Randomized, placebo-controlled, double-blind trial with interferon-α with and without amantadine sulphate in primary interferon-α nonresponders with chronic hepatitis C

In primary interferon-α (IFN-α) nonresponders with chronic hepatitis C, retreatment with IFN-α has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-α alone or in combination with amantadine sulphate in nonresponders to previous IFN-α monotherapy. Fifty-five IFN-α nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-α 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate ( n =26) or a matched placebo ( n =29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-α dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-α/amantadine sulphate, one patient; IFN-α/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-α and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue ( P  < 0.05) and vigor ( P  < 0.05) in patients receiving combined IFN-α/amantadine sulphate treatment compared with those treated with IFN-α alone. IFN-α/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-α and amantadine sulphate does not increase the low sustained virological response rates of IFN-α therapy in primary IFN-α nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.     

Interferon-α-2B and ribavirin in combination for chronic hepatitis C patients not responding to interferon-α alone: an italian multicenter, randomized, controlled, clinical study

Objective: The aim of the study was to assess the efficacy of interferon (IFN)-α-2b and ribavirin in combination in the treatment of chronic hepatitis C (CHC) patients unresponsive to a previous treatment with IFN-α−2b alone.
Methods: We conducted a randomized study in 303 CHC patients. One hundred fifty-two patients received subcutaneous administration of recombinant IFN-α−2b (3 MU thrice weekly) and ribavirin (1000–1200 mg/daily per os ), whereas 151 received IFN-α−2b alone (6 MU thrice weekly). Both ribavirin and IFN-α-2b were given for 24 wk, regardless of treatment response. Alanine aminotransferase (ALT) levels and HCV RNA titer were checked during the treatment period and for a further 24 wk.
Results: Normal ALT levels were observed in 64.5% of the patients treated with IFN-α and ribavirin and in 22.6% of the patients treated with IFN-α alone. In the group of patients receiving IFN-α and ribavirin HCV RNA was not detectable in 40% of patients responders and remained undetectable in 44.2% of sustained responders. In the group of patients receiving IFN-α alone HCV RNA was not detectable in 24.2% of patients responders and remained not detectable in 33.3% of sustained responders.
Conclusion: A 24-wk treatment course with IFN-α and ribavirin given to patients with a previous lack of response to IFN-α alone offers a chance of a sustained biochemical and virological response, at least in a subset of such patients. The role of long-term therapy in inducing prolonged remission still remains to be explored.     

Human leucocyte interferon-α in chronic hepatitis C resistant to recombinant or lymphoblastoid interferon-α: a randomized controlled trial

Patients with biopsy-proven chronic hepatitis C, who failed to respond to a previous course of either recombinant (rIFN-α) or lymphoblastoid (LyIFN-α) interferon-α, were randomized to receive either leucocyte (Le) IFN-α (patients) or a second course of the same IFN-α (controls), to compare the efficacy and safety of these treatment schedules. All patients received the same dose of IFN-α as was used during their previous treatment (3 million units (MU) or 6MU three times weekly) for 6 months. Patients with a normal alanine aminotransferase (ALT) value at month 6 were treated for a further 6 months. All patients were followed-up for 12 months after treatment. A total of 69 patients were enrolled, 44 in the LeIFN-α group and 25 in the control group. At the end of the treatment period, 13 of the 44 patients (29.5%) in the LeIFN-α group had a biochemical response (normal ALT) and six of 44 (13.6%) patients had undetectable serum hepatitis C virus (HCV) RNA. At the end of the follow-up period, 10 patients (22.7%) had normal ALT values and serum HCV RNA was undetectable in three (6.8%). None of the patients in the control group showed normal ALT values at any time. Genotype 1b tended to be more frequent among non-responders (61 vs 45%); basal γ-glutamyl transpeptidase (γ-GT) values were lower in responders than in non-responders (33.3±11.70 Ul^–1 vs 58.4±33.04; P =0.01). LeIFN-α was well tolerated by all patients. These results support the use of LeIFN-α in patients with chronic hepatitis C who are non-responders to a previous treatment with recombinant or lymphoblastoid IFN-α.     

