| Abstract|| |
There has been considerable progress in the treatment of hepatitis B in the past two decades. However, currently approved treatments have significant limitations, and the long-term management of patients with chronic HBV infection is as much an art as a science. Selection of the optimal treatment option is very important in the treatment of chronic hepatitis B. In this review, the focus is on current treatment strategies of chronic hepatitis B
Keywords: Antiviral resistance, Antiviral therapy, Chronic hepatitis B, Nucleos(t)ide analogues, Peg-interferon
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Amarapurkar D. Selection of treatment options in the management of chronic Hepatitis B. Hep B Annual 2010;7:45-56
Disease progression during chronic hepatitis B virus infection
Patients in the immune tolerant phase have no or minimal disease progression as long as serum ALT remains normal. In contrast, an earlier 3-year clinical study in patients with chronic hepatitis B, or patients in the immune clearance phase, showed that cirrhosis developed at an estimated annual incidence of 2.1%, being higher in those seropositive for HBeAg at entry (2.4%/year). A recent long-term (1.1-16.5, median 6.8 years) follow-up study further revealed that chronic hepatitis B patients with persistent HBeAg seropositivity developed cirrhosis at a higher incidence of 3.5%/year. Among patients who had undergone HBeAg seroconversion, the incidence of cirrhosis development was highest in those with HBeAg reversion, followed by those who developed HBeAg-negative hepatitis (2.9%/year during 1-18 years), and almost zero (1 of 184) in those with sustained remission. In agreement with this trend, a 7-year prospective study in 1495 asymptomatic male HBsAg carriers (80% seronegative for HBeAg) showed a low annual incidence of 0.7%, and that age, HBeAg seropositivity and ALT elevation 46 months were independent factors for cirrhosis development.
About 50% of the patients are still seropositive for HBeAg and/or HBV-DNA at their onset of cirrhosis. Further disease progression after the development of cirrhosis may continue to occur in these patients.
HCC develops at an annual incidence of 3-6% in patients with cirrhosis and far less frequently in noncirrhotic patients. Large community-based studies have confirmed that age, sex, HBeAg serostatus and ALT levels are factors for the development of liver cirrhosis and HCC. These studies further indicate that serum HBVDNA level is associated with cirrhosis and HCC development in a dose-dependent manner starting from serum HBV-DNA level >2000 IU/ml. These findings suggest that HBV replication, with subsequent immune-mediated liver injuries, is the primary driving force for liver disease progression. Besides viral factors (viral load, genotype and genomic mutations) and host factors (age, sex and immune status), other factors may also contribute to the progression of liver disease. These include habitual alcohol consumption, cigarette smoking exposure to aflatoxin and other viral superinfections, as shown in [Figure 1]. 
|Figure 1: Schematic representation of factors that influence the progression of hepatitis B virus (HBV)-related liver disease|
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| Annual Rates of Progression during Chronic HBV Infection|| |
Emerging data indicate that the mortality rate of hepatocellular carcinoma (HCC) associated with cirrhosis is rising in some developed countries, whereas mortality from non-HCC complications of cirrhosis is decreasing or is stable. Cohort studies indicate that HCC is currently the major cause of liver-related death in patients with compensated cirrhosis. Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively), followed by hereditary hemochromatosis (5-year cumulative incidence, 21%). In hepatitis B virus (HBV)-related cirrhosis, the 5-year cumulative HCC risk is 15% in high endemic areas and 10% in the West. In the absence of HCV and HBV infection, the HCC incidence is lower in alcoholic cirrhotics (5-year cumulative risk, 8%) and subjects with advanced biliary cirrhosis (5-year cumulative risk, 4%) [Figure 2]. There are limited data on HCC risk in cirrhosis of other causes. Older age, male sex, severity of compensated cirrhosis at presentation, and sustained activity of liver disease are important predictors of HCC, independent of etiology of cirrhosis. In viral-related cirrhosis, HBV/HCV and HBV/HDV coinfections increase the HCC risk (2- to 6-fold relative to each infection alone) as does alcohol abuse (2- to 4-fold relative to alcohol abstinence). Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis. Further studies are needed to investigate other viral factors (e.g., HBV genotype/mutant, occult HBV, HIV coinfection) and preventable or treatable comorbidities (e.g., obesity, diabetes) in the HCC risk in cirrhosis. 
Long term outcomes with seroconversion in chronic hep B
During the third phase of chronic HBV infection, serum HBsAg persists but HBeAg has seroconverted to anti-HBe, a hallmark event that usually represents a transition from chronic hepatitis B to an 'inactive carrier state'. Although serum HBV DNA becomes undetectable by hybridization assays (levels < 10 4 -10 5 copies/ml), it is often detectable by polymerase chain reaction. These low HBV DNA concentrations probably reflect a low level of HBV replication, but do not associate with chronic hepatitis in most patients. During this phase, patients are usually asymptomatic, have no or mild hepatitis activity and intrahepatic HBcAg is absent; however, some patients may have progressed to cirrhosis and may develop hepatocellular carcinoma (HCC) afterwards.
