Aril Frydén

Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C

Summary Background Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon α-2b and ribavirin than with interferon α-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon α-2b and ribavirin compared with interferon α-2b alone. Methods In this double-blind trial 100 patients were randomly assigned to treatment with interferon α-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. Findings 18 (36%) of the 50 patients in the interferon α-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon α-2b and placebo group (p=0·047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon α-2b and ribavirin group than the interferon α-2b and placebo group (42 vs 20%, p=0·03), respectively. More patients with baseline HCV-RNA concentrations greater than 3×10 6 genome equivalents (Eq) per ml had a sustained response with interferon α-2b and ribavirin than with interferon α-2b and placebo (12/29 vs 1/26, p=0·009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3×10 6 Eq per ml (6/21 vs 8/24, p=0·67), respectively. Interpretation More patients with chronic hepatitis C have a sustained virological response with interferon α-2b and ribavirin than with only interferon α-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon α-2b and ribavirin.

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study

BACKGROUND/AIMS Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not of fibrosis in asymptomatic patients with mild/moderate abnormalities of liver transaminases.

AIMS To investigate whether hyperechogenicity of liver can reliably be interpreted as liver steatosis and if any concomitant or isolated fibrosis can be disclosed. PATIENTS AND METHODS A series of 165 patients with no signs or symptoms of liver disease referred because of slightly to moderately raised aminotransferases (alanine aminotransferase and/or aspartate aminotransferase 0.7-5.0 microkat/l) for more than 6 months were prospectively investigated with a comprehensive laboratory profile, ultrasound examination of liver and percutaneous liver biopsy Fibrosis was assessed quantitatively and according to Metavir. Steatosis was graded as none, mild, moderate or severe. RESULTS Of 98 (59.4%) patients with raised echogenicity, 85 (86.7%) had liver steatosis of at least moderate degree, 9 patients with same degree of steatosis had normal echogenicity and 13 patients with no or only mild steatosis had a hyperechogenic liver (sensitivity 0.90, specificity 0.82, positive predictive value 0.87, negative predictive value 0.87). About the same relations were found regardless of body mass index and degree of fibrosis. With increased echogenicity together with high attenuation (n = 591 and reduced portal vessel wall distinction (n = 79), positive predictive value increased to 0.93 and 0.94, respectively. Quantitatively assessed fibrosis (mean +/- SD) was 3.2 +/- 4.6% of biopsy area with normal and 2.3 +/- 1.8% with raised echogenicity (ns). Echogenicity was normal in 5 out of 9 patients with septal fibrosis and in 4 out of 6 patients with cirrhosis. Any structural, non-homogenous findings at ultrasound were not associated with architectural fibrotic changes and none had nodular contours of liver surface. CONCLUSIONS Assessment of liver echogenicity is of value for detection or exclusion of moderate to pronounced fatty infiltration (correct classification 86.6%) but cannot be relied upon in diagnosing fibrosis, not even cirrhosis in asymptomatic patients with mild to moderately elevated liver transaminases.

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response

A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment‐naïve HCV RNA–positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon α‐2b (1.5 μg/kg) subcutaneously weekly and ribavirin (800‐1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one‐sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention‐to‐treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7‐17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, −0.1 to +13.9). Conclusion: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks. (HEPATOLOGY 2007.)

The Clinical Significance of Slightly to Moderately Increased Liver Transaminase Values in Asymptomatic Patients

The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients.

Excellent Response Rate to a Double Dose of the Combined Hepatitis A and B Vaccine in Previous Nonresponders to Hepatitis B Vaccine

BACKGROUND Hepatitis B vaccine has been shown to be highly efficient in preventing hepatitis B. However, 5%-10% of individuals fail to develop protective levels (>or=10 mIU/mL) of antibodies to hepatitis B surface antigen (anti-HBs) and are considered to be nonresponders. METHODS A total of 48 nonresponders and 20 subjects naive to the HBV vaccine received a double dose of combined hepatitis A and B vaccine (Twinrix) at 0, 1, and 6 months. The levels of anti-HBs and antibodies to hepatitis A virus (anti-HAV) were determined before vaccination and 1 month after each dose. RESULTS Among 44 nonresponders, protective anti-HBs levels were found in 26 (59%) after the first dose and in 42 (95%) after the third dose. Among the control subjects, the corresponding figures were 10% and 100%, respectively. All subjects seroconverted to anti-HAV. The titers of both anti-HBs and anti-HAV were lower in the previously nonresponsive subjects (P< .01). CONCLUSION Revaccination of nonresponders to the standard hepatitis B vaccine regimen with a double dose of the combined hepatitis A and B vaccine was highly effective. This is most likely explained by the increased dose, a positive bystander effect conferred by the hepatitis A vaccine, or both.

