Hepatitis: Brouwer JT

de Bruijne J, Buster EH, Gelderblom HC, Brouwer JT, de Knegt RJ, van Erpecum KJ, Schalm SW, Bakker CM, Zaaijer HL, Janssen HL, Reesink HW, Anonymous00041. · Department of Gastroenterology and Hepatology, Academic Medical Centre Amsterdam, the Netherlands. · Neth J Med. · Pubmed #18663263 links to  free full text

Abstract: The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.

Buster EH, van Erpecum KJ, Schalm SW, Zaaijer HL, Brouwer JT, Gelderblom HC, de Knegt RJ, Minke Bakker C, Reesink HW, Janssen HL, Anonymous00062. · Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, the Netherlands. · Neth J Med. · Pubmed #18663260 links to  free full text

Abstract: The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.

Schalm SW, Brouwer JT, Bekkering FC, van Rossum TG. · Department of Hepatology & Gastroenterology, Erasmus Medical Center Rotterdam, The Netherlands. · J Hepatol. · Pubmed #10622584 No free full text.

Abstract: There is solid evidence that retreatment of non-responders with standard regimens of interferon monotherapy is of no clinical value. On the other hand, combination therapy with interferon and ribavirin now produces sustained response rates in non-responders similar to those of interferon monotherapy in untreated patients. Consequently, retreatment of non-responders with the combination of interferon-ribavirin appears to be a valid treatment option. The efficacy of retreatment with the interferon-ribavirin combination can probably be increased by modifying the first weeks of interferon therapy from standard (3 MU tiw) to induction (10 MU daily), and by extending the treatment period to 12 months. In the next few years, the additive value of amantadine to interferon or to interferon-ribavirin combination in inducing sustained viral clearance should be explored. For the many patients who still do not respond with viral clearance despite these new approaches, the goal of therapy might be shifted towards persistent ALT normalization in order to reduce the progression of liver disease. Drugs that can normalize serum ALT such as interferon, ursodeoxycholic acid, ribavirin and glycyrrhizin should be evaluated for this objective.

Orlent H, Hansen BE, Willems M, Brouwer JT, Huber R, Kullak-Ublick GA, Gerken G, Zeuzem S, Nevens F, Tielemans WC, Zondervan PE, Lagging M, Westin J, Schalm SW. · Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands. · J Hepatol. · Pubmed #16905220 No free full text.

Abstract: 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.

Brouwer JT, Nevens F, Bekkering FC, Bourgeois N, Van Vlierberghe H, Weegink CJ, Lefebvre V, Van Hattum J, Henrion J, Delwaide J, Hansen BE, Schalm SW, For The Benelux Study Group On Treatment Of Chronic Hepatitis C. · Department of Hepatogastroenterology, Erasmus Medical Center, Rotterdam, The Netherlands. · J Hepatol. · Pubmed #15030987 No free full text.

Abstract: BACKGROUND/AIMS: Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months. METHODS: Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05). CONCLUSIONS: Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months.

Veldt BJ, Brouwer JT, Adler M, Nevens F, Michielsen P, Delwaide J, Hansen BE, Schalm SW, Anonymous00368. · Department of Gastroenterology of the Erasmus Medical Center Rotterdam, The Netherlands. · BMC Gastroenterol. · Pubmed #12948399 links to  free full text