Leucocyte interferon-α retreatment for chronic hepatitis C patients previously intolerant to other interferons

The activity and tolerability of a retreatment cycle with leucocyte interferon-α (IFN-α) (6 million units (MU) three times weekly for 12 months) was evaluated in a group of 22 hepatitis C patients who had been intolerant to a previous course of lymphoblastoid IFN-α. Seven patients (31%) discontinued the new therapy owing to either a lack of response (six patients) or to severe leucopenia (one patient). Fifteen patients (68%) completed the 12-month treatment: all had a biochemical response and 10 (45%) also had disappearance of serum HCV RNA (complete response). Mild adverse reactions (fever, headaches and diarrhoea) were seen in these patients during retreatment. After 12 months of follow-up, 11 patients (50%) still maintained the biochemical response (long-term response); seven of these patients (32%) were also negative for serum HCV RNA. Biochemical and complete responses, at the end of both treatment and follow-up, were similar to those seen with lymphoblastoid IFN-α. The full dose of leucocyte IFN-α, when used in patients previously intolerant to the same dosage of lymphoblastoid IFN-α, was better tolerated: only one of the 15 patients who completed the 12-month treatment had a severe adverse event leading to withdrawal vs 22 of 68 patients treated with lymphoblastoid IFN-α. Furthermore, there were no manifestations of serological or clinical autoimmunity caused by leucocyte IFN-α, even in patients with autoantibodies associated with previous IFN therapy.     

Interim analysis of a randomized controlled trial of combination of ribavirin and high dose interferon-α in interferon nonresponders with chronic hepatitis C

This trial investigated the efficacy of a combination of high-dose interferon-α (IFN-α) with ribavirin in IFN nonresponders. Study protocol: 304 patients with chronic hepatitis C were treated with 5 MU IFN-α2b (IntronA^®, Schering-Plough) per TIW for 3 months. Nonresponders (defined by HCV-RNA positivity in serum after the 3 months of therapy) were randomized either to continue with IFN (5 MU IFN per TIW followed by 10 MU per TIW for each 3 months) alone (group A) or in combination with ribavirin (1–1.2 g per day) (group B). ALT was measured in monthly intervals, HCV-RNA in 3 monthly intervals. Pretreatment characteristics of the randomized patients were as follows: group A, n = 76; m/f, 54/22; 16% cirrhosis, age, 45.7 ± 12 years; ALT (U per litre), 66 ± 35; group B, n = 81; m/f, 57/24; 17% cirrhosis, age, 48.2 ± 12; ALT, 71 ± 40. After 9 months of treatment, nine (11.6%) and 27 (32.5%, 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 group A and 15 in group B. Six months after treatment only two patients in group A (2.5%) and five (6%, P = 0.06) in group B had normal ALT and no detectable HCV-RNA in serum. In addition to the well-known side-effects of IFN the mean haemoglobin concentration dropped by 2 g per litre in group B. These data indicate that a combination of high-dose IFN with ribavirin is effective in inducing a short-lasting complete response in one-third of IFN nonresponders. Prolonged treatment with IFN/ribavirin may be necessary to obtain a sustained response.     

Predictive value of IgM antibodies to hepatitis C virus in patients with chronic hepatitis C undergoing interferon-α therapy. Analysis by two different methods

SUMMARY. To determine the predictive value of IgM anti-hepatitis C virus (HCV) testing in patients with chronic hepatitis C infections undergoing interferon-α (IFN-α) therapy, IgM anti-HCV reactivity was analysed by two different methods (non-commercial and commercial) in 19 patients and monitored at times 0 (pre-treatment), 3, 6, 12. and 24 months during follow-up. Eight patients were non-responders, five remained in sustained response 1 year after stopping treatment, and six had a relapse. No correlation between alanine transaminase (ALT) levels and IgM anti-HCV reactivity was found by either method in baseline samples. In addition, neither the presence nor absence of IgM anti-HCV in baseline samples, nor the loss of specific IgM reactivity during treatment, had any predictive value. Finally, no other parameters analysed (age, sex, risk group and histological diagnosis), were significantly associated with IgM anti-HCV reactivity in our study. In summary, these results suggest that baseline detection and monitoring of IgM anti-HCV reactivity are not useful in predicting the sustained response to IFN-α therapy in chronic hepatitis C infection.     

