New Strategies in the Treatment of Hepatitis B

Introduction

Despite the introduction of a successful, commercially available vaccine in late 1981, hepatitis B virus (HBV) infection remains an important public health concern worldwide. Endemic in Asia, the South Pacific, Africa, South America, Eastern Europe, the Arctic, and the Middle East,[1] chronic HBV infection is estimated to affect 400 million individuals globally[2] and 1.25 million individuals in the United States.[3]

Of those with chronic infection, 15% to 40% will go on to develop serious sequelae, including cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[1] HBV-related liver disease and HCC account for over 1 million deaths annually and 5% to 10% of cases of liver transplantation.[4] Without transplantation, 5-year mortality among those with cirrhosis reaches approximately 16% and is as high as 65% to 86% in patients with hepatic decompensation.[5-7] The mortality rate of HCC is even more dismal, reported to be approximately 95% without transplantation.[8]

Recent studies have demonstrated that the risk of developing cirrhosis and HCC correlates directly with a patient's level of serum HBV DNA.[9-10] Multiple therapeutic agents currently available demonstrate potent and durable activity against HBV, resulting in undetectable levels of HBV DNA in a majority of patients. For this reason, early detection and treatment of HBV infection is important in preventing long-term complications and decreasing mortality.

Current therapeutic options fall into 2 classes: (1) nucleos(t)ide analogs that directly inhibit HBV DNA replication; and (2) interferon-based therapies that modulate host immune response and also inhibit viral replication. Hepatitis B treatment is evolving rapidly, with 3 antiviral agents having received US Food and Drug Administration (FDA) approval only in the last few years. This clinical update focuses on the key issues and evidence involved in the decision of when and how to initiate appropriate treatment and when to stop or alter it.

Natural History of Hepatitis B Infection

Chronic hepatitis B infection can be divided into 4 distinct phases: (1) the immune-tolerance phase; (2) the immune-clearance or immune-active phase; (3) the inactive carrier phase; and (4) reactivation. Clinical course is variable, however, and not all patients will experience every phase of infection.[11] See Figure 1.

Figure 1. Schematic of different phases of HBV infection.

The immune-tolerance phase is a latent period that typically occurs in individuals from HBV-endemic areas, where infection is most often acquired at birth or during early childhood. Due to incomplete development of the immune system at the time of infection, there is minimal host response to HBV despite high rates of viral replication. As a result, liver inflammation is minimal or absent. Liver disease is rarely progressive during this period and treatment is not effective.[12,13] In this phase, serum HBV DNA is elevated, hepatitis B e antigen (HBeAg) is present, and alanine aminotransferase (ALT) levels are normal. The immune-tolerance phase can last for as long as 2-3 decades.[13]

In most patients, a more vigorous cytotoxic T-cell response eventually occurs, heralding the immune-clearance phase. Viral replication remains high, and apoptosis and necrosis of hepatocytes occur, leading to elevated serum ALT, liver inflammation, and fibrosis. HBeAg seroconversion can occur during this period, resulting in the appearance of antibodies to HBeAg (anti-HBe) and suppression of viral replication.[14]

In nonendemic areas such as the United States, HBV infection is most often acquired during adulthood, when the immune system is fully constituted. In these areas, the immune-tolerance phase is therefore very short or nonexistent, and immune clearance occurs shortly after infection.[15]

HBeAg seroconversion is usually followed by clinical remission (the inactive carrier phase). This is characterized by normal serum ALT, low HBV DNA, and improvement in liver histology.[12] Treatment is therefore not indicated in this patient group. A minority of inactive carriers will eventually lose hepatitis B surface antigen (HBsAg), resulting in resolution of infection.[16]

Conversely, it is not uncommon for patients in the inactive phase to experience reversion to HBeAg positivity or reactivation of disease, either spontaneously or as a result of immune suppression (eg, chemotherapy).[16] This is likely due to the integration of HBV DNA into hepatocyte DNA in the form of covalently closed circular DNA (cccDNA). This can occur despite low or undetectable levels of serum HBV DNA and explains why inactive carriers are still at risk for the development of HCC.[17]

In addition, approximately one third of inactive carriers go on to develop HBeAg-negative chronic hepatitis B.[18-19] In these patients, mutations in the precore or core promoter regions of viral DNA result in downregulation of HBeAg production despite ongoing viral replication.[20] As a result, high levels of HBV DNA and increased serum ALT are seen even though HBeAg is absent. This mutation occurs most frequently in patients with viral genotypes B, C, and D.[21] HBeAg-negative chronic hepatitis B is associated with a lower rate of spontaneous remission and a poorer long-term prognosis than is HBeAg-positive chronic hepatitis B.[19]

In patients with chronic hepatitis B, either HBeAg-positive or HBeAg-negative, repeated disease flares over time lead to fibrosis, cirrhosis, and carcinogenesis.[22] Treatment is therefore essential in these individuals.[1,4,11,22]

