Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

26. Viral Hepatitis

Paulina Deming


KEY CONCEPTS

 Images Hepatitis A is transmitted via the fecal–oral route. Transmission is most likely to occur through travel to countries with high rates of hepatitis A, poor sanitation and hygiene, and overcrowded areas.

 Images Hepatitis A causes an acute, self-limiting illness and does not lead to chronic infection. There are three stages of infection: incubation, acute hepatitis, and convalescence. Rarely, the infection progresses to liver failure.

 Images Treatment of hepatitis A consists of supportive care. There is no role for antiviral agents in treatment.

 Images Hepatitis B causes both acute and chronic infection. Infants and children are at high risk for chronic infection.

 Images Several therapies are available for hepatitis B, including lamivudine, interferon-alfa, pegylated interferon-alfa, entecavir, adefovir, telbivudine, and tenofovir. Patient status, extent of disease, viral load, and viral resistance are all considered when deciding on treatment.

 Images Chronic hepatitis B patients may require long-term therapy. Long-term therapy poses a challenge because of the potential for developing resistance. Resistance to lamivudine and telbivudine is most common, limiting the use of these treatments. Optimal treatment of resistant strains is unknown.

 Images Prevention of hepatitis B infections focuses on immunization of all children and at-risk adults.

 Images Hepatitis C is an insidious, blood-borne infection. Many people are unaware of their infection and risk significant morbidity and mortality.

 Images Combination pegylated interferon and ribavirin therapy with either boceprevir or telaprevir is the treatment of choice for hepatitis C genotype 1 infections. Treatment duration varies depending on response, previous treatment history, and the presence of cirrhosis. For genotypes 2, 3, and 4 the treatment of choice includes pegylated interferon and ribavirin.

 Images Boceprevir and telaprevir offer significant improvements in outcome for the treatment of hepatitis C genotype 1 infections but pose additional challenges and new concerns for multiple drug interactions.


The major hepatotrophic viruses responsible for viral hepatitis are hepatitis A, hepatitis B, hepatitis C, delta hepatitis, and hepatitis E. All share clinical, biochemical, immunoserologic, and histologic findings. Both hepatitides A and E are spread through fecal–oral contamination, whereas hepatitides B, C, and delta are transmitted parenterally. Infection with delta hepatitis requires coinfection with hepatitis B. Although the rates of acute infection have declined, viral hepatitis remains a major cause of morbidity and mortality with a significant impact on healthcare costs in the United States. Compared with human immunodeficiency virus (HIV), there are three to five times as many people infected with chronic viral hepatitis. In the United States, there is a general lack of knowledge among healthcare providers, social service providers, and the public regarding the risks of chronic hepatitis B and C infections.1

Unprecedented therapeutic advances have occurred with the treatment for hepatitis C with the approval of new agents, updated guidelines for care, and more novel therapies eagerly anticipated. For both hepatitides B and C, the challenge remains to increase awareness of the viral hepatic epidemic and to prevent the profound morbidity and mortality associated with chronic infection. This chapter focuses on hepatitides A, B, and C.

HEPATITIS A

Hepatitis A virus (HAV), or infectious hepatitis, is often a self-limiting and acute viral infection of the liver posing a health risk worldwide. The infection is rarely fatal. According to the Centers for Disease Control and Prevention (CDC), rates of reported cases of acute clinical hepatitis A infection in the United States continue to decline with 1,670 cases in 2010.2 The significant declines in rates of acute HAV are associated with major vaccination campaigns that successfully reduced the incidence rate.

Epidemiology

Various patient groups are at increased risk for infection with HAV. Children pose a particular problem with the spread of the disease because they often remain clinically asymptomatic and are infectious for longer periods of time than adults. Traditionally, the most likely patient group affected is household or close personal contacts of an infected person. Images Infection primarily occurs through the fecal–oral route, by person-to-person, or by ingestion of contaminated food or water. Incidentally, HAV’s prevalence is linked to regions with low socioeconomic status and specifically to those with poor sanitary conditions and overcrowding. International travel and immigration also mitigate potential exposure to the virus.

International travel, in particular travel to HAV endemic areas, continues to be a major risk factor for HAV infection. Other identified risk factors include sexual and household contact with an HAV-infected person, men who have sex with men (MSM), and injection-drug users (IDUs).2 Additional patient groups that are at risk include patients with chronic liver disease and persons working with nonhuman primates. In 2010, 75% of case reports of acute HAV reported no identifiable risk factor.2 Among MSMs, specific sexual practices may be associated with an increased risk for infection.3 Foodborne outbreaks also occur. In general, mortality rates are low but highest among persons ≥75 years of age.2

Despite low endemic rates and successful vaccination programs in the United States, travel to HAV endemic areas is a recognized risk for acquiring acute HAV infections. According to the CDC, the majority of travel-related cases correspond to travel to Central and South America and Mexico.2 Most Americans traveling to Mexico do not consider that country to be a risk in part because of Mexico’s proximity to the United States. Moreover, most tourists falsely believe that higher-end resorts imply safety and that short visits to foreign countries are not associated with a risk for infection. Travel related to international adoptions can also be of risk. In 2009, HAV vaccination was recommended for household members and close personal contacts of newly adopted children from countries of high or intermediate HAV endemicity.4

Etiology

Hepatitis A is a RNA virus belonging to the genus Hepatovirus of the Picornaviridae family. Humans are the only known reservoir for the virus and transmission occurs primarily through the fecal–oral route.6The virus is stable in the environment for at least a month and requires heating foods to a minimum of 85°C (185°F) for 1 minute or disinfecting with a 1:100 dilution of sodium hypochlorite (bleach) in tap water for inactivation.5,7

Multiple genotypes of the virus exist and although the clinical implications of infection by particular type are unknown, types I and III are the most commonly identified in human outbreaks.6

Pathophysiology

HAV infection is usually acute, self-limiting, and confers lifelong immunity. HAV’s life cycle in the human host classically begins with ingestion of the virus. Absorption in the stomach or small intestine allows entry into the circulation and uptake by the liver. Replication of the virus occurs within hepatocytes and GI epithelial cells. New virus particles are released into the blood and secreted into bile by the liver. The virus is then either reabsorbed to continue its cycle or excreted in the stool. The enterohepatic cycle will continue until interrupted by antibody neutralization.6 The exact mechanism of replication and secretion is unknown; however, the initial viral expansion does not seem to be associated with hepatic injury as peak viral fecal excretion precedes clinical signs and symptoms of infection.5

Clinical Presentation

Images The incubation period of HAV is approximately 28 days, with a range of 15 to 50 days. Viremia occurs within 1 to 2 weeks of exposure as patients begin to shed the virus.5 Table 26-1 summarizes the clinical features of acute hepatitis A. Peak fecal shedding of the virus precedes the onset of clinical symptoms and elevated liver enzymes. Acute hepatitis follows, beginning with the preicteric or prodromal period. The phase is marked by an abrupt onset of nonspecific symptoms, some very mild.5 Other, more unusual symptoms include chills, myalgia, arthralgia, cough, constipation, diarrhea, pruritus, and urticaria. The phase generally lasts 2 months. There are no specific symptoms unique to HAV. Liver enzyme levels rise within the first weeks of infection, peaking approximately in the fourth week and normalizing by the eighth week. Conjugated bilirubinemia, clinically evident as dark urine, precedes the onset of the icteric period. GI symptoms may persist or subside during this time and some patients may have hepatomegaly. Duration of the icteric period varies and corresponds to disease duration. It averages between 7 and 30 days.6

TABLE 26-1 Clinical Presentation of Acute Hepatitis A

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Symptoms and severity of HAV vary according to age. Children younger than 6 years of age typically are asymptomatic. Symptoms, if they do occur, do not include jaundice. In older children and adults, the majority of patients present with symptoms that last less than 2 months and 70% of adults experience jaundice. Peak viral shedding precedes the onset of GI symptoms in adults. In young children, shedding can occur for months following diagnosis.5Because children are often asymptomatic and will shed the virus for long periods of time, they can serve as a reservoir for the spread of HAV.

Serum HAV RNA is detectable approximately 2 weeks prior to the onset of symptoms or peak alanine aminotransferase (ALT) levels and can persist for an average of 79 days after the onset of symptoms. In some patients, serum HAV is detectable for more than a year.11 The use of nucleic acid sequencing to detect HAV RNA is limited to research and instead immunoglobulin (Ig) M antibody to HAV (anti-HAV) is required for a diagnosis of acute infection in clinical settings. IgM anti-HAV is detectable 5 to 10 days prior to symptomatic HAV infections in the majority of patients. IgG anti-HAV replaces IgM and indicates host immunity following the acute phase of the infection.7 FDA-approved assays for serologic testing detect IgM anti-HAV only and total anti-HAV (IgM and IgG anti-HAV). Patients who have detectable total anti-HAV with a negative IgM have resolved their infection. Patients who are successfully immunized or who receive Ig may have lower levels of total anti-HAV that are below the levels of detection of most commercial assays.5,7 Concentrations of antibody often fall to 10 to 100 times lower than what would be expected after a natural course of infection. Although a positive anti-HAV result confirms protection, undetectable concentration of anti-HAV may not necessarily imply that protective levels were not achieved.7

HAV does not lead to chronic infections. Some patients may experience symptoms for up to 9 months. Rarely, patients experience complications from HAV, including relapsing hepatitis, cholestatic hepatitis, and fulminant hepatitis. Fatalities from HAV are generally rare, although more likely in patients older than age 50 years and in persons with preexisting liver disease.7

A diagnosis of HAV is based on clinical criteria of an acute onset of fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting, jaundice or elevated serum aminotransferase levels, and serologic testing for IgM anti-HAV. Serologic testing is necessary to differentiate the diagnosis from other types of hepatitis.

TREATMENT

Desired Outcome

Images The majority of people infected with HAV can be expected to fully recover without clinical sequelae.6 Nearly all individuals will have clinical resolution within 6 months of the infection, and a majority will have done so by 2 months. Rarely, symptoms persist for longer or patients relapse. The ultimate goal of therapy is complete clinical resolution. Other goals include reducing complications from the infection, normalization of liver function, and reducing infectivity and transmission. Prevention of HAV infection is important because significant costs are accrued during acute HAV infections, from both direct costs of hospitalizations and indirect costs from loss of work days.