A Randomized Controlled Open Study of Interferon Alpha-2b Treatment of Chronic Non-A, Non-B Posttransfusion Hepatitis: No Correlation of Outcome to Presence of Hepatitis C Virus Antibodies

33 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis (NANB PTH) were randomized 2:1 to treatment with interferon alpha-2b (Introna) or to controls. The treatment group received 3 MU interferon 3 times weekly subcutaneously for 36 weeks. 22/33 (67%) patients were reactive for antibodies against hepatitis C virus (anti-HCV). 11/19 (58%) treated patients versus none of the 12 controls had a complete response with normalization of serum alanine aminotransferase levels (p less than 0.001). Another 4/29 (21%) treated patients had a partial response which was also seen in 4/12 (33%) controls; 4 treated patients were nonresponders, all with chronic active hepatitis. Nonresponders had a significantly higher mean weight than responders (p less than 0.05) and tended to have a longer duration of their disease before therapy. During the 6-month follow-up period post treatment 4/11 (36%) complete responders had a sustained response and 7/11 (64%) relapsed. All who were retreated responded again. We conclude that a majority of patients with chronic NANB PTH will respond to 9 months interferon alpha-2b treatment, but that only 1 out of 3 will have a sustained response 6 months post treatment, and that the reactivity for anti-HCV was not correlated to the outcome of therapy.

A clinical and epidemiological study of "ornithosis" caused by Chlamydia psittaci and Chlamydia pneumoniae (strain TWAR).

Ornithosis is a notifiable disease in Sweden since 1954. In 1981 and 1982 a sharp increase in the number of notifications occurred. Since then the number has declined but is still high. A changed epidemiology characterized by no history of bird contact and no common source, raised the suspicion of a new agent. Serological data now suggest that the epidemic was to a substantial part due to Chlamydia pneumoniae (strain TWAR) (48% of the patients during 1981-1982 compared to 9% during 1984-1987). During recent years TWAR infections have thus become uncommon but reappearance can be expected in the near future. The clinical picture as well as the complications appear to be very similar in infections caused by C. pneumoniae and C. psittaci.

B and T lymphocytes in cerebrospinal fluid and blood in multiple sclerosis, optic neuritis and mumps meningitis

B and T cells were defined in cerebrospinal fluid (CSF) and blood of 18 multiple sclerosis (MS), five optic neuritis, and 17 mumps meningitis patients by counting immunoglobulin‐bearing lymphocytes for B cells, and the capacity of rosette formation with sheep erythrocytes for T‐cell determination. Patients with MS and mumps meningitis had significantly higher T‐cell values in CSF compared to blood, while the B cell value was significantly lower in CSF in mumps meningitis only. MS patients also displayed significantly lower B‐cell values in blood compared to mumps meningitis patients and blood donors. No significant differences were observed between MS patients in exacerbation and in remission.

Health-related quality of life in patients with different stages of liver disease induced by hepatitis C

Objective. Patients with hepatitis C have been shown to have impaired health-related quality of life (HRQoL). The aim of this study was to determine HRQoL in patients in different stages of hepatitis C virus (HCV) and to compare HRQoL in HCV cirrhosis with non-HCV-induced cirrhosis. Material and methods. Out of 489 consecutive patients who fulfilled the inclusion criteria, 472 (96%) agreed to participate in the study: 158 patients with mild/moderate fibrosis with chronic hepatitis C (CHC group), 76 patients with HCV compensated cirrhosis (CC), 53 patients with HCV decompensated (DC) cirrhosis, 52 non-cirrhotic patients with sustained viral response (SVR), and a control group consisting of 32 patients with non-HCV CC and 101 with non-HCV DC who completed the Short Form-36 (SF-36) and EQ-5D questionnaire. Results. The CHC group had significantly lower SF-36 scores than healthy controls, with the exception of scores for the dimensions physical function and bodily pain. HCV patients with DC had lower scores in all SF-36 dimensions in comparison with those of the CHC group, as well as in physical and mental component summaries (p<0.001). In comparison with the CHC group, the HCV CC group had lower scores on the SF-36 general health dimension (p<0.05) and lower SF-36 physical component summary (PCS) scores (p<0.05). No major differences were seen in patients with HCV- and non-HCV-induced cirrhosis. Conclusions. Impairment in HRQoL in patients with HCV was associated with the severity of liver disease, patients with decompensated cirrhosis exhibiting the highest impairment in HRQoL. The etiology of liver disease does not seem to be important in determining HRQoL in cirrhosis.