Prednisone withdrawal followed by interferon alpha for treatment of chronic hepatitis C infection: results of a randomized controlled trial

Immunosuppressive therapy increases levels of hepatitis C virus (HCV) RNA, and when combined with interferon, corticosteroids have been reported to variably improve or have no effect on sustained response rates. We conducted a randomized double-blind placebo-controlled trial in 39 patients with biopsy-proven chronic HCV infection and elevated alanine aminotransferase levels. Patients received either 6 weeks of a tapering dose of prednisone (60 ng, 40 mg, and 20 mg in 2-week intervals) or an identical placebo. All patients then received recombinant interferon alpha-2b, 3 million units three times a week for 24 weeks. Patients were then followed for a further 24 weeks. At the end of the study there was no significant difference in the sustained biochemical response rates between the two groups (4/20 vs. 3/19, p value was not significant). Prednisone-treated patients had a significant increase in HCV RNA from baseline during steroid treatment (400 +/- 60% increase vs. -280 +/- 140% decrease; p = 0.005). Two prednisone-treated patients were withdrawn from the study secondary to serious complications related to therapy. Prednisone priming before interferon alpha therapy in patients with chronic HCV infection does not improve the sustained response rate. This therapy was associated with an increase in viral burden and significant morbidity.     

Glycyrrhizin withdrawal followed by human lymphoblastoid interferon in the treatment of chronic hepatitis B.

Seventeen patients with chronic hepatitis B were treated with a 4-week administration of glycyrrhizin followed by a 4-week treatment with human lymphoblastoid interferon, then followed for 6 months after the end of treatment. All were positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B virus-associated DNA polymerase (DNA-p) for at least 6 months before entry. All patients were Japanese and none of them were homosexuals. Eleven patients lost DNA-p activity and 10 of them lost HBeAg. Three of these 10 patients had antibody to HBeAg. In 10 patients who became HBeAg-negative, alanine aminotransferase levels after glycyrrhizin administration were higher and initial DNA-p activities relatively lower than the levels found in seven patients who remained HBeAg-positive. The immunomodulator provided by a short course of glycyrrhizin before administration of human lymphoblastoid interferon may be an effective treatment for patients with chronic hepatitis B.     

Glycyrrhizin withdrawal followed by human lymphoblastoid interferon in the treatment of chronic hepatitis B

Seventeen patients with chronic hepatitis B were treated with a 4-week administration of glycyrrhizin followed by a 4-week treatment with human lymphoblastoid interferon, then followed for 6 months after the end of treatment. All were positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B virus-associated DNA polymerase (DNA-p) for at least 6 months before entry. All patients were Japanese and none of them were homosexuals. Eleven patients lost DNA-p activity and 10 of them lost HBeAg. Three of these 10 patients had antibody to HBeAg. In 10 patients who became HBeAg-negative, alanine aminotransferase levels after glycyrrhizin administration were higher and initial DNA-p activities relatively lower than the levels found in seven patients who remained HBeAg-positive. The immunomodulater provided by a short course of glycyrrhizin before administration of human lymphoblastoid interferon may be an effective treatment for patients with chronic hepatitis B.     

A controlled study of treatment with recombinant interferon alpha of chronic hepatitis due to the B virus in childhood

