mycophenolic-acid and Hepatitis-C--Chronic

Hepatitis C virus infection affects around 3% of the world population or approximately 160 million people. A variable proportion (5% to 40%) of the infected people develop clinical symptoms. Hence, hepatitis C virus is a leading cause of liver-related morbidity and mortality with hepatic fibrosis, end-stage liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae. Combination therapy with pegylated (peg) interferon-alpha and ribavirin achieves sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs.. To assess the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection by conducting a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.. The Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013. Furthermore, full text searches were conducted until December 2013.. Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection.. Two authors independently extracted data. RevMan Analysis was used for statistical analysis of dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). Methodological domains were used to assess the risk of systematic errors ('bias'). We used trial sequential analysis to assess risk of random errors ('play of chance').. Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). Amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups, except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response (low quality of evidence). One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons.. This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.

Topics: Amantadine; Antiviral Agents; Hepatitis C, Chronic; Humans; Interferon-alpha; Interferon-gamma; Mycophenolic Acid; Randomized Controlled Trials as Topic; Ribavirin

Diagnosis and treatment of hepatitis C virus (HCV) -related autoimmune features has become a clinical challenge in HCV-infected patients, in whom chronic liver disease associated with severe autoimmune features may contribute to a very poor prognosis. Both antiviral and immunosuppressive therapies, either alone or in combination, seem likely to have a key role. Based on the experience of mycophenolate mofetil (MMF) use in HCV patients receiving organ transplantation, this new immunosuppressive agent might represent a safe and effective therapeutic option to treat HCV-related extrahepatic features. Recent data are available for the use of MMF in HCV patients with autoimmune manifestations, mainly for autoimmune cytopenias and vasculitic features. MMF may be used as monotherapy or in association with other drugs for cases of HCV-related autoimmune diseases refractory or intolerant to common immunosuppressive treatments, allowing the reduction of the drug dosage and avoiding serious side effects.

Topics: Antiviral Agents; Autoimmune Diseases; Drug Therapy, Combination; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Mycophenolic Acid

In our series of 1374 renal transplantations performed between February 1970 and December 2002, we observed 6 cases of infection due to Nocardia asteroides. There were 4 males and 2 females, aged 49.8 +/- 12 years (29 to 63 years). One patient received his first transplantation and the 5 others retransplants. Three patients had PRA > 80%, one 28% and one 40%. One patient was diabetic and two had HCV infection. Two of 6 patients experienced acute rejection episodes. Nocardiosis localisation was pulmonary in 5 cases, cerebral in two and mediastinal in one. All patients recovered after reduction of immunosuppression and appropriate antibiotherapy with trimethoprim-sulfamethoxasole (TMP-SMX). When we analyzed the role of immunosuppression, we observed that only two cases were observed in the 933 recipients transplanted between 1985 and 2002 and receiving cyclosporin, contrasting with 4 cases among 174 recipients transplanted between 1996 and 2002 and receiving tacrolimus. Our data suggest that high immunologic risk patients, heavy immunosuppression, and perhaps tacrolimus-based immunosuppression are risk factors of nocardial infection. Early diagnosis of this severe infection, reduction of immunosuppression and appropriate therapy with TMP-SMX resulted in complete recovery in all our patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Azathioprine; Cyclosporine; Diabetes Complications; Disease Susceptibility; Female; Graft Rejection; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia asteroides; Nocardia Infections; Postoperative Complications; Reoperation; Risk Factors; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

1. Approximately 10% to 25% of hepatitis C virus-infected recipients of liver allografts will develop cirrhosis within 5 years of transplantation; this acceleration of the natural history of hepatitis C is caused in part by immunosuppression. 2. Risk factors for aggressive recurrence, graft loss, and death are treated acute cellular rejection, methylprednisolone pulse therapy, and use of OKT3. There appears to be no consistent difference between cyclosporine and tacrolimus in their effects on hepatitis C. 3. The benefit of steroid withdrawal, although commonly practiced in transplant recipients with hepatitis C, has not been proven. 4. Mycophenolate mofetil may show synergistic antiviral properties when used with interferon; however, posttransplantation use has not been associated with consistent beneficial or deleterious effects. 5. Effects of other agents, such as sirolimus or interleukin-2-receptor antibodies, have not been adequately defined. Early reports suggest that disease activity may be more aggressive when these agents are constituents of the immunosuppressive regimen.

