| Abstract|| |
Currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and Thymosin alpha, four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine), two agents Tenofovir and emtricitabine approved in the HIV HBV co-infection are likely to be approved for HBV infection in immediate future. These treatment strategies are either therapies of finite duration that aim to achieve sustained off-therapy responses, or long-term treatments that aim to maintain on-therapy remission. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy; therefore, new agents and treatment strategies are needed. Although therapy of hepatitis B is evolving, which between single and/or combined agents are most effective, how long therapy should last, which criteria should be used to start or continue and switch or stop therapy are to be defined. This paper provides a review of management with the available treatment options for HBV associated liver diseases.
Keywords: Lamuviduine, adefovir, entacavir, telbuviduine, peg interfereon alpha, standard interferon alpha
|How to cite this article:|
Amarapurkar DN. Management overview of chronic hepatitis B with established therapies. Hep B Annual 2007;4:118-32
| Introduction|| |
Chronic hepatitis B (CHB) is caused by persistent infection with the hepatitis B virus (HBV), a unique DNA virus that replicates through an RNA intermediate produced from a stable covalently closed circular DNA molecule. Viral persistence appears to be due to inadequate innate and adaptive immune responses. Chronic infection with HBV accounts for an enormous burden of disease worldwide, including up to half of all cases of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.  In India nearly 3%-4% of the population is infected by the virus, and chronic hepatitis B constitutes more than 50% of the chronic hepatitis cases in the country.  In the context of a large population, and inability to implement an universal immunization program, the HBV epidemiology in India becomes relevant not only nationally, but also internationally, because of the possibility that India may soon have the largest HBV infection pool in the world.
A number of therapies for CHB have been developed and are directed at reducing or interrupting replication of the virus and thereby reducing liver and serum levels of HBV DNA and/or enhancing host immune control of infection. The overall goal of therapy in CHB is to reduce progression to cirrhosis, hepatic decompensation with liver failure, development of HCC, and need for liver transplantation. Achievement of these treatment goals has been hampered by the limited efficacy of current therapy. However, the introduction of nucleos(t)ide analogues holds promise in revolutionalizing therapy due to their advantage of oral administration, relative safety, lower incidence of resistance with the newer agents and induction of a sustained antiviral response over a long term in a majority of patients.  The FDA of the USA approved the use of lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005.  The most recent approval has been for telbivudine.
The actual availability of a high number of antiviral drugs adds complexity to the management of therapy against hepatitis B. In fact, the choice of therapy depends on some predictive factors of the treatment response, clinical circumstances and the stage of disease, the potency of different agents, the likelihood and consequences of resistance to treatment, as well as the personal choice of the patient and physician. , In this report, we summarize an overall view of current and new available developing treatment options for HBV infection, and their comparative efficacy. Strategies are proposed for managing patients in different categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug.
| Established Therapies|| |
A well-planned evaluation of the efficacy and efficiency of a therapy against HBV infection is based on three endpoints: biochemical, virological and histological responses. Currently, six antiviral agents between immunomodulators (standard and Pegylated interferon) and nucleoside analogues (lamivudine, adefovir, entecavir and telbivudine) have been approved for use in chronic hepatitis B.
In [Table 1] and [Table 2] an overview of the efficacy, efficiency and limitations of each of these agents is presented in HBeAg-positive and negative patients.  [Table 3] presents long term data with these agents. ,,,,, 2 year data for all nucleoside analogs in HBeAg negative patients is not available and moreover cannot be compared as methodology and endpoint evaluation varies with different agents (e.g. entecavir).
| Which Endpoint Measurement is the key to Successful Management of Patients with CHB?|| |
Current guidelines recommend the measurement of the following to manage patients with CHB:
- Serum alanine aminotransferase (ALT) levels
- HBeAg seroconversion (for e positive patients)
- HBV DNA levels
Serum ALT levels
The normalization of serum ALT levels in patients with increased levels before initiating therapy usually is considered predictive of improvement in necroinflammatory disease. However, the role of ALT levels as a predictor of liver injury has recently been questioned. 
ALT activity, the variable most commonly measured to assess hepatic disease, fails to identify many patients with hepatic injury. A retrospective review was done to determine whether normal ALT is associated with liver injury in a cohort of HBV patients undergoing liver biopsy. The results showed that there was significant fibrosis and inflammation in 37% of patients with persistently normal ALT levels. 
In patients with normal levels at baseline, including patients with cirrhosis, ALT levels may not be helpful in assessing the response to therapy. Lowering of the upper limit of normal (to 30 U/L in men, and to 19 U/L in women) has been proposed  to help guide therapy, but this recommendation is not accepted universally.  Studies show that even patients with high-normal serum ALT (levels of 0.5-1x upper limit of normal) are at risk of liver disease progression. 
