Viral Hepatitis

Hepatitis A

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.

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Hepatitis A virus as viewed through electron microscopy.

Epidemiology of HAV

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.Beginning in 1996, the US Centers for Disease Control and Prevention (CDC) recommended vaccination against HAV for: individuals traveling to endemic regions, men who have sex with men, and users of illicit drugs. Beginning in 1999, the CDC recommended vaccination for children living in 17 states with consistently elevated rates of HAV infection. Since 2006, the CDC has recommended vaccination for all children at 1 year of age. It has encouraged "catch-up" vaccination programs for unvaccinated children.^[1]

Other groups of individuals who should be vaccinated include persons with an occupational risk for infection (eg, persons working with HAV-infected primates), patients who may receive clotting factor concentrates, "susceptible persons with chronic liver disease" and "susceptible persons who are either awaiting or have received liver transplants."^[1]The latter recommendation stemmed from the observation that patients with chronic liver disease —although not at increased risk for exposure to HAV — were at increased risk for fulminant hepatic failure if they were infected with the virus.^[2]Interestingly, there are data to suggest that workers exposed to raw sewage do not have a higher prevalence of antibodies to HAV than a comparator population.^[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. The FDA has approved its use in adults. Typical administration involves 3 injections of 1 mL given intramuscularly on a 0-, 1-, and 6-month schedule. Alternatively, a 4-dose schedule can be used, with Twinrix administered on days 0, 7, and 21-30, followed by a booster dose at month 12.^[3]

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.

References

Hepatitis B

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, it is is premature to routinely incorporate HBV genotype testing into clinical practice.

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, 350 million people) is chronically infected with HBV. Approximately 20% of these individuals will eventually develop HBV-related cirrhosis or hepatocellular carcinoma (HCC). According to the World Health Organization, these HBV-related complications lead to 0.5 to 1.2 million deaths each year, making HBV the 10th leading cause of death worldwide.^[4]

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.

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 1.25 million 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 antibodies against HBsAg (ie, anti-HBs), clear HBsAg (and HBV virions), and fully recover. Five percent of adult patients and 90-95% of infected infants develop chronic infection.

Some patients, particularly individuals who are infected as neonates or as young children, have elevated serum levels of HBV DNA and a positive blood test for the presence of HBeAg, but normal ALT levels and minimal histologic evidence for liver damage. These individuals are said to be in the "immune-tolerant" phase of disease.^{[5, 6]}

Years later, some but not all of these individuals may enter the "immune-active" phase of disease. The HBV DNA may remain elevated as the liver experiences active inflammation and fibrosis. An elevated ALT is noted during this period. Typically, the immune-active phase ends with loss of HBeAg and the development of anti-HBe.^{[5, 6]}

An individual who "seroconverts" from an HBeAg-positive state to an HBeAg-negative state may enter the "inactive carrier state" (see below). Here, the serum HBV DNA level is less than 2000 IU per milliliter (mL) and there is minimal inflammation and fibrosis. Other patients who seroconvert may enter the "reactivation phase" of disease. These individuals remain HBeAg-negative, but have evidence for serum HBV DNA levels greater than 2000 IU/mL and evidence for active liver inflammation. These patients are said to have HBeAg-negative chronic hepatitis (see below).^[5]

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 0-2000 IU/mL.^{[5, 7]}

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 the image below).

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Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

Patients with chronic hepatitis may be considered either HBeAg-positive or HBeAg-negative. See Diagnosis of acute self-limited HBV infection, 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 the following image). See HBV and HCC, below, for recommendations regarding screening.

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

Patients with HBeAg-positive chronic hepatitis have signs of active viral replication with an HBV DNA level greater than 2 x 10⁴ IU/mL.^{[5, 7]}HBV DNA levels may be as high as 10¹¹ IU/mL.

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.^[8]The vast majority of patients with HBeAg-negative chronic hepatitis B have a serum HBV DNA greater than 2000 IU/mL. Typically, HBeAg-negative patients have lower HBV DNA levels than do HBeAg-positive patients. Commonly, the HBV DNA is no higher than 2 x 10⁴ IU/mL.^{[5, 7]}

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.^[9]

Multiple studies have demonstrated an association between elevated serum HBV DNA levels and patients' increased risk for developing HCC.^[10]Conversely, successful suppression of HBV infection by antiviral therapy can decrease patients' risk for developing HCC.^{[11, 12]}

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.

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

Ultrasonography of the liver and alpha-fetoprotein (AFP) testing every 6 months is recommended for these patients. No specific recommendations have been made for patients at low risk for HCC. Some authors recommend that patients at low risk (including inactive carriers) undergo AFP testing and liver chemistry testing, only, every 6 months. The author's practice is to screen all patients with chronic hepatitis B with ultrasonography of the liver and AFP testing every 6 months; inactive carriers undergo liver chemistry testing and AFP testing every 6months. However, this is controversial.

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.

The following table summarize diagnostic tests for HBV.

