Combined interferon and ribavirin therapy for chronic hepatitis C in Taiwan

Chronic hepatitis C virus (HCV) infection, including its sequelae, is an important healthcare problem in Taiwan. The seroprevalence of HCV infection in first-time blood donors in Taiwan is 1.2% and an estimated 2-5% in the general population, with a great geographic variation. Genotype 1b is the most prevalent HCV genotype in Taiwan, with a prevalence rate of 50-70%. An increasing incidence of hepatocellular carcinoma (HCC) is mainly attributed to HCV infection, while the declining role of HBV is observed in Taiwan. The seroprevalence of hepatitis B surface antigen among patients with HCC was 90% three decades ago, while recently, chronic HCV infection accounts for more than 30% of HCC patients in the National Taiwan University Hospital. With the advent of a combined conventional interferon (IFN)-alpha and ribavirin therapy, to which Taiwan has contributed in the early study phase, the sustained virological response rate has been greatly improved compared with IFN monotherapy. The sustained virological response rate in Taiwanese patients treated with the combination therapy for 6 months has reached up to 50-60%, which is higher than that reported in patients from the Western countries receiving a 12-month regimen. It is necessary to search for the underlying mechanisms for the better treatment outcome with IFN plus ribavirin combination therapy in Taiwanese patients. Whether long-term effects of IFN plus ribavirin therapy can reduce the incidence of HCC needs to be established.     

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Serine protease inhibitors as anti-hepatitis C virus agents

Approximately 3% of the worldwide population (i.e., more than 170 million people) are chronically infected with the hepatitis C virus (HCV). An estimated 20% of these patients will develop liver cirrhosis within a mean of 20 years, and 2–5% of cirrhotic patients will die of end-stage liver disease or hepatocellular carcinoma. The currently approved antiviral therapy with pegylated interferon (pegIFN) and ribavirin induces a sustained virological response (SVR) in 40–50% of patients infected with genotype 1, the most prevalent HCV type. In this review, we focus on the development and clinical application of serine protease inhibitors as anti-HCV agents. Although highly active in inducing a significant decline of serum HCV RNA, the rapid development of resistance must be counteracted in combination with other antiviral agents, currently pegIFN-α and ribavirin. Two serine protease inhibitors have reached clinical Phase III trials, increasing SVR rates and shortening treatment duration when combined with pegIFN and ribavirin. Trials of interferon-free targeted combination therapies are currently underway.     

A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan

BACKGROUND: The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors. METHODS: A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospective-prospective cohort study. RESULTS: The incidence of HCC and survival during a follow-up period of 1.0-15.3 (mean 5.18) and 1-16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively (P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively (P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in nonresponders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV genotype-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality. CONCLUSION: A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients.     

Impaired response to interferon-alpha2b plus ribavirin in cirrhotic patients with genotype 3a hepatitis C virus infection

Patients with chronic infection with the 3a genotype of hepatitis C virus (HCV) are considered as 'easy-to-treat' with interferon/ribavirin (IFN/RBV), independent of liver disease severity. However, patients with extensive fibrosis or cirrhosis were under-represented in all the registration Phase III trials performed so far. To assess the influence of liver fibrosis on the outcome of anti-HCV therapy, all patients with genotype 3a hepatitis C who were naive to IFN-based therapies, and received RBV combined with standard IFN or pegylated IFN-(alpha2b (peg-IFN-alpha2b) as standard of care for their disease, were investigated at our centre. A sustained virological response (SVR) was achieved in 68 of 91 patients (75%) independent of IFN type, pretreatment viraemia, clearance of HCV RNA at week 4 and relevant co-morbidities. A SVR was less common in cirrhotics (6 of 17) than in non-cirrhotics (62 of 74; 35% vs 84%; P<0.0005). Compared to non-cirrhotics, the age and sex adjusted odds ratio (OR) of treatment failure for cirrhotics was 10.1 (95% confidence interval: 2.4-41.7). By multivariate analysis, cirrhosis was the only predictor of non-SVR. In conclusion, cirrhosis is an independent predictor of IFN/RBV treatment failure in patients chronically infected with HCV 3a and is associated with an increased risk of post-treatment hepatitis relapse. Evaluation of liver fibrosis is important in the management of patients with genotype 3a hepatitis C, since it helps to predict response to IFN/RBV therapy.     

Viral etiology of hepatocellular carcinoma and HCV genotypes in Taiwan

Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.     

