The primary goal of HBV treatment is to convert active replicative infection to the inactive nonreplicative state. If this state is achieved and sustained, the risk of liver-related morbidity and mortality is significantly reduced. The following three treatments are currently FDA-approved therapies for HBV: (1) interferon-a, (2) lamivudine, and (3) adefovir dip-ivoxil. Several other agents are in late-stage clinical study.
Interferons are both antiviral and immunostimulatory. It is believed that the dominant beneficial effect of interferon-a in chronic HBV infection is due to immunostimulation. In fact, when interferon is effective in HBV infection it induces a heightened immune response against infected hepatocytes resulting in more marked liver inflammation and increased serum aminotransferases. If the inflammatory reaction is sufficiently vigorous, it may result in conversion from an active replicative infection to an inactive infection.
Interferon-a is given by subcutaneous injection and most patients can be taught to self-administer the drug. The usual dose in chronic HBV infection is 5 MU daily or 10 MU thrice weekly for a duration of 16 weeks. I find that the daily dosing schedule is usually better tolerated by patients. Interferon almost always causes flu-like symptoms, which may vary from mild to debilitating. Usually these symptoms improve after the first few weeks of treatment despite continued therapy. Interferon is myelosup-pressive and patients must be monitored for neutropenia and thrombocytopenia. Autoimmune disorders can be exacerbated or unmasked by interferon and the treatment is generally contraindicated in patients with autoimmune diseases with the exception of stable hypothyroidism. Depression may occur, especially in patients with a prior history. This treatment should not be used in patients with a history of major depression, suicidal attempts or ideation, or major affective disorders. As effective treatment triggers an exacerbation of hepatitis, interferon should not be used in patients with decompensated liver disease (Child's class B or C) since they may not have the hepatic reserve required to survive the disease flare.
A widely quoted meta-analysis of 15 HBV interferon-a studies has shown that approximately one-third of patients who begin treatment HBeAg and HBV DNA positive will lose these markers, (Wong et al, 1993) although the response may be delayed until up to 6 months after completing therapy. When HBeAg clearance is induced by inter-feron-a, liver histology improves and it is rare for viral replication to reactivate. Patients most likely to respond to interferon therapy have increased serum aminotransferases, relatively low HBV DNA levels, and a history of acute hepatitis (as opposed to subclinical or perinatal infection).
With HBeAg negative, HBV DNA positive infection, HBV DNA loss may occur during or following interferon-a therapy. Unfortunately, in most of these cases viral replication reactivates some time after treatment is stopped. There is data to suggest that patients with presumed pre-core mutant virus HBV infection may have a better sustained viral response rate when treated for 12 or more months with interferon-a.
Two PEGylated formulations of interferon-a have recently been approved for the treatment of chronic HCV infection. These agents have the advantage of a prolonged duration of action and once weekly administration. Studies are ongoing to determine the efficacy of these agents in chronic HBV infection. It is not yet known what the appropriate dose and treatment duration will be with these PEGylated interferons.
Lamivudine is an orally administered nucleoside, which integrates into the elongating DNA chains of replicating HBV, thus terminating viral replication. This agent has been shown to be highly efficacious in reducing HBV DNA when given at a dose of 100 mg/d. After 3 years of continuous treatment with lamivudine, approximately one-third of patients who were originally HBeAg positive will have converted to HBeAb. It appears that seroconversions induced by lamivudine are less durable than those induced by interferon, as a significant proportion of patients will reactivate replication if and when lamivudine is stopped. Patients with presumed precore mutant HBeAg-negative chronic HBV infection respond to lamivudine therapy but in the vast majority of cases, viral replication resumes after drug is withdrawn. As with interferon-a, high pretreatment aminotransferases are predictive of a good response to lamivudine treatment. Although lamivudine is extremely well tolerated, the major problem in its use is its propensity to select for resistant escape mutants. The most common mutant affects the YMDD motif of the DNA polymerase and allows the virus to replicate despite continued exposure to lamivudine. Although some studies suggest that this mutated virus is less harmful than the wild-type virus, this finding has not been consistent. About 15% of chronic HB patients develop resistance to lamivudine after 1 year of treatment and this increases to approximately 50% at 3 years.
