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Lege Artis Medicinae

MARCH 20, 2014

[Crucial points in the therapy of hepatitis C]

MAKARA Mihály, HUNYADY Béla

[The first generation of direct acting antivirals represented a milestone in the therapy of hepatitis C but other breakthroughs are on the way with imminent authorization of new antiviral drugs and interferon-free combinations. The prices of these new agents necessitate the rational use of limited financial capacities: relatively cheaper interferon-based treatments could be used first for those who can be cured with these combinations, while the most expensive treatments are to be reserved for those with no other options. In the future, interferonfree regimens will likely be used first in those patients who did not respond to firstgeneration interferon-based regimens and in whom interferon therapy is contraindicated. To avoid complications of the disease, currently it is reasonable to treat all eligible patients with advanced fibrosis, particularly those with compensated cirrhosis, with interferon-based treatments. In some instances other medical or social conditions warrant prompt treatment. The triage of treatments is based on the Priority Index in Hungary. Current triple therapies with protease inhibitors are complicated by drug and food interactions as well as by frequent (sometimes severe) side effects. General practitioners and other specialists need to be involved in managing these issues. It is of utmost importance to refer patients to hepatology care before decompensation or development of hepatocellular carcinoma. The key of timely and accurate diagnosis is organized anti-HCV screening in populations at risk and in the age group with the highest prevalence.]

Lege Artis Medicinae

FEBRUARY 14, 2014

[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.]

Lege Artis Medicinae

AUGUST 20, 2013

[“War of numbers” and the facts about pegylated interferon based treatment of chronic hepatitis C]

MAKARA Mihály, HUNYADY Béla

[Further to the traditional pegylated interferon and ribavirin products, used since 2001 in the treatment of chronic hepatitis C, two new direct antiviral protease inhibitors were licensed in 2011: telaprevir and boceprevir. Added to the traditional dual combination either of these drugs increase significantly the rate of sustained viral response. Discussions over the relative efficacy of two different bands of interferons with different pharmacokinetic properties as well as of the different protease inhibitors are arising regularly. After critical review of the relevant literature the authors did not identify any clinically meaningful differences in efficacy of the two pegylated interferons (α 2a or α 2b) neither in dual nor in triple combination therapies. There has been no convincing evidence found to support superiority of one protease inhibitor over the other, either: Generally both drugs can be recommended for patients previously or actually not responding to dual therapy. However, there is a tendency towards a potential difference between the relapse rates after treatments with the two pegylated interferons in dual therapy, attributable potentially to the difference of their pharmacokinetic profiles. In special cases the choice of protease inhibitors can be influenced by cost-effectiveness and side effect profile.]

Lege Artis Medicinae

JUNE 20, 2013

[Optimizing the efficacy of triple combination therapy of chronic hepatitis C]

TORNAI István

[The outcome of chronic hepatitis C (CHC) therapy has been improved significantly. If sustained virologic response (SVR) is achieved, then it may prevent the occurrence of liver failure and hepatocellular carcinoma. With the currently used double combination therapy (peginterferon and ribavirin) SVR can be achieved in 40-50% of patients with genotype 1. In treatment naive patients, triple combination with protease inhibitors can result in 70-75% SVR. In treatment experienced patients, however, the result of the previous therapy, which mostly depends on the reaction to interferon (IFN), has a significant influence on the outcome of triple combination. INF sensitivity is the highest in relapsers, triple combination can achieve about 85% SVR, while in null responders this is only 30%. Viral resistance is a new phenomenon during triple combination therapy of CHC. In poorly IFN responsive patients the virus is effectively exposed to protease inhibitor functional monotherapy, leading to the rapid emergence of resistant virus. IFN sensitivity is well represented by the on-treatment viral response, therefore the knowledge of the previous viral response, relapse, a partial response or a null response is absolutely important. Optimization of triple therapy is crucial, since for a lot of patients with advanced liver disease it might be the last chance to achieve an SVR. The selection of the patients seems very important. Relapsers are the best candidates, there is no doubt with the indication. However, there are many debates for cirrhotic nullresponders, since the most virological failures are expected in this group. Prevention of viral resistance is crucial. PegIFN and ribavirin suppress both wild-type and resistant virus. PegIFN α-2a based treatment proved to be the most effective backbone for triple combination. This combination should be preferred especially for treatment experienced patients. Adherence to therapy is also critically important to prevent resistance. If resistant mutants appear, treatment should be stopped promptly.]

