Long-term follow-up of chronic hepatitis C patients with sustained virological response to various forms of interferon-based anti-viral therapy

BACKGROUND: Combination anti-viral therapy achieves a sustained virological response (defined as HCV-RNA negativity 6 months after the end of therapy) of 56% of patients with chronic hepatitis C. Little is known about long-term durability of HCV-RNA negativity in patient treated with pegylated interferon. AIM: To evaluate the durability of virologic response in patients with sustained virological response to anti-viral therapy treated at our centre. METHODS: A total of 187 sustained virological responses (50% genotype 1, 42% genotype 2 or 3 and 8% genotype 4; 20% with cirrhosis) with a follow-up of >12 months post-therapy were studied. Twelve patients received monotherapy with interferon-alpha2a or -2b. One hundred and seventy-five received combination therapy with ribavirin and standard interferon-alpha (n = 73) or pegylated interferon-alpha2a or 2b (n = 102). Qualitative serum HCV-RNA was tested by COBAS AMPLICOR HCV test, v2.0. RESULTS: Median follow-up time was 29 months (range 12-172). Recurrence of HCV infection was not observed in any of the 187 sustained virological responders. Alanine aminotransferase values were normal in 90% and two patients showed minimal elevation of alpha-fetoprotein levels. CONCLUSIONS: No recurrence of HCV infection was seen in any patient. Thus, long-term prognosis in chronic hepatitis C patients with a sustained virological response to therapy with pegylated interferon +/- ribavirin is promising, but long-term studies need to continue.     

Current and future therapy for chronic hepatitis C virus liver disease

Therapy with recombinant human interferon alpha remains pivotal to the treatment for chronic hepatitis C virus liver disease. Semi-synthetic protein-polymer conjugates of interferon with polyethylene glycol have also been recently developed. These conjugates protect the protein from degradation; reduce the immunogenicity; and prolong exposure to drug by a sustained absorption, restricted volume of distribution and sustained high serum concentration. Therapy with pegylated interferons is associated with significantly greater sustained virological response rates (SVR) compared to the non-pegylated formulation. Ribavirin is a guanosine analog with minimal antiviral activity against HCV. It demonstrates significant clinical synergism when administered in combination with interferon. Amantadine blocks entry of influenza A virus into cells. Used in combination with ribavirin and interferon as triple therapy, it may have some benefit compared to dual or monotherapy. Current treatment with pegylated interferons combined with weight-based ribavirin, provides the highest sustained virological response rates. In the absence of suitable animal models, HCV dynamic studies in man have been helpful in defining the mechanisms of action of interferon in chronic HCV liver disease. Novel therapeutic agents are being developed as the replication cycle of HCV is being understood. However, their safety and efficacy remain to be established and availability for clinical use is unlikely within the next 3 to 5 years. This review describes current antiviral therapy in chronic HCV liver disease, addresses the potential role of viral dynamics in elucidating the mechanisms of action of the drugs and discusses future potential therapeutics agents.     

Management of hepatitis C infection after liver transplantation

Recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) has been associated with progression to cirrhosis in approximately 20% of patients, 5 years postoperatively. Accelerated decompensation has also been noted when compared with cirrhosis in non-transplant patients. Different treatment strategies are available for recurrent HCV infection post-OLT, but efforts are hindered by the modest response rates, poor tolerability and the risk of rejection as well as graft loss. Anti-HCV immunoglobulin therapy to prevent graft infection with HCV has no established role at present but studies are ongoing. Treatment prior to transplantation in patients with decompensated cirrhosis has been evaluated but the results are too preliminary to make firm recommendations. Prophylactic interferon-based antiviral therapy in the early postoperative period to prevent graft infection was shown to have low response rates and high rates of adverse effects. Treatment of established recurrent HCV infection with combination peginterferon (pegylated interferon) and ribavirin is associated with 10-59% sustained virological response and the predictive value of a positive early virological response has been validated in the post-transplant setting. Improvement in inflammatory activity after viral eradication is well established, but fibrosis regression or stabilisation is less predictable and factors such as rejection and biliary complications may still contribute to graft loss. Most studies have initiated therapy at least 6 months postoperatively in order to optimise patient tolerance and enable the addition of ribavirin. The use of adjuvant agents to treat drug-induced neutropenia and anaemia in this population is evolving and becoming a crucial part of therapy. Determination of optimal doses of both pegylated interferon and ribavirin, and guidance on when to stop treatment, as well as improving tolerability are important steps in achieving higher response rates and minimising drug toxicity.     