The natural history of chronic hepatitis B virus (HBV) infection in children may lead to hepatic cirrhosis and hepatoma. Since the antiviral effect of recombinant interferon alpha (rIFN-alpha) in the treatment of chronic hepatitis in adults has been proven, a controlled study of therapy using rIFN-alpha in children chronic hepatitis due to HBV has been carried out. Twenty-four children (4-14 years old) HBsAg, HBeAg and HBV-DNA positive were randomly allocated to one of three groups: 1) n = 8, control; II) n = 8, who received 10 MU/m2 of rIFN-alpha (Boehringer Ingelheim)/m2 body surface, I.M., twice a week for six months and III) n = 8, treated with 7.5 MU/m2 under the same conditions. No basal differences between the three groups were observed. No intolerable toxicity was observed and all children completed the treatment period. At the end of the therapy, 5 patients in groups I (1 case), II (2 cases) and III (2 cases), had lost circulating HBV-DNA. With respect to HBeAg, 3 patients (one from each group) were negative by the sixth month, developing anti-HBe. Decreases in ALT levels among rIFN-alpha responder patients were observed, while no changes occurred in the rest. A significant decrease in the percentage of HBcAg positive hepatocytes was detected only among treated patients, when comparing the basal and final liver biopsies. In summary, rIFN-alpha therapy in children is well tolerated. In addition, these results suggest that rIFN-alpha has an antiviral effect.     

Failure of acyclovir to enhance the antiviral effect of alpha lymphoblastoid interferon on HBe-seroconversion in chronic hepatitis B. A multi-centre randomized controlled trial.

Serum HBeAg levels and HBe-seroconversion were investigated in patients with chronic HBeAg-positive hepatitis who were randomized to receive either alpha lymphoblastoid interferon (5 megaunits subcutaneously daily for 16 weeks) plus acyclovir (2 g intravenously daily during weeks 1 and 2 and weeks 9 and 10) (n = 49) or no treatment (n = 48). HBeAg levels in serial dilutions of patient serum were assessed quantitatively by radioimmunoassay and compared with the values found for negative control serum. One year after the start of therapy 44 treated patients and 43 control patients were available for follow-up. A complete response (HBe-seroconversion) occurred in 11 treated patients (25%) and six controls (14%) (difference: 11%, 95% CI-5-28%). A partial response (HBeAg less than 50% of initial level) was found significantly more often for treated patients (n = 13, 30%) than for controls (n = 2, 5%) (difference: 25%, 95% CI 10-40%). During acyclovir-interferon combination therapy the decrease in HBeAg level was similar to that achieved during therapy with interferon alone. We conclude that acyclovir does not enhance the effect of interferon on serum HBeAg levels. Since HBeAg levels continue to decline during interferon treatment and rebound thereafter to pretreatment levels, prolongation of therapy may yield a higher response rate.     

Randomised controlled trial of recombinant human interferon -αA for chronic active hepatitis B

The efficacy of interferon treatment for Australian patients with chronic active hepatitis B (CAH-B) was assessed by a three-centre randomised controlled trial in Sydney and Brisbane. Thirty patients (29 with histologically-proven CAH-B with and without cirrhosis and one with chronic persistent hepatitis) were allocated to receive either thrice weekly intramuscular injections of recombinant human leucocyte interferon -αA (either 2.5, 5.0 or 10.0 million units/m²) for six months followed by 12 months of observation, or to be observed for 18 months without active treatment. Three of 23 treated patients but none of seven controls underwent clinical, biochemical and histological resolution of their disease with loss of HB_sAg, HB_eAg and HBV-DNA from serum. An additional six treated and two control patients underwent a sustained partial remission of their disease. This was characterised by resolution of symptoms and serum aminotransferase abnormalities in association with seroconversion from HB_eAg positive to negative, loss of HBV-DNA from serum but persistent hepatitis B surface antigenaemia. In such patients, there was significant improvement in histological appearances but some necroinflammatory activity remained and fibrosis was unchanged. Although total response rates were similar in treated and control subjects, they appeared to occur earlier after interferon treatment. Treatment with interferon was associated with predictable but minor side effects that usually did not necessitate dose reduction and rarely compromised the patient's life style. Interferon is thus a feasible treatment for CAH-B. Complete responses occurred only in treated patients and partial responses appeared to occur earlier in treated than in untreated patients. However, differences in the partial response rate at 18 months were not significant and seroconversion from HB_eAg positive to negative was not associated with complete histological resolution of disease activity. Hence, while interferon is a promising agent for treatment of CAH-B, efforts must continue to define more optimal treatment regimes and to identify those patients most likely to respond to this agent.     

