Cessation Of Interferon Therapy Research Articles

Sick sinus syndrome induced by interferon and ribavirin therapy in a patient with chronic hepatitis C

The therapeutic effect of interferon (IFN) on chronic hepatitis C and its adverse effects have been well documented. Although the incidence of IFN-related cardiotoxicity is low, careful observation is necessary because of its possible fatal outcome. We describe a 45-year-old woman who suffered from sinus node dysfunction after the combination therapy of pegylated IFN-alpha and ribavirin for chronic hepatitis C. Despite the cessation of IFN therapy, sinus node dysfunction was not reversible, and led her to the implantation of permanent pacemaker. Physicians should therefore be aware of the possibility of sinus node dysfunction in patients receiving IFN therapy.<Learning objective: Pegylated interferon-alpha has been widely used to treat hepatitis C virus infection, which is associated with a wide variety of adverse effects. There is a limited number of case reports regarding suspected interferon-induced cardiotoxicity, especially bradyarrhythmia. We report a case with chronic hepatitis C who developed sick sinus syndrome after interferon-alpha therapy.>

Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C

Interstitial pneumonitis (IP) is an uncommon pulmonary complication associated with interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection. Pneumonitis can occur at any stage of HCV treatment, ranging from 2 to 48 wk, usually in the first 12 wk. Its most common symptoms are dyspnoea, dry cough, fever, fatigue, arthralgia or myalgia, and anorexia, which are reversible in most cases after cessation of IFN therapy with a mean subsequent recovery time of 7.5 wk. Bronchoalveolar lavage in combination with chest high resolution computed tomography has a high diagnostic value. Prompt discontinuation of medication is the cornerstone, and corticosteroid therapy may not be essential for patients with mild-moderate pulmonary functional impairment. The severity of pulmonary injury is associated with the rapid development of IP. We suggest that methylprednisolone pulse therapy followed by low dose prednisolone for a short term is necessary to minimize the risk of fatal pulmonary damage if signs of significant pulmonary toxicity occur in earlier stage. Clinicians should be aware of the potential pulmonary complication related to the drug, so that an early and opportune diagnosis can be made.

High serum leptin is an independent risk factor for non-response patients with low viremia to antiviral treatment in chronic hepatitis C

To determine whether body weight and/or serum leptin were independent predictors of response to antiviral treatment in patients with chronic hepatitis C. A retrospective evaluation was performed in 139 patients with chronic hepatitis C treated with interferon (IFN) from 1996 to 2000. Sustained response was defined as negative by hepatitis C virus (HCV) RNA analysis using PCR and normal transaminase at 24 wk after cessation of IFN therapy. Patients who remained positive for HCV RNA at the end of IFN treatment were defined as resistant to IFN therapy. Sex, age, body mass index (BMI) (> or =25 vs <25), complication of diabetes mellitus, serum leptin level (> or =8.0 microg/L vs < 8.0 microg/L), and the stage of liver fibrosis by needle biopsy (F1/F2 vs F3/F4) were examined. Sustained response was achieved in 33 patients (23.7%), while others failed to show a response to IFN therapy. Overall, the factors associated with sustained antiviral effects were HCV-RNA load, HCV genotype, serum leptin level, and stage of liver fibrosis evaluated by univariate analysis. BMI was not associated with any therapeutic effect of IFN. Multivariate analysis indicated that HCV-RNA load was a significant risk factor, but among the patients with low viremia (HCV-RNA <100 MU/L), leptin level was an independent risk factor for IFN resistance. Namely, a high level of serum leptin attenuated the effect of IFN on both male and female patients with low viremia. High serum leptin level is a negative predictor of response to antiviral treatment in chronic hepatitis C with low viremia.

P.244 Pegylated interferon alpha-2a for treatment of acute hepatitis C in Egypt (ANRS 1213 trial)

The therapeutic effect of interferon (IFN) on chronic hepatitis C and its adverse effects have been well documented. Although the incidence of IFN-related cardiotoxicity is low, careful observation is necessary because of its possible fatal outcome. We describe a 45-year-old woman who suffered from sinus node dysfunction after the combination therapy of pegylated IFN-alpha and ribavirin for chronic hepatitis C. Despite the cessation of IFN therapy, sinus node dysfunction was not reversible, and led her to the implantation of permanent pacemaker. Physicians should therefore be aware of the possibility of sinus node dysfunction in patients receiving IFN therapy.<Learning objective: Pegylated interferon-alpha has been widely used to treat hepatitis C virus infection, which is associated with a wide variety of adverse effects. There is a limited number of case reports regarding suspected interferon-induced cardiotoxicity, especially bradyarrhythmia. We report a case with chronic hepatitis C who developed sick sinus syndrome after interferon-alpha therapy.>

Early decrease in serum IV-7S levels during IFN treatment predicts anti-fibrogenic effect in nonresponders with chronic hepatitis C.

