eMedicine Specialties > Gastroenterology > Liver

Hepatitis, Viral

Author: David C Wolf, MD, FACP, FACG, Medical Director of Liver Transplantation, Westchester Medical Center, Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College
Contributor Information and Disclosures

Updated: Jul 1, 2009

Introduction

Definition

The term hepatitis describes inflammation of the liver. Hepatitis may be caused by alcohol, drugs, autoimmune diseases, metabolic diseases, and viruses. Viral infection accounts for more than 50% of the cases of acute hepatitis in the United States.

The term viral hepatitis is often thought to be synonymous with diseases caused by the known hepatotropic viruses, including hepatitis viruses A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). However, the term hepatotropic is itself a misnomer. Infections with hepatitis viruses, especially hepatitis viruses B and C, have been associated with a wide variety of extrahepatic manifestations. Infrequent causes of viral hepatitis include adenovirus, cytomegalovirus, Epstein-Barr virus, and, rarely, herpes simplex virus infection. Newly discovered pathogens (eg, virus SEN-V) may account for additional cases of non-A/non-E hepatitis.

For excellent patient education resources, visit eMedicine's Hepatitis Center; Liver, Gallbladder, and Pancreas Center; Sexually Transmitted Diseases Center; and Public Health Center. Also, see eMedicine's patient education articles Hepatitis A; Hepatitis B; Hepatitis C; Cirrhosis; Immunization Schedule, Children; and Immunization Schedule, Adults.

Epidemiology of viral hepatitis

HAV; HBV; HCV; HDV, which requires coexisting HBV infection; and HEV cause 95% of cases of acute viral hepatitis observed in the United States. Whether hepatitis G virus (HGV) is pathogenic in humans remains unclear. HAV is the most common cause of acute hepatitis in the United States; HCV is the most common cause of chronic hepatitis. Typical patterns of virus transmission are as follows, with + symbols indicating the frequency of transmission (more + symbols indicated increased frequency):

• Fecal-oral transmission
  • HAV (+++)
  • HEV (+++)
• Parenteral transmission
  • HBV (+++)
  • HCV (+++)
  • HDV (++)
  • HGV (++)
  • HAV (+)
• Sexual transmission
  • HBV (+++)
  • HDV (++)
  • HCV (+)
• Perinatal transmission
  • HBV (+++)
  • HCV (+)
  • HDV (+)
• Sporadic (unknown) transmission
  • HBV (+)
  • HCV (+)

Natural history of acute viral hepatitis

The term viral hepatitis can describe either a clinical illness or the histologic findings associated with the disease. Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure. Adults with acute hepatitis A or B disease are usually symptomatic. Persons with acute hepatitis C disease may be either symptomatic or asymptomatic (ie, subclinical).

Fulminant hepatic failure is defined as acute liver failure that is complicated by hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the encephalopathy of fulminant hepatic failure is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting brain edema is a potentially fatal complication of fulminant hepatic failure.

Fulminant hepatic failure may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B. Hepatitis E is a common cause in Asia. Whether hepatitis C is a cause remains controversial. Although fulminant hepatic failure may resolve, more than one half of all cases result in death unless liver transplantation is performed in time.

Providing that acute viral hepatitis does not progress to fulminant hepatic failure, many cases resolve over a period of days, weeks, or months. Alternatively, acute viral hepatitis may evolve into chronic hepatitis. Hepatitis A and hepatitis E never progress to chronic hepatitis, either clinically or histologically.

Natural history of chronic viral hepatitis

Approximately 90-95% of cases of acute hepatitis B in neonates, 5% of cases of acute hepatitis B in adults, and as many as 85% of cases of acute hepatitis C demonstrate histologic evolution to chronic hepatitis. Some patients with chronic hepatitis remain asymptomatic for their entire lives. Other patients report fatigue (ranging from mild to severe) and dyspepsia.

Approximately 20% of patients with chronic hepatitis B or hepatitis C eventually develop cirrhosis, as observed histologically. Although some patients with cirrhosis are asymptomatic, others develop life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months, years, or decades to evolve.

Hepatitis A

History

The first modern descriptions of the clinical illness associated with HAV appeared during World War II. Infectious hepatitis, as it was called, was transmissible by the fecal-oral route in human volunteers. The virus had a short incubation before the onset of symptoms. In contrast, what was known as serum hepatitis (later ascribed to HBV infection) had a long incubation period. These observations were confirmed during the early 1950s by studies of virus A and virus B at the Willowbrook State School in Staten Island, NY. Hepatitis A virions were first identified in the stool of patients by electron microscopy in 1973.

Hepatitis A virus

HAV is a picornavirus. It consists of a 7.5-kb RNA virus with a diameter of 27 nm. The virus has 1 serotype but multiple genotypes.

HAV is transmitted commonly most via the fecal-oral route. Cases of transfusion-associated HAV or illness caused by inoculation are uncommon. HAV is a common infection in the lesser-developed nations of Africa, Asia, and Central and South America. The Middle East has a particularly high prevalence of HAV infection. Most patients in these regions are infected when they are young children. Uninfected adult travelers who visit these regions are at risk for infection. Epidemics of HAV infection may be explained by person-to-person contact, such as occurs at institutions, or by exposure to a common source, such as consumption of contaminated water or food.

As sanitation has improved, the overall prevalence of hepatitis A in the United States and in other parts of the developed world has decreased to less than 50% of the population. Because fewer individuals enter adulthood with previous exposure to HAV, adults in the United States are actually at a higher risk for developing significant HAV infection today than they were a generation ago.

Natural history of HAV

The incubation period of HAV is 15-45 days (average, 4 wk). The virus is excreted in stool during the first few weeks of infection, before the onset of symptoms. Young children who are infected with HAV usually remain asymptomatic. Acute hepatitis A is more severe and has higher mortality in adults than in children. The explanation for this is unknown.

Typical cases of acute HAV infection are marked by several weeks of malaise, anorexia, nausea, vomiting, and elevated aminotransferase levels. Jaundice develops in more severe cases. Some patients experience a cholestatic hepatitis, marked by the development of an elevated alkaline phosphatase (ALP) level, in contrast to the classic picture of elevated aminotransferase levels. Other patients may experience several relapses during the course of a year. Less than 1% of cases result in fulminant hepatic failure. HAV infection does not persist and never causes chronic hepatitis.

Pathologic findings of hepatitis A

Classic findings of acute HAV infection include a mononuclear cell infiltrate, interface hepatitis, focal hepatocyte dropout, ballooning degeneration, and acidophilic (Councilman-like) bodies.

Diagnosis of hepatitis A

Acute infection is documented by the presence of immunoglobulin M (IgM) anti-HAV, which disappears several months after the initial infection. The presence of immunoglobulin G (IgG) anti-HAV merely demonstrates that an individual has been infected with HAV at some point in the past, from 2 months ago to decades ago. IgG anti-HAV appears to offer patients lifelong immunity against recurrent HAV infection.

Treatment for acute of HAV infection

Treatment for acute hepatitis caused by HAV is supportive in nature, because no antiviral therapy is available. Hospitalization is needed for patients whose nausea and vomiting places them at risk for dehydration. Patients with acute liver failure require close monitoring to ensure they do not develop fulminant hepatic failure.

Prevention of HAV infection

The US Food and Drug Administration (FDA) approved the first vaccine for HAV in 1995. The US Centers for Disease Control and Prevention (CDC) recommends vaccination against HAV for individuals traveling to endemic regions, and vaccination is recommended for any patient with chronic liver disease.¹ The HAV vaccines (inactivated), Havrix (GlaxoSmithKline, Research Triangle Park, NC) and Vaqta (Merck, Whitehouse Station, NJ), are 1-mL intramuscular (IM) injections (0.5 mL in children), given more than 1 month before anticipated travel. This results in a better-than-90% likelihood of stimulating production of IgG anti-HAV, with resulting immunity against HAV infection. A booster dose of the vaccine is recommended 6 months after the initial vaccination. Whether HAV vaccine administration should be mandated in children (as is HBV vaccination) remains unclear.

An alternative vaccine (HAV inactivated and HBV recombinant vaccines) is Twinrix (GlaxoSmithKline). This product is immunogenic against both HAV and HBV. Typical administration involves 3 injections of 1 mL given intramuscularly on a 0-, 1-, and 6-month schedule. The FDA has approved its use in adults.

The administration of hepatitis A immune globulin is an alternative to vaccination against HAV infection. The dose is 0.02 mL/kg given intramuscularly for individuals who anticipate spending less than 3 months in an endemic region. Travelers should receive 0.06 mL/kg intramuscularly every 4-6 months if they are planning to spend more than 3 months in a region where HAV is endemic.

Postexposure prophylaxis with hepatitis A immune globulin is appropriate for household and intimate contacts of patients with HAV. It is also recommended for contacts at daycare centers and institutions. Typical dosing of immune globulin is 0.02 mL/kg, given intramuscularly as a single dose. Postexposure prophylaxis is not recommended for the casual contacts of patients, such as classmates or coworkers.

