Hepatitis: Ferenci P

Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J, Anonymous00255, Ferenci P, Holm E, Vom Dahl S, Müller MJ, Nolte W, Anonymous00256. · Department Internal Medicine, Staedtisches Klinikum, Dessau, Germany. · Clin Nutr. · Pubmed #16707194 No free full text.

Abstract: Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in patients with liver disease (LD). It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for patients with chronic LD in whom undernutrition is very common. ONS improve nutritional status and survival in severely malnourished patients with alcoholic hepatitis. In patients with cirrhosis, TF improves nutritional status and liver function, reduces the rate of complications and prolongs survival. TF commenced early after liver transplantation can reduce complication rate and cost and is preferable to parenteral nutrition. In acute liver failure TF is feasible and used in the majority of patients.

Ferenci P, Staufer K. · No affiliation provided · Liver Int. · Pubmed #18339069 No free full text.

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Ferenci P. · No affiliation provided · Gastroenterology. · Pubmed #16952564 No free full text.

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Zeuzem S, Rizzetto M, Ferenci P, Shiffman ML. · JW Goethe University Hospital, Frankfurt, Germany. · Antivir Ther. · Pubmed #19430089 No free full text.

Abstract: Current guidelines recommend a full 24-week regimen for all patients undergoing treatment for genotype 2 or 3 hepatitis C virus (HCV) infection. Recent data from two large randomized studies, one with pegylated interferon-alpha2a plus ribavirin (RBV) and one with pegylated interferon-alpha2b plus RBV assessed treatment duration and on-treatment predictors, such as rapid virological response (RVR; HCV RNA <50 IU/ml at week 4) or sustained virological response rates. Overall, these studies have shown that abbreviated regimens are generally less effective than standard 24-week regimens in genotype 2 or 3 patients because of a higher rate of relapse. However, abbreviated treatment might be offered to selected patients with an RVR provided that they have a low baseline viral load and minimal hepatic fibrosis.

Ferenci P. · Univ. Klinik für Innere Medizin III, Medical University of Vienna, AKH, Wien, Austria. · Best Pract Res Clin Gastroenterol. · Pubmed #19187870 No free full text.

Abstract: Peginterferon alfa in combination with ribavirin is and will remain for the next years the current standard for treatment of chronic hepatitis C. The new antivirals currently investigated in phase II of III trials may augment the overall response rates but require peginterferon/ribavirin as backbone. The cure rate of peginterferon/ribavirin treatment can be improved by better education of treating physicians to identify and treat conditions which negatively influence the final outcome of therapy. Specific focus is the prevention and/or early treatment of common side effects of therapy including anaemia, cytopenia and depression. In selected patients increasing the dose of peginterferon and/or ribavirin may augment response rates. Measuring the viral response at various time points during treatment allows individualization of treatment duration. Treatment duration may be shortened in patients with undetectable HCV-RNA after 4 weeks of therapy, on the other hand slow virologic responders may benefit from prolonged treatment.

Lee SS, Ferenci P. · Liver Unit, University of Calgary, Calgary, Alberta, Canada. · Antivir Ther. · Pubmed #18432158 No free full text.

Abstract: Currently, many decisions for the treatment of hepatitis C virus (HCV) are based on genotype, which is the most significant baseline predictor of response to therapy; however, it has become increasingly apparent that fixed treatment durations might not be appropriate for all patients. The use of on-treatment predictors such as rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 can be used to predict the likelihood of achieving a sustained virological response (SVR), helping to tailor treatment to the individual. Until now, EVR has been defined as achieving either undetectable HCV RNA (< 50 IU/ml) or a > 2 log drop in HCV RNA, but still detectable, at week 12. However, rates of SVR in patients achieving an EVR are heterogeneous. It has recently been suggested that by subdividing EVR into RVR (< 50 IU/ml at week 4), complete EVR (HCV RNA < 50 IU/ml at week 12) or partial EVR (HCV RNA > 2 log drop in HCV RNA but still detectable [> 50 IU/ml] at week 12), it might be possible to further improve the prediction of patients likely to achieve an SVR and may allow for tailoring of treatment duration. Genotype 1 and 4 patients achieving an RVR have high rates of SVR and may be candidates for shorter treatment duration. Patients with a complete EVR achieve high SVR rates with the current treatment duration of 48 weeks, whereas patients achieving a partial EVR have lower rates of SVR and could benefit from treatment intensification to 72 weeks. Here, we discuss the importance of baseline predictors of response and the emerging concept of response-guided therapy in genotype 1 and 4 patients.

