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New Strategies for the Treatment and Supportive Care of Veterans with Hepatitis C Conference
San Francisco, California. January 16-18, 2002

Alan Franciscus
Editor-in-Chief

Part I

A very important conference on the treatment and care for Veterans with HCV was held in San Francisco, CA on January 16-18, 2002. The conference was particularly important and timely because the Veterans Health Administration recently issued new treatment guidelines for Veterans with HCV. Such guidelines by the Veterans Health Administration are a widely utilized resource outside of the VA by other health entities such as the Departments of Corrections, Managed Care Organizations and State and Federal Health Systems looking to implement their own disease state management and treatment guidelines for hepatitis C.

Coverage of this conference by the HCV Advocate will be broken up into various postings with an in-depth review in the areas of New Treatment Strategies and Treatment in Special Populations. Coverage by the HCV Advocate of the conference sessions that focused on End Stage Complications will be summarized following these in-depth reviews.

Opening remarks to the conference were by Lawrence R. Deyton, Chief Consultant of Public Health for the Department of Veterans Affairs and Director of the Public Health Strategic Health Care Group (PHSHG), which oversees the VA's hepatitis C program.

In its continuing efforts to provide care to more than 80,000 veterans infected with hepatitis C, the Department of Veterans Affairs (VA) on Jan. 1, 2002, funded four new centers to evaluate and improve hepatitis C screening, testing, clinical care and education. Each of the centers will receive annual funding of up to $500,000 for five years, plus start-up costs. The centers are located in Minneapolis, San Francisco, West Haven (Connecticut) and Seattle in conjunction with the Portland, Ore. VA medical center.

Dr. Deyton acknowledged the four new centers and described the Veterans Affairs commitment to hepatitis C as follows:

"The VA screens, tests and treats more people with hepatitis C than anyone else in the country," said Dr. Lawrence Deyton. "Even so, VA continues to explore new ways to improve its programs. These new centers will function as field-based clinical laboratories to evaluate current practices and develop new tools for improving the quality of care". The new centers will build on the success of the previous Centers of Excellence in Hepatitis C program, established by the VA in 1999.

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Session One

“New and Emerging Treatments for Hepatitis C: A focus on Pegylated Interferons” Dr. Timothy Morgan, Chief of Hepatology, Long Beach VAMC

Dr. Morgan opened his presentation discussing the current standard of care in the treatment of hepatitis C; combination therapy with Intron A plus ribavirin (Rebetron). Intron-A is delivered by a multi-dose pen dosed at 3MU three times a week. Ribavirin is in 200mg tablets and is dosed at 1000mg/day (divided into two doses of 400mg and 600mg) for patients <75kg (165 pounds) and 1200mg/day (divided into two doses of 600mg) for patients >75kg (165 pounds).

Approximately 28% of patients that have genotype 1 hepatitis C can expect to achieve a sustained virological response (SVR) with Rebetron. Dr. Morgan reiterated the recommendation to treat genotype 1 patients for 48 weeks. Approximately 60% of patients that have genotype 2 or 3 can expect to achieve an SVR with Rebetron and for patients with genotype 2 or 3 the recommended duration of treatment is 24 weeks. The overall SVR that can be achieved with Rebetron is approximately 40% and Dr. Morgan recommends stopping treatment if PCR is HCV positive at 12 weeks.

Next, Dr. Morgan discussed “What is a PEG?” The word PEG comes from Polyethylene Glycol. PEG is a long molecule composed of repeating units of HO-(CH2CH20) n-CH2CH2-OH. PEG is inert, non-toxic and non-immunogenic. PEG is water soluble, mainly renally excreted and FDA approved for internal use.

Dr. Morgan then differentiated the two pegylated interferons that are or will shortly be used to treat hepatitis C; peginterferon alpha 2b (PEG-Intron™) and peginterferon alpha 2a (Pegasys™). Dr. Morgan stated “We hold this truth to be self evident – that all PEG’s are not created equal….” The characteristics of a PEG vary depending on whether the chain is branched or linear, the length of the PEG chain, whether the PEG is attached to the interferon at a single site or at multiple sites and lastly the type of bond that attaches the PEG to the interferon.

