A Rising Tide: The Next Wave of Treatment Options in HBV and HCV

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A Rising Tide: The Next Wave of Treatment Options in HBV and HCV

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Introduction

Chronic viral hepatitis—an important risk factor

for hepatic insufficiency, cirrhosis, hepatocellular

carcinoma, and death—affects millions of persons

worldwide. According to the World Health

Organization, more than 350 million persons

(1.25 million in the United States) are chronically

infected with hepatitis B virus (HBV)1 and another

170 million (2.7 million in the United States) are

chronically infected with hepatitis C virus (HCV).1

Although standards of care exist for the management

of each of these chronic viral infections,

viral resistance and patient intolerance—along

with efforts by both the National Institutes of

Health and consumer advocacy groups2-4—have

spawned a myriad of investigations in search for

improved and more individualized therapeutic

regimens. Clinical trial progress thus far—along

with better understanding of viral dynamics—

has engendered optimism among healthcare

providers and patients alike. These emerging findings

also challenge clinicians, researchers, and

scientists to stay abreast of the rising tide of

treatment strategies on the horizon. The goal of

this satellite symposium—intended for scientific

investigators and for clinicians who treat patients

infected with HBV or HCV—is to provide participants

with an understanding of current and

future challenges in the management of chronic

viral hepatitis among adults. Special emphasis will

be placed on the mechanisms of action of investigative

agents and the emerging data from clinical

trials of these agents.

An Algorithmic Approach to Treatment

Success for HBV Infection

The primary goals of treatment for patients

chronically infected with HBV are achieving the

elimination or a meaningful sustained suppression

of HBV DNA replication, and preventing the

progression of liver disease.5 Measuring HBV DNA

levels by using polymerase chain reaction (PCR)

is quickly becoming the most useful method

of monitoring treatment response and patient

follow-up. One review of 26 prospective studies

found significant correlations between longlasting

suppression of HBV DNA replication and

improvements in histologic findings, alanine

aminotransferase (ALT) activity, and serologic

response.6 It is clear, however, that the virologic

response is significantly correlated with HBV

heterogeneity, and this correlation adds value to

HBV DNA trending—as opposed to established

thresholds—with a high level of specificity. A

retrospective study of 165 Chinese patients with

different stages of chronic HBV infection found

that a relative decrease in HBV DNA levels of 3

log10 IU/mL occurred in association with hepatitis

e antigen (HBeAg) clearance; importantly,

however, no absolute HBV DNA threshold could

be established. In fact, 51% of these patients had

HBV DNA levels >105 copies per mL at the time

of conversion.7 Finally, persistently elevated HBV

DNA levels are predictive of negative patient outcomes,

independent of ALT activity and HBeAg

status. In two prospective studies of patients

with HBV infection in Taiwan and China (>2000

patients in each study), Chen and colleagues

found that the rates of hepatocellular carcinoma

and cirrhosis were significantly higher among

patients with HBV DNA levels >105 copies per mL

than among those with undetectable HBV DNA

levels (<300 copies per mL).8,9 Taken together,

these findings demonstrate the association of

viral suppression with hindrance of disease progression,

and they highlight the need for sensitive

monitoring of viral levels by PCR.

At present, 5 agents are approved for treating

patients who have tested positive for hepatitis B

surface antigen (HBsAg) for >6 months and have

HBV DNA levels & #8805;1 x 105 copies per mL ( & #8805;1 x 104

copies per mL for patients with HBeAg-negative

disease, those who have cirrhosis, or both

characteristics), persistent or intermittent elevations

of serum ALT or aspartate aminotransferase

(AST) activity, and chronic hepatitis as confirmed

2

the Food and Drug Administration’s approval of

entecavir and pegylated interferon (PEG IFN) alfa-

2a for the management of HBV infection.12 Figures

1 through 4 illustrate the guidelines set forth for

the management of HBV infection according to

HBeAg status, liver histology, viral load, and ALT

activity. Table 1 provides an indirect comparison

of the efficacy of each of these agents administered

as monotherapy or in combination during

clinical trials; data are presented according to the

HBeAg status of the infection. A cursory review

of these data demonstrates the limited long-term

efficacy of currently available therapies.

