Lege Artis Medicinae

[THE SAFETY OF TREATMENT WITH PEGYLATED INTERFERON-ALPHA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION, BASED ON HUNGARIAN EXPERIENCE]

WERLING Klára, DALMI Lajos, GERVAIN Judit, HORVÁTH Gábor, NAGY István, NEMESÁNSZKY Elemér, RIBICZEY Pál, TELEGDY László, VARGA Márta, TORNAI István, TULASSAY Zsolt

JULY 14, 2007

Lege Artis Medicinae - 2007;17(06-07)

[INTRODUCTION - Adverse effects of treatment for chronic C virus hepatitis present an important problem both for the patient and the clinician. The reduction of drug doses or the suspension of therapy lessen the likelihood of recovery. PATIENTS, METHODS - Between 2001 and 2004, 66 patients with chronic hepatitis C received 180 μg pegylated interferon-alpha-2a per week and 800-1200 mg ribavirin per day, 6 of whom for 24 weeks and 60 patients for 48 weeks. During treatment, patients were closely followed in order to recognize any adverse effects early. RESULTS - Of the patients treated for 48 weeks, 48.3% developed adverse effects, with changes in the differential in 41.7%, and anaemia, low platelet count, neutropenia in similar rates. Further side effects included cardiac complications, skin symptoms, persisting high fever, autoimmune thyroiditis and liver failure, altogether in 9 cases. Dose reduction or temporary suspension of pegylated interferon-alpha-2a was necessary in 21 cases (31.7%), while complete cessation of this treatment was decided in 7 cases, most of them because of blood count changes. The 1000 to 1200 mg per day ribavirin had to be reduced in 30.8% of patients, while treatment was stopped in 3 cases. Long-term virological remission occurred in 48% of patients who received treatment for 48 weeks, whereas no such result was observed among any of those treated for 24 weeks. CONCLUSION - Adverse effects of variable severity developed in nearly half of the patients with chronic hepatitis C infection who received antiviral treatment for 48 weeks, but treatment had to be stopped in only a small proportion of this group. Early treatment of adverse effects can prevent the need to cease therapy and may improve its efficiency.]

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NAGY László

[Controlled clinical studies on statins have produced evidence that the aggressive lowering of LDL-cholesterol (LDL-C) level reduces the mortality rate of ischaemic heart disease. About 40% of treated patients achieve the cholesterol target level. The observance of medication instructions on a daily basis (compliance) and willingness for long-term taking of the drug (persistence) are crucially important to avoid severe complications. In the long term, patients take only about 50% of their medicines according to the instructions. As a result of the generally poor compliance and persistence in taking the medications, the decrease in morbidity and mortality observed in clinical studies do not occur under real-life conditions. Patients with poor compliance (<80%) will experience only a minimal health benefit and the cost-effectiveness of the therapy will markedly decrease. For patients with poor persistence who discontinue their treatment before benefits at the clinical endpoints could manifest, the resources invested into the therapy will be lost. Both compliance and persistence deteriorate as the number of concurrently taken medicines increases. Since less than 50% of the programmes aimed at improving patient co-operation are successful, therapeutic decisions should preferably be made by taking into consideration the expected compliance/persistence already at the time of choosing the medication. By widening the use of fixed-dose combination therapies, the efficiency of treatment can substantially be increased in patients who concurrently take several medicines and require aggressive lowering of blood pressure or LDL-C level.]

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PAPP Zoltán, BORBÉLY Attila, ÉDES István

[Disturbances in ventricular relaxation may lead to the development of diastolic heart failure. The analysis of left ventricular endomyocardial biopsy specimens may help understand the underlying structural and functional changes. Such analyses have lead to the recognition that at the optimal sarcomere length of the Frank- Starling mechanism (i.e., at 2.2 μm), passive force values of the cardiomyocytes are significantly higher in individuals with diastolic heart failure than in healthy controls. As a probable explanation to this finding, increased expression of the stiffer N2B isoform of the myofilamental titin protein, at the expense of the more elastic N2BA titin isoform, has been recognized. Moreover, decreased phosphorylation of the contractile proteins was also suggested to contribute to the development of diastolic heart failure. These changes together, and along with an increase in extracellular collagen content, may greatly contribute to the relaxation disturbance observed in diastolic heart failure.]

