Termination Of Interferon Therapy Research Articles

Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy

The aim of this retrospective cohort study is to assess the development incidence and predictive factors for chronic kidney disease (CKD) after the termination of interferon therapy in hepatitis C virus (HCV) positive Japanese patients with liver cirrhosis. A total of 650 HCV positive, liver cirrhotic patients who were treated with interferon and showed an estimated glomerular filtration rate (eGFR) of ≥60 mL/min per 1.73 m(2) after the termination of interferon therapy were enrolled. CKD was defined as an eGFR of <60 mL/min per 1.73 m(2) . End-stage-CKD was defined as an eGFR of <15 mL/min/1.73 m(2) . The primary goal is the new development of CKD and end-stage-CKD. Eighty-five patients developed CKD, and six patients progressed to end-stage-CKD. The development rate of CKD was 5.2% at the 5th year, 14.5% at the 10th year and 30.6% at the 15th year. Multivariate Cox proportional hazards analysis showed that CKD occurred when patients had age increments of 10 years (hazard ratio: 2.32; 95% confidence interval [CI] 1.61-3.35; P < 0.001), eGFR decrements of 10 mL/min per 1.73 m(2) (hazard ratio: 1.66; 95% CI 1.27-2.16; P < 0.001), hypertension (hazard ratio: 2.00; 95% CI 1.13-3.53; P = 0.017), diabetes (hazard ratio: 1.79; 95% CI 1.02-3.14; P = 0.042), and non-clearance of HCV (hazard ratio: 2.67; 95% CI 1.34-5.32; P = 0.005). The development rate of end-stage-CKD was 0.4% at the 5th year, 1.6% at the 10th year and 2.8% at the 15th year. The annual incidence for CKD among cirrhotic patients with HCV was determined to be about 1.0-1.5%. In addition, the annual incidence for end-stage-CKD is one order of magnitude lower than that of CKD.

Development of hepatocellular carcinoma in patients with chronic hepatitis C more than 10 years after sustained virological response to interferon therapy

The risk factors for the development of hepatocellular carcinoma (HCC) in patients who have achieved a long-term sustained viral response (SVR) to interferon (IFN) are not fully understood. This study aimed to investigate the characteristics of patients who developed HCC after 10 years of achieving SVR. We retrospectively studied 5 patients with HCC which developed more than 10 years after the termination of IFN therapy. The clinical characteristics at the induction of IFN therapy were male gender, a mean age of 51.6±9.1 years, while 2 patients were moderate alcohol consumers. None of the 5 patients were positive for either HBs Ag or anti-HBc Ab. A histological examination at the initial IFN therapy showed the activity scores to be A2 in all cases, and the fibrosis scores at least F2. The clinical parameters at the diagnosis of HCC included fluctuating transaminase levels in all cases. These levels scarcely fell below the upper limits even after SVR was achieved. In 3 patients, liver tissues were obtained at the treatment of HCC. These tissues showed marked improvement in both activities and fibroses, but severe steatosis in 1 patient. To conclude, chronic hepatitis C patients who respond to IFN therapy should undergo long-term follow-up, even after the eradication of HCV, with special attention particularly to patients who had elevated transaminase levels and steatosis.

Re-evaluation of the Serum Alanine Aminotransferase Upper Normal Limit in Chronic Hepatitis C Patients

The aim of this study was to re-evaluate the upper limit of normal range (ULN) for serum alanine aminotransferase (ALT) in chronic hepatitis C (CH-C) patients who achieved sustained virological response (SVR) to interferon therapy. Enrolled in this study were 136 consecutive patients, 84 males and 52 females, mean age 52.1+/-14.8 years, with CH-C who received interferon therapy during 1992 to 2008 and achieved SVR. AST and ALT levels (3 serial measurements) were measured every 3 to 4 months over one year after termination of interferon therapy and then the measurements were averaged for each patient. The distribution of AST and ALT showed normal distribution. Overall, AST levels were 19.7+/-3 IU/L and ALT levels were 13.8+/-3.1 IU/L in all patients, AST levels were 19.8+/-3 IU/L and 12.9+/-2.9 IU/L and ALT levels were 14.4+/-3.2 IU/L and 9.9+/-3.5 IU/L in male and female patients, respectively. AST level was the highest in the 6th decade and ALT level was in the 5th decade. In this study on CH-C patients with SVR to interferon therapy, ULN of serum ALT and AST were far lower than the current accepted value. We propose that a suitable ULN of serum AST is <25 IU/L and ALT is <20 IU/L in CH-C patients.