Latest Advances in the Treatment

of HBV Infection

As a result of suboptimal effectiveness, poor

tolerability, emergence of resistance, or any combination

of these factors, currently approved

therapies for the treatment of HBV infection

fail to produce a durable response for many

patients. The eradication of HBV is difficult

to achieve because of the presence of extrahepatic

reservoirs of HBV, the integration of HBV

into the host genome, and the presence of an

intracellular conversion pathway that replenishes

the pool of transcriptional templates in the

hepatocyte nucleus without the need for reinfection.

13 Accordingly, withdrawal of antiviral

treatment is usually accompanied by a rapid viral

rebound. For these and other reasons, a number of

novel agents are currently under investigation

by liver biopsy. Those 5 approved agents are the

following:10,11

• Interferon alfa-2b

• Lamivudine

• Adefovir

• Entecavir

• Pegylated interferon alfa-2a

Characterization of Chronic HBV Infection

The clinical presentation and spectrum of disease

vary widely among patients chronically infected

with HBV. Therefore, treatment recommendations

require vigilant tailoring according to the hepatitis

B e antigen (HBeAg) status and the virologic

or histologic presentation of the infection, as well

as the patient’s age, the probability of response,

the drug-resistance profile, and the potential for

adverse events and toxic effects. Emerging treatment

algorithms, based on therapeutic response

markers, are providing clinicians with guidelines

for managing the complex and varied presentation

of HBV infection.

In 2004, a panel of leading U.S. hepatologists

published a comprehensive algorithm for the

diagnosis, treatment, and monitoring of chronic

HBV infection. Recommendations from this group

were largely evidence-based; when data were

lacking, recommendations were based on expert

opinion and clinical experience.11 These recommendations

were recently updated in response to

Figure 1. HBeAg-Positive, Compensated Disease11,12 Figure 2. HBeAg-Negative,

Compensated Disease11,12

3

Comparison of the Percentages of Patients Who Experienced Responses to

Treatments for Hepatitis B*

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Adapted from Lok A. N Engl J Med. 2005;352:2743-2746.

† Responses to PEG IFN monotherapy at week 48 were lower for patients with

either HBeAg-positive or HBeAg-negative chronic hepatitis

B than those for patients treated with a combination of PEG IFN and

lamivudine, but responses at week 72 (24 weeks after treatment) were

similar for the two groups.

‡ The percentages for conventional IFN alfa and lamivudine were determined

with the use of hybridization or branched DNA assay, and

those for adefovir and entecavir, with the use of a polymerase chain

reaction assay.

§ Response rates varied widely among the studies;13,16 thus, the percentages

are based on the results of a meta-analysis.

¶ In the PEG IFN trials, follow-up biopsies were performed at week 72 (24

weeks after treatment); in the lamivudine, adefovir, and entecavir

trials, they were performed at week 48 or 52.

|| Additional patients in both groups experienced HBeAg seroconversion after

the cessation of treatment; 32% of patients in the PEG IFN

monotherapy group and 19% of patients in the lamivudine group had

experienced HBeAg seroconversion at week 72.

Table 1. Indirect Efficacy Comparison of Therapies for HBV Infection

According to HBeAg Status13-18

Figure 3. HBeAg-Positive or -Negative, Compensated

Cirrhosis11,12

Figure 4. HBeAg-Positive or -Negative,

Decompensated Cirrhosis11,12

4

in clinical trials. Most of these agents, including

emtricitabine, valtorcitabine, clevudine, and

telbivudine, are nucleoside analogues with structures

similar to that of lamivudine. Of these,

clevudine and telbivudine are furthest along in

development.

