Efficacy of interferon therapy in elderly patients with chronic hepatitis C

OBJECTIVE: We assessed the efficacy and safety of interferon (IFN) monotherapy in 84 elderly patients aged > or =65 years with chronic hepatitis C in a retrospective cohort study. METHODS: Twenty-two of the 84 elderly patients were treated with IFN at a dose of 6 million units daily for 6-8 weeks, 18 patients were treated 2-3 times a week for 24 weeks and 44 patients were treated daily for 2-8 weeks and 2-3 times a week for 16-24 weeks. RESULTS: A sustained virological response (SVR) occurred in 35.7% (30/84) of the patients by intention-to-treat analysis. Multivariate analysis showed that patients achieved a significant SVR when: (1) serum HCV-RNA level before IFN therapy was <100 KIU/ml (p < 0.0001) and (2) staging of liver fibrosis was mild (p = 0.040). Eleven (13.1%) patients discontinued the IFN regimen due to adverse events. Regarding factors predicting discontinuation of IFN, univariate analysis showed that patients aged >70 years were prone to drop out of therapy due to adverse events in IFN therapy (p = 0.009). CONCLUSION: Our results suggest that IFN administration is suitable for 65- to 70-year-old patients with chronic hepatitis C without genotype 1b and high virus load.     

Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C

OBJECTIVE: The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients. METHODS: We studied the incidence of hepatocellular carcinoma (HCC) and survival probability after the initiation of IFN therapy in 500 Japanese chronic hepatitis C patients >60 years. The mean age of initiation of IFN was 63 years and the mean follow-up period was 7.4 years. Cox proportional hazard regression analysis was used to evaluate the long-term outcome after initiation of IFN therapy. Sustained virological response (SVR) was defined as negative HCV-RNA by RT-nested PCR 6 months after the completion of long-term IFN therapy. Non-response (NR) was applied to patients who did not show SVR. Hepatic fibrosis was defined as the fibrosis score (score 0-4) according to Knodell et al. RESULTS: 140 patients (28%) had an SVR and 360 patients (72%) had an NR. 71 of 500 patients developed HCC during follow-up. The cumulative incidence of HCC was 9.6% at the 5th year, 17.4% at the 10th year, and 31.3% at the 15th year. HCC developed with significance when: (1) HCV was not cleared after IFN therapy (p < 0.0001), (2) sex was male (p < 0.0001), and (3) staging of liver fibrosis was >2 (p = 0.008). 53 of the patients died. The cumulative survival probability was 95.7% at the 5th year, 86.4% at the 10th year, and 78% at the 15th year. Patients achieved a long survival with significance when: (1) staging of liver fibrosis was 1 (p < 0.0001), (2) HCV was cleared after IFN therapy (p = 0.034), and (3) sex was female (p = 0.015). CONCLUSION: Chronic hepatitis C patients with clearance of HCV after IFN therapy had a significantly reduced risk of HCC appearance and achieved prolonged survival even if they are > or =60 years.     

Detection of hepatitis C virus RNA in patients with chronic hepatitis C virus infections during and after therapy with alpha interferon.

In 24 patients with hepatitic C virus (HCV) infection who participated in a randomized trial with alpha 2B interferon, HCV RNA analysis by the polymerase chain reaction with two separate primer sets was performed at weeks 0, 4, and 24 and during a follow-up period of 6 to 9 months. Prior to therapy all patients were HCV RNA positive. During therapy, HCV RNA decreased to an undetectable level (< 1 chimpanzee infectious dose per ml) in nine patients at week 4. After week 4, no additional cases of HCV RNA disappearance (< 1 chimpanzee infectious dose per ml) were observed. During follow-up, HCV RNA could not be detected in four of the six patients with a sustained alanine aminotransferase response. These results suggest the probable predictive value of HCV RNA levels for detecting the failure of therapy in an early stage of HCV infection.     

A trial of new interferon therapy for the patients with chronic hepatitis C resistant to interferon therapy

HCV-RNA clearance rates are reported to be about 30-40% of the patients treated with IFN for less than 6 months. But IFN therapy is ineffective for chronic hepatitis C patients with HCV-genotype 1b and a high virus load. We evaluated the efficacy of different IFN therapy compared with standard IFN therapy for chronic hepatitis C patients resistant to interferon therapy. That is, we assessed the following therapy; 1) prolonged IFN therapy, 2) IFN-beta therapy of twice a day, 3) IFN-beta therapy daily for 24 weeks, 4) combination therapy of IFN-alpha and IFN-beta. In some cases, these IFN therapies were effective than a standard IFN therapy.     

