Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program

Injection drug users constitute 60% of the more than 4 million people in the United States with hepatitis C virus (HCV), including many methadone maintenance patients. Few data exist describing clinical outcomes for patients receiving HCV treatment on-site in methadone maintenance settings. In this retrospective study, we describe clinical outcomes for 73 patients receiving HCV treatment on-site in a methadone maintenance treatment program. Fifty-five percent of patients achieved end-of-treatment response, and 45% achieved sustained viral response. These treatment response rates are nearly equivalent to previously published HCV treatment response rates, despite high prevalences of ongoing drug use (49%), psychiatric comorbidity (67%), and HIV coinfection (32%). These data show that on-site HCV treatment with pegylated interferon and ribavirin is effective in methadone-maintained patients, many of whom are active drug users, psychiatrically ill, or HIV coinfected, and that methadone maintenance treatment programs represent an opportunity to safely treat chronic hepatitis C.     

Epoetin alfa for the treatment of combination therapy-induced hemolytic anemia in patients infected with hepatitis C virus

In the United States, about 2.7 million people are chronically infected with the hepatitis C virus, accounting for nearly 1.8% of the population. The current standard of therapy is a combination of pegylated interferon products and ribavirin. A common adverse effect associated with this therapy is anemia, which is frequently referred to as mixed anemia because of the synergistic contribution of the interferons and ribavirin. The effect of ribavirin on the development of anemia is considered greater than that of interferon. The current standard of practice for treating this adverse effect is reduction of the dosages of both drugs, at prespecified hemoglobin levels. However, recent findings underscore the importance of maintaining adequate dosages of interferon and ribavirin, which may be crucial in achieving an early virologic response and a sustained virologic response in treating patients with hepatitis C infection. Treatment with epoetin alfa for this mixed anemia significantly improved hemoglobin levels and quality of life, and enabled adequate dosages of ribavirin to be maintained. Future studies should address several issues: when to start epoetin alfa treatment, the duration of treatment, the drug's optimal dosage, its effects on end-of-treatment and sustained virologic response rates, and a cost analyses.     

Interferon alfa-2b plus ribavirin for chronic hepatitis C patients who have not responded to interferon monotherapy

BACKGROUND: The role of combination therapy is poorly defined in chronic hepatitis C patients who are non-responders to interferon. AIM: To assess the efficacy, safety and tolerance of interferon alfa-2b plus ribavirin in chronic hepatitis C patients who do not respond to interferon monotherapy. METHODS: A total of 127 non-responder patients with chronic hepatitis C received 3 mU t.i.w. of interferon alfa-2b plus 1000-1200 mg ribavirin daily for 48 weeks. Effects of therapy were evaluated by serum aminotransferases and hepatitis C virus (HCV) RNA levels. RESULTS: Twenty-nine (23%) patients had an end-of-treatment response. Six months after treatment, 20 (16%) patients were sustained responders. Early loss of HCV RNA was the strongest predictor of a sustained response (P < 0.0001). Remission was also more frequent in patients with genotype 1b (P < 0.02), elevated alanine aminotransferase (P < 0.03) and low gamma glutamiltranspeptidase (P < 0.002). Treatment was discontinued in 21 (17%) patients: in 14 for intolerance and in seven due to side-effects. CONCLUSIONS: Combination therapy with interferon plus ribavirin produced a sustained response in 16% of chronic hepatitis C patients who were non-responders to interferon. This combination was safe and well tolerated.     

Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

Background: With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in ≥ 30 – 40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol. Methods: This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors. Results/conclusions: Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.     

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.     

Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy

Aliment Pharmacol Ther 2010; 32: 969–983

Summary

Background The efficacy of re‐treating genotype I hepatitis C virus (HCV) patients who failed combination therapy with interferon/pegylated interferon (PEG‐IFN) and ribavirin remains unclear. Aims To quantify sustained virological response (SVR) rates with different re‐treatment regimens through meta‐analysis of randomized controlled trials (RCTs). Methods Randomized controlled trials of genotype I HCV treatment failure patients that compared currently available re‐treatment regimens were selected. Two investigators independently extracted data on patient population, methods and results. The pooled relative risk of SVR for treatment regimens was computed using a random effects model. Results Eighteen RCTs were included. In nonresponders to standard interferon/ribavirin, re‐treatment with high‐dose PEG‐IFN combination therapy improved SVR compared with standard PEG‐IFN combination therapy (RR = 1.49; 95% CI: 1.09–2.04), but SVR rates did not exceed 18% in most studies. In relapsers to standard interferon/ribavirin, re‐treatment with high‐dose PEG‐IFN or prolonged CIFN improved SVR (RR = 1.57; 95% CI: 1.16–2.14) and achieved SVR rates of 43–69%. Conclusions In genotype I HCV treatment failure patients who received combination therapy, re‐treatment with high‐dose PEG‐IFN combination therapy is superior to re‐treatment with standard combination therapy, although SVR rates are variable for nonresponders (≤18%) and relapsers (43–69%). Re‐treatment may be appropriate for select patients, especially relapsers and individuals with bridging fibrosis or compensated cirrhosis.     