General Approach to Treatment

No specific treatment options exist for HAV infections. Instead, patients should receive general supportive care. Prevention and prophylaxis are key to managing the virus. The importance of good hand hygiene cannot be overemphasized in preventing disease transmission. Ig is used for preexposure and postexposure prophylaxis, and offers passive immunity. Active immunity is achieved through vaccination. Vaccines were approved for use in 1995 and implemented in the routine vaccination of children, as well as at-risk adults, to reduce the overall incidence of HAV.7

Prevaccination serologic testing to determine susceptibility is generally not recommended. In some cases, testing may be cost-effective if the cost of the test is less than that of the vaccine and if the person is from a moderate to high endemic area and likely to have prior immunity. Prevaccination serologic testing of children is not recommended. Similarly, because of high vaccine response, postvaccine serologic testing is not recommended.7

Prevention of Hepatitis A

HAV is easily preventable with vaccination. Because children often serve as reservoirs of the disease, vaccine programs have targeted children as the most effective means to control HAV. Two vaccines for HAV are available and are incorporated into the routine childhood vaccination schedule. In October 2005, the FDA reduced the minimum age for the vaccines to 12 months of age. In response, the Advisory Committee on Immunization Practices (ACIP) recommended expanding vaccine coverage to all children, including catch-up programs for children living in areas without existing vaccination programs. The new recommendations were enacted in the attempt to further reduce HAV incidence rates and possibly to eradicate the virus.13 Following a CDC health advisory report of HAV infection from international adoptees, in 2009 ACIP updated its guidelines to include hepatitis A vaccination for previously unvaccinated persons anticipating close personal contact with international adoptees from a country of high or intermediate endemicity. Complete HAV vaccination recommendations are available from the CDC (Table 26-2).

TABLE 26-2 Recommendations for Hepatitis A Virus (HAV) Vaccination

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Routine prevention of HAV transmission includes regular hand washing with soap and water after using the bathroom, changing a diaper, and before food preparation. For travelers to countries with high endemic rates of HAV, even short-term stays in urban and upscale resorts are not risk-free.7 In particular, contaminated water and ice, fresh produce, and any uncooked foods pose a risk.6

Vaccines to Prevent Hepatitis A

The inactivated virus vaccines currently licensed in the United States are the single-antigen HAVRIX® and VAQTA® and the combination of HAV and hepatitis B virus (HBV) antigen vaccine TWINRIX®. Both single-antigen vaccines are available for pediatric and adult use while the TWINRIX is indicated for adults only (Table 26-3). The differences in the vaccines are in the use of a preservative and in expression of antigen content. VAQTA is formulated without a preservative and uses units of HAV antigen to express potency. HAVRIX and TWINRIX use 2-phenoxyphenol as a preservative and antigen content is expressed as enzyme-linked immunosorbent assay (ELISA) units.7 Although high seroconversion rates of ≥94% are achieved with the first dose, VAQTA and HAVRIX recommend a booster shot to achieve the highest possible antibody titers. Although seroconversion exceeds 90% for HAV after the first dose of TWINRIX, the full three-dose series is required for maximal HBV seroconversion. An accelerated dosing schedule is available but requires a total of four doses for optimal response. The combined vaccine offers the advantage of immunization against both types of hepatitis in a single vaccine.

TABLE 26-3 Recommended Dosing of Hepatitis A Vaccines

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In situations of postexposure prophylaxis, either the vaccine or Ig can be used. The use of the vaccine is advantageous as vaccination confers the benefit of long-term immunity against HAV; however, experience in patients aged >40 years or with underlying medical conditions is limited.8 Both vaccines may be given concomitantly with Ig and the two brands are interchangeable for booster shots.7

Vaccine is recommended for international travel to areas of high or intermediate endemicity and can be given regardless of scheduled dates of departure. For older patients, immunocompromised, or any patients with chronic liver disease or any other chronic medical conditions traveling within 2 weeks, both Ig and vaccine are recommended.8

The most common side effects of the vaccines include soreness and warmth at the injection site, headache, malaise, and pain. More than 65 million doses of the vaccine have been administered and despite routine monitoring for adverse events, there are no data to suggest a greater incidence of serious adverse events among vaccinated people compared with nonvaccinated. The vaccine is considered safe.7

Immunoglobulin

Ig is used when preexposure or postexposure prophylaxis against HAV infection is needed in persons for whom vaccination is not an option. Vaccination is preferred for multiple reasons, including that it induces active immunity and therefore a longer time of protection against HAV than Ig. Ig is preferred for children <12 months of age and for postexposure prophylaxis in patients aged >60 years, patients with chronic liver disease, and persons allergic to any part of the vaccine. Among this patient population, Ig is preferred because it is effective and these populations are the most likely to experience fulminant hepatitis and mortality secondary to active HAV infections.

A sterile preparation of concentrated antibodies against HAV, Ig provides protection by passive transfer of antibody. Ig is most effective if given in the incubation period of the infection. Receipt of Ig within the first 2 weeks of infection will reduce infectivity and moderate the infection in 85% of patients. Patients who receive at least one dose of the HAV vaccine at least 1 month earlier do not need preexposure or postexposure prophylaxis with Ig.7 Ig is available as both an IV and IM injection, but for HAV exposure, only the IM is used. If given to infants or pregnant women, the thimerosal-free formulation should be used.

Serious adverse events are rare. Anaphylaxis has been reported in patients with IgA deficiency. Patients who had an anaphylaxis reaction to Ig should not receive it. There is no contraindication for use in pregnancy or lactation.

Dosing of Ig is the same for adults and children. For postexposure prophylaxis and for short-term preexposure coverage of <3 months, a single dose of 0.02 mL/kg is given intramuscularly. For long-term preexposure prophylaxis of ≤5 months, a single dose of 0.06 mL/kg is used. Either the deltoid or gluteal muscle may be used. In children younger than 24 months of age, Ig can be given in the anterolateral thigh muscle.7

For people who were recently exposed to HAV and who had not been previously vaccinated, postexposure prophylaxis with vaccination is preferred for most patients. Ig prophylaxis is preferred in the following situations: patients are <12 months of age or >40 years of age, are immunocompromised, have chronic liver disease or have underlying medical conditions, or for whom vaccine is contraindicated.8

Ig can be given concomitantly with the HAV vaccine. Although the antibody titer will be lower than if the vaccine were administered alone, the response is still protective and coadministration should be considered for the advantages of long-term HAV protection. However, Ig can interfere with the response of other live, attenuated vaccines and should be delayed.

Personalized Pharmacotherapy

Vaccine efficacy may be reduced in certain patient populations. In HIV-infected patients, greater immunogenic response may correlate with higher baseline CD4 cell counts. Response to the HAV vaccine as determined by detection of anti-HAV after vaccination found that among HIV patients, patients with CD4 counts <200 cells/mm3 (<200 × 106/L) at vaccination had a reduced response rate.9

HEPATITIS B

Hepatitis B is highly infectious, approximately 50 to 100 times more so than HIV.10 Although a vaccine was made available in 1981, HBV has acutely infected more than 2 billion people globally, leading to chronic infection in more than 240 million people.10 Chronic infection with HBV is a major public health issue as it serves as a reservoir for continued HBV transmission and poses a significant risk of death resulting from liver disease. More than 600,000 people per year die as a result of liver cirrhosis and hepatocellular carcinoma (HCC). In the United States, estimates of prevalence and incidence of viral hepatitis are difficult because there is no national chronic hepatitis surveillance program.1

Epidemiology

According to the World Health Organization (WHO), an estimated 2 billion people have been infected with HBV; only 12% of the global population lives in an area of low prevalence for hepatitis B, defined as an area where <2% of the population is hepatitis B surface antigen (HBsAg) positive.10 Prevalence can vary regionally; however, areas commonly associated with high infectivity rates include sub-Saharan Africa, most of Asia, as well as the Amazon and southern parts of Eastern and Central Europe.10 Areas of high prevalence, approximately 45% of the global population, are of special concern because most infections are of infants and children and >90% of cases lead to a chronic carrier state. Myths and misinformation about hepatitis B abound and can result in discrimination and social injustice.1 There are approximately 1.4 million chronically infected HBV people in the United States. Rates of acute infection in the United States continue to decline and in 2010, an estimated 38,000 people developed new infections. In 2010, the highest incidence rate was among persons aged 30 to 39 years and among non-Hispanic blacks. Data from a limited chronic surveillance program indicate Asian/Pacific Islanders account for the highest proportion of chronic HBV infections.2 Annually, 3,000 people die from chronic liver disease attributable to HBV.1

HBV is transmitted sexually, parenterally, and perinatally. In areas of high HBV prevalence, perinatal transmission from mother to infant at birth is most common, whereas in areas of intermediate prevalence, horizontal transmission from child to child is most common. Sexual contact, both homosexual and heterosexual, and injection-drug use are the predominant forms of transmission in low endemic countries such as the United States.10Concentration of HBV is high in blood, serum, and wound exudates of infected persons. Transmission occurs via blood-to-blood contact or semen or vaginal fluid of an infected person. The virus can be stable in the environment for at least 7 days and can cause infection during this time but is not spread via contaminated food or water and is not casually transmitted in the workplace.10 In the United States in 2010, no risk factor could be identified for the majority of acute infections with HBV. Among patients with identifiable risk factors, the most common risk continues to be sexual contact, specifically multiple sexual partners, MSM, and sexual contact with a known HBV-positive person. Sexual contact was a consistent risk among all patients but especially among those aged 45 years or younger. Other known risk factors include IDU and household contact of HBV-positive person.11

PERSONS AT HIGH RISK FOR HBV: RECOMMENDED SCREENING

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The mode of transmission has clinical implications because chronic infections are associated with infection acquired in younger patients, especially those infected perinatally and in early childhood.10


Clinical Controversy…

A total of 19 healthcare-associated HBV outbreaks have been identified and linked to lapses in infection control. Inappropriate use of glucose meters without cleaning and disinfection was the suspected mode of transmission in the majority of cases occurring in long-term care facilities.