Hepatitis B

History

Serum hepatitis received its name in 1942 after an outbreak of hepatitis among American soldiers. The outbreak was traced to yellow fever vaccine that was contaminated with human serum. In 1965, Baruch Blumberg and colleagues described the Australia antigen, which later was called hepatitis B surface antigen (HBsAg). Antigen in serum from an Australian aborigine precipitated with antibody from the serum of a patient with hemophilia who had a history of blood transfusions. In 1970, D. S. Dane used electron microscopy to describe hepatitis B viral particles in human serum.

Hepatitis B virus

HBV is a member of the Hepadnaviridae family. It is a 3.2-kb partially doubled-stranded DNA virus. Its positive strand is incomplete. The complete negative strand has 4 overlapping genes. Gene S codes for HBsAg, also known as surface antigen, a viral surface polypeptide. Gene C codes for HBcAg, also known as core antigen, the nucleocapsid protein. It also codes for HBeAg, whose function is unknown. Gene P codes for a DNA polymerase that has reverse transcriptase activity. Gene X codes for the X protein that has transcription-regulating activity.

The viral core particle consists of a nucleocapsid, HBcAg, which surrounds HBV DNA, and DNA polymerase. The nucleocapsid is coated with HBsAg. The intact HBV virion is known as the Dane particle. Dane particles and spheres and tubules containing only HBsAg are found in the blood of infected patients. In contrast, HBcAg is not detected in the circulation. It can be identified by immunohistochemical staining of infected liver tissue.

Eight genotypic variants of the HBV (genotypes A-H) are described. Although preliminary studies suggest that particular HBV genotypes may predict the virus's response to therapy or may be associated with more aggressive disease, incorporating HBV genotype testing into clinical practice is premature.

Mechanism of hepatocyte necrosis in HBV infection

HBV may be directly cytopathic to hepatocytes. However, immune system–mediated cytotoxicity plays a predominant role in causing liver damage. The immune assault is driven by human leukocyte antigen (HLA) class I–restricted CD8 cytotoxic T lymphocytes that recognize HBcAg and HBeAg on the cell membranes of infected hepatocytes.

Epidemiology of HBV

Infection with HBV is defined by the presence of HBsAg. Approximately 90-95% of neonates with acute infection and 5% of adults with acute infection develop chronic HBV infection. The infection clears in the remainder of patients, and these patients develop a life-long immunity against repeated infections. Approximately 5% of the world's population (ie, 300 million people) is chronically infected with HBV. More than 10% of people living in sub-Saharan Africa and in East Asia are infected with HBV. Maintenance of a high HBsAg carriage rate in these parts of the world is partially explained by the high prevalence of perinatal transmission and by the low rate of HBV clearance by neonates.

Of cases of chronic HBV infection, 20% progress to cirrhosis or hepatocellular carcinoma (HCC), resulting in more than 1 million deaths each year. This makes hepatitis B the ninth leading cause of death in the world.

Approximately 200,000 new cases of HBV infection occur each year in the US. About 250-350 patients die from HBV-associated fulminant hepatic failure each year. A pool of approximately 800,000 chronic HBV carriers exists in the US. Of these patients, 4000 die from HBV-induced cirrhosis each year and 1000 die from HBV-induced HCC each year.

Transmission of HBV

HBV is readily detected in serum. It is seen at very low levels in semen, vaginal mucus, saliva, and tears. The virus is not detected in urine, stool, or sweat. HBV can survive storage at -20°C (-4°F) and heating at 60°C (140°F) for 4 hours. It is inactivated by heating at 100°C (212°F) for 10 min or by washing with sodium hypochlorite (bleach).

Perinatal transmission of HBV

The vast majority of HBV cases around the world result from perinatal transmission. Infection appears to be due to contact with a mother's infected blood at the time of delivery, as opposed to transplacental passage of the virus. Neonates infected via perinatal infection are usually asymptomatic. Although breast milk can contain HBV virions, the role of breastfeeding in transmission is unclear.

Sexual transmission of HBV

HBV is transmitted more easily than human immunodeficiency virus (HIV) or HCV. Infection is associated with vaginal intercourse, genital-rectal intercourse, and oral-genital intercourse. An estimated 30% of sexual partners of patients infected with HBV also contract HBV infection. However, HBV cannot be transmitted through kissing, hugging, or household contact such as sharing towels, eating utensils, or food. Sexual activity is estimated to account for as many as 50% of HBV cases in the US.

Parenteral transmission of HBV

HBV was once a common cause of posttransfusion hepatitis. Screening of US blood donors for HBcAb, beginning in the early 1970s, dramatically reduced the rate of HBV infection associated with blood transfusion. Currently, approximately 1 HBV transmission occurs per 250,000 individuals transfused.

Patients with hemophilia, those on renal dialysis, and those who have undergone organ transplantations remain at increased risk of HBV infection. Intravenous drug use accounts for 20% of US cases of HBV. A history of HBV exposure is identified in approximately 50% of persons who use intravenous drugs.

The risk of acquiring HBV after a needle stick from an infected patient is estimated to be as high as 5%.

Sporadic cases of hepatitis B

The cause of HBV infection is unknown in approximately 27% of cases. Some these cases, in fact, may be due to sexual transmission or contact with blood.

Natural history of HBV

The incubation period of HBV is 40-150 days, with an average of approximately 12 weeks. As with HAV, the clinical illness associated with acute HBV infection may range from mild disease to a disease as severe as fulminant hepatic failure (<1% of patients).

After acute hepatitis resolves, 95% of adult patients and 5-10% of infected infants ultimately develop anti-HBV antibody, clear HBsAg (and HBV virions), and fully recover. Five percent of adult patients and 90-95% of infected infants develop chronic infection.

Inactive carrier state

With the development of chronic infection (as marked by a positive HBsAg finding), 70-90% of HBsAg carriers enter the inactive carrier state (previously known as the healthy carrier state). They have no symptoms, normal liver chemistry test results, and normal or minimally abnormal liver biopsy results. Blood test evidence of HBV replication should be nonexistent or minimal, with a serum HBV DNA level in the range of 0-30,000 copies (genomes) per milliliter (mL).

Inactive carriers remain infectious to others through parenteral or sexual transmission. Inactive carriers may ultimately develop HBsAb and clear the virus. However, some inactive carriers develop chronic hepatitis, as determined by liver chemistry results, liver biopsy findings, and HBV DNA levels. Inactive carriers remain at risk, albeit low, to develop HCC. See HBV and HCC, below, for recommendations regarding screening.

At this point, no effective antiviral therapies are available for patients in an inactive carrier state.

Chronic hepatitis B

Of HBsAg carriers, 10-30% develop chronic hepatitis. These patients are often symptomatic. Fatigue is the most common symptom of chronic HBV infection. Patients may occasionally experience an acute flare of their disease, with symptoms and signs similar to those of acute hepatitis. Patients also may have extrahepatic manifestations of their disease, including polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis.

Chronic hepatitis B patients have abnormal liver chemistry results, blood test evidence for active HBV replication, and inflammatory or fibrotic activity on liver biopsy specimens (see Image 4 or below).

Ultimately, approximately 20% of HBsAg carriers (approximately 1% of all adult patients infected acutely with HBV) go on to develop cirrhosis or HCC (see Image 3 or below). See HBV and HCC, below, for recommendations regarding screening.

Patients with HBeAg-negative chronic hepatitis were presumably infected with wild-type virus at some point. Over time, they acquired a mutation in either the precore or the core promoter region of the viral genome. In such patients with a precore mutant state, HBV continues to replicate but HBeAg is not produced. Patients with a core mutant state appear to have downregulated HBeAg production. HBeAg-negative patients typically have lower HBV DNA levels than do HBeAg-positive patients. More than 50% are noted to have an HBV DNA level less than 10⁵ copies/mL.

In North America and Northern Europe, about 80% of chronic hepatitis B cases are HBeAg positive and 20% are HBeAg negative. In Mediterranean countries and in some parts of Asia, 30-50% of cases are HBeAg positive and 50-80% are HBeAg negative.

HBV and HCC

The incidence of HCC parallels the incidence of HBV infection in various countries around the world. Worldwide, up to 1 million cases of HCC are diagnosed each year. Most appear to be related to HBV infection. In HBV-induced cirrhosis, as in cirrhosis due to other etiologies, hepatic inflammation and regeneration appear to stimulate mutational events and carcinogenesis. However, in HBV infection, in contrast to other liver diseases, the presence of cirrhosis is not a prerequisite for the development of HCC. The integration of HBV into the hepatocyte genome may lead to the activation of oncogenes or the inhibition of tumor suppressor genes. As an example, mutations or deletions of the p53 and RB tumor suppressor genes are seen in many cases of HCC.²

HCC is a treatable and potentially curable disease, whether the treatment entails tumor ablation (eg, with percutaneous injection of ethanol into the tumor), liver resection, or liver transplantation. The American Association for the Study of Liver Diseases recommends screening for HBV-infected individuals who are at high risk for HCC, including men older than 45 years, persons with HBV-induced cirrhosis, and persons with a family history of HCC.

