Biomedical subjects
Publications and source records attributed to Solko W Schalm.
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OBJECTIVES: Antiviral therapy leads to HBeAg seroconversion in 10-40% of the patients with HBeAg-positive chronic hepatitis B. Nonresponse may result in progression of liver disease and increased risk of hepatocellular carcinoma. As part of a global randomized controlled trial we investigated the efficacy (i.e., loss of HBeAg at the end of follow-up) of peginterferon alfa-2b (Peg-IFN alpha2b) in patients who failed to respond to previous courses of standard interferon (IFN) or lamivudine. METHODS: We analyzed a total of 76 previous nonresponders: 37 were nonresponders to standard IFN, 17 were nonresponders to lamivudine, and 22 were nonresponders to both therapies. All patients received a 52-wks course of 100 microg Peg-IFN alpha2b weekly combined with either 100 mg lamivudine daily or a placebo. After therapy patients were followed for 26 wks. RESULTS: Thirteen (35%) nonresponders to previous IFN, five (29%) nonresponders to previous lamivudine, and four (22%) nonresponders to both IFN and lamivudine responded to treatment with Peg-IFN alpha2b. No difference in response was found for those treated with Peg-IFN alpha2b alone or in combination with lamivudine. Nonresponders to prior IFN therapy with baseline ALT (alanine aminotransferase) > 4 x ULN (upper limit of normal) responded better to Peg-IFN alpha2b than those with ALT levels <or= 4 x ULN (53%vs 20%, respectively, p= 0.036). CONCLUSIONS: Peg-IFN alpha2b is effective in approximately one-third of patients who failed to respond to previous treatment with standard IFN or lamivudine. High serum ALT level at baseline of Peg-IFN alpha2b therapy was the best predictor for response in these patients.
BACKGROUND: We investigated associations between interferon (IFN)-gamma-inducible protein (IP)-10 and liver histological results, viral kinetic response, and treatment outcome in patients infected with hepatitis C virus (HCV) genotypes 1-4. METHODS: Plasma IP-10 was monitored before, during, and after treatment with pegylated IFN- alpha 2a and ribavirin in 265 HCV-infected patients. RESULTS: In univariate analyses, a low baseline IP-10 level was significantly associated with low baseline viral load, rapid viral response (RVR), a sustained viral response (SVR), body mass index <25 kg/m2, and less-pronounced fibrosis, inflammation, and steatosis (for HCV genotypes other than 3). When the results of the univariate analyses were included in multivariate analyses, a low plasma IP-10 level, low baseline viral load, and genotype 2 or 3 infection were independent predictors of an RVR and SVR. IP-10 levels decreased 6 weeks into treatment and remained low in patients with an SVR. By contrast, plasma levels of IP-10 rebounded in patients who had detectable HCV RNA after the completion of treatment. Using cutoff IP-10 levels of 150 and 600 pg/mL for predicting an SVR in patients infected with HCV genotype 1 yielded a specificity and sensitivity of 81% and 95%, respectively. CONCLUSION: Baseline IP-10 levels are predictive of the response to HCV treatment.
BACKGROUND AND AIMS: The therapeutic potential of ursodeoxycholic acid (UDCA) treatment in primary biliary cirrhosis (PBC) remains controversial. In addition, relatively few data have been reported on the outcome of patients who have been treated long term. The aim of the present study was to document long-term survival of a prospectively followed large cohort of UDCA treated patients in comparison to that predicted by the Mayo model and of a matched control cohort of the Dutch population. METHODS: Two hundred ninety-seven patients were included and followed during a median period of 68 (range 3-126) months until death or the end of the study. RESULTS: Survival free of transplantation (1 yr 99.7%, 5 yr 87%, and 10 yr 71%) was significantly better than predicted by the Mayo model (p= 0.01). However, for patients with abnormal serum bilirubin and/or albumin concentrations at entry, observed and predicted survival did not significantly differ. Compared with survival for a standardized cohort of the Dutch population, observed survival for the total group was significantly decreased (p= 0.0003); for noncirrhotic patients and patients with normal entry bilirubin and albumin concentrations survival was comparable. Serum bilirubin and albumin concentrations were the prognostic factors most consistently associated with survival. CONCLUSIONS: A 10-year prognosis for most UDCA-treated patients with PBC, i.e., those with a normal bilirubin and albumin concentration, is comparable to that of a matched general population. Our finding that observed survival was significantly better than predicted by the Mayo model may suggest that this model did not accurately predict prognosis in our cohort. Alternatively, this finding indicates an important therapeutic effect of long-term UDCA treatment in PBC, particularly in patients with noncirrhotic, nonadvanced disease.