Combination therapy with ribavirin and alpha interferon for the treatment of chronic hepatitis C refractory to interferon

BACKGROUND: Up to 80% of hepatitis C patients are refractory to treatment with interferon-alpha. These patients are not likely to benefit from higher dosages or longer duration of interferon alone. The addition of ribavirin has been shown to improve the response rate in patients resistant to a previous course of interferon-alpha alone. AIM: To evaluate whether a sustained hepatitis C virus (HCV) RNA response could be obtained with combination therapy of interferon-alpha and ribavirin in patients who did not respond to or relapsed after a standard interferon-alpha treatment. METHODS: A total of 73 patients, 59 non-responders and 14 relapsers after interferon-alpha alone, were treated with a combination of ribavirin (1000-1200 mg/day) and interferon-alpha (3 MU three times a week) for 24 weeks. Alanine aminotransferase levels and HCV RNA were checked for 24 weeks after completion of therapy. RESULTS: At the end of the combination therapy, 36 patients (49%) showed alanine aminotransferase normalization and in 20 patients (27%), HCV RNA was undetectable in serum. At the end of the 24 weeks follow-up period, only 12 patients (16%) had a sustained response with serum negativity of HCV RNA. This response was significantly higher in relapsers than in non-responders: five (36%) vs. seven (12%) patients (P=0.03), respectively. Adverse effects were restricted to flu-like symptoms and moderate haemolytic anaemia. CONCLUSIONS: Combination of interferon-alpha and ribavirin is quite limited, both in scope and efficacy, in HCV patients who had a non-response to monotherapy with interferon. Better results may be expected in relapsers, but larger studies are necessary.     

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.     

聚乙二醇干扰素α-2a联合利巴韦林对丙型肝炎肝硬化患者抗病毒治疗的疗效观察

目的观察聚乙二醇干扰素(Peg-IFN)α-2a联合利巴韦林对丙型肝炎肝硬化合并脾功能亢进患者在脾切除或部分脾栓塞术后抗病毒治疗的疗效。方法将31例丙型肝炎肝硬化(基因Ⅰ型HCV感染)合并脾功能亢进而未作抗病毒治疗的患者,在行脾切除术或部分脾栓塞术,脾功能亢进改善2个月后,给予Peg-IFNα-2a 135μg或180μg皮下注射,每周1次,联合利巴韦林800~1200mg/d治疗,疗程48周。治疗期间,第1、2、4、6、8、12周随访,之后每4周随访1次,停药后继续观察24周。治疗及随访期间观察肝功能、血常规、肾功能、HCV RNA及用药期间的不良反应。结果丙型肝炎肝硬化合并脾功能亢进患者采用脾切除或部分脾栓塞术治疗脾功能缓解后,给予Peg-IFNα-2a联合利巴韦林抗病毒治疗其持续病毒学应答率为64.51%。结论丙型肝炎肝硬化合并脾功能亢进的患者,在脾切除或部分脾栓塞术后给予Peg-IFNα-2a联合利巴韦林治疗有较好的SVR,延缓了丙型肝炎肝硬化的进展,减少了肝衰竭及肝癌的发生。     

Telaprevir for the treatment of hepatitis C

INTRODUCTION: More than 180 million people worldwide are infected with the chronic hepatitis C virus (HCV), a major cause of liver cirrhosis, and its life-threatening complications including liver failure, portal hypertension and hepatocellular carcinoma. For patients infected with HCV genotype 1, the chances of a sustained virologic response (SVR) with the previous standard of care treatment (Peg-IFN-α + ribavirin) are only 40 - 50%. Neither drug targets a specific HCV protein, and treatment is not only compromised by insufficient SVR rates but also associated with several side effects. With a better understanding of the HCV life-cycle, and of the structural features of HCV proteins, several promising direct antiviral drugs (DAAs) have entered clinical development. AREAS COVERED: This review summarizes the clinical development of telaprevir and discusses the possible role of telaprevir in combination with Peg-IFN-α and ribavirin as a new standard treatment against HCV infection, as well as any possible challenges in the future. EXPERT OPINION: Triple therapy, with telaprevir in combination with Peg-IFN-α + ribavirin, is the new standard for chronic hepatitis C treatment in genotype 1-infected patients. At present, there are several next-generation DAAs in clinical development in combination with Peg-IFN-α. The future, however, may also include new treatment strategies, such as oral DAA combinations.     

