New Paradigms for the Treatment of Chronic Hepatitis B - 1 of 2

October 8, 2008

http://www.medscape.com/viewarticle/579413?src=mp & spon=20 & uac=31238BR

From Journal of Gastroenterology and Hepatology

New Paradigms for the Treatment of Chronic Hepatitis B

Posted 09/26/2008

Fung; Ching-Lung Lai; Man-Fung Yuen

Abstract and Introduction

Abstract

The main goals of chronic hepatitis B treatment should be the long-term

suppression of viral replication to minimize disease progression and the risk

for the development of hepatocellular carcinoma. Treatment end-points, depending

on surrogate markers alone, in particular hepatitis B e-antigen seroconversion,

may not be ideal for patients who acquire the disease early in life.

Currently-available drugs include interferons and oral nucleoside/nucleotide

analogs. Although interferon therapy provides a finite treatment period, a

significant proportion of patients may not respond, and long-term outcome is

inconclusive. Long-term efficacy has been demonstrated for both lamivudine and

adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated

with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide

analogs with a high genetic barrier and potent antiviral activity, such as

entecavir, should be used to reduce the chance of developing drug-resistant

mutations. Drugs with a low genetic barrier, including lamivudine and

telbivudine, should be used in conjunction with early testing for antiviral

response. This can predict favorable outcomes in the long term. The early

detection of drug-resistant mutations should prompt clinicians to either add or

switch to another agent with a different drug-resistance profile. There are

currently no treatment models in the use of combination or sequential therapy in

treatment-naÃ¯ve patients.

To date, long-term treatment appears to be the most effective option. Despite

recent advances made with better understanding on the natural history of chronic

hepatitis B infection and with newer antiviral drugs available, challenges

remain with respect to treatment criteria, treatment end-points, and duration of

treatment.

Introduction

An estimated 400 million people worldwide are infected with chronic hepatitis B

(CHB), constituting a major health problem.[1] Approximately 1 million people

die annually as a result of hepatitis B virus (HBV)-related liver cirrhosis and

hepatocellular carcinoma (HCC). Over 70% of CHB patients are of Asian origin.

The numbers of people with CHB in the USA and UK have been estimated to be

approximately 1.25 million and 180 000, respectively.[2]

The age of acquisition of HBV plays an important part in determining the natural

history of HBV infection, and is best illustrated by the difference observed

between Asian and Caucasian patients. The majority of Asian patients acquire HBV

either via vertical transmission or early horizontal transmission, that is,

within the first few years after birth. This is in contrast to the majority of

Caucasian patients who acquire the infection during adolescence or in early

adulthood. The course of those infected early in life is characterized by a

prolonged immunotolerant phase followed by a prolonged phase of immunoclearance,

typically during the third and fourth decades of life. These patients will

eventually undergo hepatitis B e-antigen (HBeAg) seroconversion with the

development of antibodies to HBeAg (anti-HBe). Disease progression to

symptomatic cirrhosis and HCC has been shown to occur in a proportion of

patients after HBeAg seroconversion. In fact, the majority of these

complications occur in patients who are anti-HBe positive. In contrast, the

majority of patients infected during later childhood or adolescence will

immediately enter the immunoclearance phase without going through the

immunotolerant phase, and the disease usually becomes more quiescent after HBeAg

seroconversion. The differences in natural history between these two groups of

patients must be considered when considering CHB treatment.

Goals of Therapy

The ideal goal of CHB therapy is the complete eradication of HBV. However,

despite recent advances in treatment strategies with newer and more potent

antiviral agents, complete eradication of HBV is still not possible. The

persistence of highly-stable, covalently-closed circular DNA within the nuclei

of hepatocytes provides an intracellular reservoir of HBV replication, leading

to persistent infection. The virus may also integrate into the host genome.

Therefore, the long-term goals of treatment should be the prevention of liver

cirrhosis, liver failure, and HCC.

For the purpose of clinical trials, treatment end-points for CHB have focused on

more short-term goals, such as normalization of serum alanine aminotransferase

(ALT) levels, HBV-DNA suppression, HBeAg seroconversion, and improvement in

liver histology. Recent treatment guidelines and algorithms have realized the

importance of viral suppression in the prevention of disease progression and

HCC.[3,4] However, the treatment of CHB remains complex and is dependent on

multiple factors. These include the biochemical, virological, and immunological

profiles, as well as the underlying disease severity and its natural history.