BACKGROUND/AIMS: Phase I/II studies of 4 weeks duration have confirmed the ALT lowering effect of glycyrrhizin in Western chronic hepatitis C patients. Our aim was to determine the dose frequency of glycyrrhizin required to maintain the ALT response beyond 4 weeks and evaluate its effect on liver histology and quality of life. METHODS: HCV-RNA-positive patients with elevated ALT and marked fibrosis or necro-inflammation who were not eligible for interferon therapy were treated for 4 weeks with six infusions weekly of glycyrrhizin. Patients with an ALT response at week 4 were randomized to continue treatment for 22 weeks in three dose frequency groups: 6x, 3x or once weekly. RESULTS: 72/121 (60%) patients were randomized. At the end of treatment the ALT response was maintained in 60%, 24% and 9% of patients in the 6x, 3x, and once weekly groups, respectively (p<0.001). In ALT responders the necro-inflammation score improved non-significantly compared to ALT non-responders. Quality of life assessed by SF-36 increased in patients treated with the study drug, albeit unrelated to the occurrence of ALT response. CONCLUSIONS: ALT responses induced by 4 weeks glycyrrhizin therapy can be maintained in a subset of chronic hepatitis C patients receiving at least three injections weekly. The observed ALT response did not translate in a significant histological improvement after 6 months treatment.
BACKGROUND/AIMS: Characteristics of the intrahepatic virus-specific T-cell response in patients with acute hepatitis B virus (HBV) infection have not been studied due to the risk of complications associated with standard liver biopsies. In this study we aimed to characterize the virus-specific CD8 + T-cell response in the liver of patients with acute HBV infection using fine-needle aspiration-biopsy (FNAB). METHODS: In HLA-A2 positive patients with acute HBV infection a FNAB was performed at first presentation, at the time of HBsAg-seroconversion and 3 months after HBsAg-seroconversion. HLA-A2 tetramers were used to identify HBV-specific CD8 + T-cells in FNAB-cytology and peripheral blood (PB). RESULTS: At first presentation there was a correlation between the frequency of intrahepatic CD8 + T-cells and the degree of liver damage. At all time points there was sequestering of HBV-specific CD8 + T-cells in the liver, and the percentage of intrahepatic HLA-DR expressing HBV-specific CD8 + T-cells was higher than in PB. Three months after HBsAg-seroconversion the frequency of intrahepatic HBV-specific CD8 + T-cells remained high. CONCLUSIONS: HBV-specific CD8 + T-cells are compartmentalized in the liver during acute HBV infection. Their presence in the liver may suggest a role in the resolution of the infection. Intrahepatic HBV-specific CD8 + T cells remain detectable at high frequencies after HBsAg-seroconversion.
BACKGROUND/AIMS: To determine the response to pegylated interferon-alpha treatment of HBeAg-positive hepatitis B patients with proven lamivudine resistance. METHODS: Sixteen HBeAg-positive HBV patients with YMDD mutations were treated with pegylated interferon. Median treatment duration was 52 weeks (range 20-53), with a 26-week follow-up. RESULTS: Two of 16 (12.5%) patients seroconverted to HBeAg negative and achieved sustained virological (HBV-DNA levels below 10log 5 copies/ml) together with biochemical (normalization of serum ALT levels) responses. Compared with the strong signal in all other patients, only these two patients had a faint signal in the lamivudine resistance assay. For all patients, the median viral load decreased from 10log 9.4 to 7.9 copies/ml (P = 0.001) during treatment but rebounded to a median of 10log 8.7 copies/ml after treatment cessation. Similarly, elevated median ALT levels at baseline decreased with treatment but rebounded after the end of treatment. CONCLUSIONS: In the largest cohort study to date, pegylated interferon-alpha therapy showed marginal efficacy in the presence of lamivudine resistance but such therapy may be beneficial in patients with only small amounts of mutant virus. In our opinion, an analysis of the patient subgroup harbouring an YMDD-mutation should be included in all future studies of pegylated interferon-alpha in chronic hepatitis B.
