AASLD Update: Novel Agents & Strategies for HCV Tx

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Improving Outcomes in Hepatitis CBased on data presented at AASLD 2008*

CME/CE

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Program Description & Educational ObjectivesThis activity provides the latest

information on new agents and novel therapeutic strategies for the treatment of

hepatitis C virus based on emerging data from the 59th Annual Meeting of the

American Association for the Study of Liver Diseases and recent publications.

Upon completion of this activity, participants will be able to:

•

Apply the most recent data on relative benefits and risks of standard and

emerging therapies for hepatitis C to point-of-care actions

•

Create individualized treatment regimens for patients with hepatitis C, based on

specific patient and disease factors

•

Integrate novel and emerging therapies into regimens for patients with hepatitis

C

Target AudienceThis activity has been designed to meet the educational needs of

US-based gastroenterologists, infectious disease specialists, hepatologists, and

nurses.

Requirements for Successful CompletionIn order to receive credit, participants

must view the activity and complete the post-test and evaluation form. There are

no pre-requisites and there is no fee to participate in this activity or to

receive CME/CE credit. Certificates are awarded upon successful completion of

the post-test and evaluation form.

Media:

Internet

Release and Expiration Dates:

December 15, 2008 - December 14, 2009

Time to Complete:

30 minutes

Faculty & Disclosures

CME Reviewers

M. , MDClinical Assistant Professor and Program DirectorDepartment of

Internal MedicineUniversity of FloridaGainesville, Florida

M. , MD, currently has no financial interests/relationships or

affiliations in relation to this activity.

L. Barkley, MDDirector and Clinical

Associate ProfessorFamily Health and Student

Health CareUniversity of FloridaGainesville, Florida

L. Barkley, MD, has a financial interest/relationship or affiliation in

the form of:

Speakers Bureau participant with Merck & Co., Inc. and Sanofi Pasteur Inc.

Planning Committee Member

is Houck, RN, MAHealth PartnersMinneapolis, Minnesota

Sponsorship, Credit & SupportThis activity has been planned and implemented in

accordance with the Essential Areas and policies of the Accreditation Council

for Continuing Medical Education (ACCME) through the joint sponsorship of the

University of Florida College of Medicine and PVI, PeerView Institute for

Medical Education. The University of Florida College of Medicine is accredited

by the ACCME to provide continuing medical education for physicians.

The University of Florida College of Medicine designates this educational

activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM. Physicians should

only claim credit commensurate with the extent of their participation in the

activity.

Amedco, St. , MN, is an approved provider of continuing nursing education by

the Wisconsin Nurses Association Continuing Education Approval Program

Committee, an accredited approver by the American Nurses Credentialing Center's

Commission on Accreditation.

The course is co-provided by Amedco and PVI, PeerView Institute for Medical

Education. 0.5 contact hour(s). Note: Not all state nursing boards will accept

programs 0.5 hours in length for credit. Please click here to find out the

status of your state.

This CME/CE activity is jointly sponsored by the University of Florida College

of Medicine, Amedco, and PVI, PeerView Institute for Medical Education.

This activity is supported by educational grants from , and

Post-Test

Printable Transcript

Educational Objectives

•

Apply the most recent data on relative benefits and risks of standard and

emerging therapies for hepatitis C to point-of-care actions

•

Create individualized treatment regimens for patients with hepatitis C, based on

specific patient and disease factors

•

Integrate novel and emerging therapies into regimens for patients with hepatitis

C

Overview

The primary goal of therapy for patients with hepatitis C virus (HCV) infection

is to achieve a sustained virologic response, defined as undetectable HCV-RNA in

peripheral blood determined with the most sensitive polymerase chain reaction

technique 24 weeks after the end of treatment. This goal is achievable with

current standard treatment for hepatitis C, which consists of combination

regimens of pegylated interferon (alfa-2a or alfa-2b) with ribavirin (RBV),

particularly in patients with HCV genotype 2 and 3 infections.1,2 However,

challenges remain in achieving this treatment goal in all patients with HCV:

adverse effects may limit treatment efficacy, and not all genotypes of HCV

respond equally to therapy.3 Thus, strategies that help maximize treatment

adherence, reduce side effects, and avoid treatment discontinuation or dose

reduction are essential for successful treatment of hepatitis C. Furthermore,

side effects associated with peginterferon plus ribavirin therapy preclude

treatment of some persons and substantially diminish the quality of life of

those who initiate treatment for HCV.4

HCV Therapy Driven by Viral Kinetics The current standard of care for hepatitis

C infection is combination therapy with pegylated interferon alfa and ribavirin,

which leads to a sustained virologic response (SVR) in approximately 80% of

patients infected with HCV genotype 2, approximately 60% to 65% infected with

genotype 3, and approximately 40% of patients infected with HCV genotype 1.5-7

Patients who achieve SVR are likely to have a durable response, with good

prospects for long-term viral eradication.

