[Indications for liver biopsy in liver tumors].
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Biopsy↗
Biomedical subjects
U Hopf
Publications and source records attributed to U Hopf.
Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation.
BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.
2-Aminopurine↗
Randomized, placebo-controlled, double-blind trial with interferon-alpha with and without amantadine sulphate in primary interferon-alpha nonresponders with chronic hepatitis C.
In primary interferon-alpha (IFN-alpha) nonresponders with chronic hepatitis C, retreatment with IFN-alpha has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-alpha alone or in combination with amantadine sulphate in nonresponders to previous IFN-alpha monotherapy. Fifty-five IFN-alpha nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-alpha 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate (n=26) or a matched placebo (n=29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-alpha dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-alpha/amantadine sulphate, one patient; IFN-alpha/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-alpha and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue (P < 0.05) and vigor (P < 0.05) in patients receiving combined IFN-alpha/amantadine sulphate treatment compared with those treated with IFN-alpha alone. IFN-alpha/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-alpha and amantadine sulphate does not increase the low sustained virological response rates of IFN-alpha therapy in primary IFN-alpha nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.
Adolescent↗
Occurrence and clinical outcome of lamivudine-resistant hepatitis B infection after liver transplantation.
Lamivudine treatment of hepatitis B after orthotopic liver transplantation (OLT) is often accompanied by fast viral-resistance formation. Although no clinical data are available, in vitro data indicate that lamivudine-resistant reinfection has a mild course because of defective viral replication. Between 1996 and 1999, a total of 34 patients were treated with lamivudine because of hepatitis B recurrence after OLT. All patients developed reinfection despite long-term passive immunoprophylaxis with hepatitis B immunoglobulin, diagnosed by positive hepatitis B surface antigen and positive hepatitis B virus (HBV) DNA. Before treatment with lamivudine, 21 of these patients underwent a course of famciclovir and developed resistance. Monthly laboratory tests and sequential liver biopsies were performed during the follow-up period. Nineteen of 34 patients (56%) developed lamivudine resistance during the follow-up period of 12 to 49 months. One- and 3-year graft survival rates after the diagnosis of lamivudine resistance were 89% and 66%, respectively. In most cases, lamivudine resistance was associated with high viral replication (3,012 +/- 574 pg/mL 1 month after the diagnosis of lamivudine resistance); however, liver enzyme levels were only moderately elevated (alanine aminotransferase [ALT], 45 +/- 16 U/L). Only 3 patients (15%) showed a rapid increase in ALT level to more than 500 U/L within 3 months after resistance developed. All other patients had mildly elevated liver enzyme levels during the first 6 to 8 months after lamivudine resistance. In the later course, liver enzyme levels increased in most patients. Fourteen patients with elevated transaminase levels were switched to lamivudine plus interferon alfa (n = 8) or lamivudine plus famciclovir therapy (n = 6). This combination was successful in most cases, decreasing HBV DNA and liver enzyme levels. Four patients with lamivudine resistance died during follow-up, only 1 patient because of HBV reinfection. In addition, 2 patients underwent retransplantation because of hepatitis B cirrhosis of the first graft. Compared with historic courses of wild-type recurrence, lamivudine-resistant reinfection is characterized by a milder clinical course. Fulminant cases were not observed; however, in three cases, chronic liver failure developed. The combination of different antivirals diminished viral replication after lamivudine resistance. In the future, new antiviral agents, such as adefovir, might further expand therapeutic options.
Drug Resistance, Microbial↗
Pilot study of interferon-alpha high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C.