Etiology

The HBV is a DNA virus that preferentially replicates within the liver.12 There are at least 10 HBV genotypes (A to J) with distinct geographic and ethnic distribution (Table 26-4). Genotype prevalence may depend on mode of transmission as types B and C are found in areas where vertical transmission is the primary mode of infection.13 Additionally, various subtypes of genotypes exist with varying clinical outcomes. Correlations between clinical outcomes and HBV genotypes suggest infections with genotype C are associated with more severe liver injury, including liver cirrhosis and progression to HCC. Noted limitations of studies are frequently small sample sizes and a predominance of research from Asia, primarily comparing genotypes B and C.13 Nonetheless, risk of more severe liver fibrosis was significantly higher in HBV genotype A-, C-, and D-infected patients. Genotype B may be more benign because it is associated with faster seroconversion, although clinical studies suggest genotype A may have equivalent, if not higher, rates of seroconversion.13 Patients with genotype C tend to have persistently higher viral DNA levels. Higher viral DNA levels are associated with increased incidence of cirrhosis and HCC. Resistance mutations may contribute to genotype virulence and hence impact severity of liver disease in infection.1315 Testing for HBV genotype is not currently recommended for clinical practice.14

TABLE 26-4 Worldwide Distribution of Hepatitis B Virus Genotypes

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Pathophysiology

On infection, replication of the virus begins by attachment of the virion to the hepatocyte cell surface receptors. The particles are transported to the nucleus where the DNA is converted into closed, circular DNA that serves as a template for pregenomic RNA. Viral RNA is then transcribed and transported back to the cytoplasm where it can alternatively serve as a reservoir for future viral templates or bud into the intracellular membrane with the viral envelope proteins and infect other cells.13 The viral genome has four reading frames coding for various proteins and enzymes required for viral replication and spread. Several of these proteins are used diagnostically (Table 26-5). The HBsAg is the most abundant of the three surface antigens and is detectable at the onset of clinical symptoms. Its persistence past 6 months after initial detection corresponds to chronic infection and indicates an increased risk for cirrhosis, hepatic decompensation, and HCC. Development of antibody to HBsAg (anti-HBsAg) confers immunity to the virus and clearance of HBsAg is associated with favorable outcomes.16 The precore polypeptide encodes for the secretory protein hepatitis B e antigen (HBeAg) and the hepatitis B core antigen (HBcAg) proteins. HBeAg is present in an acute infection and is replaced by antibodies (anti-HBeAg) once an infection is resolved. HBeAg was assumed to be a marker of viral replication and infectivity; however, it is now known that some viral mutants exist that are unable to have or have downregulated expression of HBeAg, although their ability to replicate is not affected.14 HBeAg-negative mutants pose a particular clinical challenge because they are refractory to treatment. The HBcAg is a nucleocapsid protein that, when expressed on hepatocytes, promotes immune-mediated cell death. High levels of antibodies (IgM anti-HBcAg) are detectable during acute infections. Patients who respond to vaccine will have anti-HBsAg only.7

TABLE 26-5 Interpretation of Serologic Tests in Hepatitis B Virus

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HBV itself does not seem to be pathogenic to cells; rather, it is thought that the immune response to the virus is cytotoxic to hepatocytes.13 The immune response is critical to viral clearance. If the response is weak, chronic infection is likely. Liver injury is likely caused by secondary, nonspecific inflammation activated by the initial cytotoxic lymphocyte response and as an attempt by the immune system to clear the virus by destroying HBV antigen-presenting hepatocytes. Destruction of hepatocytes results in release of circulating, and hence increased, ALT levels.

Cirrhosis

Cirrhosis results as the liver attempts to regenerate while in an environment of persistent inflammation. Most patients with compensated cirrhosis either are asymptomatic or have mild symptoms of epigastric pain. During cirrhosis, the liver enters a cycle of ongoing liver damage, fibrosis, and attempts at regeneration. The classical appearance of a small and knobby liver reflects the irreversible effect of nodules of regenerating cells integrated with infiltrates of inflammation-induced fibrous tissue. Both viral and clinical factors affect the outcome of cirrhosis (Table 26-6). Cirrhosis develops at an annual incidence rate of 2.1% to 3.5%.13 The development of cirrhosis is mostly insidious and patients can remain stable for years before disease progression. An estimated 20% of all chronic hepatitis B patients develop complications of hepatic insufficiency and portal hypertension as their compensated cirrhosis progresses to decompensated cirrhosis within a 5-year period.14

TABLE 26-6 Factors Associated with Hepatitis B Virus (HBV) Cirrhosis and Disease Progression

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Hepatocellular Carcinoma

HBV is a known risk factor for the development of HCC and in areas of high HBV endemicity, a major complication of the infection.10 The development of HCC can be insidious, occurring in the absence of cirrhosis or in the presence of clinically silent, compensated cirrhosis. Many patients with HCC have no signs of cirrhosis.14 The virus itself is not likely the causative agent of the cancer. In most cases, HCC develops after years of inflammatory processes provoked by ongoing HBV infection. Compared with HCV, however, HBV does seem to provoke a more direct carcinogenic effect as evidenced by its presence in less severe liver disease, and among patients with advanced HCC, HBV infection is associated with a worse survival rate.17 Several factors influence the development of HCC, as well as predict survival (see Table 26-6). HCC is more prevalent in males; in older patients; in patients coinfected with HCV or delta hepatitis; and in patients with serologic markings of past or present HBV infection, preexisting cirrhosis, or continued alcohol ingestion. Risks for death and decompensation increase with underlying liver disease. Other host-specific or environmental factors may impact the course of liver disease. Persistently elevated HBV DNA levels (≥10,000 copies/mL [≥10 × 106 copies/L]) predict HCC development, even after adjusting for sex, age, cigarette smoking, alcohol consumption, HBeAg status, ALT level, and liver cirrhosis.18 Smoking is a risk factor among European and Asian patients.19,20 HBeAg status is not a risk factor. In otherwise healthy patients without coinfection or who do not have HCC or decompensation at the time of seroclearance, HBsAg seroclearance does predict a favorable long-term outcome.16

Clinical Presentation

Images The clinical symptoms and course of an HBV infection are indistinguishable from other types of viral hepatitis. Several phases of an HBV infection exist and are dynamic.15 During the initial or acute phase of an HBV infection in adults and older children, the HBV enters a 4- to 10-week incubation period, during which antibodies toward the HBV core are produced and the virus replicates profusely. Active viral replication results in high serum HBV DNA levels and HBeAg secretion. ALT levels may rise slightly, but most patients will remain asymptomatic. Symptoms, if they do occur, include fever, anorexia, nausea, vomiting, jaundice, dark urine, clay-colored or pale stools, and abdominal pain. Most neonates and children are anicteric and have no clinical symptoms; many adults are also asymptomatic.10 HBsAg does not become detectable until after significant viremia. The initial phase is considered immunotolerant because no hepatic injury is sustained, as evidenced by generally normal ALT levels, and the virus replicates profusely. Patients are highly infectious during this time.15 In perinatally acquired infections, and in young children, the phase can last for decades—until adulthood.15 Infected children pose a particular risk because they are often asymptomatic, undiagnosed, and highly infectious.

The immunoactive phase marks a decrease in HBV DNA levels with ongoing secretion of HBeAg. Patients are symptomatic with intermittent flares of hepatitis and marked increases in ALT levels. More frequent flares are associated with disease progression and reflect host immune response against HBV-infected hepatocytes, increased cell death in an attempt to clear the virus.13,19 The phase can last a few weeks in acute disease, and for years in patients with chronic disease. As the host immune system attempts to gain control of the infection by stopping active viral replication, serum HBV DNA levels drop to undetectable, ALT levels normalize, and liver necroinflammation resolves.13

If the infection is self-limiting, HBV DNA quickly subsides, HBeAg disappears within weeks, and HBsAg usually resolves within 4 months. The final phase is seroconversion and is defined by the replacement of HBeAg with anti-HBeAg. Factors favoring seroconversion include female sex, older age, biochemical activity, and genotype. Flares of hepatitis with ALT levels >5 times the upper limits of normal, compared with <5 times the upper limits of normal, correspond to increased immune system activity and precede seroconversion.

Chronic HBV

Images Patients who continue to have detectable HBsAg for more than 6 months have chronic HBV.13 Table 26-7 lists the clinical features of chronic hepatitis B. The most predictive factor for developing a chronic infection is age. Perinatal infections almost always result in chronic infections because of immune tolerance to the virus. Risks of chronicity decline to a rate of 30% in infants and to less than 5% of acute adult infections.14

TABLE 26-7 Clinical Presentation of Chronic Hepatitis Ba

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Chronic infections can be controlled in many cases, but cure is not possible because the HBV template is integrated into the host genome. In patients with recurring cycles of viral expression and host immune response, progressive liver damage ensues.21 Patients can be divided into two types of chronic hepatitis B: those who are HBeAg positive and those who are HBeAg negative. The ability to express HBeAg by the virus differentiates the two types of chronic infection. Patients are considered to be in the “immune-tolerant” phase when HBeAg is positive, high serum HBV DNA levels are detected, and ALT levels are normal. Typically these patients were infected early in life and develop elevated ALT levels later in life. Spontaneous HBeAg clearance is possible and is associated with older age, higher ALT, and infection with HBV genotype B.14

Patients who are HBeAg negative can be further subdivided into the active or inactive carrier. HBeAg-negative chronic HBV patients who are active carriers have a worse clinical course with a very low rate of spontaneous remission. Patients may have long periods of disease remission, but recurring flares of hepatitis with increased frequency and severity can progress to cirrhosis and HCC. In contrast, HBeAg-negative chronic HBV patients who are inactive carriers have detectable HBsAg and anti-HBeAg, normal ALT, and either low or undetectable levels of HBV DNA. This patient population usually experiences a more benign course of disease, with the possibility of long-term remission, even seroconversion, although reactivation is possible with the progression to cirrhosis and HCC. Up to 20% of patients in the inactive carrier state may revert to detectable HBeAg, emphasizing the need for lifelong followup to confirm quiescence.14

Reactivation of hepatitis B, defined as the recurrence or abrupt rise in HBV replication by an increase in serum HBV DNA of at least 1 log10 and a marked increase in transaminase levels, can occur and is well described in the literature in patients receiving cancer chemotherapy, steroids, and other immunosuppressive agents.22,23 Reactivation can occur in anyone with a prior or current HBV exposure, but patients who are HBsAg positive are most likely to experience a reactivation.23 The causes of reactivation include spontaneous mutations of the virus that allow it to escape immune control, development of resistance to HBV drug therapy or the cessation of HBV therapy, or changes in immunity, such as those that occur in patients undergoing immunosuppressive therapies or coinfection with HIV.

The CDC recommends testing for hepatitis B for all patients who are to receive chemotherapy or other immunosuppressive agents.

HBV Mutations

Images Among the DNA viruses, HBV is notable for its significantly higher mutation rate.24 Long-term therapy is problematic because of the high likelihood of developing viral resistance. One of the most common mutations consists of a nucleotide substitution either preventing or causing downregulation of the production of HBeAg. The mutation results in a chronic infection that may have a poorer long-term prognosis. Typically, the mutation emerges during the infection and represents a later stage in the course of chronic HBV infection with more advanced liver disease.

