breakthrough followed by biochemical breakthrough and, in some patients, can be associated with an acute exacerbation of hepatitis or, in marginally compensated cirrhotics, with hepatic decompensation.

Most patients with confirmed lamivudine resistance should receive rescue therapy with antiviral agents, such as adefovir or the now favored tenofovir, that are effective against lamivudine-resistant HBV mutants. When adefovir or tenofovir is used to treat patients with lamivudine resistance, the new drug should be added to lamivudine therapy; for example, switching to adefovir monotherapy renders the patient susceptible ultimately to adefovir resistance.

Because of the need for long lamivudine treatment courses in most patients, because of its low barrier to resistance, and because its efficacy is inferior to that of later-generation antivirals, lamivudine is no longer a first-line treatment for chronic HBV; now that more potent, less resistance-prone antiviral agents are available, lamivudine, despite its established safety, has been supplanted as an antiviral agent for hepatitis B.

Adefovir Dipivoxil

Adefovir is a nucleotide analog of adenosine monophosphate that can inhibit both reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA, resulting in chain termination. Adefovir is effective in suppressing wild-type HBV as well as lamivudine-resistant HBV. The recommended dose for adults with normal renal function is 10 mg orally daily. Adefovir has been shown to produce a histologic response in 53% of HBeAg-positive patients versus 25% of placebo recipients after 48 weeks of therapy, HBeAg seroconversion in 12% of patients versus 6% of placebo recipients, a 3.5 log10 copies/mL decrease in HBV DNA in patients versus 0.6 log10 copies/mL in placebo recipients, and normalization of ALT levels in 48% of patients versus 16% of placebo recipients. Approximately 30% of patients with no prior nucleotide analog treatment have a primary nonresponse to adefovir (<2 log10 drop in HBV DNA after 6 months of treatment), and in approximately half of adefovir-treated patients, the antiviral response is slow. This suboptimal profile, which reduced the appeal of adefovir initially, led to its replacement by tenofovir (see below) when the newer agent became available.

In HBeAg-negative patients, suppression of HBV DNA, normalization of ALT, and histologic improvement occur as well, but the therapeutic effect is lost once the drug is stopped. Thus, as is the case for therapy with other oral agents, in HBeAg-negative patients, continued treatment is needed to maintain the antiviral response. In HBeAg-negative patients who have completed 5 years of adefovir treatment, HBV DNA was undetectable in 67% and ALT was normal in 69%.

Adefovir has been shown to be effective in liver allograft recipients and in HIV-HBV coinfected patients as well as in lamivudine-resistant HBV. Adefovir resistance occurs at a slower rate than with lamivudine treatment; the cumulative probabilities of genotypic resistance to adefovir at 1, 2, 3, 4, and 5 years have been reported to be 0%, 3%, 11%, 18%, and 29%, respectively, in HBeAg-negative patients (data in HBeAg-reactive patients are not available). As previously mentioned, in patients with lamivudine-resistant HBV, if adefovir is used, lamivudine should not be switched to adefovir; instead, adefovir should be added to lamivudine therapy.

Entecavir

Entecavir, a carbocyclic analog of 2′-deoxyguanosine, inhibits HBV replication at three steps: priming of the HBV polymerase, reverse transcription of the negative-strand HBV DNA from the pregenomic RNA, and synthesis of the positive-strand HBV DNA. Entecavir, which suppresses HBV DNA by almost 7 log10 copies/mL in HBeAg-positive patients (5.2 log10 copies/mL in HBeAg-negative patients), is more potent than lamivudine and adefovir and, although cross-resistance occurs between entecavir and other L-nucleosides, has such a low median effective concentration in vitro that in vivo levels of drug are sufficient to be effective against lamivudine-resistant HBV. Like other L-nucleosides, entecavir is effective against adefovir-resistant HBV mutants as well. The approved oral daily dose of entecavir is 0.5 mg for treatment-naïve patients but 1.0 mg for lamivudine-resistant patients.

In HBeAg-positive patients, after 48 weeks of treatment, when compared with lamivudine, entecavir had significantly higher rates of histologic (72% vs 62%), virologic (67% vs 36% undetectable HBV DNA by highly sensitive amplification assay), and biochemical (68% vs 60% with normal ALT) responses. Among HBeAg-positive patients who underwent HBeAg seroconversion during the first year (21%) and who stopped treatment at 48 weeks, 70% remained HBeAg negative. In HBeAg-negative patients, similar rates of histologic, virologic, and biochemical improvement have been seen; however, the majority of patients relapse if treatment is stopped after 1 year.

Entecavir has a very high barrier to resistance; in nucleoside-naïve patients, entecavir resistance has not been encountered during the first year of therapy and has emerged in 1.2% of patients through year 5. In lamivudine-resistant patients, however, entecavir resistance was observed in 7% of patients at 1 year, 16% of patients at 2 years, and 51% of patients after 5 years. Therefore, although entecavir is favored above other L-nucleosides for treatment of previously untreated patients, entecavir is not recommended and should not be used as replacement therapy for lamivudine-resistant hepatitis B, FDA approval for this indication notwithstanding.

L-Deoxythymidine (Telbivudine)

Telbivudine is an L-nucleoside analog that was shown in clinical trials to be more potent than lamivudine in suppressing HBV replication. The approved dosage of telbivudine is 600 mg orally daily.

In HBeAg-positive patients, HBV DNA was undetectable in 60% of telbivudine recipients versus 40% of lamivudine recipients after 1 year and in 54% versus 8% after 2 years. Patients taking telbivudine also had significantly higher rates of normal ALT after 1 and 2 years of treatment compared with those taking lamivudine; however, as was true for entecavir, despite the substantially higher potency of telbivudine over lamivudine in suppressing HBV DNA, no difference was observed between telbivudine and lamivudine recipients in the rate of HBeAg seroconversion at the end of 1 and 2 years of treatment. In HBeAg-negative patients, telbivudine was superior to lamivudine in treatment measures by the same degree that entecavir exceeded lamivudine.

Unfortunately, telbivudine is associated with substantial resistance, and telbivudine-resistant mutations are cross-resistant with lamivudine. Like lamivudine, telbivudine selects for YMDD mutations, and genotypic resistance was observed in 5% and 25%% of HBeAg-positive patients after 1 and 2 years of therapy, respectively, and in 2.3% and 10.8% of HBeAg-negative patients after 1 and 2 years. Although one of the more (albeit not the most) potent HBV DNA inhibitors, telbivudine has a disappointing resistance profile and, therefore, does not have a role in monotherapy for HBV infection; it is not favored as first-line therapy.

Tenofovir Disoproxil Fumarate

Tenofovir is a nucleotide analogue, structurally similar to adefovir that was first approved for the treatment of HIV infection either alone or in combination with emtricitabine as a single pill. Tenofovir was approved for treatment of chronic hepatitis B in 2008. The approved oral dose of tenofovir for chronic hepatitis B treatment is 300 mg daily, although adjustments must be made for creatinine clearance <50 mL/min (as is true for other oral antiviral agents for hepatitis B).

In HBeAg-positive chronic hepatitis B, after 48 weeks of treatment, patients on tenofovir, when compared to patients treated with adefovir, had significantly higher rates of virologic (76% versus 13% undetectable HBV DNA), biochemical (74% versus 68% ALT normalization), and HBsAg loss (3% versus 0%), with similar rates of histologic response (74% versus 68%) and HBeAg seroconversion (21% versus 18%). In HBeAg-negative chronic hepatitis B, after 48 weeks of treatment, patients treated with tenofovir, when compared to those treated with adefovir, were more likely to experience suppression of HBV DNA to undetectable levels (93% versus 63%); however, biochemical and histologic reponses were similar in the two groups. Three percent of HBeAg-reactive patients treated with tenofovir for 1 year lost HBsAg; in HBeAg-negative patients, none lost HBsAg

Adefovir and tenofovir are cross-resistant. In the two principal phase-III clinical trials of tenofovir, 7 patients had virologic breakthrough during the first 2 year of treatment but had no detectable tenofovir-resistant mutations. In these large tenofovir trials, anyone who had persistent detection of serum HBV DNA at week 72 received additional treatment with emtricitabine; therefore data on resistance to tenofovir monotherapy beyond 72 weeks are limited; still, in the original cohorts followed after phase-III trials, resistance has not been encountered through year 3 of monitoring. Given its potency and limited resistance profile, the approval of tenofovir in 2008 provided a welcome, equally potent alternative to entecavir, particularly as first-line treatment of chronic hepatitis B in patients with lamivudine resistance. Currently, both entecavir and tenofovir are considered first-line oral treatments for chronic hepatitis B.

