Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial.

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 µg q4wk or Peg-IFNα-2a 180 µg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 µg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3.

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-α-2b, with ∼200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-α-2a 180 µg qwk or albIFN 900, 1200 or 1500 µg q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 µg, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm(3) occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 µg vs 1500 µg and Peg-IFNα-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNα-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3.

Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin.

We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon-alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.

Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response.

BACKGROUND: The response rates and duration of peginterferon alpha (PEG-IFN-alpha) and ribavirin combination therapy in chronic hepatitis C genotype 4, the prevalent genotype in the Middle East and Africa, are poorly documented. AIMS: To compare the efficacy and safety of 24, 36, or 48 weeks of PEG-IFN-alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4. METHODS: In this prospective, randomised, double blind study, 287 patients with chronic hepatitis C genotype 4 were randomly assigned to PEG-IFN-alpha-2b (1.5 mug/kg) once weekly plus daily ribavirin (1000-1200 mg) for 24 weeks (group A, n = 95), 36 weeks (group B, n = 96), or 48 weeks (group C, n = 96) and followed for 48 weeks after completion of treatment. Early viral kinetics and histopathological evaluation of pre- and post treatment liver biopsies were performed. The primary end point was viral clearance 48 weeks after completion of treatment. RESULTS: Sustained virological response was achieved in 29%, 66%, and 69% of patients treated with PEG-IFN-alpha-2b and ribavirin for 24, 36, and 48 weeks, respectively, by intention to treat analysis. No statistically significant difference in sustained virological response rates was detected between 36 and 48 weeks of therapy (p = 0.3). Subjects with sustained virological response showed greater antiviral efficacy (epsilon) and rapid viral load decline from baseline to treatment week 4 compared with non-responders and improvement in liver histology. The incidence of adverse events was higher in the group treated for 48 weeks. CONCLUSION: PEG-IFN-alpha-2b and ribavirin for 36 or 48 weeks was more effective in the treatment of chronic hepatitis C genotype 4 than treatment for 24 weeks. Thirty six week therapy was well tolerated and produced sustained virological and histological response rates similar to the 48 week regimen.

[Autoantibodies against islet cell antigens and type 1 diabetes after treatment with interferon-alpha]. / Autoantikörper gegen Inselzellantigene und Diabetes mellitus Typ 1 unter Interferon alpha-Kombinationstherapie.

BACKGROUND AND OBJECTIVE: The aim of this study was to study the appearance of autoantibodies against islet cells and the development of type 1 diabetes in patients with chronic hepatitis C during interferon treatment. PATIENTS AND METHODS: 74 patients (24 women, 50 men, mean age: 46 years) with HCV infection were treated with interferon, ribavirin and amantadin versus placebo, after they had failed to previous interferon therapy in a prospective, randomised trial. At the end of treatment period anti-islet cell autoantibodies (anti-GAD, anti IA-2), anti-insulin antibodies, TSH, anti-thyroid autoantibodies (TPO, thyreoglobulin, TSH-receptor antibodies) were measured. RESULTS: In two patients, GAD autoantibodies were found, but both patients were negative for IA-2 and insulin antibodies. One of the patients developed type 1 diabetes five months after start of treatment. In this patient, the anti-GAD titer was initial 0 U/ml (normal: < 1.2). The titer raised to 52,2 U/ml after the interferon monotherapy. During the second interferon treatment (in combination) the titer raised from initial 41,1 U/ml to 59,6 U/ml. The anti-GAD titer of the second patient was 0 U/ml before treatment and raised to 1,7 U/ml. This patient did not develop a type 1 diabetes. CONCLUSION: Type 1 diabetes is a rare but serious complication of interferon therapy. Repetitive treatment seems to facilitate this complication. Screening for islet antibodies before a second therapy could be useful.

Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation.

