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.     

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.     

Treatment of chronic hepatitis C in southern Taiwan

Chronic hepatitis C virus (HCV) infection may lead to cirrhosis and hepatocellular carcinoma. Interferon (IFN)-alpha is effective in the treatment of chronic hepatitis C. The rate of response to IFN is enhanced by increasing the IFN dose. Extending the treatment duration can reduce the relapse rate. Addition of ribavirin to IFN increases the sustained virological response (SVR). Thus, combination therapy with IFN and ribavirin was adopted for the treatment of chronic hepatitis C in Kaohsiung Medical University Hospital in 1998. Approximately 60% of patients receiving IFN/ribavirin therapy gained SVR. IFN 6 million units three times per week combined with daily ribavirin for 6 months achieved SVR more frequently than combination therapy with 3 million units. Factors for SVR in these combination regimens were HCV genotype, viral load and early virological response. Long-term follow-up of patients treated with IFN has shown that SVR might reduce the risk of progression to cirrhosis and hepatocellular carcinoma. Pegylated (peg)-IFN has a longer half-life and better efficacy. Combination therapy with peg-IFN and ribavirin accomplished higher SVR than conventional IFN and ribavirin. A multicenter clinical trial was conducted in Taiwan to compare the efficacy of combination therapy between peg-IFN/ribavirin and conventional IFN/ribavirin for 6 months. SVR was higher in patients receiving peg-IFN and ribavirin, especially in those infected with HCV genotype 1b. Based on the results obtained, the national health insurance started to sponsor the combination therapy in October 2003, with a suggested duration for 6 months. Some small-scale studies in Taiwan have postulated higher SVR for treatment duration of 12 than of 6 months in patients with genotype 1b. Further investigation should be conducted in the near future.     

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.     

Hepatic interferon receptor mRNA expression: clinical relevance and its relationship with effectiveness of interferon plus ribavirin therapy in patients with genotype 1b hepatitis C virus infection

BACKGROUND/AIMS: Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection. METHODS: A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR. RESULTS: There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 +/-0.042 versus 0.053 +/-0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores (P=0.006) and younger age (P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34. CONCLUSIONS: Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.     

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.     

Sustained virological response following HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients

BACKGROUND: Chronic hepatitis C leads to progressive liver fibrosis, which is accelerated in HIV-coinfected patients. Unfortunately, hepatitis C virus (HCV) therapy provides sustained virological response (SVR) to only 40% of coinfected patients. Little is known about the regression of hepatic fibrosis in treated patients. METHODS: All coinfected patients who had completed a full course of HCV therapy at our institution were identified. Liver fibrosis staging was estimated using non-invasive procedures at the time of initiating HCV therapy and reassessed at the last patient's follow-up using elastometry (FibroScan). RESULTS: A total of 103 coinfected patients were identified. HCV genotype distribution was 1 (63%), 3 (29%) and 4 (8%). SVR had been attained by 34 individuals, while the remaining 69 were non-responders and/or relapsers. The mean lag time between the end of HCV therapy and the current assessment of liver fibrosis was 40 months, without differences between groups. Metavir score estimates were comparable before initiating HCV therapy in SVR and non-SVR patients. By contrast, current Metavir scores were lower in SVR than in non-SVR patients; for instance, F3-F4 estimates were 12% versus 54%, respectively (P < 0.001). Moreover, the longer the time elapsed after HCV therapy, the lower the liver fibrosis in SVR patients (rho = -0.39; P = 0.02). Conversely, liver fibrosis staging directly correlated with the lag following HCV therapy in non-SVR patients (rho = 0.25; P = 0.03). CONCLUSIONS: SVR after HCV therapy is associated with non-progression of liver fibrosis in HCV/HIV-coinfected patients, although this benefit may not be universal and improvement only been recognizable after several years of follow-up.     

Low response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C treated with abacavir

BACKGROUND: There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV). METHODS: All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4. RESULTS: A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/microl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31-4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50-14.29], < 0.001) and lower RBV plasma trough concentrations (1.74 per microg/ml [1.15-2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91-5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels < 2.3 microg/ml (7.63 [1.39-41.67], 0.02). CONCLUSIONS: The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.     