Ribavirin plus interferon-alpha (IFN alpha) combination has led to a marked advance in the treatment of IFN alpha-naive or relapser patients with chronic hepatitis C but was shown to be only marginally effective in IFN alpha-nonresponders. We therefore conducted a pilot study to see whether an intensified treatment protocol might be more effective in inducing a virological response in patients who had not responded virologically to previous IFN alpha monotherapy. 14 nonresponder patients with histologically proven chronic hepatitis C were included in the study. Patients received 9 MU IFN alpha-2a daily for one week followed by 9 MU IFN alpha every second day for further 5 weeks. With the beginning of the seventh week, patients were treated with 6 MU IFN alpha thrice in week (tiw) for a period of 6 weeks (until week 12). IFN alpha was continued up to 48 weeks at a dose of 3 MU IFN alpha tiw. Ribavirin (1000-1200 mg/day) and amantadine sulphate (200 mg/day) was given orally for 48 weeks. One patient discontinued therapy after first IFN alpha injection and one other patient after 12 weeks of therapy because of side effects. The remaining 12 patients completed treatment according to the protocol. An initial virological response at week 24 was achieved in 2 of the 14 patients (14%) and both patients remained HCV RNA negative at the end of treatment. However, both patients relapsed 4 weeks after completion of therapy, and therefore none of the patients achieved a virological sustained response. Viral dynamics studies showed a marked decline in hepatitis C viremia during the first 6 weeks of high-dose IFN alpha. After IFN alpha dose reduction, however, viremia stabilized or increased in most patients. These data indicate, that even triple therapy with high-dose IFN alpha plus ribavirin and amantadine fails to improve significantly the response rates in IFN alpha-nonresponders.
Adult↗
Sustained remission of chronic hepatitis C after a change to human leukocyte interferon-alpha in a difficult-to-treat patient with breakthrough phenomenon associated with antibodies against recombinant interferon-alpha.
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Antiviral Agents↗
[Therapy of problem cases in hepatitis B].
In the management of hepatitis B new therapeutic options have been established in the last years. Patients with fulminant course are rarely observed and should be submitted in a hepatological center. In chronic hepatitis B today we see mainly HBeAg negative/anti-HBe positive patients with replication of HBV-mutants. The tendency is to treat these cases with lamivudine (LAM) for some years. This is also true for HBV-cirrhosis in stage Child A. The progressed cirrhosis (Child B/C) without option for liver transplantation is not an indication for nucleosidanaloga and a contraindication for interferon. However before liver transplantation the viraemia should be diminished lower than 5 pg/ml. That means the HBV-hybridization test should become negative, which can be achieved with LAM in most cases. During and after liver transplantation the HBV-infected patients receive passive immunoprophylaxis with anti-HBs-hyperimmunoglobulin. In the situation of reinfection and hepatitis, nucleosidanaloga are indicated, in the first line LAM. In the case of LAM-resistance, interferon alpha is a further option. Patients after renal transplantation and HBV-infection should also be treated with LAM. In these patients IFN should be avoided, because graft rejection can be induced. Combined infection with HBV plus HDV, HCV or HIV need an individual concept for treatment. Extrahepatic manifestations of HBV-infection with clinical relevance, e.g. panarteriitis or glomerulonephritis are indications for antiviral treatment. If treatment with glucocorticosteroids is necessary in these situations, the steroids should be given only in combination with LAM. In non-cirrhotic patients with normal aminotransferases but quantify-able viraemia the liver histology is helpful for the indication of treatment.
Antiviral Agents↗
Additional interferon alpha for lamivudine resistant hepatitis B infection after liver transplantation: a preliminary report.
Resistance formation is a major problem in antiviral treatment of hepatitis B recurrence after liver transplantation. One possible therapeutic approach is an antiviral combination therapy with synergistic drugs. Four patients who were transplanted for chronic hepatitis B were analyzed retrospectively. All patients had reinfection of the graft and breakthrough of hepatitis B virus (HBV) during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy of lamivudine and interferon alpha 2a (3 times 3 million units weekly) was initiated. Addition of interferon markedly reduced viral replication rate in all patients. Three patients became HBV-DNA negative despite lamivudine resistance, but only two had a sustained response. No patient seroconverted to anti-HBe or lost HBsAg, but all patients showed a normalization of alanine aminotransferase and aspartate aminotransferase levels. No severe complications, and especially no rejection episodes occurred. Therefore lamivudine combined with interferon might be used for the therapy of hepatitis B reinfection after liver transplantation.