Pegylated interferon-alpha2b plus ribavirin: an efficacious and well-tolerated treatment regimen for patients with hepatitis C virus related histologically proven cirrhosis

BACKGROUND: Little is known about the efficacy, safety and tolerability of pegylated interferon plus ribavirin treatment in patients with chronic hepatitis Cvirus (HCV) infection and histologically proven fully established cirrhosis. We aimed here to evaluate the safety of this regimen in such patients and to identify baseline and on-treatment predictors of a sustained virological response (SVR). METHODS: Patients with histologically proven, HCV-induced cirrhosis were randomized to receive pegylated interferon-alpha2b (PEG-IFN-alpha2b; 1.0 microg/kg/week, n=56; group A) or recombinant interferon-alpha2b (IFN-alpha2b; 3 million IU three times/week, n=36; group B), each in combination with a weight-based dose of ribavirin (800-1,200 mg/day) for up to 48 weeks. The primary endpoint of the study was the assessment of SVR, defined as undetectable HCV RNA 24 weeks after treatment cessation. RESULTS: Overall, 40% (37/93) of patients attained SVR: 44% (25/57) in group A and 33% (12/36) in group B (P=0.31). SVR rates were significantly higher in genotype 2/3 patients than in genotype 1 patients (69% versus 25%; P<0.0001). Platelet count at baseline, rapid virological response, and early virological response were predictors of SVR. Twelve patients discontinued treatment because of an adverse event and 20 patients required ribavirin dose reduction for the management of anaemia. CONCLUSIONS: PEG-IFN-alpha2b plus ribavirin for 48 weeks is an efficacious and well-tolerated treatment regimen for patients with HCV-induced cirrhosis. Although SVR rates were more satisfactory in genotype 2/3 than in genotype 1 patients, our study identified additional predictors of response that could allow physicians to better manage treatment in this 'difficult-to-cure' subset of patients.     

Response to interferon-based therapies in HIV-infected patients with chronic hepatitis C due to genotype 4

BACKGROUND: The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported. METHODS: All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype. RESULTS: A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) (P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 (P=0.53). CONCLUSIONS: Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.     

Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin

Hepatitis C virus (HCV)-RNA clearance seems to occur more slowly in HIV/HCV-coinfected patients than in HCV-monoinfected subjects treated with pegylated interferon alpha (peg-IFN) plus ribavirin (RBV). As a consequence, concern has arisen over the feasibility of following the treatment rules applied to HIV-negative patients with chronic hepatitis C. A total of 89 HIV/HCV-coinfected patients who had fully completed a course of peg-IFN plus RBV were analysed. Of these, 29 (32.6%) reached sustained virological response (SVR). Reductions >2 logs in plasma HCV-RNA occurred in 52 (58%) patients at week 12 of treatment (early virological response; EVR). None of patients who showed HCV-RNA drops <2 logs at week 12 reached SVR (negative predictive value: 100%). The positive predictive value of EVR was 56%. On the other hand, relapses occurred in 19 (39.6%) out of the 48 patients who had negative HCV-RNA at the end of treatment, and there were no differences noted when comparing patients with HCV genotypes 2/3 and 1/4. In summary, the quantitative assessment of plasma HCV-RNA at week 12 predicts the chance of SVR using peg-IFN plus RBV in HIV-positive patients with chronic hepatitis C, as it does in HIV-negative individuals. Thus, discontinuation of anti-HCV therapy, which is associated with frequent side effects, might be warranted in HIV/HCV-coinfected patients showing HCV-RNA reductions <2 logs at week 12 of treatment. On the other hand, relapses in virological responders were unexpectedly high in HIV/HCV-coinfected patients when treatment was provided following the rules applied to HIV-negative subjects. This is particularly relevant for HCV genotypes 2/3, which only rarely relapse in HIV-negative patients. Therefore, extending therapy (for 12 months in HCV genotypes 2/3 and perhaps for 18 months in HCV genotypes 1/4) might be warranted in HIV/HCV-coinfected patients showing EVR.     

Retreatment of patients who do not respond to initial therapy for chronic hepatitis C

Despite improvements in the treatment of chronic hepatitis C virus (HCV) infection, nearly half of all patients do not respond to initial therapy. Retreatment of these patients with pegylated interferon and ribavirin has been successful in only a limited percentage of cases. Factors associated with sustained virologic response (SVR) following retreatment include prior treatment with interferon monotherapy, HCV genotype 2 or 3, a low serum HCV RNA level, and the absence of cirrhosis. Fewer than 6% of nonresponders who were previously treated with interferon and ribavirin and who have cirrhosis, genotype 1, and a high viral load achieve SVR following retreatment with pegylated interferon and ribavirin. No therapy has been shown to yield SVR in patients who do not respond to pegylated interferon and ribavirin. Long-term maintenance therapy with pegylated interferon is currently being evaluated in nonresponders with advanced fibrosis and cirrhosis. Its use should be considered investigational at this time.     

