Základem léčby je pro většinu pacientů s chronickou infekcí virem hepatitidy B nebo C interferon alfa (IFN alfa), původně ve formě, kterou bylo nutno podávat třikrát týdně a kterou nyní označujeme jako konvenční nebo klasický IFN alfa. V posledních letech jsou konvenční IFN alfa postupně nahrazovány pegylovanými interferony alfa (PEG-IFN), které se podávají jen jednou týdně, jsou účinnější a obvykle lépe tolerované. Po létech výzkumu se do klinické praxe dostaly dvě formy pegylovaných interferonů alfa, PEG-IFN alfa-2a a PEG-IFN alfa-2b, které se navzájem liší velikostí a strukturou použitého polyetylénglykolu (PEG) a způsobem vazby PEG na IFN alfa. Tím jsou významně ovlivněny farmakokinetické a farmakodynamické vlastnosti obou preparátů. Kombinovaná léčba PEG-IFN a ribavirinem je v současnosti standardem léčby naprosté většiny nemocných s chronickou hepatitidou C. Podle předběžných výsledků klinických studií nahradí v krátké době pegylované interferony konvenční interferony i v léčbě chronické hepatitidy B. Všechny dosud publikované studie přitom potvrdily srovnatelnou bezpečnost pegylovaných i konvenčních interferonů a lepší snášenlivost PEG-IFN ze strany pacientů.

Polyethylene glycol (PEG) is a water-soluble, non-toxic polymer that can be covalently linked to different proteins. Pegylation increases protein half-life by reducing renal clearance and proteolysis. Pegylation leads to less antigenicity, increased solubility, and thermal as well as chemical stability of the base protein. Pegylated interferons (PEG-IFN) have a significantly increased plasma half-life and thus it can be administered only once a week. PEG-IFN alfa-2a and PEG-IFN alfa-2b are two forms of commercially available pegylated interferons. These forms of PEG-IFN are chemically dissimilar due to different types of PEGs used, linear or branched, and different types of chemical bonds between PEG and IFN alfa - stable amide bond in PEG-IFN alfa-2a or unstable urethane (carbonyl) bond in PEG-IFN alfa-2b. These characteristics affect differences in pharmacokinetics and pharmacodynamics of both forms of pegylated interferons. Despite these differences, efficacy of the two drugs was quite similar in registration trials, particularly when used in combination with ribavirin. In these studies PEG-IFNs were compared with standard IFN alfa, being used alone as monotherapy or in combination with ribavirin. Monotherapy studies clearly indicated that both forms of PEG-IFNs were significantly superior to standard IFNs in relation to end-of-treatment (EVR) and sustained virologic responses (SVR). At present, combination of PEG-IFN and ribavirin is a standard of the treatment in chronic hepatitis C patients according to the results of three pivotal trials. The main findings from these studies were: 1. The rates of sustained virologic response were almost identical with PEG-IFN alfa-2a (56 %) or PEG-IFN alfa- 2b (54 %) combined with ribavirin and were significantly higher than those observed with standard IFN alfa plus ribavirin combination therapy. 2. The benefit of using of PEG-IFN instead of conventional IFN alfa in combination with ribavirin was not uniform in different patients subgroups: PEG-IFNs significantly improved SVR in patients with genotype 1 infection (HCV-1) but not in those with genotypes 2 or 3 infections (HCV-2,3). 3. In a study using PEG-IFN alfa-2a in combination with ribavirin for 24 or 48 weeks, it was clear that patients with HCV-1 significantly improved SVR when treated for longer, independently of pre-treatment viral load while no such difference was seen for patients HCV-2,3 again independently of pre-treatment HCV RNA levels. Furthermore, a fixed dose of 800 mg of ribavirin was sufficient to maximise SVR rates in patients with HCV-2,3 while patients with HCV-1 responded better to higher dosages (1000 - 1200 mg daily) of ribavirin. 4. In the studies conducted with PEG-IFN alfa-2b post hoc analysis showed that SVR was dependent on the ribavirin dose expressed as mg/kg body weight with a threshold value of 10.6 mg/kg below which, rates of SVR become unsatisfactory. 5. Adherence to the intended dosage of PEG-IFN and ribavirin and duration of therapy in important to maximise SVR rates, particularly for HCV-1 patients. Probably, PEG-IFN in monotherapy or in combination with lamivudine will be the standard of the treatment in chronic hepatitis B patients in the near future. The clinical trials of Phase II and III showed that pegylated interferons alfa-2a and alfa-2b provide good on-treatment and sustained response rates both in HBeAg-positive and HBeAg-negative chronic hepatitis B patients. PEG-IFN alfa-2a in monotherapy was well tolerated and was associated with substantially greater efficacy compared with conventional IFN alfa-2a in the overall HBeAg-positive patient population, as well as in patients with difficult-to-treat disease. PEG-IFN alfa-2a monotherapy had significantly superior efficacy compared with lamivudine in HBeAg-negative patients. In addition, the combination of lamivudine a PEG-IFN alfa-2a did not improve response rates over PEG-IFN monotherapy. Combination of PEG-IFN alfa-2b and lamivudine had a superior anti-viral effect to lamivudine monotherapy in the treatment of HBeAg-positive chronic hepatitis B. Prolonged, one-year treatment with PEG-IFN alfa-2b had a comparable safety profile to short term conventional interferon alfa-2b therapy. In all published clinical studies with chronic hepatitis B or C patients, the safety of therapy with pegylated interferons was similar to standard IFN alfa and the tolerability of pegylated interferons was even better.

Klinika infekčních chorob Fakultní nemocnice Brno

Pegylated interferons in the treatment of chronic viral hepatitis

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