Abstract: BACKGROUND: Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared to placebo therapy and to ribavirin monotherapy, which has not been published until now. METHODS: One hundred and twenty one patients with chronic hepatitis C and elevated transaminases who did not respond to previous treatment with standard interferon monotherapy, were included from 16 centers in Belgium, the Netherlands and Luxembourg between 1992 and 1996. Patient poor-response characteristics were: genotype 1 (69%), HCV RNA above 2 x 10(6) copies/ml (55%) and cirrhosis (38%). Patients were randomized to 6 months combination therapy with interferon alpha-2b (3 MU tiw) and ribavirin (1000-1200 mg/day), 6 months ribavirin monotherapy (1000-1200 mg/day) or 6 months ribavirin placebo. The study was double blinded for the ribavirin/placebo component. One patient did not fit the entry criteria, and 3 did not start. All 117 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 35% of patients on combination therapy and in none of the patients treated with ribavirin monotherapy or placebo. The sustained virological response rate at 6 months after therapy was 15% for patients treated with interferon and ribavirin.During the 6 months treatment period 13% of patients on interferon ribavirin combination therapy, 13% of patients on ribavirin monotherapy and 11% of patients on placebo withdrew due to side effects or noncompliance. At 24 weeks of treatment the mean Hb level was 85% of the baseline value, which means a mean decrease from 9.1 mmol/l to 7.8 mmol/l. The Hb levels at the end of treatment were not significantly different from patients treated with ribavirin monotherapy (p = 0.76). End of treatment WBC was significantly lower in patients treated with combination therapy, compared to ribavirin (p < 0.01) as well as for patients treated with ribavirin monotherapy compared to placebo (p < 0.01). DISCUSSION: This belated report on the only placebo controlled study of interferon ribavirin combination therapy in non responders to standard doses of interferon monotherapy documents the effectiveness, be it limited, of this approach as well as the dynamics of the effects on blood counts.

Bekkering FC, Brouwer JT, Hansen BE, Schalm SW. · Department of Hepatogastroenterology, Erasmus University Hospital Rotterdam, The Netherlands. · J Hepatol. · Pubmed #11322206 No free full text.

Abstract: BACKGROUND/AIMS: Hepatitis C viral (HCV) kinetic studies have demonstrated the increased antiviral effect of higher than standard dosages of interferon and of daily treatment schedules. Since interferon has a short half-life, twice-daily administration of interferon may be even more effective. METHODS: We evaluated the HCV kinetics in daily vs. twice-daily high dose interferon (IFN) therapy in combination with ribavirin in 24 difficult to treat patients. Patients were randomised to 10 MU IFN daily or 5 MU twice-daily for 4 weeks. RESULTS: Interferon efficacy (epsilon) was similar and very high for both groups (range 99.83-99.97%). Clearance of infected cells (beta phase) tended to be slightly faster for patients on 5 MU bd (T1/2 70 vs. 90 h, ns). Clearance of infected cells was strongly related to initial viral load (T1/2 103 vs. 53 h, P = 0.002, for above versus below 2 x 10(6) copies/ml). In this study an additional phase with a temporary rise in viral load was observed between the alpha and the beta phase. CONCLUSION: Daily high induction dose is associated with nearly complete inhibition of viral replication even in difficult to treat patients. A twice-daily schedule did not lead to further improvement. Clearance rate of infected cells was significantly correlated with initial viral load.

Depraetere S, Van Kerschaever E, Van Vlierberghe H, Elewaut A, Brouwer JT, Niesters HG, Schalm SW, Maertens G, Leroux-Roels G. · Center for Vaccinology, University of Ghent, University Hospital, Ghent, Belgium. · J Med Virol. · Pubmed #10596010 No free full text.

Abstract: Interferon (IFN) alfa has been used widely for the treatment of chronic hepatitis C virus (HCV) infections but only a small number of patients treated have shown a sustained biochemical and virological response. Anti-envelope E1 and E2 antibody titers were assessed retrospectively before, during, and after treatment with IFN in order to evaluate their usefulness for the prediction and monitoring of therapy outcome in 115 patients infected chronically with HCV genotype 1b. At baseline, E2 induced more frequent and stronger immunogenic responses than E1, irrespective of patient response to therapy. E1 and E2 antibodies also tended to be higher in patients with a long-term or a transient response to IFN treatment than in patients who were absolute non-responders. In most patients, E1 and E2 antibody levels tended to be lower after treatment. This reduction was most pronounced and occurred most frequently in long-term responders to therapy. In this patient group, the reduction of E1 antibodies was more pronounced than that of E2 antibodies. In contrast to E2 antibodies, the decrease of E1 antibodies could already be observed at the end of therapy (week 24) and was significantly larger (p<0.05) than that observed in relapsers and non-responders. Thus, a sustained elevation of E1 antibodies seems to be associated with ongoing infection even when HCV RNA levels were undetectable in serum. Monitoring of E1 antibody titers may represent a useful additional marker to discriminate sustained responders from those who relapse in patients receiving interferon therapy.

van Rossum TG, Vulto AG, Hop WC, Brouwer JT, Niesters HG, Schalm SW. · Department of Hepatogastroenterology, Erasmus Medical Center, Rotterdam, The Netherlands. · J Gastroenterol Hepatol. · Pubmed #10574137 No free full text.