Goals of Treatment

In the short term, the primary goal of treatment is the long-term suppression of viral replication, as measured by serum HBV DNA. Published literature demonstrates HBV DNA level to be the single most reliable predictor of disease outcome.[23] Analyses of the Risk Evaluation Viral Load Elevation and Associated Liver Disease (REVEAL) cohort have demonstrated that the risk for HCC, cirrhosis, and liver-related mortality all correlate with HBV DNA level in a dose-response relationship.[9-10,24] Controversy exists over the degree of HBV DNA suppression that should be achieved, but given that HBV DNA levels as low as 300 copies/mL have been associated with ongoing liver damage,[24,25] many experts agree that complete suppression or undetectable HBV DNA levels by a high-sensitivity assay, should be the goal.[11]

Additional short-term goals of treatment are the reduction of necroinflammatory damage to the liver, as demonstrated by normalization of serum ALT and improvement in liver histology, and HBeAg seroconversion in patients who are HBeAg positive. Loss of HBsAg, indicating resolution of chronic infection, is desirable but rarely achieved.[1]

Over the long term, treatment aims to reduce morbidity and mortality from hepatitis B by preventing or slowing the progression of major disease sequelae, namely cirrhosis, hepatic decompensation, HCC, and the need for liver transplantation. Several studies have demonstrated that antiviral therapy, especially when instituted early, can delay the progression and reduce the severity of liver disease due to HBV.[26,27] Moreover, data have suggested that the number of liver transplants performed specifically for patients with decompensated liver disease has likely decreased as a result of antiviral therapy.[28]

Guidelines for Treatment

Various guidelines have been published regarding when to initiate, stop, and alter therapy for hepatitis B. These include those published by the American Association for the Study of Liver Diseases (AASLD) in 2007,[1] the Asian Pacific Association for the Study of the Liver (APASL) in 2008,[22] a panel of Swedish experts in 2008,[29] a panel of US hepatologists led by Emmet Keeffe (the "US guidelines") in 2008,[11] the National Institutes of Health in 2009,[2] and the European Association for the Study of the Liver (EASL) in 2009.[4] The most frequently used guidelines are summarized and compared in Table 1 .

In general, physicians should consider treatment for patients who are at high risk for liver-related morbidity and mortality in the near future (5-10 years) or foreseeable future (10-20 years) and who have a high likelihood of maintaining viral suppression.[1]

Candidates for therapy typically have increased liver enzyme levels, detectable HBV DNA, and/or histologic liver damage. However, thresholds for initiating therapy may vary according to severity of liver disease (ie, cirrhosis) and HBeAg status.[1,2,4,11,22,29] See Figure 2. Less established but equally important thresholds may include a family history of cirrhosis or HCC.

Figure 2. Simplified treatment algorithm for patients with chronic HBV infection. Viral and biochemical thresholds differ across guidelines.[1,4,11,22]

HBeAg-Positive Chronic Hepatitis B

In patients with HBeAg-positive chronic hepatitis B, treatment is clearly indicated when serum HBV DNA is = 20,000 IU/mL (105 copies/mL) and ALT level is persistently elevated after 3-6 months of monitoring.[1,11,22] The AASLD and APASL guidelines state that ALT should be at least 2 x the upper limit of normal (ULN),[1,22] while the US guidelines simply require ALT to be above a threshold level of 30 IU/L in men and 19 IU/L in women.[11]

In patients who have HBV DNA levels = 20,000 IU/mL but a serum ALT that is normal or < 2 x ULN, all 3 groups recommend that a liver biopsy be considered, particularly in patients over 35-40 years of age. Treatment should then be started in those with moderate inflammation or fibrosis.[1,11,22]

The AASLD and APASL guidelines recommend no therapy for individuals with HBV DNA levels < 20,000 IU/mL,[1,22] whereas the US guidelines suggest that physicians consider liver biopsy on a case-by-case basis and initiate therapy when significant histologic disease is found.[11]

The EASL guidelines differ from the other 3 groups' by requiring that all patients with HBV DNA levels > 2000 IU/mL or a serum ALT above the ULN undergo liver biopsy. They then recommend treatment for those with moderate-to-severe necroinflammation or moderate-to-severe fibrosis.[4]

All of the guidelines aim to distinguish HBeAg-positive patients in the immune-clearance phase from those in the immune-tolerance phase, in whom treatment is not indicated.[2]

Treatment duration varies by guideline and the antiviral agent that is used; this will be discussed in more detail later. Generally, treatment should be administered until HBV DNA levels are undetectable or HBeAg seroconversion is achieved.
HBeAg-Negative Chronic Hepatitis B

HBeAg-negative patients tend to have lower levels of serum HBV DNA than their HBeAg-positive counterparts but still may have active disease.[11] As a result, the APASL and US guidelines recommend a lower HBV DNA threshold of 2000 IU/mL (104 copies/mL) for initiation of treatment.[11,22] As with HBeAg-positive patients, this must be coupled with a persistently elevated serum ALT after 3-6 months of monitoring, defined as > 2 x ULN by the APASL[22] and = 30 IU/mL in men and = 19 IU/mL in women by the US guidelines.[11] The AASLD guidelines recommend treatment in patients with an HBV DNA level > 20,000 IU/mL and an ALT > 2 x ULN.[1]

