Adult beta-thalassemic patients with chronic hepatitis C: long-term efficacy of alpha-IFN treatment

Background: The purpose of this study was to assess the effectiveness of alpha-IFN in adult beta-thalassemic patients with chronic hepatitis C. After a long-term follow-up, we describe the special pattern of biochemical and virological response of thalassemics. Methods: Thirty-two anti-HCV-positive adult thalassemic patients (19 female and 13 male, mean age 23.4+/-5.5 years) with biopsy-proven chronic hepatitis were treated with IFN alpha2beta at a dose of 3 MU thrice weekly for 6-12 months. The patients were followed up until 45-62 months after the end of treatment. Results: A sustained response was obtained in eight patients (25%). Only two of the sustained responders (25%) normalized ALT during the first 3 months of treatment. Both early and late biochemical responders cleared HCV-RNA after 6 months of treatment. Eight patients (25%) responded with ALT normalization within 2 months of treatment but relapsed soon after stopping IFN. Sixteen patients (50%) did not respond to IFN. Conclusion: The response rate in multitransfused thalassemic patients with chronic hepatitis C treated with IFN is similar to that in non-thalassemics. The special feature of thalassemics is that early biochemical response does not predict a sustained response; on the contrary, patients who normalize ALT after 6 months of IFN treatment usually do not relapse.     

Viral kinetics can predict early response to alpha-interferon in chronic hepatitis C

ABSTRACT— Aims/Background: Response rates to alpha-interferon therapy for chronic hepatitis C are poor. An early indication of efficacy would reduce the need for prolonged therapy, leading to significant cost savings. It was established that a change in quantitative hepatitis C virus RNA (HCV-RNA) titre at 4 weeks could predict the outcome of alpha-interferon therapy in chronic hepatitis C. Methods: Serum HCV-RNA titres were quantified using branched chain DNA (bDNA) assay in 26 patients who responded to alpha-interferon (serum HCV-RNA negative after 12 weeks therapy) and 11 age and sex matched non-responders. Quantitative bDNA and qualitative RT-PCR assays for HCV-RNA were measured pre-treatment and at 4 weeks. The change in quantitative HCV-RNA titre between pre-therapy and after 4 weeks was compared in the two groups. Results: Seventeen of the 37 patients had become RT-PCR negative at 4 weeks (early responders) and had an undetectable HCV-RNA titre on bDNA assay. Nine patients were RT-PCR positive at 4 weeks but negative by 12 weeks (delayed responders), and of these, 8 had an undetectable viral titre at 4 weeks on bDNA assay. The patient with a detectable HCV titre did become RT-PCR negative after 12 weeks, but subsequently became RT-PCR positive again at 24 weeks. All the non-responders had a detectable bDNA titre (>0.2 Meq/ml) at 4 weeks. Conclusions: Change in quantitative HCV-RNA titre measured by bDNA assay at 4 weeks predicts response to alpha interferon. If HCV-RNA remains detectable on bDNA assay at 4 weeks, no sustained response to treatment is found and alpha-interferon can be discontinued.     

Interferon treatment in patients with chronic hepatitis C with normal alanine-aminotransferase activity.