Virus-specific antibodies and interferon therapy in chronic hepatitis C

AIM: To study the spectrum of antibodies in chronic hepatitis C (CHC) against various antigenic structures of hepatitis C virus (HCV) and changes in their quantity in response to interferon treatment. MATERIAL AND METHODS: Enzyme immunoassays (kits by Diagnostic Systems, N. Novgorod) were used in examination of 144 CHC patients with circulation of HCV antibodies in peripheral blood. RESULTS: IgG antibodies to cor, NS3, NS4 HCV antigens were present in the highest percentage (75-100%) and concentration (2.5-1.9 units). IgM antibodies to cor HCV, IgM and IgG to HS5 HCV were detected in 36-63%, concentration of the antibodies ranged 0.7-1.7 units. Interferon therapy reduced frequency and amount of virus-specific antibodies to various antigenic structures of HCV, primarily IgM to cor, NS5-HCV, anti-IgG NS5-HCV. CONCLUSION: In CHC a wide spectrum of antibodies to HCV antigenic structures are produced. They have different biological properties. Interferon treatment diminished their frequency and amount. This allows to consider changes in the amount of virus-specific antibodies in CHC as a criterion of antiviral treatment effectiveness.     

Side effects of interferon therapy for chronic hepatitis C

A total of 3,882 Japanese patients with chronic hepatitis C were given interferon (IFN) alone or combination therapy of IFN and ribavirin. Two hundred sixty-one (7.7%) patients stopped IFN therapy due to the adverse events after initiation of IFN alone therapy. About a half of patients with side effect discontinued the IFN regimen due to owing to general fatigue, psychiatric disorder, thrombocytopenia, and leukopenia. On the other hand, 82 (16.2%) patients stopped combination therapy of IFN and ribavirin due to the adverse events. We should carefully observe the patients treated with IFN. If patients treated with IFN have IFN-related adverse effects, we should stop IFN therapy or reduce the dose of IFN.     

HCV genotype as a predictor of response to interferon therapy in patients with chronic hepatitis C

Hepatitis C virus(HCV) genotype is one of the most important predicting factors of response to interferon(IFN) therapy in patients with chronic hepatitis C. According to the molecular evolutionary analysis, HCV is classified into six major genotypes. The patients infected with genotype 1 show high HCV RNA levels and poor response to IFN therapy compared to those with genotype 2 or 3. No sufficient data are observed on response to IFN in patients with genotype 4 to 6. When PEG-IFN plus ribavirin therapy is introduced, high proportion of patients without genotype 1 must show complete response. In the near future, to predict good response to IFN therapy, it will be necessary to know whether patients have HCV genotype 1 or not.     

Prospects for interferon therapy in chronic hepatitis C with normal transaminase levels

AIM: To study effectiveness of recombinant interferon-alpha (Ifna) in patients with chronic hepatitis C with normal transaminases. MATERIAL AND METHODS: 26 patients with positive tests for abHCV and RNA HCV with a normal level of alaninaminotransferase (AlAT) entered the study. 16 patients of the test group received recombinant Ifna three times a week in a dose 3 mln IU. Mean duration of interferon therapy was 7.44 +/- 4.27 months. Control group consisted of 10 patients with natural course of the disease. Biochemical, virusological and morphological examinations were conducted in all the patients. The patients were followed up for 1.5-2 years, on the average. RESULTS: Treatment with recombinant Ifna was well tolerated. A persistent positive virusological response after the treatment was achieved in 25% of the test patients. They exhibited improvement of histological structure of the liver. In control group the dynamics was opposite. CONCLUSION: In patients with chronic hepatitis C with normal transaminases level interferon therapy improves structure of hepatic tissue. Puncture biopsy of the liver is the main method which determines the validity of the treatment and its efficacy.     

Depressive symptoms after initiation of interferon therapy in human immunodeficiency virus-infected patients with chronic hepatitis C

BACKGROUND: Interferon alpha (IFN-alpha) therapy for chronic hepatitis C (CHC) infection is commonly associated with neuropsychiatric side effects including depressive symptomatology. In this study, we evaluated the incidence and management of depressive symptoms during IFN-alpha therapy in HIV-infected patients with CHC. METHODS: HIV-infected patients with CHC who began IFN-alpha and ribavirin therapy during the recruitment period April 2001 to April 2003 were included in the study. Patients with a history of major depressive disorder were excluded. RESULTS: Of 113 co-infected patients who started IFN-alpha therapy during the recruitment period, 45 (40%) developed symptoms of depression (sadness, tiredness and apathy). Twenty of them (44%) were treated with citalopram, a selective serotonin re-uptake inhibitor, resulting in a significant improvement in their symptoms. Most of the patients (60%) showed depressive side effects in the first 3 months after initiation of IFN-alpha. In addition, during the study, three patients developed psychotic symptoms and one committed suicide. CONCLUSIONS: The incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN-alpha is high. Most of the depressive symptoms were not severe and improved with antidepressant therapy, without reduction or cessation of IFN-alpha therapy. During the first weeks after initiating IFN-alpha therapy for HIV/HCV co-infection, close assessment of psychiatric symptoms is recommended. Early treatment of these side effects with antidepressants would help avoid early dropouts from interferon therapy.     