In those patients with HBV DNA levels > 2000 IU/mL and an ALT level between 1 and 2 x ULN, the APASL and AASLD guidelines recommend that a liver biopsy be performed, with treatment reserved only for those with moderate inflammation or fibrosis.[1,22]

As with HBeAg-positive patients, the EASL guidelines recommend a liver biopsy in all patients with HBV DNA > 2000 IU/mL or an elevated serum ALT. Again, treatment is indicated only for those with moderate-to-severe inflammation or fibrosis.[4]

Because HBeAg seroconversion is not an endpoint in these patients, treatment is typically administered indefinitely. However, variations do occur according to guideline or particular antiviral agent. This will be addressed further in another section.
Cirrhosis

In HBV-infected patients with compensated cirrhosis, treatment is indicated regardless of ALT level when HBV DNA = 2000 IU/mL.[1,4,11,22] In individuals with HBV DNA levels < 2000 IU/mL, the AASLD guidelines suggest treatment if serum ALT is elevated,[1] whereas the EASL guidelines recommend treatment in any patient with a detectable level of HBV DNA.[4] The US guidelines assert that both treatment and observation are acceptable, as existing data are insufficient to make a recommendation.[11] Regardless of whether they are observed or treated, all patients with cirrhosis should undergo regular screening for HCC and other complications (eg, esophageal varices).[30]

Treatment is universally indicated for patients with decompensated cirrhosis, regardless of HBV DNA level. However, therapy must be coupled with referral for liver transplantation.[1,4,11,22]
Special Populations

Treatment for hepatitis B is also indicated in all HBsAg-positive patients undergoing potent immunosuppressive therapy or chemotherapy, regardless of their phase of infection (Figure 3).[1,4,11,22] Reactivation of HBV replication has been reported in approximately 20% to 50% of HBsAg carriers in this setting. Although most flares are asymptomatic, hepatic decompensation and even death have been observed.[31] Most guidelines recommend that prophylactic antiviral therapy be started at the onset of chemotherapy or immunosuppressive therapy and be continued for at least 3-6 months after treatment is complete.[1,11,22] The EASL guidelines argue for a longer duration of therapy, up to 12 months after cessation of treatment.[4] In patients with high pretreatment HBV DNA levels (= 2000 IU/mL), antiviral therapy should be continued until the same treatment endpoints are achieved as in immunocompetent patients.[1,11]

Figure 3. Algorithm for antiviral therapy in patients on chemotherapy or immunosuppressive therapy.[32-35]

*Therapy should be considered strongly in patients receiving rituximab, as the majority of cases of reactivation in these patients occurred in those receiving rituximab-containing chemotherapy.

A controversial indication for antiviral prophylaxis prior to chemotherapy is the presence of an isolated positive hepatitis B core antibody (HBcAb). Although such patients are considered to have resolved infection, recent studies have suggested that up to 25% are at risk for flare when exposed to chemotherapy regimens containing rituximab. Although other chemotherapeutic agents potentially pose the same risk, the majority of cases of reactivation have occurred in patients receiving rituximab-containing regimens.[32,33] Therefore, it is recommended that patients with isolated HBcAb positivity be monitored closely during and after the administration of chemotherapy for signs of HBV reactivation. Those patients who develop reactivation or who are HBeAg positive should receive antiviral therapy according to the same indications as for HBsAg-positive patients undergoing chemotherapy or immunosuppressive therapy.[34] Alternatively, given the nucleoside analog lamivudine's low cost and few associated adverse effects, another reasonable option in this high-risk group is to administer lamivudine prophylaxis* without waiting for signs of reactivation, particularly in patients being treated with rituximab-containing regimens (Figure 3).[34]

Antiviral therapy is also recommended for individuals coinfected with HBV and HIV, using the same criteria as for treating patients with HBV monoinfection.[1,4,11,22] In the United States, up to 10% of patients with HIV are coinfected with HBV.[36] As in patients undergoing chemotherapy or immunosuppressive therapy, screening must take into account those patients with an isolated positive HBcAb. In HIV-coinfected patients, this can be associated with low levels of viral replication, resulting in detectable levels of HBV DNA.[37] HIV-coinfected patients in general tend to have higher levels of HBV DNA than do HBV-monoinfected patients, as well as lower rates of spontaneous HBeAg seroconversion and more severe liver disease.[38] The approach to hepatitis B therapy in these patients depends on the management and status of their HIV.

HBV-infected patients can also be coinfected with hepatitis C virus (HCV) or hepatitis delta virus (HDV). The worldwide prevalence of HBV-HCV coinfection is unknown, although small studies have demonstrated anti-HCV antibodies in 5% to 20% of individuals with chronic hepatitis B, and HBsAg in 2% to 10% of individuals with chronic hepatitis C.[39] HBV-HDV coinfection is much less common. In both cases, the risk of developing cirrhosis, hepatic decompensation, and HCC is significantly higher than in HBV monoinfection.[39-41] Furthermore, in almost all cases of HCV and HDV coinfection, HBV is the nondominant virus (ie, nonreplicating). Given that treatment should be directed against the dominant virus, patients with HCV-dominant coinfection should be given pegylated interferon and ribavirin according to standard protocol for HCV infection, and patients with HDV-dominant coinfection should receive high-dose interferon (9 MU 3 times a week) or pegylated interferon.[1,11,22]