Treatment Choices

There are currently six antiviral agents available for the treatment of CHB:

lamivudine, adefovir, entecavir, telbivudine, interferon (IFN)-Î±, and pegylated

IFN (peg-IFN). Newer antiviral drugs, such as tenofovir, will become available,

increasing the options available for CHB treatment. The choice of therapy should

always take into consideration the antiviral efficacy, risk of developing drug

resistance, long-term safety profile, methods of administration, and costs of

the agent.[3]

IFN-Î± and Peg-IFN. Previous meta-analyses have shown IFN-Î± to be effective in

promoting hepatitis B surface antigen (HBsAg) and HBeAg seroconversion, and in

suppressing HBV-DNA.[5] Peg-IFN has largely surpassed standard IFN in CHB

treatment. In the only head-to-head comparison from a phase II study,

peg-IFN-Î±2a was superior to standard IFN in HBeAg clearance, HBV-DNA

suppression, and the normalization of ALT. However, the standard IFN in this

trial was given at a fixed dose of 4.5 MIU three times a week rather than the

conventional doses of 5 MIU/m2 daily or 10 MIU/m2 three times a week.[6]

Compared with lamivudine, 48 weeks of peg-IFN-Î±2a (180 Âµg/week) resulted in a

higher rate of HBeAg seroconversion (32% vs 19%, P < 0.001).[7] The majority of

recent studies have focused on combination or sequential therapy with

lamivudine.[8] In one small study from India, lowering viral load with

lamivudine prior to IFN therapy has been shown to improve sustain viral response

when compared to using IFN alone.[9] However, most studies have not shown any

additional benefit of adding lamivudine to IFN therapy in either HBeAg-positive

or HBeAg-negative disease when assessed at 6 months after the cessation of

therapies.[7,10-14] It should be noted that in all these studies lamivudine was

stopped after 48 weeks, irrespective of HBeAg seroconversion or the extent of

viral suppression, a practice which is not advocated in any of the current

guidelines, and which on its own may be hazardous for presaging post-treatment

hepatitis flares. Although no additional antiviral efficacy is observed, there

is evidence that combining IFN with lamivudine therapy decreases the development

of lamivudine-resistant mutations.[12,13]

The long-term effectiveness of standard IFN has not been consistently shown.

Long-term benefits, including preventing cirrhosis and HCC, were not observed in

Japanese and Chinese patients.[15,16] In a more recent retrospective study of

233 IFN-treated Taiwanese patients with pretreatment mean ALT levels greater

than 175 U/L, IFN was shown to reduce HCC and cirrhosis in HBeAg-positive

patients compared to untreated controls. However, a subgroup analysis comparing

HBeAg non-seroconverters in the control group, non-seroconverters in the IFN

group, seroconverters in the control group, and seroconverters in the IFN group,

statistical differences were only observed between the first group versus the

third and fourth groups. There were no differences among the latter three

groups.[17] Also a mean ALT level of 175 U/L at recruitment is an unusually high

ALT level for Asian patients with CHB, so that the results obtained from this

study can only apply to those patients with ALT levels of>150 U/L. Further

results regarding peg-IFN with long off-treatment follow up will be awaited to

determine its long-term efficacy.

Lamivudine. Lamivudine was the first oral antiviral drug approved for the

treatment of CHB. It is effective in inducing viral suppression, normalization

of ALT, HBeAg seroconversion, resolving histological hepatitis, and decreasing

the progression of liver fibrosis.[18,19] The long-term benefits of lamivudine

in reducing the complications of cirrhosis, including decompensation and HCC,

have been shown in two long-term studies with precirrhotic/cirrhotic and

non-cirrhotic patients.[20,21] However, lamivudine is associated with high rates

of viral resistance of approximately 50% after 3 years. After 8 years' treatment

with lamivudine, the prevalence of genotypic resistance was 76%.[21]

Resistance to lamivudine occurs as a result of rtM204V or rtM204I mutations with

or without concomitant rtL180M mutation of the HBV polymerase gene.[22] It has

been shown that the initial benefits conferred by lamivudine are reduced in

patients who develop lamivudine-resistant mutations during long-term follow

up.[23] However, even among those with drug resistance, the outcome remains

better than that for untreated patients.[20,21] Caution must be taken when

stopping therapy without replacement with another effective antiviral agent.

There is the potential for hepatitis flares to occur after stopping treatment

due to rapid rebound replication of wild-type virus. Both adefovir and entecavir

are effective against lamivudine-resistant CHB; the factors that need to be

considered in making the choice of second agent are discussed later.

