Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C

BACKGROUND: Histological recurrence of the hepatitis C virus (HCV) occurs in the majority of persons transplanted for cirrhosis as a result of HCV. Herein we analyze our experience with the use of both conventional and pegylated (PEG) interferon (IFN) in combination with ribavirin (RBV) in liver transplant recipients with recurrent HCV. Methods: Patients transplanted between 1992 and 2001 with post-orthotopic liver transplantation (OLT) histological recurrence of HCV, and who were treated with at least 6 months of IFN or PEG-IFN in combination with RBV were included in this analysis. A retrospective chart review was performed. Results: A total of 31 patients were included. Fifteen were treated with IFN/RBV and 16 with PEG-IFN/RBV. Of these 16, 11 had been begun on IFN/RBV and were changed to PEG-IFN/RBV because of persistent viremia. Three patients (20%) in the IFN/RBV group and six patients (37.5%) in the PEG-IFN/RBV group experienced a virologic response (VR) on therapy. Of the six patients experiencing VR in the PEG-IFN/RBV group, three (50%) were IFN/RBV non-responders. There were two sustained VRs (SVR). The 65.6% of all patients experienced a biochemical response (BR) on therapy. Seven deaths were observed. Dose modifications of IFN or PEG-IFN (87.1%) and RBV (80.6%) and the requirement for hematopoietic growth factors were frequent. Conclusions: Treatment of recurrent HCV infection with combination of IFN or PEG-IFN and RBV produced an on-therapy VR in 29% and BR in 65% of patients. Hematologic toxicity and dose modifications were frequent. Our experience with antiviral therapy for HCV post-OLT remains disappointing but PEG-IFN + RBV appears to produce VR in a sizable portion of IFN + RBV non-responders.     

Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection

AIM: Pegylated interferon (PEG-IFN) combined with ribavirin is recommended for the treatment of chronic hepatitis C virus (HCV) infection in patients without renal failure. The optimal treatment of hepatitis C in dialysis patients remains to be established. A high incidence of adverse effects has been observed with conventional interferon and PEG-IFN alpha-2b in dialysis patients. METHODS: We conducted a prospective study to investigate the tolerability and efficacy of PEG-IFN alpha-2a (135 microg weekly for 48 weeks) in six dialysis patients with chronic HCV infection. RESULTS: Two patients completed 48 weeks of treatment. Treatment was stopped in three patients (beyond 24 weeks) when they developed unrelated complications, and stopped in one patient due to failure of viral clearance. None required treatment discontinuation due to adverse effects, and PEG-IFN alpha-2a was subjectively well tolerated. Marrow suppression with mild anaemia, leucopenia, or thrombocytopenia remained common. Two patients (infected with genotypes 3a and 1b, respectively) had sustained virological response. CONCLUSIONS: Results from this pilot study showed that PEG-IFN alpha-2a appeared relatively well tolerated in dialysis patients with chronic HCV infection, and about one-third of patients could achieve sustained virological response.     

Outcome of treatment with pegylated interferon and ribavirin in heart transplant recipients with chronic hepatitis C

Background/aim

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC.

Methods

From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies.

Results

All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score ≥ 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction.

Conclusions

Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.     