The prevalence of serum HBeAg in HBsAg carriers correlates significantly with the age. Spontaneous HBeAg seroconversion occurs before 40 years of age in more than 90% of HBsAg carriers. Studies have shown that the average rate of spontaneous HBeAg seroconversion during the immune clearance phase is 10% per year. On the contrary, a longitudinal study involving 240 HBeAg-positive adult patients with normal baseline ALT showed that the mean age of HBeAg seroconversion was 31.3 ± 7.0 (standard deviation) years. Spontaneous HBeAg seroconversion occurs before 26 years of age in 25% but after 40 years of age in only 10% of HBsAg carriers. It seems appropriate to define 'delayed' HBeAg seroconversion as persistent HBeAg seropositivity over 40 years of age.
Three long-term studies that evaluated serologic and laboratory outcomes in patients with chronic hepatitis B who were treated with interferon reported that there was a low frequency of viral reactivation and that conversion to HBeAg seronegativity was usually followed by the return of serum aminotransferase levels to normal. A single report shows that long term interferon therapy also has a positive effect on histologic findings in the liver. Although the few long-term studies suggest that treatment with interferon alfa reduces inflammatory activity in patients with chronic hepatitis B, antiviral therapy has not been proved to affect the prognosis. In patients with chronic hepatitis B infection, the clearance of HBeAg after treatment with interferon alfa is associated with improved clinical outcomes [Figure 3].
|Figure 3: HBeAg clearance with IFN Alfa Therapy is associated with improved clinical outcome|
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HBeAg and Risk of HCC
Because most patients with cirrhosis or HCC were HBeAg negative and anti-HBe positive, it was argued that HBeAg seroconversion might implicate unfavourable outcome in chronic HBV infection. This suggestion is not compatible with the results of a matched case control study showing that HBeAg-positive status increased the risk of HCC 3.6-fold when compared with HBeAg-negative HBsAg carriers. This association has been confirmed by a recent prospective 8.5-year follow-up study involving 11 893 Taiwanese men, 30-65 years of age.  In that study, the annual incidence of HCC was 1.2% for those who were HBsAg and HBeAg positive at enrolment, 0.3% for those who were HBsAg positive only, and 0.04% for those who were HBsAg negative. After adjusting for age, hepatitis C virus status, and use of cigarettes and alcohol, the relative risk for HCC was 9.6 (95% confidence interval, 6.0-15.2) among men who were positive for HBsAg alone and 60.2 (95% confidence interval, 35.5-102.1) for those who were positive for both HBsAg and HBeAg. However, this study did not provide data comparing the incidence of HCC among carriers who underwent HBeAg seroconversion during follow-up vs those who remained HBeAg positive. In one cohort of 233 patients with HBeAg-positive chronic hepatitis B followed for a mean of 6.1 years without treatment, the annual incidence of cirrhosis and HCC was 1.8% and 0.4%, respectively, for 86 patients who had spontaneous HBeAg seroconversion and 3.7% and 1.6%, respectively (both P < 0.05), for those who remained HBeAg positive during follow-up. Moreover, in one study on the natural course of chronic HBV infection after spontaneous HBeAg seroconversion in 283 patients reported from Taiwan, the overall annual incidence of cirrhosis and HCC development was estimated to be only 0.9% and 0.2%, respectively, during a mean follow-up of 9 years. All these data implicate a favourable outcome of spontaneous HBeAg seroconversion in chronic HBV infection.
Therapy induced HBeAg seroconversion is associated with reduced incidence of cirrhosis
Patients who undergo HBeAg seroconversion are more likely to experience improved long-term outcomes, including disease remission, a lower incidence of cirrhosis and HCC, increased rates of survival, and the possibility of HBsAg loss or seroconversion.
Treatment-induced HBeAg seroconversion has also been shown to confer favourable outcomes and is a strong predictor of prolonged survival. Niederau  and colleagues conducted a follow-up study of 103 CHB patients treated with conventional interferon (IFN)-a and 53 untreated patients. After a median of 50 months after completing therapy, 53 of the 103 IFN-a-treated patients ultimately lost HBeAg (a cumulative rate of 56% at 5 years) and seroconverted to anti-HBe with HBV-DNA undetectability by hybridization assay. Of note is that HBsAg seroclearance occurred in 10 (19%) of the 53 patients who had undergone HBeAg seroconversion (with a calculated cumulative rate of 12% at 5 years). In contrast, only 7 of the 50 untreated individuals experienced spontaneous HBeAg conversion (cumulative rate of 28% at 5 years), and all remained positive for HBsAg. Of the 50 treated patients with persistent HBeAg positivity, 6 patients died of liver failure, 2 patients required liver transplantation, and 8 patients developed cirrhosis during follow-up. Overall survival and survival without clinical complications were significantly longer in patients who experienced HBeAg seroconversion after therapy with IFN-a than in those who remained HBeAg positive (P = 0.004 and P = 0.018, respectively). In a regression analysis, the clearance of HBeAg was the strongest predictor of survival.