The selective pressures of the L-nucleoside analog antivirals, including lamivudine, cause the YMDD mutation. The mutation is associated with the active site of the DNA polymerase and causes an altered active site. The incidence of lamivudine resistance increases with each subsequent year of therapy and may be associated with a more severe disease progression.14 An added risk of developing resistance is the retention of the mutation within the virus even 4 years after lamivudine therapy.25 Cross-resistance of lamivudine-resistant mutants to telbivudine has been demonstrated and patients treated with lamivudine and telbivudine showed resistance mutations to both drugs. Telbivudine-specific resistance can also occur at rates lower than that seen in lamivudine.26 Other mutations include resistance to adefovir and entecavir. Resistance to adefovir is associated with substitutions of aspargine by threonine (rtN236T) and substitution of alanine by valine or threonine (rtA181V/T), as well as other possible mutations to the HBV polymerase gene. The addition of lamivudine in adefovir resistance may overcome resistance, although the optimal management of either adefovir- or entecavir-resistant strains is not clear.1315,24

Prevention of Hepatitis B

The development of the HBV vaccine represented the first vaccine against a major human cancer.10 Despite the availability of the HBV vaccine in 1982, rates of HBV did not decline in the early 1980s. Initial declines in incidence were likely attributable to behavioral changes among high-risk groups as a result of the acquired immune deficiency syndrome (AIDS) epidemic. A 94% decline in rates between 1990 and 2004 was seen in children and adolescents, which began with the initiation of screening of pregnant women and subsequent immunizations of infants and recommendations set forth in the 1990s to immunize adolescents. Regulations enacted by Occupational Safety and Health Administration (OSHA) further reduced overall U.S. rates by 75%.12

Images Prophylaxis against HBV can be achieved by vaccination or by passive immunity in postexposure cases with hepatitis B Ig. Vaccination is the most effective strategy to prevent infection and a comprehensive vaccination strategy has been implemented in the United States (Table 26-8). Vaccines use HBsAg for the antigen via recombinant DNA technology using yeast to prompt active immunity. More than 60 million adolescents and more than 40 million infants and children have received an HBV vaccine in the United States since 1982. The vaccine is considered safe. Since 2000, vaccines licensed in the United States contain either none or trace amounts of thimerosal as a preservative. Available vaccines include two single-antigen products and three combination products. The two single-antigen products are Recombivax HB and Engerix-B. TWINRIX is a combination vaccine for HAV and HBV in adults. Comvax and Pediarix are used for children and are used for HBV along with other scheduled vaccines.

TABLE 26-8 Recommendations for Hepatitis B Virus (HBV) Vaccination

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Passive immunity in the form of anti-HBsAg offers temporary protection against HBV and is used in conjunction with the hepatitis B vaccine for postexposure prophylaxis.12

TREATMENT

Desired Outcome

HBV infections are not curable; rather, the goals of therapy are to suppress HBV replication and prevent disease progression to cirrhosis and HCC. The loss of HBsAg is becoming an increasingly more important goal in therapy.

General Approach to Treatment

Images Response to therapy is monitored by biochemical, histologic, and virologic response (Table 26-9).14 Maintenance of viral suppression is defined as durability of response. In HBeAg-positive patients, successful therapy includes loss of HBeAg status and seroconversion to anti-HBeAg. Other serologic markers are typically not evaluated in clinical trials. Recommendations for treatment consider the patient’s age, serum HBV DNA and ALT levels, as well as histologic evidence and clinical progression of disease (Fig. 26-1 and 26-2). Not all chronic HBV patients are candidates for treatment. In general, treatment is indicated if the risk of liver-related morbidity and mortality is within the foreseeable future and the likelihood for achieving sustained viral suppression is high.14 Some patients may be best managed with periodic monitoring for disease progression because the chances for therapeutic response are unlikely and do not outweigh the risks and costs associated with treatment. The major organizations providing guidelines on the management of HBV infections are the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of Liver Disease, and the Asian Pacific Association for the Study of the Liver.1315

TABLE 26-9 Definitions of Response in HBV Therapy

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FIGURE 26-1 Suggested management algorithm for chronic hepatitis B virus infection based on the recommendations of the American Association for the Study of Liver Diseases. (ALT, alanine transaminases; HBeAg, hepatitis B e antigen; peg-IFN, pegylated interferon; HBV DNA concentration of >20,000 international units/mL is equivalent to >20 × 106 international units/L.) (Adapted from reference 14.)

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FIGURE 26-2 Suggested management algorithm based on the recommendations of the American Association for the Study of Liver Diseases for chronic hepatitis B virus–infected patients with cirrhosis. (HBV DNA concentrations of >20,000, >2,000, and ≤2,000 international units/mL are equivalent to >20 × 106, >2 × 106, and ≤2 × 106 international units/L, respectively.) (Adapted from reference 14.)

Nonpharmacologic Therapy

All chronic HBV patients should be counseled on preventing disease transmission. Sexual and household contacts should be vaccinated. To minimize further liver damage, all chronic HBV patients should avoid alcohol and be immunized against HAV. No level of alcohol use has been established as safe.14 Moreover, patients are encouraged to consult their medical provider before using any new medications, including herbals and nonprescription drugs.12

Herbal medicines are an intriguing option to many patients. Although some of the products may have some physiologic benefits, there are insufficient data and the methodologic qualities of the trials evaluating the herbs are poor. Randomized, placebo-controlled studies and long-term followup data are lacking.27

Pharmacologic Therapy

Images Because hepatic damage is sustained by ongoing viral replication, drug therapy aims to suppress viral replication by either immunomodulating agents or antivirals—the nucleos(t)ide agents. In the United States, the immune-mediating agents approved as first-line therapy are interferon (IFN)-alfa and pegylated (peg) IFN-alfa. The antiviral agents lamivudine, telbivudine, adefovir, entecavir, and tenofovir are all approved as first-line therapy options for chronic HBV.14 A major difference in therapy is duration of use: IFN-based therapies are typically administered for a predefined duration, whereas nucleos(t)ide analogs are used until a specific end point is achieved. For HBeAg-positive patients, treatment is recommended until HBeAg seroconversion and an undetectable HBV viral load are achieved and for 6 months of additional treatment. In HBeAg-negative patients, treatment should be continued until HBsAg clearance.14

Interferon

IFN-alfa therapy was the first approved therapy for treatment of HBV and improves long-term outcomes and survival. Acting as a host cytokine, it has antiviral, antiproliferative, and immunomodulatory effects in chronic HBV.14Several factors correlate with improved response to IFN therapy, including increased ALT and HBV DNA levels, high histologic activity score at biopsy, and being non-Asian. Asian patients tend to have more normal ALT levels in chronic infection, confounding the actual impact of ethnicity on infection.14 The main mechanism of action of the IFNs is to enhance the host immune system to mount a defense against HBV.

Patients who respond to IFN therapy tend to have a more durable response than that seen with lamivudine, likely as a consequence of IFN’s stimulation of the immune response for seroconversion. Seroconversion rates range from 30% to 40% and are often permanent, although relapse is more likely in HBeAg-negative patients.21,28 The duration of therapy is finite, although the optimal duration of treatment is unclear. Treatment for a minimum of 12 months is associated with greater sustained virologic response (SVR) rates than treatment for 4 to 6 months. Seroconversion can occur during or after therapy is complete. An extended treatment duration of 24 months may benefit the difficult-to-treat HBeAg-negative patient.21 Conventional IFN therapy is plagued with numerous problems, including the inconvenience of thrice-weekly injections; however, standard IFN therapy has virtually been replaced by the use of peg-IFN because of the benefits in ease of administration, decreased side effect profile, and improvements in efficacy. Compared with conventional IFN, peg-IFN has a longer half-life enabling once-weekly injections. Studies comparing peg-IFN monotherapy with peg-IFN–lamivudine combination therapies suggest that combination therapy caused greater HBV DNA suppression than peg-IFN monotherapy; peg-IFN monotherapy better achieved HBeAg seroconversion than lamivudine monotherapy with no difference in combination therapy; and combination therapy resulted in less lamivudine resistance than lamivudine monotherapy. IFN-based therapies are still limited by multiple adverse effects (Table 26-10). The high risk of infection precludes use of IFN in decompensated cirrhotic patients.14 In patients with compensated cirrhosis, IFN appears to be safe and effective, although it can provoke hepatic flares and precipitate hepatic decompensation.14,21 Ongoing clinical trials are investigating the use of either sequential or combination therapy with peg-IFN and nucleos(t)ides. The optimal role of IFN-based therapies in HBV treatment is not defined.

TABLE 26-10 Recommendations for Hepatitis C Virus (HCV) Screening

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Lamivudine

Lamivudine, a nucleoside analog, has antiviral activity against both HIV and HBV. It inhibits HBV DNA synthesis by being incorporated into growing DNA chains causing premature chain termination.14 The optimal duration of treatment for HBV is unknown and can be limited by virologic breakthrough. In both HBeAg-positive and -negative patients, lamivudine at a 100 mg daily dose demonstrates profound viral suppression. HBV DNA serum levels are undetectable in 90% of lamivudine-treated patients after 4 weeks.21 Normalization of ALT levels occurs gradually over 3 to 6 months in most patients. Additionally, fibrotic changes are reduced and may be reversed in some cases. Response to lamivudine is dependent on baseline ALT levels, with higher levels corresponding to greater likelihood of seroconversion. Seroconversion rates increase with duration of therapy and are at 50% by the fifth year of therapy.14 The advantages of lamivudine-based therapy include its safety profile and patient tolerability and the convenience of an oral tablet. Moreover, lamivudine can safely be used in immunosuppressed and cirrhotic patients.28Patients who can maintain long-term viral suppression have reduced and possibly reversed cirrhotic changes. However, lamivudine therapy is not without problems. There is no clear duration of treatment and HBeAg-negative patients have a less than 20% viral suppression rate after 12 months of therapy. Serum HBV DNA levels return to baseline on cessation of therapy.14 Seroconversion rates are less than 20% after 1 year of therapy and will relapse in up to 58% of patients. Relapse rates are highest among Asian patients.28 Resistance is inevitable and can undermine the value of treatment. The emergence of resistant mutants increases with each subsequent year of therapy, with rates approaching 80% after 5 years of therapy, and is associated with returns of serum HBV DNA and elevated ALT levels.24 Relapse is associated with reversion of histologic benefits.14 Although seroconversion can occur even after the appearance of resistant mutants, the prognosis is poor for most patients who develop resistance.21 In HBeAg-negative chronic hepatitis B, where therapy is long-term and the exact duration of therapy unknown, resistance is an especially daunting problem.14 Given the availability of more potent antivirals and the low threshold for resistance with lamivudine, lamivudine is not recommended as first-line therapy for chronic HBV infections.

