Case Report: Agranulocytosis induced by interferon-α therapy for chronic hepatitis C

A 60-year-old woman presented with chronic active hepatitis C whose HCV-RNA genotype was II according to Okamoto's classification and serum HCV-RNA concentration was 10⁴ copies/mL. Agranulocytosis was induced 13 days from the commencement of interferon (IFN)-α 2b (6 MU/day) therapy, so the IFN therapy was immediately discontinued. The agranulocytosis improved rapidly with the administration of a granulocyte colony stimulating factor (G-CSF). The possibility that IFN was associated with maturational arrest of myeloid progenitor cells was considered. During the course of 3 years of follow-up, her liver function has remained normal and serum HCV-RNA remains negative.     

Interferon therapy for patients more than 60 years of age with chronic hepatitis C

Abstract Nineteen patients aged > 60 years with chronic hepatitis C (CHC) received interferon (IFN) therapy and a complete response (CR) was achieved by five of them (26%). The incidence of CH with severe fibrosis in this elderly group was significantly higher than in another 52 patients with CHC who were < 60 years of age (the younger group; P < 0.05). There was no significant difference in the hepatitis C virus (HCV) genotype distribution between the elderly group and the younger group. However, the HCV-RNA titre was significantly higher in the elderly group than in the younger group ( P < 0.05). There was no significant difference in the efficacy rate of IFN in the elderly and younger groups after standardization of the background factors. In the elderly group, the HCV-RNA titre was significantly lower in the patients achieving CR than in those with no response ( P < 0.05). These data suggest that elderly patients with a low HCV-RNA titre can still respond well to IFN therapy.     

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.     

Interferon treatment for chronic hepatitis C in haemodialysis patients: Suggestions based on a small series

Chronic hepatitis C is endemic among chronic haemodialysis patients. There have been a number of reports on hepatocellular carcinoma developing in such patients in Japan. The present study reports on the treatment of 15 patients who showed elevated ALT levels due to biopsy proven chronic hepatitis C with interferon α-2a (IFN). The dose schedule was 6 mega units (MU) daily for the first two weeks followed by 3 doses per week for 5.5 months. Side effects were so severe that IFN treatment was discontinued early in one patient, the dosage reduced in 11 and only tolerated in the original schedule by three patients. Excluding one patient who only recently completed the therapy, 13 were able to be evaluated for therapy efficacy by assessment of serum ALT and viral RNA. The overall results showed that IFN was effective in eight of 13 patients, a rate somewhat higher than the reported figures in this country. It is concluded that IFN therapy is indicated in haemodialysis patients with progressive chronic hepatitis C, but the dose administered should be lower and the dose schedule more flexible, perhaps 3 MU three times a week, in order to minimize untoward side effects.     

Interferon receptors during treatment of chronic hepatitis B with interferon

The in vitro binding of 125I-labelled human alpha-interferon to peripheral blood mononuclear cells from 13 patients with chronic hepatitis B during interferon therapy was assayed in order to identify changes in the number of interferon receptors during treatment. Nine patients were treated with human alpha-interferon (Hu alpha-IFN) or human beta-interferon (Hu beta-IFN) daily for 4 weeks. During therapy, receptor sites per cell decreased by 40%. Two weeks after therapy ceased, this number had returned to the pretreatment level. The other four patients were given Hu alpha-IFN daily for 2 weeks, no injections for 2 weeks, and daily injections for 2 weeks. During both periods of therapy, receptor sites decreased by 40%. The number increased to 94% of the pretreatment level 1 week after the first period and to 101% 2 weeks later. It was 80% 1 week after the second period of injections and 108% 2 weeks later.     