Pregnant patients with hepatitis B also present a special management problem. If possible, treatment should be postponed in HBV-infected women until childbearing is complete.[1,11] For HBV-infected patients who become pregnant while on treatment, the decision to continue treatment should be individualized, taking into consideration the severity of the mother's liver disease and her potential benefit vs the risk to the fetus.[11] Some studies advocate nucleos(t)ide analog therapy during the third trimester in order to decrease HBV DNA levels and reduce the risk for vertical transmission of the virus.[42,43] However, the viral threshold prompting nucleos(t)ide analog use during pregnancy has not been defined, and a clear advantage for oral antiviral therapy over standard prophylaxis with hepatitis B immune globulin (HBIG) and HBV vaccination has not been shown.[22]

A final group meriting special consideration is HBV-infected patients who have undergone liver transplantation. Therapy is important in these individuals because recurrence of HBV infection is seen in approximately 67% of patients when prophylactic antiviral therapy is not administered. This rate increases to as high as 83% in patients who have detectable levels of HBV DNA prior to transplant. When prophylactic antiviral therapy is administered, HBV recurrence decreases to as low as 0% to 15%.[44-47]

Treatment Options

Options for the treatment of hepatitis B have expanded significantly since the introduction of interferon alfa over 2 decades ago (Table 2, Table 3). FDA-approved treatment options can be divided into interferon agents (interferon alfa-2b and pegylated interferon alfa-2a) and nucleos(t)ide analogs (lamivudine, adefovir, entecavir, tenofovir, and telbivudine). Newer agents such as emtricitabine* and clevudine* also demonstrate promise in treating hepatitis B, but have not yet received FDA approval.
Interferon Agents

The interferons have both antiviral and immunomodulatory effects They can be administered for finite courses with durable responses and virtually no risk for resistance. These agents confer the highest rates of HBsAg clearance, with a rate of approximately 3% at 72 weeks in patients receiving pegylated interferon.[48,49] Although standard interferon is still available, it has largely been replaced by pegylated interferon in routine clinical practice due to the latter's improved efficacy and less demanding injection schedule.[50]

Pegylated interferon is given at a dose of 180 µg weekly for 24-48 weeks in HBeAg-positive patients and for 48 weeks in HBeAg-negative patients.[51] A large phase 3 randomized trial conducted in HBeAg-positive patients in 2005 demonstrated that pegylated interferon (both alone and in combination with lamivudine) resulted in significantly higher rates of HBeAg seroconversion, HBV DNA undetectability, and ALT normalization than lamivudine alone.[48] A similar trial in HBeAg-negative patients also demonstrated higher rates of HBV DNA undetectability and ALT normalization in pegylated interferon-treated patients.[49] No significant difference in efficacy has been demonstrated thus far between pegylated interferon monotherapy and the combination of pegylated interferon and lamivudine*.[48]

High pretreatment levels of ALT (= 2 x ULN) and low levels of serum HBV DNA are the most important predictors of a response to interferon therapy.[52-54] If HBV DNA has not decreased by at least 1 log unit in HBeAg-positive patients or by at least 2 log units in HBeAg-negative patients by week 24 of therapy, it is likely that pegylated interferon treatment will fail.[55] Patients with HBV genotypes A and B also respond better to pegylated interferon than do those with genotypes C and D.[56]

The major drawback of interferon-based therapy is its subcutaneous mode of administration and extensive side-effect profile, which most commonly includes influenza-like symptoms and mood changes. Interferon agents are also contraindicated in patients with decompensated liver disease, as they can precipitate worsening hepatic function.[57]

Pegylated interferon is a reasonable choice for first-line therapy in patients infected with HBV genotypes A or B who are young, lack significant comorbidities, and have HBV DNA levels < 109 copies/mL and ALT levels = 2-3 x ULN.[11]

Nucleos(t)ide Analogs

The use of nucleos(t)ide analogs has gained "popularity" over the use of the interferons as a result of their oral route of administration, less frequent side effects, and increased potency in reducing HBV DNA and ALT levels. They must be administered for longer periods of time, however, and are associated with a risk for resistance.[1,11]

For HBeAg-positive patients, the AASLD guidelines recommend that oral nucleos(t)ide therapy be continued for at least 6 months after documented HBeAg seroconversion.[1] The APASL, EASL, and US guidelines are more stringent, recommending that treatment be continued until HBV DNA levels are undetectable by a high-sensitivity real-time polymerase chain reaction assay for 12 months after HBeAg seroconversion[4,11] or on 2 separate tests performed 6 months apart.[22] In patients who achieve HBeAg seroconversion but in whom HBV DNA levels remain at a stable detectable level, the US guidelines recommend continuing therapy for 6 months after seroconversion.[11]

In HBeAg-negative patients, treatment must be administered indefinitely, due to high rates of relapse despite prolonged HBV DNA undetectability.[58] According to the AASLD guidelines, discontinuation of treatment can only be considered if HBsAg clearance is achieved.[1] The APASL guidelines, however, state that discontinuation of therapy can also be considered if HBV DNA levels are undetectable on 3 occasions at least 6 months apart.[22]

In patients with cirrhosis, treatment is usually administered lifelong,[1,4,11,22] although the US guidelines suggest that treatment cessation can be considered in patients who achieve HBsAg clearance with an undetectable HBV DNA.[11] The AASLD guidelines also allow for cessation of therapy in patients with compensated cirrhosis after HBsAg clearance (HBeAg-negative patients) or 6 months post-HBeAg seroconversion (HBeAg-positive patients).[1] However, the potential for icteric flare, given the uncertain durability of seroconversion, must be carefully considered.