Overview of the PROVE studies evaluating the use of telaprevir in chronic hepatitis C genotype 1 patients

Current treatment for genotype 1 HCV infection with pegylated interferon (PEG IFN) and ribavirin (RBV) is effective in less than 50% of patients. The advent of direct-acting antiviral agents that target replication of HCV promises to improve therapy for the disease. Telaprevir is a new peptidomimetic serine protease inhibitor that specifically targets the NS3/4a HCV serine protease to cause rapid reduction in HCV RNA levels. Three Phase II Protease Inhibition for Viral Evaluation (PROVE) studies have assessed the efficacy and safety of telaprevir in genotype 1 patients. The studies examined sustained virological response (SVR) rates and also the adverse events related to the use of this drug in different groups. The results of these studies suggested that the addition of this specific protease inhibitor to PEG IFN alfa-2a and RBV can significantly improve the results of treatment in patients affected with chronic HCV infection with genotype 1, when compared with the standard treatment, PEG IFN alfa-2a and RBV alone. The key observations in these Phase II trials of telaprevir were higher rate of SVR above current standard of care (61-69% for T12PR24 treatment-naive patients compared with 46-48% for standard of care in naive patients). Low rates of relapse were observed in T12PR24-treated patients (2-14% vs 22-23%). The studies suggest that the duration of treatment could be reduced for rapidly responsive naive patients from 48 to 24 weeks while maintaining improved SVR rates. RBV remains an essential component of treatment with protease inhibitors combined with PEG IFN. The main adverse reactions of note with its use were rashes, anemia and nausea.     

Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C

OBJECTIVE: The purpose of this study was to elucidate the long-term outcome after interferon (IFN) therapy in chronic hepatitis C elderly patients. METHODS: We studied the incidence of hepatocellular carcinoma (HCC) and survival probability after the initiation of IFN therapy in 500 Japanese chronic hepatitis C patients >60 years. The mean age of initiation of IFN was 63 years and the mean follow-up period was 7.4 years. Cox proportional hazard regression analysis was used to evaluate the long-term outcome after initiation of IFN therapy. Sustained virological response (SVR) was defined as negative HCV-RNA by RT-nested PCR 6 months after the completion of long-term IFN therapy. Non-response (NR) was applied to patients who did not show SVR. Hepatic fibrosis was defined as the fibrosis score (score 0-4) according to Knodell et al. RESULTS: 140 patients (28%) had an SVR and 360 patients (72%) had an NR. 71 of 500 patients developed HCC during follow-up. The cumulative incidence of HCC was 9.6% at the 5th year, 17.4% at the 10th year, and 31.3% at the 15th year. HCC developed with significance when: (1) HCV was not cleared after IFN therapy (p < 0.0001), (2) sex was male (p < 0.0001), and (3) staging of liver fibrosis was >2 (p = 0.008). 53 of the patients died. The cumulative survival probability was 95.7% at the 5th year, 86.4% at the 10th year, and 78% at the 15th year. Patients achieved a long survival with significance when: (1) staging of liver fibrosis was 1 (p < 0.0001), (2) HCV was cleared after IFN therapy (p = 0.034), and (3) sex was female (p = 0.015). CONCLUSION: Chronic hepatitis C patients with clearance of HCV after IFN therapy had a significantly reduced risk of HCC appearance and achieved prolonged survival even if they are > or =60 years.     

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.     

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.     

My Treatment Approach to Chronic Hepatitis C Virus

The treatment of chronic hepatitis C virus (HCV) is evolving rapidly. In 2014, the standard of care and new backbone of HCV treatment is the polymerase inhibitor sofosbuvir (SOF). Our treatment approach in patients with HCV genotype 1 is 12 weeks of SOF, peginterferon (PEGINF), and ribavirin (RBV). In patients with cirrhosis or extrahepatic manifestations of HCV who cannot tolerate PEGINF, we use 12 weeks of SOF and simeprevir. The latter is less costly and more effective than SOF and RBV for 24 weeks. Our treatment approach in all patients with genotype 2 is SOF and RBV for 12 weeks. Hepatitis C virus genotype 3 is now the most costly and difficult to cure. Our approach to treatment-naive patients with genotype 3 is SOF and RBV for 24 weeks. In patients who have previously undergone PEGINF and RBV treatment, we use PEGINF, SOF, and RBV for 12 weeks, which is equally if not more effective and less costly than SOF and RBV for 24 weeks. Patients with cirrhosis who cannot tolerate PEGINF should be treated for 24 weeks with SOF and RBV, although the sustained virologic response is suboptimal.     