抗丙型肝炎病毒新药波普瑞韦和替拉瑞韦

波普瑞韦（boceprevir,BOC）和替拉瑞韦（telaprevir,TVR）均为丙型肝炎病毒NS3/4A丝氨酸蛋白酶抑制剂,用于治疗基因1型慢性丙型病毒性肝炎（chronic hepatitis C,CHC）。与现行的CHC的标准治疗方案比较,BOC或TVR联合聚乙二醇干扰素α和利巴韦林的三联疗法可大大提高初治病人的持久病毒应答率,且对既往聚乙二醇干扰素α联合利巴韦林治疗无效的病人也有较好的疗效。BOC和TVR的三联疗法比现行的标准治疗方案有更好的疗效和安全性。可以说,BOC和TVR的临床应用,使基因1型CHC的治疗进入新纪元。     

Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin

Background Most reports suggest that mutations in the interferon sensitivity‐determining region (ISDR) correlate with response to conventional interferon‐based therapies in hepatitis C virus‐1b (HCV‐1b) patients. However, the correlation between ISDR region mutations and response to pegylated interferon plus ribavirin therapy in HCV‐1b patients remains unclear. Aim To assess whether ISDR mutations correlate with response to Peg interferon plus ribavirin therapy in HCV‐1b patients. Patients and methods Sixty HCV‐1b naive patients who had undergone 6 months of Peg interferon α‐2b plus ribavirin and a 6‐month follow‐up were enrolled. The amino acid sequences of the nonstructural 5A‐interferon‐induced RNA‐dependent protein kinase (NS5A–PKR)‐binding domain were determined by polymerase chain reaction and sequencing. Results Thirty (50%) patients achieved sustained virological response (SVR). Univariate analysis showed that the proportion of patients with ISDR mutations ≥4 and rapid virological response rate was higher in the sustained virological response group than in the non‐SVR group. Viral load was lower in the SVR group than in the non‐SVR group. Multivariate analysis revealed that ISDR mutations ≥4 and ribavirin ≥14 mg/kg/day were independent predictors of SVR. Conclusion Mutations of the ISDR correlate with SVR to Peg interferon α‐2b plus ribavirin therapy in HCV‐1b patients.     

Sustained virological response to pegylated interferon and ribavirin is maintained during long‐term follow‐up of chronic hepatitis C patients

Aliment Pharmacol Ther 31 , 502–508

Summary

Background There are few data in the literature regarding the long‐term virological follow‐up of chronic hepatitis C patients who obtain sustained virological response (SVR) to pegylated interferon (PEG‐IFN) and ribavirin therapy. Aim To assess the durability of SVR to PEG‐IFN and ribavirin therapy during long‐term follow‐up of chronic hepatitis C patients. Methods We evaluated a cohort of 231 chronic hepatitis C patients who had at least 48 weeks of follow‐up after SVR to PEG‐IFN and ribavirin treatment. Median duration of follow‐up after SVR was 164 weeks, and exceeded 5 years in 30% of the cohort. Patients underwent consistent clinical, biochemical and virological evaluations every 6 months during follow‐up. Results Sustained virological response was maintained in 211 patients (91%) while HCV‐RNA became positive in two patients (<1%) within 1 year after SVR, and in 18 patients (8%) serum HCV‐RNA was transiently positive in at least one follow‐up evaluation. Clinical outcome was not significantly different between patients with persistently negative and transiently positive serum HCV‐RNA. Conclusions Sustained virological response to PEG‐IFN and ribavirin is maintained in 99% of patients during long‐term follow‐up. Late virological relapse occurred within 1 year after SVR and, from a clinical perspective, patients can be considered cured of infection after this period.     

