Overview of CHB Infection and Current Treatment

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[B]By David B. Purow, MD, and Ira M. Jacobson, MD [/B]


[B]Introduction[/B]

About 350 million people worldwide have chronic hepatitis B virus (HBV) infection. Up to 40% of persons infected with the virus may go on to have complications related to cirrhosis or hepatocellular carcinoma. Antiviral therapy can suppress viral replication and halt the progression of liver disease in persons with chronic infection.

In the following article, authors D.B. Purow and I.M. Jacobson explore the modes of HBV transmission, describe the characteristics of chronic infection, and review the drugs available to treat it. This overview provides an excellent general review of the treatment and management of chronic hepatitis B.
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Chronic HBV infection is prevalent in Southeast Asia, China, and Africa, where over 10% of the population may be infected. In Western Europe and North America, the disease affects less than 1% of the population (1), but more than 1 million people in the United States have chronic infection. Immunization and greater public awareness have significantly decreased the incidence of new HBV infection, but the treatment of persons already infected remains an important international health concern.



[B]Transmission and Chronicity[/B]

Perinatal spread and intrafamilial transmission are the major modes of HBV transmission in high-prevalence areas. In areas of low prevalence, HBV is usually transmitted by sexual contact or injecting drug use.

The risk of chronic infection is related to age at time of exposure. Newborns of actively infected mothers become long-term carriers in over 90% of cases. Immunocompetent adults have a risk of chronicity of 5%. Older infants and children have intermediate rates of chronic infection. Nearly all infants and most adults who progress to chronic infection have no symptoms during the acute phase.

Antiviral therapy has not been shown to alter the course or affect the risk of chronicity in patients with clinically recognized acute HBV infection. However, in patients with chronic HBV infection, antiviral therapy to suppress viral replication and halt the progression of chronic liver disease has been the focus of intense interest for more than two decades.

The US Food and Drug Administration (FDA) has approved three drugs for this disease, and approval of additional drugs is anticipated in the near future.



[B]Characteristics[/B]

The cardinal feature of chronic HBV infection is the long-term presence of hepatitis B surface antigen (HBsAg) in the blood. In contrast, persons who are no longer infected have hepatitis B surface and core antibodies. Most patients receive the diagnosis of chronic HBV infection long after chronicity is established.

When approaching chronic HBV infection, it is important to recognize that chronic HBV infection can exist in either an active replicative phase or an inactive replicative phase and that virologic, serologic, and biochemical tests can help distinguish between the two. Early detection is important because ongoing active viral replication results in progressive liver damage.

Assays to assess the replicative state of HBV and its pathogenicity measure levels of the hepatitis B e antigen (HBeAg) and antibody (anti-HBe), HBV DNA, and liver enzymes (especially alanine aminotransferase [ALT]).

Historically, the presence of HBeAg and high levels of HBV DNA have been used to identify patients with active HBV replication. HBeAg is derived from the core portion of the HBV genome. Many patients with these markers have active necroinflammatory liver disease and elevated ALT levels. In cohorts of such patients, roughly 10% per year have spontaneous clearance of HBeAg, usually with the appearance of anti-HBe, concomitant clearance or reduction of HBV DNA, and normalization of the ALT level.

Seroconversion from HBeAg to anti-HBe or the loss of HBeAg alone has been the major end point in most trials of antiviral therapy.

Some patients with high HBV DNA levels and active liver disease lack HBeAg and often are positive for anti-HBe. Although such patients may have been infected with the wild-type virus initially, they generally have a preponderance of an HBV strain that has a mutation in the precore region of the HBV genome (an extension of the region that codes for hepatitis B core antigen).

This precore mutation results in a failure to translate HBeAg despite ongoing active viral replication and production of intact core antigen. This mutant strain is most common in Asia and the Mediterranean, but its prevalence is also significant in northern Europe and North America.

