Spontaneous clearance of hepatitis C after liver and renal transplantation

Spontaneous clearance of hepatitis C virus (HCV) is rare in immunocompromised patients, such as those who have undergone organ transplantation. It has been recognized that patients receiving liver transplantation for HCV-related disease have decreased graft and patient survival compared with those transplanted for other etiologies. There is a growing trend toward treating HCV recurrence aggressively after liver transplantation. For other organ transplant recipients with concurrent HCV, treatment is not often an option, given the high rates of graft rejection and loss secondary to interferon and its immunomodulatory effects. Although spontaneous clearance of HCV has been reported in recipients of solitary liver and renal transplants, a common factor arising in these cases has been previous exposure to interferon. To date, no reports of spontaneous clearance of HCV RNA have been reported in a multiorgan transplant recipient. A case of spontaneous clearance of HCV RNA in an immunocompromised patient, within five months of simultaneous liver and kidney retransplantation is described. Importantly, this patient had no previous exposure to interferon.     

Surgical approach for hepatitis C virus-related hepatocellular carcinoma

Hepatitis C is a strong prognostic factor for patients with hepatocellular carcinoma(HCC). Although liver resection and liver transplantation offer the chance of a cure for HCC,adequate management of co-existing infection with hepatitis C virus(HCV) is important to enable better long-term outcomes after surgery for HCV-related HCC. For patients undergoing liver resection,perioperative anti-viral treatment is recommended,since a decreased HCV viral load itself is reportedly associated with a lower tumor recurrence rate and a longer overall survival. For patients undergoing transplanatations for HCC complicated by end-stage liver disease,the post-transplant management of HCV infection is also necessary to prevent progressive graft injury caused by active hepatitis under the immunosuppressive condition that is needed after liver transplantation. Although only a few lines of solid evidence are available for postoperative antiviral treatment because of the limited indication and frequent adverse events caused by conventional high-dose combination interferon therapy,new direct acting anti-viral agents would enable interferon-free anti-viral treatment with a higher virologic response and minimal side effects.     

丙型肝炎肝硬化抗病毒治疗现状

目前干扰素联合利巴韦林是慢性HCV感染的主要抗病毒治疗方案,但丙型肝炎肝硬化患者对于抗病毒治疗耐受性差.目前研究报道对于丙型肝炎肝硬化患者进行抗病毒治疗,如能获得持续病毒学应答(SVR),有利于缓解肝纤维化进展,并减少肝移植术后HCV再感染的发生.因此,应对丙型肝炎肝硬化患者进行仔细评估,对于进行抗病毒治疗的患者可给予适当干预以维持抗病毒治疗的进行,并在治疗过程中密切监测不良反应的发生.     

Hepatitis C virus and kidney disease

Hepatitis C virus (HCV) infection remains frequent in patients on renal replacement therapy and has an adverse impact on survival in infected patients on chronic hemodialysis as well as renal transplant (RT) recipients. Nosocomial spread of HCV within dialysis units continues to occur. HCV is also implicated in the pathogenesis of renal dysfunction often mediated by cryoglobulins leading to chronic kidney disease as well as impairing renal allograft function. The role of antiviral therapy for hepatitis C in patients with renal failure remains unclear. Monotherapy with conventional interferon (IFN) for chronic hepatitis C is probably more effective in dialysis than in non-uraemic patients but tolerance is lower. Limited data only are available about monotherapy with pegylated interferon and combination therapy (pegylated IFN plus ribavirin) for chronic HCV in the dialysis population. Clinical experience with antiviral therapy for acute HCV in dialysis population is encouraging. Interferon remains contraindicated post-RT because of concerns about precipitating graft dysfunction. Sustained viral responses obtained by antiviral therapy in renal transplant candidates are durable after renal transplantation and may reduce HCV-related complications after RT (post-transplant diabetes mellitus, HCV-related glomerulonephritis, and chronic allograft nephropathy).     