Sheehan's syndrome: differential diagnosis in the acute phase

Dejager S, Gerber S, Foubert L&Turpin G (La Pitié Salpétrière, Paris, France). Sheehan's syndrome: differential diagnosis in the acute phase (Case Report). J Intern Med 1998; 244: 261–66.
Many studies have been done in the later course of Sheehan's syndrome, but very few have documented the acute phase with clinical, endocrine and imaging data. We present the case of a young woman complaining of severe headache after delivery, who developed hypopituitarism. Magnetic resonance imaging (MRI) disclosed the presence of an enlarged non haemorrhagic pituitary gland. Follow-up MRI showed a spontaneous and rapid shrinkage of the pituitary, within 20 days, which appeared as an empty sella 3 months later. Sheehan's syndrome may initially closely mimic hypophysitis, or the necrosis of an adenoma. We discuss the differential diagnoses, important for the best therapeutic management.     

Interferon increases serum thrombopoietin in patients with chronic hepatitis C

We measured serum thrombopoietin (TPO) in chronic hepatitis C treated with interferon (IFN). The platelet count before the therapy was 161.9 ×10⁹ ± 64.1 × 10⁹/l, which decreased to 116.3 × 10⁹ ±  48.4 × 10⁹/l 1 week after IFN therapy ( P  <0.01). On the other hand, serum TPO increased from 1.96 ± 0.60 fmol/ml to 2.68 ± 0.69 fmol/ml ( P  < 0.02). Contrary to a recent report that serum TPO was not altered in liver cirrhosis, these data indicate that serum TPO was increased in chronic hepatitis C in response to thrombocytopenia by IFN therapy.     

Interferon responsiveness in patients infected with hepatitis C virus 1b differs depending on viral subtype

BACKGROUND: Genotype 1b of hepatitis C virus (HCV) comprises mainly three subtypes, each named for its geographic prevalence (worldwide, W; Japan, J; and not in Japan, NJ). AIM: To characterise the newly identified subtypes of genotype 1b and to review factors associated with response to interferon (IFN) for each subtype. PATIENTS: Chronic hepatitis patients (80 men and 41 women; mean age 48.5 years, range 20.7--69.3) with HCV genotype 1b (W type, n=41; J type, n=38) or genotype 2a (n=42) were treated according to the same IFN protocol. Forty four patients (36.4%) negative for serum HCV RNA six months after cessation of treatment were considered complete responders. METHODS: Factors associated with complete response were investigated. RESULTS: Genotype 2a patients had lower viral loads (odds ratio 0.11 (95% confidence intervals (CI) 0.049--0.256)) and a better IFN response (odds ratio 0.25 (95% CI 0.117--0.552)) than genotype 1b patients whereas W type and J type patients had similar viral loads and responses to IFN. IFN response in W type patients was associated with female sex (odds ratio 0.23 (95% CI 0.055--0.983)) and low viral load (odds ratio 84.00 (95% CI 14.04--502.6)) whereas response in J type patients was related to transfusion history (odds ratio 7.20 (95% CI 1.443--35.91)), low viral load (odds ratio 117.0 (95% CI 17.82--768.3)), and genetic mutation in the interferon sensitivity determining region of the virus (odds ratio 0.08 (95% CI 0.013--0.553)). Multivariate analysis found low viral load (odds ratio 64.19 (95% CI 14.66--281.06)) to be the only significant independent factor associated with IFN response. CONCLUSIONS: Factors associated with IFN responsiveness in HCV infection differ with viral subtype.     

CASE REPORT: A patient who developed an amoebic liver abscess during treatment with interferon

A 65-year-old female received recombinant interferon (IFN) α-2b daily for the treatment of chronic hepatitis C. Fever (39°C or higher) developed 14 days after the start of administration. Abdominal computed tomography suggested multiple liver abscesses, which had not been detected before IFN administration. An autopsy revealed an amoebic liver abscess. A subclinical infection of Entamoeba histolytica in this case developed into amoebic liver abscess during IFN administration.     

