Treatment of chronic hepatitis C with amantadine

Treatment of chronic hepatitis C infection with interferon has been disappointing, with less than one third of patients achieving a sustained response and most experiencing significant side effects. For these reasons, an open-labeled prospective pilot study was conducted to test the safety and efficacy of the antiviral drug, amantadine, in patients with chronic hepatitis C infection who had previously failed therapy with interferon-alpha 2b. Twenty-two patients with chronic hepatitis C were enrolled into the study and treated with amantadine 100 mg orally twice daily for six months. Control groups included the same cohort followed off therapy for 29-36 months or during therapy with interferon. Serum alanine aminotransferase (ALT) values decreased in 64% (P = 0.01) of patients with amantadine therapy compared to intervals without therapy or to interferon therapy. Twenty-seven percent of patients treated with amantadine had normalization of ALT values and loss of HCV RNA after six months while 18% achieved a sustained response with loss of HCV RNA by PCR six months after discontinuation of amantadine. Therapy with amantadine improved both biochemical and virological markers in patients with hepatitis C who had previously not responded to treatment with interferon.     

Interferon alpha treatment of chronic hepatitis C in HIV-infected patients receiving zidovudine: efficacy, tolerance and response related factors

BACKGROUND/AIMS: In our area most of the human immunodeficiency virus (HIV) infected patients are intravenous drug users; HIV and hepatitis C virus infections often coexist in these patients. Due to the repercussions of both infections, we designed a trial to evaluate the efficacy, response-related factors and tolerance during an eight-month regime of recombinant interferon alpha-2b on hepatitis C virus infection. METHODOLOGY: We included 79 patients in an open, prospective and multicentric trial with zidovudine and interferon alpha-2b. Response to interferon treatment was evaluated by biochemical and histopathological criteria. RESULTS: A complete response (alanine aminotransferase normalization) was obtained in 57.4% of patients. The significant response-related factors were: degree of histopathological activity, CD4+ cell number and initial leukocyte number. CONCLUSIONS: Recombinant interferon therapy seems to be effective for chronic hepatitis C in HIV infected patients; the best response was in those with active chronic hepatitis and CD4+ cell counts > or = 200/mm3. General tolerance was variable, although side effects were not different from those seen in non-HIV patients. The most common side effect was flu-like syndrome (constitutional manifestations), with no interference on treatment continuity; however, hematological toxicity prevents the indiscriminate use of interferon.     

Immunoglobulin M antibody response to hepatitis C virus core protein in patients with chronic hepatitis C

We retrospectively assessed the frequency and clinicopathologic and virologic significance of production of immunoglobulin M (IgM) antibody to hepatitis C virus (HCV) core protein in patients with chronic hepatitis C. Sera from 60 patients with chronic hepatitis C were tested for IgM anti-HCVcore (anti-HCc). Twenty of these patients received ribavirin plus interferon-alpha for 24 weeks, and were classified as sustained, transient, or nonresponders on the basis of alanine aminotransferase levels and the presence of HCV RNA at the end of treatment and 24 weeks later. IgM anti-HCc was detected in 21 patients. There was no correlation between the presence of IgM anti-HCc and clinical features such as sex, age, mode of transmission, serum levels of alanine aminotransferase, HCV genotype, serum HCV titer, or histologic findings. Among the patients who received ribavirin plus interferon-alpha, the mean IgM anti-HCc level before therapy was comparable between sustained (n = 10), transient (n = 8), and nonresponders (n = 2). A statistically significant decrease in IgM anti-HCc response during antiviral therapy was observed in the 18 responders who became negative for serum HCV RNA at the end of therapy. These data suggest that IgM anti-HCc is of limited clinical usefulness as a marker of chronic HCV infection. Serial testing for IgM anti-HCc may provide a marker of antiviral response.     