We evaluated whether early changes in serum levels of fibrogenic markers during interferon (IFN) treatment can predict long-term anti-fibrogenic effects in patients with chronic hepatitis C (CHC). We retrospectively examined the serum levels of N-terminal peptide of type III procollagen (P-III-NP) and 7S domain of type IV collagen (IV-7S) in 56 patients with CHC who were revealed to be IFN-nonresponders. We measured these markers before (T0) and 1 month (T1) after the commencement of IFN therapy, at the end of 24 weeks' IFN therapy (T24), and 1 year (T24-1) and more than 2 years (T24-2) after the cessation of IFN therapy. We also measured these markers twice, at intervals of more than 2 years, in 43 IFN-untreated patients with CHC as controls. In nonresponders, both P-III-NP and IV-7S levels at T24-2 were significantly decreased compared with those at T0. P-III-NP levels at T1 were significantly decreased compared with those at T0, and remained at significantly low levels until the end of the observation period. IV-7S levels at T1 were not significantly different from those at T0. In patients whose IV-7S levels at T24-2 were decreased compared with those at T0, IV-7S levels at T1 were significantly lower than those at T0. In patients whose IV-7S levels at T24-2 were elevated or unchanged compared with those at T0, IV-7S levels at T1 were significantly higher than those at T0. In untreated patients, both P-III-NP and IV-7S levels at more than 2 years after the initial time were significantly increased compared with those at the initial time. An early decrease in IV-7S levels after IFN treatment is a useful indicator of anti-fibrogenic effects in nonresponders.

Randomized trial of prolonged interferon retreatment for chronic hepatitis C patients with HCV-genotype 1b and high virus load

The aim of this study was to examine whether 78 week course of interferon (IFN) retreatment could improve the beneficial effect of IFN in chronic hepatitis C patients compared with 52 week course of IFN retreatment. Inclusion criteria were biopsy-proven chronic hepatitis, serum HCV–RNA level of more than 1 Meq/ml, HCV-genotype 1b, abnormal serum alanine aminotransferase (ALT), and transient negative conversion for HCV–RNA during the initial course of IFN therapy. Forty-one patients were randomly assigned to two groups, receiving total doses of: 1410 MU for 52 weeks (a 52 week-group: n=20), or 1995 MIU for 78 weeks (a 78 week-group: n=21). But three patients (one in the 52 week-group and two in the 78 week-group) were withdrawn from the study due to a transfer, refusal after randomization, and occurrence of malignant lymphoma before IFN retreatment, respectively. Therefore remainder 38 patients were studied about efficacy of IFN administration. A virological response (VR) to IFN therapy was defined as HCV–RNA negativity by the reverse transcription nested polymerase chain reaction both 3 and 6 months after the completion of IFN retreatment. A biochemical response (BR) was defined as normalization of ALT but positive HCV–RNA both 3 and 6 months after the cessation of IFN therapy. According to these criteria, VR was 36.8% (7/19) in the 52 week-group and 21.1% (4/19) in the 78 week-group. BR was 5.3%(1/19) in the 52 week-group and 21.1% (4/19) in the 78 week-group. There was no significant difference between the 52 week-group and the 78 week-group with respect to the effect of IFN. We conclude that 52 week course of IFN retreatment may be a sufficient strategy if patients, who have HCV-genotype 1b and high virus load, show negative HCV–RNA and normal ALT level during the first IFN therapy.

Clinical significance of TT virus in chronic hepatitis C.

Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A-G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5' untranslated region (5' UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5' UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV.

Development of small hepatocellular carcinoma 80 months after clearance of hepatitis C virus with interferon therapy

We describe a patient who had a complete and sustained response to interferon (IFN) therapy for chronic hepatitis C but developed small hepatocellular carcinoma (HCC) 80 months later. A 55-year-old Japanese man with hepatitis C virus (HCV) infection and histological features of chronic active hepatitis was treated with recombinant IFN alpha-2a, 9,000,000 U daily for 2 weeks followed by three times a week for 22 weeks. He successfully responded to IFN therapy with a normalization of serum alanine aminotransferase and continuous disappearance of serum HCV-RNA. However, 80 months after the cessation of IFN therapy, the patient's alpha-fetoprotein (AFP) level became elevated for the first time and HCC, 12 mm in diameter, was detected by routine ultrasonographic screening. Laparotomy revealed a small HCC with no metastasis, and the nontumorous liver demonstrated chronic inactive hepatitis. This case indicates the need for careful follow-up using ultrasonography and AFP testing for at least 7 years after completing IFN therapy in all patients with chronic hepatitis C, even if the patients have a complete response to the therapy.