Efficacy and side effects of intermittent recombinant interferon-α2a in chronic aggressive hepatitis C: With or without initial daily administration

To investigate the therapeutic effect and incidence of side effects of recombinant interferon-α2a (IFN-α) in chronic aggressive hepatitis C under stratification by administration mode, a study was conducted by assigning patients to either group A (daily consecutive administration of 9 million units (MU) IFN-α for 2 weeks and, thereafter, 3 MU intermittently 3 times weekly for 22 weeks) or group B (exclusively intermittent administration; 9 MU IFN-α twice weekly or 6 MU IFN-α thrice weekly for 24 weeks). The 28 patients in group A received IFN-α for 24 weeks up to a total dose of 324 MU and the 53 patients in group B received the same for 24 weeks up to a total dose of 432 MU. When recovery was defined as the absence of hepatitis C virus (HCV)-RNA 6 months after the completion of treatment, the rate of recovery for group A was 32.1% and that for group B was 37.7%, the latter being higher but without significance. Side effects in groups A and B consisted of leucopenia occupying 14.3 and 7.5%, respectively, and thrombocytopenia occupying 42.9 and 11.3%, respectively; group B exhibited lower values for both side effects. No difference was detected between these groups in other side effects, including pyrexia, generalized malaise, arthralgia or psilosis. Intermittent administration from the outset permitted shortened duration of hospitalization and earlier rehabilitation. Intermittent administration of INF-α is required when treating patients with chronic hepatitis C showing lower leucocyte or platelet counts.     

Sheehan's syndrome: clinical profile, pituitary hormone responses and computed sellar tomography

Twenty patients with the typical clinical presentation of Sheehan's syndrome were studied. All had a severe degree of hypopituitarism. The circulating mean basal levels of thyroid hormones, Cortisol and prolactin were significantly lower (p< 0.05 to <0.02) compared to those in 50 age matched controls. The provoked pituitary responses to combined pituitary stimulation in 13 patients were markedly lower (p <0.02 to <0.001) than those in ten age matched control subjects. Sellar computed tomography revealed an empty sella in all the patients; partial in five and complete in the remaining. A secondary empty sella is considered a characteristic finding in the classical form of Sheehan's syndrome. (Aust NZ J Med 1993; 23: 26–31.)     

Interferon alpha in the treatment of chronic hepatitis C in children: a meta-analysis [correction of metanalysis

Summary. Children with chronic hepatitis C may be ideal candidates for treatment with interferon alpha (IFN α ) as they have liver disease at an early stage. However, adverse drug reactions need to be considered. The aim of this study was to conduct a systematic review of literature on interferon therapy of chronic hepatitis C in children, and to perform a metanalysis of pooled data. A computerized search gave 18 articles on IFN α therapy in children with chronic hepatitis C; after exclusion of uncontrolled trials and of trials including patients with comorbidities, data from two studies could be pooled (48 patients). The outcomes assessed were biochemical, defined as normalization of alanine transaminase, and virologic, defined as HCV-RNA loss, both sustained at 24 months after enrolment. Results of the studies were homogenous. Risk difference was 37% (95%CI: 12.9–61) in favour of IFN α treated children for sustained biochemical response, and 36.8% (95%CI: 14.3–59.3) in favour of treated children for sustained HCV clearance, respectively. The differences were highly significant ( P  = 0.007 and P  = 0.004, respectively). The histological end-point, as well as side-effects, could not be analysed, due to lack of data. This review identifies the poor methodology of the majority of the published trials. The study provides support for the efficacy of IFN α in improving both biochemical and virologic outcomes in chronic hepatitis C in children, but evidence is confined to these surrogate end-points.     