国产聚乙二醇化重组集成干扰素变异体联合利巴韦林治疗慢性丙型病毒性肝炎患者甲状腺功能异常及其对疗效的影响

目的观察国产聚乙二醇化重组集成干扰素变异体注射液（PegIFN-SA）联合利巴韦林（RBV）治疗慢性丙型病毒性肝炎（CHC）患者时甲状腺功能异常（TD）或甲状腺自身抗体（TAs）产生情况及对疗效影响。 方法前瞻性观察2013年9月至2015年12月于本中心接受国产PegIFN-SA联合RBV治疗的CHC病例45例。试验组患者给予PegIFN-SA皮下注射（1.5 μg/kg、1次/周）,对照组患者给予聚乙二醇化干扰素α-2a（PegIFN-α-2a）皮下注射（派罗欣180 μg、1次/周）,两组患者均联合口服利巴韦林（000~1 200 mg/d）,HCV基因2、3型患者治疗24周,非HCV基因2、3型患者治疗48周,停药后均随访6个月。在治疗前、治疗后每3个月及停药后6个月监测两组患者甲状腺功能及HCV RNA水平。 结果试验组慢性丙型肝炎患者30例,其中男性14例,女性16例,平均年龄为（36.5 ± 12.0）岁（19~56岁）,HCV基因2、3型患者6例,HCV非基因2、3型患者24例。治疗结束停药半年后HCV持续应答率为83.3%（25/30）,共13例患者出现TD或TAs,其发生率为43.3%（13/30）;9例发生TD患者中4例（44.4%）丙型肝炎复发,高于未出现TD者（1/21,4.8%）,差异具有统计学意义（P = 0.02）。 结论国产PegIFN-SA联合RBV治疗慢性丙型病毒性肝炎患者甲状腺功能异常及抗体阳性较为常见,发生甲状腺功能异常者CHC更易复发。     

Histological Benefit of Retreatment by Pegylated Interferon Alfa-2b and Ribavirin in Patients with Recurrent Hepatitis C Virus Infection Posttransplantation

We conducted a study to evaluate the efficacy of pegylated interferon/ribavirin in patients who did not respond to previous posttransplant recurrent HCV treatment with IFN/ribavirin combination. Twenty-seven patients were consecutively included in this study and retreated with pegylated interferon alfa-2b (1.5 microg/kg/week) with ribavirin (800-1000 mg daily) for 48 weeks for genotype 1 and 4 and 24 weeks for other genotypes. We compared them with 21 untreated patients enrolled during the same period. Primary endpoint was the SVR and secondary endpoint was histological evaluation 24 weeks after ending therapy. Twenty-seven patients started therapy but 2 (7%) stopped because of side effects. On an intent-to-treat basis, eight patients (30%) had an SVR. Cyclosporine as immunosuppressive therapy during antiviral therapy (p = 0.03) and EVR (p = 0.02) were significantly associated with viral clearance. In 46 patients in whom paired graft biopsies were available, fibrosis score was improved in 76% of treated patients versus 5% in untreated patients. Among treated patients, improvement of fibrosis was not correlated to SVR. Our data show that 30% of patients who have failed prior posttransplantation treatment achieved an SVR when retreated with pegylated interferon alfa-2b/ribavirin. More interesting is that fibrosis score was improved in 65% of treated patients despite failure of HCV eradication.     

Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence.

Sustained virologic response (SVR) after antiviral therapy for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients is consistently lower than that achieved in non-LT patients. We evaluated efficacy and safety of pegylated interferon (IFN) and ribavirin (RBV) therapy in LT recipients with recurrent HCV and factors associated with SVR. All subjects with histologic evidence of recurrent HCV were intended to be treated for 48 weeks with full-dose pegylated IFN; target dose of RBV was 800 mg/day. Thirty-five LT recipients with recurrent HCV, median age 48.5 years, 77% genotype 1, and median pretreatment HCV RNA 6.4 log10 IU/mL were treated between January 2000 and February 2006. Antiviral therapy was discontinued prematurely in 15 subjects as a result of adverse events. Median overall treatment duration was 46 weeks. Early virologic response at week 12 was seen in 17 (49%) and an end-of-treatment virological response in 19 (54%) patients. SVR was achieved in 13 patients (37%), and all 9 patients followed for >1 year after treatment had durable response. Patients with SVR had significantly lower pretreatment HCV RNA (5.7 vs. 6.5 log10 IU/mL, P=0.003), more likely to have a week 12 virological response (85% vs. 27%, P=0.0009) and received higher cumulative doses of pegylated IFN (75% vs. 33%, P=0.029) and RBV (90% vs. 26%, P=0.016) compared with patients whose disease did not respond to therapy. In conclusion, SVR was achieved in 37% of patients with recurrent hepatitis C after LT. Similar to non-LT patients, those with lower pretreatment HCV RNA, a week 12 virological response, and pegylated IFN and RBV dose adherence were more likely to achieve SVR.     