Interferon Therapy for Chronic Hepatitis C in Hemodialysis Patients: Increased Serum Levels of Interferon

Background/Aims: The efficacy and side effects of interferon (IFN) therapy have not been well clarified in hemodialysis patients with chronic hepatitis C. Methods: In 6 of 9 hemodialysis patients with chronic hepatitis C, 3 million units (MU) or 6 MU of recombinant IFN-α2b or natural IFN-α were administered intramuscularly daily for the first 2 weeks, followed by three times a week for 22 weeks. In the remaining 3 patients, 3 MU of IFN-α2b were given three times a week for 24 weeks. Serum concentrations of IFN-α2b were measured sequentially after the injection of interferon. Responders were defined as the patients with normal serum aminotransferase and negative serum HCV RNA 6 months after the cessation of IFN therapy. Results: Three of the 6 patients who were administered IFN daily in the first 2 weeks were responders, while the other 3 withdrew from the therapy due to serious adverse events such as depression, loss of consciousness and persistence of high-grade fever. Serious adverse events were not observed in the 3 patients without daily administration. Half-lives of IFN-α2b in hemodialysis patients were significantly longer than those in nonuremic patients (10.0 vs. 6.0 h, p < 0.05). Moreover, the areas under the serum concentration curve of the hemodialysis patients were significantly larger than those of nonuremic patients (756 ± 223 vs. 324 ± 223 IU·h/ml, p < 0.05), despite the fact that the dose of IFN-α administered to hemodialysis patients was half that administered to nonuremic patients. Conclusions: In hemodialysis patients with chronic hepatitis C, pharmacokinetic parameters of IFN may be different from those in nonuremic patients, and daily or high-dose administration of IFN may lead to serious adverse events in those patients.

Interferon-associated thyroid dysfunction in anti-D-related chronic hepatitis C.

To assess the frequency and nature of thyroid abnormality in association with interferon (IFN) therapy alone and in combination with ribavirin, 19 patients receiving IFN therapy for hepatitis C virus (HCV)-induced liver disease had thyroid function tests assessed on a monthly basis. Group I (n = 9) patients received 5 million U of IFN s.c. daily for 2 weeks, followed by 3 million U three times per week for 6 months. Group II (n = 10) patients received 3 million U IFN s.c. three times per week together with ribavirin 400 mg twice daily orally for 6 months. Five of 19 patients (26.3%) developed thyroid abnormalities, 3 (33.3%) in group I and 2 (20%) in group II. Three patients developed thyroid function tests consistent with hyperactivity, and 2 of these normalized on cessation of IFN therapy. One patient continued on IFN but remained clinically euthyroid with antithyroid treatment. Two patients developed thyroiditis and required thyroid supplementation. (One of the 2 had pretreatment antimicrosomal thyroid antibodies and a positive family history of thyroid disease.) Of the 3 patients with HCV type 1b, 1 had pretreatment thyroid antibodies, and all 3 had antibodies during IFN therapy. Neither of the 2 patients with genotype 3 had pre-IFN or post-IFN thyroid antibodies. Patients on IFN therapy need regular thyroid function testing. The frequency of abnormal thyroid tests may be dose related. HCV genotype may influence the development of thyroid antibodies.

Detection of hepatitis C virus RNA in serum and peripheral blood mononuclear cells in patients with chronic hepatitis C treated with interferon alpha.

PCR was used to detect hepatitis C virus (HCV) RNA in serum and peripheral blood mononuclear cells (PBMCs) for evaluation of a six-month course of interferon therapy in 18 patients with histologically confirmed chronic hepatitis C. At follow-up six months after the end of therapy positive-stranded (genomic) and negative-stranded (anti-genomic, presumptive replicative intermediate) HCV RNA could be detected in PBMCs of all ten patients who either did not respond to therapy or suffered a relapse; genomic strand RNA was detected in five patients who responded but then relapsed. The study confirms that interferon therapy leads to inhibition of HCV replication but not eradication of the virus. Persistence of the virus at extrahepatic sites may explain its reactivation after cessation of interferon therapy.