Therapy for treatment-refractory chronic hepatitis C virus genotype 1b infection: A retrospective analysis

Background:

The most effective current therapy for hepatitis C virus (HCV) infection is the combination of pegylated interferon (peg-IFN) plus ribavirin (RBV).

Objective:

The aim of this retrospective analysis was to determine the rateof response to this therapy, and the factors affecting outcome, in patients with treatment-refractory chronic HCV genotype l b.

Methods:

The records of patients with chronic HCV infection and HCV geno-type1b who failed (nonresponse or relapse) previous treatment with standard interferon (IFN) + RSV were retrospectively analyzed for demographic data, virologic load, liver histology, biochemistry, treatment-related adverse effects (AEs), and the effects of dose reduction during treatment with peg-IFN + RBV for 48 weeks. Early virologic response (EVR) was defined as ≥2-log (copies/mL) decrease from baseline in serum HCV RNA concentration or the absence of detectable serum HCV RNA at treatment week 12. End-of-treatment response (ETR) was defined as the absence of detectable serum HCV RNA at treatment week 48. Sustained virologic response (SVR) was defined as the absence of detectable serum HCV RNA 24 weeks after treatment was discontinued. Factors affecting treatment outcome were determined using correlation analyses.

Results:

Data from the files of 17 patients (12 men, 5 women; mean [SD] age, 48 [2] years) were analyzed. EVR was achieved in 7 patients; however, viral breakthrough occurred in 2 of these patients during the treatment period, and 5 of these patients discontinued treatment because of severe treatment-related AEs (depression [1 patient] and neutropenia [4]). Seven patients achieved ETR, but HCV infection relapsed during the follow-up period. Three (18%) patients achieved SVR. Data concerning previous patterns of response to IFN + RBV therapy were available in 10 patients. Of these, 3 of 6 patients who had experienced relapse with the previous treatment achieved SVR with peg-IFN + RBV; neither of the 2 patients with nonresponse to the previous treatment achieved SVR. Major determinants of failure to reach SVR in these patients included previous nonresponder pattern, noncompliance with the therapy, and advanced-stage liver fibrosis. Tolerability was similar to that with the previous treatment.

Conclusions:

In this study in patients with chronic HCV genotype lb infectionand a history of relapse or nonresponse to standard IFN + RSV treatment, treatment with peg-IFN + RBV achieved an SVR rate of 18%. Further research is needed to determine the role of peg-IFN + RBV in the re-treatment of HCV infection.     

Response to combined interferon and ribavirin is better in patients infected with hepatitis C virus genotype 6 than genotype 1 in Hong Kong

Data on the treatment efficacy of interferon (IFN)-alpha and ribavirin in patients with chronic hepatitis infected with hepatitis C virus (HCV) of genotype 6 are lacking. A study has been reported from Hong Kong which compared the treatment efficacy of IFN-alpha and ribavirin in the treatment of chronic HCV infection with genotypes 1 and 6. Twenty-four patients with HCV genotype 1 and 16 patients with HCV genotype 6 were studied. The baseline demographic data including median age, gender ratio, alanine aminotransferase levels, bilirubin levels, HCV RNA levels and histological scores were comparable between the two groups of patients. All patients received IFN-alpha 5 million units three times per week and ribavirin (1,000 mg for those weighing 75 kg) for 1 year. Patients infected with HCV genotype 6 achieved virological response significantly higher than those with HCV genotype 1 (67 vs. 33% at week 24, p = 0.02; 75 vs. 42% at the end of treatment, p = 0.05; 63 vs. 29% at 6 months after completion of treatment, p = 0.04). Histological improvement in inflammatory activity and fibrosis in the liver were observed in 25% and 25% of patients infected with HCV genotype 6 in contrast to only 13 and 8% in patients infected with HCV genotype 1; however, the differences were not statistically significant. In conclusion, patients with HCV genotype 6 gain a better response to combined treatment with IFN-alpha and ribavirin than those with HCV genotype 1 and achieve a significantly higher rate of sustained virological response.     