In chronic hepatitis B, it is difficult to predict an early therapeutic response. We investigated the viral decline during therapy with pegylated interferon alpha-2b (PEG-IFN) with or without lamivudine in 266 HBeAg-positive chronic hepatitis B patients. In patients treated with PEG-IFN and lamivudine, a uniform biphasic viral decline pattern was found during therapy and there were no marked differences in viral load between those who lost HBeAg at the end of follow-up (response) or not. In contrast, those treated with PEG-IFN monotherapy exhibited different viral decline patterns. A delayed decline of at least two log from baseline HBV DNA after week 4 but before week 32 was associated with the highest response rate (63%). In comparison, response was 52% for patients with an early decline (week 0-4), 38% for a late decline (week 32-52), 27% for a posttreatment decline (week 52-78) and 11% for patients with no substantial decline. The HBsAg loss was 22% in the delayed decline pattern compared to 4% for those with early decline and none for other decline patterns. In conclusion, different patterns of decline in viral load during treatment with PEG-IFN monotherapy were associated with different rates of HBeAg and HBsAg loss at the end of follow-up. Since there was a considerable response, even in patients with a late or posttreatment decline pattern, prediction of response based on viral decline during the first months of therapy was difficult.
Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP-10 levels prior to treatment with pegylated interferon-alpha-2a and ribavirin. Significantly lower IP-10 levels were observed in patients achieving a rapid viral response (RVR) (P < .0001), even in those with body mass index (BMI) > or = 25 kg/m2 (P = .004) and with baseline viral load > or = 2 million IU/mL (P = .001). Similarly, significantly lower IP-10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P < .05), higher viral load (P = .0005), and both higher BMI and viral load (P < .03). In multivariate logistic regression analyses, a low IP-10 value was independently predictive of both RVR and SVR. A baseline cutoff IP-10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1-infected patients, which was comparable with that observed using a reduction in HCV-RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut-off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP-10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP-10 level is low. Thus, pretreatment IP-10 analysis may prove helpful in decision-making regarding pharmaceutical intervention.
OBJECTIVE: Patients with chronic hepatitis C who do not respond to interferon can be treated with glycyrrhizin to reduce disease activity. The objective of this study was to evaluate the effect of glycyrrhizin on the incidence of hepatocellular carcinoma (HCC) during long-term follow-up after non-response to interferon. MATERIAL AND METHODS: We analyzed individual patient data of all consecutive patients treated with interferon in 12 major Japanese hospitals between 1990 and 1995 who showed no sustained response. RESULTS: The study comprised 1093 patients. During a mean follow-up of 6.1 +/- 1.8 years, 107 patients developed HCC. The Cox regression analysis with time-dependent variables showed that older age, male gender, higher alanine aminotransferase (ALAT) and higher fibrosis stage were significantly associated with a higher risk of developing HCC. Response to glycyrrhizin, defined as ALAT < 1.5 x upper limit of normal, was significantly associated with a decreased incidence of HCC: hazard ratio 0.39 (95% CI 0.21-0.72; p < 0.01). G-estimation, used to correct for ALAT as the confounder, showed no significant benefit of glycyrrhizin in the overall study population. CONCLUSIONS: This study provides some evidence to show that interferon non-responder patients with chronic hepatitis C and fibrosis stage 3 or 4 may have a reduced incidence of HCC if glycyrrhizin therapy leads to normalization of ALAT levels.