Abstract: BACKGROUND: In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C and reportedly reduces the progression of liver disease to hepatocellular carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on serum alanine aminotransferase (ALT), hepatitis C virus (HCV)-RNA and its safety in European patients. METHODS: Fifty-seven patients with chronic hepatitis C, non-responders or unlikely to respond (genotype 1/cirrhosis) to interferon therapy, were randomized to one of the four dose groups: 240, 160 or 80 mg glycyrrhizin or placebo (0 mg glycyrrhizin). Medication was administered intravenously thrice weekly for 4 weeks; follow up also lasted for 4 weeks. RESULTS: Within 2 days of start of therapy, serum ALT had dropped 15% below baseline in the three dosage groups (P < 0.02). The mean ALT decrease at the end of active treatment was 26%, significantly higher than the placebo group (6%). A clear dose-response effect was not observed (29, 26, 23% ALT decrease for 240, 160 and 80 mg, respectively). Normalization of ALT at the end of treatment occurred in 10% (four of 41). The effect on ALT disappeared after cessation of therapy. During treatment, viral clearance was not observed: the mean decrease in plasma HCV-RNA after active treatment was 4.1 x 10(6) genome equivalents/mL (95% confidence interval, 0-8.2 x 10(6); P > 0.1). No major side-effects were noted. None of the patients withdrew from the study because of intolerance. CONCLUSIONS: Glycyrrhizin up to 240 mg, thrice weekly, lowers serum ALT during treatment, but has no effect on HCV-RNA levels. The drug appears to be safe and is well tolerated. In view of the reported long-term effect of glycyrrhizin, further controlled investigation of the Japanese mode of administration (six times weekly) for induction appears of interest.

Schalm SW, Weiland O, Hansen BE, Milella M, Lai MY, Hollander A, Michielsen PP, Bellobuono A, Chemello L, Pastore G, Chen DS, Brouwer JT. · Department of Hepatogastroenterology and Biostatistics, Erasmus University Hospital Rotterdam, Rotterdam, The Netherlands. · Gastroenterology. · Pubmed #10419923 No free full text.

Abstract: BACKGROUND & AIMS: The aim of this study was to compare interferon (IFN)-ribavirin combination therapy with IFN monotherapy in chronic hepatitis C with particular focus on its efficacy in cirrhosis. METHODS: A multivariate analysis of individual patient data of all randomized controlled trials using an IFN-ribavirin arm, reported between 1991 and March 1998, was performed. Centers included 1 Asian and 5 European university-based referral centers for liver disease. A total of 197 patients with chronic hepatitis C received IFN-alpha (3 MU three times weekly) and ribavirin (1-1.2 g daily) for 6 months, and 147 patients received IFN-alpha (3 MU three times weekly) for 6 months. Patients were characterized according to previous IFN therapy, presence of cirrhosis, and genotype 1. Efficacy of therapy was evaluated by assessing the sustained response rate by logistic regression analysis. RESULTS: Patients without cirrhosis treated with IFN-ribavirin had a significantly higher sustained response rate than those treated with IFN, approximately 3-fold for previously untreated patients (IFN-ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis, sustained response rates with IFN-ribavirin (previously untreated: genotype 1, 7%; genotype 2/3, 24%) were also significantly higher than those with IFN (previously untreated: genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority of combination therapy over IFN monotherapy was also observed for relapse; the same trend was observed for nonresponders. Tolerance for IFN-ribavirin was similar for patients with or without cirrhosis. CONCLUSIONS: Combination with ribavirin significantly enhances the sustained response rate of IFN therapy in major patient types (cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN-ribavirin combination is likely to become the antiviral therapy of choice for cirrhosis caused by hepatitis C.

Brouwer JT, Hansen BE, Niesters HG, Schalm SW. · Department of Hepatogastroenterology, Erasmus University Hospital - Dijkzigt, Rotterdam, The Netherlands. · J Hepatol. · Pubmed #10068095 No free full text.