The typical antiviral regimen consists of 48 weeks of pegylated interferon and

ribavirin for patients with genotype 1 HCV, and 24 weeks of therapy for patients

with genotype 2/3. Although the current recommendation for making decisions

regarding continuation of therapy is based on virologic testing at treatment

weeks 12 and 24, recent research indicates that time to achieve undetectable

serum HCV RNA levels is the best predictor of a patient's likelihood of

achieving SVR. This ability to predict which patients are likely to achieve SVR

is critical to minimize potential adverse effects of peginterferon plus

ribavirin therapy, as well as the risk of unnecessary therapy in patients who

are not likely to respond.

The emerging models of treatment are based on measuring viral kinetic data at

weeks 4, 12, and 24, and adjusting duration of therapy based on HCV RNA

clearance at these time points. Patients who achieve a rapid virologic response

(RVR), defined as undetectable HCV RNA (<10 IU/mL) after 4 weeks of therapy, are

most likely to achieve SVR with 48 weeks of therapy.5,6 Patients who achieve an

early virologic response (EVR) by week 12 of treatment, defined as a minimum of

2-log drop in HCV RNA from baseline, also are likely to achieve SVR with 48

weeks of therapy. Patients who achieve a partial EVR may require a longer

duration of therapy, up to 72 weeks, to achieve SVR. Those who fail to achieve

EVR are unlikely to achieve SVR; alternative treatment strategies should be

considered for these patients.

Taken together, these data indicate that time to undetectable HCV RNA is an

important predictor of viral relapse following treatment. These data also

suggest that HCV treatment outcomes may be improved by selecting the duration of

treatment according to time to undetectable HCV RNA rather than a

" one-size-fits-all " approach of a fixed-duration regimen.

back to top HCV, Insulin Resistance, and Anemia

Specific patient- and disease-related factors can affect response to therapy for

HCV, as well as disease course. Insulin resistance has recently been identified

as one of these factors.8,9 Recent studies have shown that metformin improved

insulin sensitivity and virologic response when added to standard

interferon-ribavirin therapy in patients with insulin resistance and HCV.10 This

study included 123 patients with genotype 1 HCV and homeostasis model assessment

of insulin resistance (HOMA) > 2. The primary endpoint was SVR (HCV RNA < 10

IU/mL) 24 weeks after the end of treatment. By intention-to-treat analysis,

52.5% of the metformin group had sustained virologic response compared with

42.2% of the placebo group (P = .25). The rate of sustained virologic response

favored the metformin group at 12 weeks (54.2% vs 48.4%), 24 weeks (76.3% vs

75%), and 48 weeks (71.2% vs 62.5%).

The mean HOMA value declined from 4.3 at baseline to 2.5 at 24 weeks, compared

with a drop from 4.4 to 3.8 in the placebo group. Moreover, the proportion of

patients with HOMA of less than 2 at 24 weeks was significantly greater in the

metformin group—55% versus 13.6% (P = .001). Adverse events occurred in a

similar proportion of patients in the 2 treatment arms; diarrhea was

significantly more frequent in the metformin arm than in the placebo group

(35.6% vs 10.9%, P = .05).

A smaller study demonstrated that rosiglitazone plus diet and exercise improved

24-hour viral kinetic response to interferon. This study included 34 patients

with HCV genotype 1 who had not responded to previous therapy with

interferon-ribavirin. Improved fasting glucose and HOMA were associated with

significant improvement in 24-hour viral kinetic response to interferon.11

Larger, randomized clinical trials are underway to help determine whether

patients with HCV should be routinely assessed for insulin resistance, and the

impact of treating insulin resistance prior to antiviral therapy.

Ribavirin exposure is another critical element in the standard of care, both

from tolerability as well as efficacy perspectives. In general, higher ribavirin

exposure is associated with better chance for cure; however, since ribavirin

cannot be measured in serum the optimal dose or exposure is not well defined. An

analysis of data from the IDEAL trial, the largest head-to-head trial of

pegylated interferon alfa-2a versus alfa-2b, found that anemic patients

(hemoglobin < 10 g/dL) were more likely to have virologic response, and

significantly more likely to achieve SVR despite less exposure to ribavirin

during treatment.12 These results suggest that the development of anemia in

patients receiving treatment for HCV may be a biomarker for ribavirin exposure,

and ultimately for response to therapy. The use of erythropoietin did improve

quality of life in patients with anemia, but did not improve SVR.