Interferon-α plus amantadine in chronic hepatitis C resistant to interferon alone: a pilot randomized study

The optimal therapy for patients with chronic hepatitis C who have not responded to interferon (IFN) is still an unsolved issue. The aim of this study was to evaluate the efficacy and tolerability of a high dose of IFN-α2a plus amantadine for chronic hepatitis C patients who were non-responders to a previous course of IFN.
Forty consecutive patients with chronic hepatitis C, genotype 1b, who had not responded to IFN-α, were randomized to receive: (i) IFN 4.5  M U daily plus amantadine 200 mg/day for 4 weeks and then IFN 6  M U thrice weekly plus amantadine 200 mg/day for an additional 5 months (group A) or (ii) IFN alone at the same dosage and duration (group B). After 1 month of therapy, normal alanine aminotransferase (ALT) values were observed in three of 21 (14.3%) patients in group A and in three of 19 (15.8%) in group B; serum hepatitis C virus (HCV)-RNA clearance was observed in one patient (4.8%) in group A and in six (31.6%) in group B. At the end of treatment, six patients (28.6%) in group A and three (15.8%) in group B had normal ALT levels; however, HCV-RNA in serum was detectable in all of them at levels comparable to the basal values; an ALT relapse occurred within 3 months of stopping therapy. The combination of daily IFN plus amantadine was ineffective in this setting.     

Clinical efficacy of intramuscular human interferon-βvs interferon-α2b for the treatment of chronic hepatitis C

Summary. We have conducted a randomized study to compare the efficacy and tolerance of human interferon (IFN) β vs recombinant IFN-α2b in patients with chronic active hepatitis C. Forty patients were included: 21 received IFN-α (group A) and 19 IFN-β (group B). IFN was administered intramuscularly at a dose of 6 MU three times a week (tiw) for 2 months (induction phase), followed by 3 MU tiw for 4 months. Clinical, epidemiological and pathological features were similar in the two groups. Normal alanine aminotransferase (ALT) values at the end of treatment was regarded as a response to therapy and the response rate was 57% (12/21) in group A and 5.2% (1/19) in group B ( P < 0.01). Both types of IFN induced a significant decrease in mean ALT values by the end of the induction phase ( P < 0.01). When the dose was reduced to 3 MU, a marked, but not significant increase in ALT, was seen in group B, whereas no increase was seen in group A. IFN-β was better tolerated and haematological adverse effects (platelet and leucocyte decrease) were less pronounced with IFN-β. Hence, human IFN-β was less effective than IFN-α in treating chronic hepatitis C virus (HCV). Doses of IFN-β of 3 MU intramuscular (IM) tiw were clearly insufficient and it remains to be established whether higher doses of intramuscularly IFN-β can be useful.     

Response to interferon-α of Egyptian patients infected with hepatitis C virus genotype 4

Summary. Hepatitis C virus (HCV) genotype 4 is the principal HCV genotype found in Egypt and the Middle East. Little is known concerning its propensity to cause disease and the frequency with which infected individuals respond to interferon-α (IFN-α). We have investigated the response to treatment in a cohort of 100 chronic hepatitis C patients infected with genotype 4. All patients had biopsy-proven chronic active liver disease. Each was treated with 3 million units (MU) IFN-α, thrice weekly. Response was monitored, in 92 patients who completed treatment, by alanine aminotransferase (ALT) measurements and by polymerase chain reaction (PCR) for HCV. ALT levels remained abnormal in 64 patients during treatment (69.6%). Of the 28 patients who showed a biochemical response during treatment (30.4%), 18 maintained this over the 6-month post-treatment period. Amongst the sustained biochemical responders, HCV RNA was cleared from serum in only four of the 18 (22.2%) in this period. Histological improvement was observed in 26/51 (50.9%) of the patients who had a second biopsy.
Hence, patients infected with HCV genotype 4 show a poor response to IFN-α therapy compared with genotypes 2 and 3, but a similar response to IFN-α compared with those infected with type 1b HCV. These findings have major implications for treatment strategies in the Middle East, including Egypt, where HCV genotype 4 is widely distributed.     

Long-term titrated recombinant interferon-α2a in chronic hepatitis C: a randomized controlled trial

Summary. The efficacy and tolerability of 12-month treatment with titrated doses of recombinant interferon-α2a (IFN-α2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN-α2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response ( n = 35), or to no therapy ( n = 32; controls). End-of-treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls ( P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) ( P = 0.031). Follow-up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls ( P < 0.001). The eight sustained responders and 2 7 non-responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti-IFN neutralizing anti-bodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long-term clearance of HCV RNA and normal ALT levels in 23% of patients.     

Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection – a pilot study

Standard treatment for chronic hepatitis C is with interferon (IFN)-α and ribavirin for 6–12 months. In dialysis patients only interferon therapy is currently used due to the lack of knowledge concerning ribavirin dosage and side-effects. The aim of this study was to investigate if ribavirin can be added to interferon when treating dialysis patients with hepatitis C.
Five patients on haemodialysis and one patient on peritoneal dialysis with chronic hepatitis C, five with genotype 1 and one with genotype 4, were given interferon-α2b 3  M U thrice weekly for 4 weeks, whereafter ribavirin 200–400 mg was added, for an intended total treatment period of 28 weeks. Ribavirin plasma concentrations were monitored, using HPLC.
Four patients completed the treatment. One patient suffered marked side-effects from interferon and therapy was terminated. One patient developed heart failure and died after 14 weeks of treatment but the death was not considered treatment related. Based on plasma concentrations, ribavirin doses were frequently adjusted initially. The target concentration (10–15 μmol/L) was reached with average daily doses of 170–300 mg ribavirin. Ribavirin induced anaemia was managed with high doses of erytropoietin (20 000–30 000 IU/week). Five of six patients became hepatitis C virus (HCV)-RNA negative during treatment, but four relapsed post-treatment; one is HCV-RNA negative.
Hence ribavirin, in combination with IFN-α, can be used to treat dialysis patients with HCV. However, this requires reduced ribavirin doses and close monitoring of ribavirin plasma concentrations and haemoglobin. Ribavirin-induced anaemia can be managed with high doses of erythropoeitin.     

The pattern of response to interferon alpha (alpha-IFN) predicts sustained response to a 6-month alpha-IFN and ribavirin retreatment for chronic hepatitis C. TVVH Study Group

BACKGROUND/AIMS: In chronic hepatitis C, interferon-alpha (alpha-IFN) and ribavirin combination therapy improves sustained response compared to alpha-IFN monotherapy, both in naive patients and in previous alpha-IFN relapsers, but the efficacy of such therapy remains limited in non-responder cases. The aim of this study was to assess whether the pattern of response to alpha-IFN alone may predict sustained response to combination therapy during retreatment. METHODS: Fifty previous alpha-IFN relapsers and 50 previous alpha-IFN non-responders were retreated with a high alpha-IFN dose (6 MU/thrice weekly for 2 months; induction phase) and then randomised to continue with alpha-IFN alone (3 MU/thrice weekly) or to receive combination therapy (3 MU/thrice weekly of alpha-IFN and 1000-1200 mg/daily of ribavirin) for an additional 6 months according to the biochemical response to alpha-IFN shown after the induction phase. All patients were also evaluated for virological and histological response. RESULTS: Eleven of 25 (44%) relapsers treated with combination therapy and 4/25 (16%) treated with alpha-IFN alone achieved a sustained response. The corresponding figures among non-responders were 1/25 (4%) and 0/25, respectively. Among 26 patients with a complete ALT and HCV-RNA response after 2 months of alpha-IFN, sustained response was seen in 11/14 (79%) treated with combination therapy and in 4/12 (33%) treated with alpha-IFN alone (p=0.05). On the other hand, of 74 cases still HCV-RNA positive after 2 months of alpha-IFN alone, biochemical and virological end of therapy response was better with combination therapy (11/36; 30.5%) compared to alpha-IFN alone (4/38; 10.5%), but only one patient developed a sustained response (1/36; 3%). CONCLUSIONS: The retreatment with a 6-month combination therapy was associated with a high rate of sustained response only in patients showing a complete biochemical and virological response to alpha-IFN alone. Longer retreatment with combination therapy may be needed to achieve a sustained response in patients without a prompt virological response to alpha-IFN.     

Statistical models for predicting a beneficial response to interferon-α in patients with chronic hepatitis B

Therapy with interferon-α has been reported to induce remissions in 35% of patients with chronic hepatitis B. The ability to identify patients likely to respond would be helpful in making recommendations for treatment. In this statistical analysis we included 82 patients with chronic hepatitis B who received interferon-α in clinical trials at the National Institutes of Health between 1984 and 1991. A response was defined as the loss of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) within 1 year of therapy. Multiple clinical parameters measured at pretreatment (month 0) and after the first month (month 1) of therapy were selected by stepwise regression to support the development of the prognostic models: the two-stage logistic regression model and a neural network that utilized higher-order non-linear interactions between variables. Among the 82 patients, 24 (29%) were responders. The two-stage logistic model using pretreatment variables: sex, hepatic fibrosis and alanine aminotransferase (ALT) levels correctly identified 61% of responders and 76% of non-responders. When HBV DNA at month 1 along with sex, initial ALT and fibrosis was included, the resultant model correctly identified 69% of responders and 77% of non-responders. The neural network, by incorporating interactions between variables, correctly identified 77% and 86% of responders, and 87% and 92% of non-responders, using pretreatment factors alone and the combination of pretreatment and month 1 factors respectively. Hence, the neural network was more accurate than the simple logistic regression model in predicting a response to interferon-α in chronic hepatitis B. The universality of these models needs to be further verified.     