BACKGROUND/AIMS: Chronic hepatitis C virus carriers may have repeatedly normal alanine aminotransferase activity despite detectable viremia and histological hepatitis. We aimed to evaluate the effect of interferon treatment in these cases. METHODOLOGY: Twelve patients with persistently normal alanine aminotransferase levels at least 6 months before therapy were treated with recombinant interferon (IFN)alpha-2b for 6 months, totaling 840 MU in amount. Alanine aminotransferase levels were measured monthly during treatment and after treatment withdrawal, and HCV-RNA levels were measured by polymerase chain reaction before treatment, and 6 and 12 months after treatment withdrawal. RESULTS: At treatment withdrawal, HCV-RNA levels had significantly decreased and HCV-RNA disappeared in 9 of the 12 patients by polymerase chain reaction. At 6 months after treatment withdrawal, HCV-RNA reappeared in 6 of the 9 patients whose HCV-RNA was negative at treatment withdrawal. Over all, only 4 of the 12 patients (33%) were sustained virological responders (HCV-RNA is negative more than 6 months after treatment withdrawal). Pre-treatment HCV-RNA levels in a sustained virological responder was significantly lower than that of transient and non-responders (4.9 +/- 1.6 vs. 7.7 +/- 1.6 log10[copies/ml], p < 0.05). Of 8 patients who did not achieved sustained virological response, alanine aminotransferase levels had transiently increased above normal during treatment in one patient and after treatment withdrawal in 6 patients; however, in the remaining one patient abnormal values have continued from 8 months after treatment withdrawal till now for 24 months. CONCLUSIONS: In patients with chronic hepatitis C with normal alanine aminotransferase levels, the response to interferon therapy was by no means satisfactory. However, if it would be used in cases with the lower pre-treatment HCV-RNA levels with careful attention to a transient alanine aminotransferase elevation, the more a sustained virological response might be expected.     

Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum

Background/Aims: Prediction of response to interferon therapy is important in the management of chronic hepatitis C. Pre-therapy data are valuable but they may be inaccurate in some cases. Our aim was to investigate whether the biochemical and virological events that occur early during interferon therapy in chronic hepatitis C may predict the final result of the treatment.Methods: ALT and serum HCV-RNA were serially measured in 53 HCV-RNA-positive patients who received a standard 6-month course of interferon therapy. Eleven patients with a sustained response, 23 who responded but subsequently relapsed and 19 who did not respond were studied. HCV-RNA was measured with a commercial kit (Amplicor HCV).Results: After 4 weeks of treatment, HCV-RNA became negative in 73% of sustained responders, in 26% of transient responders (p=0.02) and in none of the non-responders. Corresponding figures after 8 weeks of therapy were 82% in sustained responders, 61% in transient responders and 9% in non-responders. The difference between sustained and transient responders at this times was not significant. After 4 weeks of therapy, 82% of sustained responders, 52% of transient responders and none of the non-responders presented normalization of alanine transferase. The difference between sustained and transient responders was not significant. Corresponding figures for normalization of alanine transferase at 8 weeks were 82%, 96% and 0% respectively. At the end of treatment, all sustained responders, 70% of transient responders and none of the non-responders had cleared HCV-RNA from serum.Conclusions: A rapid normalization of alanine transferase induced by interferon therapy is associated with response, but does not differentiate between transient and permanent response. In contrast, clearance of HCV-RNA after 4 weeks of treatment, but not after 8 weeks, is significatively associated with sustained response. Testing for HCV-RNA early during interferon administration may be valuable for further decisions concerning therapy in patients with chronic hepatitis C.     

Retreatment of Chronic Hepatitis C with Interferon

Objective: We analyzed the retreatment of chronic hepatitis C with interferon to get the standpoint for the selection of patients to receive it. Methods: A complete response was defined as continuous normalization of the serum alanine aminotransferase (ALT) level and continuous disappearance of serum hepatitis C virus RNA (HCV-RNA) during interferon administration and more than 6 months after. Patients without complete response were classified as noncomplete responders. From August 1990 to May 1993, we retreated 23 noneomplete responders on initial treatment with interferon and studied the factors that alter the effectiveness. Results: Complete response was achieved in eight (34.8%) patients; the other 15 patients did not achieve this degree of response. Three patients were of genotype U and five were of genotype III in these eight complete responders. All complete responders were patients with relapse who had had normalized serum ALT levels during the initial administration and undetectable HCV-RNA at the end of the period. No patient who failed to achieve normalization of the serum ALT level on initial treatment achieved a complete response on retreatment. HCV-RNA concentrations before retreatment were significantly less than hefore initial treatment in the eight complete responders. Conclusion: Interferon retreatment of patients who do not achieve a complete response may be effective in relapsed cases with undetectahle HCV-RNA at the end of initial treatment. Selection of patients to receive interferon retreatment requires careful review and consideration of genotype, HCV-RNA concentration, and the clinical response on initial treatment.     

Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group.