Infection with the precore mutant strain may result in the same adverse outcomes as infection with the wild-type strain, and several reports have suggested the possibility of even greater pathogenicity. HBeAg seroconversion cannot be used as a marker in HBeAg-negative patients, whose levels of viral replication are monitored to detect a response to therapy.

Measurement of HBV DNA Levels

This measurement is a critical aspect of patient evaluation and assessment of response to therapy. As technology has improved, more sensitive HBV DNA assays have emerged. The initial quantitative HBV DNA assays incorporated hybridization techniques with lower sensitivity (lower limit, 105 to 106 genome copies/mL). Recently, more sensitive HBV DNA assays, including polymerase chain reaction (PCR), have enabled detection of levels as low as 2 X 102 copies/mL.

At a recent National Institutes of Health conference, an HBV DNA level of 105 was proposed as the marker that distinguishes patients with chronic HBV infection from those with inactive infection. However, this level is not always applicable, because some patients with active liver disease have lower HBV DNA levels, particularly those who lack HBeAg, in whom HBV DNA levels are commonly under 105 copies/mL.

  

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[B]Antiviral Therapy[/B]

Patients with a persistently normal ALT level generally undergo periodic laboratory tests even if active viral replication is present; they are not treated with any antiviral agent because response rates are low. However, the potential benefit of viral suppression in such patients, particularly those with cirrhosis, is of increasing interest since the advent of new oral agents with a low frequency of resistance. Other patients may receive interferon alfa-2b (recombinant) (Intron A), lamivudine (Epivir), or adefovir dipivoxil (Hepsera).
Intron A (interferon alfa-2b)
Interferon has been used for the treatment of hepatitis B for more than two decades. It has antiviral, immunomodulatory, and anti-proliferative properties, although its exact mechanisms of action are not clearly defined.

In a meta-analysis of 15 trials (2), 837 patients observed for 6 to 12 months after therapy showed a statistically significant response to interferon; in the studies, most patients were given interferon in a dosage of 5 MU daily or 10 MU three times weekly for 16 weeks. HBeAg loss was noted in 33% of patients; 37% of patients had no detectable virus in their bloodstream (in most cases, measured with older hybridization technology). Histologic improvement occurred concomitant with virologic response.

Subsequent studies have demonstrated a durable treatment response to interferon: 80% to 90% of successfully treated patients observed for up to 8 years remained HBeAg-negative. Indeed, in some patients, HBsAg clearance occurs years after clearance of HBeAg in response to a course of interferon (3).

Although clearance of the virus is the immediate goal of hepatitis B therapy, preventing further complications from liver disease is the ultimate objective. Data show that advanced liver disease is less likely to occur in responders to interferon therapy than in nonresponders (4,5).

Patients who do not have HBeAg are more refractory to interferon therapy. Sustained response rates of only 15% to 18% have been seen (defined as persistently undetectable HBV DNA as measured with hybridization techniques) (6).

Viral suppression after the initiation of therapy is common, but relapse is more common than with wild-type HBV infection. Increasing the duration of therapy to 12 or 24 months raises response rates in these patients, but compliance is a challenge because of significant adverse effects (6,7).

Patients with sustained response to therapy have lower HBV DNA levels at the end of treatment than patients who respond but then relapse.

Adverse Effects

Adverse effects of interferon are numerous and include flu-like symptoms (e.g., fever, headache, fatigue), myalgias, hair loss, diarrhea, difficulty concentrating, depression, peripheral neuropathy, nausea, rash, injection site reactions, neutropenia, thrombocytopenia, and thyroid dysfunction.

Serious adverse effects are uncommon but can include exacerbation of bronchospasm, cardiac ischemia or arrhythmias in predisposed patients, seizures, and retinopathy. The drug must be self-injected. Dose reductions or even discontinuation may be necessary.