BACKGROUND: The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double-blinded, randomized, multi-center study we assessed histological changes in 110 hepatitis B e-antigen (HBeAg)-positive CHB patients treated for 52 weeks with Pegylated interferon alpha-2b (PEG-IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system. RESULTS: Necroinflammatory score improved (defined as a decrease of at least two points) in 25 patients (48%) of the PEG-IFN/lamivudine combination therapy group and in 31 patients (53%) of the PEG-IFN monotherapy group. The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combination therapy group vs. 13 patients (22%) of the PEG-IFN monotherapy group (P=0.23). Responders (n=42), defined as serum HBeAg negative at the end of therapy, showed a larger decline in necroinflammatory score than non-responders (mean decline 2.3 and 1.2 points, respectively, P=0.02). Among patients receiving PEG-IFN monotherapy necroinflammation improved more frequently in responders (78% of responders vs. 43% of non-responders, P=0.01) and in patients who showed normalization of ALT (76% of patients with normal ALT vs. 40% of patients with abnormal ALT, P=0.01). Fibrosis score in the PEG-IFN monotherapy group improved more often in responders (39%) than in non-responders (15%, P=0.04). In the PEG-IFN/lamivudine combination therapy group, we found no significant association between virological and biochemical endpoints and histological improvement. CONCLUSIONS: Treatment with PEG-IFN therapy improves liver necroinflammation in HBeAg-positive CHB patients, particularly in responders to therapy. PEG-IFN also improves fibrosis in responders. Addition of lamivudine to PEG-IFN did not further improve the histological outcome.
BACKGROUND AND AIMS: Hepatitis B surface antigen (HBsAg) loss is the hallmark of a complete response to antiviral therapy for chronic hepatitis B. In this study, we investigated the frequency of HBsAg loss after treatment with pegylated (Peg)-interferon alpha-2b. METHODS: In a multicenter randomized controlled trial, 266 HBeAg-positive patients were treated for 52 wks with Peg-interferon alpha-2b (100 microg/wk) in combination with either lamivudine (100 mg/day) or placebo. Posttreatment follow-up was 26 wks. RESULTS: At the end of follow-up, 95 (36%) of the 266 patients exhibited HBeAg loss, 18 (7%) HBsAg loss, and 16 (6%) HBsAg seroconversion. Addition of lamivudine did not enhance HBeAg loss, HBsAg loss, or development of anti-HBs. All 18 patients who showed HBsAg loss had normal ALT; 11 (61%) of these patients were also hepatitis B virus (HBV) DNA negative (<400 copies/mL) at the end of follow-up. Loss of HBsAg differed according to HBV genotype: 14% for genotype A, 9% for genotype B, 3% for genotype C, and 2% for genotype D (A vs D: p = 0.006). CONCLUSIONS: One year of Peg-interferon alpha-2b for HBeAg-positive patients led to HBsAg loss in 7%. Our study indicates that treatment with Peg-interferon alpha-2b is the best therapy to achieve HBsAg clearance in patients with genotype A.
BACKGROUND/AIMS: To determine which immune cells contribute to HBV-clearance during antiviral therapy, we performed a longitudinal analysis of intrahepatic immune cells during interferon-alpha therapy of chronic HBV-patients using the FNAB technique. METHODS: Twenty chronic HBeAg+-patients were treated with pegylated alpha-interferon combined with lamivudine or placebo for 52 weeks. FNAB and blood specimens were obtained at week 0, 2, 8 and 52. CD4+- and CD8+ T-lymphocytes, CD56+ cells, IFNgamma and granzyme B (GrB) were immunocytochemically quantified. RESULTS: The relative numbers of CD56+ cells and CD8+ T-lymphocytes were significantly higher in FNAB compared to blood at all time-points. Responders (n=9) exhibited significant increases in intrahepatic CD8+ and CD8+GrB+ lymphocytes, a small elevation in CD8+IFNgamma+ T-lymphocytes, no change in CD4+ T-lymphocytes, and a decrease in intrahepatic CD56+ cells during the first weeks of therapy. In non-responders (n=11) no significant changes in CD4+- and CD8+ T-lymphocytes and an increase in intrahepatic and CD56+ cells were observed during therapy. CONCLUSIONS: The intrahepatic CD8+ T-lymphocyte, but not the CD4+ T-lymphocyte or NK/NKT-cell response, is important for HBV clearance during interferon-alpha therapy, and the antiviral effect may be mediated by both cytolytic and non-cytolytic mechanisms.