Therapy of chronic hepatitis C virus infection in HIV co-infected people

The introduction of highly active anti-retroviral therapy (HAART) for Human Immunodeficiency Virus (HIV) infection has significantly improved the life expectancy of HIV positive patients. Hepatitis C virus (HCV) co-infection is common in HIV infected patients and is now a significant cause of morbidity and mortality. Optimal management and treatment of HCV in HIV infected patients is therefore essential. Interferon-alpha (IFN-alpha) and ribavirin is the mainstay of treatment for HCV infection in HIV infected people. The sustained virological response rate (SVR) with combination therapy is lower than that commonly observed in HCV mono-infected patients. This is, at least in part, due to the very high treatment drop out rates. Ribavirin in combination with HAART is associated with particular side effects such as mitochondrial toxicity. Therefore, vigilant monitoring of patients during therapy, in specialist centers is essential. Pegylated interferon (PEG-IFN) plus ribavirin is particularly promising as it is easier to administer and will probably become the treatment of choice for co-infected patients. A SVR is associated with genotype 2 and 3, in addition to a high CD4+ cell count and a low HCV load prior to therapy. The progression of HCV related liver disease in HIV positive patients is faster than in subjects with HCV infection alone. As a result, there is an increasing incidence of cirrhosis and end-stage liver disease in co-infected patients. Liver transplantation is being evaluated in many centers. To date the experiences are very limited but encouraging in term of survival rate.     

Virological response in patients with hepatitis C virus genotype 1b and a high viral load: impact of peginterferon-alpha-2a plus ribavirin dose reductions and host-related factors

BACKGROUND and objective: In Japan the prevalence of the hepatitis C virus (HCV) antibody is highest in the elderly population. Therefore, it is important for elderly patients to undergo interferon (IFN) therapy. In patients with HCV genotype 1b and a high viral load, the sustained virological response (SVR) rate is lower in older compared with younger patients receiving combination antiviral therapy. In addition, inadequate adherence to combination therapy is often seen in elderly patients, and is associated with reduced response rates. The aim of this retrospective analysis was to evaluate the effects of host-related factors (i.e. sex, age, baseline HCV RNA level, bodyweight and fibrosis stage) and peginterferon (PEG IFN)-alpha-2a plus ribavirin dose reductions on SVR rates. METHODS: A total of 192 treatment-naive patients with a HCV genotype 1b infection and a high viral load were included in the analysis. Patients had been enrolled into a phase III trial of 48 weeks of treatment with PEG IFN-alpha-2a plus ribavirin or PEG IFN-alpha-2a plus placebo. All patients were evaluated for effect of drug exposure on SVR. In addition, the impact of host-related factors or dose reductions on SVR was assessed. RESULTS: Approximately 30% of patients were considered elderly (> or =60 years of age). The overall SVR rate was significantly higher in patients treated with combination therapy versus monotherapy (59.4% vs 24.0%, p < 0.001). Attainment of an SVR following combination therapy was not influenced by any factor evaluated in the analysis, although elderly males were associated with decreased SVR rates. Younger age (odds ratio [OR] 1.081; 95% CI 1.125, 1.034; p = 0.0009), lower baseline HCV RNA levels (OR 1.003; 95% CI 1.006, 1.001; p = 0.006) and a severe fibrosis stage (F3/4) [OR 6.194; 95% CI 1.037, 37.000; p = 0.0455] significantly increased the likelihood of achieving an SVR with monotherapy. In the combination therapy group, patients maintaining a full dosage schedule of PEG IFN-alpha-2a and ribavirin and those requiring dose reductions of either study drug had similar SVR rates (64.5% vs 61.9%). However, the SVR rate was reduced to 33.3% among patients who discontinued combination therapy. Three out of the 31 patients who received the full dosage schedule were elderly patients. In addition, of the 15 patients who discontinued combination therapy, three were <50 years of age and six were > or =60 years of age. The SVR rate was reduced in patients with cumulative PEG IFN-alpha-2a and ribavirin doses of <60%; the majority of these patients were elderly. CONCLUSION: The attainment of an SVR following PEG IFN-alpha-2a plus ribavirin combination therapy was not influenced by any of the host-related factors evaluated in this analysis, although elderly males were associated with a decreased SVR rate. Younger age, male sex and lower baseline HCV RNA levels significantly increased the likelihood of achieving an SVR with monotherapy. In addition, dose reductions appeared to have a negative impact on SVR in elderly patients. Therefore, it is important to minimize PEG IFN-alpha-2a and ribavirin dose reductions by effectively managing treatment-related adverse events in elderly patients.     