Abstract: BACKGROUND/AIMS: There is consensus that interferon for hepatitis C should be stopped if alanine aminotransferase (ALT) remains elevated after 12 weeks; however, this may lead to unjust treatment withdrawal in around 20% of potential sustained responders. No consensus exists for interferon-ribavirin combination therapy. The aim of this study was to assess the predictive value of an HCV RNA test at 4 weeks in comparison with ALT, both in interferon monotherapy and in interferon-ribavirin combination therapy. METHODS: Plasma HCV RNA was tested at 4 weeks in 149 naive patients undergoing 6 months and 187 undergoing up to 12 months of interferon monotherapy, and in 40 non-responders treated for 6 months with interferon-ribavirin combination therapy. RESULTS: For 6 and up to 12 months of interferon monotherapy, the predictive value for non-response was 99% resp. 97% for a positive HCV RNA at week 4, versus 97% resp. 91% for an elevated ALT at week 12. Using a positive HCV RNA at week 4 as a stopping rule would lead to missing 5% resp. 12% of potential sustained responders, versus 10% resp. 28% for an elevated ALT at week 12. In interferon-ribavirin combination therapy, the predictive value for non-response was 100% for week 4 HCV RNA versus 95% for week 12 ALT, and 0% potential sustained responders were missed by a test for week 4 HCV RNA versus 20% for week 12 ALT. The overall sensitivity and specificity of a week 4 HCV RNA test was significantly better (area under ROC 0.85) as compared to testing ALT at week 4 (0.78, p<0.001), week 8 (0.76, p<0.001) or week 12 (0.78, p<0.001). CONCLUSION: A positive HCV RNA test (> or =10(3) copies/ ml) at 4 weeks is highly predictive for non-response and leads to significantly less misidentification of potential sustained responders than ALT at week 4, 8 or 12, both in 6 or up to 12 months interferon monotherapy and in 6 months interferon-ribavirin combination therapy of chronic hepatitis C.

Ahmed AI, Vreede RW, Al-Saudi N, Herremans M, Brouwer JT. · Afd. Inwendige Geneeskunde, subafd. Maag-, Darm- en Leverziekten, Reinier de Graaf Gasthuis, Delft. · Ned Tijdschr Geneeskd. · Pubmed #19137970 No free full text.

Abstract: A 55-year-old man was admitted to our hospital because of malaise, jaundice en cholestatic liver function impairment, 4 days after his return from vacation in Surinam. Serological tests were positive for IgG and IgM antibodies to hepatitis E virus (HEV) and serum PCR was positive, consistent with HEV infection. The infection was acquired in the Netherlands and not abroad, considering the incubation period. The patient recovered spontaneously. HEV infection is rare in the Netherlands and is associated with travel to tropical or subtropical areas. The virus is transmitted by the faecal-oral route through contaminated water or food. Since 2000 there have been cases reported in the Netherlands, without any association with travelling abroad and in which the infection might be related to zoonotic transmission. The diagnosis is primarily based upon serologic tests for the detection of IgM and IgG antibodies to HEV in serum confirmed by immunoblot. It is important that HEV infection is considered in patients with acute hepatitis in whom no other cause can be found for hepatitis, even without any travel history to endemic areas.

Bergmann JF, Vrolijk JM, van der Schaar P, Vroom B, van Hoek B, van der Sluys Veer A, de Vries RA, Verhey E, Hansen BE, Brouwer JT, Janssen HL, Schalm SW, de Knegt RJ. · Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Liver Int. · Pubmed #17919233 No free full text.

Abstract: BACKGROUND: High-dose peginterferon-alpha (PegIFN-alpha) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-alpha may intensify side effects. METHODS: We randomized 53 patients, who previously failed with standard IFN-alpha+/-ribavirin, to a high-dose induction and an extended regimen with PegIFN-alpha-2b [3.0 microg/kg once weekly (q.w.) 12 weeks-->2.0 microg/kg q.w. 12 weeks-->1.5 microg/kg q.w. 48 weeks] or a standard regimen (1.5 microg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). RESULTS: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P=0.01] and gamma-glutamyltransferase (GGT) levels <2 x ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 x ULN (OR: 7.3, 95% CI: 1.4-38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P<0.001) were independently predictive for SVR. CONCLUSION: Retreatment with PegIFN-alpha-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome.