Viral interaction and responses in chronic hepatitis C and B coinfected patients with interferon-alpha plus ribavirin combination therapy

BACKGROUND/AIMS: We conducted a case-control study to investigate the efficacy of interferon-alpha (IFN-alpha) and ribavirin combination therapy for patients with chronic hepatitis C and B virus (HCV/HBV) coinfection and to elucidate the interaction of these two viruses. METHODS: Forty-two chronic HCV/HBV-coinfected patients (29 IFN-naive, 13 IFN-relapsed) and 84 HCV-monoinfected controls, matched for age, sex and previous history of IFN-alpha therapy, were enrolled. All patients were treated with IFN-alpha-2b 6 MU three-times weekly plus ribavirin 1000-1200 mg daily for 24 weeks. Serum HCV RNA and HBV DNA were determined every 24 weeks for 72 weeks. RESULTS: The rate of HCV sustained virological response (SVR) was comparable among IFN-naive and IFN-relapsed HCV/HBV-coinfected patients and IFN-naive and IFN-relapsed HCV-monoinfected patients (69.0%, 69.2%, 67.2% and 57.7%, respectively; intention-to-treat analysis). HCV genotype 1b, high pretreatment HCV RNA levels and liver fibrosis were significantly associated with a lower HCV SVR. Of 16 baseline HBV viraemic patients, five (31.3%) achieved HBV SVR, which correlated negatively to HCV genotype non-1b and HCV SVR. Only one (6.3%) had simultaneous seroclearance of HCV and HBV. Antibodies to HBV surface antigen seroconversion developed in five (11.9%) patients during long-term follow-up. HCV responders had significantly higher rates of HBV DNA resurgence than HCV non-responders during and after treatment. Reciprocal viral interference was noted between HCV and HBV after IFN-alpha/ribavirin therapy. CONCLUSIONS: IFN-alpha/ribavirin combination therapy is effective for HCV/HBV-coinfected patients in eradicating HCV infection and might promote HBV seroclearance, and there is a mutual viral response and reciprocal viral interaction between HBV and HCV.     

Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study

Summary. Background: Hepatitis C is a major co‐morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long‐term follow‐up after treatment.Objectives: To assess the effect of interferon‐based (IFN‐based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end‐stage liver disease (ESLD) after completing antiviral therapy.Patients and methods: In a multicenter cohort study, 295 treatment‐naïve hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan–Meier survival table.Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co‐infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8–20.5], and combination therapy (IFN and ribavirin OR 3.7, 95% CI: 1.7–8.4), PegIFN and ribavirin (OR 4.2, 95% CI: 1.8–9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%.Conclusions: Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.     

The early HCV RNA dynamics in patients with acute hepatitis C treated with pegylated interferon-alpha2b

Interferon and pegylated interferon (peg-IFN) are highly effective in patients with acute hepatitis caused by hepatitis C virus (acute hepatitis C, AHC), but the optimal timing of treatment is still under debate. In this open-labelled, uncontrolled trial, 19 patients with AHC, including 12 intravenous drug users (IVDUs), were treated early in the course of the infection with peg-IFN-alpha2b for 12 weeks. Diagnosis was made according to standardized criteria. The HCV RNA decay was analysed during the first 4 weeks of treatment by quantitative branched-DNA and by qualitative RT-PCR. Of the patients, 11 (58%) had genotype 1. Sustained virological response (SVR) was achieved in 14 out of 19 patients (74%) and the mean time to achieve a negative RT-PCR for HCV RNA was 2.5 weeks. The SVR was associated by univariate analysis with peg-IFN dosage < or = 1.33 microg/kg/week (P = 0.026) and HCV RNA level at onset of therapy (P = 0.017). Using a logistic regression model, only peg-IFN dosage > or = 1.33 microg/kg/weekly was significantly associated with SVR (P = 0.0379, OR: 14.7; 95% CI: 1.16-185.2). The SVR was 100% and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage equal to or higher than 1.33 microg/kg, compared with 40% and 50%, respectively, in those who received a lower dosage. Efforts should be made to propose a 12-week treatment with peg-IFN-alpha2b for AHC, and to maximize peg-IFN dosage. Early treatment is associated with early disappearance of HCV RNA.     

Sustained negativity for HCV-RNA over 24 or more months by long-term interferon therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load

OBJECTIVE: We assessed whether sustained negativity for HCV-RNA over 24 or more months by long-term interferon (IFN) therapy correlates with eradication of HCV in patients with hepatitis C virus genotype 1b and high viral load or not. METHODS: The number of patients with HCV-genotype 1b and high viral load exceeding 1 Meq/ml who received 6 MU of natural IFN-alpha daily for 2-8 weeks, followed by three times/week for 16-22 weeks and negativity for HCV-RNA during IFN administration was 403. Forty-one of 403 patients received 6 MU of natural IFN-alpha three times/week for more than 18 months after the initial IFN therapy (long-term-IFN-group). Three hundred and two patients did not receive any IFN treatment for 6 months after the termination of the 6-month course (6-month-IFN-group). Sustained virological response (SVR) was defined as negative HCV-RNA at both 3 and 6 months after the completion of IFN therapy. RESULTS: SVR was noted in 73.2% (30/41) of long-term-IFN-group and 18.2% (55/302) of 6-month-IFN-group. Multivariate analysis showed that long-term IFN therapy was the most significant contributor to SVR (p < 0.0001). CONCLUSION: Sustained negativity of HCV-RNA for 24 or more months by long-term IFN therapy correlated with SVR in patients with genotype 1b and high viral load.     