Diagnosis of acute self-limited HBV infection

HBsAg is the first serum marker seen in persons with acute infection. It represents the presence of HBV virions (Dane particles) in the blood. HBeAg, a marker of viral replication, is also present. When viral replication slows, HBeAg disappears and anti-HBe is detected. Anti-HBe may persist for years.

The first antibody to appear is anti-HBc (HBcAb). Initially, it is of the IgM class. Indeed, the presence of IgM anti-HBc is diagnostic for acute HBV infection.

Weeks later, IgM anti-HBc disappears and IgG anti-HBc is detected. Anti-HBc may be present for life. The anti-HBc (total) assay detects both IgM and IgG antibodies. The presence of anti-HBc (total) demonstrates that the patient has had a history of infection with HBV at some point in the past.

In patients who clear the HBV, HBsAg usually disappears 4-6 months after infection, as titers of anti-HBs (HBsAb) become detectable. Anti-HBs is believed to be a neutralizing antibody, offering immunity to subsequent exposures to HBV. Anti-HBs may persist for the life of the patient.

Knowing key points helps in the interpretation of serology findings in acute HBV infection. The presence of HBsAg does not indicate whether the infection is acute or chronic. The presence of anti-HBc (IgM) is the sine qua non of acute HBV infection. The presence of anti-HBc (total) indicates that a patient has been infected with HBV at some point. The anti-HBc (total) remains positive both in patients who clear the virus and in patients with persistent infection.

The presence of anti-HBc (total) with a negative HBsAg and a negative anti-HBs indicates 1 of 4 things. First, the test result is a false positive. Second, the patient is in a window of acute hepatitis, between the elimination of HBsAg and the appearance of anti-HBs. This scenario is not observed in patients with chronic HBV infection. Third, the patient has cleared the HBV virus but has lost anti-HBs over the years. Fourth, the patient is one of the uncommon individuals with active HBV replication who is negative for HBsAg. This situation is diagnosed when either a positive HBeAg or a positive HBV DNA result is found. In the author's opinion, the discovery of a lone positive anti-HBc (total) finding in the setting of negative HBsAg and negative anti-HBs findings mandates the performance of an HBV DNA assay by polymerase chain reaction (PCR).

Diagnosis of chronic HBV infection

HBsAg may remain detectable for life in many patients. Individuals who have positive findings for HBsAg are termed carriers of HBV. They may be inactive carriers or they may have chronic hepatitis. Anti-HBc is present in all patients with chronic HBV infections. HBeAg and HBV DNA may or may not be present. They reflect a state of active viral replication. HBV DNA levels are typically low or absent in inactive carriers. HBV DNA levels are higher in patients with chronic hepatitis B. High HBV DNA levels are associated with increased infectivity. Anti-HBs are usually absent in patients with chronic infection. If anti-HBs are present in a patient who has positive HBsAg findings, it reflects the presence of a low level of antibody that was unsuccessful at inducing viral clearance.

Table 1. Diagnostic Tests for Hepatitis B (Adapted from Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. Feb 2004;2(2):87-106.³ )

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Markers after vaccination for HBV

The HBV vaccine delivers recombinant HBsAg to the patient, without HBV DNA or other HBV-associated proteins. More than 90% of recipients develop protective anti-HBs. Vaccine recipients are not positive for anti-HBc unless they were previously infected with HBV.

Pathologic findings of HBV infection

Inactive carriers of HBV have no or minimal histologic abnormalities detected on liver biopsy specimens.

Patients with chronic hepatitis B may have a number of classic histologic abnormalities. Inflammatory infiltrates composed of mononuclear cells may either remain contained within the portal areas or disrupt the limiting plates of portal tracts, expanding into the liver lobule (interface hepatitis). Periportal fibrosis or bridging necrosis (between portal tracts) may be present. The presence of bridging necrosis places the patient at increased risk for progression to cirrhosis. Ground-glass cells may be seen (see Image 2 or below). This term describes the granular homogeneous eosinophilic staining of cytoplasm caused by the presence of HBsAg. Sanded nuclei reflect the presence of an overload of HBcAg. Special immunohistochemical stains may help detect HBsAg and HBcAg.

Treatment of acute hepatitis B

As with the treatment of acute hepatitis A, no well-established antiviral therapy is available for acute HBV infection. Supportive treatment recommendations are the same as for acute hepatitis A. Lamivudine, adefovir dipivoxil, or other antiviral therapies appear to have a positive impact on the natural history of severe cases of acute HBV infection. A study by Schmilovitz-Weiss described a rapid clinical and biochemical response in 13 of 15 patients with severe acute hepatitis B who received lamivudine.⁵

Treatment of chronic hepatitis B

The key goal of antiviral treatment of HBV is the inhibition of viral replication, as marked by the loss of HBeAg and HBV DNA. Secondary goals are to reduce symptoms, if any, and to prevent or delay the progression of chronic hepatitis to cirrhosis or HCC.

Antiviral therapy infrequently leads to viral eradication, as marked by the loss of HBsAg. Currently, no antiviral therapy is available for inactive carriers who have low or undetectable levels of actively replicating virus.

Candidates for antiviral therapy must have evidence of active HBV infection. Until recently, this was generally defined as the presence of HBV DNA levels of greater than 10⁵ copies/mL in patients who were positive for HBeAg or HBV DNA levels of greater than 10⁴ copies/mL in patients who were negative for HBeAg. As noted above, some experts recently defined the thresholds for treatment as follows: HBV DNA levels of greater than 2 X 10⁴ IU/mL for patients with HBeAg-positive chronic hepatitis and greater than 2 X 10³ IU/mL for patients with HBeAg-negative chronic hepatitis.

Patients with chronic hepatitis tend to have abnormal liver chemistry findings. Treatment may be offered to patients with a normal ALT level, but it may be less efficacious. Although performing a liver biopsy is not mandatory before treatment, the author recommends it. Liver biopsy is helpful for confirming the clinical diagnosis of chronic hepatitis B and for documenting the severity of liver disease. Detailed treatment recommendations have been published.^3,4 Another resource is the practice guidelines of the American Association for the Study of Liver Diseases.⁶

IFN-alfa treatment for chronic hepatitis B

Interferons have both antiviral and immunomodulatory effects. Treatment with IFN-alfa is appropriate for some patients with chronic hepatitis B.

Until recently, the most commonly used interferon was IFN-alfa-2b. The medication was dosed at 5 million U given subcutaneously (SC) every day for at least 16 weeks or 10 million U given subcutaneously 3 times per week for at least 16 weeks. An elevation in the ALT level was common 8-12 weeks after the start of therapy. This change may have represented interferon-induced activation of the cell-mediated immune system. Loss of HBeAg and HBV DNA occurred in as many as 37% of treated patients.⁷

Interferon was most effective when it was used in patients with a brief history of hepatitis B infection, an ALT level >100 U/L, and a low HBV DNA level. Interferon was less effective in patients with (1) lifelong HBV infection, (2) an ALT level <100 U/L, (3) a high HBV DNA level, (4) end-stage renal disease (ESRD), (5) HIV infection, or (6) a need for immunosuppressive therapy (eg, after organ transplantation). However, these guidelines may be changing in view of studies of PEG-IFN.

Data have demonstrated the increased effectiveness of PEG-IFN-alfa-2a. In one study of HBeAg-positive chronic hepatitis B, patients received a 48-week course of PEG-IFN-alfa-2a 180 mcg given subcutaneously once weekly.⁸  Thirty-two percent of patients experienced seroconversion from HBeAg positivity to HBeAb positivity. HBeAg loss was seen in 34% of patients, and 32% of patients had a reduction in HBV DNA from a mean of 10¹⁰ copies/mL to < 10⁵ copies/mL. ALT levels normalized in 41% of patients. Liver histology also improved in treated patients.⁸

In HBeAg-negative chronic hepatitis B, a 48-week course of PEG-IFN-alfa-2a 180 mcg given subcutaneously once weekly also produced promising results.⁹ 43% of patients experienced a reduction in HBV DNA from a mean of 10⁷ to <20,000 copies/mL. Nineteen percent of patients had a reduction in HBV DNA to <400 copies/mL, and ALT values normalized in 59% of patients.⁹ Liver histology improved in a significant number of patients.

Adverse effects of interferon are common but lead to discontinuation of the drug in only 5-10% of patients. Adverse effects include flulike symptoms (eg, fatigue, fever, headache, myalgia, arthralgia), neuropsychiatric symptoms (eg, depression, irritability, somnolence), hematologic effects (eg, granulocytopenia, thrombocytopenia), and other miscellaneous effects (eg, pain at injection site, dyspepsia, alopecia, thyroid function abnormalities).