Epithelioid granulomas in chronic hepatitis C: A transient pathological feature

Multiple hepatic granulomas in chronic hepatitis C patients treated with alpha interferon were recently observed. To assess the presence of hepatic granulomas in chronic hepatitis C, and to determine whether their presence is related to interferon therapy or primarily related to chronic hepatitis C viral (HCV) infection, 446 liver biopsy specimens from 239 Japanese patients with chronic hepatitis C were reviewed. Well-formed non-caseating epithelioid granulomas were found in five (1.1%) of 446 liver biopsy specimens from five (2.0%) of 239 patients. All five patients had been followed up for 1 to 3 years, having between one and six liver biopsy specimens taken at intervals of 6 months to 1 year. Four of these five patients received alpha interferon therapy during the follow-up period. Hepatic granulomas were found in one of the pretherapy liver biopsy specimens in four patients and in one of the post-therapy specimens in one patient. Extensive investigation of the aetiology of hepatic granulomas yielded no conclusive findings. The presence of hepatic granulomas could not be demonstrated in follow-up liver biopsy specimens taken from the four patients who had undergone alpha interferon therapy. These findings suggest that hepatic granulomas may appear as an expression of non-specific reaction in HCV-related chronic hepatitis, and are not related to alpha interferon therapy.     

Interferon monotherapy for patients with chronic hepatitis C and normal serum aminotransferase levels at commencement of treatment

Background Approximately 30% of patients with chronic hepatitis C have normal serum alanine amino transferase (ALT) levels. While interferon (IFN) monotherapy is approved for patients with chronic hepatitis C infection, the effectiveness of such therapy for chronic hepatitis C patients with normal ALT levels at commencement of treatment remains poorly understood.Methods Ninety-four individuals (M/F, 54:40; median age, 46 years) with normal ALT levels (<50IU/l) at the commencement of treatment who were positive for both anti-hepatitis C virus (HCV) and serum HCV-RNA were studied. Among this group, 18 individuals (M/F, 9:9; median age, 50 years) had had persistently normal ALT levels for at least 3 months prior to treatment. All patients received their first course of IFN therapy in this study.Results Forty-three (45.7%) of 94 individuals had lost serum HCV-RNA at 6 months after cessation of therapy (complete response; CR). The proportion of patients with genotype 2a and HCV-RNA level over 1Meq/ml who showed CR was significantly lower in those with normal ALT levels than in those with elevated ALT levels (23.8% vs 55.6%; P = 0.0189). Two patients who had persistently normal ALT levels and HCV-RNA level over 1Meq/ml were nonresponders (NR) and had ALT flare-ups after IFN therapy. Patients with HCV-RNA levels of less than 1Meq/ml did not show differential responses based on ALT levels.Conclusions Our data suggest that IFN therapy is effective for patients with normal ALT levels and less than 1Meq/ml HCV-RNA. Thus, such patients should be considered for curative IFN therapy.     

Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C: Comparison between Non-Drinkers and Drinkers

Okazaki T, Yoshihara H, Suzuki K, Yamada Y, Tsujimura T, Kawano K, Yamada Y, Abe H. Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol 1994;29:1039-1043.

Background: Alcohol has been reported to be an important factor that modulates the development and prognosis of chronic viral hepatitis; however, little is known about interaction of alcohol intake and chronic hepatitis C. The aim of this study was to examine whether alcohol drinking affects the effectiveness of interferon (IFN) therapy for chronic hepatitis C.

Methods: Thirty-nine patients with chronic hepatitis C were divided into three groups on the basis of the amount of alcohol intake before IFN therapy: group I (n = 15), non-drinkers; group II (n = 14), less than 70 g/day; and group III (n = 10), more than 70 g/day of ethanol intake for at least 10 years. The IFN (total dose, 330 ± 206 MU) was administered daily for 2 weeks and then intermittently. Drinkers stayed abstinent for at least 1 month before, during, and after IFN therapy. The sustained responder was denned as the patient who showed normal alanine aminotransferase (ALAT) levels continuously for more than 6 months after the therapy. The liver histology (HAI score) and serum hepatitis C virus (HCV) RNA were also examined before and after the therapy.

Results: There was no significant difference among the three groups in the level of ALAT before IFN therapy, age, total dose of IFN, and liver histology. The rates of sustained responders in groups I, II, and III were 53.3%, 42.9%, and 0%, respectively, resulting in a significantly lower rate in group III than in groups I (p < 0.01) and II (p < 0.01). The serum HCV-RNA turned negative after the therapy in 58.3%, 20.0%, and 12.5% of groups I, II, and III, respectively, leading to a significantly lower rate of disappearance of HCV-RNA in group III than in group I (p<0.05).