In any case, initiating therapy with a nucleos(t)ide analog requires consideration not only of the potency of each agent but also its resistance profile and rapidity of onset of action.

Lamivudine. The first oral anti-HBV therapy, lamivudine, received FDA approval in 1998. An enantiomer of 2'-3' dideoxy-3'-thiacytidine, lamivudine inhibits HBV DNA synthesis by incorporating into growing DNA chains and causing premature termination.[59] It is administered at a dose of 100 mg daily and has been shown in trials to be safe and well tolerated.[60] Although lamivudine is effective in reducing HBV DNA levels (undetectable levels have been achieved in 44% of HBeAg-positive patients at 48 weeks and 63% of HBeAg-negative patients at 24 weeks) and bringing about HBeAg seroconversion (16% to 17% at 48 weeks), durable response is seen in only 50% to 80% of HBeAg-positive patients and 20% to 25% of HBeAg-negative patients.[11,61-63]

Furthermore, the use of lamivudine is hindered by its high rate of resistance, associated with a known mutation in the reverse transcriptase region of the HBV polymerase, designated YMDD. Lamivudine leads to resistance in approximately 20% of patients per year, with a rate as high as 70% after 5 years of therapy in HBeAg-positive patients or after 4 years in HBeAg-negative patients.[64,65] As a result, lamivudine is not currently considered first-line therapy for the treatment of hepatitis B.[1,4,11,22]

Adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate. It was approved by the FDA in 2002 for the treatment of chronic hepatitis B. Like lamivudine, it is incorporated into HBV DNA, causing chain termination and inhibition of both reverse transcriptase and DNA polymerase activity.[66] Adefovir is administered at a dose of 10 mg daily[67] and has been demonstrated to reduce serum HBV DNA in 21% of HBeAg-positive individuals[68] and 71% of HBeAg-negative individuals.[69] HBeAg seroconversion occurs in 12% of HBeAg-positive patients, with 91% exhibiting a durable response.[68,70] Response to adefovir is similar across all HBV genotypes, although approximately 10% to 20% of treatment-naive patients demonstrate primary nonresponse, perhaps as a result of suboptimal dosing.[71]

Resistance to adefovir develops at a slower rate than with lamivudine, but several mutations have been described, typically developing after 1 year of treatment. Cumulative resistance rates of 0%, 3%, 11%, 18%, and 29% were reported in HBeAg-negative patients after 1, 2, 3, 4, and 5 years, respectively, of therapy.[72] Although adefovir resistance occurred in 0% of HBeAg-positive patients after 1 year of treatment, there are no long-term data on resistance in this group.[68] Adefovir resistance is most likely to occur in patients with a history of lamivudine resistance who are switched to adefovir monotherapy; it develops at a lower rate in those who have had adefovir added to lamivudine.[73] Resistance is also more likely to develop when HBV DNA levels remain > 200 IU/mL (103 copies/mL) after 48 weeks of treatment.[72]

The most notable side effect associated with adefovir is nephrotoxicity, which has been reported in 3% of patients with compensated liver disease after 4-5 years[72] and in 6% of transplant recipients[74] and 28% of patients with decompensated cirrhosis during the first year of therapy.[69,74] The drug is otherwise well tolerated, with a side-effect profile similar to that of placebo.[1]

Recent studies, however, have shown the superiority of the most recently approved nucleotide analog, tenofovir, over adefovir. In both HBeAg-positive and HBeAg-negative patients, tenofovir was associated with a greater mean reduction in serum HBV DNA level than adefovir, as well as higher rates of HBeAg seroconversion, ALT normalization, and improvement in liver histology.[75,76] As a result, the US and EASL guidelines, the only guidelines to be updated after FDA approval of tenofovir for the treatment of chronic hepatitis B, state that tenofovir should replace adefovir as a first-line drug in treatment-naive patients.[4,11]

Entecavir. Entecavir, an analog of cyclopentyl guanosine that results in potent inhibition of the priming and elongation functions of HBV polymerase,[77] is considered by all guidelines to be a first-line therapeutic agent for the treatment of chronic hepatitis B.[1,4,11,22,78]

In treatment-naive patients with HBeAg-positive hepatitis, 0.5 mg daily of entecavir resulted in a greater mean reduction in viral load and a higher rate of HBV DNA undetectability than either lamivudine or adefovir.[79,80] The HBeAg seroconversion rate was similar at 21%, with durable response seen in 69%.[11,79,81] In HBeAg-negative patients, entecavir was associated with HBV DNA loss in 90%, ALT normalization in 78%, and histologic improvement in 70% to 72%.[78,82] Entecavir has similar activity across all HBV genotypes and races, although HBeAg seroconversion rates are lower in patients with normal ALT.[83]