Lamivudine for chronic hepatitis B

Lamivudine (Epivir; GlaxoSmithKline) is the negative enantiomer of 2'3'-dideoxy-3'-thiacytidine. This synthetic nucleoside analogue inhibits DNA polymerase–associated reverse transcriptase and can suppress HBV replication.

In patients with HBeAg-positive chronic hepatitis, treatment with a dose of 100 mg/d orally for 1 year results in HBeAg loss in up to one third of patients. In patients with HBeAg-negative chronic hepatitis, treatment with 100 mg/d orally for 2 years results in loss of HBV DNA in up to one third of patients. Treatment also improves ALT levels, induces histologic improvements, and reduces the rate of development of hepatic fibrosis in a significant number of patients. In general, treatment is discontinued in HBeAg-positive patients 3-6 months after a patient achieves seroconversion from HBeAg to anti-HBe. However, in patients with HBeAg-negative chronic hepatitis, the rate of virologic relapse is high when treatment is discontinued. Therefore, patients may need indefinite treatment with a nucleoside analogue to maintain viral suppression.

The advantages of lamivudine over interferon include its ease of application and the virtual absence of adverse effects (see Warnings about therapy for HBV). Lamivudine is effective in populations whose HBV disease was generally not responsive to older formulations of IFN-alfa (eg, persons with high HBV DNA levels). Lamivudine is also successful in some patients with decompensated hepatitis B-induced cirrhosis and those with recurrent hepatitis B after liver transplantation. However, approximately 24% of those whose condition initially responds to lamivudine develop drug resistance within the first year of therapy. The incidence of lamivudine resistance increases to 69% after 5 years of therapy. This finding is explained by the development of a mutation at the YMDD locus in the HBV DNA polymerase gene. The development of lamivudine resistance may also lead to a reversion of the improvements seen on some liver biopsy specimens.

Adefovir dipivoxil for chronic hepatitis B

Adefovir dipivoxil (HepSera; Gilead Sciences, Inc, Foster City, CA) is a synthetic nucleotide analogue. It received FDA approval for the treatment of chronic hepatitis B in adults in September 2002. It inhibits HBV DNA polymerase and causes DNA chain termination after its incorporation into viral DNA. It is typically dosed at 10 mg orally once per day. Dose adjustments should be made for patients with creatinine clearance < 50 mL/min. It is recommended that patients with renal insufficiency undergo monitoring of their serum creatinine and phosphate while under treatment.

Adefovir dipivoxil 10 mg orally once per day for 48 weeks resulted in a mean drop in the HBV DNA by 3.52 log₁₀ copies/mL in patients with HBeAg-positive chronic hepatitis and by 3.91 log₁₀ copies/mL in patients with HBeAg-negative chronic hepatitis. In patients with HBeAg-positive chronic hepatitis, negative HBV DNA findings were achieved in 6% of patients by week 48 of treatment and 46% of patients by week 144 of treatment.¹⁰ In patients with HBeAg-negative chronic hepatitis, negative HBV DNA findings were achieved in 64% of patients by week 48 of treatment and 79% of patients by week 144 of treatment.¹¹ Most HBeAg-positive and HBeAg-negative patients experienced improvements in both ALT and liver histology results while receiving adefovir dipivoxil.

Resistance mutations develop in less than 2% of patients taking long-term therapy with adefovir dipivoxil. The drug is also useful in patients who had previously developed resistance to lamivudine. Substitution of adefovir dipivoxil for lamivudine in such patients produces a 3-log₁₀ drop in the number of HBV DNA copies/mL. Treatment with adefovir dipivoxil costs approximately $5300/y, as opposed to approximately $1700/y for lamivudine.

Tenofovir versus adefovir for chronic hepatitis B

In 2 double-blind, phase 3 studies, Marcellin et al evaluated tenofovir versus adefovir in the treatment of chronic hepatitis B. Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B virus (HBV) infection were randomized to receive tenofovir disoproxil fumarate (DF) (300 mg) or adefovir dipivoxil (10 mg) (ratio, 2:1) once daily for 48 weeks.¹² The primary efficacy end point was a plasma HBV DNA level of less than 400 copies/mL (69 IU/mL) and histologic improvement (defined as a reduction in the Knodell necroinflammation score of >2 points without worsening fibrosis) at week 48. The investigators included secondary end points such as viral suppression (HBV DNA level <400 copies/mL), histologic improvement, serologic response, normalization of ALT levels, and development of resistance mutations.¹²

At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir than of those receiving adefovir had reached the primary end point (P <0.001), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than patients in the adefovir group (63%) (P <0.001), as well as in more HBeAg-positive patients receiving tenofovir (76%) than those receiving adefovir (13%) (P <0.001).¹² In addition, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%) (P = 0.03) but also loss of HBsAg (3% tenofovir group vs 0% adefovir group) (P = 0.02).¹²

At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B virus (HBV) infection; tenofovir  produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not; and the 2 treatments in both studies had similar safety profiles.¹² Marcellin et al concluded that among patients with chronic hepatitis B virus (HBV) infection, tenofovir at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir at a daily dose of 10 mg through week 48.¹²

Entecavir for chronic hepatitis B

Entecavir (Baraclude; Bristol-Myers Squibb Company, New York, NY) is a deoxyguanine nucleoside analogue. It inhibits priming of HBV DNA polymerase with a resulting decrease in HBV replication. Entecavir received FDA approval for the treatment of chronic hepatitis B in adults in March 2005. It is dosed at 0.5 mg orally once per day in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. In patients with a history of lamivudine-resistant chronic hepatitis B, it is dosed at 1 mg orally once per day. As with adefovir dipivoxil, dose adjustments should be made for patients with creatinine clearance <50 mL/min and for patients receiving dialysis.

Entecavir 0.5 mg orally once per day for 48 weeks resulted in a mean drop in the HBV DNA by 6.98 log₁₀ copies/mL in patients with HBeAg-positive chronic hepatitis and by 5.20 log₁₀ copies/mL in patients with HBeAg-negative chronic hepatitis.¹³ By 48 weeks, a negative HBV DNA was achieved in 69% of HBeAg-positive patients and 91% of HBeAg-negative patients. These results were superior to patients who received lamivudine 100 mg once per day for 48 weeks.¹³

Telbivudine for chronic hepatitis B

Telbivudine (Tyzeka; Novartis Pharmaceuticals Corp, East Hanover, NJ) received FDA approval in 2006. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. By 52 weeks, treatment with telbivudine (600 mg/d) led to a reduction in HBV DNA by 6.45 log₁₀ copies/mL in patients with HBeAg-positive chronic hepatitis and 5.23 log₁₀ copies/mL in patients with HBeAg-negative chronic hepatitis. A negative HBV DNA was achieved in 75% of patients with HBeAg-positive chronic hepatitis and in 88% of patients with HBeAg-negative chronic hepatitis. Drug resistance is reported in 8-21% of patients.

Combination therapy

Increasingly, combination therapy with more than one nucleoside or nucleotide analogue is contemplated for patients with chronic hepatitis B. Combination therapy may be more effective than monotherapy in patients who have exhibited drug resistance. It remains to be determined whether combination therapy is appropriate for patients with chronic hepatitis B who are drug naive.

Shamliyan et al recently conducted a systematic review regarding the effectiveness of antiviral therapy for adults with chronic hepatitis B infection for the National Institutes of Health (NIH) Consensus Development Conference.¹⁴ The investigators extracted data from randomized controlled trials of interferon (IFN) (alpha2b and pegylated [PEG] alpha2a), lamivudine, adefovir, entecavir, and telbivudine published in English from 1990 to 2008. Extracted data included death; incidence of HCC or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of HBeAg or HBsAg, viral load of HBV DNA; aspartate aminotransferase (AST) and ALT levels; or fibrosis scores after therapy with INF-alpha2b, PEG-IFN-alpha2a, lamivudine, adefovir, entecavir, and telbivudine.¹⁴   Shamliyan et al's findings included the following¹⁴ :

• Drug treatment did not improve clinical outcomes of chronic hepatitis B infection in 16 RCTs (4431 patients), but the trials were underpowered.
• In 60 trials that examined intermediate outcomes, no single treatment improved all intermediate outcomes.
• Evidence suggesting HBsAg clearance after treatment with IFN-alpha2b (2 RCTs; 211 patients) was of low quality. 
• There was moderate quality evidence to suggest:
  • ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients).
  • HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients) with IFN-alpha2b therapy.
• PEG-IFN-alpha2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. PEG-IFN-alpha2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients).