Advanced fibrosis was also shown to be a negative predictive factor for cure in

patients with genotype 1 HCV and good histology.13 This study included 718

patients who were treated with standard pegylated interferon and ribavirin.

Those with advanced fibrosis had an SVR of 22% compared with 48% for those

without advanced disease. This study represents one of the larger data sets to

demonstrate that treating HCV earlier in the course of disease, before the

development of advanced fibrosis or cirrhosis, is more likely to be successful.

With all the exciting small molecule data coming in, patients and clinicians may

be inclined to defer treatment for certain patients. However, these data

indicate that waiting and allowing more fibrosis progression may risk success of

future treatment.

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Improving the Standard of Care: New Formulations and Strategies

Existing therapies are far from perfect, with burdensome side effects for a

significant percentage of patients, and the rates of SVR that are achieved with

these therapies need to be improved. Accordingly, research efforts in hepatitis

C have focused on improving the efficacy of pegylated interferon and ribavirin,

as well as on specifically targeted antiviral therapies for hepatitis C

(STAT-C).

Data on a novel interferon formulation, interferon-lambda, were presented

recently.14 This interferon activates the interferon signaling pathways within

the liver cell, but does not have activity in other cells of the body.

Interferon-alfa receptors are present in most cells of the body, including bone

marrow, nerves, and peripheral mononuclear cells. Administration of interferon

alfa results in significant activation of interferon-alfa receptors throughout

the body, leading to the systemic side effects observed with this therapy.

However, receptors for interferon-lambda are restricted to the liver in

hepatocytes, with little to no expression in bone marrow and mononuclear cells.

In this phase 1b dose-escalation study, PEG-interferon-lambda showed comparable

antiviral activity to interferon-alfa, with no impact on bone marrow.

Another interferon formulation holds promise for reducing the frequency of

injections required. Albinterferon was developed by genetically fusing human

albumin to interferon alfa. The concept is that this recombinant agent will have

a longer sustainable half-life and thus allow a reduction in the frequency of

interferon administration. In a phase 2, randomized, multicenter, open-label

study, albinterferon alfa-2b administered at 4-week intervals was safe and

well-tolerated and demonstrated significant antiviral activity in patients with

genotype 2/3, chronic hepatitis C virus.15 Insulin resistance appeared to have

an independent effect on treatment response. This study included 43 patients who

were randomly assigned to receive subcutaneous albinterferon alfa-2b 1500 mcg

every 4 weeks or every 2 weeks with oral ribavirin 800 mg/day for 24 weeks. The

primary efficacy endpoint was SVR (undetectable hepatitis C virus RNA 24 weeks

after completion of treatment). Insulin resistance was also assessed. Rapid

viral response rates at week 4 were 68.2% and 76.2% for the every-4-week and

every-2-week arms, with corresponding SVR rates of 77.3% and 61.9%. Insulin

resistance at baseline was significantly associated with lower sustained

virologic response rates independent of body mass index. The safety profile of

albinterferon alfa-2b was acceptable and similar across treatment arms.

Discontinuation due to adverse events, as well as dose reductions due to adverse

events, was more common in the every-2-week arm; no dose reductions due to

adverse events were reported in the every-4-week arm.

Data from phase 2 clinical trials using 900 to 1200 mcg of albinterferon every 2

weeks in addition to weight-based dosing of ribavirin suggested similar efficacy

but better health-related quality of life when compared with the standard

combination regimen.16 Phase 3 clinical trials of this agent for the treatment

of hepatitis C are currently ongoing.

Several novel targeted antiviral therapies are in development, and a few have

shown real promise in difficult-to-treat populations. Results from the PROVE-3

study provide compelling evidence that a cure may be possible even in patients

who have failed to respond to pegylated interferon and ribavirin, or those who

have relapsed.17 Response to telaprevir plus peginterferon alfa and ribavirin

was superior to that seen with standard therapy alone: 70% of patients who

received a 12-week induction period of telaprevir followed by 24 weeks of

standard therapy achieved undetectable HCV RNA after 24 weeks. However, dramatic

increases in cure rates are likely to result in regimens that are less well

tolerated. Adverse events were more commonly reported in telaprevir treatment

arms compared with the control arm and included gastrointestinal events,

fatigue, headache, anemia, and skin irritation. Sixteen percent of patients in

the telaprevir treatment groups discontinued due to adverse events through week

36, compared with 4% of the control arm. Skin irritation was the most common

cause for treatment discontinuation in the telaprevir arms.