In a 36-year-old male with ileocolic Crohn's disease (CD) no long-lasting remission was obtained by treatment with corticosteroids, mesalazine, azathioprine and antibiotics. Surgical interventions due to relapsing fistulae and abscesses resulted in the removal of >1.5 m of small bowel and left only 40 cm of large bowel. In July 2000, a new fistula and abscess developed. The combination of corticosteroids, mesalazine, ciprofloxacin, metronidazol, azathioprine, formula diet and anti-TNF-alpha antibody largely reduced clinical activity, and resection of fistula and abscess were successful. Despite clinical remission, histology showed activity in the small bowel and the colon. In March 2001, stem cell mobilization chemotherapy with cyclophosphamide was performed. It induced an endoscopic remission for 9 months, which was maintained on azathioprine and corticosteroids. After relapse, in March 2002, high-dose chemotherapy with cyclophosphamide and reinfusion of T-cell-depleted autologous peripheral CD34+ blood stem cells were performed. This led to a complete clinical, endoscopical and histological remission for 9 months without any treatment. Thereafter, endoscopy showed initial aphthous lesions with minimal histological signs of inflammation. The patient is asymptomatic, but low-dose prednisolone and methotrexate are prophylactically given. Immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation may be a beneficial therapeutic option in complicated refractory CD.

Veno-occlusive disease in a fetus caused by pyrrolizidine alkaloids of food origin.

We report the occurrence of veno-occlusive disease in a preterm neonate who was symptomatic with hepatomegaly and ascites and was delivered by caesarean section for threatening fetal asphyxia and died shortly afterwards. Post mortem examination revealed veno-occlusive disease typical for pyrrolizidine alkaloid poisoning. The content of pyrrolizidine alkaloids in the liver could be confirmed. Analysis of a herbal mixture which was used for cooking in the family revealed high amounts of the respective alkaloids clarifying the source of the poison and the causal relationship.

Specific cellular immune response and cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni.

Patients coinfected with hepatitis C virus (HCV) and Schistosoma mansoni show high incidence of viral persistence and accelerated fibrosis. To determine whether immunological mechanisms are responsible for this alteration in the natural history of HCV, the HCV-specific peripheral CD4(+) T cell responses and cytokines were analyzed in patients with chronic hepatitis C monoinfection, S. mansoni monoinfection, or HCV and S. mansoni coinfection. An HCV-specific CD4(+) proliferative response to at least 1 HCV antigen was detected in 73.3% of patients infected with HCV, compared with 8.6% of patients coinfected with HCV and S. mansoni. Stimulation with HCV antigens produced a type 1 cytokine profile in patients infected with HCV alone, compared with a type 2 predominance in patients coinfected with HCV and S. mansoni. In contrast, there was no difference in response to schistosomal antigens in patients infected with S. mansoni alone, compared with those coinfected with HCV and S. mansoni. These findings suggest that the inability to generate an HCV-specific CD4(+)/Th1 T cell response plays a role in the persistence and severity of HCV infection in patients with S. mansoni coinfection.

Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4(+) T-cell and cytokine response.

BACKGROUND & AIMS: Immune responses during the first few months of acute hepatitis C virus (HCV) infection seem crucial for viral control, but the relationship of these responses to natural history is poorly characterized. METHODS: This prospective study investigated the HCV-specific CD4(+) and cytokine responses in patients with acute HCV hepatitis with or without Schistosoma mansoni coinfection, a parasitic infection with T helper (Th) 2 immune bias. HCV-specific CD4(+) proliferative responses and cytokine production in peripheral blood mononuclear cells were correlated with liver biopsy results at 6 months and at the end of follow-up. RESULTS: Whereas 5 of 15 patients with HCV alone recovered from acute HCV, all (17 of 17) patients with S. mansoni coinfection progressed to histologically proven chronic hepatitis. Coinfected patients had either absent or transient weak HCV-specific CD4(+) responses with Th0/Th2 cytokine production. The magnitude of the HCV-specific CD4(+) response at week 12 was inversely correlated with the fibrosis progression rate in chronically infected patients. CONCLUSIONS: Patients with acute hepatitis C and schistosomiasis coinfection cannot clear viremia and show rapid progression once chronic infection is established. This rapid progression is associated with a strong Th2 response in peripheral immune responses, suggesting that early development of vigorous Th1 responses not only facilitates clearance but delays disease progression.

