Risks and benefits of nucleosides before and after liver transplantation.
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Hepatitis B↗
Biomedical subjects
H L Tillmann
Publications and source records attributed to H L Tillmann.
[Helper cells, viral load, genetic factors, co-infections. Prognostic factors in HIV-1 infection].
The ideal time to initiate antiretroviral therapy in asymptomatic patients with chronic HIV infection remains to be defined. The most relevant laboratory parameter is the CD4 cell count. Therapy should be started before the CD4 cells drop below 200/microliter and the immune system becomes compromised. In contrast to past recommendations, viral load should not be used as a single laboratory parameter for initiation of antiretroviral therapy in asymptomatic untreated patients. The determination of genetic factors to assess the prognosis of HIV patients has not yet been incorporated into daily clinical practice. While co-infection with GBV-C is a prognostically favorable factor for the course of the HIV infection, replicative hepatitis C is associated with increased mortality.
AIDS-Related Opportunistic Infections↗
Hepatitis C virus infection.
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Chronic Disease↗
Infection with GB virus C and reduced mortality among HIV-infected patients.
BACKGROUND: The flavivirus GB virus C (GBV-C, also designated hepatitis G virus) was identified in a search for hepatitis viruses, but no disease is currently known to be associated with it. We investigated the relation between coinfection with GBV-C and the long-term outcome in patients infected with the human immunodeficiency virus (HIV). METHODS: A total of 197 HIV-positive patients were followed prospectively beginning in 1993 or 1994. Of these patients, 33 (16.8 percent) tested positive for GBV-C RNA, 112 (56.9 percent) had detectable antibodies against the GBV-C envelope protein E2, and 52 (26.4 percent) had no marker of GBV-C infection and were considered unexposed. We assessed the relation between GBV-C infection and the progression of HIV disease. We also tested 169 GBV-C-positive plasma samples with a quantitative branched-chain DNA (bDNA) assay in order to investigate possible correlations between GBV-C viral load and both the CD4+ cell count and the HIV load. RESULTS: Among the patients who tested positive for GBV-C RNA, survival was significantly longer, and there was a slower progression to the acquired immunodeficiency syndrome (AIDS) (P<0.001 for both comparisons). Survival after the development of AIDS was also better among the GBV-C-positive patients. The association of GBV-C viremia with reduced mortality remained significant in analyses stratified according to age and CD4+ cell count. In an analysis restricted to the years after highly active antiretroviral therapy became available, the presence of GBV-C RNA remained predictive of longer survival (P=0.02). The HIV load was lower in the GBV-C-positive patients than in the GBV-C-negative patients. The GBV-C load correlated inversely with the HIV load (r=-0.33, P<0.001) but did not correlate with the CD4+ cell count. CONCLUSIONS: Coinfection with GBV-C is associated with a reduced mortality rate in HIV-infected patients. GBV-C is not known to cause any disease, but it is possible that its presence leads to an inhibition of HIV replication. However, GBV-C infection could also be a marker for the presence of other factors that lead to a favorable HIV response.
Adult↗
GB virus-C infection in patients infected with the human immunodeficiency virus.
Hepatitis virus infections are frequent in patients suffering from HIV infection due to similar transmission routes of these viruses. In addition, hepatitis virus infections lead to impaired survival in HIV positive patients. The recently discovered flavivirus GB virus C (alias Hepatitis G Virus) was initially believed to be another hepatitis virus. While there is still some minor discussion whether GB virus C (GBV-C) plays a role in fulminant hepatic failure, there is no evidence that this virus is responsible for chronic liver disease. Thus this 'orphan virus' still seeks its disease. In this review we concentrate on the published data concerning the co-infection of GBV-C and HIV. By summarizing the studies available, we show evidence for a beneficial influence of GBV-C on HIV infection. Many studies demonstrated a high prevalence of GBV-C infection in HIV positive patients due to its parenteral and sexual transmission. However, in contrast to the expectations, GBV-C does not aggravate the course of patients suffering from HIV infection. Even though not uniformly found, one often sees higher CD4 counts in patients with ongoing GBV-C viral replication. Likewise, a lower viral load appears to be accompanied by the presence of GBV-C RNA in the serum. In addition, longitudinal studies indicate that GBV-C infection slows down the progression to AIDS and eventually to death. GBV-C probably influences HIV infection associated disease by either directly inhibiting HIV replication or enhancing the immune competence to cope with HIV. Still the definitive mechanism how GBV-C could inhibit the progression to AIDS and eventually death needs to be identified.
