Treatment of Chronic Hepatitis C: the Benelux Studies

__Abstract__ In the eighties and early nineties of the last century, acute hepatitis occurred in 5-10% of patients receiving blood transfusions in the USA, and in more than 90% of cases this could not be attributed to hepatitis A or B (“Non-A, Non-B hepatitis”). More than 50% of the hepatitis infections became chronic, and Non-A, Non-B hepatitis led to liver cirrhosis in about 20% of patients, thereby being a serious health burden. In 1989 the hepatitis C virus was discovered as the major cause of this post-transfusion hepatitis, but it was also found in many cases of unknown chronic hepatitis without known blood contacts in the past (sporadic HCV). It is estimated that more than 170 million people are infected with hepatitis C worldwide, leading to more than 280.000 deaths each year due to decompensated liver cirrhosis and liver cancer

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis C patients: a case control study

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

Prospective comparative study of spiral computer tomography and magnetic resonance imaging for detection of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is often detected at a relatively late stage when tumour size prohibits curative surgery. Screening to detect HCC at an early stage is performed for patients at risk. AIM: The aim of this study was to compare prospectively the diagnostic accuracy and classification for management of the two state of the art secondline imaging techniques: triphasic spiral computer tomography (CT) and super paramagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). PATIENTS: Sixty one patients were evaluated between January 1996 and January 1998. Patients underwent CT and MRI within a mean interval of 6.75 days. METHODS: CT and MRI were evaluated blindly for the presence and number of lesions, characterisation of these lesions, and classification for management. For comparison of the data on characterisation, the CT and MRI findings were compared with histopathological studies of the surgical specimens and/or follow up imaging. Data of patients not lost to follow up were available to January 2001. RESULTS: SPIO enhanced MRI detected more lesions and overall smaller lesions than triphasic spiral CT (number of lesions 189 v 124; median diameter 1.0 v 1.8 cm; Spearman rank's correlation coefficient 0.63, p<0.001). There was no significant difference in accuracy between CT and MRI for lesion characterisation. The agreement in classification for management was very good (weighted kappa 0.91, 95% CI 0.83-0.99). CONCLUSION: SPIO enhanced MRI detects more and smaller lesions, but both techniques are comparable in terms of classification for management. SPIO enhanced MRI may be preferred as there is no exposure to ionising radiation

Sequence analysis of the 5' untranslated region in isolates of at least four genotypes of hepatitis C virus in The Netherlands

The RNAs of hepatitis C virus (HCV) isolates from 62 patients with chronic HCV infection were analyzed by direct sequencing of the 5' untranslated region. Two important sequence motifs were recognized: one between positions -170 and -155 and the other between positions -132 and -117. These motifs are partly complementary. All three previously published genotypes were observed; 34 (55%) isolates were classified as type 1 (including prototype [from the United States] and HCV-BK [from Japan] sequences), 11 (18%) were classified as type 2 (including HC-J6 and HC-J8), and 12 (19%) were classified as type 3 (including EB1); one patient was infected with genotypes 1 and 2. Four (6%) isolates showed aberrant sequences and were therefore provisionally classified as genotype 4. These results indicate the significance of sequence variation among the 5' untranslated regions of different HCV genotypes and indicate that this region could possibly be used for consistent genotyping of HCV isolates

Rapid genotyping of hepatitis C virus RNA-isolates obtained from patients residing in Western Europe

Two rapid genotyping methods for hepatitis C virus (HCV), the line probe assay (Inno‐LiPA) and the subtype‐specific core amplification system [Okamoto et al., (1992b) Journal of General Virology 73:673‐679], were applied to 58 HCV isolates which were typed as type 1 (n=37) and type 2 (n=21) by sequence analysis of the 5′ untranslated region (5′UTR). The line probe assay targets the 5′UTR and recognized 12 subtype 1a, 25 subtype 1b, 18 subtype 2a, 2 subtype 2b and 1 subtype 2d in accordance with sequence analysis of this region. Subtype‐specific core amplification revealed 7 discrepancies among the 37 type 1 isolates when compared to LiPA. A different subtype was observed in 3 isolates (la versus 1b), 2 isolates remained untyped and 2 isolates showed a coinfection of subtype la and 1b. The first 5 discrepancies were confirmed by sequence analysis of the core region whereas the coinfection could not be confirmed. Of the 21 type 2 isolates only one could be typed by subtype‐specific core amplification. HCV RNA was detected in all 21 cases after the general first round of polymerase chain reaction (PCR). Direct sequencing of the core region indicated sequence variation as a source of failure. It is concluded that LiPA results are conclusive for typing of HCV. However, LiPA is hampered occasionally for subtyping by lack

Retreatment of hepatitis C non-responsive to Interferon. A placebo controlled randomized trial of Ribavirin monotherapy versus combination therapy with Ribavirin and Interferon in 121 patients in the Benelux [ISRCTN53821378]

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 untill 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 × 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

Translation and validation of the Revised Dental Beliefs Survey (DBS-R) in China

Patient perceptions of behaviours and attitudes of dentists are associated with dental fear and poor dental attendance in Western countries. However, there is a paucity of research exploring patient perceptions of the dentist in China. One reason for this may be the lack of a valid and reliable scale in Chinese (Standard Mandarin) to measure this. This study aimed to translate the Revised Dental Beliefs Survey (DBS-R) into Chinese and then explore the reliability and validity of this measure (both the short and longer versions) in a Chinese population. We translated the DBS-R using the forwards-backwards method and pilot tested it on a small sample of adults in China. Following this, 480 Chinese adults completed the newly translated scale, as well as well as a standardised dental anxiety questionnaire (the Modified Dental Anxiety Scale Chinese version) to test convergent validity. 109 participants completed the DBS-R again 2 weeks later for test-retest reliability. Both versions of the Chinese DBS-R were internally consistent and demonstrated convergent validity; test-retest reliability was also good. Both versions of the scale performed similarly, but for now we would suggest the 28-item version may be superior as items relating to the technical competence of the dentist appear important to Chinese adults