Induction therapy in chronic hepatitis C with pegylated interferons?
- NATAP - www.natap.org
Induction therapy in chronic hepatitis C with pegylated interferons?
Journal of Hepatology, Volume 41, Issue 3, (September 2004)
Stefan Zeuzem, Department of Internal Medicine II, Saarland University Hospital, Homburg/Saar, Germany
Sustained virologic response rates in 'difficult-to-treat' patients infected with HCV genotype 1 and high baseline viral load may be improved by combining induction and prolonged maintenance therapy (up to 72-76 weeks); study of higher dosing of peginterferon is ongoing.
A biphasic decline of serum HCV RNA is typically observed in patients with chronic hepatitis C during the first weeks of interferon-�� based antiviral treatment. After initiation of therapy, with a delay of a few hours, a sharp first-phase decay of serum HCV RNA can be observed for approximately 1-2 days. Then, a slower second-phase decay begins [1,2]. In both phases, the decline is nearly exponential, i.e. in plots of serial measurements of HCV RNA against time with a logarithmic scale, the first and second phase decay can often be approximated by straight lines. The first-phase decay is clearly dose-dependent and can be explained by partial but not complete blocking of viral replication. The second-phase decline is more variable, less dose-dependent and assumed to be related to the death rate of infected hepatocytes [2-4].
The initial decline of HCV RNA predicts the end-of-treatment and sustained virologic response better than any single or any combination of baseline parameters (HCV genotype, HCV RNA before initiation of therapy, presence of fibrosis/cirrhosis, and other host factors) [5,6]. Therefore, attempts have been made to improve early virologic responses by so-called induction therapies. Such intensified regimens included higher doses (more than 3MIU) and daily application of standard interferon 7. Indeed, these regimens showed a steeper decline of serum HCV RNA and shorter treatment durations to achieve undetectable HCV RNA levels 8. Disappointingly, however, these improved initial virologic responses in general did not translate into improved sustained virologic response rates [9-12].
The largest multicenter, randomized, controlled trial comparing high dose daily induction interferon-�� plus ribavirin versus standard interferon-�� plus ribavirin in previously untreated patients with chronic hepatitis C has only been presented at the Annual Meeting of the American Association for the Study of the Liver (AASLD) 9 but has unfortunately not yet been published as a full paper. A total of 637 patients were randomly assigned to receive either interferon alfa-2b 10MIU daily for 2 weeks, 5MIU daily for 6 weeks, and 3MIU daily for 16 weeks, followed by 3MIU three times per week for 24 weeks or 3MIU interferon alfa-2b three times per week for 48 weeks. All patients received daily oral ribavirin in doses of 1000-1200mg for 48 weeks. Despite the more aggressive treatment of patients who received the induction regimen, there was no substantial difference in sustained virologic response rates between the two treatment groups (49% vs. 46%; P=0.41).
All patients who received induction therapy had a faster, and HCV genotype 1 infected patients also a more pronounced decline in mean HCV RNA levels. However, differences in HCV RNA levels narrowed considerably at later time points, in particular in the second half of therapy where patients in both groups received 3MIU interferon-�� three times per week. Even in patients infected with HCV genotype 1 and high baseline HCV RNA levels, end-of-treatment and sustained virologic response rates were similar in the two treatment groups (38% vs. 35% and 34% vs. 28%, respectively) 9. The failure to enhance virologic outcome was not because of a higher drop-out rate among patients who received induction therapy. Despite induction therapy was generally rather less well tolerated than was standard therapy, 75% of patients in the induction arm completed 48 weeks of treatment compared with 79% of patients in the standard treatment arm. Sustained virologic response rates were similar among those in
both treatment groups who received 80% of both drugs for at least 80% of the time 9.
Higher daily doses than 10MIU of interferon-�� are unlikely to achieve a more pronounced initial viral decline [2,3]. Perhaps a period of induction therapy with high interferon-�� doses for longer than 2 weeks may affect virologic response rates. Ferenci et al. compared three different interferon-�� doses during the first 14 weeks of therapy in previously untreated patients with chronic hepatitis C 13. Patients in group A (n=130) received an induction regimen consisting of 10MIU interferon-�� daily for 2 weeks followed by 10MIU every other day for an additional 12 weeks compared with patients who received 5MIU interferon-�� either daily (group B, n=124) or every other day (group C, n=119). Treatment in all three groups was followed by 5MIU interferon-�� every other day for 24 weeks and for the complete 38 weeks, treatment was combined with ribavirin (1000-1200mg per day). No differences in virologic response rates were observed on treatment, at the end of treatment or at the end of
the follow-up period. When data were analyzed according to HCV genotype, the sustained virologic response rate was highest in patients infected with HCV genotype 1 who received the high dose interferon induction therapy (group A: 44.2%, group B: 28.6%, group C: 27%) 13.