聚乙二醇化干扰素联合利巴韦林治疗慢性丙型肝炎疗效的影响因素

目的探讨聚乙二醇化干扰素（PegIFN）联合利巴韦林（RBV）治疗慢性丙型肝炎疗效的影响因素。 方法回顾性分析2008年1月至2011年12月于宝鸡市中心医院接受PegIFN和RBV联合治疗的148例HCV感染者的临床资料。采用持续性病毒应答24周（SVR24）、早期病毒学应答（EVR）、治疗结束病毒应答（ETR）、持续性病毒应答12周（SVR12）、复发、无效应答、病毒学突破评估疗效,Logistic回归分析影响疗效的因素。 结果148例HCV感染者失访12例（8.1%）。136例HCV感染者中128例（94.1%）患者出现EVR、118例（86.8%）患者出现ETR、114例（83.8%）患者出现SVR12、112例（82.4%）患者出现SVR24、8例（5.9%）患者无效应答、6例（4.4%）患者复发、4例患者出现病毒学突破（2.9%）。HCV RNA、HCV基因型和UA均为影响HCV感染者SVR24的因素（P均< 0.05）。 结论PegIFN联合RBV治疗HCV感染疗效显著。HCV基因型2/3、HCV RNA水平较低和尿酸与HCV SVR相关。     

聚乙二醇化干扰素联合利巴韦林治疗肝移植后丙型肝炎复发四例

目的 探讨聚乙二醇化干扰素(PEG-IFNα-2a)联合利巴韦林(RIB)方案治疗肝移植后丙型肝炎复发的临床疗效.方法 回顾性分析4例肝移植术后丙型肝炎复发患者的临床资料.4例患者中,术前诊断丙型肝炎合并肝硬化3例,丙型肝炎后肝硬化合并肝细胞肝癌1例,术后均采用他克莫司+霉酚酸酯+皮质激素的三联免疫抑制方案.术后8～12周时,患者均经移植肝组织活检证实丙型肝炎复发.复发后,立即采用PFG-IFNα-2a联合RIB方案进行抗丙型肝炎治疗,连续治疗48周.PEG-IFNα-2a的用量为180μg,皮下注射,每周1次;RIB的用量为1000 mg/d,口服.在治疗期间,检查患者的血常规、肝肾功能、丙型肝炎病毒核糖核酸及移植肝组织活检,观察生化学应答、持续病毒学应答及组织学应答等指标.结果 除1例外,其他患者经治疗后出现持续病毒学应答,移植肝功能均恢复正常,在术后0、48和72周,移植肝组织病理学炎症坏死和纤维化情况改善.1例在术后第7天经组织学证实发生急性排斥反应,给予连续3 d皮质激素冲击治疗后,病情好转.无患者因严重的不良反应而停药或退出治疗.结论 PEG-IFNα-2a联合RIB方案是治疗肝移植后丙型肝炎复发的有效方法,患者的耐受性好,不良反应少.     

Real‐world experience with daclatasvir plus sofosbuvir ± ribavirin for post‐liver transplant HCV recurrence and severe liver disease

Optimizing therapy of post‐transplant HCV recurrence remains important, especially in advanced liver disease. We evaluated daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in patients with post‐liver transplant recurrence in a real‐world European cohort at high risk of decompensation or death within 12 months. Recommended treatment was DCV 60 mg plus SOF 400 mg once daily for 24 weeks; RBV use/shorter treatment duration was at physicians’ discretion. Patients (N = 87) were 70% male, 93% white, and mostly infected with HCV genotypes 1b (48%), 1a (32%), or 3 (9%); 37 (43%) had cirrhosis (16 decompensated), five had fibrosing cholestatic hepatitis. Sustained virologic response at post‐treatment week 12 (SVR12) was 94% (80/85) in a modified intention‐to‐treat analysis: 95% (58/61) without RBV and 92% (22/24) with RBV, with no virologic failures. SVR12 was 100% (80/80) in an as‐observed analysis excluding five nonvirologic failures. Four patients (5%) discontinued therapy for adverse events (AEs); 16 (18%) experienced serious AEs. One patient died on treatment and five during follow‐up. Most AEs were associated with advanced liver disease and unrelated to therapy. No clinically significant drug–drug interactions were observed. DCV + SOF ± RBV was well tolerated and achieved high SVR12 (94%) in patients with post‐transplant HCV recurrence, including patients with severe liver disease.     