Table 1. Diagnostic Tests for Hepatitis B (Adapted from: Keeffe EB, Dieterich DT, Han SH, et al. Clin Gastroenterol Hepatol [2004]^[8]and Keeffe EB, Dieterich DT, Han SH, et al. Clin Gastroenterol Hepatol [2008].^[5])

View Table

See Table

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 the first image 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.

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

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Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

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

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.^[13]

Treatment of chronic hepatitis B

In an ideal world, the treatment of patients with chronic hepatitis B would routinely achieve the loss of HBsAg. Indeed, the loss of HBsAg is associated with a decreased incidence of HCC and a decreased incidence of liver-related death in patients with HBV-induced cirrhosis.^[14]However, loss of HBsAg is only achieved infrequently in patients with chronic hepatitis B: in 3-7% of patients undergoing treatment with pegylated interferon (PEG-IFN)^{[15, 16, 17]}and in 0-5% of patients undergoing treatment with oral nucleoside or nucleotide agents.^[18]

At this time, the key goal of antiviral treatment of HBV is the inhibition of viral replication. This is marked by the loss of HBeAg (in patients with HBeAg-positive chronic hepatitis B) and by the suppression of HBV DNA levels. Secondary aims are to reduce symptoms, if any, and prevent or delay the progression of chronic hepatitis to cirrhosis or HCC.

The agents currently in use for the treatment of hepatitis B include PEG-IFN-alfa 2a and the oral nucleoside or nucleotide analogues. Typically, PEG-IFN treatment is continued for 48 weeks for both HBeAg-positive and HBeAg-negative chronic hepatitis. The oral agents may be used for as little as 1-2 years. However, the majority of HBeAg-positive chronic hepatitis patients and almost all HBeAg-negative chronic hepatitis patients require indefinite therapy with the oral agents. Withdrawal of oral nucleoside/nucleotide analogue therapy in these individuals usually results in virologic relapse.

Candidates for antiviral therapy must have evidence of active HBV infection. At present, the typical threshold for treatment is a viral load of 2 X 10⁴ IU/mL or more for patients with HBeAg-positive chronic hepatitis, 2 X 10³ IU/mL or more for patients with HBeAg-negative chronic hepatitis, and 200 IU/mL or more for patients with decompensated cirrhosis.^[19]

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.^[5]Another resource is the practice guidelines of the American Association for the Study of Liver Diseases.^[7]

Interferon-alfa and pegylated interferon alfa-2a for chronic hepatitis B

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

In th 1990s, 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.

Data have demonstrated the increased effectiveness of PEG-IFN-alfa-2a compared with the nonpegylated IFN-alfa.^[20]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.^[16]Seroconversion from HBeAg positivity to HBeAb positivity was seen in 32% of patients. A reduction of the serum HBV DNA from a mean of 10¹⁰ copies/mL to < 10⁵ copies/mL was seen in 32% of patients. ALT levels normalized in 41% of patients. Liver histology also improved in treated patients.

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.^[17]A reduction of the serum HBV DNA from a mean of 10⁷ to < 20,000 copies/mL was seen in 43% of patients. HBV DNA levels were reduced to < 400 copies/mL in 19% of patients. ALT values normalized in 59% of patients. Liver histology improved in a significant number of patients. However, enthusiasm about using PEG-IFN-alfa-2a in HBeAg-negative patients is tempered by the relatively high rate of virologic relapse that occurs.

Patients with HBV genotypes A and B appear to be good candidates for treatment with PEG-IFN-alfa-2a. The drug might also be considered in young patients with a relatively brief history of HBV infection, ALT >100 U/L, and a relatively low serum HBV DNA level. Interferon is 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).

Adverse effects of interferon are common and lead to discontinuation in about 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).

The relative lack of side effects of the oral nucleoside and nucleotide analogues and their high rate of achieving undetectable HBV DNA levels have made them attractive as potential first-line agents for HBV infection. However, treatment with PEG-IFN-alfa-2a offers the hope of a finite course of treatment and the potential for achievement of HBsAg negativity. This contrasts with the oral agents, which are frequently prescribed indefinitely and infrequently produce HBsAg negativity.

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, lamivudine 100 mg/d orally for 1 year resulted in HBeAg seroconversion in about 20% of patients and achieved HBV DNA negativity in 36-44% of patients.^{[21, 18]}

In patients with HBeAg-negative chronic hepatitis, lamivudine 100 mg/d orally for 1 year achieved HBV DNA negativity in 60-73% of patients.^[18]

In both HBeAg-positive and HBeAg-negative patients, ALT levels and liver histology improved significantly. The rate of the development of hepatic fibrosis was reduced in a significant number of patients.

From early studies with lamivudine, it was learned that treatment in patients with HBeAg-positive chronic hepatitis should be continued for at least 6-12 months after patients achieved seroconversion from HBeAg-positive to anti-HBe positive. This helped to maximize the odds of maintaining a durable virologic response.

In patients with HBeAg-negative chronic hepatitis, however, it was learned that virologic relapse was almost invariable when treatment was discontinued. This led to the general dictum that patients with HBeAg-negative chronic hepatitis were likely to require indefinite treatment with a nucleoside analogue in order to keep viral loads suppressed.