Other Therapies

Other therapies currently being considered for approval for the treatment of HBV infection include emtricitabine (very similar to lamivudine in structure, potency/efficacy, and resistance profile) and combination therapies. A combination of emtricitabine and tenofovir, licensed for treatment of HIV infection, has the potential advantage of combination, non-cross-resistant L-nucleoside and nucleotide analog therapy. As patients begin to appear—in minuscule numbers to date—with mutations to both classes of these oral antiviral agents, interest in this combination and other combinations that can preempt the emergence of antiviral resistance will attract attention and be studied in clinical trials. To date, no advantage has been found for combinations of IFN-α or PEG IFN-α and oral agents.

Special Groups

HBV—HIV Coinfection

Response rates to standard IFN-α are lower in patients with HBV-HIV coinfection. Lamivudine, emtricitabine (available currently only as a combination pill with tenofovir), and tenofovir are all nucleoside analogs with activity against both HIV and HBV; however, the rate of HBV resistance to lamivudine in HBV-HIV coinfected patients approaches 90% at 4 years. Given that antiretroviral regimens may include drugs with activity against HBV and that almost any oral regimen selected will include an agent with activity against HIV, clinicians should choose a combination antiviral regimen for HBV infection, regardless of whether or not HIV treatment is ongoing or planned. Entecavir was thought initially to have no anti-HIV activity and was considered a potential monotherapy for HBV-HIV coinfected patients not receiving HAART; however, eventually, entecavir was found to have modest activity against HIV, contraindicating its use (because of the potential for early emergence of HIV resistance) as monotherapy in patients with HIV-HBV coinfection who are not receiving HAART. To reiterate, then, in HBV-HIV coinfected patients combination antiviral therapy is the recommended choice for treating hepatitis B.

HBV-HDV Coinfection

Refer to the later discussion of hepatitis D.

HBV-HCV Coinfection

Limited information is available to guide treatment in this setting. Often, such patients have relatively nonreplicative chronic hepatitis B and need to be treated for hepatitis C. When both viruses need to be treated, PEG IFN-α (with ribavirin for hepatitis C) can be used to address both infections; alternatively, both diseases can be treated independently with PEG IFN-α plus ribavirin for hepatitis C and one of the oral agents for hepatitis B. Generally, antiviral therapy for hepatitis C in HCV-HBV coinfected patients yields sustained virologic responses similar to those achieved in patients being treated for HCV alone; however, suppression of HCV replication has been reported, rarely, to result in rebound replication of HBV.

Immunosuppressive, Cytotoxic, or Immunomodulatory Chemotherapy

Approximately 20–50% of patients with chronic hepatitis B, including inactive carriers, have been reported to have reactivation of HBV replication associated with immunosuppressive, cytotoxic (especially if the regimen includes high-dose corticosteroids), or immunomodulatory (anticytokine) chemotherapy. This event occurs primarily as chemotherapy is withdrawn and cytolytic immune responsiveness recovers. Subclinical as well as clinically severe, even fatal, reactivations can occur, reflected initially by increases in serum HBV DNA and ALT. Prophylactic antiviral therapy should be administered to such patients with chronic hepatitis B at the onset of chemotherapy and should be maintained for at least 6 months afterward; in fact, the duration of treatment is not known, and, in some cases, discontinuing therapy proves difficult. Most of the reported experience in this setting involves lamivudine, but entecavir, similar to lamivudine in its rapid onset of action and freedom from nephrotoxicity, has also been reported to be effective as preemptive therapy to prevent chemotherapy-associated reactivation of hepatitis B and represents an appealing alternative.

Liver Transplantation

Liver transplantation is currently a successful therapy for end-stage chronic HBV-associated liver disease. Even with the 30% reduction in patients placed on the liver-transplantation waiting list in the decade following the introduction of oral antiviral therapy for hepatitis B, hepatitis B remains the seventh-most-common indication for liver transplantation in the United States, comprising about 4–5% of cases. Until the early 1990s, transplantation resulted in an 80% rate of reinfection in the absence of prophylaxis. The resulting hepatitis could be severe and was almost invariably chronic. The risk of reinfection was higher in patients with chronic liver disease versus fulminant disease and lower in those with HBV-HDV coinfection than in those with HBV infection alone. The introduction in 1993 of high-dose hepatitis B immunoglobulin (HBIG) perioperatively and postoperatively, combined with approval of lamivudine in 1998 for treatment of hepatitis B, has reduced graft infection rates to less than 5% in patients who receive both HBIG and a nucleoside analog posttransplantation. Given the need for long-term therapy and both the risk and consequences of lamivudine resistance in organ allograft recipients, newer drugs with higher barriers to resistance (eg, entecavir or tenofovir) and especially those with potent antiviral activity and limited nephrotoxicity (eg, entecavir) are favored first-line treatment to prevent recurrent HBV infection posttransplantation.

Disadvantages of prolonged HBIG use include cost, patient inconvenience, and intolerability. In some centers, switching from intravenous HBIG to intramuscular HBIG has been successful and associated with enhanced convenience and tolerability. No clear guideline exists for the duration of HBIG treatment post-transplantation; however, the risk of HBV reinfection was found to be negligible when HBIG was discontinued after 2 years and followed with continued use of a maintenance nucleoside or nucleotide analog treatment.

Patients who have undergone liver transplantation for HBV or HBV-HDV coinfection should have HBV DNA or HDV RNA, or both, followed every 3 months. Studies of combination nucleoside-nucleotide therapy after liver transplantation continue.

Postexposure Prophylaxis

For neonates born to infected mothers and any person with a percutaneous or sexual exposure, HBIG is available and is helpful to achieve immediate high-level circulating anti-HBs (passive immunization). Simultaneously, active immunization with hepatitis B vaccine should be administered as well.

Course & Prognosis

Ninety-five to 99% of healthy, immunocompetent young adult patients with clinically apparent acute HBV infection have a favorable course and recover completely. The case fatality rate is low (0.1%) but increases with age and associated comorbid systemic illnesses (eg, diabetes mellitus, congestive heart failure). The risk of chronicity is related to the age of acquisition (>90% in newborns, ~50% in young children, and 1–5% in immunocompetent adults). In addition, chronicity is more likely (>50%) in immunocompromised adults such as transplant-organ recipients, HIV-positive persons, and patients undergoing cytotoxic chemotherapy. Chronically infected patients may be inactive carriers or may have chronic hepatitis with or without cirrhosis.

Hepatitis B accounts for approximately half of all cases of fulminant viral hepatitis (see Chapter 38). The diagnosis is suggested by rising bilirubin, an increasing prothrombin time (INR), and signs of encephalopathy. Cerebral edema is common, and death usually results from a combination of brainstem compression, gastrointestinal bleeding, sepsis, respiratory failure, cardiovascular collapse, and renal failure. Survivors have complete biochemical and histologic recovery.

Patients with chronic hepatitis B, with or without HBeAg, who have highly replicative HBV infection are likely to experience the negative consequences of chronic infection, cirrhosis, hepatic decompensation, and HCC; indeed, patients with high-level HBV DNA are more likely to progress to cirrhosis and HCC than those with low-level HBV DNA, while relatively nonreplicative inactive carriers are less likely to progress to cirrhosis or to have HCC. In turn, patients with high-level HBV replication tend to progress histologically, and those with more advanced histologic stage have a worse prognosis. In one natural-history study, patients with cirrhosis had a 5-year survival of only 55% and a 15-year survival of only 40%.

Hepatitis B is a major risk factor for HCC. In HBV-endemic regions, HCC is the leading cause of cancer-related death. Cirrhosis is present in 70–80% of HBV-related HCC, and the chronic inflammation and regenerative cellular proliferation associated with cirrhosis may predispose to cellular transformation and malignancy. A proportion of patients with HBV-associated HCC, up to 20–30% in some series, do not have cirrhosis, contrasting with hepatitis C-associated HCC, almost all of which occurs in cirrhotic patients. In otherwise healthy, inactive hepatitis B carriers, the HCC incidence is 0.06–0.3% per year; in patients with chronic hepatitis, the annual incidence is 0.5–0.8%; and in those with cirrhosis, the rate of HCC is 1.5–6.6% per year. The cumulative risk of HCC almost doubles over 15 years in patients with high-level HBV DNA compared with those who have low-level HBV DNA. Furthermore, the risk of HCC is also significantly higher among men and older patients as well as in patients with a family history of HCC, a history of serologic reversion from anti-HBe to HBeAg, HBV genotype C, and coinfection with HCV. Population- and clinic-based screening programs that rely on serum α-fetoprotein (AFP) and liver imaging (primarily ultrasound) have led to identification of patients with small and potentially resectable tumors. Despite achieving earlier detection of HCC, however, such screening programs have not been shown to reduce mortality resulting from HCC (see Chapter 49). Furthermore, because of the nonspecificity of AFP elevations in chronic viral hepatitis, AFP screening is no longer recommended as part of HCC surveillance.