Data on the first oral nucleoside polymerase inhibitor, R7128, were also

presented recently.18 This study evaluated R7128 in combination with

peginterferon and ribavirin for 28 days in patients with HCV genotype 2 (n = 10)

or 3 (n = 15) who had not previously achieved SVR with interferon-based therapy.

Patients received R7128 1500 mg BID or placebo along with standard therapy for

28 days, followed by standard therapy alone for a minimum of 20 weeks. All

patients were non-cirrhotic and all had been previously treated with at least 12

weeks of interferon-based therapy. Preliminary, blinded data from 25 patients

through day 14 and 18 patients through day 29 show mean plasma HCV RNA decrease

of 4.3 log10 IU/mL at day 14 and 4.6 log10 IU/mL at day 29. Sixteen out of 18

patients with available data on day 29 had HCV RNA < 15 IU/mL. No serious

adverse events have been reported. Laboratory assessments to date revealed no

grade 3/4 changes in hematocrit/hemoglobin, absolute neutrophil count, or

platelets, nor clinically significant changes in other safety laboratory

parameters, vital signs, or ECGs.

Data on a first-in-class potent NS5A inhibitor were also encouraging.19 This

randomized, double-blind, placebo-controlled, single ascending-dose study

included 18 patients with genotype 1 HCV. The mean decline in HCV RNA 24 hours

after a single 1, 10 or 100 mg dose of BMS790052 was 1.8 log10 (range 0.18 to

3.0 log10), 3.2 log10 (range 2.9-4.0 log10) and 3.3 log10 (range 2.7-3.6 log10),

respectively. Furthermore, the 100-mg dose resulted in a mean decline of 3.6

log10 (range 3.0-4.1 log10) observed at 48 hours after dosing, which was

maintained at 144 hours. BMS-790052 was safe and well tolerated in single doses

of up to 100 mg and has a pharmacokinetic profile that potentially supports

once-daily dosing.

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CME/CE INFORMATION

Post-Test

References

Poynard T et al. Lancet. 2003;362:2095-2100.

Flamm SL. JAMA. 2003;289: 2413-2417.

Zeuzem S et al. J Hepatol. 2004;40:993-999.

Hassanein T et al. J Hepatol. 2004;40:675-681.

McHutchison JG, Galhenage S. Chronic Hepatitis C: Practical Management of Liver

Diseases. First edition. New York, NY: Cambridge University Press; 2008:39-60.

Shiffman ML. Clin Liver Dis. 2008;12:488-505.

Mulhall BP, Younossi Z. J Clin Gastroenterology. 2005;39(1 suppl):S23-S27.

Moucari R et al. Gastroenterology. 2008;134(2):416-23. Epub 2007 Nov 12.

Petta S et al. Am J Gastroenterol. 2008;103:1136-1144.

Romero-Gomez M et al. Hepatology. 2008;48(4):380A. Abstract LB6.

on SA et al. 59th Annual Meeting of the American Association for the Study

of Liver Diseases (AASLD 2008). Abstract 1870.

Sulkowski M et al. AASLD 2008. Abstract 1851.

Marotta P et al. AASLD 2008. Abstract 1216.

Lawitz E et al. AASLD 2008. Oral presentation 272.

Bain VG et al. Clin Gastroenterol Hepatol. 2008;6(6):701-6. Epub 2008 May 7.

Zeuzem S et al. AASLD 2008. Oral presentation 243.

McHutchison JG et al. AASLD 2008. Abstract 269.

Gane EJ et al. AASLD 2008. Abstract LB10.

Nettles R et al. AASLD 2008. Abstract LB12.

Materials are based on data presented at the 59th Annual Meeting of the American

Association for the Study of Liver Diseases (AASLD 2008). PeerView Press is an

independent publisher of conference news and medical education programs. The

materials presented here are used with the permission of the authors and/or

other sources. These materials do not necessarily reflect the views of PeerView

Press or any of its supporters.

This CME/CE activity is jointly sponsored by the University of Florida College

of Medicine, Amedco and PeerView Institute for Medical Education.

Credit Available:

US Physicians – 0.5 AMA PRA Category 1 Credit(s)TM.US Nurses – 0.5 contact

hour(s).

This activity is supported by educational grants from Novartis Pharmaceuticals

Corporation, Human Genome Sciences, Inc. and Valeant Pharmaceuticals North

America.

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