Adefovir. Adefovir dipivoxil has been shown to be effective in both

HBeAg-positive and HBeAg-negative CHB, as well as lamivudine-resistant

mutations.[24-26] Although relatively slow in action, the long-term efficacy of

adefovir in maintaining viral suppression, and biochemical and histological

responses has been shown in patients treated for 5 years.[27] With newer and

more potent antiviral agents now available, adefovir is mainly used in patients

who have developed resistance to lamivudine or telbivudine. Some studies have

shown that adefovir monotherapy in lamivudine-resistant patients is as effective

for suppressing HBV-DNA as combination therapy with lamivudine.[28-30] Despite

this, several studies, including a large randomized controlled trial,[31] report

a substantially lower rate of resistance to adefovir when treatment is continued

in combination lamivudine versus " switching " to adefovir in patients with

lamivudine resistance.[31-34] In general, the recommendation for

lamivudine-resistant patients would be adding adefovir as soon as genotypic

resistance is detected. This strategy will achieve the best outcome in terms of

minimizing adefovir resistance and hence maintaining HBV-DNA suppression in the

long term, thereby providing the sought-after surrogate condition for preventing

adverse disease outcomes.

Adefovir has a higher genetic barrier than lamivudine, meaning that the rates of

resistance in treatment-naÃ¯ve patients are lower. Thus after 5 years of follow

up, 29% of HBeAg-negative patients developed genotypic resistance to

adefovir.[35] Mutations at rtA181V/T and rtN236T of the HBV polymerase gene are

responsible for adefovir resistance.[36] Adefovir-resistant HBV is sensitive to

both entecavir and lamivudine.[37]

Entecavir. Entecavir is a carboxylic analog of guanosine, and the third oral

antiviral agent approved for CHB treatment. In phase III trials for both

HBeAg-positive and HBeAg-negative CHB, entecavir was superior to lamivudine in

HBV-DNA reduction and in inducing histological improvement.[38-40] Furthermore,

no virological breakthrough from entecavir resistance has been observed after 2

years of treatment in treatment-naÃ¯ve HBeAg-positive patients.[41] In a

dose-finding phase II trial, entecavir has been shown to be effective against

tyrosine-methionine-aspartate-aspartate (YMDD) mutant strains of HBV, albeit at

the higher daily dose of 1 mg instead of the recommended 0.5 mg daily dose for

treatment-naÃ¯ve patients.[42] A subsequent phase III trial has shown

significantly better histological, virological, and biochemical outcomes with

entecavir compared to lamivudine in lamivudine-refractory patients.[43]

Resistance to entecavir in treatment-naÃ¯ve patients is rare, occurring in 1.1%

of patients after 4 years of therapy.[44] However, in patients with pre-existing

lamivudine-resistant mutations, there is a lower viral response rate, and a

correspondingly higher rate of developing entecavir resistance, 39% after 4

years.[45] The reason for the higher rate of resistance is because the rtM204V

and rtL180M mutations that characterize lamivudine resistance are a prerequisite

for subsequent (third or fourth) mutations that lead to the emergence of

entecavir resistance. Thus rtM204V and rtL180M mutations are not sufficient by

themselves to confer resistance to entecavir unless an extra mutation occurs at

rtT184G, rtS202I, or rtM250V.[45,46] As the corollary of this sequence of

mutations, the pre-existence of lamivudine resistance predisposes patients to

develop subsequent resistance to entecavir. For this reason, entecavir-switching

therapy may be less optimal than adefovir add-on therapy for CHB associated with

lamivudine resistance. However, studies of direct comparisons are required to

establish this.

Telbivudine. Telbivudine has been shown to be more potent than lamivudine

against HBV.[47] An open-label trial comparing telbivudine and adefovir also

showed greater HBV-DNA suppression in patients treated with telbivudine than

adefovir after 52 weeks.[48] Despite its superior antiviral efficacy and lower

resistance rate compared to lamivudine, telbivudine is still associated with

higher resistance rates than adefovir or entecavir.[49]

Resistance to telbivudine occurs at the same mutation site responsible for

lamivudine resistance. The rate of genotypic resistance after 2 years of

telbivudine treatment is 22% and 8.6% among HBeAg-positive and HBeAg-negative

patients, respectively.[49] Compared with lamivudine, the lower resistance rate

of telbivudine is partly because of the greater antiviral potency of

telbivudine, but possibly also because only the M204I mutant is observed and not

the M204V/L180M.[47]

Comparison of Available Treatments

There are few head-to-head comparisons of currently-available antiviral agents.