Patients with chronic hepatitis C who have not had a sustained hepatitis C virus (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month course of interferon (IFN) may respond to higher dose retreatment with consensus interferon (CIFN). Some nonresponders to initial IFN treatment have a transient response defined as undetectable HCV RNA or normalization of ALT during treatment, but subsequently have a "breakthrough" while still on treatment. The aim of this study was to determine if nonresponders who had breakthroughs responded differently to CIFN retreatment than nonresponders without breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN-alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%) of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%) of all treated patients. There was no association between breakthroughs and the presence of either binding or neutralizing anti-IFN antibodies. When the patients who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg) for 12 months, 27% of those with viral breakthroughs had a sustained viral response compared with 8% in prior nonresponders without breakthroughs (P =.102). Sustained ALT responses were observed in 39% with breakthroughs compared with 10% in those without breakthroughs (P =.014). The data suggest that prior nonresponders with breakthroughs have a greater chance of responding to retreatment than do nonresponders without breakthroughs. However, most breakthrough patients would be missed unless repeated HCV-RNA testing were conducted during therapy.     

Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus-infected patients with congenital coagulation disorders.

We have conducted an open, prospective trial to assess the safety and efficacy of interferon alfa-2b and ribavirin in combination for the treatment of chronic hepatitis C in human immunodeficiency virus (HIV)-infected hemophiliacs. Twenty hemophiliacs coinfected with HIV and hepatitis C virus (HCV), 18 of them under highly active antiretroviral therapy (HAART), with a mean CD4(+) cell count of 490 +/- 176 cells/mm(3) and undetectable (n = 9) or low-level HIV RNA (<10,000 copies/mL; n = 11), were treated with interferon-alfa2b (3 MU thrice weekly) and ribavirin (800 mg/d) for 6 or 12 months according to virologic response. Patients were monitored for tolerance and response at 4, 8, 12, 24, 36, and 48 weeks during treatment and every other month thereafter. All 20 patients enrolled completed at least 6 months of treatment with no major side effect requiring treatment withdrawal, dose reduction, or modification of HAART. Overall, 8 patients (40%) achieved a sustained virologic response at the end of the 6-month post-treatment follow-up. Sustained responders had lower baseline HCV-RNA levels (5.7 +/- 0.8 vs. 6.3 +/- 0.4 log10 IU/mL, P =.041) but were otherwise similar to nonresponders. All sustained responders had a decrease in HCV-RNA level of at least 1 log per month during the first 2 months and undetectable levels at 6 months. In conclusion, our results provide evidence that combination therapy with interferon and ribavirin is safe in HIV-infected hemophiliacs with stable CD4 cell count and undetectable or low-level HIV replication, and leads to eradication of HCV in 40% of these patients.     

Short and long-term effects of interferon on serum markers of hepatitis C virus replication

Abstract Hepatitis C virus RNA (HCV-RNA) and serological markers of HCV infection were measured in 30 patients with chronic hepatitis C who had been treated with interferon (IFN). Patients were classified into four groups according to serum alanine aminotransferase (ALT) levels after treatment. These were: as complete responders (CR); partial responders (PR); transient responders (TR); and non-responders (NR). In all 11 patients in the CR group, HCV-RNA disappeared from serum for at least 24 months and anti-c100-3 decreased progressively during this time. In the PR group, four of five patients were positive for HCV-RNA in spite of the improvement of ALT levels and decline of anti-c100-3. In the TR and NR groups, HCV-RNA disappeared transiently or remained persistently positive. The results indicate that IFN-mediated improvement of ALT and decrease of anti-HCV (anti-c100-3) were not always related to the disappearance of HCV-RNA from serum. On the other hand, sustained disappearance of HCV-RNA from serum was demonstrated in the patients who did not have post-treatment ALT relapse. This indicates that IFN can eradicate HCV from serum in some patients and provide a clinical remission of chronic hepatitis C.     