The investigators concluded future research is necessary to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection as there was insufficient evidence to evaluate the treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates.¹⁴

Warnings about therapy for HBV

Patients should undergo testing with a PCR-based assay for HBV DNA before therapy is started. Viral loads may range from undetectable to hundreds of millions of copies/mL. Antiviral therapy is generally reserved for patients with greater than 10⁵ copies/mL for patients with HBeAg-positive chronic hepatitis. A lower HBV DNA, perhaps 10⁴ copies/mL, may be an appropriate trigger to initiate therapy in patients with HBeAg-negative chronic hepatitis (ie, patients with precore mutant viruses).

Lactic acidosis and severe hepatomegaly with steatosis have been reported rarely in patients undergoing treatment with lamivudine, adefovir dipivoxil, and entecavir. Severe acute exacerbations of hepatitis have been reported infrequently in patients who discontinue antiviral therapy. Thus, patients continuing treatment and patients who discontinue treatment require careful monitoring.

HBV vaccine

Plasma-derived and recombinant HBV vaccines use HBsAg to stimulate the production of anti-HBs in noninfected individuals. The vaccines are highly effective, with a greater than 95% rate of seroconversion. Vaccine administration is recommended for all infants and for adults at high risk of infection (eg, those receiving dialysis, healthcare workers).

The recommended vaccination schedule for infants is an initial vaccination at the time of birth (ie, before hospital discharge), repeat vaccination at 1-2 months, and another repeat vaccination at 6-18 months. The recommended vaccination schedule for adults is an initial vaccination, a repeat vaccination at 1 month, and another repeat vaccination at 6 months.

Postexposure prophylaxis

Hepatitis B immune globulin (HBIG) is derived from plasma. It provides passive immunization for individuals who describe recent exposure to a patient infected with HBV. HBIG is also administered following liver transplantation to persons infected with HBV, in order to prevent HBV-induced damage to the liver allograft. Recommendations for postexposure prophylaxis for contacts of patients positive for HBsAg are as follows:

• Perinatal exposure – HBIG plus vaccination at time of birth (90% effective)
• Sexual contact with an acutely infected patient – HBIG plus vaccination
• Sexual contact with a chronic carrier – Vaccination
• Household contact with an acutely infected patient – None
• Household contact with an acutely infected person resulting in known exposure – HBIG with or without vaccination
• Infant (<12 mo) primarily cared for by an acutely infected patient – HBIG with or without vaccination
• Inadvertent percutaneous or permucosal exposure – HBIG with or without vaccination

Hepatitis C

History

Blood tests capable of detecting HAV and HBV became available in 1973. After this, the term non-A/non-B (NANB) hepatitis was used to describe the purported virus or viruses responsible for otherwise unexplained cases of posttransfusion hepatitis, chronic hepatitis, and cirrhosis. In the mid-1980s, the antiviral agent IFN-alfa-2b was shown to be efficacious in some cases of hepatitis B and NANB hepatitis. A major breakthrough came in 1989 when Michael Houghton and colleagues cloned and sequenced the HCV genome. A clinical assay for detecting anti-HCV antibody was developed shortly thereafter.

Hepatitis C virus

HCV is a flavivirus. It is a 9.4-kb RNA virus with a diameter of 55 nm. It has one serotype and multiple genotypes. HCVs have profound genetic variability throughout the world. At least 6 major genotypes and more than 80 subtypes are described, with as little as 55% genetic sequence homology. Genotype 1b is the genotype most commonly seen in the United States, in Europe, in Japan, and in Taiwan. Genotypes 1b and 1a (also common in the US) are thought to be less responsive to interferon therapy than other HCV genotypes. The genetic variability of HCV hampers the efforts of scientists to design an effective anti-HCV vaccine.

Epidemiology of hepatitis C

Hepatitis C is prevalent in 0.5-2% of populations in nations around the world. An estimated 4 million Americans are infected with HCV. In the 1980s, as many as 180,000 new cases of HCV infection were described each year in the US. By 1995, there were only 28,000 new cases each year.¹⁵ The decreasing incidence of HCV was explained by a decline in the number of cases of transfusion-associated hepatitis (because of improved screening of blood products) and by a decline in the number of cases associated with intravenous drug use.

Transmission of HCV via blood transfusion

Screening of the US blood supply has dramatically reduced the incidence of transfusion-associated HCV infection. Before 1990, 37-58% of cases of acute HCV infection (then known as NANB) were attributed to the transfusion of contaminated blood products. Now, only approximately 4% of acute cases are attributed to transfusion. HCV is estimated to contaminate 0.01-0.001% of units of transfused blood. Acute hepatitis C remains an important issue in dialysis units, where patients' risk for HCV infection is approximately 0.15% per year.

Transmission of HCV via intravenous and intranasal drug use

Intravenous drug use remains an important mode of transmitting HCV. Intravenous drug use and the sharing of paraphernalia used in the intranasal snorting of cocaine and heroin account for approximately 60% of new cases of HCV infection. More than 90% of patients with a history of intravenous drug use have been exposed to HCV.

Transmission of HCV via occupational exposure

Occupational exposure to HCV accounts for approximately 4% of new infections. On average, the chance of acquiring HCV after a needle-stick injury involving an infected patient is 1.8% (range, 0-7%). Of importance, reports of HCV transmission from healthcare workers to patients are extremely uncommon.

Transmission of HCV via sexual contact

Approximately 20% of cases of hepatitis C appear to be due to sexual contact. In contrast to hepatitis B, approximately 5% of the sexual partners of those infected with HCV contract hepatitis C. The US Public Health Service recommends that persons infected with HCV be informed of the potential for sexual transmission. Sexual partners should be tested for the presence of anti-HCV. Safe-sex precautions are recommended for patients with multiple sex partners. Current guidelines do not recommend the use of barrier precautions for patients with a steady sexual partner. However, patients should avoid sharing razors and toothbrushes with others. In addition, contact with patients' blood should be avoided.

Transmission of HCV via perinatal transmission

Perinatal transmission appears to be uncommon. It is observed in fewer than 5% of children born to mothers infected with HCV. The risk of perinatal transmission of HCV is higher, estimated at 18%, in children born to mothers coinfected with HIV and HCV. Available data show no increase in HCV infection in babies who are breastfed. The US Public Health Service does not advise against pregnancy or breastfeeding for women infected with HCV.

Dowd et al, evaluated HCV-specific neutralizing antibody (nAb) titres in 63 mothers coinfected with HCV and human immunodeficiency virus (HIV) type 1 to determine whether lower levels of HCV nAb are associated with an increased risk of mother-to-child transmission HCV.¹⁶  Although 16 mothers transmitted HCV to their infant, the investigators reported no difference was detected between the ability of maternal plasma from transmitters and nontransmitters to neutralize heterologous HCV pseudoparticles (median nAb titer, 1:125 vs 1:100; P = 0.23). Dowd et al concluded that in the setting of HIV/HCV coinfection, there is no evidence that HCV nAbs are associated with the prevention of mother-to-child transmission of HCV.¹⁶

Natural history of acute hepatitis C

HCV has a viral incubation period of approximately 8 weeks. Most cases of acute HCV infection are asymptomatic. Even when symptomatic, the course of acute HCV infection tends to be mild, with aminotransferase levels rarely higher than 1000 U/L. Whether acute HCV infection is a cause of fulminant hepatic failure remains controversial.

Natural history of chronic hepatitis C

Approximately 15% of patients acutely infected with HCV lose virologic markers for HCV. Thus, approximately 85% of newly infected patients remain viremic and may develop chronic liver disease. In chronic hepatitis, patients may or may not be symptomatic, with fatigue being the predominant reported symptom. Aminotransferase levels may fluctuate from the reference range (<40 U/L) to 300 U/L. However, no clear-cut association exists between aminotransferase levels and symptoms or risk of disease progression.

Natural history of cirrhosis induced by hepatitis C

An estimated 20% of patients with chronic hepatitis C experience progression to cirrhosis. This process may take 10-40 years to evolve. Importantly, patients who are newly diagnosed with well-compensated cirrhosis must be counseled regarding their risk of developing symptoms of liver failure (ie, decompensated cirrhosis). Only 30% of patients with well-compensated cirrhosis are anticipated to decompensate over a 10-year follow-up period.

Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC, especially in the setting of HBV coinfection. In the United States, HCC arises in 3-5% of patients with HCV-induced cirrhosis each year. Accordingly, routine screening (eg, ultrasonography and AFP testing every 6 mo) is recommended in patients with HCV-induced cirrhosis to rule out the development of HCC.

End-stage liver disease caused by HCV leads to about 10,000 deaths in the US each year.

Extrahepatic manifestations of hepatitis C

Patients with chronic hepatitis C are at risk for extrahepatic complications. In essential mixed cryoglobulinemia, HCV may form immune complexes with anti-HCV (IgG) and with rheumatoid factor (RF). The deposition of immune complexes may cause small-vessel damage. Complications of cryoglobulinemia include rash, vasculitis, and glomerulonephritis. Other extrahepatic complications of HCV infection include focal lymphocytic sialadenitis, autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, and Mooren corneal ulcer. Some cases of non-Hodgkin lymphoma can be attributed to hepatitis C infection.

