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

NOVEMBER 20, 2005

Lege Artis Medicinae - 2005;15(11)

[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.]

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Lege Artis Medicinae

[Medical Gastronomy...]

GRÉTSY Zsombor

Lege Artis Medicinae

[PREVENTION OF INFECTIONS IN CHRONIC HEPATITIS AND CIRRHOSIS]

PÁR Alajos, NEMESÁNSZKY Elemér

[Patients with chronic liver disease, mostly the elderly, due to their impaired immune response, frequently suffer from infections worsening the clinical course. This is sometimes overlooked in the everyday praxis. In patients with alcoholic liver disease both hepatitis A virus (HAV) and acute hepatitis B virus (HBV) infections can lead to fulminant hepatic failure, therefore their immunization with HAV and HBV vaccines is highly recommended, similarly, vaccination against flu and pneumococcus also may be indicated for alcoholics. In chronic viral hepatitis, alcohol abuse can result in rapid progression to cirrhosis and reduces the efficacy of antiviral treatment. Patients with chronic hepatitis C should also be vaccinated against superinfections by HAV and HCV. Co-infections by hepatotropic viruses and human immundeficiency virus (HIV) are frequent due to the shared routes of transmission. In HIVpositive patients the efficacy of the vaccination against HAV and HBV depends on the CD4 cell count, which also determined the timing of anti- HBV or anti-HCV treatment. Concerning the bacterial infections, spontaneous bacterial peritonitis (SBP) is the most severe complication of cirrhosis. The prevention of SBP is orally administered, moderately absorbed quinolon (norfloxacin) as long-term selective intestinal decontamination against Gram-negative pathogens. Alcoholic patients are also susceptible for tuberculosis. Bacterial infections play a role even in portal hypertension and variceal rupture, furthermore, both gastrointestinal haemorrhage and invasive endoscopic procedures increase the risk of infection, therefore in such situations a short-term (5- 8 day) antibiotic profilaxis is necessary with norfloxacin or ciprofloxacin. Taking into consideration these points of view, it may be of privotal significance for the management of patients with liver disease.]

Lege Artis Medicinae

[If Time is Money, do not Spend that of Others!]

MATOS Lajos

Lege Artis Medicinae

[MANAGEMENT OF LIFE-THREATENING ENDOSCOPIC THERAPY-RESISTENT OESOPHAGUS VARICEAL BLEEDING]

ERŐSS Bálint Mihály, SZÉKELY György, SIKET Ferenc, LÁZÁR István

[INTRODUCTION - Liver cirrhosis has two serious consequences: hepatic failure and portal hypertension. Portal hypertension has two important clinical appearances: variceal bleeding and therapy resistant ascites. Variceal bleeding can be recurrent and resistant to endoscopic treatment. These complications can be prevented by implantation of Transjugular Intrahepatic Portosystemic Shunt (TIPS). CLINICAL CASE - A 59 year old male with cirrhosis due to hepatitis C, was hospitalized in our department in April 2004 with variceal bleeding. We tried to control the bleeding twice by band ligation, once by sclerotherapy and with the use of Sengstaken-Blakemore tube, but bleeding continued for three weeks despite the endoscopic treatment. The patient needed intensive care therapy and was treated with more than forty units of packed red cells and plasma. At that point we decided to implant a TIPS, which was carried out succesfully. After TIPS implantation no rebleeding occured and the shunt had good patency. Moderate hepatic encephalopathy was observed, which is a well known phenomenon, but it could be treated with pharmacologic therapy. CONCLUSIONS - In case of portal hypertension TIPS implantation can prevent from variceal rebleedings and may caus significant improvement in the quality of life.]

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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.]

