[The elder patient with advanced liver disease]. / Der betagte Patient mit fortgeschrittener Hepatopathie.

The increasing number of elder patients with advanced liver diseases requires a special medical competence in this field. The process of aging influences pharmacokinetic and pharmacodynamic properties. Medical measures in elder patients have to submit in particular a careful utility/risk-analysis. The most severe liver disease is the decompensated cirrhosis with its complications. Medical treatment of common cirrhotic complications is not age-dependent. Also the antiviral-therapy with nucleosid analoga in chronic hepatitis B, with or without cirrhosis, can be applied in elder patients without restrictions. However in elder patients with chronic hepatitis C the indication for antiviral treatment is restricted only to a limited number of patients. Important aspects justifying the therapy with PEG-Interferon plus Ribavirin also in elder patients are disease progression, a good clinical condition as well as the motivation of the patient. The established concepts for treatment of autoimmune hepatitis and primary biliary cirrhosis are applicable to elder patients in the same way. The hepatocellular carcinoma is a complication of liver cirrhosis and a frequent malignant tumor in this group of patients. For therapy of hepatocellular carcinoma surgical and interventional procedures are available, partially with a curative account. The systemic medical treatment is disappointing until now. The liver transplantation is generally not a realistic option for aged patients.

[Preoperative chemoradiation in esophageal cancer: experience of a single center in 102 patients]. / Präoperative Radio-Chemotherapie beim Osophaguskarzinom: Erfahrungen eines Zentrums mit 102 Patienten.

The (dis-)advantages of preoperative chemoradiation in patients with esophageal cancer (EC) are still controversial as data are lacking showing a clear cut benefit. Therefore, data of neoadjuvant therapy of our hospital have been analyzed. Since 1994 102 patients with an EC (33 % adenocarcinoma, 67 % squamous cell cancer, scc) were operated after receiving preoperative chemoradiation (36 Gy radiation, 1.8 Gy/day for 4 weeks, 500 mg/m (2) 5-FU for 4 weeks and 20 mg/m (2) Cisplatin, day 1-5, week 1 and 4). Operation was performed usually 8-10 weeks after treatment start. In 11.7 % of patients with an adenocarcinoma a complete pathological response (CR, pT0N0M0) was observed and a pT0 stage in 20.6 %. 38.2 % of these patients were staged as pN0. Postoperative morbidity was observed in 66 % (anastomotic leakage in 20 %, recurrent nerve palsy in 23 %). In-hospital mortality was 5.9 %. 5-year survival was calculated as 30.5 %, in patients wit a CR 66 %.26.5 % of patients with a scc revealed a CR. However no effect at all was observed in 32 % of these patients. 56 % were staged as pN0. Postoperative morbidity was observed in 87 % (anastomotic leakage in 16 %, recurrent nerve palsy in 32 %). In-hospital mortality was 11.8 %. 5-year survival was calculated as 19.2 %, in patients with a CR 45 %. The impact of pN stage was significant (p = 0.0052). These results underline the benefit of neoadjuvant therapy in patients with a CR. Further on, a pN0 stage is an important prognostic indicator. However, it remains open, whether neoadjuvant therapy leads to a downstaging of lymph node involvement, as histological confirmation in clinically positive lymph node is seldom performed prospectively.

Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy.

BACKGROUND: The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. AIMS: To assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. METHODS: Meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. RESULTS: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0-7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0-2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3-2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5-17.7) and 7.1% (95% CI 0-15.0), respectively. CONCLUSIONS: Five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up.

Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused on geographical differences.

BACKGROUND AND AIMS: There is growing evidence that the response of hepatitis C virus (HCV) genotype 1b infected patients towards interferon (IFN) therapy is influenced by the number of mutations within the carboxy terminal region of the NS5A gene, the interferon sensitivity determining region (ISDR). PATIENTS AND METHODS: In order to attain better insight into this correlation, a file comprising published data on ISDR strains from 1230 HCV genotype 1b infected patients, mainly from Japan and Europe, was constructed and analysed by logistic regression. Sustained virological response (SVR) was defined as negative HCV RNA six months after treatment. RESULTS: The distribution of wild-, intermediate-, and mutant-type ISDR sequences differed significantly between Japanese (n = 655) (44.1%, 37.6%, and 18.3%) and European patients (n = 525) (24.8%, 63.4%, and 11.8%; p<0.001). There was a significant positive correlation between the number of ISDR mutations and SVR rate, irrespective of geographical region. The likelihood of SVR with each additional mutation within the ISDR was considerably more pronounced in Japanese compared with European patients (odds ratios 1.82 v 1.39; p<0.001). Pretreatment viraemia of <6.6 log copies/ml and ISDR mutant-type infection was associated with an SVR rate of 97.1% in Japanese patients but only 52.5% in European patients. Pretreatment viraemia was a stronger predictor of SVR than ISDR mutation number in Japanese patients whereas in European patients both parameters had similar predictive power. CONCLUSION: These data support the concept that mutant-type ISDR strains may represent a subtype within genotype 1b with a more favourable response towards IFN therapy.

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.

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.

Induction of T helper cell type 1 response and elimination of HBeAg during treatment with IL-12 in a patient with therapy-refractory chronic hepatitis B.

This study reports the increase of immunoregulatory T helper cell type 1 response and elimination of HBV-DNA during IL-12 therapy in a patient with chronic hepatitis B virus infection who had not responded to three previous interferon-alpha therapies and one treatment with Famciclovir over a period of 6 years. The patient received IL-12 at a dose of 0.5 microgram/kg bodyweight weekly. Peripheral blood mononuclear cells were isolated before and during IL-12 application and incubated for 7 days with specific type 1 (purified protein derivative) and type 2 (tetanus-toxoid) TH cell antigens as well as with a macrophage/monocyte activating antigen (Bacille Calmette-Guérin). In the supernatants cytokines were determined by a double-sandwich ELISA. After 8 weeks HBV-DNA became negative and HBeAg seroconversion to anti-HBeAg occurred. Immunologically the loss of viremia was accompanied by a strong increase of the purified protein derivative-induced production of the type 1 cytokine interferon-gamma (1219 pg/mL before, 13,138 pg/mL after IL-12 therapy). Furthermore, Bacille Calmette-Guérin-induced secretion of the macrophage/monocyte-associated cytokines IL-1, tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor was higher at the end of therapy. This case indicates that IL-12 enhances type 1 T helper cell activity which may be a predisposition for elimination of HBeAg and successful treatment of hepatitis B.

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.

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.

[Therapy of recurrent hepatitis B infection after liver transplantation. A retrospective analysis of 200 liver transplantations based on hepatitis B associated liver diseases]. / Therapie der rekurrenten Hepatitis-B-Infektion nach Lebertransplantation. Eine retrospektive Analyse von 200 Lebertransplantationen aufgrund von Hepatitis-B-assoziierten Lebererkrankungen.

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.

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.

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.

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.

[Therapy of problem cases in hepatitis B]. / Therapie von Problemfällen bei 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.

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.

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.