Ola Weiland
MD
Professor
Division of Infectious Diseases
Department of Medicine
Karolinska Institute
Huddinge University Hospital
Stockholm, Sweden
E:[email protected]
Treatment of chronic hepatitis C virus (HCV) infection has steadily improved over the years. The traditional treatment option of interferon (IFN) alfa monotherapy has been replaced by combination therapy. Current prescribing practice involves IFN alfa in combination with ribavirin, according to international consensus as agreed upon in a meeting in Paris in 1999.(1)
To optimise treatment outcome different approaches are used for genotypes 2/3 (easy to treat) and genotype 1/4 (difficult to treat). Shorter treatment periods are used for genotype 2/3 (24 weeks) and longer for genotypes 1/4 (48 weeks). Standard IFN alfa dosing has been 3MU three times a week for 24 or 48 weeks, depending on the genotype.(1, 2) This dose seems to be sufficient for genotypes 2/3, but a higher dose of 5MU seems to offer better results for genotype 1/4 patients.(3)
Response to treatment
Responses are divided into the virological response – the clearing of HCV RNA from the serum – and the biochemical response – normalisation of ALT (alanine transaminase) levels in the serum. It is now well recognised that the virological response is the more important one and most often correlates with a simultaneous biochemical response. The reverse is not true – many patients with a biochemical response continue to be HCV RNA positive in serum. During long-term follow-up most of these patients will eventually develop raised ALT levels.
Patient categories
Naïve patients are patients that have never been treated before.
Relapse patients or nonsustained response patients are patients who respond during treatment with viral eradication from the serum (negative for a qualitative test for HCV RNA in serum detecting 100 HCV RNA copies/ml = 50IU/ml), but after treatment stops they again become HCV RNA positive in serum.
Nonresponders are patients who, despite treatment, never become negative for HCV RNA in serum, or who after becoming negative become positive again during continued treatment, the so-called breakthrough nonresponse.
Sustained response (SR) rates with standard combination therapy in naïve patients as noted in international studies are depicted in Table 1.(4,5)
[[HPE02_table1_38]]
Response according to viral load
Generally the response is better in patients with a low rather than high viral load at baseline. This is most obvious in the difficult-to-treat genotype 1 infections, but not in the easy-to-treat genotype 2 or 3 infections. A cutoff point of 2–3 million copies per ml serum is set which corresponds to 0.8–1.2 million IU/ml.(6)
A disadvantage inherited with IFN dosing three times weekly is the fluctuating levels seen in serum, with low or no serum levels on dose-free days. This increases the risk of resistance emerging and allows the viral replication to increase on dose-free days. This problem has been overcome by new IFN preparations with prolonged half-lives, allowing once-a-week dosing.
“Pegylation” of interferons
Polyethylene glycol (Peg) is a molecule that can be polymerised into long straight or branched chains that attach to proteins. After pegylation IFNs have a much longer half-life and become partly protected from degradation by proteolysis. This increases the time they circulate in active form. Pegylation of IFNs has led to the development of a new class of IFNs – the Peg-IFNs – of which Peg-IFN alfa-2b from Schering-Plough has reached the market and a competitor, Peg-IFN alfa-2a from Hoffman-La Roche, will do so soon.
Both preparations allow once-a-week dosing and offer more stable serum levels of IFN than their respective nonpegylated parent compounds.
Peg-IFN alfa-2b
Schering-Plough has developed a 12kD linear Peg-IFN alfa-2b with a half-life of 40 hours, compared with only four hours for the nonpegylated parent form. This allows dosing once a week. Doses of 1mg/kg body weight require >168 hours to clear.