Two-step interferon rebound therapy for refractory chronic hepatitis C

In almost all patients in whom interferon(IFN) treatment dose not result in persistent negative findings for HCV-RNA, HCV-RNA levels show a rebound after discontinuing the administration. In most patients, HCV-RNA levels after administration are increased compared to pretreatment values. When a rapid increase in HCV-RNA levels causes transient exacerbation of transaminase levels, HCV-RNA levels then rapidly decrease. In two-step interferon rebound therapy(TIRT), IFN is additionally administered when HCV-RNA levels are decreased. We previously reported that TIRT was useful for treating type 1b patients with an HCV-RNA level of 1 Meq/ml or more who did not respond to IFN treatment. In the year 2000, health insurance covered the additional administration of IFN. The use of TIRT for additional administration may further improve treatment response in patients who do not respond to IFN treatment.     

Clinical efficiency of high-dose interferon therapy in patients with chronic NCV hepatitis

11 patients with confirmed chronic HCV-hepatitis were treated with high-dose interferon. 12 matched controls were treated conventionally. Higher response was registered in patients on the interferon treatment. Side effects were not related to the variant of interferon therapy in the studied population.     

Accurate prediction of response to interferon therapy by repeated measurement of hepatitis C virus core protein in patients with chronic hepatitis C

OBJECTIVE AND METHODS: Serum levels of hepatitis C virus (HCV), a predictor of the response to interferon (IFN) therapy, can fluctuate widely in patients with chronic hepatitis C, even without antiviral therapy. In order to increase the accuracy of predicting the response to therapy, serum samples from 134 patients with chronic hepatitis C were collected twice: 1.0-4.5 months before and just before the start of IFN therapy, and were tested for HCV core protein by a fluorescent enzyme immunoassay. RESULTS: Forty-one (31%) patients had a complete response to IFN and 93 (69%) had no response. The most useful cutoff value between high and low viral loads for predicting the response to therapy was 40 pg/ml of HCV core protein. A complete response was obtained more frequently in 32 of 45 patients with persistently low viral loads than in those with persistently high viral loads (7 of 71) (p < 0.0001). In 2 of 18 patients with a low viral load at one time point but a high viral load at another, the rate of complete response was similar to that in patients with persistently high viral loads. CONCLUSION: Prediction of the response to IFN therapy based on HCV core protein measurement at two time points before therapy is more reliable than that based on HCV core protein measurement at only one time point.     

Combined interferon and ribavirin therapy for chronic hepatitis C in Taiwan

Chronic hepatitis C virus (HCV) infection, including its sequelae, is an important healthcare problem in Taiwan. The seroprevalence of HCV infection in first-time blood donors in Taiwan is 1.2% and an estimated 2-5% in the general population, with a great geographic variation. Genotype 1b is the most prevalent HCV genotype in Taiwan, with a prevalence rate of 50-70%. An increasing incidence of hepatocellular carcinoma (HCC) is mainly attributed to HCV infection, while the declining role of HBV is observed in Taiwan. The seroprevalence of hepatitis B surface antigen among patients with HCC was 90% three decades ago, while recently, chronic HCV infection accounts for more than 30% of HCC patients in the National Taiwan University Hospital. With the advent of a combined conventional interferon (IFN)-alpha and ribavirin therapy, to which Taiwan has contributed in the early study phase, the sustained virological response rate has been greatly improved compared with IFN monotherapy. The sustained virological response rate in Taiwanese patients treated with the combination therapy for 6 months has reached up to 50-60%, which is higher than that reported in patients from the Western countries receiving a 12-month regimen. It is necessary to search for the underlying mechanisms for the better treatment outcome with IFN plus ribavirin combination therapy in Taiwanese patients. Whether long-term effects of IFN plus ribavirin therapy can reduce the incidence of HCC needs to be established.     

