Johannes T. Brouwer

Suicide associated with alfa-interferon therapy for chronic viral hepatitis

We report on two attempted suicides and one successful suicide during or shortly after alfa-interferon therapy for chronic viral hepatitis. While on therapy, all three patients developed a psychiatric disorder leading to their suicidal behavior. In a survey of 15 European hospitals, three cases of attempted and two of successful suicide during alfa-interferon therapy for chronic viral hepatitis, were additionally reported. None of the patients had a psychiatric history. Alfa-interferon is known to lead to neuropsychiatric symptoms, and our observations strongly suggest that these mental disorders could lead to suicidal behavior. Therefore it is important that physicians, patients and their families are informed about the potential risk of the emotional and psychiatric disturbances that can occur during alfa-interferon therapy.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C

BACKGROUND/AIMS The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Intravenous glycyrrhizin for the treatment of chronic hepatitis C: A double-blind, randomized, placebo-controlled phase I/II trial

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.

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

A psychometric comparison of health-related quality of life measures in chronic liver disease.

Four generic [the Sickness Impact Profile (SIP-68), Short-Form Health Survey (SF-36), EuroQol instrument (EQ-5D), COOP/WONCA charts], two domain-specific health-related quality of life measures [the sexuality scale of the HIV Overview Problems Evaluating System (HOPES), Multi-dimensional Fatigue Index (MFI-20)], and a self-developed 12-item symptom index were compared in terms of feasibility, test-retest reliability, internal consistency reliability, construct validity, and known groups validity in patients with chronic liver disease. All instruments could be completed within 10 min and exhibited a good psychometric performance in patients with chronic liver disease. The SF-36 and the MFI-20 performed relatively best in terms of reliability, construct validity, and discriminative ability. The sexuality scale of the HOPES demonstrated a relatively poor performance, as the missing value rate was higher than 5%. Further research is needed into the sensitivity to important clinical changes of the instruments.

Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission

BACKGROUND & AIMS Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. METHODS A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment. RESULTS During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse. CONCLUSIONS This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients.

Early prediction of response in interferon monotherapy and in interferon-ribavirin combination therapy for chronic hepatitis C: HCV RNA at 4 weeks versus ALT

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.

Ultrarapid hepatitis C virus clearance by daily high-dose interferon in non-responders to standard therapy

BACKGROUND/AIMS To analyze the kinetics of the hepatitis C virus and the patterns of resistance to interferon alpha, we assessed HCV RNA levels early during retreatment with high-dose interferon in patients who did not respond to standard treatment. METHODS Eleven non-responders to previous therapy with 3-6 MU interferon three times a week were retreated with daily 10 MU. Plasma was sampled at days 0, 1, 2, 3, 14 and 28; all samples were prepared within 2 h and stored at -70 degrees C without thawing until analysis. The quantitative HCV RNA level was assessed by the Superquant assay (NGI, USA). The Eurohep reference panel, tested blindly, confirmed the linearity of the assay with a detection limit for genotypes 1 and 3 between 10(2) and 10(3) copies/ml. RESULTS All patients showed a fall in viral load between week 0 and week 2 (2.6 log, i.e. 99.7%, range 1.3-4.7 log), whereas no fall was detected after week 2. Closer examination in nine patients revealed that all had a dramatic fall in the first 2 days (first day 1.8 log, 0.8-3.5; second day 0.8 log, -0.2-1.3), without any significant fall thereafter. The calculated half-life of viral decay in plasma was 5 (2-8.9) h, corresponding to a clearance of 2.4 (0.2-13.7) x 10(11) virions per day. Sustained responders showed a significantly greater fall in viral load in the first day (3.2 log, 2.8-3.5) than those who did not respond (1.4 log, 0.8-2.1, p=0.001). All three sustained responders had undetectable plasma HCV RNA at day 14. CONCLUSION In patients without a response to standard interferon, the hepatitis C virus has a high daily turnover rate similar to that reported in naive patients. Our findings suggest that an early clearance of HCV RNA from the circulation is the key to a sustained response, which might be induced in about 25% of these patients by treatment with high (10 MU) daily doses of interferon. These findings have important implications for the concept of treatment of hepatitis C, which should shift its focus from long-term mild treatment towards aggressive therapy aiming at a fast viral disappearance within the first few days.

Efficacy of interferon dose and prediction of response in chronic hepatitis C: Benelux study in 336 patients

BACKGROUND/AIMS In an attempt to improve the limited efficacy of treatment of chronic hepatitis C with interferon-alpha 3 MU tiw, we studied the effects of double-dose therapy followed by downward titration, and analyzed the pre- and pertreatment factors associated with response or non-response. METHODS Three hundred and fifty-four consecutive patients in 19 centers were randomized to interferon-alpha 3 MU tiw for 6 months or 6 MU tiw for 8 weeks followed by down-titration (3,1 MU tiw) till alanine aminotransferase remained normal and plasma HCV RNA was repeatedly undetectable. The primary outcome measure was sustained alanine aminotransferase and HCV RNA response 6 months after treatment. RESULTS Three hundred and thirty-six patients received treatment. The sustained response rate for patients receiving 3 MU tiw for 6 months was 14% (9-21%,) and for patients receiving double dose tiw for 8 weeks and thereafter titrated therapy 15% (10-21%) (p=0.8). Pretreatment factors associated with a sustained alanine aminotransferase plus HCV RNA response were the absence of cirrhosis, presence of genotype 2 or 3, a low viral load and, in addition, a low alanine aminotransferase/aspartate aminotransferase ratio; a model was developed to allow estimation of the chance of response for the individual patient. The most powerful predictor of sustained response, however, was plasma HCV RNA at week 4; a positive test virtually precluded a sustained response (1.7%, 0.4-5.0%). If week 4 HCV RNA was not detectable, the chance of a sustained response was 21% (12-34%) for genotype 1 versus 40% (28-54%) for the others (p=0.02). Six MU tiw led to a significantly higher week 4 HCV RNA response (47% not detectable) than 3 MU (37%) (p=0.02). During down-titration this difference in viral on-treatment response was lost. CONCLUSIONS In the treatment of hepatitis C, an early HCV RNA response is a prerequisite for long-term efficacy. Doubling the initial interferon dose increases this early response, but subsequent downward titration negates this effect, especially in genotype 1.

Carbohydrate antigen 19-9 is extremely elevated in polycystic liver disease.

Background/Aims: Carbohydrate antigen 19‐9 (CA19‐9) is used as a biomarker to differentiate benign from malignant gastrointestinal disorders. We examined the value of CA19‐9 measurement in polycystic livers after observing high CA19‐9 cyst fluid levels in a benign polycystic liver case.