Pegylated Interferon Alpha-2b for Patients with HCV Recurrence and Graft Fibrosis Following Liver Transplantation

Chronic hepatitis C is a principal indication for liver transplantation. Recurrent viral infection is inevitable and graft disease is common. We report tolerability, safety and efficacy of pegylated interferon alpha 2b (PEG-IFN) monotherapy for patients with hepatitis C virus (HCV) recurrence and fibrosis after liver transplantation. Repeated measurements of serum HCV titer permitted assessment of the kinetics of the antiviral response for all patients. We screened 63 patients transplanted for HCV at our center for antiviral treatment, 14 were eligible and treated, but only 6 completed the proposed 52 weeks of therapy. Eight were withdrawn because of severe/life-threatening side effects/events, including liver dysfunction (4 patients). None of those 8 achieved a sustained virological response (SVR). Five of 6 who completed treatment were HCV RNA negative at the end of treatment, and 2 achieved an SVR. Viral kinetics were similar to published observations for treatment of non-transplanted HCV patients. Patients with genotype non-1 infection displayed a more rapid decline of viral titer than was observed for genotype 1 infection. Post-transplant HCV patients are frequently unsuitable for, or intolerant of PEG-IFN. Liver dysfunction was a major concern.     

Pre‐emptive antiviral therapy in living donor liver transplantation for hepatitis C: observation based on a single‐center experience

Reports of large series in living donor liver transplantation (LDLT) for hepatitis C virus infection (HCV) are scarce. Between 1996 and 2008, 105 LDLTs were performed at the University of Tokyo for HCV. Rapid induction of antiviral treatment with interferon (IFN) and ribavirin (RBV) was attempted per protocol regardless of the clinical presentation of recurrent HCV (pre‐emptive treatment approach). Treatment was continued for 12 months after serum HCV‐RNA became negative (ETR: end‐of‐treatment response) and judged as a sustained viral response (SVR) after another 6 months of negative results without treatment. A fixed treatment period was not defined unless an ETR was achieved (no‐stopping approach). Flexible dose adjustments were allowed. Ninety‐five patients were eligible for pre‐emptive therapy. Forty‐three (45%) patients experienced an ETR, and 32 (34%) achieved SVR. Nonadherence to full‐dose INF and RBV had little impact on the viral response. Evaluation using the Kaplan–Meier method to incorporate the cumulative time‐dependent nature of the no‐stopping approach estimated SVR rate at 53% by the fifth year. Survival rate at 5 years was 79% for the HCV recipients and did not differ significantly from our non‐HCV series. In LDLT for HCV, pre‐emptive IFN–RBV‐based treatment with the application of no‐stopping approach is feasible and effective.     