Peginterferon alfa-2a in patients with chronic hepatitis C.

BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

Isolation, characterization and biological significance of hepatitis B virus mutants from serum of a patient with immunologically negative HBV infection.

BACKGROUND/AIM: A low-titered hepatitis B virus infection without immunological markers was identified in a prospective study in the serum of a kidney transplant recipient by PCR. The aim of this study was to analyze HBV genomes and their biological significance. METHODS: The genome was amplified in two overlapping fragments A and B. Sequencing of 22 clones of the A- and 12 clones of the B-fragment revealed a heterogeneous virus population. A consensus and a mutant sequence were computed, representing the complete sequence of the virus population. The two sequences were compared with 41 published genomes of the different HBV geno- and serotypes. RESULTS: Ninety-five point mutations and two deletions were identified. Two mutations were observed in all clones and 17 other mutations in three or more clones. The deletions were found in ten and seven of 22 clones. They were located in the C-gene and led to stop codons yielding truncated e- and/or core proteins. In vitro transfection of DNA constructs containing these deletions demonstrated a stop of HBV replication and of HBeAg expression. Cotransfection experiments demonstrated a dominant negative effect of the mutants containing the deletions. In addition, we describe new variants of naturally occurring HBsAg mutants that may cause HBV infection less detectable by standard HBsAg measurement assays. They were characterized by two point mutations which were observed in 9 of 12 and 13 of 22 clones of the S-gene. They significantly reduced the HBsAg expression in in vitro transfection experiments. CONCLUSION: We found a patient with low-titered HBV infection, with mutations of the 'a' epitope of the Santigen as well as with mutations leading to truncated core proteins which may cause a dominant negative effect.

Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni.

BACKGROUND/AIMS: Infection with Schistosoma mansoni is endemic in Egypt leading to hepatic schistosomiasis and eventually portal hypertension. The prevalence of antibodies against hepatitis virus C among Egyptians is 14-51%. The aim of the present study was to investigate the influence of schistosomiasis on chronic hepatitis C with respect to the natural course of the disease, immunology, virology and histology. PATIENTS AND METHODS: One hundred and twenty-six Egyptian patients classified into three groups: group A: chronic hepatitis C (n=33); group B: chronic schistosomiasis (n=30) and group C: chronic hepatitis C and chronic schistosomiasis (n=63) were enrolled and prospectively followed for 62.7 +/- 22 months. Patients infected with other hepatic viruses and/or parasites were excluded. Detailed history, clinical examination, CD4+ and CD8+ lymphocyte counts in blood, hematological and blood chemical values, abdominal ultrasonography, upper endoscopy, HCV RNA titer by RT/PCR, genotype and histological activity index in the liver biopsy were determined. RESULTS: Thirty patients (48%) with HCV and schistosomiasis had liver cirrhosis and Child-Pugh class C vs. five (15%) in HCV patients and none in the schistosomal group. HCV RNA levels ranged between 0.07 and 13 x 10(5) copies/ml in group A, and between 1 and 25 x 10(5) copies/ml in group C. HCV genotype 4 was detected in 58 patients with co-infection (92%) and 21 patients with HCV alone (64%). Patients with coinfection showed higher grading and staging scores in their liver biopsies. Hepatocellular carcinoma was detected only in patients with coinfection. During follow-up, the mortality rate was 12%, 3% and 48% in group A, B and C, respectively. CONCLUSIONS: Patients with concomitant HCV and schistosomiasis infection were characterized by more advanced liver disease, higher HCV RNA titers, predominance of HCV genotype 4, higher histologic activity, higher incidence of cirrhosis and hepatocellular carcinoma as well as a much higher mortality rate.

[Hepatitis C--standard therapy]. / Hepatitis C--Standard-Therapie.