Essentials of Diagnosis

• Enzyme immunoassay (EIA) for antibody to hepatitis C virus (anti-HCV) indicates ongoing infection (rarely, past exposure).
• False-positive EIA tests occur most often in healthy blood donors and patients with rheumatoid factor; false-negative tests occur most often in immunocompromised patients (eg, hemodialysis patients, organ allograft recipients).
• Recombinant immunoblot assay (RIBA) has been supplanted by testing for HCV RNA to confirm positive tests for anti-HCV.
• HCV RNA is usually detectable in serum 7–21 days after exposure with one of the three available amplification assays (PCR, transcription-mediated amplification [TMA], and branched-chain DNA [bDNA]).
• The clinically relevant threshold between high-level and low-level HCV RNA is 800,000 IU/mL.
• Liver biopsy permits accurate assessment of the degree of inflammation and fibrosis but is not mandatory before initiating therapy.

General Considerations

Based on serologic screening (NHANES, National Health and Nutrition Examination Survey) between 1999 and 2002 of a representative cohort of the population, the U.S. Public Health Service calculated that 4.1 million people in the United States (1.6% of the population) have antibodies to hepatitis C virus (anti-HCV) and that approximately 3.2 million (1.3%) have chronic hepatitis C virus (HCV) infection. The peak prevalence observed was among persons aged 40–49 years. When a similar survey was done earlier during the 1990s, the peak prevalence of HCV infection occurred among those aged 30–39 years. In fact, this shift reflects the aging of the HCV-infected cohort who had been infected in the remote past, in the 1960s and 1970s, during an epidemic of experimentation with injection drugs. Worldwide, approximately 3% of the population (170 million people) are estimated to have chronic hepatitis C.

In the United States, HCV is the most common blood-borne infection, the leading cause of chronic liver disease, and the most common indication for liver transplantation. The Centers for Disease Control and Prevention estimates that the number of new cases of acute HCV infection has declined substantially (from 5.2 cases per 100,000 population in 1995 to 0.5 cases per 100,000 population in 2007) among persons aged 25–39, the age group that historically has highest rates of acute infection. The decline in new cases of acute hepatitis C parallels directly the decline in cases among injection drug users, which is thought to reflect the adoption of precautions in this subpopulation to minimize the risk of acquiring HIV infection. Almost all newly recognized cases of hepatitis C occur among individuals who acquired their infections several decades ago but who are just now coming to clinical recognition as they seek health care for other reasons.

Groups at risk for HCV infection include transfusion recipients (particularly those transfused before 1992, when sensitive serologic screening of donor blood began, virtually eliminating hepatitis C from the blood supply), injection drug users, hemodialysis patients, Vietnam-era veterans, and health care workers. Persons with hemophilia who received factor VIII infusions before HCV screening was initiated have a 74–90% prevalence of HCV infection. In intravenous drug users, prevalence is 72–90%. Acquisition by health care workers of hepatitis C as a result of a contaminated needle-stick is inefficient, occurring in approximately 3% of those exposed and accounting for a very small proportion of HCV infections (~1%).

Sporadic HCV infection, in which the mode of transmission is unknown, is responsible for approximately 10% of cases, but in many of these, long forgotten injection drug use is the source.

Perinatal transmission is rare and inefficient, estimated to occur in only approximately 5% of infants born to HCV-infected mothers, independent of the route of delivery.

Sexual transmission of HCV can occur, but the risk is extremely low (<5% overall and closer to 1% in stable, monogamous sexual partners), and HCV is much less efficiently sexually transmitted than HBV. In the rare instance when both sexual partners are infected with HCV (0.4–3% of the sexual partners of patients with HCV infection are also infected), almost invariably, other risk factors are identified. Because of the low risk of sexual transmission of hepatitis C, the U.S. Public Health Service currently does not recommend a change in sexual practices in stable sexual partners. In the sexually promiscuous, those with sexually transmitted diseases, and sex workers, however, the risk of sexual transmission can reach 10%. In the most recent NHANES data, the risk of HCV infection was most strongly associated, independently, with injection drug use. Anti-HCV was also associated independently with Mexican-American ethnicity, birth in the United States, low family income, noninjection illicit drug use, and a lifetime total of 20 or more sexual partners.

Pathogenesis

Hepatitis C virus is a single-stranded, 9600 base-pair RNA virus (genus Hepacivirus). Its genome encodes core and envelope structural proteins at the 5′ end and five nonstructural proteins (including a helicase, protease, and RNA polymerase) at the 3′ end that are important in viral replication. Six major HCV genotypes have been described, designated 1–6, which are divided further into subtypes (1a, 1b, 2a, etc) of which over 50 have been described. Considerable variation exists in the geographic distribution of HCV genotypes; in the United States, approximately 70% of patients are infected with genotype 1 and the other 30% with genotypes 2 and 3. Although not predictive of the outcome of HCV infection, the genotype does predict the likelihood of treatment response and also determines the duration of treatment and the dose of ribavirin, one of the two drugs used to treat hepatitis C (see later discussion). Genotypes 1 and 4 are more refractory to interferon-based therapy compared with genotypes 2 and 3. In addition to its genotypic diversity, the heterogeneity of HCV is exaggerated by the multiple quasispecies circulating in serum, reflecting the hypervariability of regions of the HCV envelope proteins that arise as a product of evolutionary changes in the virus as it evades host immunologic containment. This viral diversity accounts for the high likelihood for HCV persistence after acute infection and the limited ability of the host to mount durable neutralizing antibodies against HCV. As a result, recovery from acute infection is unusual (<15%), and attempts to develop a protective vaccine have been frustratingly disappointing.

Levels of HCV in serum are lower (up to 105–106, rarely 107, virions/mL) than levels of HBV (often exceeding 106 and ranging to >109), and HCV antigens are not detectable in blood. The clinical features of acute and chronic hepatitis C are similar to those of hepatitis B, except that acute hepatitis C tends to be milder and progression to chronicity the rule, rather than the exception. Several histologic features are characteristic of chronic hepatitis C, including the presence of microvesicular or macrovesicular steatosis, bile duct injury, and lymphocytic follicles. As is true for the other viral hepatitides, liver injury associated with HCV infection is immunologically mediated; differences in the diversity and robustness of cytolytic T-cell responses appear to be important in distinguishing between the rare patients who recover from acute hepatitis C and the vast majority of patients who progress to chronic infection. Recently, variations in the IL28B gene were shown to affect not only responsiveness to interferon-based antiviral therapy (see below) but also likelihood of recovery from acute HCV infection; >50% of patients with the C/C haplotype at this allele experience self-limited acute HCV infection, while ~80% of patients with the T/T haplotype progress to chronic infection. A direct cytopathic effect of HCV may also contribute to the damage in some situations (eg, in immunosuppressive states, such as after liver transplantation).

Clinical Findings

Acute HCV Infection

Acute hepatitis C is asymptomatic in approximately 84% of cases and is usually not recognized clinically. Jaundice, fatigue, fever, nausea, vomiting, and right upper quadrant discomfort can occur, usually within 2–12 weeks of exposure and lasting from 2 to 12 weeks. The diagnosis is established by demonstration of anti-HCV, HCV RNA, or both.

Chronic HCV Infection

Chronic hepatitis C is also asymptomatic in most patients. ALT values fluctuate in a substantial proportion of patients. Extrahepatic manifestations, which develop in approximately 15% of patients with chronic infection, include such immune-complex disorders as essential mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and leukocytoclastic vasculitis. Other extrahepatic disorders associated with chronic hepatitis C include thyroiditis, lichen planus, and porphyria cutanea tarda.

Serologic Assays

The first step in the diagnosis of HCV infection is the EIA for anti-HCV, which indicates past exposure (rarely) or ongoing infection (usually). The current, third-generation EIA is approximately 99% sensitive and specific. In hepatitis C, distinctions between IgM and IgG anti-HCV are not helpful; therefore, assays for IgM anti-HCV are not available. False-positive EIA tests are seen most often in populations with a low prior probability of true infection, such as healthy blood donors, and in patients with rheumatoid factor, which can result in nonspecific binding in the assay. False-negative tests are seen most often in immunocompromised patients, including hemodialysis patients and organ allograft recipients. In the past, a recombinant immunoblot assay (RIBA) was used to confirm positive tests for anti-HCV; however, RIBA has been supplanted by testing for HCV RNA.