A pilot study of ribavirin and interferon beta for the treatment of chronic hepatitis C

BACKGROUND: Chronic hepatitis C is a common and often progressive liver disease for which interferon alfa therapy widely spreads, but the beneficial response is frequently transient. Ribavirin is a nucleoside analog with a broad spectrum of antiviral action, and we investigated the efficacy of it in patients with chronic active hepatitis C. METHODS: We conducted a pilot study of oral ribavirin in patients with chronic active hepatitis C. Twenty-seven patients with hepatitis C virus RNA were randomly assigned to receive either 0.8-1.0 g of ribavirin daily or 3 MU of interferon beta three times weekly or combination of the two for 24 weeks. RESULTS: Ribavirin was tolerated well, and all completed the treatment schedule. Ribavirin decreased aminotransferase levels in all instances, and the mean value at termination decreased to half of the baseline level (P < 0.01), but the enzyme level increased after cessation of therapy in most cases. Ribavirin suppressed amounts of hepatitis C virus RNA in 4 of 9 patients, and 1 became negative during follow-up. Interferon alone (P < 0.05) or with ribavirin (P < 0.01) significantly decreased the viral population, resulting in sustained loss of viremia with normal enzyme levels in 2 of 9 and 3 of 9 patients, respectively, in each therapy during follow-up. CONCLUSIONS: These results indicate that ribavirin has a beneficial effect in some patients with chronic hepatitis C, although the antiviral effect is less than interferon beta. Large-scale trials are needed to determine whether the combination of interferon and ribavirin is of more benefit than interferon alone.     

Effects of interferon-alpha on serum hepatitis C virus in patients with chronic hepatitis C

Interferon is beneficial in some patients with chronic hepatitis C. To assess the efficacy of interferon, we used the polymerase chain reaction (PCR) to measure HCV RNA in serial serum samples from 13 chronic hepatitis C patients who were treated with interferon-alpha. Serum alanine aminotransferase (ALT) values normalized in association with the disappearance of serum HCV RNA in nine cases during the therapy. Serum HCV remained negative after the therapy in the three patients who had no relapse, while serum HCV RNA reappeared in the six patients with elevation of ALT values. The persistence of normal ALT levels appears to be correlated with the clearance of the serum HCV. There were two patients whose ALT became normal immediately after the cessation of interferon. Serum HCV was detectable at the end of treatment when serum ALT was elevated, and thereafter serum HCV disappeared. This result suggests an immunomodulatory effect of interferon in the clearance of HCV in some cases. Furthermore, the semiquantitative PCR assay showed that all five patients in whom ALT values were normal at the end of follow-up without detectable serum HCV genome had lower HCV titers in the pretreatment sera than the other eight patients. The detection of HCV RNA by the PCR assay is useful in determining the efficacy of interferon and its mechanisms.     

Estimation of the future numbers of patients with circulatory diseases in Japan based on the results of national patient surveys]

Virological response to treatment of chronic hepatitis B is defined as the loss of serum hepatitis B virus DNA (HBV DNA) and hepatitis B e antigen (HBeAg). The quantitative measurement of HBV DNA is useful for monitoring and predicting the response to therapy with interferon-alpha (IFN-alpha). In this study, we evaluated whether quantitative measurement of serum HBeAg and IgM antibody to hepatitis B core antigen (HBcAb) could also be used in this manner. Using a microparticle-capture enzyme immunoassay (IMx), a standard curve of fluorescence rate vs HBeAg concentration was constructed to provide quantitative results. The IgM HBcAb index was also measured using a microparticle enzyme immunoassay and serum HBV DNA was measured by a solution hybridization assay. We studied 48 patients who were initially positive for HBeAg and HBV DNA and who were treated with IFN-alpha2b. Their sera were serially evaluated for HBeAg concentration, and results were compared with HBV DNA levels. In the 14 patients who responded to IFN, similar disappearance curves were observed with good intraindividual correlation between the levels of the two markers. In the 34 non-responders, HBeAg levels decreased during treatment but never became negative; HBV DNA levels also decreased during treatment and became transiently undetectable in six patients, falsely suggesting treatment success. The IgM HBcAb index paralleled changes in alanine aminotransferase (ALT) concentration and did not provide additional information. Multiple logistic regression indicated that baseline ALT and HBeAg concentrations were independent predictors of the response to treatment and the addition of neither HBV DNA nor IgM HBcAb improved the model. We conclude that quantitative measurement of HBeAg provides information similar to that of HBV DNA in monitoring and predicting the response to treatment; this technique could be readily adaptable to clinical laboratories.     

Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group

BACKGROUND: Interferon alfa is the only effective treatment for patients with chronic hepatitis C. Forty percent of patients have an initial response to this therapy, but most subsequently relapse. We compared the effect of interferon alone with that of interferon plus oral ribavirin for relapses of chronic hepatitis C. METHODS: We studied 345 patients with chronic hepatitis C who relapsed after interferon treatment. A total of 173 patients were randomly assigned to receive standard-dose recombinant interferon alfa-2b concurrently with ribavirin (1000 to 1200 mg orally per day, depending on body weight) for six months, and 172 patients were assigned to receive interferon and placebo. RESULTS: At the completion of treatment, serum levels of hepatitis C virus (HCV) RNA were undetectable in 141 of the 173 patients who were treated with interferon and ribavirin and in 80 of the 172 patients who were treated with interferon alone (82 percent vs. 47 percent, P<0.001). Serum HCV RNA levels remained undetectable 24 weeks after the end of treatment in 84 patients (49 percent) in the combination-therapy group, but in only 8 patients (5 percent) in the interferon group (P<0.001). Sustained normalization of serum alanine aminotransferase concentrations and histologic improvement were highly correlated with virologic response. Base-line serum HCV RNA levels of 2 x 10(6) copies per milliliter or less were associated with higher rates of response in both treatment groups. Viral genotypes other than type 1 were associated with sustained responses only in the combination-therapy group. Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone. CONCLUSIONS: In patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone.     

Permanent response to alpha-interferon therapy in chronic hepatitis C is preceded by rapid clearance of HCV-RNA from serum

BACKGROUND/AIMS: Prediction of response to interferon therapy is important in the management of chronic hepatitis C. Pre-therapy data are valuable but they may be inaccurate in some cases. Our aim was to investigate whether the biochemical and virological events that occur early during interferon therapy in chronic hepatitis C may predict the final result of the treatment. METHODS: ALT and serum HCV-RNA were serially measured in 53 HCV-RNA-positive patients who received a standard 6-month course of interferon therapy. Eleven patients with a sustained response, 23 who responded but subsequently relapsed and 19 who did not respond were studied. HCV-RNA was measured with a commercial kit (Amplicor HCV). RESULTS: After 4 weeks of treatment, HCV-RNA became negative in 73% of sustained responders, in 26% of transient responders (p = 0.02) and in none of the non-responders. Corresponding figures after 8 weeks of therapy were 82% in sustained responders, 61% in transient responders and 9% in non-responders. The difference between sustained and transient responders at this time was not significant. After 4 weeks of therapy, 82% of sustained responders, 52% of transient responders and none of the non-responders presented normalization of alanine transferase. The difference between sustained and transient responders was not significant. Corresponding figures for normalization of alanine transferase at 8 weeks were 82%, 96% and 0% respectively. At the end of treatment, all sustained responders, 70% of transient responders and none of the non-responders had cleared HCV-RNA from serum. CONCLUSIONS: A rapid normalization of alanine transferase induced by interferon therapy is associated with response, but does not differentiate between transient and permanent response. In contrast, clearance of HCV-RNA after 4 weeks of treatment, but not after 8 weeks, is significatively associated with sustained response. Testing for HCV-RNA early during interferon administration may be valuable for further decisions concerning therapy in patients with chronic hepatitis C.     

Interferon (IFN)-alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression: possible relationship of induced NOS2 to the anti-hepatitis C effects of IFN-alpha in vivo

Although researchers have noted high level activation of rodent mononuclear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) gamma and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determine if IFN-alpha serves as an activator in vitro and in vivo in humans. Treatment of normal monocytes or mononuclear cells in vitro with IFN-alpha caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expression. To determine if in vivo administration of IFN-alpha also modulated NOS2, we studied blood cells from patients with hepatitis C before and after IFN-alpha therapy. Untreated patients with chronic hepatitis C virus infection had levels of NOS activity and NOS2 antigen in freshly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-alpha treatment of patients with hepatitis C infection was associated with a significant elevation in mononuclear cell NOS activity, NOS2 antigen content, and NOS2 mRNA content. IFN-alpha-treated patients had significant decreases in levels of serum alanine aminotransferase and plasma hepatitis C mRNA. The degree of IFN-alpha-enhanced mononuclear cell NOS2 antigen content correlated significantly with the degree of reduction in serum alanine aminotransferase levels. Thus, IFN-alpha treatment of cells in vitro or administration of IFN-alpha to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA expression, NOS activity, NOS2 antigen expression, and NO production. Since NO has been reported to have antiviral activity for a variety of viruses, we speculate that induced NO production may be related to the antiviral action(s) of IFN-alpha in hepatitis C infection.     