Adult↗
Lamivudine as first- and second-line treatment of hepatitis B infection after liver transplantation.
Lamivudine and famciclovir have expanded therapeutical options for HBV infection after liver transplantation. First studies confirm good antiviral effects of both, but at present the major problem seems to be a rapid resistance formation in immunosuppressed patients. Thirty-four adult patients with HBV recurrence despite passive immunoprophylaxis and seven with de novo infection after orthotopic liver transplantation (OLT) were treated with 100-150 mg lamivudine daily. Patients were either treated directly after infection (n = 14) or after breakthrough of viral replication during an initial famciclovir therapy (n = 27). All patients except two responded to treatment with a reduction of serum HBV-DNA of over 50%. Thirty-one patients (76%) turned HBV-DNA-negative during lamivudine therapy. Viral breakthrough was observed in 14 of these patients after 4-13 months of treatment. A total of 17 patients (40%) remained HBV-DNA-negative for more than 12 months. Only nine patients eliminated HBsAg, of which four had and an HDV coinfection. None of the HBeAg-positive patients converted to anti-HBe. Most patients showed a prompt and significant reduction of aspartate aminotransferase (ALAT) levels. No severe complications occurred. Therefore, a safe and effective therapy of HBV infection after transplantation is possible with lamivudine. Viral replication is suppressed even in patients who revealed breakthrough during famciclovir therapy. Resistance formation as a major drawback occurred in one third of the patients within the first year of treatment.
2-Aminopurine↗
A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B.
BACKGROUND/AIMS: Interleukin-12 (IL-12) may be active against hepatitis B virus (HBV). The objective of the study was to assess the tolerability, activity, pharmacokinetics, and pharmacodynamics of three dose levels (0.03 microg/kg b.w., n=15; 0.25 microg/kg b.w., n=15; 0.50 microg/kg b.w., n=16) of recombinant human (rHu) IL-12 given s.c. once a week for 12 consecutive weeks. METHODS: Forty-six patients with chronic hepatitis B, HBV DNA positivity and aminotransferase elevation were included in a multicenter prospective randomized phase I/II study. RESULTS: Compared with the baseline, HBV DNA levels had decreased significantly at the end of rHuIL-12 treatment and after the 12-week follow-up period (p<0.001). The response to rHuIL-12 treatment was dose-dependent: at the end of the study HBV DNA clearance was greater in patients treated with 0.50 microg/kg b.w. (25%) or with 0.25 microg/kg b.w. (13%) compared with those given 0.03 microg/kg b.w. (7%). Moreover, HBeAg became undetectable at the end of follow-up in five of the patients given the 0.25microg/kg (2/15) or the 0.50 microg/kg (3/16) dose. The drug pharmacology showed that IL-12 had an estimated half-life of 30 h with levels remaining detectable for more than 48 h after rHuIL-12 administration. The serum levels of IL-12, interferon-gamma, IL-10, neopterin and beta2-microglobulin as well as the area under the curve (AUC) were rHuIL-12 dose-related. Side effects were observed more frequently with higher doses, including moderate decreases in lymphocyte and neutrophil counts; three patients withdrew prematurely from treatment. The local reaction observed at the injection site was unrelated to the drug dose. Only one patient showed detectable antibody levels to rHuIL-12 without clinical impact. CONCLUSIONS: Treatment with rHuIL-12 at the doses investigated is safe and tolerable, and appears to be active against HBV in patients with chronic hepatitis B.
Adjuvants, Immunologic↗
Efficacy of a short-term ribavirin plus interferon alpha combination therapy followed by interferon alpha alone in previously untreated patients with chronic hepatitis C: a randomized multicenter trial.
