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Hepatits B Treatment
  -Treating Hepatitis B Virus Infection: Overview and Options
-Treatment Candidates
-A Practical Approach to Treatment Decision-Making: General Principles
-What Are the Treatment Options?
-Selecting Among the Options
-Monitoring Treatment
part 3 of 9
Adrian M. Di Bisceglie, md, facp
Professor of Internal Medicine
Chief of Hepatology
Saint Louis University School of Medicine
St. Louis, Missouri
Marion Peters, md
Professor of Medicine
University of California, San Francisco
San Francisco, California
Treating Hepatitis B Virus Infection: Overview and Options
The goals of treating chronic hepatitis B virus (HBV) infection are to prevent the longterm clinical sequelae of chronic infection: necroinflammatory disease, progression to cirrhosis, hepatocellular carcinoma (HCC), and premature death. In persons with chronic HBV, durable suppression of HBV DNA may improve clinical outcomes, including improvement of liver histology and decreased risk of HCC.1,2 Current treatment endpoints are to normalize alanine aminotransferase (ALT) levels, decrease HBV DNA levels, and induce the loss of hepatitis B e antigen (HBeAg) with seroconversion to convert to HBeAg positivity.1,3,4,10 Treatment is not recommended for all persons infected with HBVonly those with ongoing necroinflammatory liver disease.5 Lifetime monitoring of patients with chronic infection indicates if and when intervention is required.5
Treatment options for HBV infection have expanded since the approval of recombinant interferon alfa-2b in 1992. In addition to interferon, two nucleoside analogs (lamivudine, introduced in 1998, and entecavir, approved for treating HBV in 2005) and one nucleotide analog (adefovir dipivoxil [adefovir], introduced in 2003) are licensed in the United States as first-line agents for treating HBV infection.6-9
Treatment Candidates
Candidates for antiviral treatment have been delineated in several published guidelines, which differ somewhat in their recommendations but are based on the natural history of HBV and the likelihood of disease progression to serious sequelae.1,5,10,11 Overall, the predominant clinical criterion for treatment is the presence of active liver disease, but factors such as patient age, severity of liver disease, likelihood of response, and potential risks and benefits must be weighed before deciding who, when, and how to treat.5 The American Association for the Study of Liver Diseases (AASLD) guidelines and the US Treatment Algorithm for managing chronic HBV infection in the United States differ most notably in their definitions of high viral load in HBeAg negative patients (≥105 copies/mL [100,000] versus ≥104 copies/mL [10,000], respectively) and in the criterion for ALT elevation (any elevation over normal versus two times the upper limit of normal [ULN], respectively).1,5,10 The AASLD guidelines are somewhat more conservative, with the US Treatment Algorithm recommending that treatment be considered for patients with normal ALT levels or lower levels of HBV DNA in patients with known significant histologic disease or when biopsy indicates active disease.10
Ed Note: recent studies reported at DDW & EASL 2005 find that HBV DNA viral load is associated with disease progression. These studies suggest that the lower the viral load the better clinical outcomes are likely to be. HBV DNA <10,000 is better than 100,000 and 1,000 is better than 10,000 and <400 is better than 1,000.
Peginterferon- Pegasys is FDA approved for HBV & in Europe is recommended for firstline HBV therapy. Has not yet been studied in HIV. Early IFN studies showed less efficacy if any compared to HIV-negatives but studies were conducted before HAART era. So its felt that after immuno-reconstitution, CD4 increase, associated with HAART, or if used early in disease when CD4s are high has certain potential benefits: pegIFN may stimulate an immune response to HBV, has better promise for HBsAg seroconversion than oral antivirals, short-term therapy of 6 months 1, has durable response, and perhaps most important is not associated with resistance so oral drugs could be used after peginterferon. Lamivudine is associated with high rates of resistance. Adefovir- effective drug, potent, after 1-2 yrs low or no resistance; 7-15% after 4 years; the 15% was found in study where data was misplaced so unsure, it could be less. Replaced lamivudine as therapy. Avoid in cases of renal impairment, may result in nephrotoxicity. Tenofovir (not approved bt the FDA for HBV therapy, but studies do far show it to be more potent than adefovir and its in studies now to secure FDA approval. In HIV used in combination with FTC in the Fixed Dose Combination Truvada. Avoid in cases of renal impairment, may result in nephrotoxicity. Entecavir- approved for HBV therapy in 2005. Entecavir is potent, 7 log reductions seen after 1 year, np resistance observed after 2 years. Perhaps most potent drug approved. Telbivudine in phase III- is potent with 6 log reductions, 4.5% resistance after 1 year observed in studies. Combination therapy has so far not been shown to offer any additive potency. So far the only benefit studies have shown is that it might delay or prevent drug resistance. But additional combination studies will continue to explore strategies.