Nonresponse and Delayed Response

In addition to infection with the precore mutant strain of HBV, other factors have been shown to predict nonresponse to interferon therapy. These factors include low ALT levels, very high serum HBV DNA levels, immunosuppression, and coexisting hepatitis D virus infection.

Many patients who ultimately respond to interferon have a disease flare during therapy that features a sharp rise in ALT and aspartate transaminase. Although this flare is a favorable indication of subsequent response, it can result in decompensation in patients with preexisting cirrhosis. Interferon should be used with caution in patients with cirrhosis and generally should be avoided in patients with borderline or decompensated liver function.

Epivir-HBV (lamivudine)

In 1998, lamivudine became the first oral agent to be approved by the FDA for the treatment of chronic HBV infection. It is a synthetic nucleoside analogue that results in premature DNA chain termination when its phosphorylated form is incorporated into viral DNA. Lamivudine, which is a strong inhibitor of both HIV reverse transcriptase and HBV reverse transcriptase, has been a mainstay of HIV therapy.

The drug offers several advantages over interferon, including availability as an oral agent and a favorable side effect profile. The recommended dose for the treatment of chronic hepatitis B is 100 mg per day in contrast to 150 mg twice daily for HIV patients.

Two controlled trials in treatment-naive patients established the role of lamivudine in the treatment of HBeAg-positive patients with chronic HBV infection. In a US study conducted by Dienstag and colleagues (8), 137 treatment-naive patients were randomly assigned to receive either lamivudine, 100 mg once daily, or placebo for 52 weeks. Lai and associates (9) randomly assigned 358 treatment-naive patients to receive lamivudine, 25 or 100 mg once daily, or placebo for 52 weeks. The results of these trials are summarized in table 1.

Overall, lamivudine demonstrated significant improvement at a number of end points, including HBeAg clearance, HBeAg seroconversion, HBV DNA suppression, ALT normalization, and histologic improvement, when compared with placebo. However, although lamivudine achieved an initial virologic response in many patients, this response did not appear to be durable. Even though 98% of the US patients had undetectable HBV DNA at least once during therapy, only 44% had sustained viral suppression through week 52. Moreover, 16 weeks after cessation of therapy, median HBV DNA levels rose to 55% of their baseline values.

Response

A key predictor of response to lamivudine is baseline ALT level. Much better results are seen in patients with an ALT level more than twice the upper limit of normal. Important data about long-term therapy emerged from an extension of the trial by Lai and colleagues (10).

Sustained HBV DNA suppression occurred in 52% of patients who received lamivudine, 100 mg daily for 104 weeks, compared with 5% of those who received lamivudine in the first year and placebo in the second year. In a smaller group of patients treated for a third year, the HBeAg seroconversion rate increased to 40% (11).

Such observations led to the widespread practice of administering long-term (>52 weeks) lamivudine treatment in patients without clearance of HBeAg. This practice is further supported by a recent long-term study (12) demonstrating progressive histologic improvement over 3 years of lamivudine therapy, including reversal of fibrosis in patients with bridging fibrosis or cirrhosis.

Resistant Mutations

Unfortunately, the development of lamivudine-resistant HBV mutations (mutations in the tyrosine-methionine-aspartate-aspartate [YMDD] region of the HBV DNA polymerase gene) has been associated with lamivudine and has a direct correlation with the duration of therapy (10).

In the long-term lamivudine trial by Liaw and associates (10), 40% of the 154 patients treated continuously for 104 weeks had evidence of the YMDD mutation versus 14% after 52 weeks of therapy. Resistance increased to 53% after 3 years (11) and to 66% after 4 years (13).

Another study conducted by Liaw and colleagues (14) explored the clinical implications of the emergence of the YMDD mutation in 32 of 55 patients who received continuous lamivudine therapy for at least 104 weeks. Elevation of ALT levels occurred in 94% of patients, and acute exacerbation of hepatitis B (defined as an abrupt twofold increase of ALT to a level greater than five times the upper limit of normal, or 300 U/L) was seen in 41% at a median of 24 weeks after the development of the YMDD mutation.

