Wolfgang Jessner

Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study

Summary Only 30% of patients with chronic hepatitis C virus genotype 1 (HCV-1) infection achieve a sustained virological response to interferon and ribavirin combination therapy. We prospectively assessed decline in viral load 24 h after one dose of interferon alfa as a predictor of non-response to 6 months of treatment with interferon and ribavirin. Interferon sensitivity was measured before initiation of combination therapy. We measured viral load in 29 consecutive patients, who had not previously been treated with interferon and who were chronically infected with HCV-1 within 24 h after one dose of 5 MU or 10 MU interferon alfa-2b, and 14 days of daily 5 MU interferon alfa-2b. A 24 h viral load decline by less than 70% of baseline after 5 MU interferon was the best pretreatment measure to identify non-responders (specificity 100%, n=10, 95% CI 74–100], sensitivity 83% [15/18], 59–96]).

Twice-weekly administration of peginterferon-alpha-2b improves viral kinetics in patients with chronic hepatitis C genotype 1.

Summary.u2002 The decline in hepatitis C viral load on treatment with peginterferon‐α‐2b is not continuous. The aim of this study was to investigate whether twice weekly dosing of peginterferon‐α‐2b may improve viral kinetics. Ten interferon‐naïve patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0u2003μg/kg peginterferon‐α‐2b once (group A) or twice weekly (group B) for 4u2003weeks. Viral load and serum concentrations of peginterferon‐α‐2b were measured. Peginterferon‐α‐2b reached maximal blood concentrations 24u2003h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon‐α‐2b was undetectable in nine patients in group A (once weekly dosing). The same pattern was observed during the next 3u2003weeks of therapy. In group B (twice weekly dosing) peginterferon‐α‐2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2u2003days after the first dose of peginterferon‐α‐2b, but increased again on day 3. In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (Pu2003<u20030.001). To achieve continuous drug exposure and to improve initial viral clearance, peginterferon‐α‐2b has to be given at least two times weekly.

Early viral kinetics on treatment with pegylated interferon-alpha-2a in chronic hepatitis C virus genotype 1 infection.

summary. Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG‐IFN‐α‐2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN‐α‐2a (days 0 and 1), and before and during weekly 180 μg PEG‐IFN‐α‐2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty‐eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV‐RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN‐α‐2a was greater in virological responders (1.05 log [0.25–1.67]) than in nonresponders (NR) (0.34 [0.14–0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG‐IFN‐α‐2a. All patients with an initial decline >u20031.4 log became sustained responders. Five of 12 patients with a log change <u20030.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG‐IFN‐α‐2a is different to that on standard IFN. In spite of a lower initial response PEG‐IFN‐α‐2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.

Sudden hearing loss in patients with chronic hepatitis C treated with pegylated interferon/ribavirin.

BACKGROUND:Sudden hearing loss has been reported on standard interferon (IFN)-α2 therapy. This is the first report on the occurrence of sudden hearing loss in six cases of chronic hepatitis C in temporal relation to treatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy. Three patients were treated in an ongoing randomized placebo–controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 μg PEG-IFN α2a (PEGASYS®, Roche, Basel, CH)/wk and 1–1.2 g ribavirin/d (COPEGUS®, Roche, Nutley, USA) in de novo patients infected with HCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 wk of treatment, respectively.CONCLUSIONS:Sudden hearing loss may occur in about 1% of patients on PEG-IFN/ribavirin combination therapy. This rate was not different to that observed in an untreated population. Possible mechanisms involved include direct ototoxicity of IFN, autoimmunity, and hematological changes. In contrast to published cases on auditory disability due to standard IFN, hearing loss did not fully resolve after discontinuation of therapy with PEG-IFN. On the other hand, symptoms did not worsen on continued treatment. Therefore, the decision whether to continue or to stop the treatment when signs of ototoxicity appear is based on the clinical judgment of the treating physician.

Plummer-Vinson syndrome associated with celiac disease and complicated by postcricoid carcinoma and carcinoma of the tongue.

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Impact of high‐dose interferon induction and ribavirin therapy in patients with chronic hepatitis C relapsing after or not responding to interferon monotherapy

Background/aims: Initial high‐dose interferon‐α induction therapy in combination with ribavirin improves sustained response rates in treatment‐naïve patients. This prospective, randomized, controlled study tested whether non‐responders or relapsers to interferon monotherapy also benefit from induction therapy.

Retreatment of patients with chronic hepatitis C not responding to interferon/ribavirin combination therapy with daily interferon plus ribavirin plus amantadine

SummaryThere is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-α plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-α plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n=67), breakthroughs (n=16) and relapsers (n=19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-α2a 6MU daily, ribavirin 800–1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-α2a 6MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). Ontreatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p<0.05; week 48: 46% vs. 16%, p<0.01) but no such difference was found for sustained virological response (20% vs. 12%, NS).In conclusion, triple combination treatment with daily interferon-α plus ribavirin plus amantadine for 3 months can induce virological response in a considerable number of nonresponders/relapsers to previous dual combination treatment, but the sustained virological response rate remains low.