重组α干扰素治疗慢性乙型肝炎和慢性丙型肝炎的经济学分析

目的 研究干扰素α２ｂ（ＩＦＮα２ｂ）慢性乙型肝炎（Ｎ惭肝）和慢性丙型肝炎（慢丙肝）的长期经济学效果和效益。方法 根据全国１２个数学医院提供的６５００例慢乙肝资料,分成二个队列,其中２９５４例为ＩＦＮ治疗组（乙型２１９８例,丙型７５６例）;３５４６例为非ＩＦＮ治疗组（乙型２６４２例,丙型９０４例）。同时应用ＭＥＤＬＩＮＥ和中国生物医学光盘文献数据库（ＣＢＭＤ）检索有关慢乙肝、慢丙肝自然病程、转归和     

A randomized controlled trial of recombinant interferon-alpha in chronic hepatitis C in hemophiliacs

Chronic liver disease associated with hepatitis C virus (HCV) is an important cause of morbidity and mortality in hemophilia. We have used recombinant interferon alpha-2b (IFN alpha-2b) in a randomized controlled liver biopsy trial to treat hemophiliacs with chronic hepatitis. Eighteen patients entered the study, 16 of whom were subsequently shown to have antibodies to the HCV. All underwent liver biopsy at entry and were randomized to either treatment with self-administered IFN alpha-2b, 3 million units subcutaneously thrice weekly (n = 10) or no treatment (control group) (n = 8). Nine subjects had chronic active hepatitis, seven had chronic persistent hepatitis, and two had cirrhosis. Twelve months after entry into the study 17 patients underwent a second liver biopsy. All biopsies were coded, assessed, and scored according to the histologic severity of the liver disease. Ten patients were administered IFN for 1 year, and in four patients normalization of alanine aminotransferase (ALT) occurred compared with none in the untreated group. After the second liver biopsy, six of the eight initial no-treatment patients were treated with interferon 3 million units thrice weekly for 6 months, and normalization of ALT was seen in five patients. Biochemical relapse within 4 months of stopping IFN occurred in one of four patients treated for 1 year and in four of five patients treated for 6 months. IFN treatment was well tolerated. Although the histologic scores of the two groups were similar at entry into the study, after 12 months the biopsy appearances in the treated group were significantly improved compared with the controls (P less than .01). Histologic improvement was noted in the three interferon-treated human immunodeficiency virus antibody-positive patients and also in other patients who had no biochemical response. We conclude that low-dose recombinant IFN alpha is effective in normalizing transaminases and improving the histologic appearances in at least 50% of hemophiliacs with chronic hepatitis C.     

Randomised controlled trial of lymphoblastoid interferon for chronic active hepatitis B.

Thirty male patients (27 homosexual) with biopsy proven chronic active hepatitis B were randomised to receive lymphoblastoid interferon (Wellferon) or no treatment. All patients were HBeAg positive and had continuing viral replication. Patients receiving treatment were given a single daily intramuscular injection of interferon for 28 days at a starting dose of 2.5 MU/m2 increasing to a maximum of 7.5 MU/m2/day. Transient side effects of malaise and influenza like symptoms occurred in all patients and resolved rapidly after treatment. Hepatitis B viral replication was suppressed during interferon treatment in all patients but the effect was limited to the period of therapy. After one year there was no appreciable difference in viral markers between the two groups of patients and this treatment schedule appears less effective than the thrice weekly, three month regimes recently reported from other centres.     