Treatment of chronic hepatitis C in children with pegylated interferon α2a and ribavirin--a multi-center study

Pegylated interferon α and ribavirin in treatment of chronic hepatitis C in children is used rarely. The aim of the study was to find prognostic factors for sustained virological response and to analyze the safety of pegylated interferon α2a and ribavirin in children with chronic hepatitis C. The study covered a group of 44 children, mean age 14 years, with diagnosed chronic hepatitis C. Clinical, biochemical and virological parameters, as well as side effects were evaluated. Combined treatment allowed to obtain sustained virological response in a total of 77.5% of the treated children. Lower viral load and lower fibrosis grade contributed to sustained virological response. The response was not gender-related. The best response is obtained in children whose treatment was started after they attained the age of 10 years. Therapy with pegylated interferon α2a and ribavirin is well tolerated by pediatric patients.     

HCV相关肝移植前后抗病毒治疗疗效和安全性荟萃分析

目的比较分析干扰素（]FN）、聚乙二醇干扰素（PEG．IFN）单药或其分别联合利巴韦林治疗丙型肝炎病毒（HCV）感染相关肝移植患者的疗效和安全性。方法通过计算机检索1990年1月1日至2011年8月31日在PubMed、荷兰医学文摘、Ovid,万方和中国知网期刊全文数据库、维普中文期刊数据库等发表的有关丙型肝炎相关肝移植患者抗HCV治疗疗效和安全性的相关研究,并对肝移植前、后抗HCV治疗结束时病毒学应答（EDVR）率、持续病毒学应答（SRV）率和不良事件发生率进行比较研究。共纳入11项研究,296例患者,均接受IFN、PEG—IFN单药或其分别联合利巴韦林抗HCV治疗。结果其中移植前抗HCV治疗患者167例,移植后抗HCV治疗患者129例,两个时期患者抗I-ICV治疗获得的EDVR率比较,差异无统计学意义（45．O％、45．2％,X2=0．0293,P〉0．05）,但SRV率比较,差异有统计学意义（20．0％、31．8％,X2=5．5492,P〈0．05）,而不良事件发生率比较,差异无统计学意义（47．5％、41．7％X2=1．1936,P〉O．05）。结论肝移植前、后进行抗HCV感染均能获得一定的病毒学应答率,移植后抗HCV治疗可能比移植前进行抗HCV治疗获得更高的SRV率。     

Review article: specifically targeted anti‐viral therapy for hepatitis C – a new era in therapy

Aliment Pharmacol Ther 2010; 32: 14–28

Summary

Background Novel, directly acting anti‐viral agents, also named ‘specifically targeted anti‐viral therapy for hepatitis C’ (STAT‐C) compounds, are currently under development. Aim To review the potential of STAT‐C agents which are currently under clinical development, with a focus on agents that target HCV proteins. Methods Studies evaluating STAT‐C compounds were identified by systematic literature search using PubMed as well as databases of abstracts presented in English at recent liver and gastroenterology congresses. Results Numerous directly‐acting anti‐viral agents are currently under clinical phase I–III evaluation. Final results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon‐alfa and ribavirin strongly improves the chance to achieve a SVR in treatment‐naive HCV genotype 1 patient as well as in prior nonresponders and relapsers to standard therapy. Monotherapy with directly acting anti‐virals is not suitable. NS5B polymerase inhibitors in general have a lower anti‐viral efficacy than protease inhibitors. Conclusions STAT‐C compounds in addition to pegylated interferon‐alfa and ribavirin can improve SVR rates at least in HCV genotype 1 patients. Future research needs to evaluate whether a SVR can be achieved by combination therapies of STAT‐C compounds in interferon‐free regimens.     