Hepatitis C infection in hemodialysis patients: A review

Hepatitis C virus(HCV)-related liver disease is a significant cause of morbidity and mortality in patients with end-stage renal disease(ESRD) who is treated with dialysis or kidney transplantation(KT). The survival rate for HCV-infected renal transplant recipients is better than that for HCV-infected hemodialysis patients on transplant waiting lists. Early diagnosis and treatment HCV infection prior to KT prevents complications posttransplantation and reduces mortality. In addition to screening for anti-HCV antibodies and detecting HCV RNA, percutaneous liver biopsy is particularly valuable for assessing the stage of liver damage in HCV-infected patients, because the stage of fibrosis is importantdetermining optimal treatment for HCV. Studies have been demonstrated that with conventional interferon(IFN) monotherapy or pegylated IFN monotherapy are similar efficacy and safety in HCV-infected hemodialysis patients. Sustained viral responses(SVRs) with these monotherapies have ranged approximately 30% to 40%. Limited reports support the use of IFN and ribavirin combination therapy as antiviral treatment for ESRD patients or patients on hemodialysis. Ribavirin can be started at low dose and careful monitoring for side effects. Patients that show SVR after treatment are strong candidates for KT. It is also generally accepted that ESRD patients with decompensated cirrhosis and portal hypertension should be referred to the liver transplant team for consideration of combined liver-KT.     

Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review

Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.     

Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation

OBJECTIVES: Interferon-alpha (IFN) may have undesirable effects on a functioning graft. The aim of this study was to evaluate IFN treatment in kidney transplant candidates during the hemodialysis period as well as the results after transplantation. METHODS: A total of 29 noncirrhotic hemodialysis patients with chronic hepatitis C virus (HCV) infection (based on long-term rise in ALT, HCV serology, HCV RNA by polymerase chain reaction methods, and histological evidence) were included. Tolerability to IFN treatment, pre- and posttransplantation therapeutic results, and long-term outcome were recorded. IFN regimen consisted of 3 million units (MU) times per week after hemodialysis sessions for 6 months, followed by 1.5 MU after each hemodialysis session for an additional 6 months. All patients gave informed consent for participation. RESULTS: IFN therapy was fairly well tolerated. Adverse effects due to IFN toxicity, renal disease, or causes related to the immunological properties of IFN were observed in 24% of patients. At the end of treatment, ALT had normalized in 23/28 patients (82.1%), and HCV RNA had cleared in 23/28 patients (82.1%). During follow-up, HCV RNA was persistently negative in 18 patients (64%, including transplant recipients). A total of 14 patients (nine HCV RNA-negative) received a kidney transplant. Mean follow-up after the procedure was 41 +/- 28 months. In all, 12 patients had a functioning graft, one had acute vascular rejection, and one died of carcinoma. All transplanted patients maintained normal ALT levels, and eight remained HCV RNA-negative. CONCLUSIONS: Treatment results in our study population were better than those observed in the general population. The long-term response achieved, which was maintained after transplantation, supports the use of IFN for HCV hepatitis in kidney transplant candidates under hemodialysis.     

Treatment of hepatitis C virus infection

Acute and chronic hepatitis C virus （HCV） infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interferon and ribavirin. The literature indicates that therapy for HCV is becoming more individualized. In addition to considering genotype and viral RNA levels before treatment, achievement of an early virologic response （EVR） and a rapid virologic response （RVR） is now possible during therapy. Moreover, problem patients, such as non-responders, relapsers, HIV or HBV coinfected patients, patients with liver cirrhosis, and preor post-liver transplantation patients are an increasing fraction of the patients requiring treatment. This article reviews the literature regarding standard treatments and problem patients with acute and chronic HCV infection. It also includes discussion on contraindications and side effects of treatment with interferon and ribavirin, as well as new drug development.     

Effects of a 24-week course of interferon-α therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma

AIM： To assess whether a 24-wk course of interferon （IFN） could prevent hepatocellular carcinoma （HCC） recurrence and worsening of liver function in patients with hepatitis C virus （HCV）-infected patients after receiving curative treatment for primary HCC.
METHODS： Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC （IFN group）, were compared with 42 matched curatively treated historical controls not given IFN （non- IFN group）.
RESULTS： Although the rate of initial recurrence did not differ significantly between ]FN group and non-IFN group （0%, 44%, 61~, and 67% ys 4.8%, 53~, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively）, ]FN group showed a lower rate than the non-IFN group for second recurrence （0%, 10.4%, 28%, and 350/0 ys 0%, 30~ , 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively）. Among the ]FN group, patients with sustained virologic response （SVR） were less likely to have a second HCC recurrence than ]FN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival.
CONCLUSION： Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.     