Chronic hepatitis C in elderly patients: clinical, histological and virological features

Some clinical, histological and virological features, efficacy and safety of interferon (IFN) therapy were evaluated in elderly patients with chronic hepatitis C (CHC). We enrolled 22 patients aged 65-75 (mean age: 68.3 +/- 3.17 years); 15 males and 7 females. In all cases the hepatitis C virus RNA (HCV-RNA) was determined before, during and after the therapy, and HCV sub-types were established; 15 patients underwent hepatobiopsy. At entry, the duration of disease was: 6 patients 1-3 years, 2 patients 4-10 years, 14 patients 11-30 years; alanine-aminotransferase (ALT) = (3.17 +/- 1.15) x N (N = normal value); aspartate-transaminase (AST) = 2.28 +/- 1.6 x N; gamma-glutamyl-transpeptidase (gGT) = 1.4 +/- 1.1 x N; platelets = 164,000 +/- 66,000/mm(3); histological pattern: 2 mild chronic active hepatitis (CAH), 5 CAH, 2 severe CAM, 6 CAH with liver cirrhosis (LC); histological activity index (HAI) (14 patients) = 11.14 +/- 4.5 (range 5-17); scores according to Scheuer: lobular 2.28 +/- 1.13, portal 2.71 +/- 0.99, fibrosis 2.35 +/-1.33; HCV-RNA +ve: 20 patients, HCV-RNA -ve: 2 patients; HCV-subtypes: 1b 20/20 (100%), 1b+1a 1/20 (5%), 1b+ 2a 1/20 (5%). Treatment was applied to 18 patients, for 3-12 months; 5 received alpha-IFN2a; 5 received alpha-IFN2b, 3 lymphoblastoid IFN, all at a dose of 3 mU thrice per week; 3 patients received 6 mU beta-IFN thrice per week. Therapy over 6 months was applied to 16 patients: Complete response (CR) was observed in 8 patients (50%), one of them was with long-term CR (over 12 months after therapy); 5 have had relapse and 2 patients are still under treatment. Partial response (PR) was observed in 4 patients (25%), no response (NR) in 4 patients (25%). Side effects were moderate and self-limited. Loss of HCV-RNA was shown in some patients with PR and in all patients with CR, but only temporarily.     

Long-term follow up of chronic hepatitis C patients after alpha-interferon treatment: a functional study

AIM: To evaluate the long-term functional outcome of chronic hepatitis C (CHC) patients treated with interferon (IFN) therapy. METHODS: Thirty-six patients with CHC were followed up for a mean of 36 months (+/- 19, SD) after a course of IFN therapy. Biochemical, virological (qualitative hepatitis C virus (HCV)-RNA and HCV genotype), and functional (monoethylglycinexylidide (MEGX) test) evaluations were carried out at the time of liver biopsy. Patients were divided into long-term responders (LTR), relapsers (RR), or non-responders (NR) according to IFN therapy outcome. At the end of follow up, patients were non-invasively re-evaluated by means of biochemistry, qualitative HCV-RNA, MEGX test, and liver ultrasonography. RESULTS: A significant decrease in MEGX values was observed in all patients. However, when patients were examined according to treatment outcome, only NR and RR showed a significant decrease in liver function as compared to pretreatment levels (MEGX30, 80.5 +/- 26.8-62.9 +/- 24.2 ng/mL, P< 0.01; MEGX60, 72.9 +/- 18.1-60.5 +/- 19.7 ng/mL, P< 0.05; MEGXAUC, 3,816 +/- 1,243-3,095 +/- 1,205 ng/mL per h, P< 0.05). On the contrary, LTR patients showed no significant modifications in MEGX values at each sampling time (MEGX,5, 72.9 +/- 31.4-70.3 +/- 29.7 ng/mL; MEGX30, 84.0 +/- 27.6-71.5 +/- 21.8 ng/ mL; MEGX60, 69.5 +/- 26.8-63.2 +/- 14.4 ng/mL; MEGXAUC 4028 +/- 1,378-3,620 +/- 1,041 ng/mL per h). At the end of follow up, LTR patients showed normal liver biochemistry and negativity of serum HCV-RNA, while NR and RR patients showed a significant decrease in platelets. CONCLUSIONS: In CHC patients long-term response to IFN therapy, besides favoring positive clinical and virologic long-term outcome, results in maintaining preserved liver function. Furthermore, IFN therapy seems to determine a decrease in the rate of functional disease progression, even in NR and RR. The MEGX test may be considered as a useful tool for performing serial follow up of CHC patients.     