Loss of HBeAg and, perhaps more importantly, HBeAg seroconversion to anti-HBe during treatment generally has been accepted as indicative of a therapeutic response. However, quantitation of HBeAg has not been used widely, is not approved in the United States by the Food and Drug Administration, is expensive and available data about the predictive value of HBeAg serostatus remain limited. 
Most patients with end stage cirrhosis or HCC are HBeAg negative at the time of presentation. Further cirrhosis complications, including hepatocellular carcinoma, often occur despite HBeAg seroconversion, hence HBeAg seroconversion may not be an adequate end point.  Another study showed that almost 24% of inactive CHB carriers, HBeAg (-)/antiHBe (+), had a reactivation of the disease even after many years.  Serum HBV DNA remains detectable in some patients even after HBeAg seroconversion. Hence delayed HBeAg seroconversion could be a more important contributor to adverse outcome than HBeAg seroconversion per se.
Moreover the HBeAg seroconversion is very closely linked to HBV DNA serum levels and monitoring of the latter would thus be more useful. 
Serum HBV DNA levels
Suppression of serum HBV DNA while on treatment appears to be the best predictor of improved long-term outcomes. The evidence supporting this approach to monitoring and predicting response to treatment is available from a number of sources.
A review of 26 prospective trials involving more than 3400 patients found statistically significant and consistent correlations between viral load level or change and histologic grading and biochemical and serologic response.  Further, the results showed that quantitative HBV DNA has a broader dynamic range than histology, allowing demonstration of differences between 2 active treatments of unequal potency. Thus, the goal of anti-HBV therapy should be profound and durable viral suppression, as defined by very sensitive assays. 
A population-based prospective cohort study of 3582 untreated hepatitis B-infected patients showed that progression to cirrhosis in hepatitis B-infected persons is correlated strongly with the level of circulating virus. The risk for cirrhosis increases significantly with increasing HBV-DNA levels and is independent of HBeAg status and serum ALT level. 
In conclusion, available data supports the concept that suppression of serum HBV DNA to very low or undetectable levels should be the critical goal in the on-treatment management of CHB.
[Table 4] and [Table 5] summarise the recommendations for the management of chronic HBV infection in the United States in HBeAg positive and negative patients.  In [Table 6] we present management strategy at our institute based on evidence, recommendations and our clinical experiences.
| Optimal Timing for Monitoring HBV DNA Levels|| |
The current guidelines provide very little information on the use of on treatment responses (other than management of resistance) to predict outcomes. Important questions regarding management during therapy remain largely unanswered as to the time point at which monitoring should take place and how this can improve the management of patients with CHB.
A panel of international hepatologists and virologists with extensive experience in the management of patients with CHB met on September 2, 2006, in London, England, to review available data on the value of monitoring patients during treatment.  Guidelines regarding on-treatment management and available published data on the importance of HBV DNA as a marker of outcomes were reviewed. On treatment monitoring strategies to define early virologic responses that might be predictive of better outcomes and a reduced risk of viral resistance were proposed for further study. This treatment plan, labeled the roadmap strategy, recommends monitoring of serum HBV DNA levels to identify outcomes of therapy with the goal of enhancing patient management.
| The Road Map Strategy|| |
This treatment plan, recommends fixed time points in monitoring of serum HBV DNA levels to identify outcomes of therapy. Early virologic response in particular is of value in detecting primary treatment failure (defined later) and in predicting likely outcomes of continued therapy-improved histology, reduced likelihood of clinical disease progression, and/or the development of drug resistance with viral breakthrough, which in turn may lead to continuing disease progression. After reviewing the available data, the panel agreed that residual HBV DNA level was a better marker of therapeutic outcome and the emergence of resistance. Hence, baseline HBV DNA levels were not considered further, although they may be predictive of outcomes before onset of therapy. 
Monitoring at 12 weeks and further course of action
The first time point for monitoring was recommended at 12 weeks of therapy.  Primary treatment failure was defined as a reduction of serum HBV DNA levels by less than 1 log 10 IU/mL from baseline at week 12. Primary treatment failure occurring in a patient who is compliant to therapy needs a change in medication to a more potent drug.
Monitoring at 24 weeks and further course of action
The next time point proposed for monitoring the serum HBV DNA level was at week 24 of therapy. Measurement of the HBV DNA level at week 24 was considered essential to characterize virologic responses as complete, partial, or inadequate. 
Complete virologic response was defined as negative HBV DNA by a sensitive assay (<60 IU/mL or <300 copies/mL); partial virologic response was defined as HBV DNA levels less than 2000 IU/mL (4 log 10 copies/mL), and inadequate virologic response was defined as HBV DNA levels of 2000 IU/mL or greater (4 log 10 copies/mL). 