Compared with the study by Carithers et al. described above 9, the difference in the reported virologic outcome of the two trials is due not only to the higher sustained virologic response rate in the high dose induction arm but also the lower sustained virologic response rates of the two control arms in the study by Ferenci et al. 13. Even if the study by Carithers et al. were to have achieved the 44% sustained virologic response rate with the high dose induction regimen described by Ferenci et al., the study would have needed a sample size of more than a thousand subjects with HCV genotype 1 infection to have had a reasonable chance of demonstrating a significant increase in efficacy over the 35% sustained virologic response rate of the standard treatment arm in the study by Carithers et al. Taken together, the advantage of induction therapies using standard interferon-�� in combination with ribavirin is marginal, and if present at all, restricted to patients infected with HCV
genotype 1 and high baseline viral load who are able to tolerate such an intensified regimen.
What is the rationale to repeat induction-type studies in the era of pegylated interferons? Chemical modification of interferons with a polyethyleneglycol moiety produces biologically active molecules with a longer half-life than the natural molecule and more favourable pharmacokinetics allowing for once-weekly dosing 14. It is unlikely that pegylated interferons achieve better initial virologic responses than standard interferons, but the improved pharmacokinetics of pegylated interferons may be advantageous in terms of maintaining a virologic response better after high dose induction than a regimen of standard interferon-�� given three times per week.
In monotherapy for chronic hepatitis C pegylated interferons achieve sustained virologic response rates approximately twice that with standard interferons [15,16]. The advance of pegylated compared with standard interferons in combination with ribavirin is less pronounced but clinically still relevant [17,18]. While all pivotal trials for peginterferon alfa-2a used a flat dose of 180��g once per week [15,18,19], the pivotal trial leading to the approval of peginterferon alfa-2b in combination with ribavirin included one induction-type treatment arm 17. Here patients received peginterferon alfa-2b at a dose of 1.5��g/kg body weight each week for the first 4 weeks followed by 0.5��g/kg per week for the next 44 weeks plus 1000-1200mg ribavirin orally for 48 weeks. Results were compared with a cohort of patients who received standard combination therapy (3��3MIU/week standard interferon alfa-2b plus 1000-1200mg ribavirin for 48 weeks) as well as a cohort of patients who received
1.5��g/kg peginterferon alfa-2b plus 800mg ribavirin for 48 weeks. Surprisingly, sustained virologic response rates with standard combination therapy and the peginterferon alfa-2b plus ribavirin induction treatment were both 47% (all genotypes) and also no advantage from induction treatment was seen in HCV genotype 1 infected patients (34% vs. 33%, respectively) 17.
In a smaller study in patients chronically infected with HCV genotype 1 (n=55), high dose induction therapy with peginterferon alfa-2b at a dose of 3��g/kg body weight for 1 week, 1.5��g/kg for 3 weeks, and 1.0��g/kg for 44 weeks achieved a more pronounced on-treatment decline of HCV RNA compared to treatment with peginterferon alfa-2b at a dose of 0.5��g/kg for 48 weeks (in both groups peginterferon was combined with 800mg/day ribavirin) 20. However, the initial virologic advantage became progressively less after decreasing the peginterferon alfa-2b dose in the induction arm. At the end of the 48-week treatment period the log HCV RNA decline was -2.17��1.62 and -2.01��1.81, respectively. 20.
The study by Bruno et al. in this issue of the Journal compared the efficacy of an induction dose of peginterferon alfa-2b (80-100��g q.w. depending on body weight for 8 weeks, followed by 50��g q.w. for the following 40 weeks) with a standard interferon-�� regimen (6MIU on alternate days for 48 weeks) both in combination with ribavirin (1000-1200mg/day) in previously untreated patients chronically infected with HCV genotype 1 21. Although the dose of peginterferon alfa-2b was relatively low and the dose of standard interferon alfa-2b relatively high, the sustained virologic response rate in the group of patients treated with pegylated interferon was significantly higher than in the group of patients treated with standard interferon-�� (41.1% vs. 29.3%; P=0.03). However, the contribution of this study to the concept of induction dosing of pegylated interferons should not be overemphasized because a group of patients treated with a constant dose of pegylated interferon was not
included for comparison.