The next step in the diagnosis of HCV infection is detection of HCV RNA in serum. HCV RNA is generally detectable 7–21 days following exposure. Currently, three types of amplification assay are available for detecting HCV RNA: PCR, transcription-mediated amplification (TMA), and branched-chain DNA (bDNA). The most sensitive PCR and TMA assays have a sensitivity of 10–50 IU/mL and a broad dynamic range; for all practical purposes, bDNA, less sensitive (103 copies/mL), is being supplanted by the more sensitive assays.

Quantitation of HCV RNA is based on World Health Organization–standardized international units (IU) per milliliter; the clinically relevant threshold between high-level and low-level HCV RNA is 800,000 IU/mL. The HCV genotype is not necessary for the diagnosis of HCV infection but provides valuable clinical information required for management decisions about duration of therapy and drug doses.

Liver Biopsy

Because the severity of liver damage cannot be determined noninvasively with adequate reliability, a liver biopsy is necessary to assess the degree of inflammation (histologic grade) and fibrosis (histologic stage) accurately. According to the current guidelines of the American Association for the Study of Liver Diseases (AASLD), a liver biopsy should be done when the results will influence whether treatment is recommended or will provide information on prognosis, but a biopsy is not mandatory in order to initiate therapy for hepatitis C.

Although some authorities have issued recommendations against performing liver biopsies prior to therapy for chronic hepatitis C, many clinicians, in weighing the risks, benefits, and costs of biopsy versus those of treatment for hepatitis C, choose to obtain a liver biopsy in patients with HCV genotype-1 infection to inform treatment decisions. For patients with genotypes 2 and 3, with a higher likelihood of response, some authorities advocate treating all patients without liver biopsy. For patients with little or no fibrosis (ie, Metavir score <2 or Ishak score <3), in whom the prognosis for progression is relatively good and for whom, therefore, treatment may be deferred, liver biopsy can be used to monitor progression of disease; however, frequency of such histologic monitoring has not been established.

Prevention

Because the injection drug-using population represents the largest reservoir of HCV infection, prevention of high-risk, drug-related behaviors is the best way to prevent the majority of new HCV infections in the United States. Even before screening of blood donors for hepatitis C began, transfusions never accounted for more than a small proportion of all cases of HCV infection in the United States. Since the advent of routine screening of the blood donor pool began in the 1990s, the annual incidence of transfusion-related infection has become negligible, and further reduction in the frequency of posttransfusion HCV infection is unlikely to have an impact on the overall prevalence of the disease.

Although success has been reported in case studies of postexposure interferon therapy, the efficacy of such an approach has not been studied systematically, and the initiation of antiviral therapy is not recommended until the diagnosis of HCV infection is established (in the setting of acute hepatitis C, antiviral therapy is nearly universally effective). Standard immunoglobulin administered after needlestick, sexual, or perinatal exposure to HCV is ineffective and is not recommended. Currently, an effective preventive vaccine is not available, and prospects for a vaccine are dim (see the discussion of pathogenesis, earlier).

Treatment

Interferon-α or Pegylated Interferon-α and Ribavirin

The goal of treatment in patients with hepatitis C is to prevent disease progression and the complications of infection, which is achieved by eradication of HCV infection. HCV infection is considered eradicated when a patient achieves a sustained virologic response (SVR), defined as absence of HCV RNA in serum, as demonstrated by the most sensitive amplification assay, at the end of treatment as well as 6 months later. An SVR is associated with improved histologic findings in up to 94% of patients, including both fibrosis and histologic activity index, as well as a reduced risk of progression to cirrhosis, hepatic failure, and liver-related death.

Patients who achieve an SVR almost always have a dramatic earlier reduction in the HCV RNA level, defined as a ≥2-log10 drop or loss of HCV RNA at 12 weeks into therapy, referred to as an early virologic response (EVR). In one study of 453 patients who underwent 12 weeks of therapy, 86% had an EVR. Of those 86%, 65% went on to achieve an SVR. Of the 14% who did not have an EVR, only 3% achieved an SVR; in another, similar, large trial, none of the subjects who failed to achieve an EVR experienced an SVR. Furthermore, in patients with the more difficult-to-treat genotype 1, achieving a rapid virologic response (RVR), defined as a reduction in serum HCV RNA to undetectable at week 4, is associated with an SVR of ≥95%, even if treatment is confined to 24 weeks.

Currently, IFN-α and PEG IFN-α are the backbone of treatment for chronic hepatitis C. As discussed earlier, in the section on hepatitis B, IFN-α has direct antiviral activity as well as immune-modulating activity (which may or may not be involved in its activity against viral hepatitis). Pegylated interferons are produced by binding an inert polyethylene glycol moiety to interferon molecules, thereby increasing the molecular weight of the molecule, decreasing its renal clearance, and increasing its serum half-life.

In the 1990s, the sole treatment for hepatitis C was monotherapy with interferon (3 million units 3 times weekly initially for 24 weeks, then for 48 weeks), which produced low SVR rates of 10% and 20%, respectively. Later in the 1990s, ribavirin was added to interferon as combination therapy for HCV infection. Ribavirin, a synthetic guanosine analog, can inhibit several RNA and DNA viruses, including flaviruses, to which HCV is similar. Ribavirin alone has no more than a subtle antiviral effect on HCV replication; however, the combination of ribavirin with the standard interferon regimen doubled SVRs to 38–43%. Although the mechanism for ribavirin activity is not understood, ribavirin reduces the relapse rate at the conclusion of therapy, thereby increasing the SVR.

Standard interferon, administered by injection three times a week in patients with hepatitis C, has been eclipsed by PEG IFN-α. Two types of pegylated interferon, which differ in their pharmacokinetics and chemical properties, were approved by the FDA in 2001, PEG IFN-α2a and PEG IFN-α2b. In large, randomized, controlled trials, the combination of weekly injections of PEG IFN-α and twice-daily oral ribavirin yielded higher SVR rates than either three injections per week of standard IFN-α together with oral ribavirin or PEG IFN-α monotherapy. In these trials, 12-kD PEG IFN-α2b was dosed by weight (1.5 mcg/kg) and coupled with 800 mg of ribavirin; the larger, 40-kD PEG IFN-α2a was given as a fixed dose of 180 mcg with a weight-adjusted, higher dose of ribavirin (1000 mg if <75 kg and 1200 mg if ≥75 kg) for 48 weeks. In the initial two registration trials, genotype was the strongest predictor of response. In patients with genotype-1 infections, SVRs occurred in 42–46%, whereas the SVR rate in those with genotypes 2 and 3 was 76–82%. In a subsequent registration trial of PEG IFN-α2a, trial subjects were randomized to receive either 24 or 48 weeks of PEG IFN-α plus ribavirin therapy and to receive either a fixed 800-mg dose or standard 1000–1200-mg doses (based on weight <75 kg or ≥75 kg) of ribavirin. In patients with genotype 1, the SVR was highest (51%) in patients who underwent 48 weeks of treatment with PEG IFN-α and 1000–1200 mg of ribavirin; patients treated for 24 weeks or with only 800 mg of ribavirin had lower SVR rates. In contrast, among patients with HCV genotypes 2 or 3, PEG IFN-α plus a ribavirin dose of only 800 mg for 24 weeks was adequate to achieve an SVR rate of ~80%; extending therapy to 48 weeks or increasing the ribavirin dose did not increase the frequency of SVR in these genotypes. In a clinical trial, reported in 2009, weight-based daily doses of ribavirin ranging up to 1400 mg were used with PEG IFN-α2b.

Several variables are associated with an increased likelihood of achieving an SVR, among them HCV genotype other than 1, low pretreatment HCV RNA levels (<8 × 105 IU/mL), age <40 years, body weight <75 kg, absence of bridging fibrosis or cirrhosis at baseline, non–African American ethnicity, the absence of hepatic steatosis and insulin resistance, and favorable IL28B genotype C/C (~80% SVR compared to <30% with genotype T/T or to just under 40% for T/C heterozygotes). The presence of these poor predictors of responsiveness, however, does not preclude responsiveness absolutely and should not be a reason to deny a patient therapy.