Ferenci P. · Department of Internal Medicine IV, Medical University of Vienna, Vienna, Austria. · Minerva Gastroenterol Dietol. · Pubmed #16557187 No free full text.

Abstract: Approximately 123 million people worldwide are infected with hepatitis C virus (HCV). The majority of those infected with the virus develop chronic progressive liver disease that over time can result in cirrhosis, end-stage liver disease, hepatocellular carcinoma and death. The goal of treatment is viral eradication. The recognised standard of care for chronic hepatitis C is the combination of pegylated interferon plus ribavirin, which has been shown to be effective in treatment-naïve patients, including those with persistently normal ALT levels, and in patients with HIV-HCV coinfection. Two pegylated interferons are commercially available, both of which have distinct pharmacokinetic properties that necessitate different dosing strategies. With the standard of care, overall virological response rates have exceeded 50% in randomised, multinational phase III studies. Viral response rates are heterogenous and are influenced by a range of viral and host-specific factors. By far, the most important factors influencing treatment outcomes are HCV genotype and baseline HCV RNA level. Customisation of therapy based on baseline factors is recommended in treatment guidelines in order to maximise cure rates. Pegylated interferon plus ribavirin has been shown to be effective and safe in patients with HIV-HCV coinfection and is now recommended in this important and growing subpopulation. Ongoing efforts to improve treatment outcomes are focused on dynamic customisation of therapy based on the on-treatment response to therapy. Treatment of nonresponders to previous interferon-based therapies is an important area under investigation. Although several promising oral agents have been identified and are currently in clinical development, it seems likely that pegylated interferon will remain the backbone of therapy for years to come.

Ferenci P. · Department of Internal Medicine IV, Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, Wien A-1090, Austria. · Best Pract Res Clin Gastroenterol. · Pubmed #15588803 No free full text.

Abstract: Current strategies for treating hepatitis B focus on clearance of active HBV infection through suppression of viral replication by interferon-alpha (IFN-alpha) and the nucleoside analogs (lamivudine and adefovir). Lamivudine therapy for 1 year leads to HBeAg seroconversion in 16-18% of patients compared to 4-6% of untreated controls, to histological improvement in 49-56% treated patients and in 23-25% controls. HBeAg seroconversion rates increase with the duration of lamivudine therapy from 17% at 1 year to 27, 40, 47 and 50% at 2, 3, 4 and 5 years, respectively. When prescribing lamivudine, drug resistance due to the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. After 48 weeks of treatment with 10 or 30 mg of adefovir dipivoxil per day, significantly more patients with HBeAg-positive chronic hepatitis B than those on placebo had histologic improvement (53, 59 and 25%, respectively), a reduction in serum HBV DNA levels (by a median of 3.52, 4.76 and 0.55 log copies/ml), undetectable levels of serum HBV DNA (21, 39 and 0%), normalisation of ALT levels (48, 55 and 16%) and HBeAg seroconversion (12, 14 and 6%). In HBeAg negative patients treated with adefovir dipivoxil (10mg/day) for 48 weeks, ALT levels had normalised in 72% (29% in the placebo group), serum HBV DNA levels were reduced to fewer than 400 copies/ml in 51% (none in the placebo group), liver histology improved in 64% (33% in the placebo group). No adefovir-associated resistance mutations of viral DNA were detected. Ongoing studies investigate combination therapy with lamivudine or IFN.

Ferenci P. · Professor of Medicine, Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Vienna, Austria. · Semin Liver Dis. · Pubmed #15346243 No free full text.

Abstract: Pretreatment prediction of successful interferon-based therapy is less accurate than is prediction based on serum hepatitis C virus (HCV) RNA measurements taken during the first few weeks of therapy. Virological response, defined as loss of detectable virus RNA during the first weeks of treatment, identifies interferon-sensitive virus strains. Studies on viral decline kinetics have shown that interferon-based therapies produce a two-phase reduction in viral RNA levels. Sustained virological response is associated with rapid biphasic viral decline kinetics, resulting in elimination of virus from the blood within 4 to 12 weeks. Rapid viral elimination correlates positively with low incidence of relapse in end-of-treatment virological responders and is, therefore, an important parameter for determining duration or type of therapy. This article reviews the various patient and viral factors that help predict response to various interferon-based therapies, ranging from interferon alone to the new pegylated interferons.

