US Pharm. 2006;6:HS-5-HS-14.     

Hepatitis B virus (HBV) infection is a worldwide concern. An estimated 350 million people are chronically infected with HBV, a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.1 These complications of chronic hepatitis B infection lead to approximately 500,000 deaths worldwide annually.2 In the United States, there are an estimated 1.25 million hepatitis B carriers; of this group, 15% to 40% will develop serious hepatic complications during their lifetime.3 This article reviews several aspects of chronic hepatitis B, including pathogenesis of HBV, available treatment options, and implications for antiviral therapy.

Epidemiology
Although individuals with chronic hepatitis B infection live in all parts of the world, HBV is especially endemic in such areas as southeast Asia, China, and Africa, where more than half of the population is infected at some time in their lives and more than 8% are chronic carriers of the virus.1 In such high-prevalence areas, most infections are acquired at birth as a result of perinatal transmission or during early childhood as a result of transmission through open cuts and sores from one child to another. Areas with low prevalence of hepatitis B infection include North America, western Europe, and Australia, where the infections occur as a result of horizontal transmission among young adults.1 HBV infections in developed countries usually result from sexual activity, intravenous (IV) drug use, or occupational exposure. Other risk factors for acquiring HBV in low-prevalence areas, such as the U.S., are listed in table 1. HBV can survive outside the body for a prolonged period of time, and carriers of the virus can shed large quantities of viral particles through open cuts or sores.3 Since HBV is present in serum in large quantities, the virus can also be detected in semen, saliva, and cervical secretions. The risk of developing chronic HBV infection after HBV exposure ranges from 90% in infants and children, possibly due to their immature immune system, to less than 10% in immunocompetent adults. Immunocompromised adults are likewise at higher risk for developing chronic HBV infection after acute exposure.




Pathophysiology
Virology: HBV is a partially double-stranded DNA virus belonging to the Hepadnaviridae family.2 Hepatitis B surface antigen (HBsAg) coats the surface of HBV and is the major viral protein in both acute and chronic infection, as well as in chronic carriers. Hepatitis B core antigen (HBcAg) is the nucleocapsid that encloses viral DNA. The immune response crucial for killing infected hepatocytes requires HBcAg-derived peptides to be expressed on the surface of the liver cells. Hepatitis B e antigen (HBeAg) is a circulating peptide derived from the core gene antigen and exported from the hepatocytes. HBeAg is a marker of active viral replication, and therefore, is present only in individuals with circulating serum HBV DNA. The understanding of the HBV life cycle has important implications for drug therapy of chronic hepatitis B infection. The HBV polymerase is both an endogenous DNA polymerase and a reverse transcriptase involved in the synthesis of negative DNA strands from genomic RNA. Therefore, several reverse transcriptase inhibitors are currently utilized for treatment and prevention of chronic hepatitis B.

Transmission and clinical features: HBV is transmitted by the exposure of mucous and percutaneous membranes (e.g., through accidental needle stick) to infectious blood and body fluids. 1 Common routes of exposure are sexual intercourse, IV drug abuse, and perinatal transmission from infected mother to child. After HBV exposure, the incubation period is long and variable, ranging from 45 to 160 days. In most circumstances, HBV is not cytotoxic (i.e., it does not kill liver cells). It is the host immune response to the presence of HBV antigen that leads to the destruction of the liver cells and subsequent liver disease.1,2 Clinical signs and symptoms of acute HBV infection occur more often in adults than in infants or children. Despite active viral replication, less than 10% of children and only 30% to 50% of adults with acute HBV infections will have symptomatic disease. Most acute HBV infections in adults result in complete recovery. Only 1% of patients with acute HBV infection develop fulminant hepatic failure, and an average of 5% of adults with acute HBV infection develop chronic infections.1

The clinical presentations associated with chronic HBV encompass a wide spectrum of signs and symptoms, ranging from an asymptomatic carrier state to chronic hepatitis, in which patients experience complications associated with liver cirrhosis or hepatocellular carcinoma. Chronic hepatitis may progress to end-stage liver disease in approximately 15% to 40% of patients, and the risk of hepatocellular carcinoma in patients with chronic hepatitis B is 100 times higher than that of noncarriers.4 In patients with chronic hepatitis B whose condition has progressed to end-stage liver disease, chronic occurrence of jaundice and enlarged liver with elevated alanine aminotransferase (ALT) levels are typical features of the disease. Chronic hepatitis B involves an early replicative phase with active liver disease and a late phase with low or undetectable levels of viral replication and remission of liver disease. The four types of chronic hepatitis B infection are described in table 2.