不耐受标准治疗方案慢性丙型肝炎患者的低剂量干扰素治疗

目的 针对不能耐受标准治疗方案的慢性丙型肝炎(CHC)患者,探索低剂量干扰素联合利巴韦林长期维持治疗的效果,并分析与疗效相关的可能影响因素. 方法 对于白细胞低下、甲状腺功能异常等多种原因不能耐受标准治疗方案的CHC患者46例,给予个体化低剂量干扰素(标准干扰素60万～300万IU隔日一次,聚乙二醇干扰素50 ～ 90μg/周)联合利巴韦林0.6 ～ 0.9 g/d 长期维持治疗,疗程≥72周.连续变量两组间比较采用t检验或秩和检验,计数资料采用x2检验或Fisher’s exact test检验.结果 93.5％患者(43/46)可耐受不同低剂量干扰素联合利巴韦林长期维持治疗,只有3例不能耐受而被迫停药.不同节点的病毒学应答率为:快速病毒学应答10.9％、早期病毒学应答 30.4％、24周病毒学应答45.7％、48周病毒学应答47.8％.3例患者在治疗过程中肝脏B型超声显示形态学改善.快速病毒学应答、早期病毒学应答、24周病毒学应答者均可在48周时获得较高病毒学应答,尤其24周病毒学应答对48周病毒学应答具有较好预测作用,获得24周病毒学应答者其48周病毒学应答率为95.2％,而24周未获得病毒学应答者其48周未应答率为92.0％.结论 (1)对于不能耐受标准治疗方案的CHC患者予以低剂量干扰素联合利巴韦林长期维持治疗,可以获得较高的48周病毒学应答率(47.8％);(2)24周病毒学应答对48周病毒学应答具有较好预测作用;(3)疗程中严密监测、对症治疗原发病并给予患者足够的依从性教育和心理疏导是治疗得以维持的重要保证.     

Liver transplantation for hepatitis C

Hepatitis C virus (HCV) infection is the leading cause of endstage liver disease in Western and Asian countries. However, after liver transplantation, HCV recurs in virtually all patients, and estimated HCV-related graft cirrhosis at 5-year follow-up is 30%. Although immunosuppression accounts for a major part of the accelerated progression of HCV in the transplant population, the best immunosuppression for recipients with HCV that could avoid such complication remains unknown at present. Combination therapy of interferon and ribavirin is thought to be the most effective for the treatment or prophylaxis of HCV infection. However, who should be treated, when treatment should be initiated, and with what agent should patients with HCV infection be treated are still unknown. The current data on HCV recurrence in patients who have received either living- or deceased-donor liver transplantation are controversial, but they are, presumably, similar. Thus, to avoid HCV recurrence in living-donor liver transplantation, we have to take approaches similar to those used for patients receiving deceased-donor liver transplantation. Based on reports from major transplant centers around the world, we consider the best strategy for liver transplantation-related HCV infection is steroid-free immunosuppression and preemptive low-dose interferon and ribavirin combination therapy. Here we describe our experience with living-donor liver transplantion for patients with hepatitis C at Osaka University. There is a need for standardizing the treatment for HCV infection. This can only be achieved through collaborative work between various liver transplant centers worldwide.     

PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis

OBJECTIVE: Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen-driven B cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin in patients with HCV-related MC vasculitis. METHODS: Nine consecutive patients with HCV-related MC received PEG-IFN alfa-2b (1.5 microg/kg/week) subcutaneously plus oral ribavirin (800-1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup. RESULTS: The mean +/- SD duration of therapy with PEG-IFN alfa-2b plus ribavirin was 13.5 +/- 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required. CONCLUSION: Treatment with PEG-IFN alfa-2b plus ribavirin can achieve a complete clinical response in most patients with HCV-related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNalpha plus ribavirin.     