Reply

We are pleased with the interest in our article1 and appreciate the useful comments made by Dr. Tugrul Purnak. He eloquently discussed the onset of diabetes mellitus. We agree with Dr. Tugrul Purnak. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors of type 2 diabetes after the termination of interferon therapy in hepatitis C virus–positive patients. In the present study, we wanted to determine whether the clearance of hepatitis C virus reduces the risk of type 2 diabetes development. Unfortunately, in this study, we could not evaluate the smoking status, family history of diabetes, hypertension, apolipoprotein, or genetic factors. With respect to changes in the body mass index (BMI), some patients experiencing the onset of diabetes were measured during follow-up, as shown in Table 1. In patients without a sustained virological response, the BMI was almost the same. On the other hand, in patients with a sustained virological response, the mean BMI increased by about 1.0.This means that in patients without a sustained virological response, the onset of diabetes is enhanced without an increase in the BMI. Yasuji Arase M.D.*, * Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C†

Diabetes is present in patients with chronic hepatitis C virus infection. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for type 2 diabetes after the termination of interferon therapy in Japanese patients positive for hepatitis C virus (HCV). A total of 2,842 HCV-positive patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin were enrolled. The mean observation period was 6.4 years. An overnight (12-hour) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal was the onset of type 2 diabetes. Evaluation was performed by using the Kaplan-Meier method and Cox proportional hazard analysis. Of 2,842 HCV patients, 143 patients developed type 2 diabetes. The cumulative development rate of type 2 diabetes was 3.6% at 5 years, 8.0% at 10 years, and 17.0% at 15 years. Multivariate Cox proportional hazard analysis revealed that type 2 diabetes development after the termination of IFN therapy occurred when histological staging was advanced (hazard ratio 3.30; 95% confidence interval [CI] 2.06-5.28; P < 0.001), sustained virological response was not achieved (hazard ratio 2.73; 95% CI 1.77-4.20; P < 0.001), the patient had pre-diabetes (hazard ratio 2.19; 95% CI 1.43-3.37; P < 0.001), and age was >or=50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001). Our results indicate sustained virological response causes a two-thirds reduction in the risk of type 2 diabetes development in HCV-positive patients treated with IFN.

Interferon‐induced prolonged biochemical response reduces hepatocarcinogenesis in hepatitis C virus infection

The aim of this study was to elucidate indicator of interferon (IFN) therapy for reducing hepatocellular carcinoma (HCC) in chronic hepatitis C patients without eradicating hepatitis C virus (HCV) RNA during IFN therapy. Inclusion criteria were biopsy-proven chronic hepatitis or liver cirrhosis, IFN period for more than 1.5 years and persistently positive HCV-RNA during IFN therapy. Two hundred thirty-six patients satisfied above criteria were treated with IFN for 1.5-5 years (median 1.8 years, mean 2 years). Mean age was 55.1 years and male was 145 (61%). Eighty-one (34%) patients had severe fibrosis of the liver. These patients were prospectively monitored about HCC after the termination of IFN therapy. We regarded biochemical response (BR) as normalization of serum aminotransferase and alpha-fetoprotein for more than 1 year during IFN therapy. Cumulative rate of development of HCC after the termination of IFN therapy was 9.1% at 5th year and 26.5% at 10th year. Cox proportional analysis showed that HCC development after the termination of IFN therapy occurred when histological staging was advanced (P < 0.0001) and BR was not achieved (P = 0.009), age was >60 years (P = 0.026). The relative risk of HCC development in patients with BR was 0.36 compared with patients without BR. The attainment of BR during IFN therapy is effective in reducing hepatocarcinogenesis for patients with chronic HCV infection.

Clinical Course of Macular Edema in Two Cases of Interferon-Associated Retinopathy Observed by Optical Coherence Tomography

Interferon (IFN)-associated retinopathy is typically characterized by retinal hemorrhages and cotton wool spots at the posterior fundus, but visual function is usually maintained. With the use of optical coherence tomography (OCT), two patients with IFN-associated retinopathy who had developed macular edema and reduced visual acuity during the clinical course of IFN therapy were observed. A 37-year-old man with chronic hepatitis C and a 59-year-old man with chronic myeloid leukemia, both of whom had received IFN therapy, were referred to our outpatient clinic. The former patient had complained once that his visual acuity had decreased after the termination of IFN therapy, and the latter patient complained twice during IFN therapy that his visual acuity had decreased. In both patients, at the time of the visual disturbances, macular edema was clearly observed by OCT. Hypoalbuminemia and thrombocytopenia were observed at this time also. After the remission of the hypoalbuminemia and thrombocytopenia, the macular edema observed by OCT disappeared and visual acuity returned to normal. During and after IFN therapy, OCT is a useful examination technique for revealing macular edema in patients who have decreased vision. Ophthalmologists should be aware of the ocular side effects of IFN therapy and carefully monitor patients for the possible occurrence of hypoalbuminemia and thrombocytopenia. Jpn J Ophthalmol 2005;49:231-234 (c) Japanese Ophthalmological Society 2005.