Currently, based on the registration trials described above, a full 48 weeks of PEG IFN-α and 1000–1200 mg of ribavirin are recommended for patients with HCV genotype 1 (and 4) but only 24 weeks of PEG IFN-α and 800 mg of ribavirin for patients with HCV genotypes 2 and 3. Recognized more recently, tailoring therapy based on the rapidity of a patient's response can increase the SVR or shorten therapy, or both. The likelihood of an SVR is increased if the level of HCV RNA falls to undetectable within 4 weeks (a rapid virologic response, RVR). In patients with genotype 2 or 3 who achieve an RVR, a 12–16-week course of therapy may be as effective as one lasting 24 weeks, but only if the baseline HCV RNA level is low. Conversely, in patients with genotype 2 or 3 who have cirrhosis, some experts choose to treat a full 48 weeks; however, in most cirrhotic patients with genotype 2, and fewer with genotype 3, the recommended 24 weeks of therapy will suffice to achieve an SVR. In patients with genotype 1, among those with an RVR, especially in the subset with a low level of HCV RNA at baseline, 24 weeks of PEG IFN-α plus ribavirin therapy may suffice to yield SVRs as high as 90%. In the same vein, failure to achieve an RVR signals refractoriness to therapy; for such patients with genotype 1, extending therapy beyond 48 weeks to 72 weeks increases the likelihood of an SVR. Clinical trials have also shown that, in patients with risk factors for reduced responsiveness (eg, high level of HCV RNA, obesity), increasing PEG IFN-α (eg, to 270 mcg weekly) and ribavirin doses (eg, to 1600 mg daily) improves SVR rates.

In patients who failed to respond during therapy with, or who relapsed after, standard IFN-α and ribavirin therapy, retreatment with PEG IFN-α and ribavirin can result in an SVR in 25–40%. For relapsers or nonresponders to PEG IFN-α and ribavirin therapy, however, retreatment is unlikely to yield a successful SVR. Occasionally, retreatment with longer durations of therapy, higher doses of ribavirin, or aggressive attempts at maintaining adequate treatment doses with bone marrow support (erythropoietin) may yield an SVR in this setting, but none of these approaches has been validated or recommended.

Although eradication of HCV RNA is the primary goal for treatment of persons with chronic hepatitis C, early studies suggested that long-term, low-dose interferon treatment may reduce the progression of fibrosis or risk of hepatic decompensation, despite an absence of virologic response to treatment. Several trials were designed to evaluate the potential use of maintenance therapy in virologic nonresponders, but none demonstrated efficacy. For example, in 2008, the results of the HALT-C Trial were published; this was a large randomized controlled trial of 1050 patients with advanced fibrosis who had not responded to previous therapy with PEG IFN-α and ribavirin. These patients received either low-dose interferon or no therapy for 3.5 years, but no difference emerged between the treated and untreated-control groups in rates of death, hepatocellular carcinoma, hepatic decompensation, or ≥2-point increase in Ishak fibrosis score. Therefore, low-dose maintenance interferon is not recommended treatment in patients who do not respond to standard PEG IFN-α and ribavirin.

Side Effects and Monitoring

Side effects of interferon and PEG IFN-α were described earlier in relation to treatment of hepatitis B. Additional side effects are associated with combination therapy, specifically, hemolytic anemia caused by ribavirin, which reduces hemoglobin to less than 10 g/dL in 25% of patients. Red blood cell counts recover typically within 4 weeks after treatment is stopped. Because hemolytic anemia associated with ribavirin may be severe and precipitous, ribavirin is contraindicated in patients who cannot tolerate anemia, including those with unstable coronary artery, cerebrovascular, pulmonary, or renal disease as well as baseline anemia. Ribavirin can cause pruritus and rash (occasionally severe), and chest congestion or cough. In addition, ribavirin is a documented teratogen; all patients must be counseled on the danger of birth defects, and both male and female patients and their sexual partners of childbearing age should be required to use effective birth control during and for 6 months after the end of treatment.

Once a patient is started on therapy, close follow-up is essential. Monitoring of complete blood counts is necessary every 2–4 weeks during the first 2 months and then typically every 4–8 weeks during treatment. Periodic thyroid tests (thyroid-stimulating hormone levels) at the same frequency are also recommended. Virologic response should be assessed at week 4 (RVR), week 12 (EVR), end of therapy (end-treatment response), and 24 weeks after completion of therapy (SVR); many clinicians check HCV RNA levels more frequently, including at weeks 24 and 36 of therapy and at weeks 4 and 12 after completion of therapy. If an EVR is not present at 12 weeks, therapy can be stopped, especially in patients who tolerate therapy poorly. If a patient achieves an RVR, consideration may be given to shortening the duration of therapy, and if a patient has not achieved an RVR (or if HCV RNA, although reduced by ≥2 log10 is still detectable at week 12 [absence of a "complete" EVR]), some clinicians choose to prolong therapy beyond the recommended treatment period.

Special Treatment Considerations

Acute Hepatitis C

In a small study of 60 patients with acute hepatitis C, 85% of whom presented with symptomatic disease, treatment with interferon alone or in combination with ribavirin was begun immediately upon diagnosis in 6 patients. Of the 54 who were not treated, 37 (68%) cleared HCV spontaneously within a mean of 8 weeks after diagnosis; 13 relapsed later, leaving 24 (44%) persistently HCV RNA-negative. Although the numbers are small and should be interpreted with caution, none of the nine patients with asymptomatic acute hepatitis C cleared HCV RNA spontaneously, whereas 52% of those with symptomatic disease lost virus spontaneously, all within 12 weeks. Treatment given to those who did not recover spontaneously, beginning 3–6 months after onset of disease, led to SVR in 81%. Based on these results, the authors recommended delaying treatment 2–4 months after acute onset of acute hepatitis C to allow for spontaneous resolution. Others have presented evidence to show that earlier treatment (within 8 weeks) is superior in efficacy to treatment delayed thereafter. What is reassuring is that most studies of antiviral therapy in acute hepatitis C demonstrate a very high frequency of viral clearance when therapy is administered within the first 3 months after diagnosis; although earlier trials involved high-dose interferon, subsequent trials suggest that a 6-month course of PEG IFN-α plus ribavirin yields the same high SVR rate. Additional studies confirming these results continue to be reported.

Renal Disease

Historically, persons with renal disease have been at increased risk of acquiring HCV infection, predominantly through blood transfusions and exposure to HCV-contaminated equipment during hemodialysis. Ribavirin is contraindicated in this population, because the drug is not removed during conventional dialysis, and its accumulation causes a dose-dependent hemolytic anemia. Treatment of patients with mild-to-moderate impairment in renal function must be individualized; however, ribavirin is not recommended in persons with creatinine clearance <50 mL/min. Consequently, therapy for patients with substantial renal impairment or on hemodialysis should be PEG IFN-α monotherapy at a reduced dose with close monitoring for interferon toxicity. As might be expected, efficacy is reduced under these circumstances.

Decompensated Cirrhosis

Currently, interferon-based antiviral therapy is not recommended for patients with decompensated cirrhosis (ie, patients with one or more clinical complications of chronic liver disease, such as ascites, encephalopathy, variceal bleeding, or coagulopathy). Instead, liver transplantation is the treatment of choice for such patients.

In patients with decompensated cirrhosis, antiviral therapy can be complicated by an increased risk of life-threatening infections as well as accelerating hepatic decompensation. Reinfection of the donor liver allograft with HCV is almost assured, and progressive post-transplantation disease of the allograft is common. Eradication of the virus prior to transplantation is associated with a low likelihood of post-transplantation infection, providing a strong incentive to treat HCV infection before transplantation; however, treating someone with decompensated liver disease is not recommended routinely, can be associated with substantial treatment intolerability and morbidity, and should be done only in specialized centers that have experience in treating decompensated patients beginning with low drug doses that are escalated progressively, as tolerated. In addition, even in patients with such treatment-associated short-term absence of HCV RNA pretransplantation, the virus is likely to become apparent again posttransplantation after longer follow-up monitoring. If such pretransplantation antiviral therapy is initiated, low doses should be used initially and only in patients with mild degrees of hepatic compromise, with vigilant monitoring for adverse events, preferably in those who have already been accepted as candidates for liver transplantation.

Antiviral therapy for hepatitis C is indicated definitively in patients with compensated HCV-related cirrhosis who also have sufficient platelet and white blood cell counts to tolerate therapy.

Post-Solid Organ Transplantation

Immunosuppression administered to prevent allograft rejection plays a role in the accelerated liver disease observed in HCV-infected patients following transplantation. Interferon has been reported to precipitate rejection of kidney grafts; thus, the absence of clear treatment benefit and the concern about precipitating rejection weigh against treating HCV infection in heart, lung, or kidney allograft recipients. The risk of precipitating rejection with interferon in liver allograft recipients appears to be low. Because, typically, HCV-related liver disease is this group is more progressive than that observed in immunologically competent persons, in most liver transplantation centers, antiviral therapy—its limitations and tolerability issues notwithstanding—is instituted once recurrent disease is established.

Future Treatments

Direct acting antivirals (DAAs) are currently being developed against hepatitis C viral enzymes, including the viral NS3/4A protease and NS4 polymerase, as well as other proteins critical for viral replication and assembly. Several of the DAAs, administered together with PEG IFN-α and ribavirin have been shown in phase-III clinical trials to lower HCV RNA levels rapidly and profoundly, yielding higher rates of SVR with shorter-duration therapy. The two new protease inhibitors are effective primarily in patients with genotype-1 chronic hepatitis C.