BACKGROUND: Combination therapy with interferon alpha (IFNalpha) plus ribavirin has been shown to improve the sustained response rate in patients with chronic hepatitis C but there is little information regarding the lengths of time for this therapeutic regimen. In this study we therefore tried to evaluate whether the analysis of different virological parameters could provide new clues with respect to the early determination of the efficacy of this form of combination therapy. Furthermore, we also examined whether short-term induction combination therapy followed by IFNalpha alone is more effective than monotherapy in mounting an initial as well as a sustained virological response. METHODS: 185 patients with histologically proven chronic hepatitis C (mean age 42 years (range 19-65 years); 110 males, 75 females) were enrolled in the study. The patients were randomly assigned to receive, over the first 12 weeks, either interferon alpha 2a 6 million units (MU) three times weekly plus ribavirin 14 mg/kg per day (n=93) or the same dose of IFNalpha alone (n=92). Patients with a virological response (serum HCV RNA undetectable) after 12 weeks were subsequently treated with 3 MU IFNalpha alone thrice weekly for a further 40 weeks. Otherwise, treatment was discontinued. After the end of treatment, patients were followed up for 24 weeks. RESULTS: Patient characteristics at baseline were not significantly different in the two treatment groups. An initial virological response at week 12 was seen in 61 (66%) patients receiving IFNalpha plus ribavirin and in 44 (48%) being treated with IFNalpha alone (p=0.015) and this improvement in the response rate was mainly restricted to HCV genotype 1-infected patients (58% vs. 38%). In contrast, end-of-treatment (week 52) and sustained virological response rates were similar in both groups (37% vs. 29% and 26% vs. 17% [p=0.1], respectively). Interestingly, patients with HCV genotype 3, however, clearly benefited from short-term combination therapy. Thus, sustained virological response rates in these patients significantly increased from 25% (IFNalpha monotherapy) to 59% (combination therapy) (p=0.05). CONCLUSIONS: Short-term combined therapy for 12 weeks is more effective than the monotherapy with respect to the induction of an initial virological response but this effect applies only to genotype 1-infected patients. However, there is no significant difference between both therapeutic schedules with regard to the induction of sustained response. Although HCV genotype 3-infected patients seem to benefit from this short-term combined therapy, prolonged combined therapy may be necessary in HCV genotype 1-infected patients.
Adult↗
Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C.
Although the antiviral effects of amantadine sulphate (1-aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health-related quality of life (HRQOL) of interferon alfa (IFN-alpha) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN-alpha2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24-week follow-up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN-alpha plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN-alpha alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN-alpha worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN-alpha plus amantadine is as effective as IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C.
Adolescent↗
Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment.
Both a double-stranded RNA-dependent protein kinase (PKR)-phosphorylation homology domain (PePHD) within the E2 protein and a PKR-binding domain within the nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) genotype 1 isolates inhibit the function of the interferon alfa (IFN-alpha)-induced antiviral effector protein PKR in vitro. We investigated whether the mutational pattern of the E2 region (codons 618-681, including PePHD) of 81 HCV genotype 1-infected patients (HCV-1b [n = 54], HCV-1a [n = 27]) influences the response to IFN-alpha. Initial viral decline (DeltaHCV RNA) was determined at week 1 hereby covering the effector reactions of IFN-alpha-mediated first phase and the immune-mediated second phase. DeltaHCV RNA less than 50% (group 1); DeltaHCV RNA greater than 50% but less than 90% (group 2); and DeltaHCV RNA > or =90% (group 3) were differentiated. The PePHD region was highly conserved; the few mutations (5 patients) did not correlate with DeltaHCV RNA or sustained virologic response to IFN-alpha. Within the flanking regions before and after PePHD (codons 618-681) 72 of 81 patients (89%) had 2.6+/-0.17 mutations (median, 3; range, 1-8) that did not correlate with treatment response. Sequence analysis of the NS5A protein (codons 2,209-2,274, including interferon sensitivity determining region [ISDR]) in 39 of 81 patients showed a higher mean number of mutations in the ISDR (codons 2,209-2,248) in groups 2 (1.28+/- 0.43 [n = 18]) and 3 (1.89+/-0.54 [n = 9]) than in group 1 (0.67+/- 0.19 [n = 12]; P =.049 group 1 vs. 3) and a mutant type ISDR (e.g., > or =4 mutations) was significantly more frequent in sustained virologic responders than in nonresponders or relapsers (2 of 4 [50%] vs. 2 of 35 [6%]; P =.045). Thus, NS5A appears to be functionally relevant in IFN-alpha-induced effector reactions.