The advantages of lamivudine over interferon included its ease of application and the virtual absence of adverse effects (see Warnings about therapy for HBV). Lamivudine was effective in populations whose HBV disease was generally not responsive to older formulations of IFN-alfa (eg, persons with high HBV DNA levels). Lamivudine was also successful in some patients with decompensated hepatitis B-induced cirrhosis and some patients with recurrent hepatitis B after liver transplantation.

Lamivudine received FDA approval for the treatment of chronic hepatitis B in adults in December 1998. However, problems with lamivudine therapy quickly became apparent. Approximately 24% of patients whose condition initially responded to lamivudine developed drug resistance within the first year of therapy. The incidence of lamivudine resistance increased to 69% after 5 years of therapy. This finding was explained by the development of a mutation at the YMDD locus in the HBV DNA polymerase gene. The development of lamivudine resistance occasionally led 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. This agent 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. Chronic use of adefovir dipivoxil has induced nephrotoxicity, particularly in patients with underlying renal dysfunction. It is recommended that patients 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.^[22]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.^[23]Most HBeAg-positive and HBeAg-negative patients experienced improvements in both ALT and liver histology results while receiving adefovir dipivoxil.

Resistance mutations developed in less than 2% of patients taking long-term therapy with adefovir dipivoxil. The drug was also useful in patients who had previously developed resistance to lamivudine. Substitution of adefovir dipivoxil for lamivudine in such patients produced 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.

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.^[24]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.^[24]Currently, entecavir and tenofovir are regarded as first-line oral agents for patients with chronic hepatitis B.

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 was reported in 8-21% of patients.

Tenofovir disoproxil fumarate for chronic hepatitis B

Tenofovir disoproxil fumarate (Viread; Gilead Sciences, Inc., Foster City, Calif) received FDA approval for the treatment of hepatitis B in 2008. Previously, this agent had received approval for use in human immunodeficiency virus (HIV) infection. Like adefovir, tenofovir is an oral nucleotide analogue. It and entecavir are considered to be first-line oral agents for the treatment of chronic hepatitis B. As with adefovir, tenofovir has been associated with nephrotoxicity. Renal function should be monitored in patients under treatment.

Marcellin et al published their results comparing tenofovir to adefovir in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients were randomized to receive either tenofovir 300 mg or adefovir 10 mg (ratio, 2:1) once daily for 48 weeks.^[25]

At week 48 in HBeAg-positive patients, a serum HBV DNA < 69 IU/mL (400 copies/mL) was achieved in 76% of patients randomized to tenofovir versus 13% of patients randomized to adefovir (P < 0.001).

At week 48 in HBeAg-negative patients, a serum HBV DNA < 69 IU/mL (400 copies/mL) was achieved in 93% of patients randomized to tenofovir versus 63% of patients randomized to adefovir (P < 0.001).

Patients underwent liver biopsy before treatment and at 48 weeks of therapy. A histologic response -- defined as a reduction in liver inflammation without worsening fibrosis -- was seen in approximately 70% of patients treated with either tenofovir or adefovir (P >0.05). Drug resistance was not reported in any of the patients under treatment with tenofovir.

Combination therapy

Current data do not support the use of either a combination of interferon and a nucleoside analogue or a combination of 2 nucleoside analogues as first-line therapy for patients with chronic hepatitis B.^[26]

After starting treatment with a nucleoside or nucleotide analogue, viral loads are typically followed every 3-6 months by a PCR assay. Combination therapy may be appropriate for patients who have had either a suboptimal response to first-line therapy or who have evidence for virologic breakthrough, defined as a 10-fold increase from the nadir HBV DNA level in a patient undergoing treatment.^[7]

Virologic breakthrough is often the hallmark of the development of virologic resistance to drug therapy. Such an event might necessitate either a switch to a new oral analogue with no cross-resistance to the first drug or the addition of a second oral agent to the original regimen. The subject of combination therapy is an evolving topic. Some recommendations for the management of drug-resistant HBV infection are contained within the practice guidelines of the American Association for the Study of Liver Diseases^[7]and in Keeffe et al's "treatment algorithm."^[5]

Management of HBV carriers undergoing chemotherapy or immunosuppression

Reactivations of HBV infection in a common event in HBV carriers who undergo either chemotherapy or immunosuppression for another indication. Typically, this is described in patients who are already HBsAg positive. However, HBV reactivation is described in patient who are anti-HBc positive, with a negative HBsAg and a positive anti-HBs. HBV reactivation in these circumstances has the potential to be severe or even life-threatening.

The practice guidelines of the American Association for the Study of Liver Diseases recommend that HBV carriers with a baseline HBV DNA < 2000 IU/mL undergo prophylactic antiviral therapy during their treatment and for 6 months after the conclusion of chemotherapy or a finite course of immunosuppressive therapy. Patients with a higher baseline HBV DNA should be treated until "they reach treatment endpoints as in immunocompetent patients."^[7]

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 IU/mL. Antiviral therapy is generally reserved for patients with greater than 10⁴ IU/mL for patients with HBeAg-positive chronic hepatitis. A lower HBV DNA, perhaps 10³ IU/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, entecavir, telbivudine, and tenofovir disoproxil fumarate. 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. Dosing of Twinrix, the combined hepatitis A and hepatitis B vaccine, is as described above (see Hepatitis A).