Treatment of acute hepatitis C infection in HIV-infected patients: a retrospective analysis of eleven cases

Studies on hepatitis C virus (HCV) monoinfected patients suggest high sustained treatment response rates of up to 98% when interferon monotherapy is administered during the acute phase of HCV-infection. To clarify whether early treatment of acute hepatitis C is similarly efficient in human immunodeficiency virus (HIV) positive patients, we conducted a retrospective survey of HIV-positive patients with acute HCV infection. Eleven HIV-positive patients who had been treated with interferon or interferon/ribavirin were identified at eight HIV-specialty outpatient clinics. The patients had been treated over a median 25 weeks with standard interferon (two patients), pegylated interferon (four patients) and pegylated interferon in combination with ribavirin (five patients). A post-treatment response (negative serum HCV-RNA at the end of treatment) was seen in 10 of 11 patients and HCV-RNA remained undetectable 24 weeks after the end of treatment in all the 10 responders. Alanine aminotransferase (ALT) normalized in eight patients while two virological responders and one nonresponder showed persistent mild ALT elevations. In conclusion, early treatment of acute hepatitis C seems to achieve high sustained virological treatment response rates also in patients with HIV-infection.     

A severe hepatitis flare in an HBV-HCV coinfected patient during combination therapy with Α-interferon and ribavirin

We report a reactivation of hepatitis B virus infection and a severe hepatitis flare in a patient with chronic hepatitis due to dual infection with hepatitis B and C viruses during combination therapy with alpha-interferon and ribavirin. Pretreatment, HCV was the dominant virus, with detectable serum HCV-RNA but undetectable HBV-DNA. The patient responded to therapy, with the disappearance of HCV-RNA and normalization of serum alanine aminotransferase (ALT) at months 1 and 6. In the seventh month of therapy, an ALT flare was observed, and serum HBV-DNA became detectable. The patient had a severe hepatitis flare leading to impending hepatic failure. Treatment was discontinued and the patient had marked clinical and biochemical improvement and recovered with normalization of liver function test results within 1 month. Two months later, serum HBV-DNA was again undetectable, both by hybridization and polymerase chain reaction (PCR) assays. The patient had a rapid progression to cirrhosis in a year. At month 24, 17 months after the end of therapy, serum HCV-RNA reappeared, with a level of 2.4 × 10⁵ copies/ml. In conclusion, severe HBV reactivation may occur during interferon plus ribavirin therapy in patients with chronic hepatitis C who are also hepatitis B surface antigen (HBsAg)-positive, and thus more careful monitoring than usual should be considered. Longterm follow-up is recommended, because very late HCV relapses may occur in coinfected patients. These data exemplify the complexity of viral dominance in patients infected with multiple hepatitis viruses, and this has significant importance for treatment decisions. Lamivudine may be administered early in HCV-RNA/HBsAg-positive patients who are at high risk of liver failure once reactivation of HBV occurs during interferon therapy.     

Interferon therapy for non-A, non-B chronic hepatitis

We report the results of our study on 8-week consecutive interferon (IFN) treatment for chronic non-A, non-B hepatitis. In the 6 MIU/day group, most cases had continuously normalized alanineaminotransferase (ALT) levels even after IFN treatment was discontinued. In responders whose ALT levels remained normal, not only the degree of inflammation, as seen from HAI scores, but also liver histopathological features were improved. Moreover, antibody to hepatitis C virus (anti-HCV) titer in responders was continuously decreased. Antiviral effects of IFN were observed by detection of HCV-RNA using the PCR technique. HCV-RNA became negative with IFN treatment, however, in some patients who relapsed after discontinuation of IFN treatment, reelevation of ALT levels was usually preceded by re-appearance of HCV-RNA.     

A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.