A Practical Approach to Treatment
Decision-Making: General Principles

In clinical practice, three main factors contribute to treatment decisions: ALT levels, HBeAg status, and HBV DNA levels. Age and ethnicity are not primary issues. The presence of elevated ALT levels is important because the higher the ALT level, the better the response.12-14 The next consideration is HBeAg status, negative or positive, which can determine the type or length of therapy. A subset of patients who have lost HBeAg due to mutations may have active HBV replication, although HBV DNA levels may be lower than those seen in HBeAg positive infection.1,10 These mutations are of two types: precore, which prevents HBeAg production, and core promoter, which down-regulates HBeAg production. HBeAg negative chronic hepatitis with precore and/or core promoter mutations may be associated with elevated ALT levels, fluctuating elevations of ALT, disease flares, more severe disease, and significant liver disease at lower HBV DNA levels of 104 copies/mL.1,10,15,16
Ed Note: low levels of ALT suggest low viremia levels. So, if HBV DNA <400 becomes the goal than initiating therapy when ALT levels are low may be suggested.
Levels of HBV DNA that predict progressive liver disease have not been determined.1 The decision to treat is clearest when ALT is elevated and high (>105) levels of HBV DNA are detected. When ALT levels are elevated and HBV DNA levels are low in a patient who is HBeAg positive, a biopsy may show evidence of other disease.
Similarly, a liver biopsy may uncover significant liver disease when ALT values are persistently at ULN or fluctuating and HBV DNA levels are ≥104 copies/mL in HBeAg negative disease or ≥105 copies/mL in HBeAg positive disease.10 Once a candidate for treatment is identified, the next step is determining the most appropriate treatment option, which may be based in part on disease category.
What Are the Treatment Options?
See tables above, which compare the four agents currently licensed in the United States for the treatment of HBV infection.1,6-9 A number of recent publications have reviewed the clinical data on interferon, lamivudine, and adefovir in detail.1,10,17 Each of these agents is a potential first-line treatment with the choice depending on a number of variables, including the biochemical, virologic, and histologic (if available) features of the infection; patient factors such as age and preference; physician preference; and cost and reimbursement of therapy. An overview of the clinical efficacy of the four treatments for HBeAg positive chronic HBV infection is provided in Table 2.1,10,12 Most of these agents have not been studied in comparative trials, and study designs including patient characteristics and response criteria may have varied, thereby precluding direct comparisons. As the newest agent, entecavir was approved on the basis of trials conducted with an active comparator (lamivudine) rather than placebo, but experience in clinical practice is necessarily more limited at this time.9 Currently, reported resistance to lamivudine, which includes the YMDD mutant, occurs in approximately 24% of patients at 1 year, 42% at 2 years, 53% at 3 years, and 70% at 4 years in patients whose HBeAg status is positive at baseline.18,19 Reported resistance to adefovir is zero at 1 year, approximately 2% at 2 years, and 4% at 3 years.20,21 Resistance to entecavir has not been reported in nucleoside-naive, HBeAg positive or HBeAg negative patients in clinical trials. To date, approximately 1% of patients with pre-existing resistance to lamivudine develop resistance to entecavir.9
Interferon therapy is less well-tolerated than nucleoside/nucleotide analog therapy. The most common adverse events are flulike symptoms, fatigue, leukopenia, depression, anorexia, and hair loss, as well as potential exacerbation of underlying autoimmune disorders.1 Among the other agents, adverse events do not differ from placebo (or between entecavir and lamivudine) and they are generally well-tolerated.7-9 Data shown in this publication are for standard interferon alfa. However, additional data are emerging about peginterferon alfas, which are currently approved for the treatment of chronic hepatitis C.
