Pleural effusion during interferon treatment for chronic hepatitis C

A 54-year-old male patient was admitted to Osaka University Medical School Hospital for interferon treatment for chronic hepatitis C and the daily administration of recombinant interferon-alpha 2a started at the dose of 9 megaunits per day. Fourteen days later, moderate right pleural effusion was detected by abdominal magnetic resonance imaging study. He had experienced no symptom to suggest pleural effusion or any pulmonary lesions during interferon treatment. The pleural fluid was serous, showing the character of slightly bloody, turbid and positive Rivalta test, and the levels of lactic dehydrogenase and adenosine deaminase were not elevated. His serum titer of anti-nuclear antibody increased to 80 in homogenous staining, but anti-DNA antibody and anti-liver kidney microsome-1 antibody remained negative. Other laboratory tests or physical findings could not satisfy the criteria of any autoimmune diseases, such as systemic lupus erythematosus. After discontinuation of interferon administration, his pleural effusion resolved gradually and disappeared completely by use of no specific drugs. This is the first case that pleural effusion developed during interferon administration without any other clinical signs indicating autoimmune diseases. The increase of serum titer of anti-nuclear antibody prompted us to elucidate that pleuritis might be induced by immunological activation of interferon.     

Induction of interstitial pneumonitis during interferon treatment for chronic hepatitis C

A 48-year-old woman developed interstitial pneumonitis while receiving interferon treatment for chronic hepatitis C. Laboratory studies prior to treatment showed elevated serum alanine aminotransferase levels, but chest X-rays and physical examination revealed no abnormalities suggestive of interstitial pneumonitis. At the 9th week of interferon treatment (total dose, 380MU of recombinant interferon-α, without other medications), the patient began to complain of cough and exertional dyspnea. A chest X-ray film revealed diffuse reticulo-nodular shadows in bilateral lung fields, suggesting a diagnosis of interstitial pneumonitis. A marked increase in lymphocyte count was observed in bronchoalveolar lavage fluid and a diagnosis of interstitial pneumonitis was made as a result of transbronchial lung biopsy. Her clinical symptoms and abnormal lung shadows were reversible, improving within a month of the discontinuation of interferon, and disappearing promptly after exogenous corticosteroid was instituted. This may be the first case of drug-induced interstitial pneumonitis occurring during the course of treatment with interferon alone. We should be aware of the possibility of interstitial pneumonitis developing during treatment of chronic hepatitis C with interferon.     

Onset of coeliac disease during treatment with interferon for chronic hepatitis C

The immunomodulatory properties of interferon may concur to precipitate or worsen an underlying autoimmune disorders. We report the cases of two men who displayed the various features of coeliac disease during a treatment with 4-interferon (in one case associated with ribavirin) for chronic hepatitis C. The patients stopped the interferon treatment and the symptoms and histological disorders improved after a gluten-free diet. Alpha-interferon is available worldwide for treatment of chronic viral hepatitis. Before treatment with this drug, the patients would have to be monitored for coeliac disease.     

Development of transient autoimmune hepatitis during interferon treatment of chronic hepatitis B

Summary A 42-year-old man was treated with interferon- for chronic hepatitis B; during the fourth week of treatment he developed an exacerbation of liver disease, and nuclear and smooth muscle autoantibodies, which were previously negative, were detected in very high titers. After discontinuation of interferon therapy, ALT values subsided promptly and autoantibodies disappeared within a few months. This sequence of events strongly suggests a direct relationship between IFN treatment and a self-limited hepatitis with autoimmune markers in this case.     

Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C

A 57-year-old man had abnormal hepatic function identified in April 1994. In October 1994, chronic hepatitis C was diagnosed. Based on the findings of a liver biopsy, administration of recombinant interferon (rIFN)-α2b was begun. In the 16th week of treatment, the patient experienced headache and fever and developed a markedly decreased, platelet count and hemolytic anemia. He was admitted on May 19, 1995 and thrombotic thrombocytopenic purpura (TTP) was diagnosed. He died on the 3rd hospital day. The causes of TTP have yet to be elucidated, but in this patient the occurrence of TTP appeared to be related to the IFN treatment for chronic hepatitis C. (Received June 6, 1997; accepted Dec. 19, 1997)     

Development of transient thyroid disease and reaction during treatment of chronic hepatitis C with interferon

Six of 50 (12%) patients with chronic hepatitis C who were treated with interferon developed thyroid disease or an autoimmune thyroid reaction while undergoing treatment. One patient developed silent thyroiditis, with an increase in serum tri-iodothyronine (T₃), thyroxine (T₄), free T₃, free T₄, and markedly suppressed thyroid-stimulating hormone (TSH) levels, accompanied by the appearance of both antithyroglobulin (TgAb) and antimicrosomal antibodies (McAb). One patient developed hypothyroidism in association with moderately elevated TSH levels and high titers of McAb. TSH, TgAb, and McAb levels returned to the initial values at least 4 months after the end of interferon treatment (9 months of follow up). Four patients whose TgAb and/or McAb levels were elevated during treatment with interferon had been diagnosed as having subclinical autoimmune thyroiditis; however, their thyroid function remained in the normal range. These results suggested that treatment with interferon can cause a transient autoimmune thyroid reaction and disease as a side effect.     