Short-term prednisolone followed by recombinant human alpha-interferon alone or combined with adenine-arabinoside in chronic hepatitis B. A prospective and randomized trial

Twenty-nine patients with chronic hepatitis B, presenting both hepatitis B surface antigen and hepatitis B virus deoxyribonucleic acid in serum, were studied in a randomized trial treatment consisting of oral prednisolone for 28 days followed 14 days after steroid withdrawal, by either a 55 s.c. injection course of 5 M unit recombinant human alpha-interferon (group 1, 14 patients) or by adenine-arabinoside (for 21 days) combined from the fourteenth day on with the same 55 s.c. injection schedule of interferon (IFN) (group 2, 15 cases). The two groups were well matched with respect to demographic, biochemical, virological and histologic features. Significant side-effects leading to premature discontinuation of interferon were observed in only four cases in group 2 and were always reversible. Efficacy was judged on a mean follow-up period of 17 months. For the whole population, 17 patients (59%) exhibited a sustained serum hepatitis B virus deoxyribonucleic acid disappearance which corresponded to a marked improvement in liver function as demonstrated by a quasi-normalization of their serum transaminase values (ALT with n less than 22 UI/l: 23 +/- 24 vs. 139 +/- 115 before treatment; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

A controlled trial of human lymphoblastoid interferon in chronic hepatitis B in Italy

Sixty-four heterosexual Italian carriers of HBsAg with chronic HBeAg and hepatitis B virus DNA-positive hepatitis were assigned randomly either to receive human lymphoblastoid interferon (injections of 5 million units per m2 three times per week for 6 months) or to serve as untreated controls. After 18 months of follow-up evaluation, 26 of the 33 treated patients (79%) had cleared hepatitis B virus DNA, 23 (70%) had lost HBeAg and 20 (61%) had seroconverted to anti-HBe. Fifteen of the 31 controls (48%) had cleared hepatitis B virus DNA (p = 0.01), 12 (39%) had lost HBeAg and nine (29%) had seroconverted to anti-HBe (p = 0.002). Eight treated patients but only one control had lost HBsAg and seroconverted to anti-HBs (24% vs. 3%, p = 0.01). Treated patients cleared hepatitis B virus markers after a mean interval of 4 months, compared with 8 months in the controls. All responders to interferon cleared intrahepatic HBcAg, and 50% showed histological improvement. The baseline hepatitis B virus DNA levels and the original histology were not predictive of a response to therapy; women appeared to respond better than men. Lymphoblastoid interferon provides an effective therapy in the heterosexual Italian patient with chronic hepatitis B.     

Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial

OBJECTIVES: The aims of this long-term, prospective randomized study were to evaluate the clinical usefulness of alpha-interferon in treating chronic HBV infection and to establish whether clearance of viral replication markers and normalization of liver function tests induced by alpha-interferon were sustained. METHODS: Sixty-four patients with chronic wild type (HBeAg-positive) hepatitis B, enrolled between 1983 and 1987, were randomized into two groups. Thirty-three patients received alpha-interferon (5 MU/m2 three times weekly for 6 months; treated group), and 31 were not treated (controls). Treated and control patients were prospectively followed for a mean of 86.4 +/- 6.96 and 79.7 +/- 6.8 (p = NS) months, respectively. RESULTS: Clearance of the following viral markers was found in treated and control patients as follows: HBV-DNA, 26 (78.9%) and 18 (58.1%) (p = 0.106); HBeAg, 30 (90.9%) and 19 (61.2%) (p < 0.007); and HBsAg, 12 (36.4%) and three (9.8%) (p < 0.017). Persistent abnormal ALT levels were found in 11 (33.3%) treated and in 22 (70.9%) control patients (p < 0.025). Four control and three treated patients developed portal hypertension whereas two control and one treated patient developed hepatocellular carcinoma. Seven patients (five treated and two controls) were retrospectively found to have hepatitis C virus (HCV) coinfection before enrollment. To date, all coinfected patients remain positive for HCV-RNA. Also, all HCV coinfected patients, except one in the treated group, had persistent increased serum ALT levels. One of the coinfected patients developed portal hypertension. CONCLUSIONS: Chronic HBV hepatitis patients responding to interferon treatment had a faster, more complete, and sustained clearance of viral markers than controls; HCV coinfection does not seem to negatively affect the clearance of HBV replicative markers. However when coinfection occurs, hepatic disease persists despite HBV marker clearance.     