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Lege Artis Medicinae

[TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C, USING PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN - THE FIRST EXPERIENCES IN HUNGARY BASED UPON A MULTICENTRIC, OPEN, PROSPECTIVE STUDY]

TORNAI István, DALMI Lajos, GERVAIN Judit, HORVÁTH Gábor, NAGY István, NEMESÁNSZKY Elemér, RIBICZEY Pál, TELEGDY László, VÁRKONYI Tibor, WERLING Klára

[INTRODUCTION - The treatment of patients with hepatitis C virus infection is one of the most challenging tasks in hepatology nowadays. PATIENTS AND METHODS - Between 2001 and 2004, during a phase III, prospective, multicentric, international open trial 69 patients (35 naive and 34 non-responder or relapser) with chronic hepatitis C were treated, using 180 μg pegylated interferon alfa-2a once weekly and 800-1200 mg daily ribavirin. The inclusion and exclusion criteria were the same as in the normal daily practice. Five patients were treated for 24 weeks and 54 were treated for 48 weeks. The treatment was stopped in 10 additional patients. Sustained virological response was the main end-point of the trial, after 24 weeks of follow-up. RESULTS - The mean age of the patients was 46 years. In all the patients virus genotype 1 could be detected. In none of the patients, treated for 24 weeks, sustained remission could be obtained. In patients, treated for 48 weeks, the overall sustained virological remission was 48%. The outcome of the treatment was better, if the patient was naive to the treatment, could receive the full dosage of drugs and had no liver cirrhosis. The best result could be obtained if the patient was naive to the therapy and younger than age 40. Viral load, however, did not show any effect on viral remission in our patients. At week 24, a negative HCV RNA had a positive predictive value of 68%, while a positive virus test had a negative predictive value of 93%, regarding sustained remission. CONCLUSION - Considering the high rate of genotype 1, pegylated interferon alfa-2a and ribavirin proved to be a very effective therapy in Hungarian chronic hepatitis C patients.]

Lege Artis Medicinae

[Successful treatment of chronic hepatitis C infection accompanied by rare but reversible adverse effects]

ERŐSS Bálint Mihály, NEMESÁNSZKY Elemér

[INTRODUCTION - In absence of signs and symptoms characteristic of chronic hepatic disease caused by hepatitis C viral infection, its diagnosis is generally suggested by abnormal liver function tests. If viral serological activity is confirmed, combined antiviral treatment (pegylated interferon plus ribavirin) has to be considered. Antiviral treatment is accompanied by several, usually reversible adverse effects. CASE REPORT - The 62 year-old woman has had waveringly abnormal liver function results for decades. Her anamnesis included transfusions for polytraumatization that resulted in a hepatitis C virus infection. We started treatment with interferon alpha-2a plus ribavirin. At week 4 of therapy, a significant decrease in virulence and at week 12, viral negativity was confirmed, accompanied by a normalization of hepatic function markers. Because of a gradually developing anemia, beginning from month 4, the former optimal dose of ribavirin had to be reduced. At the end of week 42, severe dermatitis with fever, muscle weakness and malaise (Sweetsyndrome) developed, and antiviral therapy had to be discontinued and steroids had to be given. During a short travel abroad, the patient suffered a collaptiform episode caused by extremely high blood glucose (28.0 mmol/l). She received temporarily fractioned insulin and then combined oral antidiabetic treatment. Then, dermatosis symptoms rapidly resolved, glycemic status gradually improved, and could be controlled by low-dose metformin. Liver function tests were normal. At the end of antiretroviral treatment and 6 months later, HCV-RNA by PCR proved negative, meaning that hepatitis C virus has been eradicated successfully. CONCLUSION - Treatment with pegylated interferon alpha-2a plus ribavirin rendered viral replication undetectable at 3 months, which is - together with the normalization of abnormal liver function tests - the strongest predictor of a good outcome. The patient’s exemplary good compliance contributed to successful treatment of hepatitis C and control of these rare but reversible adverse effects.]

Hypertension and nephrology

[Nebivolol’s unique molecule structure and its effect onthe quality of life]

KERKOVITS Gábor

[The β receptor blockers have very different effects depending on their receptor selectivity, ISA effect, which gives a wide opportunity of beneficial therapeutic choice. Resulting from its unique molecule structure nebivolol has its unique effects. It consists two isomers in 1:1 ratio. D-nebivolol is a highly β1 receptor blocker, while l-nebivolol causes NO release resulting vasodilatation. As a result of this dual effect, nebivolol more strongly reduces the blood pressure. The pressure reducing effect of nebivolol is stronger than 25 mg of atenolol, and is equal with the effect of 100 mg of atenolol. Nebivolol has a significantly higher responders’ rate than bisoprolol, and significantly fewer adverse effect. Comparing to losartan nebivolol produces significantly higher reduction in systolic and in diastolic blood pressure as well. Nebivolol has beneficial haemodynamic effects. It raises the stroke volume by 20.6 percent, the cardias output by 7.1 per cent, the ejection fraction by 7.8 per cent while reduces the peripheral resistance by 13.2 per cent. Both at rest and during exercise nebivolol cases significantly higher reduction in pulmonary wedge pressure than atenolol. Nebivolol has a better profile of adverse effects. The following adverse effects were observed: fatigue in 1.3 per cent, cold extremities in 0.8 per cent, impotence in 0.08 per cent and dyspnea in 0.05 per cent. It has also a beneficial effect on erectile dysfunction. It cases a significant elevation in erectile dysfunction score from 17.22 to 22.09. The number of sexual activity also raised from 3.41 to 6.38 during nebivolol treatment. The prevalence of erectile dysfunction is also significantly lower as compared to any β receptor blocker. Nebivolol has a synergic effect on PDE5 blockers, raises the cGMP concentration in the erectile tissue. There is also a significant difference among the β receptor blockers in the reduction of exercise tolerance. The nonselective β receptor blocker cause 40 per cent, carvedilol 35 per cent, the β1 selective receptor blocker 25 per cent while nebivolol 6 per cent reduction in the duration time.]