Lege Artis Medicinae

[OUR EXPERIENCE WITH COMBINED ANTIVIRAL TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C WITH PERSISTENTLY NORMAL ALANINE AMINOTRANSFERASE LEVELS]

HORVÁTH Gábor, TOLVAJ Gyula, HALÁSZ Tünde, STOTZ Gyula

[INTRODUCTION - Persistently normal alanine aminotransferase levels, which occur in a fraction of patients chronically infected with hepatitis C virus, do not rule out the presence of chronic hepatitis C, even of that with advanced inflammation and fibrosis. Here we report our results of the treatment of these patients. PATIENTS AND METHODS - Patients with histologically confirmed chronic hepatitis C received combined antiviral treatment with pegylated interferon (alfa-2a 1×180 μg/week or alfa-2b 1×1.5 μg/kg/week) and ribavirin (800- 1200 mg/day) for 48-52 weeks. The alanineaminotransferase levels of 21 patients (14 females, 7 males, age: 20-54, mean 38 years) did not reach the upper limit of normal (40 U/l) during the period of observation (≥6 months). There were 19 and 2 cases with hepatitis C virus genotype 1b and 3, respectively. The patients' hepatitis activity index was 3.7 1.75, fibrosis score: 0.9 0.64, baseline viral titer: 1.18 1.12×106 IU/ml, alanine-aminotransferase level: 33.51 7.2 U/l. The last 100 unselected patients with elevated alanine-aminotransferase levels enrolled in treatment for chronic hepatitis C and who were followed for at least 6 months served as the control group with the following parameters: 41 females and 59 males (age: 18- 65, mean: 45.65 years), viral genotypes: 98 and 2 cases of type 1 and 3, respectively, hepatitis activity index: 5.44±4.03, stage: 1.29±1.00, baseline viral titer: 4.13±6.25×106 IU/ml. RESULTS - In the study group, all patients were hepatitis C virus RNA negative at the end of the treatment and with one exception remained so by the end of the 6-month follow-up period (20/21), while the sustained virologic response was 36% in the control group. The pretreatment normal alanine aminotransferase level decreased significantly (15.26 4.9 vs 33.51 7.2 U/l, p<0.001) by the end of the treatment, and remained at this level during the follow-up in all except one relapse case. CONCLUSION - The efficacy of the combined antiviral treatment is high in patients with persistently normal alanine aminotransferase levels, possibly due to the relatively younger age, the higher proportion of females, the lower baseline viral titer, and the less advanced liver disease (lower inflammatory activity and less or absent fibrosis) observed in this group. Combined antiviral treatment is recommended for patients with histologically confirmed chronic hepatitis C with normal alanine aminotransferase levels, even with mild inflammatory activity and minimal or absent fibrosis in the liver tissue. The previous suggestions based on published evidence to revise the upper limit of the normal range of alanine aminotransferase level are supported by the results of this study.]

Lege Artis Medicinae

[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.]

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

[RETREATMENT OF CHRONIC HEPATITIS C IN PREVIOUS NONRESPONDERS]

TORNAI István

[Only approximately 50% of patients with chronic hepatitis C virus (HCV) genotype 1, the prevailing genotype in Hungary, show a sustained virologic response (SVR) when treated with the combination of peginterferon alfa and ribavirin. The number of patients who do not respond to this treatment is continuously increasing. The appearance of increasingly efficient treatment modalities was seen in the past 15 years, but now no new drugs are expected for a few years. There is a growing need for retreatment to prevent possible progression of the disease. The best candidates for retreatment are identified based on the data of the previous treatment; the dosage of the drugs used, dose reductions and their causes, the kinetics of the virologic response, the patient’s compliance, and every correctable and non-correctable factor should be carefully analysed. When the previous treatment with peginterferon and ribavirin failed to induce response, retreatment is only recommended if correctable factors can be identified. Repeated treatment may result in sustained virologic response usually if a longer duration and/or higher dose of ribavirin is applied. Since the best possible outcome of retreatment is sustained virologic response in 10 to 30% of patients, which is significantly lower than the results achieved in naive patients, every effort has to be made to increase the efficacy of the first treatment. For patients in whom no sustained virologic response can be achieved, a maintenance therapy with low dose interferon may be considered, although its benefit is yet to be proven. New small molecules are under development, which may bring further hope for nonresponders to current standard therapy.]