Randomized, controlled trial of natural interferon-α therapy for e-antigen-positive chronic hepatitis B patients

We evaluated the efficacy of long-term interferon (IFN) therapy in patients with e-antigen-positive chronic hepatitis B. The study design was a prospective, randomized controlled clinical trial. Fifty-three patients were randomly assigned into one of two groups, treated with 3 million units (MU) of IFN (low dose group; n=27) or 6 MU IFN (high dose group; n=26), administered twice weekly for 52 weeks. Responders were defined as patients whose hepatitis B virus (HBV)-DNA level, determined by branched DNA signal amplification and hepatitis B e-antigen (enzyme immunoassay) were negative and whose serum alanine transaminase (ALT) levels fell to within the normal range (ALT<50 IU/l) at 6 month after termination of IFN therapy. One patient in high dose group was dropped out because of transfer. Remainder 52 patients were examined by intention-to-treat (ITT) analysis. The response rates by ITT analysis were 40.7% (11/27) in low dose group and 20% (5/25) in high dose group. The difference between low and high dose group was not statistically significant. Univariate analysis of clinical factors that contribute to the response demonstrated that IFN therapy had a significant effect when, (1) the serum HBV-DNA level was <200 Meq/ml prior to the commencement of IFN therapy ( P=0.0327). (2) Transient acute exacerbation of ALT was present during or after IFN therapy ( P=0.0311). Multivariate analysis showed that the risk ratio for the development of response in patients with serum HBV-DNA level of less than 200 Meq/ml was 3.60 compared with patients with that of 200 Meq/ml or more than 200 Meq/ml (95% CI, 1.012–12.81). In conclusion, the results of this trial show that: (1) long-term twice weekly IFN therapy could be a worthwhile strategy for e-antigen-positive chronic hepatitis B patients with serum HBV-DNA level of less than 200 Meq/ml and (2) patients with transient acute exacerbation of ALT during or after IFN therapy could often respond well after exacerbation of ALT.

Analysis of Background Factors Influencing Long-Term Prognosis of Patients with Chronic Hepatitis C Treated with Interferon

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.

ＩＦＮ療法中に発症した一側性高度難聴

A 43-year-old male was admitted to our clinic because of sudden hearing impairment in his left ear. The patient had received intravenous injection of interferon beta for the treatment of HCV hepatitis. On the second day of interferon administration, he complained of ear fullness and tinnitus in his left ear. Pure tone audiometry revealed up-sloping hearing impairment.An initial high-dose steroid therapy was successful for recovery of hearing loss. Interferon alpha was then administered for HCV hepatitis and hearing loss worsened 10 weeks after secondary interferon therapy. The same steroid regimen was unsuccessful and severe hearing loss developed. Hyperbaric oxygen therapy was then conducted and was the only effective treatment for this progression. One week after the recovery, left hearing impairment thrice occurred and no treatment was effective.Audiological side effects were reported in 40% of the patients who received interferon administration. The side effects were usually temporary and recovered soon after termination of interferon therapy. The present case revealed that hearing loss found during interferon therapy does not always show a fair prognosis. Further study on the audiological side effects during interferon therapy should be performed.

Prediction of response during interferon alfa 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: A comparison

Patients with chronic hepatitis C (n = 103) were treated for 24 weeks with interferon alfa 2b and followed up for 24 weeks after cessation of therapy (week 48). When hepatitis C virus (HCV) RNA at week 48 was used to assess interferon response, 15 (14.6%) were virological complete responders, and all have remained HCV RNA negative for a mean of 3 years. At week 48, 3 of 15 virological complete responders had elevated alanine transaminase (ALT) values. When serum ALT level was used at week 48 to determine response to interferon, 20 (19.4%) were biochemical complete responders. However, 8 of the 20 patients with normal ALT levels were HCV RNA positive at week 48, and 7 of these individuals have had a recurrence of elevated ALT levels within 3 years after cessation of treatment. These findings indicate that measurement of HCV RNA was more accurate than ALT in determining true responses to interferon therapy. Identification of nonresponders early during the course of interferon treatment showed that an elevated ALT level at week 12 was 92% predictive (odds ratio 3.7) but misidentified 33% (5 of 15) of the patients who were virological complete responders at week 48. In contrast, a positive HCV RNA at week 12 of treatment was 98% predictive (odds ratio 35.5) and misidentified only 6.7% (1 of 15) of the virological complete responders. Thus, positive HCV RNA at week 12 of therapy was more accurate in identifying eventual virological nonresponders than measurement of ALT at this time. Termination of interferon therapy in patients who were HCV RNA positive at week 12 would result in a 27% reduction in the direct medical costs and keep patients from undergoing unnecessary treatment. Therefore, testing for HCV RNA at week 12 to identify nonresponders and then discontinuing their treatment is practical, cost-efficient and beneficial both to patients and to third-party payers. (Hepatology 1997 Dec;26(6):1640-5)