HBV infection is endemic in Taiwan. Institution of universal vaccination for neonates in 1984 decreased the HBsAg carrier rate in children from 9.8% to 0.7%, 15 years later.^[27]There was a resulting drop in the incidence of HCC in children from 0.54 to 0.20 per 100,000.^[27]We await follow-up studies to see if the overall incidence of HCC decreases in Taiwan as these children enter adulthood.

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

References

Hepatitis C

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 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.^[28]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.^[29]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.

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 15-30% of patients acutely infected with HCV lose virologic markers for HCV. Thus, approximately 70-85% 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.

View Image

Triple phase computed tomography scan of a liver cancer, revealing classic findings of enhancement during the arterial phase and delayed hypointensity....

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.^[30]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

View Table

See Table

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 indicate the presence of liver injury. According to a study by Ruhl and Everhart, ALT can discriminate between patients infected with HCV and those at low risk for liver disease. However, using the ALT cut-off levels with the best classification, a large portion of the US population would be considered to have elevated levels.^[31]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.

The US Food and Drug Administration has approved OraQuick HCV Rapid Antibody Test.^[32]The test can be used for persons at risk for hepatitis or for those with signs or symptoms of hepatitis. The test strip can be used with a sample collected from oral fluid, whole blood, serum, or plasma.

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.

Assessment of the degree of hepatic fibrosis is important for a number of reasons. Determination of the presence of "advanced fibrosis" -- ie, or stage 3 or stage 4 disease -- might lead to a decision to initiate screening tests to rule out the interval development of HCC as a complication of advanced liver disease. Patients with previously unsuspected cirrhosis on biopsy should also be monitored to ensure they do not develop large esophageal varices. In the author's opinion, patients with stage 3 fibrosis should be regarded as "being cirrhotic until proven otherwise."

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. Determination of the presence of "significant fibrosis" -- ie, stage 2, 3, or 4 disease -- might lead to a decision to initiate antiviral therapy. The hope is that eradication of HCV will help to improve the patient’s long-term outcome. Patients with advanced histologic findings may seek experimental therapies should their condition not respond to standard antiviral therapy.

Patients with minimal fibrosis on biopsy (ie, stage 1 disease) might elect to either receive antiviral therapy or postpone therapy. Indeed, the patient with stage 1 disease might be felt to be at low risk for complications of HCV infection. Furthermore, the risks of therapy might exceed benefits in such a patient, (eg, a patient with HCV infection, stage 1 fibrosis and major depression).

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. The author also advises his patients to return for a repeat biopsy in 3-4 years to rule out progression of liver disease.

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.

Radiologic and serologic and tests for estimating the degree of fibrosis in patients with chronic hepatitis C

For the last several years, clinicians have been able to assess liver stiffness through an ultrasound technique known as Fibroscan (Echosens SA, Paris, France). It is reported that cirrhosis can be diagnosed correctly in about 95% of patients. The test is less accurate in assessing patients with lesser degrees of fibrosis.^[33]Fibroscan is not currently licensed for use in the United States.

Liver fibrosis can also be estimated by means of a number of commercial blood tests. FIBROSpect II (Prometheus Laboratories, San Diego, Calif) uses measurements of hyaluronic acid, TIMP-1 and alpha-2 macroglobulin to estimate liver fibrosis. HepaScore (Quest Diagnostics, Madison, NJ) is based on levels of hyaluronic acid, alpha-2 macroglobulin, gamma glutamyl transferase (GGT), and total bilirubin, as well as age and gender. HCV FIBROSURE (LabCorp, Burlington, NC) measures alpha-2 macroglobulin, haptoglobin, GGT, bilirubin, ALT and apolipoprotein A1. In general, it is contended that these tests are accurate in determining the presence or absence of early (stage 1) or advanced (stage 4) fibrosis. However, these tests are less accurate when it comes to differentiating patients with moderate fibrosis.

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.

Goals of HCV therapy

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.

Sustained virologic response (SVR) is defined as the absence of detectable HCV RNA on blood testing 6 months after the completion of antiviral treatment. Most experts now contend that the achievement of SVR can be equated with viral eradication or "cure" of HCV infection.^[34]

Interferon (IFN) has been the drug of choice for the treatment of hepatitis C for two decades. It is often used in combination with another drug, ribavirin. Successful interferon-based therapy, resulting in SVR, can improve the natural history of chronic hepatitis C and may reduce the risk of HCC in patients with HCV-included cirrhosis.^{[35, 36]}

Interferon-based therapy appears to reduce the rate of fibrosis progression in patients with HCV infection.^[37]One report described regression of cirrhosis in some -- but not all -- patients who had a good response to antiviral therapy.^[38]In this study, 96 patients with biopsy-proven HCV-induced cirrhosis were treated with interferon-based therapy. The patients underwent a second biopsy at a median interval of 17 months following the conclusion of antiviral therapy. 18 patients (19%) had a decrease in fibrosis score from stage 4 to less than stage 2 on follow-up biopsy. SVR had been achieved in 17 of these 18 patients. With a median follow-up of 118 months, these patients were found to have decreased liver-related morbidity and mortality compared to patients who were not histologic responders.