Dr. Morgan characterized peginterferon alpha 2b (PEG-Intron™ - Schering) as:

A 12kD, linear PEG
Absorption T1/2 = 7 hours
Elimination T1/2 = 4 days
Renally (kidney) cleared
Needs to be weight based dosed due to large volume of distribution

Dr. Morgan characterized peginterferon alpha 2a (Pegasys™ - Roche) as:

A 40kD, branched PEG
Absorption T1/2 = 50 hours
Elimination T1/2 = 11 days
Hepatically (liver) cleared
Fixed dosing due to small volume of distribution (targeted distribution in the serum, organs and plasma)

Dr. Morgan then showed a graph comparing the Mean Serum Concentrations of Pegasys versus PEG-Intron after multiple doses. Pegasys maintains consistently high concentrations and the curve shape is flat with no peaks or troughs. The graph showed consistent concentrations for Pegasys in the 1000-1400pg/ml range throughout the entire week after multiple doses. PEG-Intron on the other hand even after multiple doses has a concentration curve over the week that looks very similar to standard interferon with a pronounced peak and trough. The peak reaches concentration levels of about 1200pg/ml and then drop gradually until the end of the dosing period when there is no PEG-Intron concentration in the serum. By pegylating the interferon, which is the active antiviral agent weekly dosing is made possible by decreasing the rate of clearance as well as sustaining plasma levels for a greater period of time. The reasons that each peg yields different pharmacokinetic parameters as well as different results are due to the different PEG characteristics between PEG-Intron and Pegasys.

Dr. Morgan in his presentation then discussed the clinical trials of both pegylated interferons with and without ribavirin. The trials discussed were the pivotal trials on treatment naïve patients with chronic hepatitis C.

Monotherapy:

Peginterferon alpha 2b, 12kD, Peg-Intron™ (Schering) compared to Intron-A
Dose of PEG-Intron = 1.0µg/kg
Dose of Intron-A = 3MU tiw
This trial is published in Hepatology 2001, 34:395-403

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Results:
Genotype 2 and 3, low viral load(<2 million copies/ml)
PEG-Intron SVR = 62%
Intron-A SVR = 36%

Genotype 2 and 3, high viral load(>2 million copies/ml) PEG-Intron SVR = 42%
Intron-A SVR = 25%

Genotype 1, low viral load(<2 million copies/ml)
PEG-Intron SVR = 38%
Intron-A SVR = 21%

Genotype 1, high viral load(>2 million copies/ml)
PEG-Intron SVR = 8%
Intron-A SVR = 2%

Peginterferon alpha 2a, 40kD, Pegasys™ (Roche) compared to Roferon-A
Dose of Pegasys = 180µg
Dose of Roferon-A = 6MU followed by 3MU tiw
This trial is published in the New England Journal of Medicine (NEJM) 2000, 343:1666-72

Results:

Genotype 2 and 3, low viral load(<2 million copies/ml)
Pegasys SVR = 67%
Roferon-A SVR = 50%

Genotype 2 and 3, high viral load(>2 million copies/ml)
Pegasys SVR = 48%
Roferon-A SVR = 30%

Genotype 1, low viral load(<2 million copies/ml)
Pegasys SVR = 44%
Roferon-A SVR = 15%

Genotype 1, high viral load(>2 million copies/ml)
PEG-Intron SVR = 14%
Roferon-A SVR = 1%

Peginterferon alpha 2a, 40kD, Pegasys™ (Roche) Phase 111 Pivotal Cirrhotic Trial
Dose of Pegasys = 90µg or 180µg
Dose of Roferon-A = 3MU tiw
This trial is published in the New England Journal of Medicine (NEJM) 2000, 343:1673-80

Results:

Genotype 1
Pegasys 180µg SVR = 13%
Pegasys 90µg SVR = 5%
Roferon-A SVR = 2%

Genotype 2 and 3
Pegasys 180µg SVR = 51%
Pegasys 90µg SVR = 29%
Roferon-A SVR = 15%