The sustained virologic response rates in the study by Bruno et al. (mean weighted dose of peginterferon alfa-2b approximately 0.85��g/kg) are similar to the rates described for HCV genotype 1 infected patients treated with 1.5��g/kg peginterferon alfa-2b in the trial by Manns et al. (41% vs. 42%) [17,21]. However, a comparison between the two trials is difficult due to divergent baseline characteristics of the patients and due to the fact that the ribavirin dose in the respective treatment arm of the trial by Manns et al. was considered insufficient for HCV genotype 1 infected patients. Nevertheless, the discussion continues about the optimal dose of peginterferon not only in patients infected with HCV genotype 2 or 3 but also for those infected with HCV genotype 1.
Sustained virologic response rates in 'difficult-to-treat' patients infected with HCV genotype 1 and high baseline viral load may be improved by combining induction and prolonged maintenance therapy (up to 72-76 weeks) [22-24]. However, for this approach highly motivated patients, close patient monitoring, and experienced hepatological support are required. In the era of pegylated interferons the previous experience with induction therapies must not be ignored. Additional induction-type studies should focus on previously untreated patients infected with HCV genotype 1 and high baseline viral load and on previous non-responders to combination therapy. Such trials must be appropriately powered because the anticipated improvement in virologic response is small and in addition to induction dosing should also consider optimal dosing of ribavirin and treatment prolongation. Learning from the past should allow for optimal study design with appropriate treatment and control groups to obtain
the best possible answers for those patient cohorts who urgently require further improvement in virolgic response rates.
return to Article Outline
Zeuzem S, Schmidt JM, Lee J-H, R��ster B, Roth WK. Effect of interferon alfa on the dynamics of hepatitis C virus turnover in vivo. Hepatology. 1996;23:366-371.
Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-�� therapy. Science. 1998;282:103-107.
Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden AJ. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology. 1997;26:226-231.
Zeuzem S, Schmidt JM, Lee JH, von Wagner M, Teuber G, Roth WK. Hepatitis C virus dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover. Hepatology. 1998;28:245-252.
Zeuzem S, Herrmann E, Lee J-H, Fricke J, Neumann AU, Modi M, et al.. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a. Gastroenterology. 2001;120:1438-1447.
Neumann AU, Zeuzem S, Brunda MJ, Hoffman JH. Rapid viral response to treatment with pegylated (40kDa) interferon alfa-2A (Pegasys) is strongly predictive of a sustained virologic response in patients with chronic hepatitis C (CHC). Hepatology. 2000;32:318A.
Shiffman ML. Use of high-dose interferon in the treatment of chronic hepatitis C. Sem Liver Dis. 1999;19:25-33.
Bekkering FC, Stalgis C, McHutchison JG, Brouwer JT, Perelson AS. Estimation of early hepatitis C viral clearance in patients receiving daily interferon and ribavirin therapy using a mathematical model. Hepatology. 2001;33:419-423.
Carithers RL, Zeuzem S, Manns MP, Mc Hutchison JG, Perrillo RP, Bailey R, et al.. Multicenter, randomized, controlled trial comparing high dose daily induction interferon plus ribavirin versus standard interferon alfa-2B plus ribavirin. Hepatology. 2000;32:317A.
Van Vlierberghe H, Leroux-Roels G, Adler M, Bourgeois N, Nevens F, Horsmans Y, et al. Daily induction combination treatment with alpha 2b interferon and ribavirin or standard combination treatment in naive chronic hepatitis C patients. J Viral Hepat. 2003;10:460-466.
Bjoro K, Bell H, Hellum KB, Skaug K, Raknerud N, Sandvei P, et al.. Effect of combined interferon-alpha induction therapy and ribavirin on chronic hepatitis C infection: a randomized multicentre study. Scand J Gastroenterol. 2002;37:226-232.
Layden TJ, Layden JE, Reddy KR, Levy-Drummer RS, Poulakos J, Neumann AU. Induction therapy with consensus interferon (CIFN) does not improve sustained virologic response in chronic hepatitis C. J Viral Hepat. 2002;9:334-339.