Results of current therapies
Seven drugs are now available for the treatment of chronic hepatitis B: they include conventional interferon alpha, pegylated interferon alpha and NUCs. NUCs for HBV therapy belong to three classes: L-nucleosides (lamivudine, telbivudine, and emtricitabine), deoxyguanosine analogues (entecavir) and acyclic nucleoside phosphonates (adefovir and tenofovir). Lamivudine, adefovir, entecavir, telbivudine and tenofovir have been approved in Europe for HBV treatment, and the combination of tenofovir and emtricitabine in one tablet has been licensed for the treatment of HIV infection.
The efficacy of these drugs has been assessed in randomized controlled trials at one year (two years with telbivudine). Longer-term results (up to 5 years) are available for lamivudine, adefovir, entecavir, telbivudine and tenofovir in patient subgroups. [Figure 4] show response rates with these drugs from different trials. These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs.
|Figure 4: Rates of HBe seroconversion, undetectable HBV DNA and normal ALT at one year of therapy with pegylated interferon alpha-2a (PEG-IFN), lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir (TDF) in HBeAg-positive patients with CHB in randomized clinical trials. These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs; thus, these numbers are only indicative and should be considered with caution|
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In HBeAg-positive patients, virological response rates at one year (undetectable HBV DNA, defined variously in the different trials and differently from the present guidelines) were 25%, 36-40%, 21%, 67%, 60% and 74% with pegylated interferon alpha-2a/2b, lamivudine, adefovir, entecavir, telbivudine and tenofovir, respectively [Figure 4]. HBe seroconversion rates were of the order of 30% with conventional and pegylated interferon alpha and approximately 20% for NUCs. HBe seroconversion rates increase with continued NUCs treatment, but are affected if resistance occurs (B1). Loss of HBsAg rates after one year were 3-4% with pegylated interferon alpha, 1% with lamivudine, 0% with adefovir, 2% with entecavir, 0% with telbivudine, and 3% with tenofovir.
HBeAg Seroconversion after end of treatment
In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk-benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.  In another study a involving total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 µg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in this study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks.
After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a (PegIFN) plus lamivudine (LAM) than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per millilitre (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively) [Figure 4]. Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment - one underwent liver transplantation, and the other died.
In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion. ,
Selecting the best nucleos(t)ide for initial therapy
Conversely, treatment with nucleos(t)ide analogue(NA) therapy is usually a once-daily oral treatment. While a number of different oral drugs are available, they all inhibit the viral polymerase enzyme to suppress viral replication. Unlike pegylated interferon, oral nucleos(t)ide analogues do not induce a strong immune response and thus often require long-term administration to prevent relapse. [Table 1] summarizes the advantages and disadvantages of NAs and Interferon as First-Line Therapy for CHB.
|Table 1: Advantages and disadvantages of pegylated interferon alpha and nucleos(t)ides analogues in chronic hepatitis B |
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Approximately 20% of HBeAg positive patients per year will achieve the therapeutic end point of HBeAg seroconversion on oral nucleos(t)ide analogue therapy. Consolidation treatment is recommended for 12 months after seroconversion. However, longer-term treatment may be needed if the patient does not seroconvert, has immune escape (HBeAg negative at the start of treatment) or is cirrhotic.
In general, patients who are offered treatment have active viral replication and liver damage. Important considerations before treatment, include:
- Patient choice
- Timing of pregnancy (oral drugs are not licensed for use in pregnancy)
- Risk of progression without treatment (highest in those with high alanine aminotransferase, repeated flares or significant fibrosis already)
- Potential need for indefinite therapy (immune escape/HBeAg negative disease and cirrhosis)
- Risk of antiviral resistance with oral nucleos(t)ide analogues
- Potential treatment-related adverse effects.
- Use nucleos(t)ides as monotherapy with
- Highest antiviral potency and genetic barrier to resistance
- Low incidence of resistance over time
- Rapid and sustained to maximize cumulative benefit
- LAM/LdT/ADV not generally recommended as first-line therapy
- Combination therapy may be considered in patients where avoiding resistance is especially important
- Currently no data supporting this approach vs newer monotherapies.
- Consider individual patient characteristics in relation to safety
- Comorbidities (i.e., compromised renal function)
- Coinfections (i.e., anti-HIV activity of agents)
- Conception planning.
Financial support and sponsorship
Conflict of interest
There are no conflicts of interest.
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Consultant Gastroenterologist and Hepatologist, Hospital and Medical Research Centre, Bombay - 400 020
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]