Telaprevir, an NS3/4A protease inhibitor for which phase-III clinical trials are complete, is undergoing FDA evaluation. In previously treatment-naïve subjects, when telaprevir was used in combination with PEG IFN-α and ribavirin for 12 weeks and followed by another 12–36 weeks of PEG IFN-α and ribavirin ("response-guided," ie, another 12 weeks for the ~60% whose HCV RNA was undetectable at weeks 4 and 12 [total duration of treatment 24 weeks] versus another 36 weeks for the ~40% without such an extended rapid virologic response [total treatment duration 48 weeks]), the frequency of SVR was as high as 75%, compared to only 44% with PEG IFN-α and ribavirin alone. In phase-II trials, treatment arms lacking ribavirin were found to be substantially less effective, and telaprevir combination therapy for only 12 weeks was effective but less so than 24-week regimens (12 of triple combination followed by 12 of standard-of-care PEG IFN-α and ribavirin). Data from another phase-III trial in treatment-naïve subjects showed that, for subjects managed based on "response-guided" therapy and in whom an extended RVR (HVC RNA undetectable at weeks 4 and 12) was accomplished, the SVR was ~90%; no benefit was achieved by extending standard of care PEG IFN-α and ribavirin (after 12 weeks of triple combination therapy) from 12 to 36 weeks. In treatment-experienced patients (nonresponders [who failed to clear HCV RNA during previous treatment] and relapsers [who cleared HCV RNA during treatment but who experienced a return of HCV RNA after treatment]), telaprevir combined with PEG IFN-α and ribavirin (12 weeks of triple combination therapy, followed by 36 weeks of PEG IFN-α and ribavirin) achieved SVR in 65% of subjects, compared to in only 17% treated with the former standard of care. Among these nonresponders, the frequency of SVR was 31% for prior null responders (who failed to experience a 12-week, 2-log10 reduction with prior standard therapy, ie, the most refractory subgroup), 67% in prior partial responders (≥2-log10HCV RNA reduction at 12 weeks but virus still detectable at 24 weeks), and 86% in prior relapsers. In this trial, a 4-week lead-in phase with PEG IFN-α and ribavirin was no more effective than a treatment arm lacking a lead-in phase. The most common adverse effect of telaprevir treatment is skin rash, which occurs in a third of subjects but is sufficiently severe to result in discontinuation of triple-drug therapy in only 0.5–1.5% of patients. Anemia occurs in ~40% during telaprevir triple-drug combination therapy, which lasts only 12 weeks.

Boceprevir, another protease inhibitor that is undergoing phase-III clinical trials, is also being evaluated by the FDA. For this drug, a 4-week lead-in phase with PEG IFN-α2b and ribavirin precedes the administration of the DAA, and the triple DAA-PEG IFN-α/ribavirin regimen continues for either an additional 24 (total duration 28) or 44 (total duration 48) weeks, based on "response-guided" criteria (28 weeks if HCV RNA is undetectable at week 8 and at all time points thereafter versus 48 weeks if this criterion is not met). Triple-drug combination therapy resulted in an SVR of 65%, compared to an SVR of 38% for PEG IFN-α and ribavirin. Fewer than half of subjects qualified, based on response-guided criteria, to discontinue therapy at week 28. In experienced patients who failed to achieve an SVR during prior therapy—two-thirds relapsers, one-third partial responders, no null responders—4 weeks of PEG IFN-α and ribavirin lead-in therapy was followed by 32 weeks of triple-combination therapy (total duration of 36 weeks) or 44 weeks of triple-combination therapy (total duration 48 weeks). An SVR occurred in 59% of patients in the 36-week arm (46% of boceprevir-treated patients) and in 66% of the 48-week arm (compared to 21% of those treated with PEG IFN-α and ribavirin). The peak response to boceprevir-based triple-drug therapy in partial responders was 52% and in relapsers 75%. The most prominent adverse effect of broceprevir therapy is anemia, which occurs in half of treated patients, persists for the duration of therapy, and, in clinical trials, was treated in most cases with erythropoietin.

With FDA approval expected in 2011, the addition of a protease inhibitor to a backbone of PEG IFN-α/ribavirin will emerge as the new standard of care for patients with genotype-1 HCV infection, whether treatment-naïve or treatment-experienced (prior nonresponders and relapsers). Nucleoside polymerase inhibitors with a high barrier to resistance and with pangenotypic activity are also showing promise, and nonnucleoside polymerase inhibitors are also being studied. To date, double-combination DAA therapy without PEG IFN-α and ribavirin have been hampered by viral breakthrough. Ultimately, however, trials of potent DAA combinations with complementary mechanisms of action and a high barrier to resistance are anticipated, and the expectation is that all-oral regimens will obviate the need for IFN ± ribavirin-based therapy.

Ongoing Issues in Treatment

Patients inquire frequently about and use herbal medicines; however, none of the so-called complementary and alternative medications improves HCV RNA or ALT levels, and they do not improve the outcome of, or add to, standard antiviral therapy.

Despite the very important and substantial improvements in drug treatments, most patients are not benefited by these therapies. First, for many patients, treatment is contraindicated—specifically those with major, inadequately controlled depression or risk for suicide; uncontrolled, severe autoimmune disorders; marked cytopenias; active cardiopulmonary, cerebrovascular, or renal disease; or inadequately treated and active substance abuse. Second, many patients decline treatment because of their concern over side effects or they do not tolerate treatment. Third, until recent progress with DAAs, about half of all treated patients do not have a sustained response despite successful completion of therapy.

Among patients being treated for hepatitis C, those of European or Asian ancestry are more likely to respond to antiviral therapy than those of African ancestry. In 2009, a genetic polymorphism near the IL28B gene, which codes for interferon lambda, was found to be closely linked to IFN responsiveness in hepatitis C. As noted above (genetic variability at this locus is associated with both spontaneous clearance of HCV after acute infection and SVR after IFN-based antiviral therapy), patients with the C/C allele have a very high SVR, compared to those who have a T containing allele (T/T or T/C). Providing a partial explanation for differences among ethnic groups in treatment responsiveness, Europeans and Asians have far greater frequencies of the C/C allele, as compared to those of African origin, in whom T/T is predominant. This IL28B polymorphism is associated with on-treatment virologic responses as well as relapse rates and appears to be the most powerful pretreatment predictor of SVR. Although not yet introduced into routine clinical use, IL28B genotyping may become a critical tool to determine which patients are more likely to benefit from current standard-of-care, PEG IFN-based treatment regimens. Whether the association between IL28B genotypes and SVR will be maintained once new, DAA-containing regimens become the new standard of care remains to be determined.

Other Aspects of Disease Management

Although most patients with hepatitis C are asymptomatic, disease management goes well beyond the treatment possibilities described above. Education and counseling command attention and resources in caring for patients with hepatitis C. Because of the reported (but not universally experienced) risk of increased morbidity and mortality associated with acute hepatitis A superinfection, susceptible patients (IgG anti-HAV-negative) should be vaccinated against hepatitis A. Similarly, because of the risk of hepatitis B when superimposed on chronic hepatitis C, patients who are susceptible to HBV infection (eg, HBsAg, anti-HBs, anti-HBc-negative) should be vaccinated against hepatitis B. Excessive and frequent alcohol consumption promotes progression of chronic hepatitis C; therefore, avoidance of alcohol is recommended. Many patients inquire about diet, but no dietary restrictions or supplements have been shown to be beneficial. Finally, screening for HCC is recommended for patients with cirrhosis or advanced fibrosis. Periodic radiologic imaging (ultrasound, CT scan, or MRI) every 6–12 months is recommended. Although most clinicians still monitor α-fetoprotein (AFP) levels as part of HCC surveillance programs, AFP screening in patients with chronic hepatitis C has been shown to be highly nonspecific and is no longer recommended officially.

Course & Prognosis

In approximately 85% of persons with acute hepatitis C, chronic infection develops; the other 15% clear the virus spontaneously within the first 6 months of infection, although the rate of viral clearance appears to be less common in African Americans and those coinfected with HIV. As noted above, IL28B genetic polymorphisms are associated with likelihood of viral clearance after acute HCV infection.

