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.

Antiviral Targets for Treating HCV Infection

The goals of therapy for hepatitis C virus (HCV)

infection are more quantifiable than those of

therapy for HBV infection. The primary goal—viral

eradication—is best achieved when viral load is

reduced substantially during the early phase of

treatment and is associated with improved histologic

outcomes. Treatment of HCV infection

with the current standard of care—pegylated

interferon in combination with ribavirin (PEG

IFN-RBV)—is associated with a 54% to 56%

overall rate of viral eradication.32,33 The benefits

of achieving a sustained virologic response (SVR)

are multiple and include improved hepatic histology,

32-35 a decreased likelihood of hepatocellular

carcinoma,36-38 a low likelihood of liver failure,38

and lower liver-related mortality rates.39 However,

for patients with unfavorable treatment profiles—

including genotype 1,31,32 high viral load,32,33

hepatic steatosis,40-43 black race,44-46 and nonadherence

to therapy,47 treatment failure rates

are high.

Lack of response to treatment, along with intolerance

of or ineligibility for therapy, has propelled

the development and investigation of novel

therapies designed to improve safety, efficacy,

and tolerability. Several of these agents directly

target hepatitis C viral replication—such as protease

and polymerase inhibitors—and provide an

optimistic outlook for the future management of

HCV infection.

Preliminary Trial Data

Protease Inhibitors

The initial proof-of-principle of the efficacy of a

protease inhibitor as an antiviral therapy for HCV

infection was demonstrated by BILN-2061, the

first protease inhibitor studied in humans with

HCV infection. In a randomized, double-blind

group comparison, 10 patients with genotype

1 HCV infection and liver cirrhosis were treated

with BILN 2061 200 mg by mouth BID over 2 days

or with placebo. Patients receiving BILN-2061

demonstrated a reduction in the serum HCV RNA

level of nearly 4 log10 IU/mL after 2 days of dosing;

48 however, cardiac toxicity resulted in the

suspension of further studies with this agent.49

More recently, 2 other protease inhibitors have

been studied in Phase 1 and 2 trials: VX-950 and

SCH 503034.

VX-950 is an orally bioavailable protease inhibitor.

Recently published results of a Phase Ib dose-escalation

study (N = 60) demonstrated that patients

with HCV genotype 1 infection who are receiving

monotherapy with VX-950 (750 mg orally every

8 hours for 14 days) experienced rapid declines

in the median HCV RNA level over 3 to 4 days and

a median decline in HCV RNA levels of 4.4 log10

IU/mL at treatment day 14. This study confirmed

the safety of VX-950: no serious adverse events

were reported, and no discontinuations occurred

because of side effects. The most commonly

reported adverse event was headache. These

findings suggest that VX-950 is a highly potent

protease inhibitor for genotype 1 HCV infection.

Studies of VX-950 administered in combination

with other therapies are awaited.50

The results of a Phase Ib, multi-dose, randomized,

double-blind study of SCH 503034—a second

novel, orally administered HCV protease inhibitor—

were also recently released. In this study, 61

adult patients with HCV-1 infection whose disease

had previously not responded to PEG + RBV

were randomly assigned to receive 14 days of SCH

503034 or placebo. Oral SCH 503034 was rapidly

absorbed and exhibited dose-related increases

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in Cmax and area under the curve. Potent doserelated

antiviral activity was evident 24 hours

after exposure, with a mean viral load reduction

of 2.06 log10 IU/mL among patients receiving 400

mg TID (n = 12). A dose-related decline in ALT

activity occurred during treatment and was positively

correlated with viral load reductions. SCH

503034 was well tolerated at all doses; no serious

adverse events were reported.51

Polymerase Inhibitors

Valopicitabine—an orally bioavailable polymerase

inhibitor—is currently in Phase IIb trials for the

treatment of patients with HCV genotype 1 infection.

Valopicitabine in combination with PEG

IFN can reduce the viral load in patients with

disease that is difficult to treat. Interim data from

a Phase IIa trial demonstrate that after only 12

weeks of treatment, treatment-naïve patients

with genotype 1 HCV infection who were treated

with valopicitabine in combination with PEG IFN

experienced a mean reduction in HCV RNA levels

from baseline of 3.01 log10 IU/mL, as compared

with a reduction of 0.87 log10 IU/mL for patients

treated with valopicitabine alone. Moreover, 12

of 18 patients treated with combination therapy

experienced an early virologic response (EVR) after

12 weeks of therapy and reductions in HCV RNA

levels of >2 log10 IU/mL.52,53 No serious adverse

events were noted, and the combination was well

tolerated overall. This study is ongoing, and SVR

data will be available from this small cohort.

The encouraging data from these trials have led

to a combination study of valopicitabine with PEG

IFN alfa-2a as treatment for patients with genotype

1 HCV infection that have not previously

responded to treatment with PEG IFN. In this randomized,

open-label, Phase IIb trial, patients were

randomized at a ratio of 2:2:2:2:1 to the following

5 treatment groups:

• Valopicitabine 800 mg/d monotherapy

• Valopicitabine 400 mg/d plus PEG IFN-2a 180

& #956;g/wk

• Valopicitabine 800 mg/d plus PEG IFN-2a 180

& #956;g/wk

• Valopicitabine dose ramping 400 to 800 mg/d

followed by 800 mg/d plus PEG IFN-2a 180

& #956;g/wk

• PEG IFN-2a 180 & #956;g/wk + RBV 1000 to 1200

mg/d

Week 12 results were released during AASLD 2005

in San Francisco and indicated that the efficacy

of valopicitabine plus PEG IFN is greater than that

of the standard of care (PEG IFN plus RBV) for

patients with genotype 1 HCV infection that has

previously not responded to treatment. Mean HCV

RNA reductions were 2.50 log10 IU/mL for patients

treated in the dose-ramping arm and 2.76 log10

IU/mL for patients treated in the 800 mg combination

arm (compared with 1.90 log10 IU/mL for

patients in the PEG-RBV arm); corresponding early

virologic response rates were 70.7% in the doseramping

arm and 63.4% in the combination arm

(compared with 41.2% in the PEG-RBV arm). Side

effects were primarily gastrointestinal in nature;

no serious adverse events were reported.54

Data from these trials are encouraging, demonstrating

the safety and efficacy of direct antiviral

therapy for HCV infection through protease and

polymerase inhibition.

A Shifting Paradigm—Combination Anti-HCV

Therapy: Paralleling the Evolution of HIV

Treatment

Today’s shifting paradigm in the management of

HCV infection is similar to the treatment evolutions

seen over time with human immunodeficiency

syndrome (HIV), sparking an educational

interest among a sample of recently surveyed

clinicians and scientists.55 Hepatitis C clinical trials

are under way to investigate the safety and

efficacy of agents designed to interfere directly

with viral replication when given alone or in

combination with interferon. Full appreciation

of the mechanisms of action requires an intricate

understanding of the viral life cycle and, in

particular, genomic organization and polyprotein

processing. As was the case with HIV, important

progress in this field was achieved because of the

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development of subgenomic56 and, more recently,

full-genomic replicon systems.57-59 Although HIV

infection and HCV infection differ dramatically

in terms of virology, disease manifestations, and

clinical outcomes, each is attended by challenges

surrounding resistance, intolerance, reservoirs,

and chronicity. The surge of direct viral target

research provides hope for safer and more effective

therapies for the future management of HCV

infection.

References<cut>

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