BACKGROUND & AIMS:: At least half of patients with chronic hepatitis C virus (HCV) fail to respond to interferon or interferon/ribavirin therapy. Histological improvement is observed in some nonresponders. We conducted a randomized, controlled trial to determine if maintenance interferon therapy could prevent histological progression in this subset of nonresponders. METHODS: Fifty-three patients with chronic HCV were enrolled. All were HCV-RNA positive after 6 months of treatment with interferon alfa-2b but had a histological response. Twenty-seven of the patients were randomly assigned to continue interferon (3 MU 3 times weekly) for 24 months; 26 patients discontinued treatment and were observed prospectively. Alanine aminotransferase (ALT) level and HCV-RNA titer were monitored, and liver biopsy was repeated every 12 months. RESULTS: Before interferon therapy, the 2 groups were well matched for all demographic factors, serum ALT (94.0 +/- 15.6), log HCV-RNA titer (5. 85 +/- 0.15 copies/mL), histology score (9.5 +/- 0.2), and percentage with cirrhosis (25%). After 6 months of treatment, significant reductions (P < 0.05) in serum ALT level (62.6 +/- 9.6), log HCV-RNA titer (4.79 +/- 0.13 copies/mL), and hepatic inflammation (4.0 +/- 0.2) were observed. These improvements were maintained in the patients randomized to continue interferon. Stopping treatment was associated with an increase in serum ALT, log HCV-RNA, and hepatic inflammation back to baseline. After 30 months of treatment, mean fibrosis score declined from 2.5 to 1.7 and 80% of patients had histological improvement (P < 0.03). Discontinuation of interferon was associated with an increase in mean fibrosis score from 2.2 to 2.4 and worsening of hepatic histology in 30% of patients (P < 0.01). CONCLUSIONS: These data support the hypothesis that maintenance interferon may prevent histological progression of chronic HCV in patients who remain viremic.     

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon.

BACKGROUND/AIMS: This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA. METHODS: We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. RESULTS: At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. CONCLUSION: In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.     

Cold activation of complement in sera from patients with persistent hepatitis C virus infection on interferon therapy

The loss of haemolytic activity in sera during storage at low temperature (the cold activation of complement) was observed in 136 of 184 (74%) patients with chronic liver disease associated with hepatitis C virus (HCV) infection. This was more frequent than observed in the three of 40 (8%) patients with chronic hepatitis B (P < 0.001) or none in 43 normal controls (P < 0.001). Of 103 patients with chronic hepatitis C who had completed a full course of recombinant interferon-α2a therapy (total dose: 516×10⁶U), 40 responded completely and 21 responded partially, as judged by the normalization or decrease of alanine aminotransferase levels 6 months after the completion of therapy; 42 patients did not respond at all. The cold activation of complement persisted in five (13%) complete responders, less often than in 33 (79%) non-responders (P < 0.001). At the completion of interferon therapy, the cold activation of complement persisted in 12 of 54 patients despite the normalization of alanine aminotransferase. Spontaneous exacerbation of hepatitis occurred in seven of 12 (58%) patients with cold activation, which was more frequent than in the four of 42 patients (10%) without it (P < 0.01). The cold activation of complement disappeared along with the loss of HCV-RNA in five of six responders during the 6 month period after the completion of interferon therapy, while both cold activation and HCV-RNA persisted in all eight non-responders. These results indicate that the cold activation of complement may be useful as a marker of HCV viraemia for monitoring the response to interferon in patients with HCV infection.     

Treatment of patients with chronic hepatitis C not responding to interferon with high-dose interferon alpha with or without ribavirin: final results of a prospective randomized trial. Austrian Hepatitis Study Group.