Clevudine is a pyrimidine analogue with potent

anti-HBV activity in vitro. Safety and efficacy data

from clinical trials investigating clevudine as a

treatment for patients with either HBeAg-positive

or HBeAg-negative disease were recently reported

at the 56th Annual Meeting of the American Association

for the Study of Liver Diseases (AASLD). In

a multicenter, randomized, double-blind, phase

III clinical trial conducted in South Korea, 243

patients with HBeAg-positive chronic hepatitis B

infection, HBV DNA levels & #8805;6 log10 copies per mL,

and ALT activity 1.2 to 15 times the upper limits

of normal were randomly assigned at a ratio of

3:1 to receive clevudine 30 mg or placebo once

daily for 24 weeks. Patients were followed up

for 24 weeks after treatment. End-of-treatment

median reductions in HBV DNA levels were 5.10

log10 copies per mL in the clevudine group and

0.27 log10 copies per mL (P<.0001) in the placebo

groups; 24 weeks after treatment, median HBV

DNA reductions were 2.02 log10 copies per mL in

the clevudine group and 0.68 log10 copies per mL

in the placebo group (P<.0001). At week 24, ALT

activity had returned to normal for 68.2% of the

patients treated with clevudine and for 17.5% of

the patients given placebo. Serologic response

rates were reported at end of treatment and at

week 48, with serum HBeAg loss rates of 10.4%

(12.3% in control) and 15.3% (12% in control),

respectively. Anti-HBe antigen conversion rates in

the treatment group were 6.9% (10% in control)

at week 24 and 8.8% (12% in control) at week

48. Clevudine was well-tolerated throughout the

course of therapy.19

Similarly, among 86 patients with HBeAg-negative

HBV, HBV DNA levels & #8805;5 log10 copies per mL,

and ALT activity 1.2 to 15 times the upper limits of

normal, reductions in HBV DNA levels at the end

of treatment were 4.25 log10 copies per mL in the

group receiving clevudine 30 mg once daily and

0.48 log10 copies per mL (P<.0001) in the group

receiving placebo; 24 weeks after treatment,

respective median HBV DNA reductions were 3.11

log10 copies per mL in the clevudine group and

0.66 log10 copies per mL (P<.0001) in the placebo

group. At week 24, ALT activity had returned to

normal for 74.6% of the patients treated with

clevudine but for only 33.3% of patients given

placebo. As before, clevudine was well-tolerated

throughout the course of therapy.20

In another study, researchers aimed to evaluate

HBV viral load in nucleoside-naïve or experienced

patients following 24 weeks of treatment with

emtricitabine 200 mg plus clevudine 10 mg versus

emtricitabine monotherapy and to monitor for

development of resistance. Seventy-eight patients

with HBeAg-negative infection were enrolled with

a median baseline HBV DNA of 4 log10 copies per

mL. At week 24, a 1.6 log10 and 1.4 log10 reduction

in serum HBV DNA was observed for experienced

patients in the combination and monotherapy

arms, respectively, and a 1.9 log10 reduction

was observed among naïve patients, regardless

of treatment arm. The week 24 prevalence

of emtricitabine-associated mutations was 7%

and 0% among experienced and naïve patients,

respectively.21

Telbivudine—an HBV-specific nucleoside analogue

that targets the viral DNA polymerase enzyme—is

a promising new agent in the HBV pipeline. Firstyear

analysis of the 2-year phase III GLOBE clinical

trial comparing the efficacy of telbivudine with

that of lamivudine in 1367 patients with HBsAgpositive

infection, HBV DNA levels >6 log10 copies

per mL, ALT activity 1.3 to 10 times the upper

limits of normal, and compensated liver disease

showed that telbivudine produced greater HBV

suppression and more rapid ALT normalization.

In this study, patients were randomly assigned to

receive a daily oral dose of telbivudine 600 mg

or lamivudine 100 mg. Patients were stratified

according to the HBeAg status of the infection

and ALT activity < or >2.5 times the upper limits

of normal. The primary endpoint for this trial is a

5

reduction in the HBV DNA level to <5 log10 copies

per mL with HBeAg clearance or ALT normalization.