The mechanism of clearance has not been fully clarified but 30% is excreted by the kidney. According to monotherapy studies and combination studies with ribavirin, the optimal dose for easy-to-treat genotypes is likely to be 1mg/kg body weight, whereas the difficult-to-treat are likely to need 1.5mg/kg body weight.(7,8)
Peg-IFN alfa-2a
Hoffman-La Roche has developed a competitor branched chain Peg-IFN alfa-2a which is somewhat larger, 40kD, and which gives sustained serum levels for more than 168 hours. The 40kD IFN is predominantly metabolised in the liver. According to monotherapy and combination studies, the optimal dose seems to be 180mg irrespective of body weight.(9)
Peg-IFNs in combination therapy
When used as replacement for their mother compounds in combination with ribavirin, both Peg-IFN preparations have increased the response rates by some 10% compared with the old standard combination. Furthermore, no new unexpected adverse effects have been seen with the Peg-IFNs besides a somewhat increased tendency for bone marrow depression.
Since it is more convenient for the patient to take IFN once weekly and the response rate is somewhat improved with the use of Peg-IFN, they are likely to become standard therapy in combination treatment for chronic HCV infection. During the summer of 2001 Schering-Plough got FDA approval for this combination, while Hoffman-La Roche awaits approval. No randomised controlled trial has compared the performance of these two Peg-IFNs but differences are likely to be minor.
” Peg-IFN alfa-2a has also achieved remarkably good results in cirrhotic patients, known to be difficult to treat, with cure rates of more than 50% in genotype 2 and 3 infections and 10–16% in genotype 1 patients ”
For patients who cannot tolerate ribavirin, monotherapy with Peg-IFNs is a much better alternative than nonpegylated IFN. Hence, Peg-IFN alfa-2a has also achieved remarkably good results in cirrhotic patients, known to be difficult to treat, with cure rates of more than 50% in genotype 2 and 3 infections and 10–16% in genotype 1 patients.(10)
Is combination therapy likely to become current best practice and standard in the near future?
Currently only patients with moderate fibrosis or mild fibrosis with active inflammation are treated, according to consensus.(1,11) With the new Peg-IFNs’ improved response rates and cost-benefit increases, a larger segment of patients, possibly including all patients with signs of fibrosis, will be offered treatment.
” With the new Peg-IFNs’ improved response rates and
cost-benefit increases, a larger segment of patients will be
offered treatment ”
As with the traditional therapy, patients with easy-to-treat genotypes (2 and 3) will get Peg-IFN plus ribavirin for 24 weeks, whereas patients with difficult- to-treat genotypes (1 and 4) will get Peg-IFN plus ribavirin for 48 weeks.
References
- Anonymous. Consensus Statement, EASL International Consensus Conference on Hepatitis C. J Hepatol 1999;30:956-61.
- Weiland O. Treatment of naive patients with chronic hepatitis C. J Hepatol 1999;31(Suppl 1):168-73.
- Saracco G, Ciancio A, Olivero A, et al. A randomized 4-arm multicenter study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon alone. Hepatology 2001;34(1):133-8.
- McHutchison J, Gordon S, Schiff E, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-92.
- Poynard T, Marcelin P, Lee S, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352:1426-32.
- Pawlotsky J, Bouvier-Alias M, Hezode C, Darthuy F, Remire J, Dhumeaux D. Standardization of hepatitis C virus RNA quantification. Hepatology 2000;32:654-9.
- Lindsay K, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C [In Process Citation]. Hepatology 2001;34:395-403.
- Manns M, McHutchinson J, Gordon S, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C:a randomised trial [In Process Citation]. Lancet 2001;358:958-65.
- Zeuzem S, Feinman S, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C [Record Supplied By Publisher]. N Engl J Med 2000;343:1666-72 .
- Heathcote E, Shiffman M, Cooksley W, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis [Record Supplied By Publisher]. N Engl J Med 2000;343:1673-80.
- Weiland O. Interferon and ribavirin combination therapy: indications and schedules. Forum Genova 2000;10(1):22-8.
Resources
Hepatitis Foundation International
W:www.hepfi.org
Hepatitisweb Hoffman LaRoche: Información en español
W:www.hepatitis web.roche.com.ar
Rxlist: The Internet Drug Index
W:www.rxlist.com
Schering-Plough
Hepatitis Innovations
W:www.hep-help. com
United European Gastroenterology Federation
W:www.uegf.org
Forthcoming event
18–21 April 2002
37th Annual Meeting of the European Association for the Study of the Liver
Madrid, Spain
W:www.easl.ch