Clinical Neuroscience

NOVEMBER 20, 2012

[Clinical significance of the cardiovascular effects of fingolimod treatment in multiple sclerosis]

SZÉPLAKI Gábor, MERKELY Béla

[Fingolimod is a sphingosine-1 phosphate receptor modulator, which is effective in the treatment of severe relapsingremitting form of multiple sclerosis. Once daily oral use of fingolimod decreased the annualized relapse rate, inflammatory brain lesion activity and the rate of brain atrophy compared both to placebo and intramuscular administered interferon beta-1a. The drug targets the cardiovascular system as well via sphingosine- 1 phosphate receptors. After initiation of fingolimod therapy transient sinus bradycardia and slowing of the atrioventricular conduction develops. The onset of the effect is as early as 1 hour post administration, while heart rate and conduction normalized in 24 hours in most of the cases. According to the clinical trials symptomatic bradycardia developed in 0.5% of the cases, responding to the appropriate therapy. The incidence of Mobitz I type II atrioventricular blocks and blocks with 2:1 atrioventricular conduction was 0.2% and 0.1%, respectively. All of these cardiovascular events showed regression during observation and no higher degree atrioventricular blocks were detected at the approved therapeutic dose. Following the first dose effect, fingolimod had a moderate hypertensive effect on long-term. For the safety of fingolimod treatment detailed cardiovascular risk stratification of all patients, adequate patient monitoring after the first dose and competency in treating the possible side effects is necessary. In patients with increased cardiovascular risks, treatment should be considered only if anticipated benefits outweigh potential risks and extended monitoring is required.]

Lege Artis Medicinae

JUNE 10, 2009

[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.]

Lege Artis Medicinae

NOVEMBER 20, 2007

[HUMAN LEUKOCYTE INTERFERON IN THE TREATMENT OF CHRONIC HEPATITIS C]

TELEGDY László, HORVÁTH Gábor, TOLVAJ Gyula, MAKARA Mihály, MONTSKÓ Valéria, OZSVÁR Zsófia, NEMES Zsuzsanna, PÉTERFY Zoltán, SZENTGYÖRGYI László

[INTRODUCTION - Approximatively 50% of the patients with chronic hepatitis C do not respond properly to pegylated interferon-alpha+ribavirin treatment and according to the therapeutic guidelines their treatment must be interrupted. The authors examined whether their further medication with human leukocyte interferon is justified. PATIENTS AND METHODS - Thirty-eight patients with chronic hepatitis C were treated with human leukocyte interferon who had responded to pegylated interferon-alpha-ribavirin treatment, but dropped out of the treatment scheme based on the therapeutic criteria on week 12 or 24. RESULTS - While only 3 patients responded with persistent virological negativity, mean alanine aminotransferase (ALT) levels decreased during treatment and persistently remained lower than the baseline levels. Except for the three responders, the HCV viral load as determined by polymerase chain reaction did not decrease but even increased on average. Patients tolerated the treatment well. Known side-effects were observed in 6 cases, and treatment had to be interrupted in one case. These are proportionally far less than the respective 20 to 25% and 5 to 15% reported for peginterferon-ribavirin treatment. CONCLUSION - Even though virological recovery is rare, the reduction in inflammatory activity, the expected slowing of progression, and, in particular, the definite improvement of the cryoglobulinaemic purpura and vasculitis warrant switching to human leukocyte interferon treatment in selected cases.]

Clinical Neuroscience

DECEMBER 10, 2004

[Immunomodulatory treatment in multiple sclerosis ]

CSÉPÁNY Tünde, BERECZKI Dániel

[During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon β1b, two preparations of interferon β1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon β1a slowed the progression of disability in relapsing multiple sclerosis. One interferon β1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.]

Lege Artis Medicinae

NOVEMBER 20, 2005

[SCREENING OF PSYCHIATRIC SIDE EFFECT OF INTERFERON THERAPY WITH QUESTIONNAIRE]

GAZDAG Gábor, SZABÓ Zsuzsa

[INTRODUCTION - Interferon therapy is an effective treatment of several oncological, hematological and viral diseases but it can precipitate serious side effects too. Among others the most frequent are the psychiatric symptoms. These symptoms are also the most frequent reasons of non-compliance and early cessation of treatment which can be avoided with rapid recognition and adequate treatment. Therefore, the early recognition of the psychiatric symptoms is of high importance. METHODS AND RESULTS - Authors report a self-administered questionnaire developed to screen the most frequent psychiatric symptoms precipitated by interferon treatment. They also present the evaluation method for the questionnaire, which makes the evaluation of the data easier for non-psychiatrist doctors as well. Between September 2004 and July 2005 all interferon treated patients who also had psychiatric consultation filled in the questionnaire. The number of patients was 26. Authors set up a decision-making algorhythm for the evaluation, so the non-psychiatrist doctors were able to judge whether a psychiatric consultation was needed as well as its urgency. With the data of 26 interferon treated patients who all went through a psychiatric consultation during a 10 months period, authors discuss their first experience, going into details in the three false positive and the two false negative cases. CONCLUSION - Authors founded the questionnaire helpful in the clinical practice and recommended the use for doctors working in general practice. They also suggest to carry it further research with more patients to strengthen the results.]