干扰素对HIV／HCV合并感染者抗HCV早期疗效观察

目的通过分析HIV/HCV合并感染者使用长效/普通干扰素联合利巴韦林抗HCV早期治疗效果,探讨更适合我国国情的HIV/HCV合并感染的抗HCV治疗方案。方法 129例经HAART治疗的HIV/HCV合并感染者随机选用PEG-IFN-α-2a或IFN-α-2b联合利巴韦林治疗,利用巢氏PCR加测序分析检测HCV基因分型,COBASTM全自动病毒载量分析系统分别检测抗HCV治疗前、治疗后4周、12周的外周血HCVRNA载量,获得HIV/HCV合并感染者抗HCV快速病毒学应答率（RVR）、早期病毒学应答率（EVR）。结果我国HIV/HCV合并感染者中,HCV基因型为1型患者占34.0%,非1型者占66.0%。使用普通干扰素抗HCV治疗组RVR、EVR、cEVR与PEG干扰素组比较无显著差异;普通干扰素组中HCV非基因1型早期治疗效果优于HCV基因1型（P〈0.05）,PEG干扰素组HCV-1型和非1型早期治疗效果比较无显著差异;PEG及普通干扰素在抗HCV治疗过程中对患者肝功能的恢复均有积极效用（P〈0.05）。结论 PEG及普通干扰素联合利巴韦林抗HCV方案治疗我国HIV/HCV合并感染者均能取得较好的早期疗效。普通干扰素方案对HCV非基因1型HIV/HCV合并感染者中可获得良好的早期治疗效果。     

Treatment of chronic hepatitis C virus infection with pegylated interferon and ribavirin in cirrhotic patients awaiting liver transplantation

Successful treatment of chronic hepatitis C virus (HCV) infection can prevent reinfection after orthotopic liver transplantation (OLT). Pegylated interferon (PEG-IFN) may ameliorate virological response (VR), making the risk-to-benefit ratio of therapy favorable in waiting list patients. From January 2001 to April 2006, we treated 15 HCV cirrhotics with PEG-IFN alpha-2b (1.5 microg/kg/week) and ribavirin (RIBA; >or=10.6 mg/kg/d). Their mean age was 51.5 years. There were 9 men. In 6 cases the genotype was 1b. With Child-Pugh scores >or=9 (range 9-12) and Model for End-Stage Liver Disease (MELD) scores >or=14 (range, 14-22). Adverse events occurred in all subjects: thrombocytopenia (<40,000/microL) in 8; neutropenia (<700/microL) in 10; anemia (Hb <8.5 g/dL) in 1; grade III hepatic encephalopathy in 2; pelvic infection in 1; variceal hemorrhage in 1; and hepatocellular carcinoma (HCC) recurrence in 1. Adverse events caused treatment withdrawal in 6 (40.0%) and RIBA and/or PEG-IFN dose reduction in 10 (66.6%). Early VR (EVR) was obtained in 9 subjects (60.0%), end-of-treatment (EOT) VR in 7 (46.6%), and sustained VR (SVR) in 3 (20.0%). Three subjects--2 nonresponder and 1 breakthrough--were transplanted at 25, 23, and 16 months after the EOT, respectively. Three subjects died at 6, 8, and 15 months after the EOT due to HCC, spontaneous bacterial peritonitis, and liver failure. Nine patients are awaiting OLT. The risk-to-benefit ratio is against PEG-INF and RIBA treatment of severely decompensated cirrhotics infected with genotype 1 awaiting OLT, but therapy is probably beneficial in genotype 2 subjects, due to an expected SVR rate of more than 40%. However, one must carefully consider the high risk for severe adverse events.     

Erythropoietin requirements increase following hospitalization in end-stage renal disease patients.