Diagnosis and serology: Chronic hepatitis B infection is defined as hepatic inflammation due to the presence of HBV.3 Chronic infections are divided into HBeAg-positive and HBeAg-negative subgroups. Diagnosis is made when a positive detection of HBsAg is made in a patient on at least two occasions in a six-month period, with the presence of HBV DNA with serum levels greater than 100,000 copies per mL.3 Liver enzyme levels are either persistently or intermittently elevated over periods of six months or longer. Inactive carrier state is defined as persistent HBV infection without inflammation of the liver.3 Patients determined to be in an inactive carrier state are HBsAg-positive for greater than six months, HBeAg-negative, and HBeAg antibody-positive (anti-HBe). They also have undetectable serum HBV DNA and normal liver enzyme levels.

HBsAg can be detected from as early as week 1 after an acute infection and may remain present until resolution of the infection.2 Detection of HBsAg indicates that a person is infectious. Shortly after the presence of HBsAg, antibodies to hepatitis B surface antigen (anti-HBs) can develop and persist for years and confer immunity if a person is reinfected. HBeAg is a marker of viral replication detectable early in the acute phase that persists in chronic HBV infection. However, 20% to 30% of patients in an inactive carrier state (HBeAg-negative and anti-HBe-positive) experience reactivation of HBV replication and have elevated ALT and high HBV DNA levels, known as HBeAg-negative chronic hepatitis.5 Most of these patients harbor HBV variants in the precore or core promoter region, which abolish or decrease the production of HBeAg.3 The presence of both HBsAg and HBeAg suggests high levels of viral replication. HBcAg causes the development of hepatitis B core antibodies (anti-HBc), which appear one to two weeks after the presence of HBsAg. HBcAg does not freely circulate in the blood and therefore is not measured. Instead, the detection of immunoglobulin M anti-HBc is the most sensitive diagnostic test for acute HBV infection. During the recovery phase of the infection, immunoglobulin G is the predominant form of anti-HBc. Since anti-HBc does not develop in patients immunized against HBV, the detection of this antibody can distinguish infection from vaccination. Interpretation of the hepatitis B panel is found in table 3.




Treatment
Despite major progress in the last decade, available therapeutic options for chronic hepatitis B have limited long-term efficacy. Careful consideration of a patient's age, severity of liver disease, and likelihood of response is crucial in treatment success. Current treatment guidelines6 recommend treating patients with elevated ALT and high HBV DNA levels, whereas patients who are HBeAg-negative and have low HBV DNA and persistently normal ALT levels for more than six months are considered inactive carriers and are rarely treated. There is a 20% to 30% likelihood of HBV reactivation in inactive carriers during long-term follow-up. Treatment is recommended in patients who are HBeAg-negative and anti-HBe–positive and have elevated ALT levels and high HBV DNA detected in serum. In addition, treatment is not recommended for HBeAg-positive patients with high HBV DNA levels but normal ALT and minimal liver inflammation found on liver biopsy; in these patients, the likelihood of treatment-related seroconversion from HBeAg to anti-HBe is similar to that of patients not receiving treatment.5