A periappendiceal abscess during combination interferon and ribavirin treatment for chronic hepatitis C]

A 57-year old woman received interferon alfa-2b and ribavirin combination treatment for chronic hepatitis C. High fever and lower abdominal pain developed 10 months after the start of treatment. Antibiotic drugs were not effective. After two weeks, colonoscopic findings revealed a periappendiceal abscess. After colonoscopy study, fever decreased. We have to suspect abscess formation too as appearing a high fever during interferon and ribavirin combination treatment.     

Combination treatment with interferon and ribavirin for chronic hepatitis C

Interferon was the first drug shown to be effective in patients with chronic hepatitis C, but initial treatment regimens achieved sustained loss of virus in only a small minority of patients. The combination of IFN with ribavirin now makes sustained response rates of 30% to 40% possible. This is quite a remarkable achievement for a pharmacologic treatment of a chronic viral infection. It is now reasonable to assume that early treatment and eradication of chronic hepatitis C might reduce the growing burden of hepatitis C and its complications on the healthcare system. Future researchers will strive to optimize combination treatment regimens. Longer treatment courses and intensified induction regimens using either daily dosing, high doses, or both may improve long-term response, but this remains speculative. Other forms of IFN may improve response or increase the ease of drug administration. Conjugation of biologic compounds to polyethylene glycol can result in significant prolongation of plasma half-life while maintaining the properties of the parent molecule. Some biologic properties may be altered, however, so pegylated IFN must continue to be evaluated in clinical trials. There is limited clinical data on other recombinant or natural interferons in combination with oral ribavirin, however, these may prove to be equally effective. Combinations of IFN with one or more other antiviral, anti-inflammatory, or immune modulatory agents will need to be studied. Although amantidine is not effective against hepatitis C as a single agent or in combination with IFN, the combination of IFN, ribavirin, and rimantidine has been shown to have antiviral activity superior to the IFN-ribavirin combination against influenza virus and possibly against HCV.     

Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C

BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in determining the therapeutic response in chronic hepatitis C virus (HCV) infection is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation together with interferon (IFN)-gamma and interleukin (IL)-10 production from peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or in combination with ribavirin, prospectively, before, during, and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at baseline but increased markedly during antiviral therapy, peaking around treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production. The main difference in T-cell reactivity of patients treated with IFN plus ribavirin was a significantly lower production of IL-10, whereas lymphocyte proliferation was similar to that in patients receiving IFN monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is associated with the development of HCV-specific T-cell responses with enhanced IFN-gamma and low IL-10 production. The greater efficacy of combination therapy with IFN-alpha plus ribavirin may be related to its ability to suppress HCV-specific IL-10 production.     

Effects of genotypes of hepatitis C virus on interferon treatment for chronic type C hepatitis

Interferon is commonly used for treatment of type C hepatitis, but the effects are variable and many factors may be responsible. Hepatitis C virus (HCV) can be classified into 4 types, PT, Kl, K2a and K2b. Therefore, the responses to interferon treatment in patients with the different HCV genotypes were analyzed. Twenty-four patients with type C hepatitis were treated with 3 to 10 million units of various types of interferon for more than 8 weeks. HCV-RNA encoding the NS5 region (HCV-NS5) was positive in these 24 patients, 16 of which were classified with the Kl type and 8 with the K2 type of HCV. In all patients except for 2, HCV-NS5 became negative within 3 weeks of treatment without relation to the HCV genotypes. Serum alanine aminotransferase levels were normalized in 7 out of 8 patients in the K2 group and in 4 out of 16 patients in the Kl group at the end of 8 weeks. At the 24th week, ALT levels were normalized in 5 out of 6 patients in the K2 group, and in one out of 9 patients in the K1 group. The percentage of patients exhibiting a good response was significantly higher in the K2 group than in the K1 group at both observation periods. During the post-treatment periods, relapse following complete response was found in 3 patients in the K2 group and in one patient in the K1 group. The final effects of interferon were significantly better in the K2 group than in the K1 group. These results indicate that the effects of interferon were significantly better in patients in the K2 group than in patients in the K1 group. Normalization of serum ALT levels was found in two patients with cirrhosis in the K2 group, but in none of the cirrhosis patients in the Kl group, suggesting that effects of interferon may not be related to the progression of liver disease in patients in the K2 group. These results suggest that genotypes of HCV are one of the major determinants of the effect of interferon treatment.     

Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C*

SUMMARY: Treatment of hepatitis C virus (HCV) infection with interferon (IFN)-alpha, as monotherapy or in combination with ribavirin, is associated with significant side-effects including weight loss. The aim of our study was to describe the evolution of body weight during combination antiviral treatment and to examine the possible determinants of weight loss. This was a retrospective analysis of 126 patients who received combination therapy of pegylated IFN-alpha-2b and ribavirin at our unit. Body weight was recorded at each outpatient attendance during treatment and follow-up, and was expressed as a percentage of baseline value. We observed a decline of body weight during treatment. Median (range) weight values at 4, 12, 24, and 48 weeks (expressed as percentage of baseline weight) were 97.7 (91.5-110.2), 95.4 (84.4-109.4), 93.7 (80.8-106.5), and 91.1 (80.1-103.6) respectively. There was no significant association of increased weight loss with age, gender, pretreatment weight, ethnicity, pretreatment histological stage, cumulative IFN dose (adjusted for body weight), HCV genotype or treatment outcome. Median body weight returned to baseline within 6 months of stopping treatment. Patients experience significant weight loss during combination therapy. Those experiencing greater weight losses during therapy did not benefit from improved antiviral response.     

Immunoglobulin M antibody to hepatitis C virus during interferon therapy for chronic hepatitis C.

Testing for immunoglobulin (Ig) M antibody to hepatitis C virus (anti-HCV) as a predictive factor of therapeutic response to recombinant interferon alfa (rIFN-alpha) in chronic hepatitis C was evaluated in 122 patients with IgG anti-HCV. IgM anti-HCV was present in the pretreatment sample of 88% of patients who responded to treatment, including 20 of 21 (95%) long-term responders and 24 of 29 (83%) responders who had relapses after cessation of therapy. In contrast, IgM anti-HCV was present in only 23 of 39 (59%) nonresponders and 22 of 33 (66%) untreated controls (P less than 0.05). The number of cases with detectable IgM anti-HCV tended to decrease in responder patients, which was more evident for complete responders (42%) than for responders who relapsed (72%). During follow-up, the antibody became undetectable in the majority of long-term responders (28% were still IgM anti-HCV positive) but remained detectable in 69% of responders who relapsed (P less than 0.05). No special changes were noted in nonresponder or control patients. Thus, testing for IgM anti-HCV may help to identify a subset of patients who will benefit from rIFN-alpha therapy in chronic hepatitis C.     

干扰素治疗慢性丙型肝炎疗效分析

目的分析可能影响干扰素治疗慢性丙型肝炎疗效的因素。方法将慢性丙型肝炎62例，随机分成两组，治疗组42例应用干扰素治疗，对照组20例用一般保肝药物治疗，疗程6个月。分别于治疗前、疗程中及疗程后每隔3个月定期检测抗－HCVIgG和IgM，血清及本稍血单个核细胞（PBMC）中HCVRNA，ALT水平。疗程结束后致少随访1年．结果治疗结束及随访一年时治疗组和对照组的ALT的复常率为66．7％对300％和52．4％对15．0％，血清HCVRNAM转率分别为59．5％对15．0％和47．6％对10．0％。分析持久应答的影响因素，年轻、病程短，治疗前抗-HCVIgM抗体滴度高、PBMC中无HCV感染、病理诊断末合并肝硬化的患者对干扰素反应性较好。结论检测抗HCV-IgM及PBMC中HCVRNA可作为干扰素疗效的预测因素。     

Autoimmune hemolytic anemia presenting during treatment of chronic hepatitis C with interferon alpha

Autoimmune hemolytic anemia has been rarely described in patients with chronic hepatitis C during interferon-alpha therapy. We report a case of Coombs-positive autoimmune hemolytic anemia, occurring 9 months after the onset of monotherapy with interferon-alpha-2b (3 million units thrice in week) for chronic hepatitis C. Interferon withdrawal and prednisone treatment induced a complete remission of hematological findings after 3 months. During a follow-up period of 30 months after cessation of interferon, hemoglobin levels stabilized about 16 g/dL, and the indirect Coombs test turned negative, while the direct Coombs test remained weakly positive; besides, serum alanine aminotransferase values were normal and hepatitis C virus-RNA remained undetectable. In our patient, clinical and laboratory findings suggested a correlation between autoimmune side effects of interferon-alpha and autoimmune hemolytic anemia.     

Antiphospholipid syndrome during pegylated interferon alpha-2a therapy for chronic hepatitis C

A great variety of autoimmune side effects have been reported during interferon alpha therapy. The presence of anticardiolipin antibodies during interferon alpha therapy in chronic hepatitis C has also been reported. There are no reports on the occurrence of antiphospholipid syndrome in patients with chronic hepatitis C while on pegylated interferon alpha therapy. We report a case of a 46-year-old man who developed antiphospholipid syndrome 12 weeks after starting pegylated interferon alpha plus ribavirin for chronic hepatitis C. The clinical presentation of antiphospholipid syndrome was primary adrenal insufficiency secondary to bilateral adrenal haematoma and subclavian vein thrombosis. A pathogenic role of pegylated interferon alpha as a trigger factor for antiphospholipid syndrome development is suggested.