Long-term administration of interferon-α in non-responder patients with chronic hepatitis C: follow-up of liver fibrosis over 5 years

In chronic hepatitis C, previous data have shown that short-term treatment with interferon-α (IFN-α) can reduce collagen deposition in the liver independently of the viral response. The aim of this work was to determine, in non-responder patients, the long-term effect of IFN-α on liver fibrosis according to the total administered dose and the fibrotic stage. Fibrosis was investigated on liver biopsies from 24 non-responder patients with chronic hepatitis C retreated with successive courses of IFN-α. The degree of liver fibrosis was assessed on three successive biopsies, performed before IFN-α treatment and 1 and 5 years later, in 13 and 11 patients, respectively, treated for less (mean: 7.5 months, 313 MU) and more (mean: 21.8 months, 791 MU) than 1 year. For each biopsy, fibrosis was assessed using a histological semiquantitative fibrosis scoring system and by morphometry after picrosirius red staining. Regardless of the dose and duration of IFN-α therapy, a slight decrease of fibrosis was observed in patients 5 years after starting treatment. In cirrhotic patients, a short treatment induced an improvement followed by a relapse of fibrosis in 57%, and only 43% of patients showed constant collagen regression over the 5 years of follow-up. On the contrary, after prolonged therapy, a progressive and significant decrease occurred throughout the follow-up period in all patients ( P = 0.045). Long-term treatment with IFN-α is therefore associated with regression of liver fibrosis, particularly in cirrhotic patients. These promising results need to be confirmed in a larger series of patients.     

Hepatitis C virus RNA and long-term response to recombinant interferon-α2b in patients with chronic hepatitis C

Summary. The effectiveness of recombinant interferon-α2b (rIFN-α2b) in eradicating hepatitis C virus (HCV) RNA from serum has not been completely assessed. We studied 39 patients with compensated chronic hepatitis C diagnosed by liver biopsy and positive HCV RNA measured by polymerase chain reaction (PCR). Group I consisted of 26 patients treated with 3 MU of rIFN-α2b for 6 months; group II, 13 control patients observed for six months; and group III, 12 out of 13 patients from group n who subsequently received 5 MU of rIFN-α2b for 6 months. In group I, 11 out of 23 (47.8%) patients who completed treatment had an immediate response and five (21.7%) had a sustained response to therapy six months after treatment. No response was observed in patients from group II. In group III, 7 out of 12 (58.3%) patients who completed treatment had an immediate response and none had a sustained response. Considering all patients who completed rIFN-α2b treatment, HCV RNA remained positive at the end of therapy in three of five sustained responders (60%), six of 13 patients who relapsed (46.1%), and in all non-responders (100%). HCV RNA was positive 6 months after therapy in four (80%), 13 (100%). and 17 (100%) patients respectively. All patients with a sustained response had normal aminotransferase levels 18 months after therapy. We conclude that in chronic hepatitis C rIFN-α2b causes a significant immediate response but this is not sustained, only 2.8% of treated patients had a sustained loss of HCV RNA. Normal aminotransferase persist in the long term, despite persistence of HCV RNA.     

Development of a hepatitis C virus relapse model using genome-length hepatitis C virus ribonucleic acid-harboring cells possessing the interferon-α-resistance phenotype

Aim:  The cure rate of current interferon (IFN) therapy is limited to approximately 50% and most of the relapses after therapy are caused by genotype-1. To develop a relapse model in cell culture, we attempted to obtain genome-length hepatitis C virus ribonucleic acid (HCV RNA) harboring cells possessing the IFN-α-resistance phenotype from previously established OR6 cells, which enabled the luciferase reporter assay for monitoring of HCV RNA replication.
Methods:  The IFN-α-resistant HCV RNA-harboring cells and control cells were obtained by the treatment of OR6 cells with and without IFN-α, respectively. Then, we examined the relapse of HCV in IFN-α-resistant HCV RNA-harboring cells.
Results:  Only type I IFN (α and β) showed significantly different anti-HCV activity between IFN-α-resistant HCV RNA-harboring cells and control cells. There was no significant difference in the anti-HCV activity of IFN-γ, fluvastatin, or cyclosporine A between the two types of cells. Furthermore, we showed that fluvastatin or cyclosporine A in combination with IFN-α could prevent the relapse after therapy in the IFN-α-resistant HCV RNA-harboring cells.
Conclusion:  We developed a HCV relapse model in cell culture using IFN-α-resistant HCV RNA-harboring cells. Thus anti-HCV reagents, which have a mechanism different from IFN-α, were shown to be useful for preventing a relapse of IFN-α-resistant HCV.     