Adult↗
Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection.
BACKGROUND/AIMS: Reinfection with hepatitis B virus (HBV) after liver transplantation (OLT) is associated with an unfavourable clinical course. Lamivudine/hepatitis B immune globulin (HBIG) combination treatment reduces reinfection rates. However, it is unclear at what time point lamivudine should be started and which HBIG doses are sufficient. METHODS: Twenty-one patients receiving combination treatment were studied. Lamivudine was started up to 16.5 months before OLT and continued thereafter. HBIG was started intraoperatively and continued according to anti-HBs-titers. Median follow-up after OLT was 20 months. RESULTS: Eleven patients received lamivudine pretreatment for >2 (median 6) months due to initial HBV-DNA-positivity (median 749 pg/ml). After initial lamivudine response HBV-DNA increased in two of them to concentrations above 10 pg/ml prior to OLT. Both had developed mutations in the YMDD motif and suffered from HBV reinfection 13 and 75 days postoperatively. Individual HBIG consumption was highly variable (range 787-4,766 lU/month). Twenty-two percent of anti-HBs titers measured before HBIG administration were below 100 IU/l. CONCLUSIONS: Combined reinfection prophylaxis with lamivudine and HBIG is effective in patients with controlled viral replication at the time of OLT. However, pretransplantation lamivudine resistance is a risk factor for reinfection. Low dose HBIG maintenance therapy individualized according to anti-HBs-titers appears to be tenable.
Adolescent↗
Successful orthotopic liver transplantation.
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Antiviral Agents↗
Hepatitis C and the leptin system: bound leptin levels are elevated in patients with hepatitis C and decrease during antiviral therapy.
BACKGROUND: Serum leptin levels are elevated in alcoholic liver cirrhosis and thus might be involved in the anorexia and hypermetabolism often seen in those patients. We hypothesized that the leptin system is modulated in patients with hepatitis C and might be affected by antiviral therapy. The aim of this study was to investigate the different leptin components in serum of patients with hepatitis C before, during and after interferon alpha and ribavirin therapy and in controls. METHODS: 25 patients (11 female, 14 male) with chronic hepatitis C were compared with body mass index, gender and age-matched controls (n = 25). Patients were treated with interferon alpha alone (3 MU tiw) or in combination with ribavirin for 6-12 months. Free leptin and bound leptin levels were measured using specific radioimmunoassays before interferon therapy, at 12 weeks of therapy and after 3 months of follow-up. RESULTS: Free leptin levels were higher in female than in male subjects, both for patients (P < 0.01) and controls (P < 0.05). Bound leptin levels were elevated in both female (P < 0.05) and male (P < 0.001) patients compared to controls. No alteration of free leptin levels was found during therapy, whereas bound leptin levels decreased after 3 months of therapy (P < 0.005) and re-increased to the baseline levels 3 months after therapy was stopped. Responder but not non-responder had decreased bound leptin levels (P < 0.01) comparing pre- and posttreatment levels. However, no significant correlations were determined between any of the leptin components to virus load, ALT, TNF alpha receptor levels (sTNFR-75, sTNFR-55) and histopathology at any time point. CONCLUSION: Since no correlation was found between the different leptin components and any of the inflammatory markers, the decrease in bound leptin levels during antiviral therapy suggests either a direct interferon-dependent effect on the leptin system or an alteration of other leptin secretagogues.
Adult↗
Low frequency of HLA-DRB1*11 in hepatitis C virus induced end stage liver disease.
Hepatitis C virus (HCV) infection becomes chronic in more than 70% of patients, leading to end stage liver disease in about 20-30% of these patients. Apart from the virus itself, host factors that modulate the immune response are likely to be involved in determining the outcome of HCV infection. Studies on the association of human leucocyte antigens (HLAs) and HCV infection have shown inconsistent results. Selection of patient subgroups may be crucial. However, any association relevant to HCV disease progression will become evident, especially in those patients with end stage liver disease. Therefore, we analysed the phenotype frequencies of HLA antigens in two groups of 69 and 39 patients with HCV induced liver cirrhosis who had received a transplant or were awaiting liver transplantation. The first group was typed serologically and compared with 331 blood and liver donors. The second group, prospectively HLA typed by a polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) procedure for HLA-DRB and DQB alleles, was compared with another 170 PCR-SSO typed and randomly selected blood donors. Decreased frequencies for HLA-DR5 and HLA-DQ3 were found in one group of patients with HCV induced liver cirrhosis compared with the control groups. In the second analysis comparing 39 patients with end stage liver cirrhosis with blood donors, we confirmed the significant decrease in HLA-DRB1*11 and HLA-DQB1*03, which corresponded to serological HLA-DR5 and HLA-DQ3 antigens, respectively. Our results show that the presence of HLA-DRB1*11 and HLA-DQB1*03 alleles is associated with a reduced risk for the development of HCV induced end stage liver disease.