It is important to note that not all patients who achieved SVR experienced histologic improvements.^[38]Thus, it remains important to continue routine surveillance in patients with HCV cirrhosis - even if SVR is achieved through antiviral therapy - in order to rule out the development of HCC as a complication of cirrhosis.

Another report retrospectively assessed 920 patient with HCV-induced cirrhosis who underwent interferon therapy in the 1990s. The mean follow-up period was 96 months (range: 6-167). Achievement of SVR decreased patients' risk for hepatic decompensation, HCC, and liver-related mortality.^[36]

When approaching the patient with HCV, both the physician and the patient must be clear about the goals of therapy. As an example, in the patient with advanced fibrosis or cirrhosis, the goal of treatment is virologic cure in hopes of preventing progressive liver disease. Unfortunately, SVR cannot be achieved in everyone.

Achievement of SVR is desirable but is not always necessary in order to obtain a desired clinical result. Indeed, partial suppression of HCV through anti-viral therapy may be all that is needed to stabilize renal function in a patient with HCV-related glomerulonephritis or prevent the progression of malignancy in a patient with HCV-related non-Hodgkin’s lymphoma.

Agents for treating HCV

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; Three Rivers Pharmaceuticals, Warrendale, PA); and (4) ribavirin, which is used in combination with interferon (Rebetol [Schering-Plough], Copegus [Roche], or Ribasphere [Three Rivers]).

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) IFN-beta, (2) IFN-gamma, and (3) 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.^[39]About 98% of patients developed a sustained virologic response (SVR) (ie, undetectable level of serum HCV RNA).^[39]

Treatment of chronic hepatitis C: results of clinical trials

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.^[40]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 mcg/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.^[41]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.^[42]

The 2 currently available PEG-IFNs appear to be relatively equivalent in terms of their efficacy and tolerability in patients with HCV genotype 1. The recently published IDEAL trial (Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy) randomized previously untreated patients with HCV genotype 1 to either PEG-IFN-alfa-2b or PEG-IFN-alfa-2a, in combination with ribavirin.^[43]Treatment with PEG-IFN-alfa-2b at a dose of 1.5 mcg/kg/wk produced a 40% SVR rate. Treatment with PEG-IFN-alfa-2a produced a 41% SVR rate. Surprisingly, treatment with low-dose PEG-IFN-alfa-2b at 1 mcg/kg/wk produced a 38% SVR rate. These results were not significant statistically.^[43]

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. Ideally, HCV eradication in the cirrhotic patient may prevent or forestall the development of progressive hepatic fibrosis and liver decompensation. Patients treated with interferon may also have a decreased risk for HCC. Should a patient ultimately require liver transplantation for the treatment of complications of cirrhosis, previous eradication of the hepatitis C virus obviates any concerns about potentially severe recurrent hepatitis C after transplantation.

Treatment of chronic hepatitis C: practical issues

Patients who are infected with HCV genotype 1 and 4 typically undergo treatment for 48 weeks. Patients who are infected with HCV genotype 2 or 3 typically undergo treatment for 24 weeks. HCV RNA levels are usually rechecked 1 month and 3 months after starting treatment and every 3 months thereafter.^[44]

In HCV genotype 1 cases, patients who achieve a viral load negativity 1 month into treatment - also known as a rapid virologic response (RVR) - 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.^[45]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.^[45]

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 38% was seen in slow responders who continued treatment for 72 weeks, contrasted with the SVR rate of 18% seen in slow responders who received treatment for the traditional 48 weeks.^[46]

Recent trials explored the utility of shortened courses of PEG-IFN and ribavirin for patients with genotypes 2 and 3. Although SVR may be achieved in some patients with as little as 12 to 16 weeks of therapy, overall SVR rates may be diminished. Thus, shortened treatment courses cannot be recommended for patients with genotypes 2 and 3 at this time.^[34]

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 nonresponsive to PEG-IFN in combination with ribavirin.

Previously, chronic maintenance therapy with low dose PEG-IFN was considered for patients with advanced fibrosis who were virologic nonresponders but had achieved some reduction in viral load while under treatment. However, neither the HALT-C trial^[47](utilizing PEG-IFN-alfa-2a) nor the COPILOT trial^[48](utilizing PEG-IFN-alfa-2b) were able to demonstrate any decrease in the incidence of liver decompensation, HCC or liver-related death in patients undergoing maintenance therapy.

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. Results of the DIRECT trial were recently reported.^[49]Daily consensus interferon at a doses of 9 mcg or 15 mcg was used in combination with ribavirin in nonresponders to treatment with pegylated interferon. In the 15 mcg group, 11% of patients achieved SVR. However, when patients who had previously achieved a >2-log₁₀ decrease in HCV RNA were assessed, the SVR rate improved to 23% in the 15 mcg group. High-dose daily-consensus interferon and ribavirin recently received FDA approval for re-treatment of patients with chronic hepatitis C who were nonresponders to pegylated interferon and ribavirin.