Amino Acid Sequence↗
[Effect of ribavirin on dynamics of hepatitis C viremia in interferon alpha-treated patiens with response or no response].
Combination therapy with interferon-alpha (IFN alpha) plus Ribavirin has been shown to improve the response rate in patients with chronic hepatitis C as compared to IFN alpha alone. However, the mode of anti-viral action of Ribavirin is still unknown. To prove, whether Ribavirin has any additional effect on the decline of hepatitis C viremia during the first weeks of treatment patients with and without combination therapy were compared. Kinetic studies were performed in patients who either responded to IFN alpha alone or IFN alpha plus Ribavirin combination as well as in nonresponders to both forms of therapeutic approaches. 64 IFN alpha naive patients with histologically proven chronic hepatitis C were included in the study. Patients were randomized to receive either IFN alpha-2a (Hoffmann-La Roche) 6 MU thrice weekly or IFN alpha 6 MU tiw plus Ribavirin (Meduna) 14 mg/kg/day for 12 weeks. 37 patients (58%) became HCV RNA-negative (= responders; 17 [46%] with IFN alpha alone, and 20 [54%] with combination therapy). 27 patients remained HCV RNA-positive (= non-responders; 13 [48%] with IFN alpha alone, and 14 [52%] with combination therapy). HCV RNA concentrations were measured in all patients at baseline as well as 1, 2, 4, and 12 weeks after the start of treatment (bDNA assay, Chiron). Using nonradioactive single-stranded conformation (SSCP)-analysis of the HCV hypervariable region 1 we investigated further whether initial viral decline is correlated with changes in viral quasispecies distribution. In primary responders, ribavirin did not influence hepatitis C viremia decline which was of biphasic nature. Also in nonresponders HCV RNA levels decreased after one week of treatment irrespectively of the mode of therapy (mean 10.0 +/- 2.3 to 5.5 +/- 1.1) (phase 1). In the following weeks, however, 2 types of HCV dynamics could be observed (phase 2). In patients with combination therapy, a further reduction of viremia level could be observed, whereas viremia levels in patients with IFN alpha alone slightly increased (week 12: 3.0 +/- 0.5 MEq/mL [combination, n = 15] vs. 7.5 +/- 2.9 MEq/mL [IFN alpha-mono, n = 12]). The individual response of these nonresponder patients showed, however, marked differences (range percentage decline after 4 weeks, 0-98%). Changes in the viral population (quasispecies distribution) as cause of these differences could be excluded by SSCP-analysis of PCR products of the HCV hypervariable region 1. Ribavirin in combination with IFN alpha exerts an additional anti-viral/immunmodulatory effect which manifests itself in phase 2 of hepatitis C viremia decline. The biphasic decline of hepatitis C viremia also observed in IFN alpha-nonresponders can not be explained by the selection of primary IFN alpha-resistant viral variants. The individual differences in the dynamic of hepatitis C viremia observed in the so called "nonresponders" imply that the term "nonresponder" should be redefined, considering our observation that a marked viral decline can occur in these patients.
Adult↗
[Therapy of recurrent hepatitis B infection after liver transplantation. A retrospective analysis of 200 liver transplantations based on hepatitis B associated liver diseases].