Conclusion: The IFN therapy for chronic hepatitis C was less effective in heavy drinkers than in non-drinkers.     

Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D.     

Re-treatment of interferon-resistant patients with chronic hepatitis C with interferon-α

Summary. Non-responders to 6-months treatment with recombinant interferon (rIFN)-α, 3 MU thrice weekly (primary non-responders) were treated for 6 further months with the same therapy or with a double dose of rIFN-α or with a different type of IFN (L-IFN). 112 primary non-responders were randomly enrolled into four groups of 28 patients each over a period of 4 years and were followed up for 6 months: group A continued the same dose of rIFN-α, group B was treated with the same rIFN-α but received a double dose (6 MU thrice weekly), group C received L-IFN, 3 MU thrice weekly, and group D stopped IFN therapy and did not receive any treatment. Patients were examined at monthly intervals and response was defined as a complete normalization of alanine amino transferase (ALT). The four groups were homogeneous as to age, sex, duration of the disease, probable source of infection, histological diagnosis, ALT and γ glutamyl transferase (γGT) levels. No patient discontinued therapy for side-effects. Further treatment with rIFN-α 3MU thrice weekly (group A) induced normalization of ALT levels in four patients (14%); treatment with double-dosed rIFN-α (group B) induced normalization of liver enzymes in six cases (21%); a different type of interferon (L-IFN) (group C) achieved normalization of serum ALT in five patients (18%). None of 28 primary non-responders who did not receive any treatment (group D) showed normalization of ALT levels. None of the patients was anti-HCV negative at the end of the study and no statistically significant difference was noted between responders and non-responders to the second course of IFN therapy as to age, sex, duration of the disease, ALT and γGT levels at the end of the trial. Overall at the end of the study the primary non-responders with normal levels of ALT were 15/112 (13%), with a therapeutic advantage of 7%. No statistically significant difference in the response rate was found among patients who continued IFN therapy, but prolongation of rIFN-α treatment at double dosage seems to be the best therapeutic regimen.     

代谢综合征与慢性丙型肝炎

代谢综合征与慢性丙型肝炎关系密切.一方面,慢性丙型肝炎病毒感染在代谢综合征的发病机制中起到重要作用.另一方面,代谢综合征对慢性丙型肝炎的抗病毒治疗效果也会产生影响.回顾了代谢综合征与慢性丙型肝炎二者之间的关系,旨在提高临床医生对该问题的认识,有助于改善慢性丙型肝炎的治疗效果.     

Quantitative analysis of interferon α/β receptor mRNA in the liver of patients with chronic hepatitis C: Correlation with serum hepatitis C virus-RNA levels and response to treatment with interferon

We analysed the expression of interferon (IFN) α/β receptor mRNA in the liver of patients with chronic hepatitis C and examined the relationship between the expression of this receptor gene and the level of hepatitis C virus (HCV)-RNA as well as the response to 16 weeks of 6 × 10⁶ units IFN. The mean level of IFNα/β receptor mRNA in patients with chronic HCV infection (expressed as δ cycle; 10.8±1.9 (mean±SD); n = 39) was significantly higher than that of control subjects (9.4±0.5; n=6; P<0.01). There was a significant negative correlation between the level of IFNα/β receptor mRNA and serum HCV-RNA in 39 patients with chronic hepatitis C (R=-0.546; P<0.01). The mean level of IFNα/β receptor mRNA in six patients who showed a complete response to IFN therapy (12.3±1.6) was higher than that of 15 patients who failed to respond to therapy (10.1±1.5; P< 0.01). Our results are consistent with the suggestion that the anti-viral activity of IFN depends on the level of the IFNα/β receptor on hepatocytes in patients with chronic hepatitis C.