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, emotional irritability, depression, and alopecia. 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.

Interferon can induce the development of thyroid disease or exacerbate an underlying immune-mediated disease (eg, psoriasis, sarcoidosis).

It has long been recognized that adherence to prescribed doses of PEG-IFN and ribavirin will maximize a patient’s ability to achieve an SVR. Missed doses due to lack of patient compliance or due to physician-ordered dose reductions (eg, on account of the new onset of anemia or cytopenias) will increase the chance for treatment failure.

Patients invariably need close clinical and laboratory test follow-up during treatment. Treatment with PEG-IFN can induce neutropenia. Some patients with IFN-induced neutropenia need the addition of granulocyte colony-stimulating factor (G-SCF) (eg, Neupogen; Amgen Inc., Thousand Oaks, Calif). to their regimen in order to support a falling white blood cell (WBC) count.

Treatment with PEG-IFN can also induce thrombocytopenia. Until recently, it was assumed that most patients (typically cirrhotic) with baseline platelet counts < 70,000/µL would not be able to tolerate interferon due to the induction of severe thrombocytopenia. Eltrombopag (Promacta, GlaxoSmithKline, Brentford, Middlesex, UK) received FDA approval in November 2008 for the treatment of thrombocytopenia in cases of idiopathic thrombocytopenic purpura (ITP).

Eltrombopag was studied in patients with HCV-induced cirrhosis and platelet counts less than 70,000/µL. Treatment with eltrombopag 75 mg orally once per day successfully improved platelet counts in 95% of the patients under study, permitting a majority of them to undergo treatment with interferon.^[50]However, eltrombopag use has been associated with both venous thromboembolic events and with drug-induced liver injury. In the United States, the medication is only available through an FDA-mandated, restricted distribution program.

Ribavirin commonly produces rash and hemolytic anemia. Some patients with ribavirin-induced anemia need combination therapy with erythropoietin (eg, Procrit, Ortho Biotech, Raritan, NJ or Epogen, Amgen Inc., Thousand Oaks, Calif.) in order to support a falling hematocrit. In the author's opinion, patients should undergo baseline cardiac stress testing, given the potential for patients to develop severe anemia.

Both interferon and ribavirin have been associated with a low risk of inducing retinopathy. In the author's opinion, patients should undergo pretreatment and post-treatment ophthalmologic examinations.

The presence of insulin resistance may reduce the chance of achieving viral eradication with PEG-IFN and ribavirin.^[34]Excellent control of diabetes is recommended before patients embark on interferon-based therapy.

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 genotypes 1 and 4).

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.^[51]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.^[52]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.

There are multiple reports of successful liver transplantation being performed for decompensated HCV-induced cirrhosis in coinfected patients. Potential candidates include patients who have achieved a negative HIV viral load through antiretroviral therapy. However, on the whole, 2-year post-transplant survival rates are lower in HIV-HCV coinfected patients than in patients undergoing liver transplant in the setting of HCV infection, alone.^[53]At the present time, only a small percentage of the more than 100 transplantation programs in the US are performing liver transplantation in HIV-infected individuals.

Race, the immune system, and hepatitis C

It was recently discovered that genetic polymorphisms involving the IL28B gene can impact the odds that the hepatitis C virus can be cleared in a given patient. The IL28B gene encodes IFN-lambda-3. A single nucleotide polymorphism 3 kilobases upstream of the IL28B gene was associated with patients' ability to spontaneously clear the hepatitis C virus.

Fifty-three percent of patients with the favorable C/C genotype spontaneously cleared the virus. Only 23% of patients with the less favorable T/T genotype spontaneously cleared the virus.^[54]For those patients who were chronically infected with HCV, patients with the C/C genotype were more likely to see viral eradication after treatment with PEG-IFN plus ribavirin.^[55]The C/C genotype was more common in persons of European ancestry than African ancestry. In contrast, the T/T genotype was more common in persons of African ancestry.^[54]These observations may help to explain why black individuals typically exhibit lower SVR rates than white persons when treated with PEG-IFN and ribavirin.

New agents for the treatment of HCV

Direct acting antiviral drugs (DAAs) will improve treatment options for patients infected with hepatitis C in the coming years. Over 2 dozen DAAs are currently in clinical trials. These drugs, previously known as Specifically Targeted Antiviral Therapy for HCV drugs (STAT-C drugs), target different aspects of the HCV life cycle. These include nucleoside NS5B polymerase inhibitors, nonnucleoside NS5B polymerase inhibitors, NS5A inhibitors, NS4B inhibitors, viral entry inhibitors, and NS3/4a protease inhibitors such as telaprevir (VX-950; Vertex Pharmaceuticals Incorporated, Cambridge, Mass) and boceprevir (Schering-Plough Corporation, Kenilworth, NJ). Telaprevir and boceprevir inhibit the ability of HCV's nonstructural 3/4a serine protease to cleave the viral polyprotein into independent HCV proteins. This is an important step in suppressing the replication of the hepatitis C virus. It is hoped that these drugs -- in combination with PEG-IFN and ribavirin -- will produceearlyvirologicsuppression,improveSVR rates, and shorten treatment duration with minimal toxicity.