Systematic review: anti-viral therapy of recurrent hepatitis C after liver transplantation

Aliment Pharmacol Ther 2011; 33: 163–174

Summary

Background Hepatitis C virus (HCV) infection is the first cause of liver transplantation worldwide. Recurrence of infection is constant, and compromises patient and graft survival. Aim To provide an updated review of the main treatments of recurrent HCV. Methods MEDLINE (1990 to August 2010) and national meeting abstract search. Search terms included hepatitis C, liver transplantation, treatment, sustained virological response. An emphasis was placed on randomised trials. Results Anti‐viral therapy based on pegylated interferon and ribavirin must be considered before liver transplantation, but is poorly tolerated and has poor results in patients with cirrhosis and end‐stage liver disease or hepatocellular carcinoma. Anti‐viral therapy can be administrated systematically early after liver transplantation, or in patients with established recurrent chronic hepatitis. Combination of pegylated interferon alpha plus ribavirin results in a sustained virological response of up to 30% in patients with histological HCV recurrence. The results of a small trial of polyclonal anti‐HCV to prevent recurrence were disappointing. Conclusions Currently available anti‐viral therapy is effective only in a minority of transplanted patients infected with HCV. Specifically targeted anti‐viral therapies combining interferon alpha and ribavirin, or a combination of antiprotease and antipolymerase components, associated with a genetic prediction of anti‐viral response and blocking HCV cell entry should improve the long‐term prognosis of recurrent hepatitis C in the near future.     

Polymorphisms in the interferon-gamma gene at position +874 in patients with chronic hepatitis C treated with high-dose interferon-alpha and ribavirin

To investigate the influence of the T-to-A polymorphic sequence at position +874 in the interferon (IFN)-gamma gene (+874 IFN-gamma) on the response to combination therapy with high-dose interferon and ribavirin, the single nucleotide polymorphisms were determined by using a polymerase chain reaction sequence-specific primers approach in 150 histologically proved chronic hepatitis C (CHC) patients. The distribution of genotypes for +874 IFN-gamma were T/T: 6 (4.0%), T/A: 31 (20.7%) and A/A: 113 (75.3%) and 24.7% (37/150) of patients were inherited T allele. After undergoing combination therapy with high-dose IFN-alpha and ribavirin, 70.7% (106/150) of patients achieved sustained viral response (SVR). Based on multivariate regression analyses, the independent factors predicting HCV SVR after combination therapy were HCV genotype non-1b (P<0.001) and low pretreatment HCV RNA levels (P=0.041) (odds ratios/95% C.I.: 10.150/4.023-25.609 and 0.581/0.345-0.979, respectively). No association between genotypes, A or T alleles of +874 IFN-gamma and response to combination therapy with high-dose IFN-alpha and ribavirin. In conclusion, we found that with high SVR rates after combination therapy with high-dose IFN-alpha and ribavirin, HCV genotypes and pretreatment serum HCV RNA levels, but not inheritance of the IFN-gamma polymorphism at the position +847, were predictors for SVR.     

