U. Hopf

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.

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.

Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.

A clinical and virological study of hepatitis C virus-related cryoglobulinemia in Germany

BACKGROUND/AIMS Several reports, especially from Southern Europe, have demonstrated a close association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia. In this study we have analyzed the significance of HCV-related cryoglobulinemia in Germany. METHODS Sera from 79 patients with cryoglobulinemia of type I (n=21), II (n=28) or III (n=30) were investigated for HCV markers. Furthermore, 132 consecutive patients with chronic hepatitis C were studied for the presence of cryoglobulins. Genotypes of HCV were determined according to Simmonds, and HCV-RNA concentrations were measured in patients with and without cryoglobulinemia. RESULTS In 79 patients with cryoglobulinemia we found anti-HCV antibodies in 17 (22%) and HCV-RNA in 11 patients (14%). HCV antibodies were more frequent in essential (44%) compared to secondary mixed cryoglobulinemia (15%). In 132 patients with chronic HCV infection cryoglobulins were detected in 37 patients (28%), in 21 of them at low levels. Clinical symptoms due to cryoglobulinemia were observed in eight of the 37 patients, severe vasculitis in three patients with high cryocrit-levels and cryoprecipitation at room temperature. HCV genotype 1 and subtype 1b were most prevalent, both in patients with and without cryoglobulinemia, and mean HCV-RNA levels were not different between the two groups. Comparison of HCV-RNA levels in cryoprecipitates, supernatant and native serum suggests binding of HCV-RNA to the cryoprecipitate with different affinity in individual patients. CONCLUSIONS The lower prevalence of HCV-related cryoglobulinemia in our study compared with data from Italy and France suggests a south-north gradient in the prevalence of HCV-associated cryoglobulinemia in Europe.

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‐α (IFN‐α) nonresponders with chronic hepatitis C, retreatment with IFN‐α 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‐α alone or in combination with amantadine sulphate in nonresponders to previous IFN‐α monotherapy. Fifty‐five IFN‐α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN‐α 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‐α 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‐α/amantadine sulphate, one patient; IFN‐α/placebo, four patients). After 24 weeks follow‐up a sustained virological response was observed in only two patients receiving IFN‐α 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‐α/amantadine sulphate treatment compared with those treated with IFN‐α alone. IFN‐α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN‐α and amantadine sulphate does not increase the low sustained virological response rates of IFN‐α therapy in primary IFN‐α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health‐related quality‐of‐life.

Clinical significance of recurrent primary biliary cirrhosis after liver transplantation.

Abstract  Primary biliary cirrhosis (PBC) represents a classic indication for orthotopic liver transplantation (OLT); as an autoimmune disease, however, the existence and incidence of recurrent PBC is a matter of significant controversy. Between September 1988 and September 1994 a total of 544 OLTs was performed at our institution. Forty‐nine patients (40 female) with a median age of 50.5 years and previous surgery in 36.4 %, received a liver graft for PBC. The mean serum bi‐lirubin level was 8.9 mg/dl (range 0.7–29.7). Immunosuppression was commenced as a cyclosporine A‐based quadruple therapy or with FK 506 and prednisolone. Protocol liver biopsies were taken at defined intervals posttransplant. Two patients died due to Legionella pneumonia and hypoxic brain damage 2 and 8 weeks after OLT, resulting in an actuarial 5‐year survival rate of 95 % with 47/49 patients being alive compared to 83.5 % of all other liver recipients. Evidence of recurrence of PBC, as defined by elevated chole‐static parameters and histological features of PBC, was found in four patients, another five patients showed only histological signs. Recurrence of PBC, which might compromise the long‐term outcome after OLT, was suspected in 4/47 patients (8.5 %). This evidence of recurrent PBC is in conflict with findings of other groups that did not report recurrent PBC. OLT is still the optimal therapy for advanced PBC, with an excellent prognosis.

Famciclovir therapy for recurrent hepatitis B virus infection after liver transplantation

Abstract  Between November 1993 and June 1995 18 patients received oral famciclovir (3 times 500 mg) for treatment of hepatitis B virus (HBV) reinfection after liver transplantation. Reinfection was defined as the reoccurrence of HBsAg in the serum. In the first 15 patients, famciclovir therapy was initiated after clinical signs of graft hepatitis, whereas the last 3 patients received treatment immediately after HBV‐DNA was detected. Famciclovir was well‐tolerated in all patients. HBV‐DNA values were decreased to undetectable levels in 8 out of 18 patients. Clinical status improved in 7 patients, whereas 5 patients remained unchanged and 6 patients progressed to deteriorating graft function and death. When famciclovir was initiated early after reinfection, a response rate of approximately 66 % was observed. Late onset of therapy in patients with fulminant hepatitis generally failed to provide any clinical benefit.