Combination Therapy

Peginterferon alpha 2b, 12kD, Peg-Intron™ (Schering) and ribavirin compared to Intron-A and ribavirin
Dose of PEG-Intron/RBV = 1.5µg/kg plus 800mg ribavirin
Dose of Intron-A/RBV = 3MU tiw plus 1000mg ribavirin

Results:

Overall
PEG-Intron/RBV SVR = 54%
Intron-A/RBV SVR = 47%

Genotype 2 and 3
PEG-Intron/RBV SVR = 82% (121/147)
Intron-A/RBV SVR = 79% (115/146)

Genotype 1 Overall
PEG-Intron/RBV
SVR = 41% (141/348)
Intron-A/RBV SVR = 33% (112/343)

Genotype 1, low viral load(<2 million copies/ml)
PEG-Intron/RBV SVR = 68% (63/92)
Intron-A SVR = 43% (41/96)

Genotype 1, high viral load(>2 million copies/ml)
PEG-Intron SVR = 30% (78/256)
Intron-A SVR = 29% (71/247)

SVR by Fibrosis

No/minimal fibrosis
PEG-Intron/RBV SVR = 57% (189/333)
Intron-A/RBV SVR = 49% (164/336)

Bridging fibrosis or cirrhosis
PEG-Intron/RBV SVR = 44% (60/136
Intron-A/RBV SVR = 41% (54/132)

Change in Inflammation and Fibrosis Score (Biopsy)

Inflammation (All patients)
PEG-Intron/RBV = 68% (-3.4)
Intron-A/RBV = 69% (-3.4)

Inflammation (Patients with SVR)
PEG-Intron/RBV = 90% (-5.2)
Intron-A/RBV = 91% (-5.3)

Fibrosis (All patients)
PEG-Intron/RBV = 21% (-0.1)
Intron-A/RBV = 20% (-0.2)

Fibrosis (Patients with SVR)
PEG-Intron/RBV = 26% (-0.3)
Intron-A/RBV = 69% (-0.2)

Dr. Morgan then moved his presentation to the clinical data that is available for Pegasys™, pegylated interferon 2a (Roche). He commented that most of his experience with pegylated interferons has been with Pegasys as he has been an investigator in the pivotal trials.

Peginterferon alpha 2a, 40kD, Pegasys™ (Roche) and ribavirin compared to Roferon-A and ribavirin
Dose of Pegasys/RBV = 180µg plus 1000mg-1200mg ribavirin
Dose of Intron-A/RBV = 3MU tiw plus 1000mg-1200mg ribavirin

Results:

Overall
Pegasys/RBV SVR = 56%
Roferon-A/RBV SVR = 45%

Genotype 2 and 3
Pegasys/RBV SVR = 76%
Roferon-A/RBV SVR = 61%

Genotype 1
Pegasys/RBV SVR = 46%
Roferon-A/RBV SVR = 27%

Dr. Morgan completed his review of the pegylated clinical trial results by referring to the Veterans Health Administration revised treatment recommendations as outlined below for reference:

Treatment Recommendations for Patients with Chronic Hepatitis C 1.0

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A. Treatment Naive Patients

Interferon alfa 2b plus ribavirin

Interferon 3 MU tiw and ribavirin (1,000 mg for <75 kg, 1,200 mg for >75 kg in two divided doses daily) with a decision to continue or withdraw therapy based on virological response at 24 weeks and assessment of the clinical needs of the veteran. or

Peginterferon alfa 2b (12 kD) plus ribavirin

Peginterferon alfa 2b 1.5 mg/kg q week plus ribavirin 800mg qd with a decision to continue or withdraw therapy based on virological response at 24 weeks.

Decision to Treat with Standard Interferon versus Peg interferon

Peginterferon plus ribavirin offers the convenience of dosing once a week, yet peginterferon and ribavirin treatment offers only a slight increase in efficacy and more adverse events (injection site reactions and neutropenia) compared with standard interferon plus ribavirin. This is true for patients with a genotype 1 infection and a high viral load and for genotype non-1 infection. For patients with non-1 infection, there are more data guiding decisions regarding the duration of treatment with standard interferon plus ribavirin than with peginterferon plus ribavirin. Until additional data are available, both peginterferon and regular interferon in combination with ribavirin are appropriate for many patients and that treatment choice should be based on both efficacy data and an individualized assessment of the risks and benefits of each form of therapy in each patient.