Infection with the hepatitis C virus leads to chronic hepatitis in the majority of patients. Diagnosis is based on the presence of anti-HCV antibodies and confirmed by positive HCV RNA. The natural course of the disease is slow. Cirrhosis is found in a minority of patients two decades post infection. Nevertheless, cirrhosis is much more frequently observed than in patients with hepatitis B infection. Treatment of choice is interferon-alpha. Today combination with ribavirin is recommended for most patients. In combination therapy the sustained response rate six months after stop of treatment is about 40% in naive patients with respect to virus elimination. In patients treated with high doses of interferon-a for one year the sustained response rate is comparable. The response rate is higher in patients with HCV infections of non-1 genotype and in patients with lower virus titers, e.g. less than 2 Mill. genome equivalents per ml. Interferon-a treatment also leads to an improvement of liver histology. Necro-inflammatory scores are reduced. It has also an antifibrogenic effect. Progression of fibrosis is reduced. The antiproliferative effect of interferon-a leads a lower rate of hepatocellular carcinomas, which has been demonstrated in several retrospective studies. In patients with Child A cirrhosis the time till decompensation is delayed. Because of the slow progression, the relatively low response rate and the adverse events of interferon-a and ribavirin treatment should be instituted on an individual base depending on host factors such as age, co-morbidity and stage of liver disease.

Prefrontal cortical hypometabolism during low-dose interferon alpha treatment.

OBJECTIVE: To evaluate prospectively interferon alpha (IFN-alpha) associated effects on cerebral glucose metabolism and its correlation to neuropsychiatric symptoms during low-dose IFN-alpha-treatment. METHODS: Eleven patients treated with low-dose IFN-alpha for chronic hepatitis C were prospectively evaluated by neuropsychiatric tests and cerebral [18F]deoxyglucose positron emission tomography (FDG-PET) before and in the 12th week of treatment. PET images were spatially normalized, corrected for variance in global activity and pixel-based t-statistics were calculated for each set of PET scans using SPM96 software. Pixel-cluster with P<0.001 for hypo- or hypermetabolism were displayed in parametric images. Covariance analysis with neuropsychiatric tests was calculated for each cluster. RESULTS: In week 12 of IFN-alpha treatment, significant hypometabolism with a decrease of local activity ranging from 8 to 12% was found in all patients bilaterally in the prefrontal cortex (BA 9), which correlated in a covariate analysis with changes in depression score as measured by Beck's Depression Inventory. Additionally, hypermetabolism with a maximum increase in local activity of 6-8% was seen in all patients in putamina as well as the left occipital region (BA 18). Before IFN-alpha treatment, only 1/11 patient showed depressive symptomatology. After 3 months of treatment, 6/11 patients were classified as having mild to moderate depressive symptoms (P<0.1; Wilcoxon test). CONCLUSIONS: Low-dose IFN-alpha therapy is associated with significant prefrontal hypometabolism. This hypometabolism covaried with depression score, but was even found in clinically non-depressed patients. These findings may reflect a possible predisposing factor for IFN-alpha associated neuropsychiatric syndromes and might contribute to a pathophysiological model of affective disorders, as endogenous IFN-alpha levels are elevated in a subset of psychotic patients during acute disease.

Occurrence and management of hepatitis B virus reactivation following kidney transplantation.

A 28-year-old woman was kidney transplanted. She had an inapparent hepatitis B virus (HBV) infection 2 years previously. At the time of transplantation she was hepatitis B surface antigen (HBsAg) negative, anti-HBs, anti-HBc, anti-HBe and anti-HCV antibody positive and her transaminase activities were within the normal range. The donor of the kidney allograft was HBV negative. Twelve weeks after transplantation a life-threatening liver failure occurred with a rapid rise of alanine aminotransferase (ALT) to 1427 U/l and a decrease of the prothrombin time to 25% of normal value. Anti-HBs had become negative, anti-HBc and anti-HBe titers had decreased. HBsAg became positive, associated with a HBV DNA of 3 x 10(8) genome equivalents/ml. Azathioprine and prednisone were withdrawn and foscarnet therapy was started. This therapy led to a decrease of ALT activity associated with an elimination of HBsAg and HBV DNA. Eight months after transplantation liver function tests were within the normal range. Graft rejection did not occur despite low or intermittent cessation of immunosuppressive therapy.