Pathologic findings of hepatitis C

Lymphocytic infiltrates, either contained within the portal tract or expanding out of the portal tract into the liver lobule (interface hepatitis), are commonly observed in patients with chronic hepatitis C. Portal and periportal fibrosis may be present. Other classic histologic features of the disease include bile duct damage, lymphoid follicles or aggregates, and macrovesicular steatosis.

Pathologists who interpret liver biopsy specimens frequently use a histologic scoring system introduced by Batts and Ludwig in 1995, which is displayed in Table 2 below.¹⁷ The METAVIR scoring system (developed by the French METAVIR Cooperative Study Group) uses similar methodology.

Table 2. Histologic Grading for Hepatitis C–Induced Liver Disease

Open table in new window

The histologic staging for hepatitis C–induced liver disease is as follows:

• Stage 1: portal fibrosis
• Stage 2: periportal fibrosis
• Stage 3: septal fibrosis
• Stage 4: cirrhosis

Diagnosis of hepatitis C

The most common tests used in the diagnosis of hepatitis C include liver chemistries, serologic tests, HCV RNA tests, and liver biopsies.

Diagnosis of hepatitis C using liver chemistry testing

Elevations of AST and ALT levels merely indicate the presence of liver injury. Patients with chronically elevated aminotransferase values should undergo a workup to exclude the possibility of chronic liver disease.

Measuring aminotransferase levels is an imperfect test in patients with documented HCV infection. The values do not predict the severity of clinical findings, the degree of histologic abnormalities, the patient's prognosis, or the therapeutic response. Indeed, patients can have HCV-induced cirrhosis and have normal liver chemistry values. Increases and decreases in aminotransferase levels do not appear to correlate with clinical changes. However, normalization of AST and ALT levels following acute infection may signal clearance of HCV. Normalization of AST and ALT levels while a patient is undergoing treatment with interferon predicts a virologic response to treatment. Similarly, an increase in AST and ALT values may signal a relapse after apparently successful drug therapy.

Diagnosis of hepatitis C using serologic tests for HCV

Structural and nonstructural regions of the HCV genome have been synthesized. These can be recognized by human IgG anti-HCV. Recombinant HCV antigens are used in enzyme-linked immunosorbent assay (ELISA) to detect anti-HCV in patients' sera.

Anti-HCV test results remain negative for several months following acute HCV infection. After its appearance, the anti-HCV usually remains present for the life of the patient. This occurs even in the 15% of cases in which the patient clears the virus and does not develop chronic hepatitis. Anti-HCV is not a protective antibody and does not guard against future exposures to HCV.

Recombinant immunoblot assays (RIBAs) use recombinant HCV antigens that are fixed to a solid substrate. They are more specific than ELISA testing and have been used to confirm positive ELISA results. However, their use is being abandoned in favor of HCV RNA testing.

A positive HCV result with ELISA or recombinant immunoblot assay (RIBA) has 1 of 3 potential interpretations. First, the test result is a true positive, and the patient is infected with HCV. Second, the test result is a true positive, but the patient is no longer viremic for HCV and does not have chronic hepatitis. The results from neither the ELISA nor the RIBA distinguish resolved infection from active infection. Third, the test result is a false positive.

ELISA testing has a positive predictive value (PPV) of greater than 95% when it is used in patients at high risk for hepatitis C, such as individuals who use intravenous drugs and have abnormal liver chemistry findings. However, the positive predictive value is only 50-61% in patients who are at low risk for HCV infection. Furthermore, patients with autoimmune hepatitis or hypergammaglobulinemia frequently have false-positive ELISA test results. Thus, a positive HCV ELISA or RIBA test result does not prove the presence of HCV infection. Positive serologic tests require confirmation with HCV RNA testing.

Other limitations of ELISA testing include that it fails to detect anti-HCV in 2-5% of infected patients, and it fails to detect anti-HCV in immunosuppressed patients, such as patients with end-stage renal disease, HIV infection, or concomitant immunosuppressant therapy. The possibility of HCV infection in this patient population should prompt HCV RNA testing.

Diagnosis of hepatitis C using HCV RNA tests

PCR assays and branched DNA assays have been used since the early 1990s to detect HCV RNA in serum. In contrast to ELISA and RIBA testing, HCV RNA testing can confirm the presence of active HCV infection.

HCV RNA testing has a number of important uses. It aids in the diagnosis of (1) early cases of HCV infection, before the development of HCV antibody positivity or an elevation of the ALT level; (2) seronegative cases, such as in the setting of end-stage renal disease; and (3) cases of perinatal transmission. HCV RNA testing also helps to (1) confirm false-positive cases, such as autoimmune hepatitis; (2) assess the HCV genotype and viral load; (3) predict the response to interferon therapy; (4) guide the duration and dose of interferon therapy; and (5) assess the likelihood of relapse following a response to interferon therapy.

Diagnosis of hepatitis C using liver biopsy

Liver biopsy is an important diagnostic test in possible cases of chronic hepatitis C. Biopsy results can help confirm the diagnosis as well as help exclude other diseases that might have an impact on antiviral therapy, such as autoimmune hepatitis or hemochromatosis. Furthermore, liver biopsy offers the most reliable assessment of the severity of disease.

Patients with minimal inflammation and fibrosis on biopsy specimens may elect to not receive antiviral therapy. The author advises such patients to return for repeat biopsy in 3-4 years to rule out progression of liver disease. Before patients with stage 1 fibrosis elect to undergo a course of watchful waiting, the author counsels his patients that only virologic eradication can ensure that the patient never develops one of the extrahepatic complications of hepatitis C.

Patients with previously unsuspected cirrhosis on biopsy specimens should be monitored to ensure they do not develop large esophageal varices or HCC. Furthermore, knowledge of the severity of histologic changes may influence the patient and the physician to be more aggressive or less aggressive in the pursuit of effective antiviral therapy. Patients with advanced histologic findings may seek experimental therapies should their condition not respond to standard antiviral therapy.

Liver biopsy has a number of noteworthy limitations. First, as an invasive procedure, it may be accompanied by significant complications (eg, bleeding) in approximately 1 in 1000 patients. Second, a sampling error may occur. Indeed, the damage induced by viral infection in some patients is not uniform throughout the entire liver. Also, interobserver variability may occur when assessing histologic abnormalities. Finally, as a snapshot in time, liver biopsy findings cannot be used to predict the rate of progression of chronic hepatitis C.

Serologic tests for estimating the degree of fibrosis in patients with chronic hepatitis C

Currently, liver fibrosis can be estimated by means of 2 commercial laboratory tests. FIBROSpect (Prometheus Laboratories, San Diego, Calif) uses measurements of hyaluronic acid to estimate liver fibrosis. FibroSURE (LabCorp, Burlington, NC) measures gamma-glutamyl transpeptidase (GGT), total bilirubin, alpha-2 macroglobulin, haptoglobin, and apolipoprotein A1. Both tests can help differentiate patients with no or minimal fibrosis (METAVIR score of F0-F1) from patients with more advanced fibrosis (METAVIR score of F2-F4) with greater than 83% accuracy. Unfortunately, these tests are not yet reliable at differentiating patients with F2 fibrosis from those with F4 fibrosis (ie, cirrhosis). Furthermore, test results are indeterminate for approximately one third of hepatitis C patients.

Given these limitations, most gastroenterologists do no currently use serologic fibrosis markers as a substitute for liver biopsy. These tests may be useful in current practice for identifying patients at low risk for advanced disease (eg, asymptomatic women with HCV RNA positivity, persistently normal liver chemistry values, and no history for alcohol abuse or HIV infection). They may also be useful in the longitudinal follow-up of patients with minimal disease on biopsy specimens who have elected to not undergo antiviral therapy. Future generations of serologic fibrosis markers may have greater accuracy and may obviate the need for liver biopsy.

Treatment of HCV infection

Antiviral therapy has a number of major goals. These include (1) decrease viral replication or eradicate HCV, (2) prevent progression of disease, (3) decrease the prevalence of cirrhosis, (4) decrease the frequency of HCC as a complication of cirrhosis, (5) ameliorate symptoms such as fatigue and joint pain, and (6) treat extrahepatic complications of HCV infection such as cryoglobulinemia or glomerulonephritis.

Interferons are a class of naturally occurring compounds that have both antiviral and immunomodulatory effects. Currently, they are the backbone of antiviral strategies used against HCV infection. Future medications may target the enzymes responsible for HCV replication and may have activity against viral helicases, proteases, and polymerases.

Agents currently approved by the FDA for the treatment of HCV include (1) IFN-alfa-2b (Intron; Schering-Plough, Kenilworth, NJ); (2) IFN-alfa-2a (Roferon; Roche, Nutley, NJ); (3) consensus interferon, also known as interferon alfacon-1 (Infergen; Valeant Pharmaceuticals, Cosa Mesa, Calif); and (4) ribavirin, which is used in combination with interferon (Rebetol [Schering-Plough] or Copegus [Roche]).