Treatment Duration

Genotype 1 Infection

Patients receiving interferon plus ribavirin (whether standard interferon or peginterferon) should be treated for 24 weeks. In those who are HCV RNA negative after 24 weeks, treatment should be continued for a total of 48 weeks. In those with detectable HCV RNA after 24 weeks, treatment should be discontinued because a sustained viral clearance with an additional 24 weeks of therapy is rare. Exceptions to this algorithm include patients with advanced disease who could in theory benefit from viral suppressive therapy and patients with either a biochemical or a virological response after 24 weeks but not both. Continued treatment for up to 48 weeks may be beneficial in these latter two groups. Benefits of treatment beyond one year in preventing long-term complications of liver disease are under investigation. Long-term suppressive therapy cannot be recommended until such data are available.

Genotype Non-1 Infection

Patients receiving standard interferon plus ribavirin should be treated for 24 weeks. In those who are HCV RNA negative after 24 weeks and have favorable characteristics of response, treatment should be discontinued. In those with unfavorable characteristics, treatment should be continued for a total of 48 weeks. In those with detectable HCV RNA after 24 weeks, treatment should be discontinued for the same reasons and with the same provisos as described above for genotype 1 infection. The treatment duration is less clear for peginterferon plus ribavirin because no 24 week studies have been performed. Until such data are available, one must assume that 48 weeks of treatment is necessary in maintaining the virological response observed after 24 weeks.

Ribavirin Dose

In combination with standard interferon alfa 2b, the dose of ribavirin is either1,000mg (<75kg) or 1,200mg(>75 kg). In combination with peginterferon alfa 2b (12 kD), the dose of ribavirin is 800mg. The use of higher doses of ribavirin is under evaluation with peginterferon alfa 2b. Ribavirin is not effective as a single agent.

Ribavirin Toxicity

For patients who develop hemolytic anemia, the ribavirin dose should either be reduced or discontinued. Erythropoietin therapy to counter the anemia is only necessary if the veteran develops moderate symptoms from the anemia, or if symptomatic anemia persists despite ribavirin dose reduction.

Peginterferon alfa 2b Monotherapy as Potential First Line Therapy

While there are no prospective comparisons of peginterferon alfa 2b (12kD) monotherapy with interferon alfa 2b and ribavirin, sustained virological responses appear to be lower in the former than in the latter group. Thus, peginterferon alfa 2b monotherapy should not be administered as first line therapy in treatment naïve individuals unless the patient has contraindications to ribavirin.

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B. Treatment Naïve Patients with Contraindications to Ribavirin

Peginterferon alfa 2b Monotherapy as First Line Therapy

Pegylated interferon (1.0 mg/kg) should be given every week for one year. A decision to continue or withdraw therapy after 24 weeks is based on the virological response, regardless of the infecting genotype.

Other Interferons as Monotherapy

Given the superiority of peginterferon alfa 2b (12 kD) over standard interferon, treatment with interferon alfa 2a, alfa 2b, or alfa con-1 is no longer indicated as first line therapy in any population.

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C. Non-Responders to Interferon plus Ribavirin Combination Therapy

No Approved Treatments for Patients who have Failed Interferon and Ribavirin

There are no approved treatments for this population. However, pegylated alfa 2b (12 kD) interferon plus ribavirin can be considered, preferably as part of an experimental protocol.

The next area that Dr. Morgan covered regarding the combination clinical trials with the two pegylated interferons and ribavirin was the side effects that were seen with both products as compared to the comparator which in both cases was standard interferon and ribavirin (marketed in the United States as Rebetron). The adverse events that Dr. Morgan felt were worthy of discussion were the following:

Rebetron PEG-Intron/RBV
Injection reaction 49% 75%
Fatigue 63% 66%
Headache 58% 62%
Fever 46% 33%
Rigors 41% 48%
Nausea 33% 43%
Insomnia 41% 40%
Depression 34% 31%
Anxiety 47% 47%