Topics: Cyclosporine; Disease Progression; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Risk Assessment; Sirolimus; Tacrolimus

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Antiviral Agents; Biopsy; Chi-Square Distribution; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Hepacivirus; Hepatitis C, Chronic; Humans; Immunoglobulin G; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; RNA, Viral; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; United States

There are no established therapeutic regimens for hepatitis C virus (HCV) patients who relapse following treatment with interferon alpha-2b and ribavirin or those who break through while on interferon alpha-2b and ribavirin. We therefore evaluated various combination therapies in HCV patients who relapsed or experienced a viral breakthrough. Patients (n = 124) were randomized to 48 weeks of treatment with once-weekly subcutaneous injections of 180 microg pegylated (peg-) interferon alpha-2a plus oral ribavirin (800-1000 mg/day), mycophenolate mofetil (2 g/day), amantadine (200 mg/day), or ribavirin and amantadine and followed for an additional 24 weeks. The sustained virologic response was higher in patients administered peginterferon alpha-2a plus ribavirin (38%) or ribavirin and amantadine (45%) than in those administered peginterferon alpha-2a plus mycophenolate mofetil (17%) or amantadine (10%). As in previous studies, patients with genotype non-1 and those with lower viral loads had better responses than those with genotype 1 and high viral loads, though the differences did not reach significance. The four treatment regimens had similar safety profiles, except that patients receiving ribavirin had greater maximal hemoglobin decreases. These findings suggest that the combination of peginterferon alpha-2a plus ribavirin or with ribavirin and amantadine is effective in some HCV patients who relapse after treatment with interferon alpha-2b plus ribavirin.

Topics: Alanine Transaminase; Amantadine; Antiviral Agents; Drug Therapy, Combination; Female; Genotype; Hemoglobins; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyethylene Glycols; Recombinant Proteins; Recurrence; Retreatment; Ribavirin; Treatment Outcome; Viral Load

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in the management of liver transplant recipients. MMF inhibits the inosine monophosphate dehydrogenase that has been shown to have in vitro antiviral properties against flaviviruses, suggesting the possibility that it might also inhibit the hepatitis C virus (HCV). The goal of this short-term dose escalation study was to assess the antiviral effects of MMF on HCV replication. Patients with chronic hepatitis C who had not undergone liver transplantation were randomized to 8 weeks of treatment with one of four mycophenolate dose regimens (1000 mg orally twice daily, 500 mg orally twice daily, 250 mg orally twice daily, or a matched oral placebo twice daily). All groups were double-blinded. Quantitative HCV RNA levels and serum alanine aminotransferase were assessed at baseline, at weeks 2, 4, and 8 of dosing, and at weeks 4 and 8 of follow-up. Thirty patients met inclusion criteria, enrolled, and were randomized. HCV RNA levels did not change significantly during treatment. Specifically, no subject became virus negative or had a one-log decrease in virus level. Serum aminotransferase level did not normalize in any subject. The most common side effects were headache, nausea, and diarrhea. Mycophenolate alone does not appear to have a significant antiviral or biochemical effect in patients with chronic hepatitis C.

Topics: Adult; Aged; Double-Blind Method; Enzyme Inhibitors; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Inosine Monophosphate; Male; Middle Aged; Mycophenolic Acid; Treatment Failure

Topics: Cytoplasm; Hepatitis C, Chronic; Humans; Interferon-alpha; Mycophenolic Acid; Ribavirin

Drug adherence is one of the most important factors determining graft and patient survivals after liver transplantation. A systematic pharmaceutical educational approach has been implemented to improve adherence in immunosuppressive drugs therapy at Siriraj Hospital.. This study was a single-center cross-sectional study of liver transplant patients who received pharmaceutical care from transplant pharmacists. The clinical pharmacy services, including medication review to emphasize patients' knowledge and awareness of immunosuppressive and general drug therapies with the use of various tools, were used to educate the patients. Drug-related problems (DRPs) and pre- and post-transplantation educational tests (divided into 3 parts: immunosuppressants [12 points], drug monitoring [6 points], and general drugs [2 points]) were analyzed.. From October 2012 to September 2014, a total of 50 liver transplant recipients (86 visits) were enrolled. After the systematic pharmaceutical educational program, the average total score of post-transplantation educational test improved from 3.48 to 13.30 (P < .001). Likewise, the mean scores of all 3 parts significantly increased (part I: 2.28 vs 8.18 [P < .001]; part II: 0.75 vs 3.63 (P < .001); and part III: 0.46 vs 1.50 [P < .001]). The incidences of major DRPs, nonadherence, and adverse drug reactions were 8%, 4%, and 2%, respectively.. A systematic pharmaceutical educational approach can significantly improve patients' knowledge and awareness concerning immunosuppressive drug usage.