OBJECTIVE: To investigate the efficacy of high-dose interferon alpha (IFN-alpha) with or without ribavirin in interferon (IFN) non-responders. STUDY DESIGN: 304 chronic hepatitis C patients received 5 MU IFN-alpha2b (IntronA, Schering-Plough, Kenilworth, NJ, USA) three times a week for 3 months. Non-responders were randomized either to continue with IFN (IFN 5 MU/TIW followed by 10 MU/TIW, each for 3 months) alone (group A: n = 76, m: f = 54: 22, age 45.7 +/- 12 years, 16% cirrhosis, alanine aminotransferase [ALT] 66 +/- 35 U/l) or in combination with ribavirin (approximately 14 mg/kg/day) (group B: n = 81, m: f = 57: 24, age 48.2 +/- 12 years, 17% cirrhosis, ALT 71 +/- 40 U/l). At the end of treatment, patients were followed for 6 months. MAIN OUTCOME MEASURES: Virological response at end of treatment and 6 months thereafter. SETTING: University hospitals and tertiary referral centres. RESULTS: At the end of treatment, eight (10.8%) and 25 (31.3%, P= 0.0066) patients were HCV-RNA negative, and 51 and 39 were HCV-RNA positive, in groups A and B, respectively. There were 17 drop-outs in each group. Six months after treatment, only one patient in group A (1.3%) and seven patients (8.6%, P= 0.06) in group B had normal ALT and undetectable serum HCV-RNA. CONCLUSIONS: A combination of high-dose IFN with ribavirin induces a short-lasting complete response in about one-third of IFN-non-responders.     

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis.

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated with alpha-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN administration was classified into five types. Type 1 was characterized by normalization of ALT (< or = 25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (< or = 25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).     

Interferon plus ribavirin in chronic hepatitis C non-responders to recombinant alpha-interferon

The aim of this study was to evaluate the most appropriate therapeutic protocol for patients with chronic hepatitis C not responding to a previous course of recombinant interferon α-2b (rIFN). Sixty patients were randomly assigned to two groups of 30 subjects each: group A was treated with double dose of the same type of rIFN (6 MU t.i.w. ) plus ribavirin for 6 months; group B was treated with the same rIFN dose and duration as group A, but without ribavirin. An end of treatment complete response (ETCR) was defined as alanine transaminase (ALT) normalization with undetectable serum HCV-RNA at the end of the treatment, while an end of treatment biochemical response (ETBR) as ALT normalization with still detectable viraemia. The two groups were homogeneous. The patients with ETCR or ETBR were than followed-up for at least 1 year. A sustained biochemical response (SBR) was defined as the persistence of normal ALT with still detectable viraemia after a 12-month follow-up, and a sustained complete response (SCR) as the persistence of normal ALT with undetectable viraemia. Side-effects were only observed in patients treated with rIFN plus ribavirin: four cases (13%) discontinued the therapy owing to haemolytic anaemia. Combination therapy induced an ETCR in 11 patients (37%) and an ETBR in six (20%), while a SCR was observed in two subjects (7%) and a SBR in four (13%). The use of a double dose of rIFN alone obtained an ETCR in four cases (13%) and an ETBR in five (17%), with a SCR in two (7%) and a SBR in three (10%). Hence, both combination therapy and single treatment with higher rIFN doses were unable to show statistically significant long-term benefits in patients with chronic hepatitis C resistant to a previous course of rIFN treatment.     

原发性胆汁性肝硬化停用熊去氧胆酸治疗的前瞻性研究

目的 评价原发性胆汁性肝硬化(PBC)患者停用熊去氧胆酸(UDCA)的反应.方法 27例经UDCA治疗后肝功能正常>6个月的PBC患者分为A、B两组,A组停用UDCA,B组维持UDCA 13～15 mg·kg-1·d-1治疗,两组患者在性别、年龄、病程等方面相匹配,观察12个月.结果 随访过程中A组1例退出,B组1例失访.A组12例,B组13例.A组2例出现病情进展,占17%,均为血清胆红素升高至正常值2倍以上,分别发生在第3个月和第12个月;B组患者未出现病情进展,两组差异无统计学意义.至观察结束时,A组92%疾病复发,B组为15%,差异有统计学意义(P<0.05). A组患者丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、γ-谷氨酰转肽酶(GGT)升高,差异有统计学意义(P<0.05).血清胆红素平均水平差异无统计学意义.B组上述指标均维持稳定.结论 对UDCA治疗后肝功能正常的PBC患者需要长期维持UDCA治疗.