“Rebound” phenomenon after cessation of interferon therapy in chronic Non-A, Non-B (NANB) hepatitis

“Rebound” phenomenon after cessation of interferon therapy in chronic Non-A, Non-B (NANB) hepatitis

Treatment of chronic non-A non-B hepatitis with human interferon β: a preliminary study

Twenty-four patients with chronic non-A non-B hepatitis were randomly assigned to receive either human fibroblast interferon (HuIFN-β) at doses of 1 or 3 million international units (MIU) per day for 4 or 12 weeks (12 patients) or to receive no therapy (12 patients), and were then compared with 5 patients with chronic type B hepatitis who were treated with HuIFN-β. Elevated serum aminotransferase levels decreased more rapidly during the treatment of chronic non-A non-B hepatitis than of chronic hepatitis B. Variations in serum aminotransferases were not observed in any of the untreated chronic non-A non-B hepatitis patients. In 3 of the 9 patients with chronic non-A non-B hepatitis who responded to HuIFN-β therapy, serum aminotransferase levels remained normal 15, 21 and 31 months after therapy was discontinued; liver biopsy specimens obtained after therapy from 2 patients showed marked histological improvement. In the six other patients aminotransferase activity levels became again elevated following cessation of interferon therapy. No response to HuIFN-β was seen in the remaining 3 patients with chronic non-A non-B hepatitis.

Skeletal complications in hairy cell leukemia: diagnosis and therapy.

We identified eight patients with skeletal complications associated with hairy cell leukemia (HCL). The median time from diagnosis of HCL to the diagnosis of skeletal complications was 20 months (range, 0 to 93). All patients complained of pain and all but one lesion were located in the axial skeleton, primarily the proximal femur. Lytic lesions were seen on radiographic examination in all but one patient, and one patient additionally had multiple osteoporotic vertebral compression fractures. Radionuclide technetium bone scan was abnormal in all patients examined. Although the peripheral blood counts were variable (only two patients had a leukemic phase of the disease), all patients examined had a hypercellular bone marrow biopsy with hairy cells comprising at least 90% of the hematopoietic elements. The skeletal abnormalities responded well to local radiation therapy. Seven patients were begun on systemic therapy with interferon alpha-2b after the diagnosis of the skeletal lesion. Four of five evaluable patients had a partial hematological response and a substantial improvement in the degree of hairy cell infiltration of the bone marrow. None of these patients has had a recurrence of skeletal complications at a median follow-up time of 29 months. One patient failed to respond hematologically and developed additional bone lesions after 1 year of treatment. Another patient developed a new skeletal lesion 3 months after the cessation of interferon therapy at which time the bone marrow was essentially packed with hairy cells. This retrospective study indicates that bone involvement is a rare complication of HCL and is associated with a high tumor burden in the bone marrow. In addition to local radiation therapy, systemic treatment with interferon should be considered.

Enhancement of defective monocyte function during immunotherapy with recombinant interferon.

The influence of immunotherapy with high dose (50 X 10(6) units/m2) recombinant leukocyte A interferon on blood monocyte functions was studied in eight patients with bronchogenic carcinoma. Monocyte chemotactic responsiveness (MCR) was initially depressed (9.8 +/- 1.6 cells/field) compared to healthy controls (17.6 +/- 5.1 cells/field), P less than 0.01. Recombinant interferon was administered three times weekly, and after 7 days a significant improvement in chemotaxis was observed (16.6 +/- 3.0 cells/field), P less than 0.05. The MCR remained normal until cessation of interferon therapy (greater than 1 month). Phagocytic and candidacidal activities were normal in the patients and were not influenced by treatment with interferon. In conclusion, high dose recombinant interferon given to cancer patients caused a normalization of defective blood monocyte chemotaxis, which persisted for greater than 1 month.

Effect of low dosage of interferon on natural killer activity in patients with HBsAg-positive chronic active hepatitis.

The effect of human leukocyte interferon (IFN) on natural killer (NK) activity in 7 patients with HBsAg-positive chronic active hepatitis was investigated. Human leukocyte IFN was intramuscularly given once a week for 4 consecutive weeks (10 X 10(5), 5 X 10(5), 2 X 10(5) and 1 X 10(5) U). 1 week after the initial injection, NK activity showed a significant rise compared with the preinjection levels (p less than 0.001) and remained elevated during the 1-month treatment, while it fell after the cessation of IFN therapy. 4 of 5 patients showed a marked decrease in Dane particle-associated DNA-polymerase activity. Serum HBeAg disappeared in 3 of 6 patients and serum transaminase levels markedly improved in all patients. Only a transient reduction in HBsAg was observed in 2 patients after the treatment period. The findings indicate that a low dosage of human leukocyte IFN such as 18 X 10(5) U, administered in decreasing doses, enhances NK activity in patients with HBsAg-positive chronic active hepatitis, and that the effect of IFN is involved in the immune mechanisms associated with natural cytotoxicity.