The effect of hospitalization on an ESRD patient's hemoglobin (Hgb) level and erythropoietin (Epo) requirement has not been investigated. We postulated patients with end stage renal disease required an increased Epo dose to maintain stable Hgb during hospitalization and for a period following discharge. To evaluate this hypothesis, we conducted a retrospective chart review on 65 hemodialysis patients. All hemodialysis patients admitted for more than 2 days who did not have more than the index hospitalizations for 2 months prior to and following discharge were included. Multiple parameters including Hgb, Epo dose, intravenous iron dose, serum iron, TIBC, and ferritin during the 2 months before and the two months after hospitalization, Hgb at admission and discharge, Hgb trough, surgery, blood transfusions and co-morbid factors were evaluated. Statistical significance was evaluated using ANOVA or rank-sum testing, as appropriate. In 65 hemodialysis patients (24 M/41 F, age 58 +/- 2.2 years, mean +/- SEM), Hgb levels following discharge and for 2 subsequent months were significantly lower than 2 months prior to admission (11.4 +/- 0.25 vs. 10.7 +/- 0.22 g/dl, p < 0.01). This occurred in spite of an increase in Epo dose (128 +/- 14 vs. 185 +/- 21 U/kg/week, p < 0.0001) over this 2-month period. There was no difference in the iron saturation before and after hospitalization (22 vs. 23%,p > 0.05). There were also no apparent effects of comorbid factors, including surgery, or discharge diagnosis on the changes in Hgb or Epo requirements. However, patients who required a blood transfusion during the hospitalization had lower Hgb levels and higher Epo doses both prior to and after hospitalization, as well as lower Hgb trough levels. In addition, females had lower Hgb levels than males both prior to and after hospitalization, and were receiving a higher Epo dose 191 +/- 18 vs. 129 +/- 20 U/kg/week at 1 month and 215 +/- 18 U/kg/week vs. 134 +/- 22, p < 0.005 at 2 months after hospitalization. CONCLUSION: This study points out that hemodialysis patients experience a significant and prolonged decrease in Hgb levels after hospitalization, even despite a moderate increase in Epo dosing.     

Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation.

Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG-IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)-ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG-IFN (1.5 microg/kg/week) and ribavirin (800-1,000 mg/day) for 12 months. Follow-up was based on biochemical (ALT), virological (RNA-HCV), and histological (liver biopsy) examinations. Follow-up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low gamma-glutamyltransferase GGT (P = 0.04) and HCV-RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patient's compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG-IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy.     

Treatment of patients with recurrent hepatitis C after liver transplantation with peginterferon alfa-2B plus ribavirin

BACKGROUND: Recurrent hepatitis C virus (HCV) after liver transplantation (OLT) is a major cause of graft loss in HCV-positive patients. In this study, we evaluated the efficacy and safety of pegylated interferon alfa-2b (peginterferon) and ribavirin treatment for recurrent HCV after OLT and analyzed the influence of antiviral treatment on the histological course of recurrent hepatitis. METHODS: Twenty-five patients with recurrent HCV (genotype 1 n=20 and 2-4 n=5) received peginterferon (1 mg/kg/weekly) and ribavirin (600 mg) for 48 weeks. Viral load prior to treatment was below 1,000,000 (IU/ml) in 11 of 25 patients. Sustained antiviral response was defined as undetectable HCV-RNA in serum 6 months after stopping of therapy. All patients underwent liver biopsy prior to treatment and after 72 weeks. RESULTS: Seventeen of 25 patients became HCV-RNA-negative after treatment (68%). Sustained virologic response (SVR) was achieved in 9/25 (36%) patients. Liver specimen showed increase of fibrosis from 1.7 to 2.0 within 72 weeks. Side effects like neutropenia (60%) and anemia (36%) were treated with G-CSF, erythropoietin, and dose reduction of peginterferon and ribavirin. CONCLUSIONS: The use of peginterferon is safe and effective in patients with recurrent HCV. Treatment of side effects, especially neutropenia or anemia, helped to maintain antiviral therapy. Despite a viral response of 68% during treatment, the patients showed further progress of recurrent hepatitis in liver specimen.     

DAA‐based antiviral treatment of patients with chronic hepatitis C in the pre‐ and postkidney transplantation setting