Topics: Adult; Carcinoma, Hepatocellular; Cross-Sectional Studies; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Middle Aged; Mycophenolic Acid; Patient Education as Topic; Pharmaceutical Services; Risk Factors; Tacrolimus

Aim: Pegylated-interferon/ribavirin/simeprevir (PEG-IFN/RBV/SMV) combination therapy is widely used for hepatitis C virus (HCV) treatment after liver transplantation (LT). Here, we observed two cases of extended severe anemia during PEG-IFN/RBV/SMV therapy for HCV serological type 1 re-infected after LT. Immunosuppressants consisted of tacrolimus and mycophenolate mofetil (MMF). Case 1 was a 65-year-old-woman treated with PEG-IFN/RBV/SMV therapy and 500 mg MMF/day 9 months after LT. Her serum hemoglobin (Hb) level decreased from 10 to 8.4 mg/dL on day 25. Despite discontinuing the PEG-IFN/RBV/SMV treatment on day 32, her Hb level decreased to 5.1 mg/dL on day 40. Case 2 was a 61-year-old-woman started on PEG-IFN/RBV/SMV therapy 20 months after LT. Her serum Hb level decreased from 12.2 to 7.1 mg/dL on day 39. The MMF dose was reduced from 1,500 to 1,000 mg/day, and her Hb level was maintained. Red blood cell transfusions were required in both cases, and anemia persisted for 2 months. These patients had the C/C major type inosine triphosphatase (ITPA) polymorphism. In conclusion, MMF induced severe persistent anemia by co-treatment with IFN/RBV in patients who underwent LT. Thus, the immunosuppressant dose should be chosen carefully for patients with the high-risk ITPA allele.

Topics: Aged; Anemia; Antiviral Agents; Erythrocyte Transfusion; Female; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Middle Aged; Mycophenolic Acid; Recurrence; Ribavirin; Simeprevir; Tacrolimus

Genetic polymorphisms adjacent to IL28B have been previously associated with spontaneous clearance of hepatitis C virus (HCV) and a higher rate of sustained virological response to interferon-based treatment in HCV genotype 1-infected patients. A recent study has shown that patients with the CC genotype of the rs12979860 single nucleotide polymorphism upstream from the IL28B gene are more likely to clear HCV spontaneously relative to the CT or TT genotype. In the liver transplant cohort, HCV recurs almost universally in patients with detectable HCV RNA at the time of transplantation. The spontaneous clearance of HCV infection after transplant is very rare. We report two cases of spontaneous clearance of HCV genotype 1 infection after liver transplantation from homozygous IL28B CC donors. This finding may be explained by alterations in the host immune responses to HCV after transplantation with a CC donor liver, which has potential implications for donor selection in HCV-positive recipients.

Topics: Adult; Alcoholism; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Interleukins; Liver Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Polymorphism, Genetic; Remission, Spontaneous; Tacrolimus; Treatment Outcome

1. The natural history of recurrent hepatitis C virus (HCV) is highly variable. Old donor age is a factor that has consistently been shown to affect disease progression. 2. Overall, immunosuppression determines the progression of HCV-related disease; however, the type of immunosuppressive agent used for induction or maintenance is not a key factor. 3. Steroid boluses should be avoided; they are associated with increased viremia, fibrosis progression, and reduced survival. 4. Antiviral therapy, particularly if it is successful, is associated with improved outcomes for liver transplant recipients with HCV. 5. There are no convincing data for modifying the type of immunosuppression before antiviral therapy is started.

Topics: Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

1. The treatment of rejection is an important factor associated with the severe recurrence of hepatitis C virus (HCV) after liver transplantation. 2. The effects of calcineurin inhibitors, corticosteroids, and mycophenolate mofetil on HCV recurrence are equivocal. 3. Cyclosporine is associated with a higher sustained virological response in patients treated for HCV. 4. Because insulin resistance and diabetes are associated with fibrosis in HCV-infected liver transplant recipients, the use of immunosuppressive agents without this side effect may slow the posttransplant disease progression.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Recurrence; Risk Factors; Sirolimus

Liver transplantation (LT) for hepatitis C virus (HCV)-associated cirrhosis in human immunodeficiency virus (HIV)-infected patients was compared with non-HIV patients. Nine patients with HIV-HCV coinfection were compared with patients transplanted before and after each HIV patient (control group). Immunosuppression consisted in tacrolimus with steroids or mycophenolate mofetil. Acute cellular rejection and three-year actuarial patient survival were respectively 44% and 87.5% in HIV group and 22% and 93.7% in the control group (P=NS). Acute hepatitis C virus occurred earlier (2.3 vs. 4.3 months) and was more cholestatic (mean bilirubin: 10.8 vs. 1.6 mg/dL) in the HIV group. Eight (100%) HIV and nine (64.3%) control patients received antiviral treatment with pegylated interferon and ribavirin. One patient (11.1%) of the control group and one patient (20%) of the HIV group presented a sustained virologic response (P=NS). Short- to midterm results of LT in HIV-HCV co-infected patients were excellent and similar to non-HIV patients.