Patients on lamivudine therapy require monitoring for breakthrough infection. If patients have confirmed lamivudine-resistant mutations, therapy should be changed to include agents with activity against lamivudine-resistant HBV.14

Adefovir

Adefovir dipivoxil is an acyclic nucleotide analog of adenosine monophosphate. The drug acts by inhibiting HBV reverse transcriptase and DNA polymerase and is effective in both wild-type and lamivudine-resistant HBV. It is dosed at 10 mg daily for 1 year in adults, although the optimal duration of therapy is unknown.14 A 48-week course of treatment is effective in improving histologic findings, reducing serum HBV DNA and ALT levels, and increasing HBeAg seroconversion in both HBeAg-negative and -positive patients.29,30 The durability of the response is likely related to a long duration of treatment following seroconversion.31 Further suppression of HBV DNA and ALT levels occurred in long-term therapy over 4 to 5 years with improved histologic findings.32 In HBeAg-negative patients treated for 48 weeks, the benefits of therapy were lost within 4 weeks of stopping adefovir. In contrast, patients treated for 144 weeks maintained benefits throughout the treatment duration and saw continued improvement in fibrosis as the therapy continued. However, rates of seroconversion were low.32 Adefovir is well tolerated at the 10 mg daily dose. Previous reports of nephrotoxicity were associated with clinical trials where adefovir was dosed at 30 mg/day. In patients treated chronically at a dose of 10 mg daily, the incidence of nephrotoxicity was the same as placebo. In patients treated with 10 mg/day for a subsequent 48 weeks, the incidence of serum creatinine abnormalities did not change from the first year of therapy.32 Routine monitoring of serum creatinine is recommended every 3 months in patients at risk for renal insufficiency and in all patients treated for more than a year with adefovir.14

Resistance to adefovir has not been seen within the first year of therapy.24 Resistant mutants have been identified and do respond to lamivudine therapy, although the full impact on clinical outcomes is not known.14 The risk of adefovir resistance is higher among patients switched from lamivudine to adefovir rather than among those who received a combination therapy of lamivudine and adefovir.33 To prevent adefovir resistance, lamivudine should be continued even in patients with lamivudine-resistant HBV, although the optimal duration for combination therapy is not known.14 The optimal drug therapy in adefovir resistance is not known.14

Entecavir

Entecavir is a guanosine nucleoside analog that acts by inhibiting HBV replication at three different steps. An oral agent, it is more potent than lamivudine and adefovir in suppressing serum HBV DNA levels and is effective in lamivudine-resistant HBV.14 Rates of HBeAg seroconversion are higher in patients with elevated baseline ALT.14 The drug is dosed at 0.5 mg daily for adults with treatment-naïve or non–lamivudine-resistant infections and at 1 mg daily in lamivudine-refractory patients. In a 48-week trial comparing it with lamivudine, entecavir resulted in significantly higher rates of histologic improvement, HBV DNA reduction and undetectability, and ALT normalization. No difference in HBeAg loss or seroconversion was observed in HBeAg-positive patients.34 In HBeAg-negative patients, entecavir showed greater histologic, virologic, and biochemical responses compared with lamivudine.35Among all patients, no differences in fibrosis improvement were seen and resistance to entecavir was not detected after 2 years of therapy.34,35 In treatment-naïve patients, entecavir resistance remains low, even after 72 six years of therapy, demonstrating the high barrier to resistance of the drug.24 However, treatment response in lamivudine-resistant patients is lower overall and more likely for the development of entecavir-resistant mutants especially if lamivudine is continued during entecavir therapy.14 Patients on lamivudine who develop resistance and are switched to entecavir should stop lamivudine therapy.14 Resistance to both lamivudine and adefovir is a risk factor for entecavir resistance.36 In terms of safety, entecavir is comparable to lamivudine. Entecavir is considered to be a first-line agent for HBV therapy.

Telbivudine

Telbivudine is an HBV-specific nucleoside analog that acts as a competitive inhibitor of viral reverse transcriptase and DNA polymerase. The drug inhibits HBV DNA synthesis with no activity against other viruses or human polymerases.26 Compared with lamivudine, telbivudine is a more potent suppressor of HBV DNA with greater median HBV DNA log reductions and more patients achieving undetectable viral loads.26,37 More patients also experienced a normalization of ALT levels. Although more telbivudine-treated patients experienced seroconversion, the difference was not significant even at 2 years of therapy. Treatment failure, including an inability to suppress HBV DNA levels below 5 log, occurred significantly more often in lamivudine-treated patients than in telbivudine-treated ones.37 However, similar to lamivudine, telbivudine has a high rate of mutations that limits its efficacy. During a 2-year evaluation, resistance increased substantially from year 1 at 5% to 25.1% in year 2 in HBeAg-positive patients and from 2.3% to 10.8% in HBeAg-negative patients.37,38 Moreover, telbivudine-resistant mutations are cross-resistant with lamivudine. Telbivudine monotherapy is comparable with lamivudine in safety with few case reports of myopathy and elevations of creatinine kinase.37,38 Overall, due to resistance concerns, telbivudine monotherapy has a limited role in the treatment of HBV.14

Tenofovir

Tenofovir is a nucleotide analog first approved for use in HIV and approved for HBV in 2008. It is available either as a single-agent oral tablet or as a combination therapy with emtricitabine. Tenofovir is similar to adefovir but without the nephrotoxicity seen with adefovir, permitting adult dosing to be 300 mg versus 10 mg of adefovir. The higher dosing strategy likely confers several advantages to tenofovir in comparison with adefovir. Among HBeAg-positive patients, more patients treated with tenofovir had undetectable HBV DNA, ALT normalization, and loss of HBsAg than the adefovir-treated group. Rates of histologic response and seroconversion were similar. Among HBeAg-negative patients, more patients treated with tenofovir had undetectable HBV DNA, but there was no difference in ALT normalization and histologic response, and no patients lost HBsAg.39 In lamivudine-resistant chronic hepatitis B, tenofovir showed an earlier and greater suppression of HBV DNA than adefovir. In studies of treatment-naïve patients on tenofovir for up to 3 years, no resistant mutations were detected.40 Additional data suggest sustained viral suppression with regression of fibrosis and no resistance in patients treated with tenofovir for 6 years.41 Tenofovir can overcome adefovir treatment failure, but adefovir mutants persist, suggesting cross-resistance.42 A study of 113 treatment-experienced patients who had previously failed nucleos(t)ide therapy and were started on tenofovir demonstrated viral suppression in 100% of patients without adefovir resistance and in 52% of patients with adefovir resistance.43 The optimal management to prevent resistance is unknown at this time. Tenofovir is considered to be a first-line therapy in the treatment of HBV.14

Alternative Drug Treatments

Emtricitabine is a cytosine analog approved for use in HIV and with activity against HBV. It is currently not approved for HBV but has been used in combination with tenofovir. In a comparative study with placebo, emtricitabine showed a significant decrease in viral load to undetectable in 54% of patients, normalization of ALT levels in 65% of patients, and improvement in necroinflammatory score. However, seroconversion to anti-HBeAg and HBeAg loss did not differ between placebo and emtricitabine. Emtricitabine safety was comparable to placebo. At the end of the 48-week treatment, 20 emtricitabine-treated patients had YMDD or YMDD-related resistance mutations.43Emtricitabine is similar to lamivudine and thus induces similar mutations.14

Combination therapy has been proposed to increase drug effectiveness and to counter the issues of resistance. Potential disadvantages for combination therapy include costs, toxicity, and drug interactions. Currently no data exist that combination therapy of two antiviral agents improves effectiveness. Data for preventing resistance are mixed as complete suppression of resistance has not been achieved with combination therapy. Combination therapy with IFN and lamivudine creates less resistance than lamivudine monotherapy, but the combination did not change the posttherapy viral response in comparison to IFN monotherapy.14 Switching to peg-IFN after entecavir therapy increased the rates of HBeAg seroconversion and HBsAg loss as compared with continuing entecavir therapy.44 Adding adefovir to patients on lamivudine when HBV DNA levels began to increase better maintained normal ALT levels and suppressed HBV DNA than waiting to add adefovir until after ALT levels increased.31 Adding adefovir to lamivudine when lamivudine resistance develops in HBeAg-negative patients was associated with improved ALT normalization and a lower likelihood for virologic breakthrough or development of adefovir resistance. Both groups had similar rates of virologic response.33 In a comparison study of lamivudine monotherapy versus lamivudine–adefovir combination therapy in treatment-naïve patients, similar rates of seroconversion, HBV DNA suppression, and ALT normalization were observed. There was a lower rate of resistance in the combination therapy group at 15% versus 43% in the lamivudine monotherapy group.45 Entecavir combined with tenofovir in HBeAg-positive patients resulted in greater viral suppression but only in patients with an initial baseline viral load of ≥108 international units/mL (≥1011international units/L).46 The AASLD recommends combination therapy with lamivudine or telbivudine plus adefovir, tenofovir, or entecavir for decompensated cirrhotic patients with chronic HBV regardless of HBV DNA levels or HBeAg status.14 Moreover, current guidelines suggest combination therapy with two or more agents in patients who develop antiviral resistant HBV.1315

Special Populations

Cirrhosis

The decision to treat cirrhotic patients depends on disease progression. Patients with decompensated cirrhosis require referral for liver transplant. Most recently updated guidelines suggest lamivudine, telbivudine, adefovir, tenofovir, and entecavir are possible agents for use in cirrhotic patients (see Fig. 26-2).14


Clinical Controversy…

Although previously published guidelines do not support the use of IFN in cirrhosis because of the potential for an IFN-induced hepatic flare progressing to decompensation, some experts suggest peg-IFN alfa-2a may be an option for some patients with compensated cirrhosis. Moreover, some experts argue that lamivudine, although indicated for use in cirrhosis, may cause clinical decompensation because of the drug’s high risk for resistance and, hence, viral rebound triggering decompensation.

Coinfection with HCV

In patients coinfected with HCV, the clinical practice is to treat the more dominant form of the hepatitis virus. There are no current recommendations on management of HBV/HCV coinfection. Previously published recommendations suggested treating HCV according to published guidelines and to consider the addition of entecavir or adefovir if HBV DNA levels remained stable or rose.14

Coinfection with Hepatitis D

Patients coinfected with hepatitis D, which requires infection with hepatitis B, may be treated with high-dose IFN-alfa or peg-IFN.14 There is an overall paucity of data on HBV–HDV coinfection treatment. Lamivudine has not been shown to be effective, neither has ribavirin, a drug used in combination therapy with IFN for HCV treatment.47,48

Coinfection with HIV

In HIV-coinfected patients, therapy should be tailored specifically to the patient. If the patient is being treated for HIV, certain regimens may be optimized to include drugs with efficacy against HBV, including tenofovir, emtricitabine, or lamivudine. If patients are on a stable regimen that does not include HBV-active drugs or are not considered for highly active antiretroviral therapy (HAART), peg-IFN or adefovir may be used.14 Because of neutropenia associated with peg-IFN, patients considered for IFN therapy should have CD4 counts >500 cells/μL (>500 × 106/L). In patients being considered for HAART, combination therapy is recommended for HBV with either tenofovir and lamivudine or tenofovir and emtricitabine. Patients with confirmed lamivudine resistance should have tenofovir added to their regimens.14

Pediatrics

Although the majority of chronic HBV patients are adults, children may be treated. Lamivudine is indicated for children aged 2 years and older and IFN is approved for use in children aged 1 year and older. Entecavir is approved for adolescents aged 16 years and older and adefovir for children 12 years and older. Although peg-IFN-alfa does have indications for children 3 years and older, the approval is for the use in chronic hepatitis C infections.