Between 1986 and 1990 we performed heterotopic liver transplantation (HLT) in 17 patients with chronic liver disease. In spite of theoretical advantages and favorable short-term results, we abandoned HLT because of doubts about the long-term outcome and the improved results of standard orthotopic liver transplantation (OLT). There are, however, no studies comparing the long-term survival after HLT and OLT for chronic liver disease. We performed a case-control study of HLT vs. OLT, with long-term patient and graft survival as the main outcome measures. Known confounders and differences in baseline characteristics between HLT and OLT patients were corrected for. At 1 year, 5 of the 17 HLT patients had died, compared with 9 of the 34 OLT patients (relative risk [RR], 1.15; 95% confidence interval [CI], 0.33-4.02; P = 0.83). After correction for confounders, the long-term risk of graft failure (RR, 18.0; 95% CI, 1.5-223.5; P = 0.02) and of death (RR, 5.2; 95% CI, 0.8-34.8; P = 0.09) was higher after HLT than after OLT. The main causes of graft loss and death at more than 1 year after HLT were de novo malignancies and a variety of biliary complications. In conclusion, our data, from 1 of the largest single-center series of HLTs available, showed no significant difference between HLT and OLT in 1-year survival. However, the long-term outcome of HLT was inferior. HLT cannot be recommended as an alternative to OLT for any of the indications we studied, even though only 1 of the late deaths was definitely related to the heterotopic technique.
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BACKGROUND/AIMS: The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. METHODS: Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C (n=270) treated with peginterferon alfa-2a (180 microg/week) and ribavirin (1000-1200 mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1 mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360 microg/week) plus ribavirin for NUR patients. RESULTS: Patients were categorized as RVR (n=171), SPR (n=65), FPR (n=10), or NUR (n=22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. CONCLUSIONS: An improvement in virologic efficacy was not achieved with the available individualized treatment options.
OBJECTIVES: Despite an abundance of epidemiological evidence for horizontal transmission of hepatitis B virus (HBV), the transmission route remains to be fully elucidated. In a new approach, we evaluated quantitative HBV DNA content in serum, saliva and urine as a first step in exploring possible modes of horizontal transmission. METHODS: In an outpatient setting of an academic hospital, paired serum, saliva and urine samples were collected from 150 chronically infected HBV patients. A validated HBV DNA TaqMan assay was used to quantitatively measure HBV DNA. RESULTS: Mean log HBV DNA in serum was 5.8 (range, undetectable to 10.0 log HBV DNA) copies/ml, 50% of the patients had an HBV DNA above 10 copies/ml in serum. Mean log HBV DNA level in saliva was 3.2 (range, undetectable to 7.5) copies/ml, 15% had an HBV DNA above 10 copies/ml in saliva. Mean log HBV DNA level in urine was 2.6 (range, undetectable to 5.4) copies/ml and 1% had an HBV DNA above 10 copies/ml in urine. A high, non-linear correlation was shown between HBV DNA in serum and saliva (Spearman's rho 0.82) and between serum and urine (Spearman's rho 0.74). CONCLUSIONS: The significant amounts of HBV DNA found in saliva and urine in chronic HBV patients with high viraemia in serum may have implications for the understanding of hepatitis B epidemiology. The potential infectivity of these body fluids may provide an explanation for the 20% of cases of infection obtained through horizontal transmission for which the origin of infection is yet unknown.
The current opinion is that liver transplantation for chronic cholestatic liver disease should be done before the terminal, high-risk stage. However, most studies do not take waiting list mortality into account. We analysed 113 consecutive patients with chronic cholestatic liver disease, stratified according to estimated survival. Overall and post-transplantation survival was calculated using the Kaplan-Meier method. Including patients who died awaiting transplantation lowered the 1-year survival by 19% in the high-risk category. In this group survival at 4 years was 45%, with an estimated survival benefit of 45%. For the intermediate- and low-risk groups these numbers were 56% and 36% vs. 81% and 7%. Including the waiting list period in the analysis of the benefits of liver transplantation strengthens the case for early transplantation. Our study confirms that liver transplantation should be considered before the high-risk stage of chronic cholestatic liver disease is reached.