The clinical trials investigating telaprevir and boceprevir have used different sorts of designs. With telaprevir, the protease inhibitor was employed first, in an effort to produce a rapid reduction in HCV viral load, thus increasing the chance for SVR when PEG-IFN and ribavirin were added. In the boceprevir trials, PEG-IFN and ribavirin were used in a lead-in phase, in hopes of reducing the HCV viral load and decreasing the odds of emergence of a resistance mutation to the protease inhibitor.

Telaprevir, PEG-IFN, and ribavirin

Two similar protocols, PROVE 1^[56]and PROVE 2^[57], recently assessed the efficacy of telaprevir when it was added to a standard regimen of PEG-IFN-alfa-2a and ribavirin. Both trials studied previously untreated patients infected with HCV genotype 1.

In PROVE 1, patients who were randomized to receive telaprevir plus PEG-IFN-alfa-2a plus ribavirin for 12 weeks, followed by PEG-IFN-alfa-2a and ribavirin for 36 additional weeks, achieved a 67% SVR rate. This was significantly greater than the 41% SVR rate achieved in patients treated with a standard 48-week course of PEG-IFN-alfa-2a and ribavirin (P = 0.002).^[56]

In PROVE 2, patients who were randomized to receive telaprevir plus PEG-IFN-alfa-2a plus ribavirin for 12 weeks, followed by PEG-IFN-alfa-2a plus ribavirin for 12 additional weeks, achieved a 69% SVR rate. This was significantly greater than the 46% SVR rate achieved in patients treated with standard PEG-IFN-alfa-2a and ribavirin for 48 weeks (P = 0.004).^[57]

Note that rash and pruritus were common adverse events. Severe rash was noted in 11% of telaprevir-treated patients in PROVE 1 and 5% of telaprevir-treated patients in PROVE 2. Severe rash was uncommon in patients treated with standard therapy. Furthermore, higher rates of discontinuing treatment were seen in telaprevir-treated patients. Treatment was discontinued on account of adverse events in 21% of the telaprevir-treated patients in PROVE 1 and 12% of the telaprevir-treated patients in PROVE 2, as opposed to 11% and 7%, respectively, of patients in the 2 studies treated with standard therapy.

The results of the PROVE 3 trial in prior relapsers and nonresponders to PEG-IFN and ribavirin have been published.^[58]In this trial, patients who were randomized to one of the telaprevir arms of the study received telaprevir and PEG-IFN-alfa-2a (with or without ribavirin) concurrently for 12-24 weeks. In all, 453 patients with genotype 1 were randomized to 1 of 4 regimens: (1) T12/PR 24, (2) T24/PR48, (3) T24/P24 without ribavirin, and (4) PR 48 (ie, standard of care). Thirty-eight percent of the patients had bridging fibrosis or cirrhosis. SVR rates for prior relapsers were as follows (1) 69%, (2) 76%, (3) 42%, and (4) 20%, respectively. SVR rates for prior nonresponders were (1) 39%, (2) 38%, (3) 11%, and (4) 9%, respectively. These results demonstrate that patients who were previously nonresponders may have promising drug therapy available to them over the next year. The data also demonstrate the importance of ribavirin's inclusion in retreatment regimens.

Boceprevir, PEG-IFN, and ribavirin

The results of SPRINT 1 (Serine Protease Inhibitor Therapy-1) were recently reported. This phase II trial studied boceprevir, in combination with PEG-IFN-alfa-2b plus ribavirin in previously untreated patients infected with HCV genotype 1.^[59]In patients treated with PEG-IFN-alfa-2b, ribavirin, and boceprevir concurrently, the SVR rate was 54% (58 of 107) in patients treated for 28 weeks. In patients with a 4-week lead-in phase of PEG-IFN-alfa-2b and ribavirin, followed by 24 weeks of triple therapy, there was a similar SVR rate of 56% (58 of 103).^[59]

Longer courses of treatment resulted in an improved SVR rate. In patients treated with 48 weeks of triple therapy, the SVR rate was 67% (69 of 103).^[59]When a 4-week lead-in phase of PEG-IFN-alfa-2b and ribavirin was employed, followed by 44 weeks of triple therapy, the SVR rate increased to 75% (77 of 103).

Each of the treatment arms using boceprevir demonstrated a statistically significant improvement in the SVR rate compared with the 38% SVR rate seen in the control group receiving standard-of-care PEG-IFN plus ribavirin.^[59]

SVR rates also improved for black patients and for patients with cirrhosis. Black patients experienced an SVR rate of 13% when treated with standard-of-care PEG-IFN plus ribavirin. The SVR rate went up to as high as 53% in black patients treated with PEG-IFN, ribavirin, and boceprevir for 48 weeks.^[59]

In cirrhotic patients, the SVR rate improved from 25% in patients treated with standard-of-care PEG-IFN plus ribavirin to 67% when a long course of boceprevir was used.^[59]

The most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea, dysgeusia, and headache. Treatment was discontinued because of the adverse events in 9-19% of the patients in the boceprevir arms, as opposed to 8% of patients receiving standard-of-care PEG-IFN plus ribavirin.