The goals of therapy for chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease, leading to prevention of cirrhosis, liver failure, and hepatocellular carcinoma.5 The treatment response is assessed through normalization of ALT level, undetectable HBV DNA, loss of HBeAg, and improvement of liver histology. Complete response is defined as the decline of liver enzymes to normal range, seroconversion of HBeAg to anti-HBe, virologic response, and loss of HBsAg. For HBeAg-negative patients in whom seroconversion from HBeAg to anti-HBe cannot be used as an end point to assess response to therapy, undetectable serum HBV DNA and normalization of ALT level are used to define response. There are four FDA-approved antiviral drugs for the treatment of chronic hepatitis B infection--interferon (IFN), lamivudine, adefovir, and entecavir (table 4). In addition, there are several promising new therapeutic options currently in clinical trials. In general, high pretreatment ALT level is the most consistent factor associated with increased likelihood of seroconversion for drug therapy. Although indications for treatment are largely based on ALT levels, histologic assessment in patients with normal or mildly elevated ALT levels also has an important role in treatment decisions, as many of these patients show evidence of advanced hepatic disease on liver biopsy.5




Interferon: IFN is an endogenous cytokine that induces the immune system to exert antiviral activity. Various recombinant forms are currently available for the treatment of chronic hepatitis B. IFN was the first effective therapeutic option in both HBeAg-positive and HBeAg-negative chronic hepatitis B.7 In addition, IFN is the only medication that has been proven to reduce and eliminate HBV infection in patients with chronic hepatitis B and has not been associated with viral resistance.8,9 IFN alfa-2b (Intron-A) has been approved for the treatment of chronic HBV infection throughout the world, including adults and children in the U.S., whereas IFN alfa-2a (Roferon) and IFN alfacon-1 (Infergen) are not approved for this indication, although these drugs may also be used to treat HBV infection.10 The dosing for the different forms of conventional IFN ranges from 15 million to 35 million units per week, and dosing for new pegylated forms of IFN alfa-2a (Pegasys) is 180 mcg weekly. Conventional IFN is administered subcutaneously or intramuscularly daily or three times per week, and pegylated forms are administered once weekly. The most common side effects of IFN include flu-like symptoms, fatigue, irritability, depression, and bone marrow suppression.11 In addition to low HBV DNA concentration of 200 pg/mL, high pretreatment ALT level is also a reliable predictor of a positive response to IFN. Liver injury and elevated ALT concentrations are due to active host immune response to viral infection, and IFN requires cell-mediated immune responses to exert antiviral immunoregulatory activities by augmenting the host immune system.

Early controlled studies showed that a four- to six-month course of IFN alfa achieved seroconversion from HBeAg to anti-HBe in 33% of patients with chronic hepatitis B, compared to 12% of untreated controls.12 The responses after IFN alfa, including normalization of ALT, appeared to be durable in the majority of these patients. IFN alfa treatment of chronic HBV has also been reported to reduce the risk of hepatocellular carcinoma.13 Pegasys and PEG-Intron (IFN alfa-2b), pegylated forms of IFN, have been used in phase III trials, and Pegasys is now FDA approved for chronic hepatitis B. A large phase III trial of pegylated alfa-2a in HBeAg-negative patients showed a significant rate of sustained viral suppression that was better than lamivudine alone but was not improved by the addition of lamivudine.9 The factors predictive of sustained response to IFN alfa are low pretreatment HBV DNA levels, high ALT levels, and active liver disease demonstrated by liver biopsy.3 High pretreatment ALT level appears to be the most important factor associated with sustained response.5

The major drawback of IFN alfa is the side effects from which many patients experience difficulty with the therapy (table 5). Approximately one third of patients treated with IFN alfa may require dose reduction, and up to 5% may discontinue the therapy due to adverse events. 14 The adverse events associated with the drug also lead to poor drug adherence and intermittent discontinuation. Up to 40% of patients treated with IFN reportedly developed IFN-induced depression and other psychological disturbances. Depressive symptoms, anxiety, and irritability may persist throughout the course of IFN treatment and for a few weeks after cessation of therapy.3 Patients with advanced cirrhosis usually have leukopenia and thrombocytopenia that can be exacerbated by the drug. In addition, many patients experience flare of liver disease during the administration of IFN alfa, and though this may be a marker of enhanced responsiveness to the therapy, many patients do not tolerate this drug-induced exacerbation of liver disease.2 Treatment with IFN is generally contraindicated in decompensated liver disease, since flares in these cases may precipitate overt liver failure.2 Other contraindications for IFN therapy include ongoing alcohol or drug abuse and autoimmune disease.