Topics: Adult; Aged; Antiviral Agents; Case-Control Studies; Female; Hepatitis C, Chronic; HIV Infections; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Steroids; Tacrolimus; Treatment Outcome

If myasthenia gravis is not a usual complication of interferon therapy, several cases have been described with the use of theses molecules in the treatment of hepatitis C, cancer or multiple sclerosis. We report a new case of serious myasthenia gravis during interferon alpha and ribavirin therapy for hepatitis C.

Topics: Aged; Antiviral Agents; Cholinesterase Inhibitors; Follow-Up Studies; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interferon-alpha; Male; Myasthenia Gravis; Mycophenolic Acid; Prednisone; Pyridostigmine Bromide; Ribavirin

We report two cases of hepatitis C virus (HCV) associated autoimmune haematological disorders successfully treated with an unusual protocol (mycophenolate mofetil: MMF). The first case was a male patient with chronic HCV infection who developed, during interferon (IFN)/ribavirin therapy, severe autoimmune thrombocytopenia unresponsive to steroids. MMF was then administered and, simultaneously, the steroid dose was gradually reduced until withdrawal. Following this strategy, a progressive increase in platelet count and complete negativity of anti-PLT antibodies were achieved without changes in HCV-RNA quantitative determination. The second case was a woman with HCV liver cirrhosis with severe anaemia and Coombs test positivity partially responsive to continuous administration of steroid high doses. However, this treatment unmasked a severely painful vertebral osteoporosis. For this reason we introduced MMF and simultaneously steroid therapy was progressively reduced until withdrawal. Haemoglobin reached a normal value and the Coombs test became negative within 60 days. These case reports suggest that MMF may represent an interesting therapeutic approach for autoimmune HCV associated haematological disorders.

Topics: Aged; Anemia, Hemolytic; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Autoimmune Diseases; Drug Resistance; Female; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Thrombocytopenia; Withholding Treatment

Since ribavirin was able to improve the antiviral efficacy of interferon alfa in patients with chronic hepatitis C, several other adjuncts have been studied. It has been shown that mycophenolate mofetil (MMF) is a more potent inhibitor of the inosine 5'-monophosphate-dehydrogenase (IMPDH) than ribavirin. The present study is a pilot study evaluating the efficacy and safety of combination therapy with interferon alfa-2a and MMF in interferon alfa nonresponder patients.. Thirty-eight adult patients with chronic hepatitis C who did not respond to a previous interferon alfa monotherapy were enrolled to receive 6 million units of interferon alfa-2a tiw in combination with MMF (1 week 500 mg/day, 1 week 1000 mg/day, 22 weeks 2000 mg/day).. An interim analysis of 29 patients after 12 weeks of therapy showed that only one patient had negative hepatitis C virus-RNA at this time point. There was no significant reduction of the viral load during therapy. Due to inefficacy the study was discontinued.. Combination therapy of interferon alfa-2a and MMF is ineffective in improving virological response rates in nonresponder patients with chronic hepatitis C. These data suggest that inhibition of the IMPDH seems not to be the major mechanism of ribavirin in enhancing the antiviral effect of interferon alfa in chronic hepatitis C.

Topics: Adult; Antiviral Agents; DNA, Viral; Drug Resistance; Drug Therapy, Combination; Enzyme Inhibitors; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Recombinant Proteins; Retreatment; Safety; Treatment Failure; Viral Load

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent and might inhibit chronic rejection, at least in primates. The prevalence of chronic hepatitis C virus (HCV) infection is high in renal transplant (RT) patients. To date, it has not been demonstrated whether MMF has any effect upon HCV viremia.. Fourteen long-term HCV(+) RT patients with chronic allograft dysfunction whose maintenance immunosuppression was based on cyclosporine, were given MMF therapy either in place of azathioprine (n=11) or in addition to baseline therapy (n=3). HCV viremia levels were measured by the Amplicor HCV-Monitor RT-PCR assay (Roche Diagnostic Systems) on two separate occasions before the introduction of MMF, and 1 year after changing to MMF or at the last follow-up visit.. MMF therapy was associated with a significant rise in HCV viremia, i.e., 5.8+/-0.5 vs. 5.2+/-0.7 log copies/ml (P=0.01), although there were no significant changes in liver enzymes. The increase in HCV viremia was not related to HCV genotypes either. At the patient level, HCV RNA concentrations changed in only seven patients (group B), i.e. >1 log copies/ml, whereas it remained stable in the others (group A). Before conversion, the only significant difference between group A and B was the level of HCV RNA, i.e., 5.5+/-0.4 log copies/ml in group A and 4.9+/-0.7 log copies/ml in group B (P=0.05).. Our study suggests that MMF should be used with caution in stable HCV RT patients whose maintenance immunosuppressive therapy is based on cyclosporine, at least in the case of patients with a low HCV RNA titer.

Topics: Adult; Cyclosporine; Drug Therapy, Combination; Female; Gene Dosage; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Osmolar Concentration; RNA, Viral; Time Factors; Viremia