Effectiveness of pegylated interferon/ribavirin combination in 'real world' patients with chronic hepatitis C virus infection

Background  Clinical trials have shown that the combination of pegylated interferon/ribavirin induces a sustained virological response in 54–63% of patients with chronic hepatitis C virus infection, but its effectiveness in day-to-day clinical practice is less clear.
Aim  To verify if the efficacy of pegylated interferon/ribavirin combination in 'real world' patients is comparable to that observed in trials.
Methods  The medical records of 397 consecutive naïve patients with chronic hepatitis C virus infection treated with pegylated interferon/ribavirin combination in nontertiary hospital settings were reviewed in order to assess the response to anti-viral treatment.
Results  The sustained virological response rate achieved in this population was similar to that recorded in registration trials (total population: 64%; genotype 1: 46%; genotypes 2–3: 84%). Also, the premature discontinuation rate (15%) was similar to that observed in registration trials, but there were fewer dose reductions in one or both medications (26%). We confirmed the association between adherence and sustained virological response among the patients infected with hepatitis C virus genotype 1 who were treated for ≥80% of the planned duration of treatment.
Conclusion  The effectiveness of pegylated interferon/ribavirin therapy and factors predicting an sustained virological response in everyday clinical practice mirror those reported in randomized-controlled studies.     

Ribavirin with either standard or pegylated interferon to treat recurrent hepatitis C after liver transplantation

AIM: To investigate the efficacy of two anti-viral protocols in hepatitis C virus-reinfected liver transplant recipients. METHODS: In this prospective study, 26 liver transplant patients were treated with standard interferon-alpha2b for 12 months or standard interferon-alpha2b for 3 months followed by pegylated interferon-alpha2b for 9 months. Interferon was combined with ribavirin in all patients. The histological course of the study population was compared with an untreated historic control group (n = 38) with similar baseline characteristics. RESULTS: The sustained virological response rates in the standard interferon group and in the pegylated interferon group were 27.3% and 26.7%, respectively. Only 29% of patients with sustained virological response had end of treatment histological response, whereas 47% of viral non-responders showed end of treatment histological response. The percentage of patients with histological improvement was significantly higher in the study population when compared to the controls. Univariate analysis indicated that hepatitis C virus genotype non-1, high baseline alanine aminotransferase, the time interval between liver transplant and interferon therapy and the body mass index predicted sustained virological response. In the multivariate model, baseline alanine aminotransferase and the body mass index remained a significant predictor of sustained virological response. CONCLUSIONS: Both treatment regimens offer similar efficacy profiles. Failure to eradicate hepatitis C virus should not lead to treatment discontinuation if serial liver biopsies demonstrate histological response.     

Review article: adherence to medication for chronic hepatitis C – building on the model of human immunodeficiency virus antiretroviral adherence research

Background  Treatment of hepatitis C virus (HCV) infection with pegylated interferon/ribavirin achieves sustained virological response in up to 56% of HCV mono-infected patients and 40% of HCV/human immunodeficiency virus (HIV)-co-infected patients. The relationship of patient adherence to outcome warrants study.
Aim  To review comprehensively research on patient-missed doses to HCV treatment and discuss applicable research from adherence to HIV antiretroviral therapy.
Methods  Publications were identified by PubMed searches using the keywords: adherence, compliance, hepatitis C virus, interferon and ribavirin.
Results  The term 'non-adherence' differs in how it is used in the HCV from the HIV literature. In HCV, 'non-adherence' refers primarily to dose reductions by the clinician and early treatment discontinuation. In contrast, in HIV, 'non-adherence' refers primarily to patient-missed doses. Few data have been published on the rates of missed dose adherence to pegylated interferon/ribavirin and its relationship to virological response.
Conclusions  As HCV treatment becomes more complex with new classes of agents, adherence will be increasingly important to treatment success as resistance mutations may develop with suboptimal dosing of HCV enzyme inhibitors. HIV adherence research can be applied to that on HCV to establish accurate methods to assess adherence, investigate determinants of non-adherence and develop strategies to optimize adherence.     

Review article: indicators and predictors of response to anti-viral therapy in chronic hepatitis C

The complications of chronic hepatitis C, including cirrhosis and hepatocellular carcinoma, are expected to increase dramatically world-wide over the next 10-20 years. Immunomodulatory/anti-viral therapy, employing interferon alfa both alone and in combination with ribavirin, affords the only effective treatment for hepatitis C. Accurate early prediction of response to interferon therapy may decrease or eliminate unnecessary or ineffective treatment, permit greater flexibility in tailoring therapy on an individual basis, and enhance the cost-effectiveness of treatment. Liver biopsy provides valuable information about the baseline severity and subsequent progression of hepatitis C. Severe fibrosis or cirrhosis on the pre-treatment liver biopsy is associated with decreased response rates. The measurement of viral RNA levels and genotyping may be used to optimize individual patient treatment. Genotype non-1 and a low viral load are the most significant pre-treatment indicators of sustained virological response. The most reliable predictor of a poor virological response is continued seropositivity for viral RNA during therapy. Therefore, a decision to stop or continue treatment can be based on a positive viral RNA test at 12 weeks for interferon-naive patients receiving interferon or pegylated interferon therapy.     