DAA‐based regimens for chronic hepatitis C infection encourage treatment of “difficult‐to‐treat” cohorts. This study investigated efficacy and safety of DAA‐based regimens in HCV patients on dialysis or postkidney or liver/kidney transplantation. Twenty‐five patients treated with DAA combinations were evaluated: 10 were on dialysis (eight: hemodialysis, two: peritoneal dialysis), eight were kidney transplant recipients, and seven were liver/kidney transplant recipients. Except for one patient treated with daclatasvir ([DCV]/60 mg/QD)/simeprevir ([SMV]/150 mg/QD), the others received sofosbuvir‐based regimens ([SOF];400 mg/QD) combined with SMV:eight, DCV:13 or either ledipasvir ([LDV]90 mg/QD), ribavirin ([RBV];weight based) or pegylated interferon/RBV. HCV‐RNA was determined by Abbott RealTime (LLOQ]:12 IU/ml) or Roche AmpliPrep/COBAS TaqMan assay (LLOQ:15 IU/ml); treatment response evaluated every 4 weeks, at the end of treatment, and 4 and 12 weeks thereafter. Twenty‐four (96%) patients achieved SVR 12/24 (ITT‐analysis). Mean treatment duration was 15.1 ± 5.1 weeks (±SD), and two patients terminated prematurely – both reached SVR12. Six patients were hospitalized due to complications of underlying disease. One patient achieved SVR24 but was re‐infected (week 27). Kidney function remained stable; serum creatinine increased in only one patient – SOF was reduced to 400 mg/48 h. Treatment with DAA combinations in renally impaired HCV patients is highly effective and well tolerated. These findings call for further controlled trials and data from real‐life cohorts.     

Pharmacokinetics help optimizing mycophenolate mofetil dosing in kidney transplant patients

BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is now routinely used as immunosuppressant in solid organ transplantation in a fixed daily dose regimen (2 g/d) in association with cyclosporine (CsA) and steroids. However, no correlation has been shown between fixed MMF dose and clinical outcome. METHODS: Here we examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring in 46 stable kidney transplant recipients. MPA plasma concentration profiles were measured by a reverse-phase high-performance liquid chromatography method 6-9 months after transplantation and related with routine laboratory analysis tests. Since MPA is extensively bound to serum albumin and only the free fraction is pharmacologically active, in a subgroup of 23 patients free plasma MPA was also determined. RESULTS: Despite a comparable MMF dose, a large interindividual variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10.1-99.8 microg/mL. h) and in trough levels (range 0.24-7.04 microg/mL) was found. Patients with AUC >40 microg/mL. h showed a better (p<0.05) renal function than patients with lower AUC (creatinine clearance 85.7+/-23.2 versus 64.5+/-17.5 mL/min), despite no difference in CsA dose, CsA AUC and blood CsA trough level. The percentage of free plasma MPA but not total MPA correlated with the red blood cell and leukocyte count. CONCLUSIONS: Therapeutic MMF drug monitoring might contribute to a better management of kidney transplant recipient with the goal of optimizing drug dosing and limiting the risk of MMF-related toxicity.     

Recurrent hepatitis C after liver transplantation: on-treatment prediction of response to peginterferon/ribavirin therapy.

Sustained virologic response (SVR) in the treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) remains suboptimal. We evaluated efficacy of pegylated interferon alfa (PEG) and ribavirin (RBV) (PEG/RBV) combination therapy in LT recipients with recurrent HCV and predictive values of rapid virological response (RVR) and early virologic response (EVR). Between January 2001 and October 2005, LT recipients with recurrent HCV were intended to be treated for 48 weeks with PEG/RBV combination therapy independent of genotype or virologic response [53 patients (79% genotype 1)]. On-treatment predictor of response at week 4 (RVR) was defined as undetectable HCV RNA, and at week 12 (EVR) as undetectable HCV RNA or a >2 log(10) drop from pretreatment viral load. SVR was seen in 19 (35%) patients. Patients with genotype 2/3 were more likely to achieve SVR than those with genotype 1 (87% versus 23%; P = 0.001). The highest rate of SVR was seen in patients with RVR [specificity and positive predictive value (PPV) = 100%] while the highest rate of treatment failure was seen in those who did not have EVR [sensitivity and negative predictive value (NPV) = 100%]. The NPV of RVR to identify those who will not achieve SVR was also very high (88%). EVR had low PPV (63%) to identify those with SVR. In conclusion, PEG/RBV combination therapy is effective in the treatment of post-LT recurrent HCV. On-treatment virologic monitoring is highly predictive of SVR and may optimize the virologic response and minimize toxicity. Given its high PPV and NPV, RVR appears to be the most appropriate decision time point for continuation of therapy.