Pregnant Females

Perinatal transmission of HBV is a major cause of chronic HBV globally. To prevent mother-to-child transmission, the use of lamivudine or telbivudine in the third trimester is recommended for women. Tenofovir is an alternative.13

Immunosuppressive or Cytotoxic Therapy

Patients who will undergo chemotherapy or immunosuppressive therapy should be assessed for risk of HBV. Prophylactic therapy is recommended prior to initiation of cancer chemotherapy or immunosuppressive therapy. Patients who have undetectable HBV DNA and who are expected to be on treatment for 1 year or less should be treated for 6 months after completion of chemotherapy or immunosuppressive therapy with either lamivudine or telbivudine. Tenofovir or entecavir should be used in patients where the duration of therapy is expected to be longer.14

Resistance Concerns

Current guidelines favor the use of potent agents with low rates of resistance. Resistance potential in HBV is evaluated by an antiviral agent’s genetic barrier to resistance, or the number of primary mutations needed for antiviral drug resistance to occur. Other factors include cross-resistance and drug potency. Viral suppression is important because the HBV virus requires ongoing viral replication in the setting of antiviral drug pressure to mutate. HBV therapy can be cost prohibitive for many patients and can favor the use of lamivudine. Unfortunately lamivudine-based therapies are prone to resistance and may have long-term implications on viral activity, notably the concerns for development of vaccine-resistant mutants.12,24

Another major factor in resistance is patient adherence to therapy. Studies on adherence suggest suboptimal adherence is common with approximately 40% of patients missing doses.49 Moreover, in patients experiencing virologic breakthrough, studies have shown that 40% of cases were not related to antiviral drug resistance, emphasizing the impact of medication adherence on viral suppression.50

PERSONALIZED PHARMACOTHERAPY

Vaccination for HBV is less effective than for HAV and requires multiple doses for improved response. Several host factors are implicated in a reduced response. Patients who are immunocompromised and patients on hemodialysis may require additional doses to induce antibody response. Some patients may require repeat vaccination.51 Sleep deprivation may also contribute to decreased antibody response.52

The role of IFN sensitivity in treatment response is known for hepatitis C where allelic variants of interleukin 28B (IL28B) are strongly associated with spontaneous clearance and associated with responsiveness to treatment.53Currently, the role of IFN sensitivity is not well understood for hepatitis B.

HEPATITIS C

HCV is approximately 5 times as common as HIV and is responsible for an estimated 10,000 chronic liver disease–associated deaths per year.1 More than 190,000 deaths from HCV-related disease are expected between 2010 and 2019, with projected costs exceeding $10 billion.54 Most acute infections are asymptomatic and the course of the infection is insidious. As a result, many patients are not diagnosed until significant disease progression.

Epidemiology

Images HCV is the most common blood-borne pathogen. In the United States, approximately 3.2 million people are chronically infected with HCV.1 An estimated 17,000 new HCV infections occurred in 2007; however, because of the clinically silent nature of acute infections and the 20- to 30-year disease progression to cirrhosis, it is the 200,000 patients infected per year in the late 1980s who contribute to today’s HCV burden.54 In 2007, the number of deaths attributable to HCV exceeded the number of deaths due to HIV.55 The impact of undiagnosed and untreated HCV is expected to increase dramatically over the next 40 to 50 years with 1.76 million persons developing cirrhosis, 400,000 developing HCC, and 1 million persons dying from HCV-associated complications.56 Considering that HCV infection is prevalent in high-risk populations such as prisoners, IDUs, and the homeless, and that this population is generally excluded from most surveys, the actual number of chronically infected people is significantly higher. Nearly 75% of infected people may not be identified.1,54 The single largest risk factor for infection is injection-drug use. Some experts also consider other illicit drug use, for example, intranasal cocaine, as a risk factor because of the possible contamination of drug paraphernalia not limited to syringes and needles. Historically, blood transfusion posed a major risk for infection. Improved screening of blood in 1992 decreased the risk of transfusion-related HCV.57 Currently both hemodialysis and transfusions represent less than 1% of risk factors in known HCV exposures.4Healthcare-associated transmission is rare; however, a much publicized outbreak linked to an endoscopy center in Nevada in 2007 prompted an examination of HCV outbreaks associated with healthcare. Since 1998, over 58,000 patients have been screened for possible exposure to HCV in nonhospital healthcare venues, including the Nevada incident. The identified risk in Nevada was unsafe injection practices.

Screening

Although acute HCV infections are often not recognized and many progress to chronic infections, routine screening for infection is not recommended. Various guidelines and position papers for the screening and treatment of chronic HCV infection exist. In 2012, the CDC released recommendations to perform a one-time screening of all patients born between 1945 and 1965. The recommendation was made due to the high rates of HCV in this birth cohort. The CDC estimates approximately 75% of adults with HCV were born in that age range. Screening is also warranted in patients who are at high risk for infection (Table 26-10). Although the risk of HCV in monogamous relationships is very low and barrier methods are not recommended, sexual partners are recommended to be tested for the sake of reassurance.57 No specific sexual practices are associated with an increased risk of transmission.58 Although sexual contact is considered an inefficient means of HCV transmission, multiple sexual partners and coinfection with sexually transmitted diseases, including HIV, increase the risk for HCV sexual transmission. The risk of infection from other needle-borne exposures, such as acupuncture, tattooing, and body piercing, is unclear and at this time not an indication for routine screening for HCV.57

Etiology

HCV is a single-stranded RNA virus of the family Flaviviridae notable for lacking a proofreading polymerase and enabling frequent viral mutations.54 The virus replicates within hepatocytes and, like hepatitis B, is not directly cytopathic. HCV replicates copiously with an estimated serum half-life of 2 to 3 hours, posing an immense challenge for host immune control.

HCV is differentiated into six major genotypes, numbered 1 to 6. Genotypes are further classified into subtypes (a, b, c, etc.). The most widely distributed genotypes are 1 and 2, with genotype 1 the most common. In the United States, the majority of infections are caused by genotypes 1a and 1b, followed by genotypes 2 and 3. Although infection caused by any of the genotypes can lead to cirrhosis, end-stage liver disease (ESLD), or HCC, the significance of the infecting genotype is related to therapeutic response. Historically genotype 1 infections were least likely to respond to therapy, but with the release of protease inhibitor (PI) therapies, major advances in response are now possible. Genotypes 2 and 3 respond well to therapy; however, genotypes 4, 5, and 6 continue to pose a therapeutic challenge.

Pathophysiology

In the vast majority of cases, an acute HCV infection leads to chronic infection. The immune response in an acute HCV infection is mostly insufficient to eradicate the virus. The extent of hepatocyte apoptosis may correlate with the course of the disease. Liver damage and HCC are associated with high levels of hepatocyte apoptosis. Low levels of apoptosis are associated with viral persistence and may promote an environment conducive for other immune responses damaging to the liver. Although HCV infects less than 10% of hepatocytes, up to 20% of cells are activated for apoptosis.59

HCV poses a daunting challenge for immune control because of its rapid viral diversification. HCV genomic mutations are detectable within 1 year of infection. Resolved cases of HCV are defined by a vigorous T-cell response with highly active CD8 and persistent CD4 cell response. It is hypothesized that the CD8 activity mediates protective immunity but requires the aid of CD4 cells to maintain the response during viral mutations.59

Clinical Presentation

In an acute HCV infection, most patients are asymptomatic and undiagnosed. HCV RNA is detectable within 1 to 2 weeks of exposure and levels rise quickly during the initial weeks. The HCV RNA levels plateau at 105 to 107international units/mL (108 to 1010 international units/L) and precede a peak in ALT levels and the onset of symptoms. Rising ALT levels indicate hepatic injury and cell necrosis and may exceed values 10 times the upper limits of normal. Although HCV RNA serum levels can show interpatient variability, the levels tend to be stable for the individual patient.48 Typically, symptoms occur 7 weeks after the infection, with a range of 3 to 12 weeks. Approximately one-third of adults will experience some mild and nonspecific symptoms, including fatigue, anorexia, weakness, jaundice, abdominal pain, or dark urine.54 Acute infections rarely progress to fulminant hepatitis, although the course can be severe and prolonged. If the infection is self-limiting, symptoms last several weeks as ALT and HCV RNA levels subside. Almost all patients, including immunosuppressed patients, will develop antibodies to HCV. Typically, antibodies are not detectable until either at the time of or shortly after the development of symptoms, limiting their usefulness in diagnosing an acute infection.

Up to 85% of acutely infected patients will go on to develop a chronic HCV infection, defined as persistently detectable HCV RNA for 6 months or more. HCV RNA levels and ALT levels can fluctuate and even have periods of undetectable HCV RNA and normal ALTs. Most patients will have few, if any, symptoms. The most common symptom is persistent fatigue. Additional symptoms include right upper quadrant pain, nausea, or poor appetite. On physical examination, hepatomegaly is usually present. With advanced disease, stigmata of liver disease are evident, such as spider nevi, splenomegaly, palmar erythema, testicular atrophy, and caput medusae. However, almost all patients with chronic HCV will have some degree of necroinflammatory disease on liver biopsy. Chronic inflammation of the liver from chronic HCV infection may result in fibrosis. Fibrosis is defined by altered hepatic perfusion creating a distorted structure and affecting normal function.60 The speed of fibrosis progression can vary and is not necessarily predicative of cirrhosis development. An estimated 20% of chronic HCV patients will develop cirrhosis and half of those patients will progress to either decompensated cirrhosis or HCC. Historically, one-third of untreated patients may expect to develop cirrhosis within 20 years, while another third of patients may delay the onset of cirrhosis for 50 years or never develop it.

Viral load and genotypes other than genotype 3 are not factors for disease progression. Infection with genotype 3 may be associated with fibrosis progression.60 The development of HCV cirrhosis poses a 30% risk over 10 years for the development of ESLD, as well as a 1% to 2% risk per year of developing HCC.57 Progression to cirrhosis is the primary concern in patients infected with HCV for 2 decades or longer. Unfortunately, because acute infections are typically not recognized, the diagnosis of HCV is often not made until disease progression.