Management of chronic hepatitis C in patients co-infected with HIV: focus on safety considerations.

Hepatitis C virus (HCV) infection is a significant public health problem and one of the most important causes of chronic liver disease worldwide. Co-infection with HCV and HIV occurs frequently, mainly because both viruses share the same transmission routes. In recent years, the life expectancy of patients with HIV disease has been increased due to the introduction of highly active antiretroviral therapy (HAART). Furthermore, several studies have established that HIV infection is associated with a major progression of the HCV-related liver disease. Thus, end-stage liver disease has become a leading cause of morbidity and mortality in this population, emphasising the importance of treatment of chronic hepatitis C in HIV-infected persons.The biological and histological benefit of interferon-alpha (IFNalpha) therapy in patients co-infected with HCV/HIV is not significantly different from that noted in similar patients without HIV when the HIV infection is adequately controlled. However, patients with low CD4+ cell counts tend to respond poorly to anti-HCV therapy.Given the relatively low sustained virological response rate to IFN alone, the use of IFNalpha monotherapy has been largely abandoned in favour of combination therapy with ribavirin. In the last 2 years, IFN plus ribavirin combination therapy has been the standard care for the treatment of chronic hepatitis C. Although information on the safety and efficacy of this dual therapy in HCV/HIV co-infected patients is scarce, recent trials have reported that the combination of IFN plus ribavirin is well tolerated and feasible in patients co-infected with HCV/HIV. However, the rates of sustained virological response seem to be worse than those observed in patients without HIV infection. New IFN formulations (e.g. pegylated interferon) plus ribavirin appear to be way of the future for the treatment of chronic hepatitis C in patients both with and without HIV co-infection.     

Natural history, risk factors and management of hepatitis C after liver transplantation

Recurrent HCV is universal after liver transplantation in patients viremic at the time of transplantation and leads to cirrhosis in up to 30% of patients by five years. This has led to recurrent HCV emerging as an important yet controversial indication for liver retransplantation. Despite encouraging results with pegylated interferon and ribavirin therapy in the non-transplant HCV population, these findings have not translated to transplant recipients where viral eradication is frequently unsuccessful largely due to drug intolerance. The lack of effective therapies, severe side effects and reports of hepatic decompensation despite HCV eradication raises the question of whether recurrent HCV genotype 1 should be treated with interferon-based therapies. Although protease inhibitors were recently approved for the treatment of genotype 1 HCV patients in combination with pegylated interferon and ribavirin, these new agents are contraindicated in liver transplant patients due to severe drug toxicity.     

Combined antiviral options for the treatment of chronic hepatitis C

In the absence of antiviral treatment, chronic hepatitis C virus (HCV) infection is a liver disease characterized by the development of necroinflammatory changes and progressive liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The approval of ribavirin in combination therapy regimens with interferon (IFN) dramatically improved therapy. Another advance was the introduction of pegylated IFNs, which allow a once-weekly subcutaneous administration and show more favorable pharmacokinetics and greater efficacy. Two forms are available: pegylated IFN alpha-2b (12 kDa) (1.5 microg/kg) and pegylated IFN alpha-2a (40 kDa) (fixed dosage of 180 microg). Ribavirin is administered orally, at doses > or =10.6 mg/kg, resulting in higher sustained virological responses (SVR) than IFN monotherapy. The highest SVR rates are attained with pegylated IFNs in combination with ribavirin. Factors associated with treatment outcome include HCV genotype, viral load, body weight, age, cirrhosis or bridging fibrosis, coinfection with HIV or hepatitis B virus, and treatment adherence and tolerance. Currently, the main therapeutic challenges ahead are: (a) the dosage optimization of pegylated IFNs and ribavirin according to the patients' characteristics; and (b) to evaluate the efficacy and safety of this combination therapy for difficult-to-treat patients, such as nonresponders, cirrhotics, transplant recipients, renal disease patients or those coinfected with HIV.     