Role of viral kinetics under HCV therapy in HIV/HCV-coinfected patients

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are less responsive to anti-HCV therapies and are at a higher risk of toxicity than HCV monoinfected patients. HCV viral kinetics is the basis for the study of response to interferon-based therapy and for predicting sustained virological response (SVR). A lack of early virological response (EVR; undetectable HCV RNA or a decrease of >/=2 log(10) from baseline) after 12 weeks of pegylated interferon (peg-IFN) plus ribavirin (RBV) is an equally reliable predictor of lack of SVR in HIV/HCV-coinfected patients and in the monoinfected HCV population. Early stopping rules are particularly important in coinfected HIV/HCV patients, considering their low chances of response in the more difficult-to-treat HCV genotypes 1 and 4 (<30%). Several factors have been involved in this low efficacy, including higher baseline HCV viraemia, slower viral kinetics decay under interferon pressure and a defective immune substratum. A better understanding of HCV viral kinetics under HCV therapy may be the basis for assaying different peg-IFN plus RBV schedules, such as induction or extending strategies, and may help physicians to make tailored decisions for the management of their patients.     

HCV-HBV infection

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.     

Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection

Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to affect sustained elimination of the virus (a sustained virological response [SVR]). The success and duration of therapy with interferon is dependent on HCV genotype. The current standard of care comprises combined treatment with pegylated interferon and ribavirin. Rates of SVR in patients with genotype 1 infection, the least responsive group, are less than 50%. Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the SVR rate in both treatment-naive and previously treated patients with genotype 1 CHC. Both the US FDA and EMA have approved boceprevir for the treatment of genotype 1 CHC: the first directly-acting antiviral drug to be licensed for this indication. This article will review the pharmacology and pharmacodynamics of boceprevir, the efficacy and safety of the drug, and explore possible future developments in the management of CHC.     

The prevalence, clinical features and response to antiviral therapy of patients with chronic hepatitis C who are seropositive for liver-kidney microsome type 1 antibodies

BACKGROUND: Antibodies to liver-kidney microsome type 1 (anti-LKM-1), which are a marker of autoimmune hepatitis, are found in a minority of patients with chronic hepatitis C virus (HCV) infection. Whether interferon/ribavirin therapy is safe and effective in these patients is unclear. AIM: To describe the prevalence, clinical features and response to interferon/ribavirin therapy of anti-LKM-1 seropositive patients with chronic hepatitis C. PATIENTS AND METHODS: All anti-LKM-1 seropositive patients with chronic hepatitis C who between 1997 and 2002 underwent a diagnostic liver biopsy at the Liver Center Maggiore Hospital, Milan, were studied. Serum HCV RNA was tested by in-house PCR with a limit sensitivity of 50 IU/ml. Tissue antibodies were assessed by indirect immunofluorescence on cryostat sections from rat liver, kidney and stomach. Liver biopsies were graded and staged by the Ishak score. Autoimmune hepatitis was defined according to the International Autoimmune Hepatitis Grading (IAHG) score. RESULTS: Forty-eight (1.8%) of 2675 HCV patients circulated anti-LKM-1 (30 females, 55 years of age). Twenty-eight had genotype 2, 18 genotype 1, and two genotype 3. Aminotransferase levels had been high for 23 + 12 years, on average. Using IAHG, autoimmune hepatitis was excluded in 44 patients (92%) and found to be probable in 4 patients (8%). Chronic hepatitis was histologically mild in 34 patients (70%), moderate to severe in 7 patients (15%) and with cirrhosis in 7 patients (15%). A sustained virological response (SVR) was achieved in 20 of the 27 patients who received interferon/ribavirin (13 genotype 2c with 87% SVR, and 7 genotype 1b with 58% SVR). None of the patients had serum aminotransferases, immunoglobulins or anti-LKM-1 levels flaring following therapy. CONCLUSIONS: LKM-1 antibodies rarely occur in patients with chronic hepatitis C and do not predict autoimmune hepatitis, interferon/ribavirin hyporesponsiveness or immune-related reactions to therapy.