Subjective experience of treatment, side-effects, mental state and quality of life in chronic schizophrenic out-patients treated with depot neuroleptics

Treatment of chronic hepatitis B and C aims to achieve viral eradication. Decreasing the number of carriers subsequently reduces the transmission of the viruses. For an individual patient, therapy is aimed at preventing cirrhosis, liver failure and hepatocarcinoma. Among potential therapies, interferon alfa offers the best results. In one study involving the treatment of children from a region of intermediate endemicity, interferon alfa accelerated the clearance of hepatitis B virus (HBV) replication. In long-term follow-up, the study did not show a significant difference between patients who were treated and those who were not in the rate of disappearance of serum HBV-DNA, normalization of alanine aminotransferase (ALT) levels or seroconversion to antibodies to hepatitis B e antigen. The most important factors in predicting a rapid decrease in HBV replication were AI T levels more than twice normal, low levels of serum HBV-DNA (less than 100 pg/mL) and inflammatory activity on liver biopsy (chronic active hepatitis). A select group of children with HBV infection has thus been shown to benefit from interferon alfa therapy. Treatment should be administered in a dosage of 6 MU/m2 three times each week for 6 months. Chronic active hepatitis, develops in approximately 30% of children with a chronic hepatitis C virus (HCV) infection. Cirrhosis due to HCV appears to be a very rare complication among children. Results of interferon alfa treatment for children with HCV are scarce. A pilot study of 12 children treated with interferon alfa in a dosage of 3 MU/m2 three times each week for 6 months showed that ALT levels normalized in approximately 90% of the patients after 15 months of follow-up. All of the patients had a decrease in the histological activity of the disease. Factors predictive of a favourable response in adults were: low levels of gamma-glutamyl transferase, young age, female sex, short duration of disease, absence of cirrhosis and low histological activity of the disease. Controlled randomized studies are needed to determine the indications for interferon alfa therapy in children infected with HCV. Available data suggest that children may have a better response than adults.     

Interferon treatment for hepatitis C virus infection in patients on haemodialysis

BACKGROUND: This study examined the efficacy and tolerability of interferon alpha-2b (IFN) in the treatment of chronic hepatitis C virus (HCV) infection in patients on maintenance haemodialysis. METHODS: A 24-month prospective cohort study was performed in 11 HCV RNA-positive haemodialysis patients, who were treated with IFN at 3 MU thrice weekly for 6 months. Serial biochemical and virological monitors included serum alanine aminotransferase levels, and HCV RNA by both qualitative PCR assay and quantitative bDNA assay. HCV genotypes were determined by PCR and nucleotide sequencing. Ten patients had baseline liver biopsy. RESULTS: HCV genotypes 1b and 2b were identified in 10 and one patients respectively. Six (55%) patients had biochemical and/or histological features of chronic active hepatitis before treatment. All 11 patients became HCV RNA-negative by PCR, with normalization of deranged aminotransferase levels, within 2-8 weeks of IFN therapy. HCV RNA reappeared in eight (73%) patients 2-8 weeks after the cessation of IFN, while biochemical relapse occurred in six (55%) patients. Sustained eradication of HCV was achieved in three (27%) patients. Sustained responders were characterized by pretreatment HCV RNA level < 3.5 x 10(5) Eq/ml as determined by the bDNA assay, and less severe histological abnormalities ('Total score' 1.7 +/- 1.2 compared to 5.4 +/- 2.2 in relapsers, P < 0.05). HCV RNA levels were similar before and after IFN treatment in non-responders and relapsers. Persistent malaise and poor appetite were noted in eight (73%) patients during IFN therapy. Other side-effects of IFN included the exacerbation of anaemia, induction of resistance to erythropoietin, weight loss, and reduced serum albumin level. CONCLUSIONS: Eradication of chronic HCV infection with IFN can be achieved in 27% of haemodialysis patients. Predictors of sustained response include low baseline HCV RNA level and mild liver pathology. Virological relapse can occur despite normal liver biochemistry. Exacerbation of anaemia, erythropoietin resistance, and malnutrition constitute the side-effects of IFN that deserve special attention in uraemic subjects.     