Review article: pegylated interferons: chemical and clinical differences

Pegylated interferon therapy for the treatment of chronic hepatitis C virus provides significant increases in sustained virological response rates compared with standard interferons. Two pegylated interferons are now available and are used in conjunction with ribavirin to maximize response rates in infected patients. The two pegylated interferons, peginterferonalpha-2a and peginterferonalpha-2b, differ substantially in terms of their chemical and structural characteristics, pharmacokinetic and pharmacodynamic properties, and dosing and administration. A full understanding of the differences between the two drugs is important to maximize the clinical benefits. Controlled studies designed to characterize the effects of the two drugs on viral kinetics and sustained virological response rates are emerging and may help to shed additional light on the use of these compounds in patients with chronic hepatitis C.     

The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes

Aliment Pharmacol Ther 2011; 33: 559–565

Summary

Background Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined. Aim To establish natural history and complications of treatment of acute hepatitis C. Methods Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed. Results Twenty‐five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and hepatitis C virus (HCV) RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon‐based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4–8 weeks, and all except two (HIV‐positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%. Conclusions Among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Anti‐viral treatment with a 24‐week course of peginterferon and ribavirin was highly effective, but marked by frequent and severe side effects.     

Discontinuation of pegylated interferon plus ribavirin in patients who are not responding to therapy -- patients' views of early cessation of therapy

BACKGROUND: Current therapy for chronic hepatitis C infection involves a course of pegylated interferon and ribavirin. Patients who do not show a virological response after 12 weeks of therapy have a low probability of sustained virological response and it is therefore recommended that such patients stop treatment. AIM: To assess patients' views of early treatment cessation. METHODS: We conducted a open-labelled study in three UK centres, in which patients with biopsy-proven chronic hepatitis C requiring therapy were offered the choice of a full course of therapy with 40 kDa pegylated interferon-alpha 2a plus ribavirin (24 or 48 weeks depending on viral genotype) or early cessation if therapy had failed after 12 weeks. RESULTS: Ninety-five participants were enrolled and the majority (69%) did not wish to discontinue therapy even if it had low probability of success. In this unselected UK population, very few patients (4%) did not achieve an early virological response with the 40-kDa pegylated interferon-alpha 2a plus ribavirin and two of the four early virological non-responders decided to continue therapy. CONCLUSION: Early discontinuation of 'ineffective' anti-viral therapy may prove less popular with patients than with health care providers, and further patient-directed education regarding the cost-effectiveness of therapy will be needed if early discontinuation of unsuccessful therapy is to be accepted by patients.     

Review article: the treatment of hepatitis C virus recurrence after liver transplantation

BACKGROUND: Recurrent hepatitis C represents a major challenge for the liver transplant community. Given the potentially significant impact that hepatitis C recurrence has on graft and patient survival, several treatment strategies have been utilized to prevent/slow the progression to hepatitis C-related graft failure. AIM: To review the efficacy and applicability of treatment strategies for managing recurrent hepatitis C. METHODS: Search of MEDLINE (1990 to December 2006) and national meeting abstracts. Search terms included hepatitis C, liver transplantation, treatment, sustained virological response (SVR), and end of treatment virological response. An emphasis was placed on randomized trials. RESULTS: The largest study of treatment prior to liver transplantation (n = 124) achieved SVR in 24%. Eight randomized trials (n = 383) examined the efficacy of preemptive therapy with SVR ranging from 0-33%. Eligibility for treatment was low and dose reduction common. Four randomized trials (n = 245; all abstracts) have reported SVR from 33-42% for treating those with histological evidence of recurrent disease. CONCLUSIONS: Therapies for treating hepatitis C recurrence have limited applicability and tolerability, and they have a low SVR. Based on available results, preemptive therapy is not recommended. Pegylated interferon and ribavirin is currently the preferred choice for treating established recurrence. There is an urgent need for safer and more effective anti-viral therapy in this situation.