Long-term interferon-α treatment of children with chronic hepatitis delta: a multicentre study

Summary We assessed the efficacy of prolonged interferon-α (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN-α2b(5 MU m^-2, then 3 MU m^-2 three times weekly for 12 (medium-term group, MTG) or 24 months (long-term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow-up. Six of the eight hepatitis Be antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN-α treatment in children with chronic type D hepatitis has a transient effect, and long-term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological response.     

Development of Thyroid Autoimmunity after Administration of Recombinant Human Interferon-α2b for Chronic Viral Hepatitis

To investigate the frequency and clinical characteristics of autoantibody formation and development of autoimmune thyroid disease after interferon therapy, we measured the autoantibodies to thyrotropin receptor (TBII), thyroglobulin (ATA), and microsomal antigen (AMA) in 28 patients with histologically proven chronic viral hepatitis [25 males, three females; mean age 38.7 ± 8.7 (SD) yr] receiving recombinant interferon-α2b (IFN-α) treatment. Twenty patients with chronic hepatitis B (positive for HBsAg, HBeAg, and HBV DNA) and eight patients with chronic hepatitis C (positive for anti-HCV and HCV RNA) received IFN-α, 3 million units subcutaneously, three times a week for 6 months. Before, during, and up to 6 months after IFN-α therapy, thyroid hormone levels and titers of AMA, ATA, and TBII were measured every 2 months. None of them had thyroid dysfunction or antithyroid autoantibodies before IFN-α treatment. A 34-yr-old male patient developed Graves'disease during the last month of therapy. He required long-term antithyroid medications, even after discontinuation of IFN-α. Another 44-yr-old female patient developed AMA during IFN-a treatment; however, thyroid function remained normal and goiter did not develop in this patient. No other patient developed thyroid autoantibodies and thyroid dysfunction. In summary, only a small minority of patients will develop thyroid autoimmunity during IFN-α therapy, and much less often with this low dose of IFN-α.     

Long-term retreatment in chronic hepatitis C patients who were non-responders to an initial course of interferon-α2b

Nineteen patients with chronic hepatitis C who were virological non-responders (seven responder/relapse and 12 no response) to an initial 24-week course of interferon-α2b (IFN-α2b) at a dose of 3million units (MU) thrice weekly were retreated for an additional 48 weeks at the same dosing schedule and followed-up for another 24 weeks post-therapy. At the end of follow-up (week 72), six (32%) of the 19 patients were hepatitis C virus (HCV) RNA negative and were virological complete responders to retreatment. The viral genotypes in these six patients included two each with 1b and 3a, one with 2b, and another with 2a/2b; five of the six virological responder patients had cirrhosis. Significant predictors for successful retreatment included lower baseline HCV RNA concentrations prior to the first course of therapy, 2 log₁₀ reductions in serum HCV RNA during the initial treatment and classification into the virological ‘responder/relapse’ category after the first course of IFN (P < 0.01 for all observations). When the above factors were used to construct a predictive model to determine response to retreatment, it was found that the absence of a 2 log₁₀ drop in HCV RNA concentrations during the first course of IFN therapy was the most reliable indicator of non-response to retreatment (likelihood ratio = 10, P = 0.0014). In addition, the presence of HCV RNA at week 12 of retreatment was 100% predictive of virological non-response to the 48-week course of therapy. Our findings indicate that an additional 48-week course of IFN-α2b therapy at 3 MU thrice weekly will achieve a virological complete response in 60% of patients who had a 2 log₁₀ drop in HCV RNA during their first course of treatment, and measurement of week-12 HCV RNA during retreatment to identify non-responders is beneficial to patients as well as being cost-effective. Thus, a second course of IFN remains a viable option in a subgroup of non-responder patients, regardless of genotype or the presence of compensated cirrhosis.