Efficacy of thymosin alpha-1 and interferon alpha in treatment of chronic viral hepatitis B： A randomized controlled study

INTRODUCTION Chronic hepatitis B virus (HBV) infection is a serious problem worldwide and may result in adverse sequelae, such as cirrhosis and hepatocellular carcinoma (HCC)[1-2], which is becoming more prevalent worldwide, especially in HBV-endemic area…     

A controlled trial of interferon with or without prednisone priming for chronic hepatitis B.

In a randomized, controlled trial of recombinant interferon alfa-2b with or without prednisone priming in Chinese adults with chronic hepatitis B virus infection, stratified randomization for pretreatment serum alanine aminotransferase levels was done. Partial or complete antiviral responses were achieved in 17 (21.5%) of 79 treated patients and 3 (8.3%) of 36 controls (P = 0.14). The response to interferon treatment was significantly better in those who had elevated pretreatment transaminase levels and comparable to that reported in white patients [15 (38.5%) of 39 patients compared with 2 (5%) of 40 who had normal pretreatment transaminase levels (P = 0.0005)]. The spontaneous seroconversion rate was also higher among the controls with elevated transaminase levels [3 (18.8%) of 16 compared with 0 of 20 with normal transaminase levels], but this difference was not statistically significant (P = 0.16). Among the interferon-treated patients, prednisone priming appeared to have a marginal benefit over treatment with interferon alone in patients with elevated transaminase levels (43% vs. 33%), but not in those with normal transaminase levels (0% vs. 9.5%). It was confirmed that Chinese patients with normal transaminase levels respond very poorly to interferon alfa therapy. However, the response was significantly better in patients with elevated transaminase levels.     

A controlled trial of recombinant interferon-alpha in Caucasian children with chronic hepatitis B

Twenty-four children with chronic active hepatitis due to hepatitis B virus (HBV) infection, who were positive for HBeAg and had increased levels of transaminases, were included in a controlled study of treatment using recombinant interferon-alpha (rIFN-alpha), 10 MU/m2 body surface, intramuscularly, 3 times a week over a period of 3 months. During therapy, a significant decrease in HBV-DNAp was observed in the 12 patients treated. By the end of therapy, the HBV-DNA had disappeared in 3 children, the same occurring in 1 child (33% overall) during the course of the 4th month. By this time, all the controls remained with HBV replication markers (p less than 0.05). The 4 treated patients who responded became HBeAg-negative, developing anti-HBe during the first 12 months after therapy. In the control group, the HBV-DNA disappeared in 3 children in the 7th month of follow-up. All of the children remained HBsAg-positive. The therapy with rIFN-alpha was well tolerated, secondary effects consisting of a flu-like syndrome and a slight decrease in leukocytes and platelets. At the second biopsy, 15 months after the beginning of therapy, a significant decrease in Knodell's index of histological activity was observed in the responders. In the light of these results and since treated children lost viral replication markers in a shorter period of time than the controls, who seroconverted spontaneously, we consider that rIFN-alpha may be useful in the treatment of chronic hepatitis B in childhood.     

Vitamin E treatment for children with chronic hepatitis B：A randomized placebo controlled trial