Strategies are proposed for managing patients in each of these categories, depending in part on the rapidity with which HBV DNA suppression is achieved and the emergence of genotypic mutations that reduce the effectiveness of a specific drug 
In patients with a complete response the recommendation is for the treatment to be continued with the same drug with repeat testing at 6 month intervals.
Management of patients with a partial response depends on the genetic barrier of the drug to resistance. Genetic barrier is the threshold probability that the virus will mutate and escape from the selective action of the drug, thereby making the virus resistant to that specific drug. In this terminology, drugs with a high genetic barrier have a low risk for the emergence of viral resistance, whereas those with a low genetic barrier have a higher risk of viral resistance. 
In patients on a drug with a low barrier to resistance (e.g., lamivudine, telbivudine), a second drug with a different genetic mutation profile should be added. A patient on treatment with a potent drug having a high genetic barrier (e.g., entecavir), treatment is recommended to be continued for 48 weeks with monitoring every 3 months. In patients on a drug with a delayed antiviral effect and a relatively high barrier to resistance (e.g., adefovir), monitoring should be repeated at 3-month intervals and treatment continued for 48 weeks. If response is complete at 48 weeks, treatment with the same drug can be continued. In case of incomplete response a more potent drug needs to be added.
Patients with an inadequate response need a change in drug or addition of a more potent drug with monitoring every 3 months.
| Why do we not yet have Combination Therapy for Chronic Hepatitis B?|| |
Despite the emergence of multidrug-resistant strains of HBV and previous success with combination therapy for other chronic viral infections, we are still using sequential monotherapy for chronic HBV infection. There are several potential advantages of combination therapy with respect to monotherapy of hepatitis B, including a greater antiviral activity and lower rates of drug resistance. Unfortunately, there have been few properly controlled clinical trials demonstrating that combination therapy is more effective than monotherapy 
A number of investigators have studied combination therapy in clinical trials with mixed results. Studies of interferons combined with lamivudine have failed to show a consistent benefit in treatment outcome. , Studies combining nucleotide/nucleoside analogues (eg, lamivudine and adefovir dipivoxil) have primarily been conducted in patients with established lamivudine resistance, rather than in treatment-naοve patients, and shown equivalent efficacy whether adefovir dipivoxil was used as a single agent or combined with lamivudine. , A study comparing telbivudine and its combination with lamivudine in HBeAg-positive adults with compensated chronic hepatitis B. showed that results with the combination regimens were similar to those obtained with telbivudine alone. 
There is now an emerging and consistent body of data suggesting that combination therapy can decrease antiviral resistance, the endpoint likely to be of greatest long-term importance. A major issue here, as in HIV infection, is that it is likely to be more effective using combination therapy in treatment-naοve patients, rather than adding or replacing an antiviral agent after resistance develops.  Sung et al showed that the rate of lamivudine resistance in patients treated with a combination of lamivudine and adefovir dipivoxil was only 2%, compared with 20% in patients treated with lamivudine monotherapy. 
Combination therapy can decrease antiviral resistance in HBV infection, and, rather than adding or replacing an antiviral agent after resistance develops, it is likely to be more effective in treatment-naοve patients. Even though HBV is a different virus, the emerging data are consistent with what established virological principles would have predicted, as also seen in HIV. Further studies examining the role of de-novo combination therapy are warranted, but now is the time to move to combination therapy for patients who require long-term nucleoside analogue therapy for HBV, rather than waiting for this epidemic to evolve. 
| Conclusion|| |
The ultimate goal in managing patients with CHB is to improve long-term outcomes by decreasing deaths and liver transplantation procedures due to HBV-related cirrhosis and hepatocellular carcinoma. Active intervention and vaccination of individuals susceptible to HBV infection are key steps to decrease the risk of this global public health problem. Despite the availability of highly effective and safe vaccines for a quarter of a century, HBV infection remains the most common worldwide cause of death from liver disease. First-line therapeutic regimens for the management of HBV infection include monotherapy with a U.S. Food and Drug Administration-approved agent that has potent on-treatment viral response and low rates of resistance. New oral treatments, characterized by potent antiviral effects, good tolerability, improved histology, stable seroconversion, and minimal resistance, are available. Long-term data with oral medications have shown decreased rates of liver cancer development, liver disease reversal, and progression to liver failure. Major nongovernmental organizations devoted to the study of liver disease as well as other expert groups have developed and refined guidelines designed to aid in the management of patients with CHB. These guidelines address the criteria for patient selection, the objectives and timing of therapy, and the advantages and disadvantages of the available therapies. An expert panel of international hepatologists and virologists has recently prepared a road map strategy which proposes a schedule for monitoring and defines clinically meaningful on treatment responses to help enhance patient management.
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Deepak Narayan Amarapurkar
D 401/402 Ameya RBI Employees Co-Op Housing Society, Plot No. 947-950, New Prabhadevi Road, Prabhadevi, Mumbai-400 025
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]