Prediction of response during interferon alfa 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: A comparison

Patients with chronic hepatitis C (n = 103) were treated for 24 weeks with interferon alfa 2b and followed up for 24 weeks after cessation of therapy (week 48). When hepatitis C virus (HCV) RNA at week 48 was used to assess interferon response, 15 (14.6%) were virological complete responders, and all have remained HCV RNA negative for a mean of 3 years. At week 48, 3 of 15 virological complete responders had elevated alanine transaminase (ALT) values. When serum ALT level was used at week 48 to determine response to interferon, 20 (19.4%) were biochemical complete responders. However, 8 of the 20 patients with normal ALT levels were HCV RNA positive at week 48, and 7 of these individuals have had a recurrence of elevated ALT levels within 3 years after cessation of treatment. These findings indicate that measurement of HCV RNA was more accurate than ALT in determining true responses to interferon therapy. Identification of nonresponders early during the course of interferon treatment showed that an elevated ALT level at week 12 was 92% predictive (odds ratio 3.7) but misidentified 33% (5 of 15) of the patients who were virological complete responders at week 48. In contrast, a positive HCV RNA at week 12 of treatment was 98% predictive (odds ratio 35.5) and misidentified only 6.7% (1 of 15) of the virological complete responders. Thus, positive HCV RNA at week 12 of therapy was more accurate in identifying eventual virological nonresponders than measurement of ALT at this time. Termination of interferon therapy in patients who were HCV RNA positive at week 12 would result in a 27% reduction in the direct medical costs and keep patients from undergoing unnecessary treatment. Therefore, testing for HCV RNA at week 12 to identify nonresponders and then discontinuing their treatment is practical, cost-efficient and beneficial both to patients and to third-party payers.

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis.

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated with alpha-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN administration was classified into five types. Type 1 was characterized by normalization of ALT (< or = 25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (< or = 25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).

Histological improvement of chronic hepatitis B, and non-A, non-B with interferon treatment: Application of a numerical scoring system for evaluating sequential morphologic changes

In order to assess the sequential changes of liver pathology after interferon therapy, 70 liver biopsy specimens, collected from 23 HBeAg-positive patients with chronic hepatitis B and 12 patients with chronic non-A, non-B hepatitis, were studied using a numerical scoring system proposed by Knodell et al. The biopsy specimens were obtained immediately prior to the administration of interferon and within one week following the termination of interferon therapy. Three patients with chronic hepatitis B were negative for DNA-polymerase (DNA-P) prior to the interferon administration. Ten patients (50%) lost DNA-P activity. HBeAg became negative in 8 patients (34.8%), of whom 2 seroconverted to anti-HBe. Serum alanine aminotransferase levels normalized in 9 patients with chronic hepatitis B, and non-A, non-B hepatitis. The total Histological Activity Index (HAI) scores in both patients with chronic hepatitis B, and non-A, non-B decreased significantly (P less than 0.001 and P less than 0.005, respectively) after interferon treatment. There was also a significant improvement (0.02 less than P less than 0.001) in each histological category except for fibrosis. When the changes of the HAI scores in patients with chronic hepatitis B were correlated to the outcome in the DNA-P and HBeAg/anti-HBe system after treatment, the histological improvement did not significantly correlate to the outcome of these serological parameters.

Alpha&lt;sub&gt;2&lt;/sub&gt;-Interferon beim Nierenkarzinom: Erfahrungen an sechs Patienten

We report on 6 male patients with advanced renal cell carcinoma without prior chemotherapy. They were treated by recombinant alpha 2-interferon in a toxicity limited dosage. The maximal tolerated dose was 3 x 5 x 10(6) U/wk. to 3 x 20 x 10(6) U/wk., limited by flu-like symptoms in 5 cases, by thrombopenia in 1. We observed a response in 3 cases (2 partial remissions, 1 mixed response) lasting for 10, 11 and 13 months, respectively. This comparatively good result may be due to patient characteristics (little pretreatment, pulmonary metastasis, good performance status) as well as to a medium dosage. Occurrence of response after termination of interferon therapy in two cases are of particular interest.