Alleles↗
Autoantibodies in porphyria cutanea tarda: a controlled study.
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Adult↗
Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area.
AIMS/BACKGROUND: This study was undertaken in order to assess the main features of hepatocellular carcinoma in Germany, a country with low incidences of this tumor. METHODS: Two hundred and eighty consecutive patients with hepatocellular carcinomas admitted to the Medical School Hannover between 1993-1997 were retrospectively studied. RESULTS: Reliable data for the assessment of the etiology and the tumor stage of HCC were available for 268 patients. The female/male ratio was 1/4. In 51.9% of the patients, HCC was associated with hepatitis virus B or C (HBV, HCV) infection: 35.1% with HBV, 26.9%) with HCV and 10% coinfection with HBV/HCV This result emphasizes the major impact of HBV and HCV infection in liver cancer in Germany. Of all patients with HCC 74.6%) had liver cirrhosis. The predominant majority of the HCC (87%) were restricted to the liver: in only 5.9% could regional lymph node metastases as well as 8.5%) metastases in other organs be clinically diagnosed by chest X-ray, computed tomography scan or sonography. Data to asses the Okuda tumor stage were available for 166 patients: 47% were classified as stage I, 47% as stage II and only 6% as stage III. Serum AFP were determined in 195 patients. In 66% of the patients, the AFP value was elevated, but only in 30% did the AFP level reach the value of 500 microg/l, which is considered to be significant for HCC diagnosis in patients with liver cirrhosis. The proportion of liver cirrhosis was higher in HCV (97.8%) versus HBV (80.6%) associated HCC, which was the only significant (p<0.05) difference in the characteristics of HCC according to the etiology. CONCLUSION: Our study shows that liver cirrhosis is the prime risk factor for hepatocarcinogenesis in Germany. However, the very high proportion of hepatitis virus related HCC, in particular the high proportion of HBV infections, contradicts the common view that alcohol is by far the most important etiological factor for hepatocarcinogenesis in low hepatitis virus endemic areas such as Germany.
Adult↗
Elevated bound leptin correlates with energy expenditure in cirrhotics.
BACKGROUND & AIMS: Leptin, found to be elevated in patients with liver cirrhosis, may contribute to the inadequate energy expenditure and malnutrition associated with a negative prognosis for these patients. Our aim was to characterize leptin components and their relationships to body composition, resting energy expenditure (REE), and substrate use in patients with posthepatic liver cirrhosis. METHODS: Using specific radioimmunoassays, we measured free leptin and bound leptin in 27 cirrhotics and 27 matched control subjects. In the cirrhotic group, body composition and REE were determined. RESULTS: Free leptin was not different in cirrhotics and control subjects and was related to body mass index (controls: r = 0.34, P < 0.05; cirrhotics: r = 0.55, P < 0.005) and to fat mass (cirrhotics: r = 0.76, P < 0.0001). Bound leptin was significantly higher in cirrhotic subjects than in controls (P < 0.001) and was related to REE x fat-free mass(-1) (r = 0.57, P < 0.005) or to the difference between measured and estimated REE (r = 0.55, P < 0.005). CONCLUSIONS: Free leptin reflects fat mass in controls and cirrhotics. Increased serum leptin in cirrhotics is a result of increased bound leptin serum concentrations, which are positively related to energy expenditure. Moreover, bound leptin may be a useful marker for inadequate energy expenditure in patients with liver cirrhosis.
Adipose Tissue↗
The enhancer I core region contributes to the replication level of hepatitis B virus in vivo and in vitro.
Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. Long-term interaction of the immune system with the virus results in the selection of escape mutants and viral persistence. In this work we characterize mutations in the enhancer I region isolated prior to liver transplantation from the HBV genomes of 10 patients with chronic HBV infection. The HBV-genomes were sequenced, and the enhancer I region was cloned into luciferase reporter constructs to determine the transcriptional activity. Functional studies were performed by transfecting HBV replication-competent plasmids into hepatoma cells. Analyses of the replication fitness of the mutant strains were conducted by biochemical analysis. In all HBV genomes the enhancer I region was mutated. Most of these mutations resulted in decreased transcriptional activity. The strongest effects were detectable in strains with mutations in the hepatocyte nuclear factor 3 and 4 (HNF3 and HNF4) binding sites of the enhancer I core domain. Replication-competent HBV constructs containing these mutations demonstrated up to 10-fold-reduced levels of virus replication. Before liver transplantation, when the mutant strains were detected in the patients' sera, low HBV DNA levels were found. After transplantation and reinfection with a wild-type virus, the levels of replication were up to 240-fold higher. Our results show that mutations in the enhancer I region of HBV have a major impact on HBV replication. These mutations may also determine the switch from high to low levels of viral replication which is frequently observed during chronic HBV infection.
Binding Sites↗
Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a prospective trial.
UNLABELLED: Hepatitis B may take a rapid and aggressive course in patients under immunosuppression. Nucleoside analogues have been shown to suppress viral replication effectively. To investigate the effect of famciclovir in immunosuppressed patients, 21 heart transplant recipients with chronic hepatitis B infection were included in a prospective study. PATIENTS AND METHODS: Patients have been treated with Famciclovir for a median of 14 months. Hepatitis B virus replication and biochemical parameters were regularly tested and liver biopsies were taken before treatment and after a median time of 7 months. HBV-polymerase was sequenced in all patients before therapy and in those patients who experienced virological breakthrough. RESULTS: Nineteen patients were treated for at least 6 months. Hepatitis B virus-DNA levels declined in all patients and became negative in 8 patients. Mean hepatitis B virus-DNA levels decreased from 199+/-269 to 34+/-53 pg/ml after 24 weeks (P=0.003). During treatment HBeAg became negative in five patients. Mean alanine aminotransferase decreased from 42+/-26 to 24+/-10 U/L (P=0.006). Histological analysis revealed improved inflammatory activity according to the Ishak-score in 11/16 (69%) patients. Total inflammatory activity scores decreased from 8 to 6 (median, NS), but interface hepatitis score (P=0.02) and lobular inflammation score (P=0.006) improved significantly. Median fibrosis scores fell from 5 to 3 (P=0.002). Three patients developed virological breakthrough on famciclovir after 7, 8, and 26 months of treatment showing HBV-polymerase amino acid changes L528 M, S567A, and I581K, respectively. CONCLUSIONS: Famciclovir improves not only biochemical and virological features but also hepatic inflammation and liver fibrosis in patients with chronic hepatitis B under heavy immunosuppression. Virological breakthrough may develop and requires close monitoring.
2-Aminopurine↗
Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation.
Famciclovir (FCV) and lamivudine (LAM) reduce viral replication in patients with recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). Eighteen of 20 patients with insufficient response to FCV were treated with 100 mg LAM daily after OLT. These patients had shown nonresponse (n = 5), partial response (n = 7), or breakthrough (n = 6) during FCV therapy. Despite passive immunoprophylaxis with hepatitis B immunoglobulin after liver transplantation, HBV reinfection had occurred in 14 of 15 transplanted patients. HBV-DNA levels and the regions A to E of the HBV-DNA polymerase gene were analyzed before and after treatment failure to either therapy. Within 4 weeks on LAM, all but 1 patient showed a 95% average reduction of the HBV-DNA level. As with FCV, we did not observe any severe side-effects attributable to LAM. However, 7 patients developed a breakthrough within 12, 29 (n = 2), 32, 37, 54, and 145 weeks under treatment with LAM associated with the methionine-to-valine signature mutation (M552V) in the YMDD motif in all. With FCV, no unique, but a dominant, resistance pattern with the L528M mutation was identified for patients with breakthrough under FCV. In contrast, nonresponders or patients with partial response to FCV did not exhibit such mutations. Our results indicate that the L528M mutation is a risk factor for LAM breakthrough, because breakthrough during LAM occurred earlier in patients with this mutation (50 +/- 10 weeks vs. 120 +/- 21 weeks). Because breakthrough on either treatment is frequent for this specific group of patients, the use of combination therapy should be explored.
2-Aminopurine↗
The pre-S region determines the intracellular localization and appearance of hepatitis B virus.