The addition of a large, inert polyethylene glycol molecule to a therapeutic molecule (eg, interferon) can delay the clearance of the therapeutic molecule from the bloodstream. Long-acting PEG-IFN-alfa-2b (PEG-Intron, Schering-Plough) and PEG-IFN-alfa-2a (Pegasys; Roche) are currently the most commonly used medications for hepatitis C therapy in the US.

Other interferons under study include (1) consensus interferon, (2) IFN-beta, (3) IFN-gamma, and (4) natural interferon. Future medications may target the enzymes responsible for HCV replication. Drugs that have activity against viral helicases, proteases, and polymerases are currently under study, as are ribozymes and antisense oligonucleotides.

Treatment of acute hepatitis C

Acute hepatitis C is detected infrequently. When it is identified, early therapy with interferon should be considered. In one study, 44 patients with acute hepatitis C were treated with IFN-alfa-2b at 5 million U/d subcutaneously for 4 weeks and then 3 times per week for another 20 weeks.¹⁸ About 98% of patients developed a sustained virologic response (SVR) (ie, undetectable level of serum HCV RNA).¹⁸

Treatment of chronic hepatitis C

IFN-alfa-2b, dosed at 3 million U subcutaneously 3 times per week, was approved by the FDA in 1991 for the treatment of chronic HCV infection. Patients treated with this interferon, and with subsequently introduced IFN-alfa-2a and consensus interferon, had only an 11-12% chance of obtaining a SVR (ie, a persistently undetectable HCV RNA level).

The combination of ribavirin, a nucleoside analogue, with interferon significantly improved patients' responses to treatment. The SVR after 48 weeks of treatment improved from 13% in patients treated with IFN-alfa-2b alone to 38% in patients treated with IFN-alfa-2b in combination with ribavirin at 1000-1200 mg/d orally.¹⁹ So-called combination therapy received approval from the FDA in 1998.

Another major breakthrough came in 2000 with the FDA approval of PEG-IFN-alfa-2b in combination with ribavirin. PEG-IFN-alfa-2a received FDA approval in 2002. By delaying drug clearance from the bloodstream, pegylation allows each interferon to be administered subcutaneously once per week. Higher interferon blood levels are achieved when PEG-IFN is dosed once per week than when standard interferon is dosed 3 times per week.

Typical dosing of PEG-IFN-alfa-2b is 1-1.5 mg/kg/wk subcutaneously. PEG-IFN-alfa-2a is dosed at 180 mcg/wk. Typical ribavirin dosing is in the range of 800-1200 mg/d in 2 divided doses.

Studies with PEG-IFN-alfa-2b and ribavirin showed a 42% SVR rate in patients with genotype 1 who were treated for 48 weeks. An 82% SVR was achieved in patients with genotypes 2 and 3.²⁰ In the case of PEG-IFN-alfa-2a and ribavirin, a 46% SVR was achieved in patients with genotype 1 who were treated for 48 weeks. A 76% SVR was achieved in patients with genotypes 2 and 3.²¹ It should be stressed that these results cannot be compared head to head because of differences in both study methods and patient selection.

HCV RNA levels are usually rechecked 1 month and 3 months after starting treatment and every 3 months thereafter. A typical treatment course is 48 weeks for patients who are infected with HCV genotype 1 and 24 weeks for patients who are infected with HCV genotype 2 or 3.

Research has suggested that sustained virologic response can be achieved in some patients with HCV genotypes 2 and 3 with as little as 14-16 weeks of treatment. This is particularly true of patients in whom the HCV RNA level is undetectable 1 month into therapy.

In HCV genotype 1 cases, patients who achieve viral load negativity 1 month into treatment have a greater than 90% likelihood of achieving an SVR. The more typical situation is that patients remain HCV RNA positive at 1 and 3 months. If treatment cannot induce a 2-log₁₀ drop in the viral load from baseline by week 12, the likelihood that the patient will achieve a SVR is less than 3%. Many physicians advise discontinuation of therapy in such patients in whom an early virologic response does not occur.

Longer durations of therapy, up to 72 weeks, may be appropriate in patients infected with genotype 1 who are slow responders (ie, patients who achieved a 2-log₁₀ drop in the viral load but did not achieve an undetectable HCV RNA level by week 12). In one study, a SVR rate of 39% was seen in such patients who continued treatment for 72 weeks, contrasted with the SVR rate of 18% seen in patients who received treatment for 48 weeks. 

Factors predictive of an SVR to treatment with PEG-IFN in combination with ribavirin include (1) genotype 2 or 3 status, (2) a baseline HCV RNA level <800,000 IU/mL or <2 million copies/mL, (3) compliance with treatment, and (4) absence of cirrhosis. However, patients with well-compensated cirrhosis now have a reasonable likelihood of achieving viral eradication and should be offered interferon therapy, provided no significant contraindication (eg, severe thrombocytopenia) is present. Interferon therapy appears to be beneficial, even in patients who do not have a sustained response.

Results of a study suggested that patients treated with interferon, regardless of whether they achieved a sustained response, had a substantially decreased risk of progressing from severe fibrosis to cirrhosis compared with untreated patients. Patients treated with interferon may also have a decreased risk for HCC.

Repeat treatment of patients who were nonresponsive to antiviral therapy

Approximately 11% of patients whose HCV disease was nonresponsive to interferon and ribavirin combination therapy can achieve an SVR when treated with PEG-IFN in combination with ribavirin. A more vexing issue is the treatment of patients whose disease was a virologic nonresponder to treatment with PEG-IFN in combination with ribavirin. Chronic maintenance therapy with PEG-IFN has been recommended for patients who fulfill 2 criteria. The first is the presence of advanced fibrosis (eg, stage 3 or 4 fibrosis), and the second is a history of some reduction in viral load when previously treated with interferon.

For several years, high-dose daily consensus interferon, in combination with ribavirin, has been used in patients with HCV genotype 1 who were nonresponders to standard treatment with pegylated interferon and ribavirin. Interim results of the DIRECT trial were recently reported.²² Daily consensus interferon at a dose of 15 mcg was used in combination with ribavirin in nonresponders to treatment with pegylated interferon. Up to 29% of previous nonresponders achieved a negative viral load at 24 weeks using this regimen.

Telaprevir, PEG-IFN, and ribavirin

Despite the advent of new treatment strategies with addition of ribavirin to PEG-IFN, the current available therapies for chronic HCV infection are effective in fewer than 50% of patients with HCV genotype 1. The PROVE1 study demonstrated that addition of telaprevir, a protease inhibitor specific for HCV nonstructural 3/4A serine protease, to the current treatment regimen improved virologic response to HCV.²³   In early studies, there was a rapid reduction of chronic HCV RNA levels.

McHutchison et al and the PROVE1 study team evaluated the addition of either telaprevir (1250 mg on day 1, then 750 mg q8h) or matched placebo to the treatment regimen of weekly PEG-IFN alfa-2a and daily ribavirin.²³ The groups that received telaprevir showed significantly improved sustained virologic response rates (as defined by an undetectable HCV RNA level 24 wk after the end of therapy) in patients with genotype 1 HCV (P = 0.002). However, the telaprevir groups had a higher rate of discontinued treatment (21%) compared with the placebo group (11%) because of adverse effects, particularly rash.

Limitations of antiviral therapy

Not all patients with chronic hepatitis C are appropriate candidates for therapy with interferon and ribavirin. First, the drugs have well-known adverse effects, which lead to discontinuation in approximately 15% of patients. Interferon can induce fatigue, joint pain, depression, alopecia, neutropenia, and thrombocytopenia. Interferon can induce the development of thyroid disease or exacerbate an underlying immune-mediated disease (eg, psoriasis, sarcoidosis). Ribavirin commonly produces hemolytic anemia and can induce rash. Patients with baseline thrombocytopenia (eg, platelet count <70,000/µL) are not anticipated to tolerate interferon. Patients with underlying psychiatric disorders must be carefully screened before they receive a drug that can worsen underlying depression or schizophrenia or that can even induce suicidal ideation.

In the author's opinion, patients should undergo baseline ophthalmologic examinations (given the potential, albeit low, risk of interferon- or ribavirin-induced retinopathy) and baseline stress testing (given the potential of ribavirin to induce severe anemia).

Patients invariably need close clinical and laboratory test follow-up during treatment. Some patients with interferon-induced neutropenia need combination therapy with granulocyte colony-stimulating factor (G-SCF) (eg, Neupogen; Amgen, Thousand Oaks, Calif) in order to support a falling white blood cell (WBC) count. Some patients with ribavirin-induced anemia need combination therapy with erythropoietin in order to support a falling hematocrit. However, in spite of all of the potential concerns related to PEG-IFN and ribavirin, the vast majority of patients are able to tolerate their recommended 24- (for genotypes 2 and 3) or 48-week treatment course (for genotype 1).

