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

NOVEMBER 20, 2007

Lege Artis Medicinae - 2007;17(11)

[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.]

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[TREATMENT OF ANAEMIA IN A PATIENT WITH SMALL CELL LUNG CANCER]

TAMÁSI Lilla, WOLLÁK András

[INTRODUCTION - Anaemia is a common complication among patients with malignant tumours, and is due to the disease itself or to the oncologic treatment. Anaemia worsens the patient’s quality of life and hampers anti-cancer treatment in the appropriate intervals and doses. Erythropoiesis stimulating protein therapy in the anaemia of oncologic patients raises the haemoglobin level, reduces the need for red blood cell transfusion and improves quality of life. This drug has recently become accessible in Hungary for the treatment of chemotherapy-induced anaemia in patients with small cell lung cancer. CASE REPORT - In this paper the case of a 64- year-old woman with small cell lung cancer who survived for more than 2 years is presented. Two-line chemotherapy was administered together with irradiation and darbepoetin alpha supportation. The successful treatment of anaemia with darbepoetin alpha permitted the administration of chemotherapy in the necessary intervals and doses. CONCLUSIONS - The adequate use of erythropoiesis stimulating protein facilitates the management of patients with small cell lung cancer, and improves their quality of life.]

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[NEUROVASCULAR COMPRESSION IN THE MEDULLA OBLONGATA AS A CAUSE OF RESISTANT HYPERTENSION - THOUGHTS APROPOS OF A PATIENT]

KOVÁTS László, BRETUS Angelika, CSUTAK Kinga, NAGY Gyöngyi, GASZTONYI Beáta

[INTRODUCTION - The vasomotor centre, the central regulator of the cardiovascular system, is localised in the rostral ventrolateral medulla oblongata. Irritation of this area and/or of the ninth and tenth cranial nerves (that are involved both in the afferent and efferent pathways of the baroreceptor reflex) causes sympathetic hyperactivity, which in some cases leads to severe resistant hypertension. A common underlying cause of this is pulsatile neurovascular compression, a vascular malformation rarely sought for. CASE REPORT - The authors present the case of a middle-aged woman with what had been considered “essential” hypertension. Magnetic resonance angiography showed vascular compression of the medulla oblongata and the departing left ninth and tenth cranial nerves as the cause of her hypertension. CONCLUSIONS - After a literature review the authors draw the attention to this rarely identified cause of resistant hypertension and to the difficulties of its diagnosis.]

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[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

[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.]

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

[UP-TO-DATE MANAGEMENT OF CHRONIC HEPATITIS B]

HORVÁTH Gábor

[Hepatitis B virus infection is a significant health problem worldwide, as well as in Hungary. The chronic infection is usually symptomless, its most dangerous risks are liver cirrhosis and hepatocellular carcinoma. The latter may occur without development of liver cirrhosis, so it means a potential complication for patients with inactive phase of infection, as well. Criteria of the indication of antiviral treatment have changed in the last years due to the flare of our knowledge about the natural history of the disease. In our days quantitative determination of hepatitis B viral nucleic acid titer is essential for diagnosis. Formerly, a HBsAg positive patient with normal liver enzymes had been regarded as inactive carrier, and antiviral treatment had not been advised. In our days, the phase of the infection and the necessity of the treatment can not be determined without measurement of nucleic acid titer. Liver biopsy and, if inflammation or fibrosis is present, antiviral treatment is indicated, if the nucleic acid titer is >20 000 IU/ml in HBeAg positive, and >2000 IU/ml in HBe negative cases, respectively. Interferon alpha is the gold standard of treatment for chronic B hepatitis. Pegylated interferon alpha-2a is used because of its better pharmacokinetic properties. Oral agents include nucleoside/ nucleotide analogues with rare and mild adverse effects, and they may be given to patients with decompensated liver disease. Their main disadvantages include the development of drug-resistance, and the very low ratio of HBsAg-anti-HBs seroconversion. Recent drugs like adefovir, entecavir and tenofovir have replaced lamivudin, which has been in use for the longest time, because they are more effective and resistance against them is less frequent.]

Lege Artis Medicinae

[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.]