Usefulness of a new immunoradiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral load of serum HCV RNA genotype 1b

We investigated the clinical usefulness of a new immunoradiometric (IRM) assay of hepatitis C virus (HCV) core antigen in predicting virological response during pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b. Thirty-nine patients received a regimen of PEG-IFNalpha-2b (1.5 microg/kg/week s.c.) in combination with RBV (600-1,000 mg/day). Of the 39 patients, 18 (46.2%) achieved sustained virological response (SVR), 11 (28.2%) attained partial response (PR) and 10 (25.6%) showed no response (NR). Four weeks after the start of therapy, 1- and 2-log reductions in the amount of HCV core antigen were observed in 20 (2/10) and 0% (0/10) showing NR, 91 (10/11) and 63.6% (7/11) with PRs, and 88.9 (16/18) and 55.6% (10/18) of patients with SVR, respectively. The 1- and 2-log reductions 4 weeks after the start of therapy were not a defining condition for PR and SVR. The amount of HCV core antigen was significantly different between SVR and PR patients on days 1 and 7, and between patients with NR and SVR at all points of time. In conclusion, this new IRM assay is useful in predicting virological response during PEG-IFN/RBV therapy.     

IL-28B基因rs129798600多态性治疗HCV基因型1患者早期应答的关系

目的探讨在白细胞介素28B(IL-28B)基因多态性基础上对丙型肝炎病毒(HCV)基因型1患者的持续性病毒学应答(SVR)做出的预测,为患者治疗提供科学参考依据。方法应用荧光定量聚合酶链反应(PCR)检测HCV定量值;使用基因测序方法检测rs129798600的基因型。结果发生完全早期病毒性应答(cEVR)患者的年龄显著低于未发生cEVR(Non-cEVR)患者,而男性比例与丙氨酸转氨酶水平则显著高于后者;IL-28B基因型CC和年龄小于40岁为发生cEVR的独立相关因素。结论 HCV rs129798600位点CT基因型的患者,则可以考虑对年龄小于40岁的患者进行PEG-IFN联合利巴韦林治疗,而对其他患者可以进行三联治疗。     

Dose-dependent and genotype-independent sustained virological response of a 12 week pegylated interferon alpha-2b treatment for acute hepatitis C

OBJECTIVES: The optimal regimen for acute hepatitis C (AHC) is considered to be a 24 week treatment with interferon (IFN) alpha-2b. A 24 week treatment with pegylated IFN (PEG-IFN) alpha-2b is also effective. This study was designed to assess response rates to a 12 week regimen of PEG-IFN alpha-2b. PATIENTS AND METHODS: Patients with AHC were treated with PEG-IFN alpha-2b for 12 weeks in an open, non-randomized, prospective cohort study. Diagnosis of AHC was made with positive serum HCV RNA and elevated alanine aminotransferase (ALT) levels with a documented seroconversion or a known risk factor in the preceding 6 months. Treatment was administered within a median of 31 days (range 0-116) of the ALT level peak at a dosage varying from 1.06 to 1.66 microg/kg/week. The primary end-point was a sustained virological response (SVR). RESULTS: Nineteen patients were treated, of whom 11 patients (57.9%) had HCV genotype 1. Fourteen patients were asymptomatic. An SVR was achieved in 74% of patients and the SVR rate was 100 and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage>or=1.33 microg/kg, compared with 40 and 50%, respectively, in those who received a lower dosage. An SVR was significantly associated by multivariate analysis only with PEG-IFN dosage>or=1.33 microg/kg/week. No significant association was found with any viral genotype. CONCLUSIONS: The rate of SVR was independent of the HCV genotype and was significantly associated by multivariate analysis only with the higher PEG-IFN dosage. Early identification and treatment of AHC is likely to decrease the burden of chronic hepatitis, especially when caused by HCV genotype 1.     