Treatment of special populations – Patients with chronic renal failure

HCV infection is documented in 10-20% of patients receiving chronic hemodialysis. Anti-HCV therapy is often appropriate for such patients. Attempts to eradicate HCV should be made before renal transplantation. Indeed, the hepatic histologic abnormalities attributed to HCV infection may worsen dramatically after posttransplantation immunosuppressant therapy is started. Reduced doses of PEG-IFN are typically used. Ribavirin should be avoided in all patients with renal insufficiency and in patients receiving hemodialysis because of the increased risk of severe hemolytic anemia.

Treatment of special populations – Patients with HCV-HIV coinfection

Approximately one third of the 1 million Americans infected with HIV are coinfected with HCV. Approximately 10% of all HCV-infected Americans are coinfected with HIV. Therefore, HIV testing should be routine in patients with diagnosed with HCV infection.

HIV-infected individuals appear to have an impaired immune response to HCV infection. This translates into more rapid progression of hepatic fibrosis and higher rates of liver-related death in coinfected patients than in those with only HCV infection. Indeed, HCV-induced cirrhosis is now a major cause of death in the HIV-infected population in the US. This fact has prompted physicians to become more aggressive than they were before in the diagnosis and treatment of HCV in their HIV-infected patients. Also, suppression of HCV by interferon may improve a patient's ability to tolerate antiretroviral therapy. Drug-induced hepatotoxicity is common in patients treated with antiretroviral therapy.

Treatment with PEG-IFN and ribavirin is usually offered to patients with a CD4 cell count greater than 200/µL. CD-4 cell counts less than 200/µL, and certainly less than 100/µL, are associated with a poor response to therapy.

In general, HIV-infected patients tolerate treatment well. However, patients may be prone to significant neutropenia, thrombocytopenia, and anemia. A few case reports describe mitochondrial toxicity and lactic acidosis when interferon and ribavirin are used in combination with dideoxyinosine, zidovudine, stavudine, and efavirenz. Pancreatitis has been described in patients receiving interferon and dideoxyinosine.

Since the introduction of interferon therapy, coinfected patients have had a diminished rate of hepatitis C SVR compared with non-HIV infected patients. However, promising treatment results were reported in coinfected patients in 2004.²⁴ Patients received PEG-IFN-alfa-2a 180 mcg subcutaneously once per week and ribavirin 800 mg orally per day. Patients with genotype 1 had a 29% SVR. Patients with genotype 2 or 3 had a 62% SVR.

Increasing numbers of reports indicate successful liver transplantation being performed in coinfected patients with decompensated HCV-induced cirrhosis and negative HIV viral load who are given antiretroviral therapy. However, only a small percentage of the more than 100 transplantation programs in the US are currently considering liver transplantation for HIV-infected individuals.

New agents for the treatment of HCV

A wide array of drugs that target different aspects of the hepatitis C virus life cycle are currently in development. These drugs include protease inhibitors and RNA polymerase inhibitors, like telaprevir (VX-950; Vertex Pharmaceuticals Incorporated, Cambridge, Mass) and valopicitabine (NM283; Idenix Pharmaceuticals, Incorporated, Cambridge, Mass). These promising oral agents, among others, are in clinical trials.

Hepatitis D

History

Mario Rizzetto and colleagues discovered HDV, also known as the delta virus, in 1977.

Hepatitis D virus

HDV is a single-stranded, 1.7-kb RNA virus. The viral particle is 36 nm in diameter and contains HDAg and the RNA strand. It uses HBsAg as its envelope protein. Thus, HBV coinfection is necessary for the packaging and release of HDV virions from infected hepatocytes.

Epidemiology of HDV

HDV is believed to infect approximately 5% of the world's 300 million HBsAg carriers. The prevalence of HDV infection in South America and Africa is high. Italy and Greece are areas of intermediate endemicity and are well studied. The sharing of contaminated needles in intravenous drug use is thought to be the most common means of transmitting HDV. Persons who use intravenous drugs who are also positive for HBsAg have been found to have HDV prevalence rates ranging from 17% to 90%. Sexual and perinatal transmissions are also described. The prevalence of HDV in prostitutes in Greece and Taiwan is high.

Natural history of HDV coinfection

Simultaneous introduction of HBV and HDV into a patient results in the same clinical picture as acute infection with HBV alone (see Hepatitis B, Natural history of HBV). The resulting acute hepatitis may be mild or severe. Similarly, the risk of developing chronic HBV and HDV infection after acute exposure to both viruses is the same as the rate of developing chronic HBV infection after acute exposure to HBV (approximately 5% in adults). However, chronic HBV and HDV disease tends to progress more rapidly to cirrhosis than chronic HBV infection alone.

Natural history of HDV superinfection

Introduction of HDV into an individual already infected with HBV may have dramatic consequences. Superinfection may give HBsAg-positive patients the appearance of a sudden worsening or flare of hepatitis B. HDV superinfection may result in fulminant hepatic failure.

Pathologic findings of HDV infection

Pathologic abnormalities associated with HBV/HDV infection are the same as those observed in patients infected with HBV alone (see Hepatitis B, Pathologic findings of HBV infection).

Diagnosis of HDV infection

A serologic diagnosis of HDV infection is made by using IgM anti-HDV and IgG anti-HDV tests. HBcAb IgM should be used to help distinguish between coinfection (HBcAb IgM–positive) and superinfection (HBcAb IgM–negative). Detecting HDV RNA in serum is also possible.

Treatment of hepatitis D

Patients coinfected with HBV and HDV are less responsive to interferon therapy than patients infected with HBV alone. To date, lamivudine appears to be ineffective against HBV/HDV coinfection.²⁵

Hepatitis E

History

HEV particles were first recovered from the stool of patients in Tashkent, Uzbekistan, in 1983. In retrospect, HEV was determined to be the cause of waterborne enterically transmitted epidemics of NANB hepatitis in South, Southeast, and Central Asia. Other outbreaks have occurred throughout Africa and Mexico. Cloning of the HEV genome was reported in 1990.

Hepatitis E virus

HEV is a calicivirus. It is a 7.5-kb single-stranded RNA virus and is 32-34 nm. The virus has an incubation period of 2-9 weeks.

Epidemiology of HEV

HEV is transmitted via the fecal-oral route and appears to be endemic in some parts of the lesser-developed countries. Anti-HEV antibodies are observed in as many as 60% of Indian children younger than 5 years.²⁶ Sporadic infections are observed in persons traveling from western countries to these regions.

Natural history of HEV

HEV primarily infects adults and young adults. Acute infection is generally less severe than acute HBV infection and is characterized by fluctuating aminotransferase levels. However, pregnant women, especially when infected during the third trimester, have up to a 25% risk of mortality associated with acute HEV infection. HEV does not appear to cause chronic liver disease.

Pathologic findings of HEV infection

The classic pathologic findings include infiltration of portal tracts by lymphocytes and polymorphonuclear leukocytes, ballooned hepatocytes, acidophilic body formation, and the intralobular necrosis of hepatocytes. Submassive and massive hepatic necrosis may be observed in severe cases.

Diagnosis of HEV infection

The serologic diagnosis is made by using IgM anti-HEV and IgG anti-HEV. HEV RNA can be detected in the serum and stool of infected patients.

Treatment of hepatitis E

The treatment of those infected with HEV is supportive in nature.

Hepatitis G

HGV is similar to viruses in the Flaviviridae family, which includes HCV. The HGV genome codes for 2900 amino acids. The virus has 95% homology (at the amino acid level) with the GB virus (ie, GBV-C), a previously described virus. HGV has 26% homology (at the amino acid level) with HCV.

HGV can be transmitted by blood transfusion. HGV coinfection is observed in 6% of chronic HBV infections and in 10% of chronic HCV infections. However, whether HGV is actually pathogenic in humans remains unclear.

Multimedia

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Media file 1: Hepatitis A virus as viewed through electron microscopy.

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Media file 2: Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

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Media file 3: Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

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Media file 4: Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

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Media file 5: Hepatitis C viral genome. Courtesy of Hepatitis Resource Network.

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Media file 6: Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma (HCC) in an 80-year-old man without cirrhosis.

Keywords

acute hepatitis, chronic hepatitis, hepatitis A, hepatitis A virus, HAV, hepatitis B, hepatitis B virus, HBV, hepatitis C, hepatitis C virus, HCV, hepatitis D, hepatitis D virus, HDV, delta hepatitis, delta virus, hepatitis E, hepatitis E virus, HEV,

non-A non-B hepatitis, NANB hepatitis, NANB, non-A/non-E hepatitis, NANE, viral infection, fulminant hepatic failure, FHF, hepatocellular carcinoma, HCC, liver cancer, l iver failure, viral hepatitis, acute viral hepatitis, chronic viral hepatitis, hepatitis virus infection, hepatitis viral infection, infectious hepatitis, serum hepatitis, liver transplant, liver transplantation

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