Resistance to entecavir is relatively rare, as it requires 2 "hits": selection of an rtM204V/I or rtL180M mutation, followed by an amino acid substitution at rtI169, rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution.[84] Long-term data indicate a resistance rate of 1.2% in both HBeAg-positive and HBeAg-negative nucleoside-naive patients treated for up to 5 years.[85] Entecavir is well tolerated and safe, with a safety profile similar to that of lamivudine in clinical trials.[79,82]

Telbivudine. Telbivudine is an L-nucleoside analog of thymidine that inhibits second-strand DNA synthesis by the HBV polymerase.[86] It is administered at a dose of 600 mg daily and, like other nucleoside analogs, has been found to have an excellent safety and adverse-event profile.[87]

A phase 3 clinical trial conducted in HBeAg-positive patients demonstrated superior rates of HBV DNA suppression (60% vs 40.4%) and ALT normalization (77% vs 74.9%) with 1 year of telbivudine therapy compared with lamivudine.[88] The HBeAg seroconversion rate was similar, at approximately 22%. A higher rate of HBV DNA loss was also seen in HBeAg-negative patients for telbivudine vs lamivudine, although normalization of serum ALT levels was not significantly different.[88] Trials comparing telbivudine with adefovir in HBeAg-positive patients likewise demonstrated a higher rate of HBV DNA loss and a greater mean reduction in HBV DNA level with telbivudine.[89]

Telbivudine is limited by its high rate of resistance, second only to lamivudine. Data from HBeAg-positive patients demonstrate resistance rates of 5% and 25% at 1 and 2 years, respectively. Rates of 2.3% and 11% at 1 and 2 years are seen in HBeAg-negative patients.[11,88,90] Like lamivudine, telbivudine selects for mutations in the YMDD motif of the HBV polymerase.[87] Resistance is less likely to develop in patients who achieve early, rapid suppression of viral replication, as indicated by undetectable HBV DNA levels (< 300 copies/mL) at 24 weeks. These same patients were also more likely to achieve HBeAg seroconversion and ALT normalization.[88] Nevertheless, the role of telbivudine in clinical practice is unclear at this time.

Tenofovir. Tenofovir is a nucleotide analog that is structurally related to adefovir but has more potent antiviral activity.[91-93] Previously approved for the treatment of HIV, tenofovir gained FDA approval for the treatment of chronic hepatitis B in the third quarter of 2008.

Findings from 2 double-blind, phase 3 studies demonstrated that tenofovir 300 mg daily was more effective than adefovir 10 mg daily in the treatment of chronic HBV infection.[93,94] In HBeAg-positive patients, tenofovir resulted in HBV DNA suppression (< 400 copies/mL [< 69 IU/mL]) in 76%, ALT normalization in 69%, and histologic improvement in 74%, rates all significantly higher than those seen with adefovir. Tenofovir also resulted in HBsAg loss in 3% of patients, the highest rate seen among oral nucleos(t)ide agents.[11,93,94]

Trials in HBeAg-negative patients show a similar superiority of tenofovir over adefovir, with viral suppression occurring in 93% of patients at 48 weeks.[11,93,94] Furthermore, no patients in either trial experienced renal toxicity, and no resistance has been reported thus far for tenofovir in data for up to 2 years.93,94]

On the basis of its greater potency and superior resistance profile, tenofovir has replaced adefovir as a first-line therapeutic agent for treatment-naive patients with HBeAg-positive and HBeAg-negative hepatitis B.[4,11]
Emerging Antiviral Agents

Currently approved for the treatment of HIV infection, emtricitabine,* a nucleoside analog with structural similarity to lamivudine, is undergoing evaluation for the treatment of HBV infection.[95] Data from trials showed that a 48-week course of emtricitabine resulted in HBV DNA loss (< 400 copies/mL) in 54% of patients and improved histology in 62%. Like lamivudine, however, emtricitabine is associated with a YMDD mutation conferring resistance, with a resistance rate of 9% after 1 year and 13% after 48 weeks.[96] The role of emtricitabine is likely best restricted to combination therapy* with tenofovir.

Another agent on the horizon is the pyrimidine nucleoside analog clevudine.* Trials evaluating the efficacy of 30 mg of clevudine given once daily for 24 weeks demonstrated HBV DNA loss (< 300 copies/mL) in 59% and ALT normalization in 68.2% of HBeAg-positive patients.[97] Among HBeAg-negative patients, HBV DNA loss occurred in 92% and ALT normalization in approximately 75%.[98] The HBeAg seroconversion rate was not significantly different from that of placebo.[97]

Both emtricitabine and clevudine are well tolerated, with no significant difference in adverse effects when compared with placebo.[96,98]
Combination Therapy