Lege Artis Medicinae

[Efficacy of peginterferon alfa-2a and -2b plus ribavirin in the routine treatment of patients with chronic hepatitis C]

TUSNÁDI Anna, SZABÓ Anna

[INTRODUCTION - Combination of peginterferon plus ribavirin is the standard treatment for chronic hepatitis C virus (HCV) infection. Two types of peginterferon are available. The aim of this retrospective study was to find out whether the choice of peginterferon influenced the patient’s chance of recovery. PATIENTS AND METHODS - Between 2004 and 2007, 142 patients with HCV genotype 1 hepatitis with or without cirrhosis (107 treatmentnaive, 35 previously treated) were treated with 180 ug/week peginterferon alfa-2a (Group A) or 1.5 ug/kg/week peginterferon alfa-2b (Group B) plus ribavirin. Examination and treatment of patients followed the rules of the national guideline. Patients were not randomized in any way. Group A consisted of 78 patients and Group B included 64 patients. Eight patients dropped out for various reasons (5 from Group A, 3 from Group B). There was no statistically significant difference in the baseline characteristics and the cumulative doses of the drugs between Group A and B, so the treatment results were comparable. RESULTS - Sustained virological response (undetectable HCV ribonucleic acid serum levels 24 weeks after the end of treatment) occurred in 42.5% of patients from Group A and 37.7% from Group B. When focusing on treatment-naive patients only, sustained virological response was found in 48.2% of patients in Group A and 46.7% in Group B. Result of the treatment was better if the patient was treatment-naive, if there was no cirrhosis, and if early virological response at 12 weeks was achieved. CONCLUSION - Patients treated with peginterferon alfa-2a plus ribavirin achieved sustained virological response at a higher rate than those with peginterferon alfa-2b plus ribavirin, however, the difference was not statistically significant.]

Lege Artis Medicinae

[Treatment of hungarian chronic hepatitis C genotype 1 patients with severe fibrosis or compensated cirrhosis in the international telaprevir Early Access Program: Interim analysis of the week 16 results]

TORNAI István, BÁNYAI Tivadar, GERVAIN Judit, HORVÁTH Gábor, MAKARA Mihály, MARTYIN Tibor, NEMES Zsuzsanna, PÁR Alajos, PÁR Gabriella, PÉTERFI Zoltán, SZALAY Ferenc, SZINKU Zsolt, TÓTH Tamás, VINCZE Áron, ISABELLE Lonj

[The approval of the first two direct acting antiviral agents, boceprevir and telaprevir, has been a major step forward in the treatment of chronic hepatitis C. Both protease inhibitors must be added to the dual peginterferon and ribavirin combination therapy. The triple combination therapy resulted in significantly higher rates of recovery both in naive patients and in those previously unresponsive to therapy. Following the approval of telaprevir, an Early Access Program has been initiated in 16 countries. In Hungary 132 patients were enrolled into this program. In the first interim analysis, data from the first 16 weeks of treatment of 92 patients are included. Liver cirrhosis (F4) was detected in 70% of the patients and severe fibrosis (F3) was found in the other 30%, on the basis of either liver biopsy or transient elastography. During their previous antiviral treatment, 64% of the patients were non-responders (partial and nullresponders), 26% were relapsers, and only 10% were treatment naives. The efficacy of the triple combination was excellent, as 82% of the patients had undetectable HCV RNA at week 12. Further - more, 48% had negative HCV RNA at week 4 as well as at week 12. Cessation of i.e. negative HCV RNA at week 4 through week 12. Only 5.4% of the patients had virologic failure and needed to stop therapy prematurely. The most frequent adverse event was anemia, hemoglobin level decreased below 100 g/l in 40% of the patients. In the majority of these patients ribavirin dose reduction was sufficient to treat anemia, only 16% needed blood transfusion. The rate of severe rash was 6%. Although this group of patients represents a difficult-to-treat population, both efficacy and safety data are similar to published data in international clinical trials. A very effective, triple combination therapy with telaprevir, peginterferon and ribavirin can be provided for patients with advanced liver disease, to reduce the risk of liver failure and hepatocellular carcinoma.]