Lamivudine: Lamivudine, introduced for the treatment of chronic hepatitis B infection in the late 1990s, is a nucleoside analogue with potent activity against HBV. Lamivudine exerts its antiviral activity by inhibiting viral DNA polymerase activity. Lamivudine is a safe drug with rare and usually mild side effects. Dosing adjustment is recommended in patients with renal impairment. In general, treatment with lamivudine at a daily oral dose of 100 mg results in normalization of aminotransferase in about 70% of patients, about a 90% decrease in baseline HBV DNA, and about a 15% higher rate of seroconversion compared to placebo.15 HBeAg seroconversion after the cessation of lamivudine has been reported in 70% to 90% of patients in Western countries and 38% to 83% of patients from southeast Asia.16,17 In addition, significant reduction of progression of the liver disease, as shown in biopsy, was shown in lamivudine-treated patients compared to placebo.

Advantages of lamivudine therapy include its low side-effect profile and its relatively low cost. The main disadvantage of lamivudine is the frequent emergence of viral resistance due to mutations within the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV polymerase gene.18 Clinical presentation of viral resistance is expressed by the reappearance of serum HBV DNA after an initial clearance of viremia. This virologic breakthrough usually develops after the first six months of lamivudine monotherapy, and the rate of resistance increases progressively throughout the continued therapy, ranging from 15% to 30% at 12 months to over 50% after three years and over 70% after five years.19-22 Moreover, the emergence of this resistance has been shown to be associated with a lower likelihood of seroconversion, and eventually, a negative impact on liver histology. Another disadvantage of lamivudine therapy is that optimal duration of therapy is unknown.23 A three-year course of effective lamivudine therapy resulted in virologic and biochemical relapses in the majority of HBeAg-negative patients.10 The disadvantage of all oral agents for HBV infection, including lamivudine, is low rate of durability of response after the cessation of therapy, which occurs at less than 50%, especially in HBeAg-negative patients treated with lamivudine who relapse after discontinuation of therapy in almost all cases.

Adefovir: Adefovir is a nucleotide analogue approved for the treatment of HBeAg-negative and HBeAg-positive liver disease, including the lamivudine-resistant mutant. Adefovir is an oral prodrug that undergoes two intracellular phosphorylations to become an active moiety and also elicits its antiviral activity by inhibiting the viral polymerase. Adefovir was initially developed as a reverse transcriptase inhibitor of HIV but was found to be nephrotoxic at the dosage required for inhibition of HIV replication.2 In lower doses (10 mg daily), however, adefovir was shown to be potent against HBV, including the lamivudine-resistant HBV, with low a rate of nephrotoxicity. Although renal toxicity due to adefovir is rare, monitoring of creatinine is recommended with adefovir therapy, especially with coadministration of nephrotoxic medications. Dosing adjustments are also recommended for patients with reduced renal function and for those requiring hemodialysis.

In clinical trials, patients treated with adefovir 10 mg daily experienced significantly greater reductions in HBV DNA and ALT compared to placebo. Adefovir was also found to be effective in patients who had not responded to lamivudine therapy.24 In this study, 67% of patients treated with adefovir had improvements in liver histology and no worsening of fibrosis, compared to 19% of patients on placebo. Adefovir was generally well tolerated and had a safety profile similar to placebo. In long-term therapy with adefovir in HBeAg-negative patients, benefits were maintained in patients treated for 144 weeks with infrequent emergence of viral resistance.25 To date, resistance has been seen in 5.9% of patients at three years and 18% at four years. Combination therapy with lamivudine does not appear to be beneficial in treatment-naïve patients or those with lamivudine resistance.