The functional role of the hepatitis B virus (HBV) pre-S region for assembly and appearance of the virus is not completely understood. In this study, 3 natural-occurring mutants were investigated. Three mutants of the pre-S region-a point mutation in the CCAAT box (MUT1), a 6-bp deletion (MUT2) 3' of the CCAAT box, and a 153-bp deletion (MUT3) in the preS2 domain-were cloned alone or in combinations in replication-competent HBV plasmids and transfected in hepatoma cells. The impact on HBV assembly and appearance was studied by Northern Blot, primer extension analysis, immunofluorescence studies, enzyme-linked immunosorbent assay, and electron microscopy. An inversed ratio of pre-S/S mRNA transcripts compared with wild-type (wt) HBV was found when either MUT1 or -2 were included into the plasmid. Intracellular localization with both mutants showed retention of large S-protein in the endoplasmic reticulum and nuclear accumulation of core protein. The extracellular amount of S-protein was reduced with MUT1 and -2 or combinations in which 1 of the mutants was included. However, the extracellular appearance of viral products was comparable with wtHBV. In contrast, MUT3 showed major changes. Virion-like particles had a fried-egg, and filaments a screw-like appearance. The S-promoter mutations MUT1 and MUT2 correlated with viral retention. MUT3 leads to malformed viral particles. Therefore, different regions in the pre-S domain are essential to determine the intracellular localization and extracellular appearance of HBV, and might contribute to the prognosis of chronic HBV infection.
Hepatitis B virus↗
Antibodies against the GB virus C envelope 2 protein before liver transplantation protect against GB virus C de novo infection.
GB virus C (GBV-C) is a newly discovered RNA virus related to the Flaviviridae family. Although GBV-C is not yet associated with any cause of liver disease, a humoral immune response against the GBV-C envelope 2 (E2) protein has been observed. Therefore, we studied the prevalence and clinical relevance of GBV-C RNA and anti-E2 antibodies in patients undergoing orthotopic liver transplantation (OLT). In addition, we tested whether the prevalence of anti-E2 antibodies may protect against GBV-C infection. Of the 182 liver recipients included in this study, 117 of these were evaluated for GBV-C recurrence or de novo infection. GBV-C RNA was detected in sera or plasma using single-tube, reverse-transcriptase polymerase chain reaction, and anti-E2 antibody was detected by enzyme immunoassay (EIA). Cumulative patient and graft survival was tested by using Kaplan-Meier analysis. The independence of prognostic values was assessed by using Cox regression analysis. Before OLT, GBV-C RNA and anti-E2 were detected in 4.0% to 28.6% and 10.0% to 68.8%, respectively, of patients suffering from different forms of chronic liver diseases. GBV-C reinfection after OLT was determined in 85.7%. Of the patients without evidence of exposure to GBV-C before OLT, 30 of 65 (46.2%) became GBV-C RNA positive after OLT. None of the 38 patients who were anti-E2 antibody positive before OLT became GBV-C RNA positive after OLT. Neither patient nor graft survival was significantly affected by the presence of either GBV-C RNA or anti-E2 antibody before OLT. Our data indicate that 1) GBV-C RNA positive patients have a high risk of reinfection after OLT, and 2) the presence of anti-E2 antibodies before OLT is associated with an absence of GBV-C infection after OLT, which may indicate a protective role of anti-E2 antibodies.
Adult↗
GB virus C/hepatitis G virus infection: a favorable prognostic factor in human immunodeficiency virus-infected patients?
To investigate a possible influence of GB virus C (GBV-C) in immunocompromised patients, the prevalences of GBV-C RNA and anti-E2 antibody in 197 human immunodeficiency virus (HIV)-infected patients and in 120 control blood donors were studied. GBV-C RNA was detected in 33 of 197 HIV-infected patients (16.8%) compared with 1 in 120 blood donors (0.8%) (P < .001). Previous exposure to GBV-C (anti-E2 antibody-positive) was shown in 56.8% of HIV patients and in 9% of blood donors. GBV-C viremia was not associated with hepatitis. Despite approximately equal duration of HIV infection in all subgroups, the CD4 cell counts were significantly higher in GBV-C-viremic patients (344 cells/microL) compared with exposed (259 cells/microL) and unexposed (170 cells/microL) patients (P = .017 and P < .001). Furthermore, Kaplan-Meier analysis demonstrated significantly better cumulative survival in GBV-C RNA-positive HIV-infected patients, suggesting that GBV-C might be a favorable prognostic factor in HIV disease.
AIDS-Related Opportunistic Infections↗