In approximately 20% of patients with chronic hepatitis C, cirrhosis develops over 20–25 years of infection. By the time a patient comes to clinical attention and undergoes liver biopsy, he or she has often had chronic hepatitis C for more than two to three decades, and the biopsy provides a window on the level of liver injury during these previous decades. In addition, the levels of necroinflammatory activity and of fibrosis on such a biopsy provide prognostic information for future progression; the more severe the level of necroinflammatory activity and fibrosis found on initial biopsy, the greater the risk of progressing to cirrhosis over the ensuing 20 years. Progression to cirrhosis is more common in persons infected at older ages (particularly men), those who drink more than 50 g of alcohol daily, those who are obese or have substantial hepatic steatosis, and those with HIV coinfection. Once cirrhosis develops, the 10-year prognosis remains very good (80% survival) until signs of hepatic decompensation begin to appear (declining hepatic synthetic function, gastrointestinal bleeding associated with portal hypertension, ascites and edema, coagulopathy, hepatic encephalopathy, life-threatening bacterial infections, and hepatorenal failure); once hepatic decompensation has begun, the 10-year prognosis falls to 50% or less.

Finally, cirrhosis associated with chronic hepatitis C increases the risk of HCC dramatically. Among patients with cirrhosis and HCV infection, HCC develops at a rate estimated at between 1% and 4% annually, affecting 2–7% of cirrhotic patients over 10 years. The occurrence of HCC is confined primarily to patients who have had chronic hepatitis C for two to three decades and who have cirrhosis or, at the very least, advanced fibrosis. HCC rarely occurs in patients with chronic hepatitis C in the absence of cirrhosis or advanced fibrosis. Successful antiviral therapy in patients with chronic hepatitis C reduces, but does not eliminate, the risk of HCC; therefore, in patients with advanced fibrosis, HCC screening should be continued even after achievement of an SVR.

Children

Children who are infected with HCV are more likely to clear the virus spontaneously, to have milder hepatitis, and to progress less frequently to cirrhosis. In one study of German children who acquired hepatitis C genotype 1 as a result of cardiac surgery during infancy, 45% cleared the virus spontaneously, and, at a mean of 21 years after infection, only 3 of 17 had histologic evidence of advanced liver disease.

HCV-HIV

Coinfection with HCV and HIV is common. Approximately 25% of HIV-infected persons in the Western world have concomitant HCV infection. About 6% of HIV-infected persons fail to acquire detectable anti-HCV; therefore, HCV RNA should be tested in HIV-positive patients with risk factors for HCV infection or unexplained liver disease. Since the advent of HAART in 1996, liver disease has become an increasingly important cause of morbidity and mortality in patients with HIV/AIDS. In addition, HIV infection accelerates the course of disease associated with HCV infection. In one series, cirrhosis developed within 15 years in 25% of coinfected patients, compared with only 6.5% of those who had HCV infection alone. Finally, the likelihood of achieving an SVR after treatment for chronic hepatitis C is lower in HCV-HIV coinfection than in HCV alone: 14–29% in genotype 1 and 43–73% in genotypes 2 and 3, following 48 weeks of therapy with PEG IFN-α and ribavirin.

HCV-HBV

As discussed previously, coinfection with HCV and HBV increases the risk and rate of development of cirrhosis and HCC, relative to those observed in patients infected with either virus alone.

Hepatic Steatosis

Patients with hepatitis C and high body mass index or hepatic steatosis, or both, are at increased risk for development of fibrosis and its accelerated progression. In addition, as noted above, moderate-to-severe steatosis has been associated with advanced fibrosis and a decrease in response to interferon-based therapy.

Essentials of Diagnosis

• Infection occurs only in the presence of HBV and is detected by demonstrating anti-HDV (distinctions between IgM and IgG anti-HDV are not helpful).
• HDV RNA detected in serum by molecular hybridization or PCR assays is helpful in confirming the diagnosis.
• Testing for IgM and IgG anti-HBc helps distinguish between acute, simultaneous HBV-HDV coinfection (IgM anti-HBc–positive) and HDV superinfection in patients with chronic HBV infection (IgG anti-HBc–positive).

General Considerations

Hepatitis D virus (HDV) requires the helper function of hepatitis B virus; therefore, in nature, hepatitis D occurs exclusively in patients with hepatitis B. Infection with HDV occurs worldwide, but incidence and prevalence data vary substantially from region to region and are influenced periodically by immigration patterns of patients from high endemic areas. On a worldwide basis, 15 million people with chronic hepatitis B are estimated to harbor concomitant HDV infection. Although hepatitis D was first identified and recognized in southern Europe during the 1970s, the prevalence and incidence of HDV infection declined dramatically, presumably in parallel with measures introduced to control HBV infection and with shifts in the migration patterns that amplified its spread in the 1970s. A higher prevalence of HDV infection persists in older southern European populations, representing residual infection in the cohort of patients infected several decades ago when HDV infection was endemic there.

In nonendemic areas, HDV is transmitted primarily by percutaneous routes, especially in injection drug users and their sexual contacts. In parts of the Mediterranean and other endemic areas, transmission is perpetuated by close personal contact (eg, within families).

Pathogenesis

HDV, the agent that causes hepatitis D or "delta," as named originally, is a unique hepatitis virus with the smallest known genome (1.7 kb) of any animal RNA virus. The 36-nm HDV virion comprises an RNA genome, a single HDV-encoded antigen, and a lipoprotein envelope provided by HBV.

Although under unusual circumstances (eg, associated with immunosuppression after liver transplantation) HDV can replicate autonomously, generally it is a defective virus that requires the simultaneous presence of HBV for complete virion assembly and secretion. Consequently, as noted, HDV infection and replication can occur only in a host with HBV infection. HDV infection can be acquired during (a) simultaneous acute HBV-HDV coinfection, which is limited in duration by the duration of the HBV infection; and (b) acute HDV superinfection of a person with chronic hepatitis B (including inactive carriers), in whom HDV infection almost invariably becomes chronic, lasting as long as the underlying chronic HBV infection. Because HDV "takes over" the replicative machinery of HBV, HDV infection usually results in suppression of HBV replication; thus, patients with both HBV and HDV infection tend to have markers of low-level HBV replication (HBsAg positive, HBeAg negative, anti-HBe positive) and low-level or undetectable HBV DNA.

In acute HDV infection, microvesicular steatosis and granular eosinophilic necrosis may be seen histologically. In chronic hepatitis D, necroinflammatory activity is often severe, but no specific histologic features are noted, and HDV antigen (HDVAg) is localized by immunohistochemical staining in hepatocyte nuclei. HDV genotypes (I–III) and specific clinical features of hepatitis D seem to cluster in distinct geographic areas. Genotype I is most common in the Western world and Africa, where acute hepatitis D is more likely to be fulminant, and chronic infection is more likely to progress rapidly to cirrhosis. Genotype II is predominantly an Eastern genotype and is thought to be less pathogenic than genotype I. Genotype III is seen almost exclusively in Central and South America, where HDV superinfection in persons with underlying chronic hepatitis B tends to be associated with severe, often fulminant, hepatitis.

Clinical Findings

Acute HBV-HDV Coinfection

Acute coinfection is characterized by hepatitis, which can be severe, with hepatocellular necrosis and inflammation. The majority of cases, however, are self-limited, with clearance of HBV and therefore HDV. Fulminant hepatitis is infrequent overall, reported in approximately 5% of outbreaks of coinfection among injection drug users and their sexual partners, but is still more than 10 times more common than in patients with acute hepatitis B alone.

Chronic HBV-HDV Infection

Most cases emanate from acute HDV superinfection of a patient with underlying chronic hepatitis B, including those with chronic hepatitis and inactive carriers. In chronic HBV-HDV infection, HDV viremia continues, although at lower levels than is seen during the period of acute HDV superinfection. On biopsy, necroinflammatory lesions are notable and are typically more severe than those seen in patients with chronic HBV infection alone. Episodes that resemble acute hepatitis can also mark the course in chronic coinfection. Labrea fever is an unusual form of delta hepatitis (HDV superinfection in a population with endemic HBV infection) described in the Amazon basin and in which fulminant hepatitis results in jaundice, fever, and black vomitus.

Serologic Assays

HDV infection is detected by demonstrating the presence of anti-HDV. Distinctions between IgM and IgG anti-HDV are not helpful. The nucleocapsid HDV protein is always encapsidated within an envelope of HBsAg; therefore, circulating levels of HDVAg are undetectable, and commercial HDVAg assays are not available. HDV RNA can be detected in serum by either molecular hybridization or PCR assays, which are helpful in confirming the diagnosis and in monitoring viremia during a course of antiviral therapy.

In patients with HDV infection, testing for IgM and IgG anti-HBc helps distinguish between acute, simultaneous HBV-HDV coinfection (IgM anti-HBc–positive) and HDV superinfection in someone already harboring chronic HBV infection (IgG anti-HBc–positive).

Prevention

Because of its requirement for chronic HBV infection, HDV infection can be prevented by vaccinating susceptible persons with hepatitis B vaccine. No effective vaccine is available for preventing HDV superinfection in persons who are already HBsAg-positive.