Quality control study on the performance of GB virus C/hepatitis G virus PCR

BACKGROUND/AIMS A novel virus, GBV-C/HGV, with a genome RNA organization similar to that of the Flaviviridae family was identified in sera of patients with hepatitis. The presence of GBV-C/HGV RNA can only be determined by the amplification of genomic regions using the reverse transcriptase-polymerase chain reaction (RT-PCR). METHODS To assess the quality of the RT-PCR, 14 laboratories investigated a coded serum panel that comprised three GBV-C/HGV RNA-positive sera from three different patients, dilutions of these sera, and three GBV-C/HGV RNA-negative serum samples, two of which were collected from patients with hepatitis C but without GBV-C/HGV infection. In-house RT-PCR as well as commercially available GBV-C/HGV test kits were used in this study. RESULTS Only four laboratories (29%) reported the expected results, and four laboratories (29%) false-positive results; nine laboratories (64%) reported at least one false-negative result. Eleven laboratories (79%) detected the undiluted samples. The majority of false results were obtained with the dilutions of GBV-C/HGV RNA-positive samples. Negative results in the 10(-4) dilution were not considered to be false-negative, since during pre-screening GBV-C/HGV RNA had been detected in this dilution in only 50% of assays by the three laboratories involved in organizing the evaluation. Results obtained by commercial kits and by in-house assays were indiscriminate in quality of performance in this study. CONCLUSION To facilitate further quality assessment studies on the performance of GBV-C/HGV RNA detection, an international GBV-C/HGV RNA standard should be made available. Further efforts are required to optimize GBV-C/HGV RT-PCR.

Searching for the optimal management of hepatitis C patients after liver transplantation

Abstract The optimal immunosuppressive regimen in patients transplanted for hepatitis C (HCV) is still under discussion. High immunosuppression may promote viral replication and recurrent graft hepatitis. But acute and chronic rejection frequently seen in conjunction with HCV recurrence may require some rescue therapy. One hundred and thirty‐seven patients transplanted for HCV cirrhosis, who were HCV‐RNA positive prior to transplantation, were analyzed. Seventy‐nine patients received CSA‐based immunosuppression and 58 patients FK506‐based immunosuppression. One‐month patient survival was 100% in both groups. Three month and 1‐year survival rates and the cumulative 1–5‐year patient survival was similar in CsA‐treated [67/79 (84.8%)] and FK506‐treated patients [50/58 (86.2%)]. Re transplantations for HCV recurrence were performed in 5.1% of CsA‐treated patients and 6.9% of FK506‐treated patients; it was successful in 50% and 75% of patients, respectively. Conversion from CsA to FK506 and vice versa was high with 25 out of 79 patients (31.6%) converting in the CsA group and 8 out of 58 patients (13.8%) converting in the FK506 group. Conversion to FK506 was performed due to acute and chronic rejection and to CsA because of toxicity and HCV recurrence. In both groups, 25% of converted patients died. Five patients of the CsA group and 9 of the FK506 group received OKT3; more than one‐third of each group died. Five patients in the CsA group and 6 in the FK506 group received mycophenolate mofetil (MMF) for HCV recurrence or acute and chronic rejection in conjunction with HCV recurrence. All patients of this critical group are alive with good graft function. In conclusion, survival rates of HCV patients were similar to those seen for other indications. Conversion from CsA to FK506 and vice versa was high and reflects a critical group concerning patient survival. OKT3 treatment should be avoided. A promising therapeutic option for critical patients experiencing acute or chronic rejection in conjunction with HCV recurrence may be treatment with MMF.

Zur Frage des vermehrten Auftretens eines oralen Lichen planus bei Hepatitis-C-Infektion

In der vorliegenden Studie sollte das Risiko deutscher HCV-infizierter Patienten, an einem oralen Lichen planus (OLP) zu erkranken, evaluiert und mögliche Faktoren determiniert werden, die dieses Phänomen beeinflussen. Weiterhin sollte die Prävalenz der HCV-Infektion bei OLP-Patienten bestimmt werden. Es wurden 127 Patienten mit chronischer HCV-Infektion auf das Vorliegen eines OLP untersucht. 3 von 127 Patienten (2,4%) wiesen klinisch und histologisch einen oralen Lichen planus auf. Zusätzlich wurden 24 Patienten mit OLP auf eine bestehende Hepatitis-C-Infektion untersucht. Nur 1 Patient (4,2%) war HCV-positiv. Die Ergebnisse zeigten kein signifikant erhöhtes Risiko für HCV-Patienten in unserer Region, an einem OLP zu erkranken. Außerdem wurde bei den untersuchten OLP-Patienten keine erhöhte Rate an HCV-Infektionen festgestellt. Der endgültige Mechanismus und die ursächlichen Faktoren für die starken geographischen Unterschiede bleiben weiterhin unklar. In weiteren Untersuchungen sollte geklärt werden, ob das HCV lokal eine Wirkung im Bereich der Mundschleimhaut hervorruft oder ob eine unspezifische Immunreaktion auf das Hepatitis-C-Virus für das Entstehen eines oralen Lichen planus von Bedeutung ist. The present study evaluated the risk of hepatitis C virus-infected (HCV) patients in Germany to develop oral lichen planus (OLP). We screened 127 patients with chronic HCV-infection for OLP. In three of 127 patients (2.4%) OLP was found. Twenty-four patients with OLP were examined for hepatitis C. Only one patient (4.2%) was positive for HCV-RNA. Our data show no increased prevalence for OLP in German patients infected with HCV. Also no increased rate of HCV infection in OLP patients was found in this study. Further studies of HCV-infected patients from different geographical areas and ethnic groups are necessary to determine the rate of OLP in HCV-infection and to clarify whether HCV acts locally to develop OLP, or whether host immune response to HCV is of importance.