The recently released week-52 analysis

showed that telbivudine achieved superior results

for all virus-related efficacy parameters. Patients

receiving telbivudine experienced significantly

greater reductions in HBV DNA levels, irrespective

of the HBeAg status of the infection. Among

those with HBeAg-positive infection, the median

reduction in the HBV DNA level was 6.4 log10 copies

per mL among patients receiving telbivudine

and 5.5 log10 copies per mL among those receiving

lamivudine (P<.01); likewise, among patients with

HBeAg-negative infection, the median reduction

in the HBV DNA level was 5.2 log10 copies per

mL with telbivudine and 4.4 log10 copies per mL

with lamivudine (P<.01). Among HBeAg positive

patients, loss of detectable HBeAg at end of treatment

was similar for both telbivudine- and lamivudine-

treated patients (26% versus 23%, respectively).

Seroconversion was achieved by 22% of

telbivudine-treated patients compared to 21%

of lamivudine-treated patients. Treatment failure

and resistance were more common with lamivudine

in both groups. Preliminary analyses of data

from patients who have completed 76 weeks of

therapy indicate that the advantages of telbivudine

treatment may increase during the second

year. These data indicate that treatment with

telbivudine achieved HBeAg clearance among

39% of patients, a therapeutic response among

81%, and PCR-negative status among 73%;

treatment with lamivudine, in contrast, achieved

HBeAg loss among 28% of patients, a therapeutic

response among 64%, and PCR-negative status

among 45%. In addition, patients receiving telbivudine

experienced a higher rate of normalization

of ALT activity. Both drugs were well tolerated and

exhibited similar adverse event profiles.22

Data from the GLOBE trial were further analyzed

to assess efficacy outcomes at 1 year in relation to

4 categories of serum viral load (HBV DNA level)

at week 24 of treatment: PCR-negative (<300

copies per mL); PCR-detectable but <3 log10 copies

per mL; PCR-detectable at 3 to 4 log10 copies

per mL; and PCR-detectable at >4 log10 copies per

mL. Efficacy at 1 year was proportionately related

to serum HBV DNA levels at week 24, regardless

of the HBeAg status of the infection. Odds-ratio

analyses indicated that treatment with telbivudine

was associated with a 3- to 33-fold increase

in the likelihood of beneficial outcomes and an

8- to 62-fold reduction in the likelihood of viral

breakthrough among patients with HBeAg-positive

infection and HBV DNA levels <3 log10 copies

per mL, as well as among patients with HBeAgnegative

infection and undetectable HBV DNA

levels (P<.0001) at treatment week 24.23 Likewise,

decreased resistance at 1 year was associated

with lower levels of week 24 HBV DNA. The

results of these analyses demonstrate the importance

of early virologic response among patients

being treated for HBV infection and, likewise, the

importance of sensitive virus detection with PCR.

Debating the Future of Therapy for HBV

Infection: Interferons and Immunomodulation

or Nucleoside and Nucleotide Analogues

and Viral Targets

Results of clinical trials will drive the future management

of HBV infection. For now, however,

there is debate regarding the superiority of one

treatment over another, ie, interferon or nucleoside

analogues. Each has a unique mechanism

of action and thus is associated with distinctive

pharmacokinetic benefits; theoretically, these factors

should make the treatments complementary

to one another.

Specific variables favoring the use of interferon

include a shorter course of therapy, a 30% to 35%

rate of HBeAg clearance,24-31 early HBsAg clearance

in 6% to 9% of patients,24-31 the absence

of resistant mutations, and immunomodulation.

Nevertheless, interferon is expensive and is associated

with a potentially toxic side effect profile.

Additionally, it is contraindicated for patients with

decompensated cirrhosis. Comparatively, novel

nucleoside analogues directly suppress viral replication,

thereby resulting in greater reductions

6

of HBV DNA levels early in the course of treatment

and in improvements in viral suppression.

These agents are orally bioavailable with more

favorable side effect profiles than interferon, and

they are safe for patients with decompensated

cirrhosis.20-23

The benefits of each of these classes of drugs are

defensible. However, it is probable that the future

course of therapy for HBV infection will entail a

combination of drugs, each with a unique mechanism

of action.

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