Orlent H, Mathot RA, Van Bommel EF, Vulto AG, Schalm SW, Brouwer JT. · Department of Gastroenterology and Hepatology, Sint Jan Hospital, Brugge, Belgium. · Dig Dis Sci. · Pubmed #16187177 No free full text.

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Vrolijk JM, Tang TJ, Kwekkeboom J, Haagmans BL, Herscheid AJ, Kusters JG, Janssen HL, Brouwer JT, Schalm SW. · Department of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands. · J Viral Hepat. · Pubmed #15230857 No free full text.

Abstract: Infection of the liver with hepatitis C virus (HCV) causes compartmentalization of CD8+ cytotoxic T cells to the site of disease. These cells are thought to be involved in viral clearance during interferon therapy. The repetitive analysis of the intrahepatic immune response is hampered by the difficulty to obtain the intrahepatic T cells. The fine-needle aspiration biopsy (FNAB) technique was evaluated for its use to obtain liver-derived CD8+ T cells in a minimally invasive way. In 26 chronic HCV patients who were evaluated for Peg-interferon and ribavirin combination therapy, pre-treatment FNABs and peripheral blood specimens were obtained simultaneously with liver tissue biopsies, and CD3+ and CD8+ T cells were quantified by immunocytochemistry. The CD8+/CD3+ ratio was significantly higher in the FNABs than in peripheral blood (P < 0.01), and similar to those in portal areas in the tissue biopsies. A significant correlation was observed between numbers of CD3+CD8+ T lymphocytes in the FNABs and the numbers of CD8+ cells in the lobular fields or in the portal tracts of the liver tissue biopsies, but not with CD3+CD8+ T lymphocytes in peripheral blood. Finally, the ratio of CD8+/CD3+ T lymphocytes in FNABs was significantly higher in those patients who responded rapidly to therapy when compared with slow responders at 4 weeks of treatment (P = 0.02). These findings demonstrate that the intrahepatic T-cell composition is reflected in FNABs, and that the FNAB technique can be used for predicting early virological response to therapy of patients chronically infected with HCV.

Willems M, Munte K, Vrolijk JM, Den Hollander JC, Böhm M, Kemmeren MH, De Man RA, Brouwer JT. · Department of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. · Br J Dermatol. · Pubmed #12932249 No free full text.

Abstract: Many types of skin disorders concomitantly occur with hepatitis C virus infection. These skin lesions may be induced or worsened during antiviral therapy with interferon-alpha (IFN). To our knowledge, hyperpigmentation of the skin--and especially of the tongue--has not been reported so far. We describe two dark-skinned patients who developed hyperpigmented skin and tongue lesions during combination therapy with IFN and ribavirin. Immunohistochemical analysis of tongue biopsies confirmed the suspicion of melanin deposits in these areas of hyperpigmentation. We hypothesize that during interferon therapy, melanocytes may produce more melanin pigment in the presence of alpha-melanocyte stimulating hormone and sufficient amounts of tyrosine, leading to melanin deposits and clinical hyperpigmentation.

Vrolijk JM, Bekkering FC, Brouwer JT, Hansen BE, Schalm SW. · Dept of Hepatology & Gastroenterology, Erasmus MC/University Medical Centre Rotterdam, 3000 CA Rotterdam, the Netherlands. · J Viral Hepat. · Pubmed #12753339 No free full text.

Abstract: Chronic hepatitis C patients with genotype 1 infection, liver cirrhosis, high viral load, or those who have not responded to anti-viral treatment in the past have limited chances of clearing the virus, even with pegylated interferon-ribavirin therapy. In this study we treated such patients with a treatment schedule that combines high dose induction Interferon (IFN), prolonged daily IFN and ribavirin treatment. Twenty-four consecutive patients were included in this study with either genotype 1 infection, cirrhosis, previous non-response to IFN or a combination of these poor-response characteristics. Patients were treated with 10 million units (MU) of IFN daily for 4 weeks followed by 5 MU/day until week 24, 3 MU/day until week 52 and 3 MU thrice weekly until week 76 in combination with 1-1.2 g ribavirin daily. HCV RNA levels were assessed weekly until week 4 and at least once every 3 months thereafter, by a validated assay with a detection limit below 500 copies/mL. Both intention to treat (ITT) and per protocol (PP) analysis showed a high sustained virological response (ITT 67%, PP 80%). A virological response occurred rapidly (before 8 weeks of treatment) in all patients with a sustained response. Relapse after stopping therapy was observed in only 5%. Side-effects were observed frequently, and six patients had to be hospitalized. With this new treatment regimen that combines induction- and prolonged daily interferon treatment with ribavirin it seems possible to eliminate hepatitis C virus in the majority of patients that have an a priori limited chance of sustained response. Further clinical evaluation of intensive interferon and ribavirin combination therapy (now also including PEG-interferon) is recommended in centres that can provide close patient monitoring and experienced hepatological support.