Treatment

Despite the reliance of HDV on concomitant HBV infection, the oral polymerase inhibitors that suppress HBV replication have not been shown to be effective in the treatment of hepatitis D. IFN-α is currently the only licensed drug for treatment of HDV. Clinical trials in the early 1990s provided evidence than IFN-α is effective in the treatment of HDV infection, but the rate of relapse is high, and efficacy is proportional to the dose and duration of treatment; high-dose, long-duration therapy lasting at least 1 year is required. More recently, PEG IFN-α monotherapy for 12 months has been shown to result in a 43% SVR; the addition of ribavirin does not offer further benefit. Patients with decompensated cirrhosis resulting from chronic hepatitis D are good candidates for liver transplantation; even before the widespread use of HBIG and polymerase inhibitors to prevent recurrent hepatitis B after liver transplantation, patients with hepatitis D were less likely to experience HDV-HBV reinfection of the allograft. Currently, with efficient antiviral therapy to prevent recurrent HBV infection posttransplantation, recurrent hepatitis D after transplantation is even less of a threat.

Targeting specific steps in the HDV life cycle have been contemplated as the basis of potential new therapies for HDV, such as prenylation inhibitors. Prenylation is a site-specific lipid modification of proteins, and viruses can also make use of this posttranslational modification provided by their host cells. Depriving a virus access to prenylation can have dramatic effects on the targeted virus's life cycle, and pharmacological inhibitors of prenylating enzymes have been developed and shown to have potent antiviral effects in both in vitro and in vivo systems. Because prenylation inhibitors target a host cell function, are available in oral form, and are surprisingly well tolerated in human trials, these compounds represent an attractive new class of antiviral agents with potential for broad-spectrum activity.

Course & Prognosis

Acute HBV-HDV Coinfection

Acute coinfection resolves in 80–95% of cases, following clearance of HBV, without which HDV infection cannot continue. In 2–20% of cases, however, fulminant hepatitis develops; in series from endemic areas, 30% of cases of fulminant hepatitis B represent simultaneous acute hepatitis D. In addition, 2–5% of cases of acute HBV-HDV coinfection result in chronic infection. Finally, in acute simultaneous HBV and HDV infection among injection drug users, case fatality rates approaching 5% have been reported.

Acute HDV Superinfection

Unlike acute coinfection, HDV superinfection results in chronic HDV-HBV in almost all cases, fostered by the persistence of HBV infection. Similar to acute coinfection, acute HDV superinfection results in fulminant hepatitis in 2–20% of cases. Hepatitis D superinfection rarely resolves unless HBV infection resolves. In some outbreaks of severe HDV superinfection in populations with a high rate of HBV infection, mortality exceeding 20% has been reported.

Chronic HBV-HDV Infection

Initial descriptions of chronic hepatitis D were consistent with severe liver disease; however, some patients with chronic HDV infection have very mild liver disease and may even be inactive HDV carriers. Generally, chronic hepatitis D progresses more frequently and more rapidly to cirrhosis than chronic hepatitis B, but after years of infection, severity and progression appear to lessen as the disease becomes more quiescent. Although chronic HBV infection is a well recognized risk factor for the development of HCC, a similar association has been demonstrated for chronic HDV infection. Overall, the pattern of disease progression appears to vary with geography, genotype, and mode of transmission. Slowly progressive, mild disease is more common in endemic areas. On the other hand, HDV-associated disease appears to be more severe in nonendemic areas, where injection drug use is the main form of transmission.

Essentials of Diagnosis

• Diagnosis is established by demonstrating the presence of serum IgM antibody to hepatitis E virus (anti-HEV) by immunoassay or HEV RNA by PCR (these assays are not available routinely in the United States).
• IgM anti-HEV is detectable for only a few months after acquisition of HEV, and IgG anti-HEV for ~1 year.
• A vaccine has been developed that is effective in preventing hepatitis E, but this vaccine is not available in the United States.

General Considerations

Outbreaks occur in the Indian subcontinent, Central America, Africa, northwest China, and the Central Asian Republics (the former Soviet Union), where hepatitis E virus (HEV) infection is endemic. HEV is transmitted predominantly through the fecal-oral route, and most reported outbreaks of infection have been related to the consumption of fecally contaminated drinking water. Unusual for an enteric virus, HEV is not readily spread via person-to-person transmission. The highest attack rate occurs in young adults, a subpopulation that, ordinarily, would be immune to enterically transmitted endemic agents. Genotypes 3 and 4, more common in the United States, are relatively nonvirulent and associated with inapparent infection, whereas genotypes 1 and 2, common in endemic areas, are relatively virulent, accounting for the clinically apparent, often severe disease in these regions.

In countries where HEV infection is not endemic, the disease has been observed in travelers returning from endemic regions; in nonendemic countries, HEV accounts for fewer than 1% of cases of acute viral hepatitis. HEV can infect pigs, suggesting that some cases of human transmission may result from contact across species. Although clinically apparent hepatitis E is uncommon in the United States, as many as 20% of the population harbor antibodies to HEV, hypothesized to be attributed to low-pathogenicity genotypes acquired via exposure to a swine reservoir.

Pathogenesis

HEV is a small, 32–34 nm, nonenveloped spherical, 7600-base-pair RNA virus (genus Hepacivirus) that was identified in 1983. Transmission is through the fecal-oral route, and, like other hepatitis viruses, the main target cells are hepatocytes. Various geographically distinct isolates have been classified into at least four human genotypes (plus a fifth in nonhuman hosts), but all genotypes share at least one major serologically cross-reactive epitope, despite substantial genomic variability, permitting the development of an effective vaccine.

Clinical Findings

The incubation period for hepatitis E ranges from 2 to 10 weeks; the clinical course of acute hepatitis E is similar to that of acute hepatitis A, but generally acute hepatitis E is more severe. Like acute hepatitis A, acute hepatitis E has an insidious onset, most commonly beginning with a several-day prodromal phase with flulike symptoms, fever, abdominal pain, nausea and vomiting, dark urine and clay-colored stools, diarrhea, and, in a small proportion of cases, a transient macular skin rash. The prodromal phase is followed by the development of jaundice in icteric cases, resolution of the prodromal symptoms, pronounced elevation of amino transaminase levels, elevated bilirubin levels, and, in a proportion of patients with cholestatic features, more often in hepatitis E than in the other viral hepatitides, alkaline phosphatase elevations. Histologically, cholestasis with rosette formation of hepatocytes and polymorphonuclear leukocytes may be prominent. Acute hepatitis E can be very severe in pregnant women, in whom the mortality rate can reach 15–25%.

The diagnosis of HEV infection is established by demonstrating the presence of serum IgM anti-HEV by immunoassay or HEV RNA by PCR. IgM anti-HEV is undetectable after a few months, and even IgG anti-HEV does not persist much beyond 1 year. These assays are not available routinely in the United States but can be obtained in specialized labs (eg, at the Centers for Disease Control and Prevention).

Prevention

Immunoglobulin, produced in countries where HEV is endemic, has not been shown to confer protection against HEV. Prophylactic measures to minimize the occurrence of HEV infection involve improved sanitation and sanitary handling of food and water. Boiling water appears to reduce the risk of infection. Because person-to-person transmission is rare, isolation of affected patients is not indicated.

A recombinant polypeptide vaccine was shown to be effective in a randomized, double-blind, placebo-controlled trial involving nearly 2000 mostly male members of the Nepalese army. The volunteers received three doses of the vaccine or placebo at 0, 1, and 6 months. A total of 69 cases of definite HEV infection occurred at least 14 days after the third injection, 3 in the vaccine group (0.3%) and 66 in the placebo group (7.4%). The efficacy of the vaccine was 85.7% after two doses and 95.5% after all three. The vaccine was well tolerated, with similar serious adverse events in the two groups. Studies are underway to determine the length of protective efficacy of the vaccine and its safety in different sub-population groups, including pregnant women. This vaccine is available in endemic regions but not in the United States.

Treatment

Treatment is largely supportive (see the discussion of hepatitis A treatment earlier in this chapter).

Course & Prognosis

Acute hepatitis E is self-limited; acute illness usually lasts 1–4 weeks, although some patients have a prolonged cholestatic hepatitis lasting 2–6 months. Neither persistent viremia (chronic hepatitis E) nor cirrhosis follows acute infection. Fulminant hepatitis can occur, however, with an overall case fatality rate of 0.1–4%. For unclear reasons, as previously noted, fulminant hepatitis occurs more frequently during pregnancy, resulting in an inordinately high mortality rate of 15–25%, primarily affecting women in the third trimester. In addition, acute hepatitis E can cause hepatic decompensation in patients with preexisting liver disease and in persons who are malnourished.