Natural History and Treatment of Hepatitis C in Liver Transplant Recipients

Hepatitis C is not cured with liver transplantation. Patients with hepatitis C virus (HCV) infection have reduced graft and patient survivals compared with non-HCV patients following liver transplantation. Both HCV recurrence and fibrosis are accelerated under the influence of transplantation and immunosuppression. Antiviral therapy has been shown to reduce fibrosis progression and graft loss. The goal of therapy is sustained virologic response and reduction of damage. However, the optimal timing and treatment regimen for patients with HCV following transplant is unclear. Following transplant, sustained virologic response rates are reduced and patient tolerance is limited. Improved treatment strategies are needed to reduce patient side effects and increase efficacy in this population of patients.     

A randomized, controlled trial to determine whether continued ribavirin monotherapy in hepatitis C virus-infected patients who responded to interferon-ribavirin combination therapy will enhance sustained virologic response

This study assessed the use of ribavirin monotherapy to enhance sustained virologic response in hepatitis C virus (HCV)-infected patients who achieved virologic response to interferon (IFN)-ribavirin combination therapy. Patients who had chronic HCV infection and prior relapse were retreated with IFN-ribavirin for 6 months. Patients with an end-of-treatment virologic response were assigned randomly to either stop use of both IFN and ribavirin or to continue use of ribavirin as monotherapy for an additional 6 months. HCV RNA became undetectable during treatment in 46 patients, who then entered the randomized trial. Sustained virologic response was observed in 13 of 26 patients who continued ribavirin monotherapy and in 15 of 20 patients who stopped use of both IFN and ribavirin (P, not significant). Sustained virologic response was significantly more common in patients with HCV genotype non-1 (75% vs. 56%) and in patients with a virus titer < 2 x 10(6) copies/mL (93% vs. 43%). The results indicate that continuing ribavirin monotherapy after achieving a virologic response does not improve sustained virologic response.     

Treatment of hepatitis C in potential kidney and heart transplant patients

Hepatitis C virus (HCV) is common in certain solid organ transplant recipients, most notably in those undergoing liver or kidney transplantation. Infection typically antedates transplantation but may have been acquired at the time of transplantation via infected blood products or organs. A more rapid and aggressive course of HCV-related infection and liver disease is the major concern in organ transplant recipients compared with immunocompetent patients. HCV-related liver disease is an important cause of morbidity and mortality in patients with end-stage renal disease treated by dialysis or transplantation. The outcome of HCV infection in renal and liver transplant recipients has been extensively investigated, whereas literature on HCV-related liver disease among patients with orthotopic heart transplantation is scanty. This article reviews the literature concerning the treatment of HCV-related liver disease in renal and orthotopic heart transplantation.     

Outcomes in Hepatitis C Positive Liver Transplantation: Timing of Direct-Acting Antiviral Treatment and Impact on Graft Fibrosis

Liver transplantation for hepatitis C virus (HCV)-related disease has the lowest five-year graft survival among all liver transplant recipients. Graft failure due to accelerated fibrosis from unrestrained HCV replication is common. Optimal timing of HCV treatment with direct-acting antiviral agents remains unknown. We compared HCV liver transplant recipients successfully treated for HCV before transplant to those treated within 1 year of transplant to determine if graft fibrosis, measured by Fib-4 scores, differs with timing of treatment. Fib-4 scores less than or equal to 1.45 defined minimal fibrosis and greater than 1.45 defined greater than minimal fibrosis. We identified 117 liver transplant recipients: 52 treated before transplantation and 65 treated within 1 year of transplantation. Overall, 34% of recipients had minimal fibrosis, and the likelihood of having minimal fibrosis following treatment and liver transplantation did not differ by timing of treatment. The odds ratio of having greater than minimal fibrosis was 0.65 (95% CI 0.30, 1.42) among those treated within 1 year after transplantation compared to those treated before transplantation (p-value 0.28). Importantly, nearly 2/3 of these patients had evidence of fibrosis progression one year after sustained virologic response, supporting recommendations for early antiviral-based treatment to prevent accumulation of HCV-related disease.     