Ferenci P. · Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Waehringer Guertel 18-20, A 1090 Vienna, Austria. · J Antimicrob Chemother. · Pubmed #14645325 links to  free full text

Abstract: A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 still does not respond to pegylated interferon-alfa/ribavirin (IFN/RBV) therapy. Factors which identify potential non-responders are needed to limit exposure to drugs in patients unlikely to benefit from treatment and to save health care resources. Host predictive factors have a low negative predictive value. In contrast, viral factors have a high precision in predicting outcome of therapy. Viral kinetics are the basis for the study of response of therapy. The decrease in viral load within 24 h after administration of a single test dose of conventional IFN reflects the IFN-sensitivity of the virus strain and predicts the outcome of conventional IFN/RBV therapy even before treatment with a specificity of 100% and a sensitivity of 83%. In contrast to conventional IFN, the two available PEG-IFN preparations differ considerably in how they suppress viral replication, and cut-off values have to be prospectively established separately for each drug. Patients without an early virological response (HCV-RNA either undetectable or decrease by >or=2 log10 after 12 weeks) (EVR), do not achieve a sustained virological response (SVR; negative predictive value: 97-98%). Thus, in the absence of an EVR, treatment should be stopped. The outcome of PEG-IFN alfa-2a/RBV combination therapy is dependent on the rapidity of the virological response. Patients who become HCV-RNA negative after 4 weeks have the best chance of achieving an SVR. The rapidity of viral elimination may be a useful guide to tailoring the length of treatment in patients with an EVR.

Ferenci P. · University Clinic of Internal Medicine IV, Vienna, Austria. · Int J Clin Pract. · Pubmed #14529063 No free full text.

Abstract: Compared with conventional interferon alfa, peginterferon alfa-2a (40KD) has improved pharmacokinetics, provides sustained therapeutic plasma levels, and can be administered once weekly. In randomised, multinational trials, peginterferon alfa-2a (40KD) 180 microg once weekly was significantly more effective than three times weekly interferon alfa-2a in patients with chronic hepatitis C, including patients with cirrhosis. Peginterferon alfa-2a (40KD) and ribavirin 1000/1200 mg/day for 48 weeks produced significantly higher sustained responses than three times weekly interferon alfa-2b and ribavirin 1000/1200 mg/day in patients with chronic hepatitis C including those with HCV genotype 1, genotypes 2/3 and those with high or low viral loads at baseline. The drug is well tolerated when given alone or in combination with ribavirin. Health-related quality of life was significantly less impaired during treatment with peginterferon alfa-2a (40KD) than interferon alfa-2a in randomised trials. Peginterferon alfa-2a (40KD) is widely approved for use in patients with chronic hepatitis C.

Jessner W, Watkins-Riedel T, Formann E, Steindl-Munda P, Ferenci P. · Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital, Währinger Gürtel 18-20, A-1090 Vienna, Austria. · J Clin Virol. · Pubmed #12467775 No free full text.

Abstract: Viral dynamics is a concept analyzing the time course of treatment-induced changes in blood virion concentration (kinetics) to derive conclusions of where, when and how in the living organism virions are produced or eliminated. Originally applied to human immunodeficiency virus type 1 and hepatitis B virus, it has elucidated mechanisms of antiviral therapy in hepatitis C virus infection as well. This review summarizes key aspects of mathematical modeling as well as important clinical applications, namely induction therapy and prediction of virologic response to treatment. Furthermore, limitations of currently available quantitative assays will be discussed.

Ferenci P. · Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin IV, Währinger Gürtel 18-20, A-1090 Wien. · Wien Med Wochenschr. · Pubmed #11205179 No free full text.