A common polymorphism in the ABCB11 gene is associated with advanced fibrosis in hepatitis C but not in non-alcoholic fatty liver disease

Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) μmol/l compared with 3.5 (1-61) μmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.     

Predicting the therapeutic response in patients with chronic hepatitis C: the role of viral kinetic studies

A substantial proportion of patients infected with hepatitis C virus (HCV) genotype 1 still does not respond to pegylated interferon-alfa/ribavirin (IFN/RBV) therapy. Factors which identify potential non-responders are needed to limit exposure to drugs in patients unlikely to benefit from treatment and to save health care resources. Host predictive factors have a low negative predictive value. In contrast, viral factors have a high precision in predicting outcome of therapy. Viral kinetics are the basis for the study of response of therapy. The decrease in viral load within 24 h after administration of a single test dose of conventional IFN reflects the IFN-sensitivity of the virus strain and predicts the outcome of conventional IFN/RBV therapy even before treatment with a specificity of 100% and a sensitivity of 83%. In contrast to conventional IFN, the two available PEG-IFN preparations differ considerably in how they suppress viral replication, and cut-off values have to be prospectively established separately for each drug. Patients without an early virological response (HCV-RNA either undetectable or decrease by >or=2 log10 after 12 weeks) (EVR), do not achieve a sustained virological response (SVR; negative predictive value: 97-98%). Thus, in the absence of an EVR, treatment should be stopped. The outcome of PEG-IFN alfa-2a/RBV combination therapy is dependent on the rapidity of the virological response. Patients who become HCV-RNA negative after 4 weeks have the best chance of achieving an SVR. The rapidity of viral elimination may be a useful guide to tailoring the length of treatment in patients with an EVR.     

Very early viral kinetics on interferon treatment in chronic hepatitis C virus genotype 4 infection

BACKGROUND: Interferon (IFN)-resistant hepatitis C virus strains limit efficacy of antiviral combination therapy in patients infected with genotypes 1 and 4. A single test dose of IFN was useful to identify non-responders to IFN-alpha2b/ribavirin (RBV) or likely non-responders to pegylated (PEG)-IFN-alpha2a/RBV therapy in genotype 1 patients. Our aim was to investigate this approach in genotype 4 patients. METHODS: Viral load was measured in 46 patients before and 24 h after 10 megaunits (MU) IFN-alpha2b, and before and during 2 weeks of daily 5 MU IFN-alpha2b administration. Thereafter, patients received 48 weeks combination therapy with either 180 microg PEG-IFN-alpha2a/week (n=33), 1.5 microg/kg PEG-IFN-alpha2b/week (n=7) or 5 MU IFN-alpha2b/2 days (n=6), along with 1-1.2g RBV/day. For prediction analysis the largest group (PEG-IFN-alpha2a) was evaluated only. RESULTS: Median 24 h log10 change after 10 MU IFN-alpha2b was 1.15 (range 0.08-2.48) and after 5 MU IFN-alpha2b was 0.81 (-0.12-2.22; P<0.0001). Log10 changes after 2 weeks on 5 MU IFN-alpha2b daily and 24 h after 10 MU were the best predictors of early virological response (defined by negativity of a standard qualitative PCR) to PEG-IFN-alpha2a/RBV combination therapy (area under curve [AUC]=0.97; P<0.001, receiver operating characteristics), 24 h log10 change after 10 MU was the best predictor of sustained virological response (SVR; AUC=0.91, P=0.001). CONCLUSION: As in genotype 1 patients, there is large variation in IFN responsiveness, including the presence of resistant strains, in genotype 4 patients. A 24 h log10 change after 10 MU IFN-alpha2b is an excellent predictor of SVR on PEG-IFNalpha2a/RBV combination therapy. This test may be useful to obtain homogeneous groups for clinical studies and could help in clinical decision making.     

Impact of ribavirin exposure on early virological response to hepatitis C therapy in HIV-infected patients with chronic hepatitis C

BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.