When a subanalysis of the SPRINT 1 data was performed, up to 55% of patients who were having a null response after 4 weeks of treatment with PEG-IFN-alfa-2b plus ribavirin actually achieved an SVR when boceprevir was added to the regimen.^[59]However, it is not entirely clear how these data translate into the efficacy of triple therapy in previous nonresponders to PEG-IFN and ribavirin.

Gane et al published the results from INFORM-1, a trial using RG7128 (an oral inhibitor of the HCV NS5B RNA polymerase) and danoprevir (an oral HCV NS3/4A protease inhibitor).^[60]The combination of medicines produced up to a 5.2 log₁₀ IU/mL decrease in patients' HCV RNA viral loads over a 14-day treatment course. Resistance mutations to danoprevir did not emerge during the trial. Such work raises our hopes for the development of interferon-free regimens. The ease of administration of an oral HCV treatment regimen might improve patients' access to therapy and, ultimately, decrease the morbidity and mortality associated with hepatitis C.

References

Test	CHB HBeAg Positive	CHB HBeAg Negative	Inactive Carrier
HBsAg	+	+	+
anti-HBs	-	-	-
HBeAg	+	-	-
anti-HBe	-	+	+
anti-HBc	+	+	+
IgM anti-HBc	-	-	-
HBV DNA	>2 x 10⁴ IU/mL (>10⁵ copies/mL)	>2 x 10³ IU/mL (>10⁴ copies/mL)	< 2 x 10³ IU/mL (< 10⁴ copies/mL)
ALT level	Elevated	Elevated	Normal
ALT = alanine aminotransferase. Increasingly, experts in the field have used the nomenclature of IU/mL, as opposed to copies/mL.

Grade	Portal Inflammation	Interface Hepatitis	Lobular Necrosis
1 - Minimal	Mild	Scant	None
2 - Mild	Mild	Mild	Scant
3 - Moderate	Moderate	Moderate	Spotty
4 - Severe	Marked	Marked	Confluent

Viral Hepatitis

Introduction

Epidemiology of viral hepatitis

Natural history of acute viral hepatitis

Hepatitis A virus as viewed through electron microscopy.

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

Natural history of chronic viral hepatitis

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

Hepatitis A

Hepatitis A virus

Hepatitis A virus as viewed through electron microscopy.

Epidemiology of HAV

Natural history of HAV

Pathologic findings of hepatitis A

Diagnosis of hepatitis A

Treatment for acute of HAV infection

Prevention of HAV infection

Hepatitis B

Hepatitis B virus

Mechanism of hepatocyte necrosis in HBV infection

Epidemiology of HBV

Transmission of HBV

Perinatal transmission of HBV

Sexual transmission of HBV

Parenteral transmission of HBV

Sporadic cases of hepatitis B

Natural history of HBV

Inactive carrier state

Chronic hepatitis B

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

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

HBV and HCC

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

Diagnosis of acute self-limited HBV infection

Diagnosis of chronic HBV infection

See Table

Markers after vaccination for HBV

Pathologic findings of HBV infection

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

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

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

Treatment of acute hepatitis B

Treatment of chronic hepatitis B

Interferon-alfa and pegylated interferon alfa-2a for chronic hepatitis B

Lamivudine for chronic hepatitis B

Adefovir dipivoxil for chronic hepatitis B

Entecavir for chronic hepatitis B

Telbivudine for chronic hepatitis B

Tenofovir disoproxil fumarate for chronic hepatitis B

Combination therapy

Management of HBV carriers undergoing chemotherapy or immunosuppression

Warnings about therapy for HBV

HBV vaccine

Postexposure prophylaxis

Hepatitis C

Epidemiology of hepatitis C

Transmission of HCV via blood transfusion

Transmission of HCV via intravenous and intranasal drug use

Transmission of HCV via occupational exposure

Transmission of HCV via sexual contact

Transmission of HCV via perinatal transmission

Natural history of acute hepatitis C

Natural history of chronic hepatitis C

Natural history of cirrhosis induced by hepatitis C

Triple phase computed tomography scan of a liver cancer, revealing classic findings of enhancement during the arterial phase and delayed hypointensity....

Extrahepatic manifestations of hepatitis C

Pathologic findings of hepatitis C

See Table

Diagnosis of hepatitis C

Diagnosis of hepatitis C using liver chemistry testing

Diagnosis of hepatitis C using serologic tests for HCV

Diagnosis of hepatitis C using HCV RNA tests

Diagnosis of hepatitis C using liver biopsy

Radiologic and serologic and tests for estimating the degree of fibrosis in patients with chronic hepatitis C

Goals of HCV therapy

Agents for treating HCV

Treatment of acute hepatitis C

Treatment of chronic hepatitis C: results of clinical trials

Treatment of chronic hepatitis C: practical issues

Repeat treatment of patients who were nonresponsive to antiviral therapy