BACKGROUND: Before introduction of passive immunoprophylaxis and new antiviral nucleoside analogues the course of hepatitis B recurrence after liver transplantation could hardly be influenced. The result was a inferior graft survival. In the present retrospective analysis of the efficacy of hepatitis B therapy after liver transplantation was analysed retrospectively. PATIENTS AND METHODS: Between 1988 and 1998 in total 179 patients were transplanted due to hepatitis B related liver failure at our centre. All patients received passive immunoprophylaxis with hepatitis B immunoglobulin. In case of reinfection after 1993 an antiviral therapy with famciclovir 1500 mg daily was initiated (n = 26), since 1996 lamivudine (100-150 mg daily) was used (n = 12). In case of viral breakthrough under famciclovir treatment or prophylaxis therapy was switched to lamivudine (n = 22). In case of ineffectiveness of lamivudine an antiviral combination therapy with lamivudine and interferon (n = 4) or lamivudine and famciclovir (n = 4) was initiated. Before availability of antiviral agents or in case of viral breakthrough in total 12 patients were retransplanted due to acute or chronic reinfection. RESULTS: With passive immunoprophylaxis reinfection rate was 33%, 43% and 44% after 1, 3 and 5 years respectively. Without antiviral treatment 52% of patients died within the first year after reinfection. Antiviral therapy with lamivudine or famciclovir improved the one year survival after reinfection to 79%. Suppression of viral replication was more effective with lamivudine. Under lamivudine 26 patients (76%) became HBV-DNA negative, 9 patients HBsAg negative (26%). In contrast no patient became HBsAg negative during famciclovir therapy. Lamivudine was effective also after famciclovir breakthrough in 94% of patients. In case of lamivudine resistant reinfection viral replication could be suppressed with an antiviral combination therapy up to negative HBV-DNA in the hybridization assay. Severe side effects were not observed during any of the antiviral therapies. The graft survival after retransplantation for hepatitis B reinfection was 42% and 25% after one and 3 years. CONCLUSION: Whereas it is generally accepted, that passive immunoprophylaxis lowers the reinfection rate it could be shown in the present study, that antiviral treatment lowers mortality of hepatitis B reinfection. The major problem of lamivudine and famciclovir is viral resistance formation. In this case an antiviral combination therapy might be useful, whereas retransplantation for hepatitis B reinfection should be considered carefully due to inferior graft survival rates.
2-Aminopurine↗
Retreatment with interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C.
BACKGROUND/AIMS: Combination therapy with interferon-alpha (IFN-alpha) plus ribavirin is more efficacious than IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C and patients with IFN-alpha relapse. Only limited data are available in IFN-alpha non-responders. In a multicenter trial we therefore evaluated the efficacy of combination therapy in IFN-alpha-resistant chronic hepatitis C. METHODS: Eighty-two patients (mean age 46.8 years, 54 males, 28 females) with chronic hepatitis C were treated with IFN-alpha-2a (3 x 6 MIU/week) and ribavirin (14 mg/kg daily) for 12 weeks. Thereafter, treatment was continued only in virological responders (undetectable serum HCV RNA at week 12) with an IFN-alpha dose of 3 x 3 MIU/week and without ribavirin for a further 9 months. The primary study endpoint was an undetectable HCV RNA by RT-PCR at the end of the 24-week follow-up period. RESULTS: After 12 weeks of combination therapy, an initial virological response was observed in 29 of 82 (35.4%) patients. Due to a high breakthrough rate after IFN-alpha dose reduction and ribavirin discontinuation, an end-of-treatment response was only achieved in 12 of 82 (14.6%) patients. After the follow-up period, a sustained virological response was observed in 8 of 82 (9.8%) patients. Infection with HCV genotype 3 was the only pretreatment parameter, which could predict a sustained response (HCV-1, 5%; HCV-3, 57.1%; p < 0.001). CONCLUSIONS: Despite a high initial response rate of 35.4%, sustained viral clearance was achieved only in 9.8% of the retreated primary IFN-alpha non-responders. Higher IFN-alpha induction and maintenance dose, as well as prolonged ribavirin treatment may possibly increase the virological response rates in non-responders, particularly in those infected by HCV-1.