Abstract: Interferon-alpha is still the only drug with antiviral activity against the hepatitis C virus. However, if the outcome of treatment is measured by highly sensitive virologic test, sustained response rates to interferon monotherapy are low, especially in patients infected with subtype 1 (3-10%). Therefore better therapies are needed. The combination of interferon with ribavirin is a major advance. Although the precise mode of action of ribavirin is unknown, it seems to decrease relapse rates after successful treatment. By combination therapy, 30% of patients with subtype 1 and 65% with subtype 3 had a sustained response. Further improvements can be expected from high-dose induction therapy and from long-acting pegylated interferons. Nonresponders may benefit from antifibrotic agents, like long-term interferon therapy, IL-10 or silymarin.

Ferenci P. · Dept. Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Wien, Austria. · Ital J Gastroenterol Hepatol. · Pubmed #10470603 No free full text.

Abstract: Wilson's disease is an autosomal recessive inherited disorder of copper metabolism resulting in pathological accumulation of copper in many organs and tissues. The Wilson disease gene is localized on human chromosome 13 and codes for a copper transporting P-type ATPase, -ATP7B. About one hundred mutations occurring throughout the whole gene have been documented so far. The most common is the His1069Gln point mutation. Wilson's disease may present under a variety of clinical conditions, the most common being liver disease (ranging from acute hepatitis, fulminant hepatic failure, chronic hepatitis, and cirrhosis), haemolytic anaemia, and neuropsychiatric disturbances. The diagnosis of Wilson's disease is usually made on the basis of clinical findings (Kayser-Fleischer rings, typical neurologic symptoms) and laboratory abnormalities (low serum caeruloplasmin, increased hepatic copper content). Molecular genetic testing is now the standard for testing asymptomatic siblings. Diagnosis in patients presenting with liver diseases is difficult and requires a combination of various laboratory parameters. Lifelong treatment with chelating agents (d-penicillamine, trientine) or with zinc is usually sufficient to stabilize the patient and to achieve clinical remission in most. Patients with advanced liver disease benefit from orthotopic liver transplantation.

Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S, Anonymous00045. · Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, University of Paris 12 and INSERM Unité 955, Créteil, France. · N Engl J Med. · Pubmed #19403903 No free full text.

Abstract: BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Ferenci P, Scherzer TM, Kerschner H, Rutter K, Beinhardt S, Hofer H, Schöniger-Hekele M, Holzmann H, Steindl-Munda P. · Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. · Gastroenterology. · Pubmed #18771667 No free full text.

Abstract: BACKGROUND & AIMS: Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV). METHODS: Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ribavirin (PegIFN/RBV) were studied. First, 16 patients received 10 mg/kg/day SIL IV (Legalon Sil; Madaus, Köln, Germany) for 7 days. In a subsequent dose-finding study, 20 patients received 5, 10, 15, or 20 mg/kg/day SIL for 14 days. In both protocols, PegIFN alpha-2a/RBV were started on day 8. Viral load was determined daily. RESULTS: Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 +/- 0.55 log (mean +/- SD), P < .001 but increased again in spite of PegIFN/RBV after the infusion period. The viral load decrease was dose dependent (log drop after 7 days SIL: 0.55 +/- 0.5 [5 mg/kg, n = 3], 1.41 +/- 0.59 [10 mg/kg, n = 19], 2.11 +/- 1.34 [15 mg/kg, n = 5], and 3.02 +/- 1.01 [20 mg/kg, n = 9]; P < .001), decreased further after 7 days combined SIL/PegIFN/RBV (1.63 +/- 0.78 [5 mg/kg, n = 3], 4.16 +/- 1.28 [10 mg/kg, n = 3], 3.69 +/- 1.29 [15 mg/kg, n = 5], and 4.85 +/- 0.89 [20 mg/kg, n = 9]; P < .001), and became undetectable in 7 patients on 15 or 20 mg/kg SIL, at week 12. Beside mild gastrointestinal symptoms, IV SIL monotherapy was well tolerated. CONCLUSIONS: IV SIL is well tolerated and shows a substantial antiviral effect against HCV in nonresponders.

Jessner W, Gschwantler M, Formann E, Gurguta C, Watkins-Riedel T, Wrba F, Ferenci P. · Department of Internal Medicine III, Gastroenterology and Hepatology, Vienna Medical University, Vienna, Austria. · Antivir Ther. · Pubmed #18672537 No free full text.