Due to the success of combination therapy in the setting of HIV and HCV infection, there is a substantial degree of interest in the potential utility of combination therapy for the treatment of hepatitis B. Theoretically, such therapy would improve treatment efficacy via additive or synergistic antiviral effects. This has yet to be demonstrated in clinical trials, however, and the primary role of combination therapy thus far is to decrease the risk of developing resistance when using therapies associated with low resistance barriers.[99] This potential benefit, however, must be weighed against increased cost, risk for toxicity, and the potential for drug-drug interactions.[1]

Various combination-therapy strategies pairing nucleoside agents with nucleotide agents have been evaluated for the initial treatment of HBV infection, but none have yet proven to be superior to monotherapy.[1] Trials evaluating the use of lamivudine and adefovir in combination* demonstrated decreased lamivudine resistance as compared with lamivudine monotherapy but no difference in HBV DNA levels or rates of HBeAg seroconversion.[100] A study to determine the efficacy of adefovir monotherapy vs combination therapy with adefovir plus emtricitabine* revealed similar findings, with improved rates of HBV DNA loss (HBV DNA suppression) but no difference in the rates of HBeAg seroconversion.[101] Trials evaluating the combination of tenofovir and emtricitabine* are currently ongoing in patients with adefovir resistance. Although the combination of tenofovir and emtricitabine* leads to higher rates of HBV DNA loss compared with adefovir monotherapy,[102] it is not yet clear, on the basis of data up to 1 year, whether the combination strategy is more effective than tenofovir monotherapy.[103]

Combination regimens employing nucleos(t)ide agents plus pegylated interferon have also been studied. In a phase 3 randomized trial, combination therapy with lamivudine plus pegylated interferon* was associated with a more profound decrease in viral load than pegylated interferon alone but no significant difference in viral suppression, HBeAg seroconversion, or HBsAg clearance.[48,49] Preliminary data from trials of pegylated interferon used in combination with adefovir, however, do show promise. Data have demonstrated more profound HBV DNA suppression, a greater mean reduction in viral load at 24 weeks, and a marked decrease in intrahepatic cccDNA level.[104,105] Further data regarding this combination therapy strategy are forthcoming.

Initial Choice of Therapy

The preferred agents for initial therapy in treatment-naive patients vary from guideline to guideline (Table 4). This is likely due in large part to the US and EASL guidelines being the only sets to have been updated after tenofovir gained FDA approval in late 2008.
HBeAg-Positive and HBeAg-Negative Chronic Hepatitis B

Due to their higher potency and low rates of resistance, the US and EASL guidelines recommend tenofovir, entecavir, or pegylated interferon for initial therapy in HBeAg-positive and HBeAg-negative patients.[4,11] Although the AASLD guidelines suggest that any of the approved antiviral agents may be used, they recommend adefovir, entecavir, or pegylated interferon.[1] The APASL guidelines do not make specific recommendations except in cases in which serum ALT is > 5 x ULN. Due to the risk for rapid decompensation in this patient group, they recommend an agent with fast onset of action, such as entecavir, telbivudine, or lamivudine.[22]
Cirrhosis

In patients with compensated cirrhosis, the US and EASL guidelines recommend initial therapy with entecavir, tenofovir, or pegylated interferon,[4,11] whereas the AASLD guidelines recommend entecavir or adefovir.[1] The use of pegylated interferon in patients with compensated cirrhosis is somewhat controversial, as interferon agents carry a risk of precipitating hepatic decompensation.[1]

All of the guidelines agree that interferon agents are contraindicated in patients with decompensated cirrhosis.[1,4,11,22] For this patient group, the US guidelines recommend initial treatment with entecavir, tenofovir, or the combination of lamivudine and tenofovir*.[11] The AASLD guidelines recommend the combination of lamivudine and adefovir*,[1] and the EASL guidelines recommend entecavir or tenofovir.[4]
Special Populations

Patients undergoing immunosuppressive therapy or chemotherapy. Although lamivudine is the most extensively studied medication in patients undergoing immunosuppressive therapy,[35] entecavir and tenofovir are recommended by many experts because of their lower risk for resistance and more potent viral suppression.[4,11] This is particularly true in cases in which immunosuppressive therapy is to be administered for more than 6 months[11] and in patients who have a detectable viral load.[106] In patients with no detectable viral load by a sensitive assay, lamivudine may be a reasonable choice for therapy (Figure 3).[35]

HIV-HBV coinfection. In HIV-HBV coinfected patients, treatment regimens should be designed to avoid the potential development of drug-resistant HIV or HBV and cross-resistance among antiviral agents (Figure 4).[106] Therefore, patients not on highly active antiretroviral therapy (HAART) should undergo hepatitis B treatment with medications that do not have dual activity against HIV, such as pegylated interferon (if CD4 count is > 500 cells/µL) or adefovir.[1,11] Although telbivudine does not have activity against HIV, its use is discouraged because of its high rate of cross-resistance with lamivudine.[88] Entecavir is also not recommended due to a recent study in which HIV mutants with resistance to both lamivudine and entecavir were selected when entecavir was administered without simultaneous HAART.[107] Patients being treated for HIV alone, or who need treatment for both HIV and HBV infection, should be treated with medications that have activity against both viruses.[1,4,11,22] This regimen must include at least 2 agents with activity against HBV.[108] The combination of tenofovir plus emtricitabine* is preferred in this setting, although lamivudine plus tenofovir can also be used.[1,4,11,22] In coinfected patients with low CD4 counts and active liver disease, HBV infection should be treated first in order to avoid immune reconstitution syndrome.[22]

Figure 4. Treatment algorithm for HIV-HBV coinfection.
*This regimen must include at least 2 agents with activity against HBV to prevent development of drug resistance.