Leukocyte interferon-alpha in the treatment of chronic hepatitis C in Finland

BACKGROUND: To evaluate the efficacy of leukocyte interferon in previously untreated patients with chronic hepatitis C, 97 patients were enrolled in a prospective study in Finland with a stepped-care management protocol. METHODS: The treatment was initiated with 3 million units of interferon-alpha subcutaneously three times a week. At 3 months, if the serum alanine aminotransferase was still abnormal, the dose was doubled. If serum hepatitis C virus (HCV) RNA had turned negative at 6 months, the treatment was stopped; if it was still positive, treatment was continued for up to 12 months. All patients were followed up after treatment for 6 months. Altogether, 74 patients completed the treatment and follow-up periods. RESULTS: Of all the originally enrolled patients 36% (35 of 97) achieved sustained virologic response, defined as HCV RNA negativity 6 months after the end of treatment. The commonest HCV genotype among these patients was 3a, and as many as 52% of such patients achieved sustained virologic response. Thirty-two per cent of the patients had HCV genotype 1a, 1b, or a mixture of these; a sustained response was achieved in only 6% of such patients but in 50% of patients with a non-1 genotype. Adverse effects caused treatment cessation for 10% of the patients and IFN dose reduction for 20%. CONCLUSIONS: Monotherapy with human leukocyte interferon resulted in sustained virologic response in 36% of patients with chronic hepatitis C. In those infected with a HCV genotype other than 1, the sustained virologic response rate was 50%.     

Treatment with pegylated interferon and ribavirin for hepatitis C virus-associated severe cryoglobulinemia in a liver/kidney transplant recipient

End-stage liver disease after hepatitis C virus (HCV) infection is the most common indication for liver transplantation, accounting for over 40% of liver transplants performed. Combined liver/kidney transplantation is being performed more frequently, in part because HCV infection may coexist with conditions that damage the kidney, such as diabetes and cryoglobulinemia. Unfortunately, HCV hepatitis and cryoglobulinemia may recur after liver transplantation and adversely affect graft and patient survival. In immunocompetent patients, interferon (IFN) and ribavirin (RBV) combination therapy is often able to control cryoglobulinemic syndrome. Very little data are available on liver transplant recipients, whereas IFN usually is not indicated in kidney transplant recipients because of early reports of steroid-induced rejection after its administration. Successful treatment of cryoglobulinemia with IFN/RBV in recipients of combined liver/kidney transplant has not been previously reported. We treated 1 recipient of a combined liver and kidney transplant with pegylated-IFN/RBV combination therapy. The patient developed HCV recurrence associated with cryoglobulinemia and severe cutaneous peripheral and neurologic manifestations. Treatment with pegylated-IFN-alpha2b and RBV for 12 months cured the cryoglobulinemic vasculitis and allowed the sustained eradication of HCV with no significant changes in kidney function.     

Interferon therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after treatment of recurrent hepatocellular carcinoma: a successful case

A complete response was obtained by interferon (IFN) therapy for hepatitis C virus (HCV)-related advanced chronic hepatitis after curative treatment of initial and recurrent hepatocellular carcinoma (HCC). The patient is alive 73 months after diagnosis of initial HCC and is in a tumor-free state 53 months after diagnosis of the last HCC. This case suggest that it is possible to suppress recurrence and to prolong the life of patients with HCV-related advanced chronic hepatitis, if a complete response is obtained by means of IFN therapy after the curative treatment of the recurrent HCC.     

Treatment of chronic hepatitis C virus in allogeneic bone marrow transplant recipients

We recently reported an increased incidence of cirrhosis in hepatitis C virus (HCV)-infected stem cell transplant (SCT) recipients. Here, we describe our experience in the treatment of these patients, which has been, to date, poorly reported in the literature. Among 99 HCV-infected HCT recipients, 36 had HCV-related liver lesions on biopsy requiring therapy. Owing to HCV treatment contraindications, only 61% of patients (22/36) could be treated. In all, 12 patients received more than one course of anti-HCV treatment if they had HCV RNA still detectable after the first course of treatment and no treatment contraindications. Combined therapy (pegylated interferon (IFN): n=9, or standard IFN: n=9, in combination with ribavirin) led to sustained virological response in 4/18 (20%) patients as compared to 2/20 (10%) in patients who received IFN alone. Hematological toxicity was more frequent with combined therapy. While anemia responded to erythropoietin and/or dose modification, thrombocytopenia usually led to treatment interruption (n=3). This study thus highlights the efficacy of combined therapy and emphasizes the fact that the undue safety concerns are not a problem when treating this particular population.