Abstract: BACKGROUND: Interferon (IFN)-resistant hepatitis C virus strains limit efficacy of antiviral combination therapy in patients infected with genotypes 1 and 4. A single test dose of IFN was useful to identify non-responders to IFN-alpha2b/ribavirin (RBV) or likely non-responders to pegylated (PEG)-IFN-alpha2a/RBV therapy in genotype 1 patients. Our aim was to investigate this approach in genotype 4 patients. METHODS: Viral load was measured in 46 patients before and 24 h after 10 megaunits (MU) IFN-alpha2b, and before and during 2 weeks of daily 5 MU IFN-alpha2b administration. Thereafter, patients received 48 weeks combination therapy with either 180 microg PEG-IFN-alpha2a/week (n=33), 1.5 microg/kg PEG-IFN-alpha2b/week (n=7) or 5 MU IFN-alpha2b/2 days (n=6), along with 1-1.2g RBV/day. For prediction analysis the largest group (PEG-IFN-alpha2a) was evaluated only. RESULTS: Median 24 h log10 change after 10 MU IFN-alpha2b was 1.15 (range 0.08-2.48) and after 5 MU IFN-alpha2b was 0.81 (-0.12-2.22; P<0.0001). Log10 changes after 2 weeks on 5 MU IFN-alpha2b daily and 24 h after 10 MU were the best predictors of early virological response (defined by negativity of a standard qualitative PCR) to PEG-IFN-alpha2a/RBV combination therapy (area under curve [AUC]=0.97; P<0.001, receiver operating characteristics), 24 h log10 change after 10 MU was the best predictor of sustained virological response (SVR; AUC=0.91, P=0.001). CONCLUSION: As in genotype 1 patients, there is large variation in IFN responsiveness, including the presence of resistant strains, in genotype 4 patients. A 24 h log10 change after 10 MU IFN-alpha2b is an excellent predictor of SVR on PEG-IFNalpha2a/RBV combination therapy. This test may be useful to obtain homogeneous groups for clinical studies and could help in clinical decision making.

Sieghart W, Homoncik M, Jilma B, Formann E, Ferenci P, Gangl A, Peck-Radosavljevic M. · Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Thromb Haemost. · Pubmed #16493487 No free full text.

Abstract: Interferon alpha (IFN-alpha) is used to treat haematological and solid malignancies and is the gold standard therapy for chronic hepatitis C infection in combination with ribavirin. It has a well known platelet lowering effect and was recently shown to impair platelet aggregation in the presence of various agonists and has been accused to increase patients' bleeding risk during IFN-alpha therapy. Thus, we hypothesised that antiviral treatment decreases GpIIb/IIIa activation and affects global platelet function. In a prospective clinical trial, we examined the effects of combination therapy with pegylated IFN-alpha 2a (PegIFN-alpha 2a) and ribavirin on platelet GpIIb/IIIa activation and platelet secretion in 20 patients with chronic hepatitis C at week 2, 4, 8 and 12 after the beginning of therapy. In addition, we determined global platelet function (CEPI-CT) with the PFA-100 and vWF-Ag levels. Antiviral therapy significantly decreased GpIIb/IIIa activation in a time dependent manner, whereas markers of platelet secretion (P-selectin, beta-thromboglobulin) remained unchanged. Despite a marked elevation of vWF-Ag levels, CEPI-CT did not change compared to baseline levels. Antiviral therapy significantly decreases GpIIb/IIIa activation in patients with chronic hepatitis C, while vWG-Antigen levels are markedly increased and alpha-granule secretion is not affected. This does not result in an alteration of global platelet function as assessed by the PFA-100, because elevated vWF-Antigen levels might compensate for the acquired defect.

Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, Ibranyi E, Weiland O, Noviello S, Brass C, Albrecht J. · Clinic of Internal Medicine II, Department of Medicine, Saarland University Hospital, Kirrbergerstrasse, 66421 Homburg/Saar, Germany. · J Hepatol. · Pubmed #16290907 No free full text.

Abstract: BACKGROUND/AIMS: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). CONCLUSIONS: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.

Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxì A, Chaneac M, Reddy KR. · Medical University of Vienna, Vienna, Austria. · J Hepatol. · Pubmed #15990196 No free full text.