Cost effectiveness of peginterferon alpha-2a plus ribavirin versus interferon alpha-2b plus ribavirin as initial therapy for treatment-naive chronic hepatitis C

INTRODUCTION: In adults with previously untreated chronic hepatitis C (CHC), the combination of peginterferon alpha-2a plus ribavirin produces a higher rate of sustained virological response (SVR) than interferon alpha-2b plus ribavirin, but it is still unproven whether this increase is cost effective. The objective of this study was to determine if the gain in SVR with peginterferon alpha-2a plus ribavirin is worth the incremental cost. METHODS: We constructed a Markov model of disease progression in which cohorts of patients received peginterferon alpha-2a plus ribavirin or interferon alpha-2b plus ribavirin for 48 weeks (hepatitis C virus [HCV] genotype 1 and non-1 patients with fibrosis) or 24 weeks (genotype non-1 patients without fibrosis), and were followed for their expected lifetimes. The reference patient was a 45-year-old male with CHC without cirrhosis. The SVRs with peginterferon alpha-2a plus ribavirin and interferon alpha-2b plus ribavirin used to populate the model were 46% and 36% for patients infected with HCV genotype 1 and 76% and 61% for patients infected with HCV non-1 genotypes, respectively. QOL and costs for each health state were based on literature estimates and on Italian treatment patterns. Costs were in 2002 euros and benefits were discounted at 3%. Sensitivity analyses on key clinical and economic parameters were performed. The analysis was reported from the perspective of the Italian National Health Service. RESULTS: In patients infected with HCV genotype 1, peginterferon alpha-2a plus ribavirin increased life-years (LYs) by 0.78 years and QALYs by 0.67 years, compared with interferon alpha-2b and ribavirin. The incremental cost per LY and QALY gained was euro9433 and euro10 894, respectively. In patients infected with HCV non-1 genotypes, peginterferon alpha-2a plus ribavirin increased LYs by 1.17 and QALY by 1.01 years, compared with interferon alpha-2b plus ribavirin. The incremental cost per LY and QALY gained was euro3261 and euro3766, respectively. Using genotype distribution estimates, the weighted average ICER for all genotypes was euro6811 per LY gained and euro7865 per QALY gained. CONCLUSION: Our model suggests that peginterferon alpha-2a plus ribavirin is cost effective compared with conventional interferon alpha-2b plus ribavirin for treatment of naive adults with CHC, regardless of HCV genotype, under a wide range of assumptions regarding treatment effectiveness and costs.     

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.     

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.     

聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎疗效观察

目的观察聚乙二醇干扰素(PEG-IFNα-2a)联合利巴韦林治疗慢性丙型肝炎的临床疗效。方法将53例慢性丙型肝炎患者随机分为2组,试验组28例给予PEG-IFNα-2a和利巴韦林治疗,对照组25例给予普通干扰素和利巴韦林治疗,疗程均为48周。随访24周,比较2组病毒学及生化应答情况。结果与对照组相比,试验组患者病毒学应答率明显升高,治疗结束病毒学应答(ETVR)和持续病毒学应答(SVR)率比较差异有统计学意义(P<0.05)。与治疗前相比,2组肝功能均明显改善;疗程结束及随访24周时,试验组仍保持较高的生化应答率(P<0.05)。结论 PEG-IFNα-2a联合利巴韦林治疗慢性丙型肝炎具有良好的病毒应答和生化应答,疗效优于普通干扰素。     

Interferon-alpha2a/ribaviran versus interferon-alpha2a alone for the retreatment of hepatitis C patients who relapse after a standard course of interferon

AIM: To compare the efficacy of a descalating dose of interferon (48 weeks) versus a combination therapy of interferon and ribavirin (24 weeks) in hepatitis C positive subjects who relapsed within six months of cessation of a standard six month course of interferon three million units thrice weekly. METHODS: All 32 subjects had biopsy proven chronic hepatitis C, were PCR positive and had elevated transaminase enzymes at least one and a half times the upper limit of normal. Subjects were randomly assigned to either a descalating dose of interferon-alpha-2a; six million units thrice weekly for 24 weeks followed by 3 MIU 3x for 24 weeks or interferon three million units thrice weekly for 24 weeks plus ribavirin 1,000 mg/day for 12 weeks. A complete virological response was defined as a negative PCR for HCV RNA at 24 weeks after cessation of therapy. RESULTS: Sixteen patients were assigned to each arm and the sustained virological response was 50% for both the interferon and combination therapy arm (pNS). The biochemical response correlated with the virological response; 7/8 virological responders in the interferon alone had normalisation of transaminase 24 weeks post treatment as did 8/8 of those in the combination arm. One patient withdrew from treatment in the descalating interferon group and three required dose reduction. No subjects in the combination arm discontinued therapy but dose reduction was required in three subjects. CONCLUSION: High dose descalating interferon-alpha 2a and a combination of interferon-alpha 2a and ribavirin were effective in achieving a sustained virological response in 50% of subjects who had relapsed after a standard six month course of interferon.     

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.