Dr. Morgan then discussed the difference in the side effect profiles between PEG-Intron/RBV and Pegasys RBV (both were compared to Rebetron in the clinical trials) and determined that the main differences in side effect profiles can be seen in the ‘flu-like symptoms’ as well as depression with Pegasys/RBV having significantly less side effects than PEG-Intron/RBV as shown below

  PEG-Intron/RBV Pegasys/RBV
Fever 56% 43%
Myalgia 50% 42%
Rigors 35% 24%
Depression 30% 21%

In the combination PEG-Intron/RBV trial the discontinuation of PEG-Intron/RBV due to adverse events was 14% versus 13% for Rebetron (the range for 48 week studies with Rebetron has been 19-21%). In the combination PEG-Intron/RBV trial the dose modification due to adverse events was 42% versus 34% for Rebetron (the range for 48 week studies with Rebetron has been 10-26%)

Regarding monitoring treatment Dr. Morgan recommends the following guidelines including stopping treatment if PCR is positive at 24 weeks.

Monitoring During Treatment
Clinic Visit 2 4 8 12 18 24 36 48
CBC Diff X X X X X X X X
Liver tests   X X X X X X X
PCR qualitative           X   X

Dr. Morgan next discussed Schering’s 80-80-80 adherence theory (a patient must take 80% of the interferon, 80% of the ribavirin dose, 80% of the time). He shared some of the Schering data that shows that a patient could produce superior SVR rates if they complied with the 80/80/80 theory. Dr. Morgan stated that no conclusions can be made as to the validity of this theory until it has been shown in a clinical trial that is designed to study this adherence therapy prospectively.

Editor’s note: This theory does not carry much weight when you consider that this is retrospective data and more importantly that 42% of patients in the Peg-Intron plus Rebetol clinical trail required dose reductions, which would make it very difficult to adhere as suggested by this theory.

Dr. Morgan finished his presentation by discussing the cost of the HCV medications that are included in the VA guidelines to the VA. He shared the following table showing the cost to the VA of hepatitis C medications based upon length of therapy:

  28 days 24 weeks 48 weeks
IFN 3MU tiw + RBV (Rebetron) $870 $5,520 $10,440
PEG-Intron 60-85kg $644 $3,864 $7,728
PEG-Intron >85kg $692 $4,152 $8,304
Rebetol 800mg/day $672 $4,032 $8,064
Rebetol 1000mg/day $840 $5,040 $10,080
Rebetol 1200mg/day $1,008 $6,064 $12,128

Editor’s note: The VA automatically receives an approximate 30% cost reduction on the price of these medications

180 pound (82kg) man treated for 24 weeks with:
IFN 3MU tiw + 1200 RBV = $5,520
PEG-Intron +800 RBV = $7,896 (43% increase in cost of Rebetron)

Dr. Morgan made some concluding statements by reiterating the VA hepatitis C treatment recommendations which are as follows:
Genotype 1
IFN a-2b 3MU sc tiw plus RBV 1000-1200mg po qd
Peg IFN a2b 1.5µg/kg sc every week plus RBV 800mg GD
RBV > 800mg/day is NOT recommended
Assess response at 24 weeks, treat for 48 weeks
No difference in SVR for genotype 1/high viral load patients

Genotype Non-1
IFN a 2b 3MU sc tiw plus RBV 1000-1200mg po qd
Treat for 24 weeks
Treat for 48 weeks if patient has < 4 tolerable factors

During the question and answer period, Stephen Rossi, PharmD from the San Francisco Center of Excellence was asked how his institution is implementing the VA treatment guidelines and he commented that they are only recommending that PEG-Intron/RBV be used for genotype 1 low viral load (<2 million copies/ml) and due to the fact that in their extensive experience through clinical trials with PEG-Intron the side effect profile is significantly greater than Rebetron, in many cases where appropriate they are recommending that these patients wait for a better therapy. In addition Dr. Rossi made some comments regarding the 80/80/80 theory and he stated that the 80% is a number that has not been studied to be the threshold in hepatitis C and that the 80% comes from HIV and hypertension. He stated that the percentage that would significantly impact outcomes in HCV treatment has not been determined and needs to be studied. It was commented though that the theory could be used as a good motivational tool to keep patients adherent to therapy

Part II will feature continued coverage

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