Abstract: BACKGROUND/AIMS: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. METHODS: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 microg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. RESULTS: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or > or = 2 log10 decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximately 20% lower in those who received <80% compared with patients who received > or = 80% of the planned ribavirin dose. CONCLUSIONS: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a > or = 2 log10 reduction in HCV RNA after 12 weeks.

Chalasani N, Manzarbeitia C, Ferenci P, Vogel W, Fontana RJ, Voigt M, Riely C, Martin P, Teperman L, Jiao J, Lopez-Talavera JC, Anonymous00037. · Indiana University Medical Center, Indianapolis, USA. <> · Hepatology. · Pubmed #15660392 No free full text.

Abstract: There is currently no effective treatment for recurrent hepatitis C after orthotopic liver transplantation (OLT). We therefore performed two randomized, controlled trials--a prophylaxis trial and a treatment trial--to evaluate the safety and efficacy of peginterferon alfa-2a in patients who had undergone OLT. The prophylaxis trial enrolled 54 patients within 3 weeks after OLT, and the treatment trial enrolled 67 patients 6 to 60 months after OLT. In each trial, patients were randomized to treatment with once weekly injections of 180 microg peginterferon alfa-2a or no antiviral treatment for 48 weeks and were followed up for 24 weeks thereafter. Peginterferon alfa-2a treated patients had significantly lower hepatitis C virus RNA levels and more favorable changes in hepatic histological features compared with untreated controls. However, only 2 treated patients in the prophylaxis trial (8%) and 3 in the treatment trial (12%) achieved a sustained virological response. In the prophylaxis trial, 8 patients (31%) in the peginterferon alfa-2a group and 9 (32%) in the untreated group were withdrawn prematurely; whereas in the treatment trial, 10 patients (30%) in the peginterferon alfa-2a group and 6 (19%) in the untreated group were withdrawn prematurely. The incidence of acute rejection was similar in the treated and untreated groups in both the prophylaxis (12% vs. 21%; P = .5) and treatment (12% vs. 0%; P = .1) trials. In conclusion, peginterferon alfa-2a treatment for 48 weeks is safe and tolerable and offers some efficacy in the post-OLT setting. Randomized controlled studies are needed to establish the efficacy of pegylated interferon and ribavirin in patients who have undergone OLT.

Homoncik M, Ferlitsch A, Ferenci P, Formann E, Jilma B, Gangl A, Panzer S, Peck-Radosavljevic M. · Division of Gastroenterology and Hepatology, Department of Internal Medicine IV, Medical University, Vienna, Austria. · Aliment Pharmacol Ther. · Pubmed #15644045 links to  free full text

Abstract: BACKGROUND: A pegylated interferon-alpha-induced decrease in platelet counts may become a limiting factor for continuation of therapy. AIM: To evaluate the effect of pegylated interferon-alpha administration on platelet plug formation and von Willebrand factor antigen release in patients with chronic hepatitis C. METHODS: Thirty patients with chronic hepatitis C (genotype 1; fibrosis 1-3: n = 16, cirrhosis: n = 14) received a single dose of 9 MU interferon-alpha2a, followed by weekly administration of 180 mug of pegylated interferon-alpha2a/ribavirin for 48 weeks. Platelet counts, platelet function (collagen-epinephrine-induced closure time) and von Willebrand factor antigen were measured. RESULTS: Platelet counts and collagen-epinephrine-induced closure time decreased by 13% and 16%, respectively, 24 h after the first dose of interferon-alpha2a, and von Willebrand factor antigen levels increased by 31% (P < 0.01) compared with baseline. During a 48-week observation period, platelet counts decreased by a maximum of 33% (P < 0.001), von Willebrand factor antigen levels increased by 69% (P < 0.001) whereas collagen-epinephrine-induced closure time did not change. In noncirrhotic patients, the increase of von Willebrand factor antigen levels was maintained throughout therapy without a change in collagen-epinephrine-induced closure time. In contrast, in cirrhotics, von Willebrand factor antigen levels did not increase, while collagen-epinephrine-induced closure time was prolonged. CONCLUSION: Single-dose interferon-alpha decreases platelet counts but improves platelet function, possibly by the release of von Willebrand factor antigen. Accordingly, long-term antiviral treatment had no effect on collagen-epinephrine-induced closure time, despite the decrease in platelet count in noncirrhotic patients. Such a compensation of decreased platelet counts by increased von Willebrand factor antigen level did not occur in cirrhotics.