Adolescent↗
Occurrence of a novel DNA virus (TTV) infection in patients with liver diseases and its frequency in blood donors.
A novel DNA virus (TTV) was identified recently in Japanese patients with posttransfusion hepatitis non-A-E and has been implicated as a cause of acute and chronic liver diseases of unknown etiology in some patients. The frequency of TTV infections was investigated in 284 blood donors, 105 patients with different liver disorders before and after liver transplantation (OLT), as well as in 64 patients with chronic hepatitis C who received antiviral therapy. TTV infections were found more frequently by nested-PCR in patients with liver disorders (15%) as compared to blood donors (7%). TTV occurred independently of the aetiology of the liver disease (e.g., cryptogenic cirrhosis [12.5%], alcoholic cirrhosis [16%], fulminant hepatic failure non-A-E [35%], and chronic hepatitis C [12.5%]; p=n.s.). After OLT, a high rate of TTV de novo infections (44%) was observed. However, TTV viremia after OLT (in 56 out of the 105 patients) was not associated with graft hepatitis. Analysis of patients with chronic hepatitis C coinfected with TTV who have been treated with interferon alpha alone or in combination with ribavirin revealed that TTV is an interferon-sensitive virus. Phylogenetic analysis of TTV sequences suggest that at least four different genotypes and several subtypes exist in Germany. In conclusion, the high prevalence of TTV infections observed in patients with parenteral risk factors is an argument in favour of transmission of the virus via blood and blood products. A relevant hepatitis-inducing capacity of TTV, however, seems unlikely, considering the observation that in the majority of patients, TTV infection after OLT was not accompanied by graft hepatitis.
Adolescent↗
Dynamics of GB virus C viremia early after orthotopic liver transplantation indicates extrahepatic tissues as the predominant site of GB virus C replication.
The principal site of GB virus C (GBV-C) replication is unknown. To determine whether hepatic GBV-C replication is important for the maintenance of a measurable viremia level in GBV-C infection, the influence of hepatectomy followed by liver transplantation on GBV-C viremia was investigated. GBV-C RNA levels were determined by a quantitative TaqMan polymerase chain reaction (PCR) in 12 patients with pretransplantation GBV-C infection before and daily after orthotopic liver transplantation (OLT) for 25 to 28 days. Compared with the pretransplantation values (mean, 12.4 +/- 3.9 x 10(7) copies/mL), mean GBV-C RNA levels declined significantly by 1 log by day 1 after OLT (mean, 3.5 +/- 1.6 x 10(7) copies/mL), but subsequently remained relatively stable on this high level for the entire observation period, indicating ongoing high-level virus replication (mean GBV-C RNA levels on days 7 and 28 were: 1.7 +/- 0. 5 x 10(7) and 2.8 +/- 0.7 x 10(7) copies/mL; P = ns). Thus, at the end of the follow-up, mean GBV-C RNA levels were not significantly different from that of the 1st and 7th postoperative day and remained significantly lower compared with the pretransplantation values. However, in 2 of the 12 patients, different kinetics were observed. Both already had low-level viremia pre-OLT (0.02 and 0.002 x 10(7) copies/mL) and became persistently GBV-C RNA-negative 2 days after OLT. In 5 patients, liver tissues were collected 6 to 9 days after OLT and investigated for GBV-C RNA. All but 1 were GBV-C RNA-negative in the liver, although 2 of them had rather high serum GBV-C RNA levels at this time. The kinetics of GBV-C viremia observed in our study were neither influenced by the immunosuppressive therapy nor by the number of blood and blood product transfusions given after OLT. In addition, they were quite different from those observed in patients with chronic hepatitis C in whom early reinfection of the graft could be demonstrated by a steady increase in HCV RNA levels starting 3 days after OLT and exceeding preoperative levels by day 8. From our data, one can conclude that the liver is certainly not the major site of GBV-C replication in most patients. However, one cannot exclude that host or viral factors exist that predispose GBV-C replication predominantly in the liver.
Adult↗