Interferon alfa treatment appears to provide greater loss of HBsAg than do nucleoside or nucleotide analogs, although sufficient data on newer agents and comparative data are lacking.1
Selecting Among the Options
Guidelines to selecting a therapeutic agent have been published.1,10 Differences in recommendations arise primarily because of differences in criteria for selecting candidates for treatment. Once candidates are identified, HBeAg status can be important in formulating a treatment plan.
For HBeAg+ patients using oral antivirals, 1 year minimum; longer is usually required for durable response If HBeAg seroconversion occurs, maintain treatment for at least 36 months after confirmation of seroconversion; confirm seroconversion on two evaluations at least 2 months apart.
For HBsAg-negative using oral antivirals, 1 year minimum but longer therapy usually required Optimal treatment duration has not been determined, but may be lifelong.
HBV DNA levels should be assessed and a biopsy considered. The table also provides information about the duration of therapy and suggestions for monitoring. Various lines of evidence suggest that extending therapy with an antiviral agent may improve outcome, but additional study is needed before specific recommendations can be made.5,23-25 In particular, patients with chronic HBeAg negative infection may require longer duration of therapy to produce a sustained response. More research is needed to determine if and when one agent may be preferred over another. For example, emerging data suggest that the natural history of chronic HBV infection and response to treatment may be influenced by genotype, but data are insufficient to guide management at this time.26
Monitoring Treatment
Initial evaluations screen for treatment candidacy and provide baseline values for following patients. Pretreatment evaluation was discussed in Tx Reporter #2 in this series.
On-treatment monitoring of HBV DNA and ALT levels is used to evaluate response to treatment as well as to detect the emergence of resistance to nucleoside/nucleotide analogs. Treatment failure on therapy has been defined as the failure of a drug to induce a decrease of at least 1 log in serum HBV DNA levels by 3 months.27 Relapse is defined as a confirmed rebound in serum HBV DNA of 1 log as compared with nadir levels, provided that the patient is taking his/her medication. Increasing ALT levels may also signal emergence of resistance. In the event of on-treatment failure (resistance), a different nucleoside/nucleotide analog should be initiated. ED NOTE: there is controversy regarding discontinuing 3TC because of potential for serious ALT flares.
HBV DNA levels should be evaluated every 3 months, and liver function tests and a complete blood count should be conducted monthly for patients on interferon therapy. For patients receiving nucleoside/nucleotide analog therapy, liver function tests can be performed every 3 months. In addition, renal function (including serum creatinine and phosphate) should be assessed every 3 months for patients receiving adefovir therapy. After therapy, treatment should be reinitiated if and when relapse occurs (common in HBeAg negative disease). Posttreatment evaluations include assessment of HBV DNA levels, HBeAg status, and seroconversion 6 months and 1 year after therapy ceases. Liver function tests should be conducted every 3 months for approximately 1 year. If results remain normal, the interval can be increased to every 6 months. Posttreatment biopsy is unnecessary unless there is evidence of relapse and it becomes important to assess stage of disease.
The goal of treatment in patients with chronic HBV infection is to prevent progression to serious sequelae leading to premature death. A focus of treatment is suppression of HBV DNA to as low a level as possible. Four agents approved in the United States for the treatment of chronic HBV infection are interferon alfa, Pegasys, lamivudine, adefovir, and entecavir. Differences in safety, efficacy, cost, mode of administration, and resistance profiles (for nucleoside/nucleotide analogs) are factors in selecting therapy for treatment candidates. In addition, physician and patient preferences, and factors such as age, lifestyle, and quality of life, need to be considered. New treatment strategies that are under investigation include combination use of two antiviral agents or an antiviral agent plus an interferon.17,28,29 Many of the uncertainties in current treatment decisions are likely to be clarified as diagnostic testing methodology becomes refined and as understanding increases about the basic virology of HBV, the significance of various genotypes, and the development of mutant strains.
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