HCV is also rarely associated with extrahepatic manifestations. The most common is cryoglobulinemia, a local deposition of immune complexes that cause vasculitis. Typical manifestations involve the skin and internal organ damage, predominantly affecting the kidneys. Other, more rare symptoms include B-cell non-Hodgkin’s lymphoma, Sjögren’s syndrome, glomerulonephritis, arthritis, corneal ulcers, thyroid disease, neuropathies, and porphyria cutanea tarda.61

For many patients, a diagnosis of hepatitis C is incidental. Some patients are diagnosed after finding persistently abnormal transaminases. Unfortunately, those patients who present with symptoms typically have advanced disease. Due to the profound morbidity and mortality associated with HCV, the overall lack of awareness of the HCV epidemic, and the advances in treatment, the CDC recommends testing for HCV for anyone born between 1945 and 1965.62 Early diagnosis and treatment can prevent liver damage, cirrhosis, HCC, and death. The U.S. Preventative Task Force opposed routine screening in previous reports but released a preliminary draft of recommendations for screening of HCV in high-risk individuals and for clinicians to consider birth cohort screening.63

TREATMENT

Desired Outcome

The primary goal of therapy is to eradicate HCV infection. Resolving the infection prevents the development of chronic HCV infection sequelae including death. Even patients who are unable to achieve cure may see histologic improvements with therapy.57

General Approach to Treatment

Treatment for HCV is necessary because nearly 85% of acutely infected patients develop chronic infections and are at risk of developing cirrhosis, ESLD, and HCC. Moreover, HCV infection is the most common indication for liver transplant. Treatment is indicated for patients previously untreated who have chronic HCV, circulating HCV RNA, increased ALT levels, evidence on biopsy of moderate-to-severe hepatic grade and stage, and compensated liver disease.57 According to the AASLD, among chronic HCV patients, symptomatic cryoglobulinemia is an indication for HCV antiviral therapy irrespective of the stage of liver disease.57 Therapy is not without risk, and in some cases may not be recommended, such as in patients with decompensated liver disease, a history of severe uncontrolled psychiatric disorder, and in patients with severe hematologic cytopenias.57 Table 26-11 lists the contraindications to therapy.

TABLE 26-11 Contraindications to Hepatitis C Virus Combination Therapy

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Before therapy is initiated, quantitative HCV testing and genotyping are performed. A liver biopsy is also recommended.57 Quantitative amplification assays for HCV RNA are performed in patients who are candidates for therapy to obtain baseline information on the viral load. A baseline HCV RNA level serves as a prognostic indicator for response and is used to monitor virologic response once therapy is initiated. Genotyping is also necessary for treatment candidates because response to therapy and duration of therapy vary depending on the infecting genotype. Liver biopsy is used to determine histologic grade and stage and to guide therapy.57 Because most chronic HCV patients are not diagnosed for years, a biopsy can provide clinical information on the extent of hepatic damage incurred since infection and offer baseline data to assess disease progression.57 In some patients, liver biopsy may support a decision to delay treatment.

Adherence to therapy is a crucial component in response, especially among genotype 1–infected patients. Patients who take at least 80% of their medications for at least 80% of the treatment time are more likely to successfully respond to therapy.64 Treatment response is monitored according to the following terminology:

   1. Rapid virologic response (RVR): undetectable viral load at week 4 of treatment

   2. Extended rapid virologic response (eRVR): undetectable viral load at weeks 4 and 12 of therapy; used to evaluate response with telaprevir-based treatment regimens

   3. Early virologic response (EVR): a ≥2-log reduction in viral load by the 12th week of treatment (partial EVR) or a patient with undetectable viral load by the 12th week of treatment (complete EVR)

   4. End-of-treatment response (ETR): undetectable viral load at the end of treatment

   5. SVR: patient with no detectable viral load at the conclusion of therapy and 24 weeks later

   6. Early responder: used with boceprevir-based treatment regimens, a patient who has an undetectable viral load at week 8 of treatment

   7. Late responder: used with boceprevir-based treatment regimens, a patient who has an undetectable viral load at week 8 of treatment but subsequently an undetectable viral load at week 12 of treatment

   8. Relapser: patient who achieves an ETR but who has a detectable viral load after treatment is completed; person who fails to achieve an SVR

   9. Partial responder: a patient who achieves a ≥2 log drop in viral load but whose viral load never becomes undetectable

  10. Null responder: patient who does not achieve a ≥2 log drop in viral load at week 12 of therapy

  11. IFN sensitivity: refers to a >1 log decline after 4 weeks of peg-IFN and ribavirin lead in, as in boceprevir-based regimens; suggests a lower chance of resistance to treatment and an increased chance of successful therapy than in patients who experience a <1 log decline

Patients who achieve a RVR are highly likely to achieve cure; however, patients who do not achieve RVR should not be assumed to be nonresponsive. A negative RVR does not imply inability to achieve SVR; rather it indicates patients will require a full course of therapy and potentially an extended duration of therapy. Patients who experience a complete EVR are more likely to also have an SVR. Less than 3% of patients who fail to have an EVR can be expected to achieve an SVR.57 Achieving a complete EVR is a better marker of SVR than achieving a partial EVR.

Nonpharmacologic Therapy

All chronic HCV patients should be vaccinated against hepatitides A and B. Lifestyle changes are an important factor in reducing health consequences in hepatitis C. Continued alcohol use is a known risk factor for disease progression and severity. There is no established lower limit of alcohol consumption at which disease progression is not seen. Obesity is also a factor and patients should be encouraged to eat a balanced diet and exercise regularly to maintain a normal weight. Progression of fibrotic changes is associated with obesity. Moreover, obesity and decreased insulin resistance contribute to decreased response to IFN. Smoking may also contribute to disease progression. Marijuana smoking, especially daily use, is a risk factor for progression of liver disease in patients with HCV.65,66 Patients should be encouraged to maintain good overall health, stop smoking, and avoid alcohol and illicit drugs.57The use of herbal therapy is ineffective. Patients should consult with their physician prior to initiating any herbal therapies and minimize prescriptive drug use if possible.57

Pharmacologic Therapy

Images The treatment of chronic HCV was revolutionized with the approval of the PIs boceprevir and telaprevir in 2011 and marks the beginning of an era of direct-acting antiviral (DAA) agents in HCV therapy. The current standard of care for chronic HCV genotype 1 patients is a combination therapy of a once-weekly injection of peg-IFN, a daily oral dose of ribavirin, and either boceprevir or telaprevir. The PIs must be used in combination with peg-IFN and ribavirin to limit the development of resistance. Therapy is optimized with boceprevir and telaprevir dependent on viral response, the presence of cirrhosis, and previous treatment history. For all other genotypes, the standard of care remains peg-IFN and ribavirin. Table 26-12 lists current therapeutic regimens. For genotype 1, evaluation for RVR at 4 weeks is recommended as an indicator of the probability of achieving an SVR. Additionally, patients who are on treatment with boceprevir should be assessed for responsiveness to therapy at week 8, which corresponds to 4 weeks of boceprevir-based therapy after a 4-week lead in with peg-IFN and ribavirin. Treatment-naïve patients without cirrhosis on PI-based therapies may be treated for 24 weeks (telaprevir) or 28 weeks (boceprevir) if RVR is achieved. Patients who were previously treated, have cirrhosis, or who do not achieve RVR require longer durations of therapy.67 Current guidelines suggest patients with genotypes 2 and 3 be treated for the full 24 weeks of therapy. Patients with genotype 4 require a minimum of 48 weeks of therapy.57 A comparison of the use of the PIs in HCV management is found in Table 26-12.

TABLE 26-12 Recommended Hepatitis C Virus Treatment Algorithm

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Clinical Controversy…

Although ribavirin is dosed by patient weight for genotype 1 infections, many clinicians will dose adjust based on clinical response (decline in hemoglobin).

Interferon

Historically, treatment of HCV involved the use of IFN-alfa. Although IFN monotherapy resulted in an SVR in less than 10% of patients, the response was durable. The addition of a peg moiety to IFN improved the pharmacokinetic profile of the drug to reduce injection frequency from three times to once a week, and doubled SVR rates. Two peg-IFNs are available, peg-IFN alfa-2a (Pegasys) and peg-IFN alfa-2b (Peg-Intron). Table 26-13 lists the differences between the two drugs. Achievement of SVR may be more likely in patients with an early and intense viral suppression. The current guidelines do not address which formulation of IFN should be preferentially used in HCV treatment.

TABLE 26-13 Pegylated Interferon Comparison

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Ribavirin

Ribavirin, a synthetic guanosine analog, is ineffective as a monotherapy for HCV and its exact mechanism of action is unknown. When added to IFN, ribavirin significantly increases SVR rates, especially among genotypes 2 and 3. Ribavirin is dosed based on weight for optimal response in genotype 1 and 4 infections. Although monotherapy with peg-IFN is an option for patients with contraindications to ribavirin, ribavirin is ineffective as monotherapy and should not be used alone.57

Protease Inhibitors: Boceprevir and Telaprevir

Boceprevir and telaprevir, both inhibitors of the NS3/4A serine protease, demonstrated profound HCV inhibition when combined with peg-IFN and ribavirin for genotype 1 infections. Their approval in 2011 changed the standard of care for the treatment of HCV genotype 1 infections to include either one of the agents in combination with peg-IFN and ribavirin (Table 26-14).67 Neither boceprevir nor telaprevir should be used as monotherapy because each PI rapidly selects for HCV-resistant mutants. Similarly, neither PI should be dose adjusted during treatment. Both PIs have multiple drug interactions involving the cytochrome P450 (CYP) system (CYP2C, CYP3A4, or CYP1A).67 The package insert lists known interactions; however, there are many unknown and theoretical interactions. Pharmacy can play an integral role in evaluating the potential for clinically significant drug interactions.