Combination therapy with interferon and ribavirin in the treatment of chronic hepatitis C infection

OBJECTIVE: To review and critique the medical literature regarding the combination of interferon and ribavirin in the initial treatment of chronic hepatitis C virus (HCV) infection. DATA SOURCES: A MEDLINE search (January 1966-June 1999) was conducted to identify human clinical trials regarding the combination of interferon and ribavirin therapy for the initial treatment of chronic HCV. Bibliographies were reviewed for relevant literature. STUDY SELECTION: Clinical trials of combination interferon and ribavirin for the treatment of chronic HCV in interferon-na?ve adults were reviewed. DATA SYNTHESIS: The combination of ribavirin and interferon in the treatment of chronic HCV has been beneficial in patients who are interferon-na?ve. Patients with predictors of poor response, such as baseline cirrhosis, male gender, age >40 years, high baseline viral loads (>2 x 10(6) copies/mL), and genotype 1 respond better to combination treatment when compared with those who receive interferon monotherapy. Patients with genotype 1 and/or high viral loads may benefit most from 48 weeks of combination therapy; however, adverse effects are of greater concern in these patients. Monitoring can limit these complications. CONCLUSIONS: Combination therapy is effective in the treatment of interferon-naive patients with chronic HCV infection. Patients should be evaluated for duration of treatment with combination therapy by determination of predictors of response. Further trials are needed to more closely evaluate the duration of treatment and to determine the best patient population to receive combination therapy.     

Retreatment of patients with chronic hepatitis C not responding to interferon/ribavirin combination therapy with daily interferon plus ribavirin plus amantadine

There is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-alpha plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-alpha plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n = 67), breakthroughs (n = 16) and relapsers (n = 19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-alpha2a 6 MU daily, ribavirin 800-1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-alpha2a 6 MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/ 102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). On-treatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p < 0.05; week 48: 46% vs. 16%, p < 0.01) but no such difference was found for sustained virological response (20% vs. 12%, NS). In conclusion, triple combination treatment with daily interferon-alpha plus ribavirin plus amantadine for 3 months can induce virological response in a considerable number of nonresponders/relapsers to previous dual combination treatment, but the sustained virological response rate remains low.     

Predictors of sustained response to alpha interferon therapy in chronic hepatitis C

OBJECTIVES: To utilize cytokine levels to predict sustained response (SR) to alpha interferon (IFN alpha) therapy in chronic hepatitis C patients, and to determine the relationship between serum tumor necrosis factor alpha (TNF alpha), interleukin (IL) IL 6, IL 8, IL 12, transforming growth factor beta (TGF beta 1) and the degree of liver damage as reflected by traditional markers. DESIGN AND METHODS: Serum cytokine levels were assessed using ELISA in 18 patients included in a controlled clinical trial of IFN alpha. RESULTS: Of the 18 patients, 27% were sustained responders (SR), 27% were response and relapse responders (RR), and 46% were non-responders (NR). Multivariate analysis showed that a low serum TNF alpha level and high serum IL 8 levels were independent factors associated with SR to IFN alpha therapy. Serum TNF alpha level highly correlated with viral load and genotype predictive values (p < 0.001). Therapy lowered the IL 6 and IL 12 profile. TGF beta 1 levels in serum are positively correlated with fibrinogenesis. CONCLUSIONS: IFN alpha therapy modulates immune response to hepatitis C virus, contributing to sustained response.     

Using pegylated interferon and ribavirin to treat patients with chronic hepatitis C

Hepatitis C virus is the most common chronic blood-borne infection in the United States. The advent of new treatment regimens using pegylated interferons in combination with ribavirin has led to improved sustained viral response rates for some genotypes in large multicenter trials. Advances in the management of side effects and toxicities have expanded the pool of treatable patients. A recent National Institutes of Health consensus conference recommended that all patients who have bridging hepatic fibrosis and moderate inflammation together with detectable viremia should receive treatment with pegylated interferon and ribavirin. Unfortunately, these medications are very expensive and have significant side effects. Hematologic toxicities include anemia and leukopenia. These can be managed with close monitoring, use of growth factors, or dose reductions. Depression also can be caused or exacerbated by these medicines and may require treatment with a selective serotonin reuptake inhibitor, comanagement with psychiatry, or cessation of pegylated interferon and ribavirin treatment. Contraception is imperative because ribavirin is highly teratogenic. Influenza-like symptoms of fatigue, nausea, and mild fevers can be helped by quality patient education and support including frequent office visits. Data from randomized controlled trials demonstrating improvements in long-term survival as a result of treatment are not yet available, but it appears that patients who have no detectable virus six months after treatment have a good chance of remaining virus free for at least five years.