Watkins-Riedel T, Ferenci P, Steindl-Munda P, Gschwantler M, Mueller C, Woegerbauer M. · Division of Clinical Virology, Institute of Virology, University Hospital of Vienna, Austria. · Clin Infect Dis. · Pubmed #15578395 No free full text.

Abstract: BACKGROUND: Routine analysis of serum and/or plasma specimens for hepatitis C virus (HCV) RNA does not always correctly reflect the response to antiviral therapy. Analysis of whole-blood specimens for detection of viral RNA should provide more-accurate prognostic information. METHODS: Whole-blood, serum, and plasma specimens (268 sample sets) were obtained from 56 patients who did not respond to initial interferon (IFN)- alpha 2b monotherapy (5 MU every 2 days for 3 months). Specimens were analyzed for HCV RNA by 4 different types of reverse-transcriptase polymerase chain reaction (RT-PCR) (Cobas Amplicor HCV-2.0 [Roche], LightCycler real-time PCR [Roche], and 2 in-house RT-PCRs) to determine whether specimen type can predict the rate of virologic response to high-dose treatment with IFN (10 MU every 2 days) and ribavirin (1-1.2 g/day). RESULTS: Of the 56 patients who provided specimens, serum and plasma obtained from 18 tested negative for HCV RNA at the end of treatment, indicating a complete virologic response. In contrast, analysis of whole-blood specimens obtained at the same time revealed the presence of viral RNA in 12 of these 18 patients. All 12 subjects had relapse of HCV in serum and plasma: 11 relapsed a median of 4 weeks after the end of treatment, and 1 relapsed 20 weeks after the end of treatment. None of these 12 patients--all of whom consistently had whole-blood specimens that tested positive and plasma and serum specimens that tested negative for HCV RNA up to 20 weeks before the end of treatment--showed a sustained virologic response (P=.0002). CONCLUSIONS: Results of whole-blood tests for detection of HCV RNA were highly predictive of viral relapse (positive predictive value, 100%) and thus may be useful tools for monitoring and tailoring IFN/ribavirin therapy. Testing of only serum or plasma specimens underestimates the true circulating HCV load and leads to an overestimation of antiviral response rates.

Hofer H, Osterreicher C, Jessner W, Penz M, Steindl-Munda P, Wrba F, Ferenci P. · Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Vienna, Austria. · J Hepatol. · Pubmed #15158344 No free full text.

Abstract: BACKGROUND/AIMS: Iron overload is common among patients with chronic hepatitis C (CHC). In this study the role of hepatic iron concentration (HIC) and serum iron parameters was assessed to determine response to standard and pegylated interferon (IFN)/ribavirin combination therapy in patients with CHC. METHODS: Liver biopsies were obtained from 169 IFN-naïve patients (m=115, f=54, age: 40.8+/-10.7) with CHC. 140 patients were treated with standard IFN/ribavirin, 29 patients with pegylated-IFN/ribavirin. Biopsy specimens were evaluated according to the DiBisceglie scoring system and iron grading. HIC was determined by atomic absorption spectroscopy. Ferritin and transferrin saturation and presence of HFE-C282Y and H63D gene mutations were determined at baseline. RESULTS: Nonresponders to combination therapy had higher serum ferritin levels at baseline (p<0.01). There was no difference of HIC, transferrin saturation levels, and the HFE-mutation status between responders and nonresponders. Logistic regression analysis revealed serum ferritin as an independent predictor of response. HIC correlated with the DiBisceglie score (r=0.352, p<0.001), iron grading (r=0.352, p<0.001) and serum ferritin (r=0.335, P<0.001). CONCLUSIONS: Pretreatment liver iron concentration does not predict response to combination therapy in patients with CHC. In contrast, high baseline serum ferritin levels are predictors of poor response to antiviral therapy.

Formann E, Stauber R, Denk DM, Jessner W, Zollner G, Munda-Steindl P, Gangl A, Ferenci P. · Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria. · Am J Gastroenterol. · Pubmed #15128353 No free full text.

Abstract: BACKGROUND: Sudden hearing loss has been reported on standard interferon (IFN)-alpha2 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 microg PEG-IFN alpha2a (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.