AIM：To evaluate the safety and efficacy of vitamin E in children with chronic hepatitis B.METHODS：We randomly assigned patients with chronic hepatitis B,positive for hepatitis B e antigen（HBeAg）,to receive either vitamin E or placebo once daily for 6 mo in a 3：1 ratio and double-blind manner.The primary end point was HBeAg seroconversion,defined as the loss of HBeAg,undetectable levels of serum hepatitis B virus DNA,and the appearance of antibodies against HBeAg 12 mo after therapy.RESULTS：At baseline visit,49 patients had normal and 43 had increased serum aminotransferase levels.Twenty-nine patients did not respond to previous treatment with interferon-α or lamivudine.Seventy-six children completed the study;16 were non-compliant（n = 7）,lost to follow-up（n = 7）,or started another antiviral treatment（n = 3）.Intention-to-treat analysis showed HBeAg seroconversion in 16 children（23.2%） treated with vitamin E and two（8.7%） in the placebo group（P = 0.13）.Vitamin E was well tolerated.CONCLUSION：There is only a tendency that vitamin E may promote HBeAg seroconversion.Therefore larger studies are needed to clarify the role of antioxidants in the therapy of chronic hepatitis B.     

Efficacy of a short-term ribavirin plus interferon alpha combination therapy followed by interferon alpha alone in previously untreated patients with chronic hepatitis C: a randomized multicenter trial

BACKGROUND: Combination therapy with interferon alpha (IFNalpha) plus ribavirin has been shown to improve the sustained response rate in patients with chronic hepatitis C but there is little information regarding the lengths of time for this therapeutic regimen. In this study we therefore tried to evaluate whether the analysis of different virological parameters could provide new clues with respect to the early determination of the efficacy of this form of combination therapy. Furthermore, we also examined whether short-term induction combination therapy followed by IFNalpha alone is more effective than monotherapy in mounting an initial as well as a sustained virological response. METHODS: 185 patients with histologically proven chronic hepatitis C (mean age 42 years (range 19-65 years); 110 males, 75 females) were enrolled in the study. The patients were randomly assigned to receive, over the first 12 weeks, either interferon alpha 2a 6 million units (MU) three times weekly plus ribavirin 14 mg/kg per day (n=93) or the same dose of IFNalpha alone (n=92). Patients with a virological response (serum HCV RNA undetectable) after 12 weeks were subsequently treated with 3 MU IFNalpha alone thrice weekly for a further 40 weeks. Otherwise, treatment was discontinued. After the end of treatment, patients were followed up for 24 weeks. RESULTS: Patient characteristics at baseline were not significantly different in the two treatment groups. An initial virological response at week 12 was seen in 61 (66%) patients receiving IFNalpha plus ribavirin and in 44 (48%) being treated with IFNalpha alone (p=0.015) and this improvement in the response rate was mainly restricted to HCV genotype 1-infected patients (58% vs. 38%). In contrast, end-of-treatment (week 52) and sustained virological response rates were similar in both groups (37% vs. 29% and 26% vs. 17% [p=0.1], respectively). Interestingly, patients with HCV genotype 3, however, clearly benefited from short-term combination therapy. Thus, sustained virological response rates in these patients significantly increased from 25% (IFNalpha monotherapy) to 59% (combination therapy) (p=0.05). CONCLUSIONS: Short-term combined therapy for 12 weeks is more effective than the monotherapy with respect to the induction of an initial virological response but this effect applies only to genotype 1-infected patients. However, there is no significant difference between both therapeutic schedules with regard to the induction of sustained response. Although HCV genotype 3-infected patients seem to benefit from this short-term combined therapy, prolonged combined therapy may be necessary in HCV genotype 1-infected patients.     

Therapy of chronic hepatitis B with recombinant human alpha and gamma interferon

Eight patients with chronic hepatitis B entered a pilot study of gamma interferon and alpha interferon in combination. Gamma interferon alone had minimal inhibitory effects on serum levels of hepatitis B virus as monitored by serum HBV DNA and DNA-polymerase activity. The drug also gave troublesome side effects. In contrast, alpha interferon had more potent inhibitory effects on serum HBV levels and fewer side effects. When combined, the two interferons showed no additive or synergistic effects in inhibiting serum levels of HBV DNA or DNA polymerase. These findings indicate that the addition of gamma interferon to alpha interferon provides no additional antiviral effects but contributes significantly to side effects.