The most recent therapy approved for the treatment of chronic HB is adefovir dipivoxil. This nucleotide analog has been shown to be effective in both HBeAg positive and negative chronic HBV infection. Adefovir dipivoxil is effective against HBV infections that have acquired resistance to lamivudine. The usual dose is 10 mg/d but it must be adjusted for renal impairment. The major adverse effect of adefovir dipivoxil is nephrotoxicity. To date, resistance to adefovir dipivoxil has been exceedingly rare although there are few patients who have been treated with this agent beyond 2 years.
A number of other agents are in development for chronic HBV infection including entecavir and emtric-itabine (FTC).
With several different treatments available, there are options when it comes to the management of patients with chronic HBV infection. Treatment should only be considered in patients with actively replicating infection as indicated by significant serum levels of HBV DNA. Because none of the available therapies is likely to be effective in the immunotolerant phase of infection, patients with persistently normal aminotransferases should generally be followed conservatively and considered for treatment only when and if their liver enzymes become abnormal. However, patients with normal enzymes may be considered for therapy if their liver biopsies demonstrate moderate to severe hepatitis.
once the decision is made to treat chronic HBV, an appropriate therapy must be chosen. Although not tested head-to-head, the efficacy of interferon-a and the oral nucleoside/nucleotide agents appears to be similar. Interferon-a must be administered by injection and may be associated with significant side effects. It does, however, have the advantage of a finite course of therapy, whereas the oral agents must be given long term and possibly indefinitely. Although safe and generally well tolerated, the major downside of the oral agents is the induction of resistant escape mutants. This appears to be a larger problem with lamivudine than adefovir dipivoxal, although longer term data is awaited.
I believe that it is acceptable to use any of these three agents as first line therapy in chronic HBV infection, depending on physician and patient preference. In the patient with HBeAg positive HBV infection, especially if serum aminotransferases are more than twice normal, I prefer to use a standard 16-week course of interferon-a initially. However, many patients have contraindications to the use of inter-feron-a related to psychiatric conditions and autoimmu-nity. Furthermore, many patients are unwilling or unable to tolerate the side effects of interferon-a injections. Because of the potential for life threatening liver failure, patients with decompensated liver disease should not be treated with interferon-a. Patients who fail to clear HBV DNA and seroconvert HBeAg to HBeAb within 6 months of completing interferon-a therapy can be considered for alternate therapy.
The oral nucleoside/nucleotide drugs, lamivudine and adefovir dipivoxil are easily administered, well tolerated, and can be safely used in patients with hepatic decompensation. Their major limitation relates to the requirement for long term treatment, without clear cut parameters to stop the medications. In those patients who experience an HBeAg to HBeAb seroconversion on therapy, one can consider stopping treatment after a minimum of 3 months of "consolidation therapy." However, even after this extension of therapy, there is potential for reactivation of viral replication after medication is withdrawn. The longer treatment is continued, the greater the potential for emergence of resistant escape mutants. For these reasons, I prefer to limit the use of these agents to those patients at significant risk of progressive liver disease, so I generally advise a staging liver biopsy before initiating these drugs.
Although lamivudine is less expensive than adefovir dip-ivoxil, it appears to be associated with a higher rate of emergence of resistant mutants—at least in the short to medium term. I am concerned that resistance to adefovir dipivoxil may become more significant as we accrue more experience with the long term use of this agent. Because the resistant strains selected by each of the two drugs retain sensitivity to the other agent, it may be rational to use combination therapy in a manner analogous to the strategy used to treat HIV infection. It is anticipated that additional antiviral drugs will become available over the next few years. An initial study of combination therapy using inter-feron-a and lamivudine failed to show significant benefit. However, this strategy is being revisited in ongoing studies using PEGylated interferon and oral antivirals. Sequential use of nucleoside/nucleotide drugs following the emergence of resistance may be expected to generate multiply resistant strains. This is of particular consequence in the patient who will ultimately require a liver transplant, as recurrent HBV infection is frequently fatal when effective antiviral strategies are not available. Those patients with decompensated liver disease are best treated in concert with a liver transplant program.
The patient with HBeAg negative, HBV DNA positive infection poses particular issues. If interferon-a is used, treatment should be prolonged for at least 12 months, although many patients will have difficulty tolerating interferon for such long periods of time. If oral antivirals are used, there are no parameters to guide us in stopping therapy. I only treat patients with presumed precore mutant virus infection if they have significant hepatic fibrosis, and explain to patients that treatment will be open-ended and likely lifelong.
The treatment of chronic HBV infection is challenging and constantly evolving. With novel therapeutics and treatment strategies being developed, the approach to managing these patients will undoubtedly change in the years to come.
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