Thus, the development of the mutation with long-term lamivudine therapy has important clinical ramifications that limit the drug's overall effectiveness. However, the development of the mutation does not completely preclude the possibility of subsequent HBeAg clearance, a finding that is consistent with the progressive increase in both YMDD mutation appearance and HBeAg clearance in the long-term studies.

Studies examining the treatment of other populations (eg, HBeAg-negative patients, liver transplant recipients, and patients infected with both HBV and HIV) show similar viral-suppressive effects. Initial histologic and virologic responses are seen in HBeAg-negative patients, but these responses may be lost or reversed over time owing to a lack of durability or the development of YMDD mutants.

Development of the mutation is associated with increased graft failure after liver transplantation. A high percentage of patients who are infected with both HBV and HIV have lamivudine resistance because they have been on lamivudine therapy for years as part of their HIV treatment.

Hepsera (adefovir dipivoxil)

In September 2002, the FDA approved adefovir, an oral adenosine analogue, for the treatment of chronic HBV infection. In two major double-blind studies published recently, 342 HBeAg-positive patients with chronic HBV infection received either adefovir, 10 mg/day, or placebo for 48 weeks (15), and 185 HBeAg-negative patients with chronic HBV infection were randomly assigned to receive either adefovir, 10 mg/day, or placebo in a 2:1 ratio (16).

Both studies demonstrated the histologic, virologic, serologic, and biochemical benefits of adefovir.

Recent observations of patients who had been receiving adefovir for 72 weeks revealed significant increases in end points of success, with 44% experiencing HBeAg loss, 23% having seroconversion, and 46% experiencing a reduction of HBV DNA level to fewer than 400 copies/mL (17). Similar effects were seen in a randomized trial of 184 HBeAg-negative patients (18), in whom there was a 3.9-log drop in HBV DNA. Among these patients, 66% had fewer than 400 copies/mL at 48 weeks and 80% had fewer than 400 copies/mL at 72 weeks.

Lack of Resistant mutations

A major feature of the response to adefovir is the apparent lack of resistant mutations. In the two major phase 3 trials involving nearly 700 patients treated for 48 weeks, HBV polymerase substitutions were seen at several sites in patients given either adefovir or placebo; however, no in vitro resistance or viral rebound during therapy was seen. In a long-term extension study involving 39 patients treated for up to 136 weeks (19,20), there was again no evidence of the emergence of resistant mutations.

Adefovir could clearly have an impact on the treatment of patients with lamivudine-resistant hepatitis B mutations. A recent double-blind study (21) explored the effects of adefovir in 59 patients with the YMDD mutation. Patients were randomly assigned to receive either adefovir monotherapy, 10 mg/day; adefovir, 10 mg/day, combined with lamivudine, 100 mg/day; or lamivudine monotherapy, 100 mg/day, for 48 weeks.

Serum HBV DNA levels decreased significantly, between 3.5 and 4 logs, in both groups receiving adefovir compared with the lamivudine group. Another study (22) has examined the role of adefovir in the treatment of lamivudine-resistant hepatitis B in patients who also have HIV. Substantial histologic, virologic, and biochemical responses were evident after 96 weeks of therapy.

Another intriguing recent finding is that episomal closed circular covalent HBV DNA sharply decreases within hepatocytes after 48 weeks of therapy with adefovir (23). The importance of this observation stems from the critical role of closed circular covalent HBV DNA as the template for viral replication and the potential for viral reactivation as long as this episomal form of the HBV genome persists.



Treatment Options

Currently, several options are available for the treatment of patients with chronic HBV infection who have not previously received antiviral therapy. A number of other agents are being investigated for the treatment of chronic HBV infection.

Entecavir, a nucleoside analogue, and tenofovir disoproxil fumarate (Viread), a nucleotide analogue recently approved for the treatment of HIV, have shown particular promise (24).