Ferenci P, Brunner H, Nachbaur K, Datz C, Gschwantler M, Hofer H, et al. Combination of interferon induction therapy and ribavirin in chronic hepatitis C. Hepatology. 2001;34:1006-1011.
Zeuzem S, Welsch C, Herrmann E. Pharmacokinetics of peginterferons. Semin Liver Dis. 2003;23:23-28.
Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al.. Peginterferon alfa-2a in patients with chronic hepatitis. N Engl J Med. 2000;343:1666-1672.
Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34:395-403.
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al.. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, et al.. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.. Ann Intern Med. 2004;140:346-355.
Buti M, Sanchez-Avila F, Lurie Y, Stalgis C, Valdes A, Martell M, et al. Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2b plus ribavirin. Hepatology. 2002;35:930-936.
Bruno S, Camm� C, Di Marco V, Rumi M, Vinci M, Camozzi M, et al.. Peginterferon alfa-2b plus ribavirin for na����ve patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol. 2004;41:474-481.
Vrolijk JM, Bekkering FC, Brouwer JT, Hansen BE, Schalm SW. High sustained virological response in chronic hepatitis C by combining induction and prolonged maintenance therapy. J Viral Hepat. 2003;10:205-209.
Berg T, von Wagner M, Hinrichsen H, Buggisch P, Goeser T, Rasenack J, et al.. Comparison of 48 or 72 weeks of treatment with peginterferon alfa-2a (40KD), (Pegasys) plus ribavirin (Copegus) in treatment-naive patients with chronic hepatitis C infected with HCV genotype 1. Hepatology. 2003;38:317A.
Sanchez-Tapias JM, Diago M, Escartin P, Enriquez J, Moreno R, Romero-Gomez M. Sustained virological response after prolonged treatment with peginterferon alfa-2a (40KD) (Pegasys) and ribavirin (Copegus) in treatment-naive patients with chronic hepatitis C and detectbale HCV RNA after week 4 of therapy: teravic-4 study. J Hepatol. 2004;40:150.
[Non-text portions of this message have been removed]
- I think that the interferon while it's an option, isn't the panacea (sp) for
hep C. If it were, me doing the high dose at 20 whatevers per shot would
have gotten rid of the darn critters. I have this feeling that in some of
us, if our body isn't gonna get rid of it, it's just not gonna get rid of
it. We will need something else to do it, not interferon. (Interferon
doesn't get rid of the virus, it boosts our body's immune system, our body
gets rid of the virus).
I know, it's not scientific. It's just intuition, or a feeling, a gut
feeling. I think for some of us, esp 1b's, who "clear" (and that means not
really clear obviously) early and fast on treatment, but don't get SVR, and
don't get it at high dose either, have to look at other options.
I was in my doc's office Monday not feeling well. I had my mammogram and
ultrasound (I have fibrocysts in my breasts, have had them forever but they
always check, a good thing), and they were acting up, swollen, (I know I
know too much caffeine), and I didn't get to see my usual doc, he was very
busy, but saw a different doc and she was adamant that I should try
treatment again, or have my viral load checked because it could be high, or
why haven't I seen my gastro in the past few years (HELLO! I've been on
cancer treatment!!!) and I really felt bad and just wanted to walk out, you
know? Didn't really have the energy to explain to her that in this instance,
I felt like I knew more about "my" hep than she did, cuz if I told her that,
then I'd be dealing with an contrary doc and I didn't want that on my hands.
I wanted antibioitics, she gave me anti-inflammatories - first Celebrex last
week, this week stop the Celebrex and do Vioxx and Bextra (together???
anyone know about that?) - and I said OK but only as long as I need them,
because I'm not killing my good liver just because the pamplet says it's
good for something.
Maybe I'm nuts, but I'd rather take a pill now and then when I need it, than
a pill every day. Just seems to me that it would be better for my liver and
for me overall.
Anyway, things are better, but I just wanted to share my frustration, which
I'm sure many of you have had. I should pantent some plastic blow up "doctor
boppers". You know, my grandkids have these blow up things they put their
hands into and bop each other with, they are large and full of air, makes
them soft so they don't hurt, know what I mean?
So, when some doctor starts talking treatment, I can "bop" him or her and
set 'em straight. How bout that? :)
I'm kidding of course.... well sorta :)
Have a great week yall.