Pregnancy. Of the current oral medications available to treat hepatitis B, only telbivudine and tenofovir are pregnancy category B, as a result of animal studies showing no evidence of harm to the fetus.[109,110] However, more extensive experience has accrued with lamivudine in the pregnant HIV-infected population. As a result, the US guidelines recommend that lamivudine, telbivudine, or tenofovir can be used when treatment is required in pregnant patients.[11] The APASL guidelines recommend that only therapy with category B drugs should be continued during pregnancy.[22]

Liver transplant patients. In patients who have undergone liver transplantation for HBV infection, the standard of care for prophylactic therapy is currently lamivudine in combination with HBIG.[111] The recurrence rate decreases substantially on this regimen, with rates as low as 0% to 11% reported in studies.[112] However, the use of HBIG is hampered by its high cost and need for recurrent clinic visits. The results of several studies suggest that oral combination therapy is associated with complete viral suppression and lack of resistance and thus might be a preferable option in patients receiving transplants for HBV infection.[113,114] Moreover, a recent pharmacoeconomic study suggested that oral combination therapy may be a cost-effective alternative to HBIG and lamivudine in transplant recipients.[115]

On-treatment Monitoring of Nucleos(t)ide Analog Therapy

HBV DNA levels must be monitored routinely during nucleos(t)ide analog therapy in order to detect treatment failures and avoid the development of resistance (Figure 2).

Primary treatment failure is assessed at week 12 and is defined as a <1 log10 IU/mL drop in HBV DNA level from baseline.[4,11] If patient nonadherence to prescribed therapy has been ruled out, this finding warrants a change in therapy to a more potent drug.[11] Primary treatment failure most commonly occurs with adefovir; a rapid switch to tenofovir or entecavir is recommended in these cases.[4]

At week 24, virologic response should be categorized as complete virologic response (HBV DNA level undetectable), partial virologic response (HBV DNA = 60 to < 2000 IU/mL), or inadequate virologic response (HBV DNA = 2000 IU/mL).[11] If partial or inadequate response is encountered, nonadherence must be ruled out and therapy modified by changing to a more potent drug in the same class or adding a second drug that does not share cross-resistance.[4,11] If the patient is receiving lamivudine or telbivudine, 1 of 2 strategies may be used: either add tenofovir or switch to tenofovir or entecavir.[4] The use of lamivudine or telbivudine as initial therapy is discouraged, however, because of their high risk for cross-resistance, resulting in the limited utility of other drugs in the same therapeutic class.[64,65,87] In patients with partial or inadequate response being treated with adefovir, the strategy involves either adding entecavir or switching to tenofovir or entecavir. If entecavir or tenofovir is being used, addition of the other agent is indicated.[4]

Monitoring of HBV DNA and serum ALT levels should ensue every 3-6 months.[4,11] In HBeAg-positive patients, HBeAg should also be monitored every 6-12 months in order to detect HBeAg seroconversion.[4]
Drug Resistance

The emergence of resistance to oral nucleos(t)ide therapy is one of the most difficult issues that providers face in the treatment of patients with hepatitis B. The risk of developing resistance depends not only on the resistance profile and potency of the antiviral agent being used but also on pretreatment HBV DNA levels, duration of treatment, and prior exposure to oral antiviral therapy.[1,11]

Resistance is defined by the loss of an initial response to a drug and a rebound in HBV DNA levels. Objectively, virologic breakthrough occurs when HBV DNA levels increase by at least 1 log10 IU/mL (10-fold) from nadir in 2 consecutive samples taken 1 month apart in patients who previously responded and have been adherent to therapy.[11] Adherence must be assessed, given that up to 30% of virologic breakthroughs reported in clinical trials are related to medication nonadherence.[1] Virologic breakthrough is typically followed by biochemical breakthrough, or an increase in ALT level after previous normalization, and eventual reversion of histologic improvement. In some cases, progressive liver disease with severe exacerbations can occur.[1,11] Furthermore, cross-resistance with other nucleos(t)ide analogs can emerge, resulting in the limitation of future treatment options.[1]

Once virologic breakthrough is detected, genotypic resistance testing should be used to confirm the presence of a mutation, with treatment altered accordingly. Although the guidelines differ slightly in their recommendations (Table 5), a general principle is to either add a drug from another resistance class or to switch to a more potent drug within the same class.[11]

Conclusion

HBV infection is an important public health concern responsible for over 1 million deaths per year worldwide. Morbidity and mortality from its known complications of cirrhosis, hepatic decompensation, and HCC can be reduced by recognizing when and how to start antiviral therapy, when to stop therapy, and when to alter therapy in the setting of resistance or inadequate treatment response.

Source : http://cme.medscape.com/viewarticle/591120