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Trials are also in progress to assess the efficacy of pegylated interferon alfa-2a and alfa-2b in HBV infection.

Some physicians continue to use interferon alfa for patients with predictive factors for favorable outcome, such as HBeAg-positive status, an ALT level greater than twice the normal level, and the absence of cirrhosis. Other experts prefer to start with an oral agent. Lamivudine has the advantage of familiarity and lower cost, and adefovir is attractive because it has not yet been linked to the emergence of resistant mutations.

Discontinuation of Oral Agents

Deciding when to stop oral agents can be difficult. Some physicians, including the authors of this article, prefer to continue therapy for at least 6 months after HBeAg loss or seroconversion has been achieved; other physicians believe that such protracted therapy has not been rigorously shown to be necessary.

In the absence of HBeAg loss, most physicians continue these agents indefinitely on the basis of reports of histologic improvement (12) and the hope that the degree of viral suppression achieved will slow disease progression.

However, the emergence of YMDD mutations in patients receiving lamivudine can be associated with a significant flare of disease. Patients can be switched to adefovir if the YMDD mutation emerges during lamivudine therapy. Physicians should be aware that the emergence of this mutation may be foreshadowed by the return of a high HBV DNA level and by a flare of disease, underscoring the importance of periodic monitoring. Studies have not sufficiently addressed whether using both oral agents together confers an advantage to treatment-naive patients.

Combination Therapy

Some physicians believe combination therapy with interferon and an oral agent has a role in the treatment of chronic HBV infection. In the largest trial evaluating interferon plus lamivudine versus either drug alone (25), HBeAg seroconversion occurred in 18% of subjects who received lamivudine, 19% of those treated with interferon, and 29% of those given combination therapy.

These differences were not statistically significant, but patients given combination therapy received only 6 months of lamivudine versus 12 months in the lamivudine monotherapy group. In a study of prior interferon nonresponders who received lamivudine alone versus lamivudine combined with interferon in which the lamivudine was started first, the patients receiving lamivudine alone had better response rates (26).

When interferon and an oral agent are used together, some physicians start the two concomitantly or with a brief course of interferon preceding the oral agent; in both cases, the oral agent is continued for some time after the interferon is stopped.

With the anticipated development of additional oral viral inhibitors, it is likely that in several years combination regimens analogous to those used for HIV will be available. It will be important for the hepatology community to design and conduct appropriate trials to test such combinations. Whether an immunomodulatory drug such as interferon will be needed in addition to viral enzyme inhibitors, and what the role of pegylated interferons will be, must be determined through clinical trials.



Conclusion

More than 1 million people in the United States are chronically infected with HBV. Immunization and greater public awareness have led to fewer new infections, but the treatment of persons already infected is of vast concern. Antiviral therapy does not appear to alter the course of acute HBV infection or affect the risk of being chronically infected. Most chronically infected persons do not even know they are infected until long after chronicity has been established. However, these patients can benefit from antiviral therapy to halt viral replication and stop the progression of chronic liver disease. Three such drugs are FDA-approved for this indication, and more drugs are expected to be approved in the near future.

[B]Source[/B]

DB Purow and IM Jacobson. Slowing the progression of chronic hepatitis B: Early antiviral therapy can help minimize complications. Postgraduate Medicine 2003;114(1): 65-76. July 2003.
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25.    Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46(4):562-8

Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. Hepatology 2003;38(6):818-26
Dr Purow is a clinical fellow and Dr Jacobson is chief, division of gastroenterology and hepatology, Joan and Sanford I. Weill Medical College of Cornell University, New York. Correspondence: Ira M. Jacobson, MD, Division of Gastroenterology and Hepatology, Joan and Sanford I. Weill Medical College of Cornell University, 450 E 69th St, New York, NY 10021. E-mail: [email protected].  

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