A cross-study analysis of results at 1 year from 28 trials involving lamivudine,

adefovir, and entecavir concluded that the antiviral efficacy of entecavir was

superior to lamivudine, which in turn was superior to adefovir in

nucleoside-naÃ¯ve patients.[50]

HBeAg Seroconversion. In HBeAg-positive patients, 12-27% of patients treated

with HBV antiviral agents will seroconvert after 1 year of treatment, as shown

in Figure 1.[7,24,39,47] IFN therapy has been shown to have the highest rate of

HBeAg seroconversion after 1 year of treatment. However, patients who do not

seroconvert, that is, the majority of patients (approximately 70%), will require

an alternative form of long-term antiviral therapy. After 2 years of therapy,

HBeAg seroconversion rates are similar for all the currently-available antiviral

agents, despite differences in their antiviral efficacy.

Figure 1. (click image to zoom)

Summary of hepatitis B e-antigen (HBeAg) seroconversion at 1 (a) and 2 years (

in patients receiving different treatment. For pegylated interferon

(peg-IFN)-treated patients, the HBeAg seroconversion rate at 2 years refers to 1

year of therapy followed by 1 year of follow up. Data are not head-to-head

comparisons. Adv, adefovir; Ent, entecavir; Lam, lamivudine; Tel, telbivudine.

Normalization of ALT. In both HBeAg-positive and HBeAg-negative patients, the

rate of ALT normalization at 1 year is approximately 38-39% for IFN and 48-78%

for oral antiviral therapy, as shown in Figure 2.[7,24,38,39,47,51]

Figure 2. (click image to zoom)

Summary of alanine aminotransferase (ALT) normalization at 1 year in hepatitis B

e-antigen (HBeAg)-positive (a) and HBeAg-negative ( patients receiving

different treatments. Data are not head-to-head comparisons. Adv, adefovir; Ent,

entecavir; Lam, lamivudine; Peg-IFN, pegylated interferon; Tel, telbivudine.

Reduction in Viral Load. The 1-year rates of viral suppression between the

different antiviral agents for HBeAg-positive and HBeAg-negative CHB are

summarized in Figure 3. Approximately 21-67% of patients will have undetectable

HBV-DNA after 1 year of treatment in HBeAg-positive patients, and 51-90% in

HBeAg-negative patients.[7,24,38,39,52]

Figure 3. (click image to zoom)

Summary of HBV-DNA suppression at 1 year in hepatitis B e-antigen

(HBeAg)-positive (a) and HBeAg-negative ( patients receiving different

treatments. Data are not head-to-head comparisons. Adv, adefovir; Ent,

entecavir; Lam, lamivudine; Peg-IFN, pegylated interferon; Tel, telbivudine.

Viral Resistance

The major setback in the treatment of CHB is the development of drug resistance.

This is particularly important as the majority of CHB patients will require

long-term therapy. Flares of hepatitis, liver decompensation, and death have

been reported to occur in patients who develop viral resistance.[53] However,

there is no direct comparison of the risk of hepatitis flare, decompensation,

and death between patients with drug-resistant HBV and those not receiving

antiviral therapy. The rates of drug resistance have been described in earlier

sections and are summarized in Figure 4.

Figure 4. (click image to zoom)

Summary of genotypic resistance rates of lamivudine, adefovir, telbivudine, and

entecavir in treatment-naÃ¯ve patients. Data are not head-to-head comparisons.

â€ Rebound due to resistance.

The development of drug resistance is a challenging problem because of its

impact on further treatment. It has been shown that patients who develop

lamivudine resistant mutations will have a higher rate of developing subsequent

adefovir resistant mutations compared to those patients without lamivudine

resistant mutations.[54] Patients who have lamivudine-resistant HBV will also

have a higher rate of developing subsequent entecavir resistance.[42]

Because of the adverse impact of drug-resistant HBV on the clinical outcome and

on subsequent antiviral therapy, the risk of developing resistance should be

considered prior to starting antiviral therapy. The high resistance rate

associated with lamivudine limits its use as a first-line option with the

availability of newer and more potent antiviral agents. However, lamivudine

remains the least expensive oral antiviral agent with the longest and largest

profile of safety data. Close monitoring of patients for early response to

treatment may select those patients who will respond more favorably in the long

term with a lower rate of drug resistance. This will be detailed in a later

section. The recent development of a relational database combined with a HBV

genome sequence analysis program may potentially allow physicians to

individualize patient care based on the resistance profile.[55]

October 8, 2008