TABLE 26-14 Comparison of Protease Inhibitors in HCV Therapy

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Boceprevir Boceprevir is used in therapy after an initial 4-week lead in with peg-IFN and ribavirin. The drug is dosed at 800 mg every 8 hours. The SPRINT-2 trial of boceprevir with peg-IFN and ribavirin showed markedly improved SVR rates in treatment-naïve white patients as compared with peg-IFN and ribavirin (63% to 66% vs. 38%).68 The study also demonstrated the efficacy of response-guided therapy (RGT) that allows patients to complete a total of 28 weeks of therapy if HCV viral load is undetectable at week 8 (corresponding to week 4 of boceprevir therapy) and at week 24. Patients with fibrosis and cirrhosis have lower SVR rates and benefit for longer durations of therapy; they are not candidates for RGT. Previously treated patients also benefit from retreatment with high SVR rates in prior relapsers (75%) and partial responders (52%) with 48 weeks of therapy. Null responders were not enrolled in the boceprevir trials but are likely to experience minimal benefit based on data from the telaprevir studies.69,70 Given the toxicities and costs of therapy as well as concerns for resistance, futility rules for boceprevir exist that assess patient response at weeks 12 and 24 to identify patients who are likely experiencing viral rebound and are therefore unlikely to achieve SVR.71

Telaprevir Telaprevir is used in the initial 12 weeks of treatment in conjunction with peg-IFN and ribavirin at a dose of 750 mg every 8 hours and must be taken with 20 g of fat for adequate absorption. The SVR rate in treatment-naïve patients was 75% as compared with 44% in patients treated with peg-IFN and ribavirin. Treatment-naïve patients who achieve an eRVR are treated for a duration of 24 weeks and can expect SVR rates of >80%.72 Relapsers and partial responders also fared well when re-treated with a telaprevir-based regimen with SVR rates of 83% and 59%, respectively, when treated for a combined total of 48 weeks of therapy. The telaprevir trials did enroll previous null responders and the benefit of retreatment was significantly reduced with SVR rates at 29%.73 Patients with fibrosis and cirrhosis should be treated for a total of 48 weeks of therapy.67

Images Side effects of therapy are extensive and a major obstacle to successful patient completion of therapy (see Tables 26-15 and 26-16). The most common laboratory abnormalities are neutropenia, thrombocytopenia, and anemia. Ribavirin-induced hemolytic anemia is an inevitable effect of therapy, although varying in severity among patients. Anemia results from ribavirin uptake into erythrocytes, inducing membrane damage and resulting in hemolysis. Patients may complain of fatigue as hemoglobin levels decrease even though dose reductions are not recommended until hemoglobin levels fall to 10 g/dL (100 g/L; 6.21 mmol/L). The mean decrease in hemoglobin is 3 g/dL (30 g/L; 1.86 g/L) in the initial weeks of therapy; thereafter, levels stabilize until discontinuation of therapy. Hemoglobin levels normalize once ribavirin is stopped. Ribavirin-induced anemia is exacerbated by PI therapy. Initial clinical experience with telaprevir included profound anemia requiring blood transfusion. IFN can cause bone marrow suppression, resulting in neutropenia and thrombocytopenia. Peg-IFNs are more likely to cause neutropenia than non–peg-IFN. Dose reductions are recommended for neutrophil counts <750 cells/mm3 (<750 × 106/L); discontinuation is recommended at <500 cells/mm3 (<500 × 106/L). Risk for infection is unclear. Neither nadir neutrophil counts nor total neutrophil decrease from baseline is related to infection. One study examined the risk for total, viral, fungal, and bacterial infections and concluded that neither dose reductions of IFN nor the addition of granulocyte-stimulating factor in HCV-treatment-induced neutropenia is warranted.74

TABLE 26-15 Common Side Effects of Therapy

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TABLE 26-16 Common Laboratory Abnormalities of Therapy

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Up to one-third of patients are expected to experience some degree of depression during treatment, partly because of IFN’s interference with the serotonin pathways.57 Although many patients can be managed with selective serotonin reuptake inhibitors, various degrees of counseling and psychiatric consultations may be necessary. Severe depression and suicidal behaviors are rare but documented. More common side effects include flu-like symptoms, which can be managed by acetaminophen or nonsteroidal inflammatory drugs. Rash is common; serious rashes and death have occurred with telaprevir.

Special Populations

Clinical trials are conducted with a patient population that generally does not reflect the patient spectrum encountered in clinical practice. There are no contraindications to the treatment of IDUs, prisoners, persons with substance abuse issues, or persons with psychiatric disorders. However, barriers exist that can prevent access to care. A multidisciplinary approach to HCV treatment that includes mental health and substance abuse professionals and pharmacy should be considered in providing care to special populations.75

Published recommendations for treatment in various populations are as follows.57

Patients with Normal ALTs The decision to treat patients with normal ALTs is somewhat controversial and made on an individual patient basis. Clinicians should consider the risks and benefits of therapy, including histologic data, genotype, likelihood for response, and other factors, such as patient willingness to undergo therapy. Successful treatment significantly improves patient quality of life and reduces fatigue.76

Patients with Decompensated Cirrhosis Patients with evidence of decompensation are candidates for liver transplantation. Therapy is generally not recommended unless administered by experienced clinicians. Serious adverse events including neutropenia and anemia are more likely in cirrhotics and may be managed through the use of growth factors.


Clinical Controversy…

In patients with advanced disease, a biopsy may be risky and offer no additional clinical information of whether to treat or not. Some clinicians believe that if therapy is to be initiated regardless, the liver biopsy offers no additional information.

Histologic improvement is not limited to patients who experience an SVR. Some clinicians believe IFN-based antiviral therapies, regardless of response, can decrease the incidence of HCC development.

Although ribavirin dosing is different for the treatment of genotype 1 depending on the formulation of peg-IFN, most clinicians will dose ribavirin according to patient weight, irrespective of the formulation.

Treatment-Experienced Patients The decision to re-treat genotype 1–infected patients should consider the previous response. Retreatment with a PI-based therapy is recommended in patients who had a virologic relapse or were partial responders with a previous course of therapy that included IFN, peg-IFN, and/or ribavirin. Patients with a prior null response to a previous course of therapy may be considered for retreatment.67

Accidental Needle-Stick Exposures Prophylactic treatment immediately following an accidental needle-stick exposure is not recommended for multiple reasons. Risk of transmission is considered low and among those infected, a percentage will successfully seroconvert and not require treatment. Because an initial delay in therapy does not increase the risk for developing a chronic infection, most experts wait 8 to 12 weeks before initiating treatment to allow for spontaneous remission. No formal guidelines exist as the optimal duration of treatment is unknown. Treatment is suggested for 12 to 24 weeks.

Injection-Drug Users Injection-drug use is a major factor in the cycle of HCV transmission. There are no recommendations against treatment for active IDUs, although ongoing drug abuse can create many complications and expert opinion dictates that the decision to treat be made on a case-by-case basis. Treatment is recommended for recovering drug users, including those in drug treatment programs, assuming patients are willing to comply with close monitoring and contraception requirements. Reinfection rates are low among IDUs who achieve SVR.77 It is recommended that patients continue ongoing drug abuse and psychiatric counseling while on HCV therapy.

Alcoholism Because continued alcohol use affects disease progression and severity and thus response to therapy, the cessation of alcohol use during therapy is recommended. Moreover, a period of abstinence before initiation of therapy is also recommended.

End-Stage Renal Disease The role of chronic HCV treatment is not defined for patients with end-stage renal disease. Hemodialysis is a risk factor for acquiring HCV infection yet a contraindication for ribavirin use. Patients with mild renal insufficiency (GFR ≥60 mL/min [≥1 mL/s]) may be treated with combination peg-IFN and ribavirin. Monotherapy with IFN is an option in patients with renal insufficiency or with end-stage renal disease as ribavirin is contraindicated in these patients due to risks of ribavirin accumulation and severe hemolytic anemia. Peg-IFN can pose toxicity problems and requires careful monitoring.

HIV Coinfection Current guidelines do not recommend treatment for HIV–HCV coinfection with the PIs; however, trials are ongoing.67 A large portion of HIV-infected patients who acquired the virus via injection-drug use will be coinfected with HCV. The PIs have multiple drug interactions, including with many of the drugs used in HAART. Treatment poses additional problems because of hepatotoxicity issues associated with HAART, hepatic complications from HIV-associated diseases, as well as flares in hepatitis as CD4 counts recover. Current guidelines recommend a 48-week course of therapy regardless of genotype with peg-IFN and ribavirin only. The prognosis for an SVR is worse than in patients infected with HCV only. In general, treatment is recommended and both HIV and HCV therapies can be coadministered with the exception of didanosine and zidovudine. The combination of ribavirin and didanosine can result in fatal lactic acidosis. Ribavirin causes hemolytic anemia and when combined with zidovudine can result in severe anemia.78

Children Currently therapy is indicated for children aged 2 years and older and consists of peg-IFN-alfa dosed at 60 mcg/m2 weekly in combination with ribavirin 15 mg/kg daily for 48 weeks. Ribavirin is available in a liquid formulation. Pediatric patients tend to better tolerate therapy than adults. They should be evaluated as candidates for therapy similarly to the criteria for adults (Table 26-12).

African Americans Response rates of African Americans to HCV therapy are lower than rates observed with whites and non-Hispanic whites, and genetic mutations of HCV may partially explain the discrepancies. African Americans have higher rates of chronic HCV than non-Hispanic whites and Hispanics and have greater rates of baseline neutropenia. African Americans with HCV should be evaluated for treatment and treated according to current guidelines.

Prevention

No vaccine is available for HCV. It is unlikely that a vaccine will be developed in the near future because of the mutagenesis of the virus. Patients infected with HCV should be counseled on not being blood, organ, or semen donors. Although the likelihood of household transmission is small, patients should minimize risks by avoiding possible blood or mucus exposure, such as not sharing razors or toothbrushes and covering open wounds. Patients who continue to use illegal drugs should avoid sharing all drug paraphernalia, as risk of transmission is not limited to needles and syringes.

PERSONALIZED PHARMACOTHERAPY

It is currently not possible to definitively identify patients at risk for disease progression.60 Several factors may correlate with a decreased risk for chronicity and include host, virus, and environmental factors. Important host factors that minimize the risk of developing chronic infection include being younger than 40 years old, female, non-black, not immunosuppressed, and with a symptomatic acute HCV infection. Being older than age 20 years at infection triples the risk for chronic HCV. Blacks, especially black men, are more likely to develop chronic infection and have lower treatment responses.57 Becoming symptomatic and having jaundice is associated with a lower likelihood of chronic infection, perhaps correlating to a stronger immune response to the acute infection. Finally, immunosuppressed patients, such as those with HIV, are more prone to chronic infection, although they are not inherently unable to clear the infection.57 Similarly, disease progression is associated with increased age, male sex, continued alcohol intake, obesity, and HIV coinfection. Diabetes, as well as steatosis, may also potentiate fibrosis progression.

Variation on a gene encoding for endogenous IFN, IL28, has been described that is associated with a difference in response to treatment and may explain differences in response between patients of African American and European ancestry.53 Patients who have the CC genotype have higher rates of spontaneous clearance and higher rates of cure than patients who have IL genotype CT or TT.53 The PI-based therapies demonstrated the ability to overcome differences in IL28 genotypes due to the potent antiviral effects of the PIs. Nonetheless, IL28 variants may affect decisions on choice and duration of therapy.79

Ribavirin-induced anemia can affect dosing strategies and is likely related to polymorphisms of the ITPA gene. The exact mechanism is not fully understood and the clinical relevance is not clear.79

ABBREVIATIONS

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