Bekkering FC, Neumann AU, Brouwer JT, Levi-Drummer RS, Schalm SW. · Dept of Hepatology & Gastroenterology, University Hospital Rotterdam, The Netherlands. · BMC Gastroenterol. · Pubmed #11801193 links to  free full text

Abstract: BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.

Bekkering FC, Stalgis C, McHutchison JG, Brouwer JT, Perelson AS. · Department of Hepatogastroenterology, University Hospital Rotterdam, The Netherlands. · Hepatology. · Pubmed #11172344 No free full text.

Abstract: Patients with hepatitis C virus (HCV) genotype 1 infection are resistant to standard interferon (IFN) therapy. We used a mathematical model to estimate the duration of daily therapy necessary to maximize the number of patients achieving viral negativity before 12 weeks of therapy. Patients from a study to determine HCV RNA reduction over 4 weeks using 3 million units (MU), 5 MU, or 10 MU of IFN alfa daily plus Ribavirin were compared with a group receiving IFN alfa 3 MU three times a week. By extending the linear regression and prediction interval lines, the estimated time to negativity was greater than 12 weeks for the standard IFN group, 42 to greater than 84 days for the 3 MU IFN daily plus Ribavirin, 39 to 60 days for 5 MU IFN daily plus Ribavirin and 25 to 45 days for the 10 MU IFN daily and Ribavirin group, respectively. Thus, the use of a predictive model based on log transformation and linear regression of the early HCV RNA response suggests daily doses of 5 or 10 million units of IFN plus Ribavirin will be theoretically necessary for longer than 4 weeks to maximize the number of patients who clear virus by 12 weeks of therapy. This model may be useful in predicting response in groups of patients receiving other therapies.

Eland IA, Rasch MC, Sturkenboom MJ, Bekkering FC, Brouwer JT, Delwaide J, Belaiche J, Houbiers G, Stricker BH. · Pharmacoepidemiology Unit, Department of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands. · Gastroenterology. · Pubmed #10889173 No free full text.

Abstract: Two patients experienced episodes of acute pancreatitis shortly after starting treatment with interferon alfa-2b (IFN-alpha) for a chronic hepatitis C infection. The first patient was a 40-year-old man who developed acute pancreatitis after 15 weeks of treatment with 3 MU IFN-alpha subcutaneously (SC) 3 times weekly and 1200 mg ribavirin. After disappearance of symptoms and normalization of laboratory values, oral intake of solid foods and IFN-alpha therapy were restarted. Within hours, a relapse of acute pancreatitis occurred. A rechallenge with IFN-alpha 4 days later was followed by a prompt increase in serum lipase level, and IFN-alpha therapy was discontinued. The second patient was a 38-year-old man who developed acute pancreatitis 2 hours after SC administration of 5 MU IFN-alpha. Ultrasound endoscopy showed sludge in the gallbladder. The patient was rechallenged 5 weeks later with 3 MU IFN-alpha SC. Although serum amylase and lipase levels increased after readministration of IFN-alpha, treatment was continued. The patient was readmitted 2 weeks later with severe abdominal pain, and IFN-alpha administration was discontinued. Considering the temporal relationship between the start of IFN-alpha treatment and development of acute pancreatitis, the absence of other clear etiologic factors for acute pancreatitis, disappearance of symptoms after discontinuation of IFN-alpha, and positive reactions to rechallenge, IFN-alpha is the most probable cause for development of acute pancreatitis in these patients.

Tan AC, Brouwer JT, Glue P, van Leusen R, Kauffmann RH, Schalm SW, de Vries RA, Vroom B. · No affiliation provided · Nephrol Dial Transplant. · Pubmed #11209032 links to  free full text

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