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease. The Budesonide Study Group.

BACKGROUND: The relapse rate after steroid induced remission in Crohn's disease is high. AIMS: To test whether oral pH modified release budesonide (3 x 1 mg/day) reduces the relapse rate and to identify patient subgroups with an increased risk of relapse. METHODS: In a multicentre, randomised, double blind study, 179 patients with steroid induced remission of Crohn's disease received either 3 x 1 mg budesonide (n = 84) or placebo (n = 95) for one year. The primary study aim was the maintenance of remission of Crohn's disease for one year. RESULTS: Patient characteristics at study entry were similar for both groups. The relapse rate was 67% (56/84) in the budesonide group and 65% (62/95) in the placebo group. The relapse curves in both groups were similar. The mean time to relapse was 93.5 days in the budesonide group and 67.0 days in the placebo group. No prognostic factors allowing prediction of an increased risk for relapse or definition of patient subgroups who derived benefit from low dose budesonide were found. Drug related side effects were mild and no different between the budesonide and the placebo group. CONCLUSION: Oral pH modified release budesonide at a dose of 3 x 1 mg/day is not effective for maintaining steroid induced remission in Crohn's disease.

Effect of psychotherapy on the course of Crohn's disease. Results of the German prospective multicenter psychotherapy treatment study on Crohn's disease. German Study Group on Psychosocial Intervention in Crohn's Disease.

BACKGROUND: Our aim was to study the influence of psychotherapy in addition to a standardized corticosteroid treatment on the somatic and psychosocial course of Crohn's disease. METHODS: In a prospective, randomized multicenter study 108 of 488 patients received either drug treatment or, in the intervention group, additionally psychotherapy in the first half of the 2-year follow-up period. RESULTS: Eighty-four patients (77.8%) completed the somatic and 81 (75%) the psychosocial follow-up. Twenty-three per cent of the control group and 30% of the psychotherapy group showed episode-free courses; 29% and 17%, respectively, underwent surgery due to failure of drug treatment. The main analysis, which was based on subranking by number, duration, and severity of relapses, failed to show significant differences between the two groups (P = 0.125). The same result was obtained for the psychosocial status after 1 year in the main target criteria depression, anxiety, psychosocio-communicative status, and quality of life. CONCLUSIONS: The confirmatory analysis did not prove significantly better courses after additional psychotherapy. There was a tendency towards fewer operations.

[Hepatitis B virus mutants--clinical significance]. / Hepatitis-B-Virusmutanten--klinische Bedeutung.

Hepatitis B virus (HBV) mutants have recently been identified in patients with acute or fulminant as well as chronic infections. Naturally occurring mutations have been identified in all viral genes and regulatory elements, most notably in the genes coding for the structural envelope and nucleocapsid proteins. Mutations in the gene coding for the hepatitis B surface antigen (HBsAg) may result in infection or viral persistence despite the presence of antibodies against HBsAg (anti-HBs) ("vaccine escape" or "immune escape"). Mutations in the gene encoding the pre-core/ core protein (pre-core stop codon mutant) result in a loss of hepatitis B e antigen (HBeAg) and seroconversion to antibodies to HBeAg (anti-HBe) with persistence of HBV replication (HBeAg minus mutant). Mutations in the core gene may lead among others to an "immune escape" due to a T cell receptor antagonism. Mutations in the gene coding for the polymerase/reverse transcriptase can be associated with viral persistence or resistance to nucleoside analogues. Thus, HBV mutations may affect the natural course of infection, viral clearance and response to antiviral therapy. Apart from the precore/core stop codon mutations, the exact contribution of specific mutations to diagnosis and therapy of HBV infection as well as patient management in clinical practice remain to be established.