Recommendations for image prefetch or film digitization strategy based on an analysis of an historic radiology image database

BACKGROUND: The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined. OBJECTIVE: To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C. DESIGN: Retrospective cohort study. SETTING: One university hospital and seven university-affiliated hospitals. PATIENTS: 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls). INTERVENTION: Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-alpha2a, or recombinant interferon-alpha2b for 6 months. MEASUREMENTS: The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns. RESULTS: Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls. CONCLUSIONS: The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.     

Interferon alpha-2b in the treatment of chronic hepatitis C: early experience

The antiviral and immunomodulatory effects of interferon were assessed in the treatment of chronic Hepatitis C in multi-ethnic patients to prevent viral replication and chronic liver damage. Three million units of recombinant interferon alpha-2b were administered three times a week for 48 weeks to a group of 9 active Hepatitis C patients. A clinical response was defined as normalization of serum ALT values. Serum was frozen and stored for Hepatitis C viral assays. Four patients normalized their liver functions. When viral levels were measured only two patients had unmeasurable levels of HCV RNA after treatment. Therapeutic results were observed and much work needs to be done to improve therapy because a serious epidemic is predicted for the future.     

Maxillary sinus augmentation: histomorphometric analysis of graft materials for maxillary sinus floor augmentation

OBJECTIVE: To compare efficacy and tolerance of recombinant interferon alfa-2b in the treatment of anti-HCV-positive chronic active hepatitis (CAH) in subjects aged 65 years and above with those less than 65. DESIGN: A randomized controlled trial. SETTING: Outpatients in two hospitals. PATIENTS: 65 consecutive outpatients with anti-HCV-positive CAH for 1 to 30 years, having basal aminotransferase levels at least twice the normal value. Those 65 and over were randomized to an interferon group (A, n = 22) or a no-treatment group (B, n = 22). All those under 65 received interferon (group C, n = 21). INTERVENTION: Interferon at a dose of 3 mU 3 times a week for a 6-month period. A normalization of serum aminotransferase levels was considered a positive response to therapy. RESULTS: Response to therapy was positive in 62% of the treated elderly compared to 57% of the adults (P = 0.85). The two groups of responders showed a common highly significant reduction of aminotransferase (P < 0.001). Side effects were similar in elderly and young. Two untreated elderly showed spontaneous normalization of aminotransferase. CONCLUSION: Interferon in anti-HCV-positive CAH is useful in the elderly, allowing normalization of aminotransferase, improvement of the histology and remission of the disease in 62% of the cases. Side effects seem to be independent of age. Further studies are required to assess both duration of remission and usefulness of cyclic therapy in previous responders.     

Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.     

Neutrophil response to Pseudomonas aeruginosa in respiratory infection

The antiviral effect of natural interferon (IFN)-alpha on chronic hepatitis C virus (HCV) infection was estimated by determining quantitative changes in serum HCV-RNA compared with the serum alanine aminotransferase (sALT) improvement; the relationships of responses to IFN according to the dose and period of IFN therapy were defined to determine an appropriate IFN therapy protocol. Twenty-two patients with chronic hepatitis C were given natural IFN-alpha and in 16 (72.7%) patients the viraemia was suppressed during therapy. Five (27.7%) of them sustained the disappearance of HCV-RNA for more than 6 months after therapy accompanied with a prolonged sALT improvement. Pre-treatment viraemia levels in 5 complete responders with "complete suppression" of viraemia were significantly lower than in 11 patients with a transient loss or a decline of HCV-RNA. A favorable antiviral response was closely associated with a high total dose of IFN-alpha and a long duration of IFN therapy.