Entecavir: Entecavir is a nucleoside analogue with potent activity against HBV. It inhibits HBV replication at three different points: priming of HBV DNA, reverse transcriptase of the negative DNA strand from genomic RNA, and synthesis of the positive strand of HBV DNA.26 Entecavir is an oral drug that is FDA-approved for the treatment of HBV, with dosing at 0.5 mg daily in treatment-naïve patients and 1 mg daily in lamivudine-treated patients. Entecavir is generally well tolerated with a low side-effect profile. Dose adjustment is recommended in patients with renal dysfunction.

In a 96-week study comparing entecavir with lamivudine in HBeAg-positive chronic hepatitis B patients, 82% of entecavir-treated patients maintained their response 24 weeks after discontinuation of treatment, compared with 72% of the lamivudine-treated patients.27 At 96 weeks of treatment, 80% of the entecavir group had undetectable HBV DNA compared with 39% of the lamivudine group. In a two-year resistance study reported for entecavir, the development of entecavir resistance was shown to require preexisting lamivudine resistance substitution. 28 The one-year entecavir treatment showed no resistance in nucleoside-naïve patients and 1% resistance in patients with lamivudine resistance prior to treatment. By two years of entecavir treatment, 10% of patients with prior lamivudine resistance developed resistance to entecavir, but none of the treatment-naïve patients showed evidence of entecavir resistance.

New emerging therapies for chronic hepatitis B infection: Approved treatments for chronic hepatitis B are limited by low rates of sustained response, toxicities, or resistance. There are several new agents currently under development for the management of chronic HBV to address the need for more potent antiviral effects, fewer adverse events, and minimal or no risk for drug resistance. Clevudine is a nucleoside analogue with a long half-life currently in phase III clinical trials for chronic hepatitis B infection.29 Reported findings from these trials demonstrated that clevudine is a potent inhibitor of HBV in both HBeAg-positive and HBeAg-negative patients.30,31  However, in vitro studies suggest that clevudine is ineffective against lamivudine-resistant HBV.

Telbivudine is another nucleoside analogue currently in phase III clinical trials for treatment of chronic hepatitis B. Data from a 76-week study showed greater potency with telbivudine compared to lamivudine, but telbivudine did not confer activity against lamivudine-resistant HBV.32  

Tenofovir is a reverse transcriptase inhibitor effective against HBV, including the lamivudine-resistant HBV.29 Recently published data suggest that tenofovir may be more potent than adefovir.33

Liver transplantation: For patients with end-stage liver disease due to chronic hepatitis B infection, transplantation is an option. To prevent reinfection of transplanted liver, hepatitis B immune globulin (HBIG) is administered immediately after transplantation, which decreases the long-term reinfection rate by half and extends the two-year survival rate from 50% to 80%. The addition of lamivudine to HBIG further reduces the reinfection rate to about 10% and increases the five-year rate of infection-free survival to approximately 80%. HBIG, however, is very expensive and substantially increases the cost of liver transplantation in patients with chronic hepatitis B infection.

Role of the Pharmacist
Chronic hepatitis B infection continues to pose a serious public health problem. Several therapeutic options are currently available for the treatment of chronic HBV, and new emerging treatments for HBV continue to be studied to further advance the therapeutic outcome of the disease. Pharmacists in direct care of patients with chronic HBV should be monitoring for appropriateness of drug therapy and adverse events associated with drug treatment. Especially for patients on IFN alfa therapy, monitoring of lab values and observation for other side effects are crucial in drug adherence and treatment success. Pharmacists should counsel patients with chronic hepatitis B infection on immunization, avoiding hepatotoxic drugs and dietary supplements, including alcohol and herbal medications, and prevention of HBV transmission, including avoiding high-risk sexual activities and IV drug abuse. Patients who have been newly diagnosed with chronic hepatitis B should be encouraged to be tested for HIV, as this may have an important implication on drug therapy and viral resistance. Appropriate dose adjustment recommendations should be made when necessary, and drug information on other therapeutic options should be readily available by pharmacists. Pharmacists who are in direct contact with select population groups that should be screened for HBV infection (e.g., persons born in endemic areas and IV drug users) should be diligent in providing information on the disease and therapeutic options available.

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